Note: Descriptions are shown in the official language in which they were submitted.
1~65~5
~ 12619/+
Process for the manufacture of novel derivatives of
2-aminoethanol
.
The invention relates to a process for the manufacture of
novel derivatives of 2-aminoethanol which correspond
to the formula
Ar-(CH2) -f~-CR2~ lk-~0) ~ ~2
0
in which
Ar represents optionally substituted phenyl,
m represen~s a number from O to 3,
n represents the number O or 1,
and
alk represen~s alkylene having 2 to 5 carbon atoms,
the nitrogen atom and the oxygen atom or, if n
is 0, the phenyl radical, being separated from
each other by at least two carbon atoms,
a~
S7S
-- 2 --
and
Rl and ~ each represents, independently of the
other, hydrogen or lower alkyl, or together
represent lower alkylene, oxa-lower alkylene,
thia-lower alkylene, aza-lower alkylene or N-
lower alkyl-aza-lower alkylene,
with the proviso that, if m is 0, the phenyl radical
Ar contains at least one substituent and a phenyl
radical Ar that is substitu~ed by one or two hydroxy
groups or protected hydroxy groups contains at least
one additionall substituent which is different from
those substituents,
in the form of racemic mixtures, racemates, optical anti-
podes or salts thereof, especially acid addition salts and,
more especially, pbarmaceutically acceptable, non-toxic
acid addition salts.
Substituents of the radical Ar may be, for example,
lower alkyl, lower alkenyl or lower alkoxy each of which
is optionally substituted, especially in the manner given
below, also lower alkenyloxy, lower alkynyl, lower alkynyl-
oxy, lower alkylidenedioxy, cyano and/or nitro; and/or lower
alkanoyl, esterified or amidated carboxy, especially lower
alkoxycarbonyl, or optionally subs~ituted carbamoyl, for
example carbamoyl, lower alkylcarbamoyl, di-lower alkylcarb-
amoyl or ~hydroxy-lower alkyl1-carbamoyl, lower alkylthio,
lower alkylsulphinyl, lower alkylsulphonyl, sulphamoyl,
lower alkylsulphamoyl or di-lower alkylsulphamoyl each of
which is bonded directly or to the afore-mentioned lower
alkyl, lower alkenyl or lower alkoxy, i.e. substituting
one of the3e groups; or halogen, etherified mercapto, such
as lower alkylthio, optionally substituted amino, such as
amino, lower alkylamino, di-lower alkylamino, alkyleneamino
or oxaalkyleneamino, pyrrol-l-yl, acylamino, such as lower
alkanoylamino,lower alkoxycarbonylamino, ureido optionally
substituted especia:Lly by one or two lower alkyl
groups, by hydroxy-:Lower alkyl or by cycloalkYl, lower
575
-- 3 --
alkylsulphonylamino or optionally etherified or esterified
hydroxy, such as hydroxy, phenyl-lower alkoxy or lower
alkanoyloxy each oE which is bonded directly or to the
afore-mentioned lower alkyl or, in a position higher than
the l-position, to the afore-mentioned lower alkoxy; or,
as a substituent that is not bonded directly, again lower
alkoxy, with the proviso that, if m is 0, the aryl radical
Ar contains at least one substituent and a phenyl radical
that is substituted by one or two hydroxy, l-phenyl-lower
alkoxy or lower alkanoyloxy groups contains at least one
additional substituent which is different from those substi-
tuents.
The radicals and compounds designated ~lower~ in the
context of the present description contain preferably up
to 7, and especially up to 4, carbon atoms.
The general terms used in the list of substituents
of the radical Ar ~ay have, for example, the following
specific meanings. Lower alkyl is, for example, methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert.-
butyl; substituted lower alkyl is especially corresponding
methyl or 1- or 2-substituted ethyl; lower alkenyl is, for
example, vinyl, allyl, 2- or ~-methylallyl or 3,3-
dimethylallyl and ~ubstituted lower alkenyl is especially
2-substituted vinyl or 3-substituted allyl. Lower alkoxy
is, for example, methoxy, ethoxy, n-propoxy, isopropoxy,
n-butoxy or isobutoxy; and substituted lower alkoxy is,
for example, substituted methoxy or 1- or 2-substituted
ethoxy. Lower alkenyloxy is, for example, allyloxy, 2- or
3-methylallyloxy or 3,3-dimethylallyloxy. Lower alkynyl
is, for example, propargyl, and lower alkynyloxy i8 espe-
cially propargyloxy; lower alkylidenedioxy is, for exa~ple,
isopropylidenedioxy, ethylidenedioxy and especially
methylenedioxy, and alkylenedioxy is especially ethylene-
dioxy. Lower alkanoyl is, for example, acetyl, propionyl
or butyryl. Lower alkoxycarbonyl is, for example, ~ethoxy-
carbonyl or ethoxycarbonyl. Lower alkylcarbamoyl and di-
7S
-- 4 --
lower alkylcarbamoyl are, for example, methylcarbamoyl, di-
methylcarbamoyl, ethylcarbamoyl or diethylcarbamoyl; and
hydroxy-lower alkylcarbamoyl is, for example, (2-hy~roxy-
ethyl)-carbamoyl. Lower alkylthio is, for example, methyl-
thio, ethylthio, n-propylthio or isopropylthio. Lower
alkylsulphinyl is, for example, methyl- or ethylsulphinyl
lower alkyls~lphonyl is, for example, methyl-, ethyl- or
n-propylsulphonyl; and lower alkylsulphamoyl is, for
example, methyl-, ethyl- or isopropylsulphamoyl and di-
lower alkylsulphamoyl is, for example, dimethylsulphamoyl.
Halogen is bromine or iodine and preferably fluorine or
chlorine. Phenyl-lower alkoxy is, for example, benzyloxy
or 1- or 2-phenyle4hoxy; and lower alkanoyloxy is, for
example, formyloxy or acetoxy lower alkylamino and di-lower
alkylamino are, for example, methylamino, ethylamino, ~i-
methylamino or diel:hylaminoO Alkyleneamino and oxaalkylene-
amino are, for example, l-pyrrolidinyl, piperidino or mor-
pholino. Lower alkanoylamino is, for example, acetylamino
or butyrylamino, and lower alkoxycarbonylamino is, for exam-
ple, methoxycarbonylamino or ethoxycarbonylamino. Ureido
substituted by one or two lower alkyl groups, by hydroxy-
lower alkyl or by cycloalkyl, preferably one having S to
7 ring members, is, for example, 3-methylureido, 3,3-
dimethylureido, 3-~2-hydroxyethyl)-ureido or 3-cyclohexyl-
ureido. Lower alkylsulphonylamino is, for example, ethyl-
sulphonylamino and especially methylsulphonylamino.
As stated above, substituents of Ar may be one of the
afore-mentioned radicals that is not bonded directly but
by way of lower al~yl, lower alkoxy or optionally by way
of lower alkenyl. A selection of such substituents is given
below in general te~rms and with specific examples, without
limiting the possible combinations thereto. Lower alkanoyl-
alkyl is, for example, 2-oxopropyl (acetonyl) or 3-oxobutyl;
lower alkanoyl-lower alkenyl is, for example, 3-oxo-1-
butenyl; and lower alkanoylalkoxy is, for example, 2-oxopro-
poxy ~acetonyloxy) or 3-oxobutoxy. Optionally substituted
S~S
-- s --
carbamoyl-lower alkyl is, for example, carbamoylmethyl or
l(hydroxy-lower alkyl)-carbamoyll-lower alkyl, such as [(2-
hydroxyethyl)-carbamoyl]-methyl. Lower alkoxycarbonyl-lower
alkoxy is, for example, ethoxycarbonylmethoxy. Optionally
substituted carbamoyl-lower alkoxy is, for example, carb-
amoyl-lower alkoxy, such as carbamoylmethoxy, or [(hydroxy-
lower alkyl)-carbamoyl]-lower alkoxy, such as [~2-hydroxy-
ethyl)-carbamoyll-methoxy. Halo-lower alkyl is especially
halo-methyl, for example trifluoromethyl. Lower alkylthio-
lower alkoxy is, for example, 2-methylthioethoxy or 2-ethyl-
thioethoxy. Acylamino-lower alkyl i8, for example, lower
alkanoylamino-lower alkyl, especially lower alkanoylamino-
methyl or 1- or especially 2-lower alkanoylaminoethyl, for
example acetylaminomethyl, 2-acetylaminoethyl or 2-pro-
pionylamino-ethyl; and lower alkoxycarbonylamino-lower alkyl
is especially lower alkoxycarbonylaminomethyl or 1- or espe-
cially 2-lower alkoxycarbonylaminoethyl, for example meth-
oxycarbonylaminomethyl, 2-methoxycarbonylaminoethyl or 2-
ethoxycar~onylaminoethyl. Acylamino-lower alkoxy is, for
example, lower alkanoylamino-lower alkoxy, especially 2-
lower alkanoylaminoethoxy, for example 2-(acetylamino)-
ethoxy; and lower alkoxycarbonylamino-lower alkoxy is espec-
ially 2-(lower alkoxycarbonylamino)-ethoxy, for example
2-(methoxycarbonylamino)-ethoxy or 2-(ethoxycarbonylamino)-
ethoxy. Hydroxy-lower alkyl is preferably hydroxymethyl
or 1- or especially 2-hydroxyethyl. Lower alkoxy-lower
alkyl is preferably lower alkoxymethyl or 1- or especially
2-lower alkoxyethyl, for example methoxymethyl, ethoxy-
methyl, 2-methoxyethyl or 2-ethoxyethyl. Lower alkoxy-
lower alkoxy is especially 2-lower alkoxyethoxy, such as
2-methoxyethoxy or 2-ethoxyethoxy.
Alkylene alk may be straight-chain or branched and
i8, for example, ethylene, propylene, ~rimethylene, 1-
methyltrimethylene l,l-dimethyltrimethylene, tetramethylene
or l,l-dimethylethylene.
Rl and R2, representing lower alkyl, are, for
5~S
-- 6 --
example, propyl, isopropyl, butyl, isobutyl, sec.-butyl,
pentyl, isopentyl, neopentyl, hexyl or heptyl or, espe-
cially, methyl or ethyl. Together with the nitrogen atom
of the amide group, Rl and R2, as lower alkylene, are,
for example, l-aziridinyl, l-azetidinyl, l-pyrrolidinyl,
piperidino or hexahydro-lH-azepin-l-yl; as oxa-lower alky-
lene, for example, morpholino; as thia-lower alkylene, for
example, thia-morpholino; and as aza-lower alkylene, for
example, l-piperazinyl or hexahydro-lH-1,4-diazepin-1-yl,
wherein the two last-mentioned groups may be substituted
in the 4-position, i.e. in the imino group, for example
by lower alkyl, such as methyl, ethyl, propyl, isopropyl,
butyl or isobutyl, corresponding to the meaning of N-lower
alkyl-aza-lower alkylene for Rl and R2.
The phenyl group carrying the amide group and the ~
adjacent hydroxy group can be bonded to the rest of the
molecule in any desired position, but the latter is
preferably bonded in the 4-position of the said phenyl
group, i.e. in the para-position to the amide group, or
especially in the 5-position of the said phenyl group, i.e.
in the para-position to the hydroxy group.
The new compounds may be in the form of their salts,
such as their acid addition salts, and especially in the
form of their phar~aceutically acceptable, non-toxic acid
addition salts. Suitable salts are, for example, those
with inorganic aci~s, 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, malic, tartaric, citric, maleic,
hydroxymaleic, pyruvicO fumaric, benzoic, 4-aminobenzoic,
anthranilic, 4-hydroxybenzoic, salicylic, embonic, methane-
sulphonic, ethanesulphonic, 2-hydroxyethanesulphonic,
ethylenesulphonic, toluenesulphonic, naphthalenesulphonic
or sulphanilic acid, or with other acidic organic
575
-- 7 --
substances, such als ascor~ic acid.
The invention relates especially to compounds of the
formula I in which Ar op~ionally contains one or more, but
preferably not more than three, substituents, these being
lower alkyl, lower alkenyl or lower alkoxy each of which
is optionally substituted, especially in the manner given
below, also lower alkenyloxy, lower alkynyl, lower alkynyl-
oxy, lower alkylidenedioxy, lower alkylenedioxy, cyano and/
or nitro; and/or lower alkanoyl, esterified or amidated
carboxy, especially lower alkoxycarbonyl, carbamoyl, lower
alkylcarbamoyl or (hydroxy-lower alkyl)-carbamoyl, lower
alkylsulphinyl, lower alkylsulphonyl, sulphamoyl or lower
alkylsulphamoyl each of which is bonded directly or to the
afore-mentioned lower alkyl, lower alkenyl or lower alkoxy;
and/or halogen, lower alkylthio, amino, lower alkylamino,
di-lower alkylamino, alkyleneamino or oxaalkyleneamino,
for example l-pyrrolidinyl, piperidino or morpholino,
pyrrol-l-yl, asylamino, such as lower alkanoylamino~ lower
alkoxycarbonylamino, ureido optionally substituted by lower
alkyl, hydroxy-lower alkyl or cycloalkyl, lower alkylsul-
phonylamino, hydroxy, phenyl-lower alkoxy, for example
benzyloxy, or lower alkanoyloxy each of which is bonded
directly or to the afore-mentioned lower alkyl or, in a
position higher than the l-position, to the afore-mentior.ed
lower alkoxy; or, as a substituent that is not bonded
directly, again lower alkoxy, m represents a number from
O to 3, n represent:s the number O or 1, and alk represents
an alkylene radical having 2 to 4 carbon atoms, the nitrogen
atom and the oxyger atom or, if n is 0, the phenyl radical,
being separated frcm each other by 2 or 3 carhon atoms of
the radical alk, R and R have the meanings given under
formula I, but preferably represent hydrogen or lower alkyl,
for example methyl or e~hyl, or, together with the nitrogen
atom of the amide group, form morpholino or alkyleneamino
having 5 or 6 ring members, such as l-pyrroli~inyl or
piperidino, with the proviso that, if m is 0, the phenyl
114~75
-- 8 --
radical Ar has at least one substituent and a phenyl radical
Ar that is substituted by one or two hydroxy, l-phenyl-lower
alkoxy or lower alkanoyloxy groups contains at least one
additional substituent which is different from those substi-
tuent~, in the form of racemic mixtures, racemates, optical
antipodes, as free compounds or salts thereof, especially
acid addition salts and, more especially, pharmaceutically
acceptable~ non-toxic acid addition salts.
The invention relates preferably to compounds of the
formula I in which Ar optionally contains one to three sub-
-stituents, these being lower alkyl, lower alkenyl or lower
alkoxy each of which is optionally substituted in the manner
given below, also lower alkenyloxy, lower alkynyl, lower
alkynyloxy, lower alkylidenedioxy, cyano and/or nitro;
and/or lower alkanoyl, lower alkoxycarbonyl, carbamoyl,
lower alkylcarbamoyl, (hydroxy-lower alkyl)-carbamoyl, lower
alkylsulphinyl, lower alkylsulphonyl, sulphamoyl or lower
alkylsulphamoyl each of which is bonded directly or to the
afore-mentioned lower alkyl, lower alkenyl or lower alkoxy;
and/or halogen, lower alkyithio, amino, lower alkylamino,
di-lower alkylamino, alkyleneamino or oxaalk~leneamino,
~or example l-pyrrolidinyl, piperidino or morpholino, pyrrol-
l-yl, lower alkanoylamino, lower alkoxycarbonylamino,
ureido optionally substituted by lower alkyl, hydrosy-lower
alkyl or cycloalkyl, lower alkylsulphonylamino, phenyl-lower
alkoxy, for exa~ple benzyloxy, or lower alkanoyloxy each
of which is bonded directly or to the afore-mentioned lower
alkyl or, in a position higher than the l-position, to the
afore-mentioned lower alkoxy; or, as a s~!bstituent that
i8 not bonded directly, again lower alkoxy, m represents
a number from O to 3 and n represents the number O or 1,
and alk represents an alkylene radical having 2 to 4 carbon
atoms, tbe nitrogen atom and the oxygen atom or, if n is
0, the phenyl radical, being separated from each other by
2 or 3 carbon atoms of the radical alk, Rl a~d R2 have
the meanings given ~nder formula I, but preferably represent
S
- 9 -
hydrogen or lower alkyl, especially methyl or ethyl, or,
together with the nitrogen atom of the amino group, form
l-pyrrolidinyl, piperidino or morpholino, with the proviso
that, if m is 0, the phenyl radical Ar contains at least
one subs~ituent and a phenyl radical Ar that is substituted
by one or two hydroxy, l-phenyl-lower alkoxy or lower
alkanoyloxy groups contains at least one additional substi-
tuent which is different from those substituents, in the
form of racemic mixtures, racemates, optical antipodes,
as free compounds or salts thereof, especially 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 Ar optionally contains one to three sub-
stituents, these being lower alkyl, lower alkenyl or lower
alkoxy each of which i8 optionally substituted in the manner
given below, also lower alkenyloxy, lower alkynyloxy, lower
alkylidenedioxy, nitro and/or cyano: and/or lower alkanoyl,
lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl,
(hydroxy-lower alkyl)-carbamoyl, lower alkylsulphinyl, lower
alkylsulphonyl, sulphamoyl or lower alkylsulphamoyl each
of which is bonded directly or to the afore-mentioned lower
alkyl, lower alkenyl or lower alkoxy; and/or halogen, lower
alkylthio, amino, lower alkylamino, di-lower alkylamino,
alkyleneamino or oxaalkyleneamino, for example 1-
pyrrolidinyl, piperidino or morpholino, pyrrol-l-yl, lower
alkanoylamino, lower alkoxycarbonylamino, ureido
optionally substituted by lower alkyl or cycloalkyl, lower
alkylsulphonylamino, hydroxy, phenyl-lower alkoxy, for
example benzyloxy, or lower alkanoyloxy each of which is
bonded directly or to the afore-mentioned lower alkyl or,
in a position higher than the l-position, to the afore-
mentioned lower alkoxy; or, as a substituent that is not
bonded directly, again lower alkoxy, m represents a number
from O to 3, with the proviso that, if m is 0, the phenyl
radical Ar contains at least one substituent and a phenyl
~1~6575
-- 10 -- .
radical Ar that is substituted by one or two hydroxy, 1-
phenyl-lower alkoxy or lower alkanoyloxy groups contains
at least one additional substituent which is different from
those substituents, n repregents the number 0 or 1, and
alk represents an alkylene radical having 2 to 4 carbon
atoms, the nitrogen atom and the oxygen atom or, if n is
0, the phenyl radical, being separated from each other by
2 or 3 carbon atoms of the radical alk, and Rl and R2
each represents, independently of the other, hydrogen or
lower alkyl, especially methyl or ethyl, or, together with
the nitrogen atom of the amide group, form morpholino, in
the form of racemic mixtures, racemates, optical antipodes,
as free compounds or salts thereof, especially acid addition
salts and, more especially, pharmaceutically acceptable,
non-toxic acid addition salts.
The invention relates more especially to compounds of
the formula I in which Ar optionally contains one to three
substituent~, these being lower alkyl or lower alkoxy each
optionally substituted in the manner given below, also lower
alkenyl, lower alkenyloxy, lower alkynyloxy, lower alkyli-
denedioxy, nitro and/or cyano; and/or lower alkanoyl, lower
alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl or (hydroxy-
lower alkyl)-carbamoyl, lower alkylsulphinyl, lower alkyl-
sulphonyl or sulpbamoyl each of which is bonded directly
or to the afore-mentioned lower alkyl or lower alkoxy and/
or halogen, lower alkylthio, amino, alkyleneamino or oxa-
alkyleneamino, for example l-pyrrolidinyl, piperidino or
morpholino, pyrrol--l-yl, lower alkanoylamino, lower alkoxy-
carbonylamino, ureido optionally substituted by lower alkyl,
lower alkylsulphonylamino, hydroxy, or phenyl-lower alko%y,
for example benzyloxy, each of which is bonded directly
or to the afore-~e!ntioned lower alkyl or, in a position
higher than the l-;position, to the afore-mentioned lower
alkoxy; or, as a slbstituent tha~ is not bonded directly,
again lower alkoxy, m represents a number from 0 to 3,
with the proviso t.nat, if m is 0, the phenyl radical Ar
119165~5
contains at least~one s~bstituent and a phenyl radical Ar
that is substituted by one or two hydroxy, l-phenyl-lower
alkoxy or lower alkanoyloxy groups contains at least one
additional substituent which is different from those substi-
tuents, n represents the number O or 1, and alk represents
an alkylene radical having 2 to 4 carbon atoms, the nitrogen
atom and the oxygen atom or, if n is 0, the phenyl radical,
being separated from each other by 2 or 3 carbon atoms of
the radical alk, and Rl and R2 each repre~ents, indepen-
dently of the other, hydrogen or lower alkyl, but preferably
represents hydrogen or methyl, in the form of racemic mix-
tures, racemates, optical antipodes, as free compounds or
salts thereof, especially acid addition ~alts and, more
especially, pharmaceutically acceptable, non-toxic acid
addition salts.
The invention relates more especially to compounds
of the formula I in which Ar optionally contains one to
three substituents, these being lower alkyl, for examPle
methyl, or lower alkoxy, for examPle methoxy or ethoxY~
each optionally substituted in the manner qiven below. also
lower alkenyl, for example allyl, lower alkenyloxy, for
example allyloxY, hower alkvnyloxy, for examPle propargyl-
oxy, nitro, lower alkylidenedioxy, for example methylene-
dioxy, and/or cyano; and/or lower alkanoyl, for examPle
acetyl, carbamoyl, lower alkylcarbamoyl, for exam~le N-
methylcarbamoyl, or (hYdroxv-lower alkYl~-carbamoyl, for
example N-hydroxymethylcarbamoyl, lower alkylsulphonyl,
for examPle methylsulPhonyl~ or sulphamoyl each of which
is bonded directlv or to the afore-mentioned lower alkYl
or lower alkoxY: and/or fluorine or chlorine bonded directlY
or to the afore-mentioned lower alkyl, for exam~le meth~l,
for examPle trifluoromethYl~ oc hydroxy bonded directlY
or ~o the afore-mentioned lower alkYl; or, as directly
bonded substituents, PhenYl-lower alkoxY, for examPle
benzyloxy, lower alkoxy-lower alkoxy, for example 2-methoxy-
ethoxy, benzyloxy~ amino, lower alkanoylamino, for examPle
6575
- 12 -
acetylamino, lower alkoxycarbonylamino, for example methoxy-
carbonylamino, or-~ower ~lkylsulphonylamino, for example
methylsulphonylamino, m ~epresents a number from O to 3,
with the proviso that, if m is 0, the phenyl radical Ar
contains at least one substituent and a phenyl radical Ar
that is substituted by one or two hydroxy or l-phenyl-lower
alkoxy ~roups contains at least one additional substituent
which is different from those substituents, n represents
the number 1, and alk represents an alkylene radical having
2 to 4 carbon atoms, the nitrogen atom and the oxygen atom
being separated from each other by 2 or 3 carbon atoms of
the radical alk, a:nd Rl and R2 represent hydrogen, and the
phenyl radical carrying the amide group and the adjacent
hydroxy group is bonded preferably in its 4- or 5-position
to the rest of the molecule, in the form of racemic mix-
tures, racemates, optical antipodes, as free compounds or
salts thereof, especially acid addition salts and, more
especially, pharmaceutically acceptable, non-toxic acid
addition salts.
The invention relates in particular to compounds of
the formula I in which Ar is optionally mono- to tri-
substituted, substltuents mentioned being lower alkyl,
lower alkoxy, hydroxy-lower-alkyl, amino, lower-alkanoyl-
amino, lower alkylsulfonylamino, nltro, phenyl-lower alkoxy,
ureido, halo-lower alkyl, halogen and hydroxyl, and m is
0, with the proviso that a phenyl radical Ar that is
substituted by one or two hydroxy groups contains at least
one additional substituent which is different from those
substituents, n is the number O or 1, and alk is an
alkylene radical having 2 to 5 carbon atoms, the nitrogen
atom and the oxygen atom or, if n is 0, the phenyl
radical, being separated from each other by at least two
carbon atoms, and Rl and R2 independently of one another
each represent lower al~yl having up to 4 carbon atoms,
or Rl and R2 together represent lower alkylene having 4-6
- 13 -
carbon atoms in the unbranched chain, especially however
hydrogen, in the form of racemic mixtures, racemates,
optical antipodes, as free compounds or salts thereof,
particularly acid addition salts, and more par~icularly
pharmaceu~ically acceptable, non-toxic acid addition salts.
The:invention relates more especially to compounds
of ~he fonmula I in which Ar is substituted by lower alkyl-
sulfonylamino, such as methylsulfonylamino, optionally
in addition by halogen, such as chlorine, m is 0, and
n is the number Q or 1, and alk represents an alkylene
radical having 2 or 3 carbon atoms, the nitrogen atom and
the oxygen atom or, if n is 0, the phenyl radical, being
separated from each other by at least two carbon atoms,
and Rl and R2 each represent hydrogen, in the form of
racemic mixtures, racemates, optical antipodes, as ree
compounds or salts thereof, especially 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 Ar is substituted by lower alkyl-
sulfonylamino, such as methylsulfonylamino, optionally
in addition by halogen, such as chlorine, or by sulfamoyl,
halogen, such as chlorine, or lower alkoxy, such as
methoxyg m is 0, and n is the number O or 1, and alk is
an alkylene radical having 2 or 3 carbon atoms, the
nitrogen atom and the oxygen atom or, if n is 0, the
phenyl radical, being separated from each other by at least
two carbon atoms, and Rl and R2 each represent hydrogen,
in the fonm of racemic mixtures, racemates, optical anti
podes, as free compounds or salts thereof, espPcially acid
addition salts, and more especially phan~aceu~ically
acceptable, non-toxic acid addition salts.
5~5
- 14 -
The invention relates particularly to compounds of
the formula I in which Ar i-s substituted by sulfamoyl and
halogen, such as chlorine~ or by sulfamoyl and lower alkoxy, such
as methoxy, m is 0, and n is ~he number 1, and alk represents
an alkylene radical having to 2 or 3 carbon atoms, the
nitrogen atom and the oxygen atom being separated from
each other by at least two carbon atoms, and Rl and R2
each represent hydrogen, in the~form of racemic mixtures,
racemates, optical antipodes, as free compounds or salts
thereof, especially acid addition salts, and more especially
pharmaceutically acceptable, non-toxic acid addition salts.
The novel derivatives of 2-aminoethanol according
to the invention correspond to the formula I described above
in which Ar represent~ optionally substituted
phenyl, m represents a number from 1 to 3, n represents
the number O or 1, and alk represents alkylene having 2
to 5 carbon atoms, the nitrogen atom and the oxygen atom
or, if n is 0, the phenyl radical, being separated from each
other by at least two carbon atoms, and R and R each
represents, independently of the other, hydrogen or lower
alkyl, or together represent lower alkylene, oxa-lower
alkylene, thia-lower alkylene, aza-lower alkylene or N-lower
alkyl-aza-lower alkylene, in the form of racemic mixtures,
racemates, optical antipodes or salts thereof, e~pecially
acid addition salts and, more especially, pharmaceutically
acceptable, non-toxic acid addition salts.
The invention relates ec.pecially to compounds of the
formula I in which Ar optionally contains one or more, but
preferably not more than three, substituents, these being
lower alkyl, lower alkenyl or lower alkoxy each of which
is optionally substituted, especislly in the manner given
below, also lower alkenyloxy, lower alkynyl, lower alkynyl-
oxy, lower alkylidenedioxy, lower alkylenedioxy, cyano and/
or nitro: and/or lower alkanoyl, esterified or amidated
carboxy, especially lower alkoxycarbonyl, carbamoyl, lower
alkylcarbamoyl or ~hydroxy-lower alkyl)-carbamoyl, lower
S75
-- 15 --
alkylsulphinyl, lower alkylsulphonyl, sulphamoyl or lower
alkylsulphamoyl eaeh of which is bonded directly or to the
afore-mentioned lower alkyl, lower alkenyl or lower alkoxy;
and/or halogen, lower alkylthio, amino, lower alkylamino,
di-lower alkylamino, alkyleneamino or oxaalkyleneamino,
for example l-pyrrolidinyl, piperidino or morpbolino,
pyrrol-L-yl, acylamino, such as lower alkanoylamino, lower
alkoxycarbonylamino, ureido optionally substituted by lower
alkyl, hydroxy-lower alkyl or cycloalkyl, lower alkylsul-
phonylamino, hydroxy, phenyl-lower alkoxy, for example
benzyloxy~ or lower alkanoyloxy each of which is bonded
directly or to the afore-mentioned lower alkyl, or, in a
position higher than the l-position, to the afore-mentioned
lower alkoxy or, as a substituent that is not bonded
directly, again lower alkoxy, m represents a number from
1 to 3, n represents the number O or 1, and alk represents
an alkylene radical having 2 to 4 carbon atoms, the nitrogen
atom and the oxygen atom or, if n is 0, the phenyl radical,
being separated from each other by 2 or 3 carbon atoms of
the radical alk, Rl and R have the meanings given under
formula I, but preferably represent hydrogen or lower alkyl,
for example methyl or ethyl, or together with the nitrogen
atom of the amide group, form morpholino or alkyleneamino
having 5 or 6 ring members, such as l-pyrrolidinyl or
piperidino, in the form of racemic mixtures, racemates,
optical antipodes, as free compounds or salts thereof, espe-
cially a~id addition salts and, more especially, pharmaceu-
tically acceptable, non-toxic acid addition salts.
The invention relates preferably to compounds of the
formula I in which Ar optionally contains one to three sub-
stituents, these bein~ lower alkyl, lower alkenyl or lower
alkoxy each of which i8 optionally substituted in the manner
given below, also lcwer alkenyloxy, lower alkynyl, lower
alkynyloxy, lower alkylidenedioxy, cyano and/or nitro; and/
or lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower
alkylcarbamoyl, (hydroxy-lower alkyl)-carbamoyl, lower
alkylsulphinyl, lower alkylsulphonyl, sulphamoyl or lower
7~
-- 16 --
alkylsulpha~oyl each of which is bonded directly or to tAe
afore-mentioned ~ower alkyl, lower alkenyl or lower alkoxy;
and/or halogen, lower alkylthio, a~ino, lower alkylamino,
di-lower alkylamino, alkylenea~ino or oxaalkyleneamino,
for example l-pyrrolidinyl, piperidino or morpholino,
pyrrol-l-yl, lower alkanoylamino, lower alkoxycarbonylamino,
ureido optionally substituted by lower alkyl, hydroxy-lower
alkyl or cycloalkyl, lower alkylsulphonylamino, phenyl-lower
alkoxy, for example benzyloxy, or lower alkanoyloxy each
of which is bonded directly or to the afore-mentioned lower
alkyl or, in a position higher than the l-position, to the
afore-mentioned lower alkoxy; or, as a substituent that
is not bonded directly, again lower alkoxy, m represents
a number from 1 to 3, and n represents the number O or 1,
and alk represents an alkylene radical havin~ 2 to 4 carbon
atoms, the nitrogen atom and the oxygen atom or, if n-is
0, the phenyl radical, being separated from each other by
2 or 3 carbon atoms of the radical alk, Rl and R have
the meanings given under formula I, but preferably represent
hydrogen or lower alkyl, especially methyl or ethyl, or,
together with the nitrogen atom of the amino group, form
l pyrrolidinyl, piperidino or morpholino, in the form of
racemic mixtures, racemates, optical antipodes, as free
compounds or salts thereof, especially 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 Ar optionally contains one to three sub-
~tituen~s, these being lower alkyl, lower alkenyl or lower
alkoxy each of which is optionally substituted in the manner
given below, also lower alkenyloxy, lower alkynyloxy, lower
alkylidenedioxy, nitro and/or cyano; and/or lower alkanoyl,
lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl,
(hydroxy-lower alkyl)-carbamoyl, lower alkylsulphinyl, lower
alkylsulphonyl, sulphamoyl or lower alkylsulphamoyl each
of which is bonded direotly or to the afore-mentioned lower
alkyl, lower alkenyl or lower alkoxy; and/or halogen, lower
1 i 46S7~
- 17 -
alkylthio, amino, lower alkylamino, di-lower alkylamino,
alkyleneamino or oxaalkyleneamino, for example l-pyrroli-.
dinyl, piperidino or morpholino, pyrrol-l-yl, lower
alkanoylamino, lower alkoxycarbonylamino, ureido optionally
substituted by lower alkyl or cycloalkyl, lower alkylsul-
phonylamino, hydroxy, phenyl-lower alkoxy, for example
benzyloxy, or lower alkanoyloxy each of which is bonded
directly or to the afore-mentioned lower alkyl or, in a
position higher ~han the l-position, to the afore-mentioned
lower alkoxy; or, as a substituent that is not bonded
directly, again lower alkoxy, m represents a number from
1 to 3, n represents the number O or 1, and alk represents
an alkylene radical having 2 to 4 carbon atoms, the nitrogen
atom and the oxygen atom or, if n is 0, the phenyl radical,
being separated from each other by 2 or 3 carbon atoms of
the radical alk, and R and R each represents, inde-
pendently of the other, hydrogen or lower alkyl, especially
methyl or ethyl, or, together with the nitrogen atom of
the amide group, form morpholino, in the form of racemic
mixtures, racemates, optical antipodes, as free compounds
or salts thereof, especially acid addition salts and, more
especially, pharmaceutically acceptable, non-toxic acid
addition salts.
The invention relates more especially to compounds
of the formula I in which Ar optionally contains one to
three substituents, these being lower alkyl or lower alkoxy
each of which is optionally substituted in the manner given
below, also lower alkenyl, lower alkenyloxy, lower alkynyl-
oxy, lower alkylidenedioxy, nitro and/or cyano; and/or lower
alkanoyl, lower alkoxycarbonyl, caebamoyl, lower alkylcarb-
amoyl or (hydroxy-lower alkyl)-carbamoyl, lower alkylsul-
phinyl, lower alkylsulphonyl or sulphamoyl each of which
is bonded directly or to the afore-mentioned lower alkyl
or lower alkoxy; and/or halogen, lower alkylthio, amino,
alkyleneamino or oxaalkyleneamino, for example l-pyrroli-
dinyl, piperidino or morpholino, pyrrol-l-yl, lower
alkanoylamino, lower alkoxycarbonylamino, ureido optionally
1~4~575
- 18 -
substituted by lower alkyl, lower alkylsulphonylamino,
hydroxy, or phenyl-lower alkoxy, for example benzyloxy,
each of which is bonded directly or to the afore-mentioned
lower alkyl or, in a position higher than the l-position,
to the afore-mentioned lower alkoxy; or, as a substituent
that i5 not bonded directly, again lower alkoxy, m repre-
sents a number from 1 to 3, n represents the number O or
1, and alk represents an alkylene radical having 2 to 4
carbon atoms, the nitrogen atom and the oxygen atom or,
if n is 0, the phenyl radical, being separated from each
other by 2 or 3 carbon atoms of the radical alk, and R
and R each represents, independently of the other, hydro-
gen or lower alkyl, but preferably represent hydrogen or
methyl, in the form of racemic mixtures, racemates, optical
antipodes, as free compo~nds or salts thereof, especially
acid addition salts and, more especially, pharmaceutically
acceptable, non-toxic acid addition salts.
The invention relates more especially to compounds
of the formula I in which Ar optionally contains one to
three substituents, these being lower alkyl, for example
methyl, or lower alkoxy, for example methoxy or ethoxy,
each of which is optionally substituted in the manner ~iven
below, also lower alkenyl, for example allyl, lower alkenyl-
oxy, for example allyloxy, lower alkynyloxy, for example
propargyloxy, nitro, lower alkylidenedioxy, for example
methylenedioxy, and/or cyano; and/or lower alkanoyl, for
example acetyl, carbamoyl, lower alkylcarbamoyl, for example
N-methylcarbamoyl, or (hydroxy-lower alkyl)-carbamoyl, for
example N-hydroxymethyl-carbamoyl, lower alkylsulphonyl,
for example methylsulphonyl, or sulphamoyl each of which
is bonded directly or to the afore-mentioned lower alkyl
or lower alkoxy; and/or fluorine or chlorine bonded directly
or to the afore-mentioned lower alkyl, for example methyl,
for example trifluoromethyl, or hydroxy bonded directly
or to the afore-mentioned lower alkyl; or, as directly
bonded substituents, phenyl-lower alkoxy, for example
benzyloxy, lower alkoxy-lower alkoxy, for example 2-methoxy-
-- 19 --
ethoxy, benzyloxy, amino, lower alkanoylamino, for exampleacetylamino, lower alkoxycarbonylamino, for example methoxy-
carbonylamino, or lower alkyls~lphonylamino, for example
methylsulphonylamino, m represents a number from 1 to 3, n
represents the number 1, and alk represents an alkylene
radical havinq 2 to 4 carbon atomsy the nitrogen atom and
the oxygen atom being separated from each other by 2 carbon
atoms of the radical alk, and R and ~ represent hydro-
~en, and the phenyl radical carrying the amide group and
the adjacent hydroxy group is bonded preferably in its 4-
or S-position to the rest of the molecule, in the form of
racemic mixtures, racemates, optical antipodes, as free
compounds or salts thereof, especially acid addition salts
and, more especially, pharmaceutically acceptable, non-toxic
acid addition salts.
The novel compounds of the formula I have valuable
pharmacological properties. In particular, they act in
a specific manner on ~-adrenergic receptors. This action,
which is a property common to all compound~ of the formula
I, can be attributed to their affinity to these receptors,
which manifes~s ltself as a pure blockade when the inherent
stimulating action of the receptors is absent or very
slight, as a blockade with simultaneous ISA, i.e. intrinsic
~ympathomimetic activity, when the inherent action of the
receptors is slightly to moderately stimulating, and as
actual stimulation of the ~-adrenergic receptors when the
inherent action of the latter is relatively strong. The
boundaries between ~-receptor blockers without ISA or with
at the most moderately strong ISA are fluid, just as
therapeutic areas of application of these types of compounds
are. Of the compounds of the formula I which act as
~-receptor blockers with or without ISA~ for instance those
which are substituted in the phenyl nucleus by a lower alkyl-
sulfonylamino group, a- 1N- [2-(4-carba~oyl-3-hydroxyphenoxy)-1-
methylethyll-aminomethyll-4-~methylsulfonylamino)-benzyl
s~s
- 20 -
alcohol for example, and e3pecially that of an enantiomer
pair having a melting point of 16~-167,
exhibits, as its principle action, a blocking action on
~-receptors (with a slightly preferred inhibition of cardiac
receptors), together with the additional activities of a
slight ~lood-pressure-reducing action and a-receptor-blocking
action. Compounds of this type, for exampLe ~he stated
a-[N-~2-(4-carbamoyl-3-hydroxyphenoxy)-1-methylethyl]-amino-
methyl]-4-(methylsulfonylamino)-benzyl alcohol and also
its twn enantiomer pairs having melting points of 165-167,
and 144-145, respectively, or a-[N-[2-(4-carba~oyl-3-
hydroxyphenoxy)-ethyl]-aminomethyl~-4-(methylsulfonylamino)-
benzyl alcohol or a-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-
ethyl]-aminomethyl]-4-(methylsulfonylamino)-benzyl alcohol,
exhibit urthermore a clear diuretic and saluretic action,
which can be demonstrated for example after p.o.
administration of 1 or 5 mg/kg of such compound~ to
the dog.
In the case of other compounds of the formula I, both
~-receptor-blocking and ~-receptor-stimulating actions
can clearly be detected. These compounds prove to be
with regard to their action on cardiac ~-receptors, on
the one hand in in vitro experiments on the hearts of guinea
pigs, potent blockers with relatively distinct ISA, and,
on the other hand in in vivo experinents on narcotised cats
mainly strongly acting stimulators. Concerning the action
on vascular ~-receptors, the said compounds are sh~wn to
be chieflyblockers with a moderately strong ISA, whereas
compounds of the fon~ula I which are substituted in the
phenyl nucleu~ Ar by lower alkyl, for instance methyl,
for example ~-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-
methylethyl]-aminomethyl]-4-methylbenzyl alcohol, are found
to be strong stimulators of tracheal ~-receptors.
- 21 -
Belonging to the last-mentioned group are for example
those compounds in-which Ar is an etherified hydroxyphenyl
radical, such as a-lN-[2-53-carbamoyl-4-hydroxy-phenoxy)-
ethyl]-aminomethyl]-3,4-methylenedioxy-benzyl alcohol, with
which a cardioselective ~-stimulation can be demonstrated
in in vivo tests on the cat. Additional activities which
can be verified, for example in the case of a-[N-[2-
(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl]-aminomethyl]-
3,4-methylenedioxybenzyl alcohol, are a lowering of the
blood pressure and a slight blockade of adrenergic
a-receptors.
The above information regarding pharmacological
properties is based on the results of appropriate pharm-
cological experiments in customary test procedures. Thus,
the novel ~-blocking compounds exhibit inhibition of
tachycardia induced by isoproterenol in the isolated
hearts of guinea pigs in a concentration range of from
approximately 0.001 to approximately l~ug/ml, and in
narcotised cats in a dosage range of from approximately
0.001 mg/kg to approxLmately 1 mg/kg in the case of
intravenous administration. The inhibition of vasodilatation
induced by isoproterenol in narcotised cats with perfusion
of the Arteria femoralis can be demonstrated by intravenous
administration, in a dosage range of fr~m approximately
0.003 mg/kg to approximately 3 mg/kg. The ISA of the
~-blocking compounds of the formula I, provided that such ISA
is present, is apparent from the increase in basal
heart frequency in narcotised cats treated beforehand with
reserpinol, in the case of intravenous administration in
a dosage range of from 0.001 to 1 mg/kg. In a dosage range
of from approximately 0.1 mg/kg to approximately 10 mg/kg
i.v., the novel ~-blocking compounds also bring about a
reduction in the arterial blood pressure in narcotised
cats. The additional ~-blocking activity which, for
57~;i
- 22 -
example, may promote a blood pressure-reducing action is
demonstrated, for~~xample-, by the antagonisation of
noradrenalin-induced contraction of the isolated Vas
deferens of rats by such compounds in a concentration of
from 0.1 ~g/ml to appxoximately 10 ~g/ml. The novel ~-
blocking compounds of the formula I can be used as, to some
extent cardioselective, ~-receptor blockers, for example
for the treatment of Angina Pectoris and cardiac rhythm
disorders and a'so as agents for reducing blood pressure.
The additional diuretic and saluretic action present in
the case of certain types of compounds of the formula I,
for instance as shown in the foregoing, could lead to a
substantial intensifying of the antihypertensive effect,
and render the combination of ~-receptor-blockers with
diuretics unnecessary.
The clearly ~-receptor-stimulating compounds of the
formula I, such as a-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-
e~hyl]-aminomethyl~-3,4-methylenedioxy-benzyl alcohol,
bring about an increase in the heart frequency and
myocardial contraction force in the isolated atrium of
guinea pigs in a concentration range of from approximately
O.OOOl~ug/ml to O.l~ug/ml and an increase in the heart
frequency and maximum rate of pressure increase in the
left ventricle (dp/dt max.) in narcotised cats in a dosage
range of from approximately 0.001 mg/kg to approximately
1 mg/kg i.v.. The novel compounds stimulate, to some
extent selectively, the cardiac ~-receptors (~l-receptors)
in comparison with the ~-recep~ors in the blood vessels
(~2-receptors) and, in this respect, clearly differ
qualitatively from isopro~erenol which stimulates the
~-receptors of the heart and those of the blood vessels
to approximately the same extent. The compounds of the
formula I have in part also relatively distinct stimulating
actions on ~2-receptors (blood vessels, trachea).
575
- 23 -
The novel compounds of the fonmula I having a
stimulating action can accordingly be used
1) as stimulators of cardiac ~-receptors for the treatment
of insufficient cardiac output and of cardiac rhythm
disorders,
2) as stimulators of tracheal and vascular ~-receptors as
broncho- and vaso-dilators for the treatment of asthma~
cardiac insufficiency and circulatory disorders.
/
/
/
. _ . _ . . _ . . _
~ S7 5
- 24 -
The novel compounds of the formula I are manufactured
in a manner known per se. They can ~e obtained, for
example, by reacting a compound of the formula
11
Ar-(CH ) -CH - CH - Z (II~
with a compound of the formula
OH
Z - alk - (0) ~ ON (III)
in which one of the groups Z and Z2 represents a
reactive esterified hydroxy group and the other represents
the primary amino group, and X represents hydroxy, or
in which X and Z together represent the epoxy group
and Z represents the primary amino group, and Ar,
~ ,
57~
- 25 -
alk, m and n have the meanings given above, and, if desired,
converting a resulting compound into a different compound
of the formula I, and/ or, 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 racemic mixture into the racemates or a resulting
racemate:into tbe optical antipodes.
A reactive esterified hydroxy group Z or Z 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 a strong organic acid, especially
a strong organic sulphonic acid, such as an aliphatic or
aromatic sulphonic acid, for example methanesulphonic acid,
4-methylbenzenesulphonic acid or 4-bromobenzenesulphonic
acid, and is especially halogen, for example chlorine,
bromine or iodine, or aliphatically or aromatically
substituted sulphonyloxy, for example methylsulphonyloxy
or 4-methylphenylsulphonyloxy.
The above reaction is carri~d out in a manner
known per se and, especially when using a starting
material having a reactive esterified hydroxy group,
advantageously in the presence of a basic agent, such as
an inorganic base, for example an alkali metal or alkaline
earth metal carbonate or hydroxide, or of an organic basic
agent, such as an alkali metal lower alkoxide, and/or of
an excess of the basic reactant and usually in the presence,
but optionally also in the absence, of a solvent or solvent
mixture and, if necessary, while cooling or heating, for
example within a temperature range of from approximately
-20 to approximately 150 C, in an open or closed vessel
and/or in an inert gas atmosphere, for example in a nitrogen
atmosphere.
Starting materials of the formula II or III are known
or can be manufactured in a manner known ~er se. Thus,
for the manufacture of a starting material of the formula
II in which m is 0, a compound of the formula Ar-H, in
1~6S75
-- 26 --
which optionally present amino or hydroxy groups can be
protected by a pr~tecting-group, for example one of those
described below, can be haloacetylated, according to the
Friedel-Crafts method, at a carbon atom of the radical Ar
with a haloacetyl halide, for example chloroacetyl chloride,
in the presence of a suitable Lewis acid, for example
aluminium chloride, and, in the Ar-haloacetyl compound so
obtained, the carbonyl group can be reduced to the carbinol
group, for example by treating with a suitable hydride
reducing agent; if desired, a halogen Zl can be converted
into the primary amino group Zl~ for example by treating
with ammonia or a suitable derivative thereof, such as
hexamethylenetetramine, and decomposing the resulting
compound with a dilute mineral acid, or by reacting with
an alkali metal salt of phthalimide and splitting the
resulting phthalimide compound, for example with hydrazine.
Starting materials of the formula II in which X and 2
together represent epoxy can be obtained, for example, by
cyclising a compound of the formula II in which Xl
represents hydroxy and Z represents a reactive esterified
hydroxy yroup, for example chlorine or methylsulphonyloxy,
by means of alkaline reagents, for example a mix~ure of
dilute sodium hydroxide solution and tetrabutylammonium
chloride, in a suitable solvent, for example methylene
chloride.
Starting materials of the formula II in which m has
the meaning given above and Xl and Zl together represent
the epoxy group, and optionally present amino or hydroxy
groups are protected by a protecting group, for example
as stated below, can be obtained by converting the group
- C~ = CH2 in a compound of the for~ula
Ar-(CH2) -CH-CH2 (IIa) in~o the group -CH - CH
by introducing the epoxy group, for example by reacting
with a peroxy compound, such as hydrogen peroxide, or with
an organic pera~id, such as, for example, an optionally
substituted, such as halogenated, aliphatic or aroma~ic
S~S
- 27 -
peracid, for example peracetic acicl or trifluoroperacetic
acid, perbenzoic acid or m-chloroperbenzoic acid, in an
anhydrous solvent, such as chloroform. This reaction is
carried out in the usual manner.
Starting materials of the formula III can be obtained,
for example, by reacting a hydroxysalicylamide with a dihalo-
alkane that corresponds to the meaning of alk, for example
a chlorobromoalkane or dibromoalkane, in the presence of
an alkaline condensation agent, such as an alkali metal
carbonate and, if desired, replacing the remaining halogen
Z2 by a primary amino group in the manner described above
f' Zl- These reactions are carried out in the usual
manner, the protecting groups at the amino and hydroxy
groups being split off simultaneously or subsequently, for
example as described.
The compounds of the for~ula I can fur thermore be
manufactured as follows:
in a compound of the formula
0 _ ~4
1 2)m fH C~2_~-alk-(o) ~ ~ ~
X2 ~3 R2
in which Arl has the meaning of Ar or represents a radical
Ar that is substituted by 1 or 2 groups which can each be
oonverted into hydroxy and/or amino, X , X and X
each represents hydrogen or a substituent that can be
replaced by hydrogen and X represents ~ , or X and
X and/or X and X together represent a bivalent
radical that can be replaced by two hydrogen atoms, with
the proviso that at least one o the radicals X , X
and X is different from hydrogen, or at least Ar
represents a radical Ar that is substituted by 1 or 2 groups
which can each be converted into hydroxy and/or amino, or
at leaqt X2 and X3 together or X and X together
represent a bivalent radical that can be replaced by two
7~
- 28 -
hydrogen atoms, and m and n have the meanings given above,
or in a salt theresf, the X , X or X or the X
and X together or the X and X together which is
different from hydrogen is replaced by hydrogen, and/or
substituted hy~roxy and/or amino present in a radical Ar
is converted into free hydroxy and/or amino, and, if
desiredr the additional process steps mentioned in
connection with the first process are carried out.
The splitting off of the groups X , X or X ,
or X and X together or X and X together and
al50 of the protecting groups, optionally present in a
radical ~r , of the hydroxy and/or amino substituents
is carried out by means of solvolysis, such as hydrolysis,
alcoholysis, aminolysis or acidolysis, or by means of
reduction including hydrogenolysis.
Especially suitable groups X and X or hydroxy-
and/or amino-protecting groups that can be split off in
a radical Ar are mainly ~-aryl-lower alkyl groups that
can be split off by hydrogenolysis, such as an optionally
substituted l-polyphenyl-lower alkyl or l-phenyl-lower alkyl
group, in which the substituents, especially of the phenyl
moiety, may be, for example, lower alkyl, such as methyl,
or lower alkoxy, such as methoxy, and especially benzyl.
~roups X and especially X2 and X and also hydroxy-
and/or amino-protecting groups in a radical Ar may alter-
natively be radicals that can be split off by solvolysis,
such as hydrolysis or acidolysis, or by reduction, including
hydrogenolysis, especially corresponding acyl radicals,
such a~ the acyl radical of an organic carboxylic acid,
for example lower alkanoyl, such as acetyl, or aroyl, such
as benzoyl, or the acyl radical of a ~emiester of carbonic
acid, such as lower alkoxycarbonyl, for example methoxycar-
bonyl, ethoxycarbonyl or tert.-butoxycarbonyl, 2-halo-lower
alkoxycarbonyl, for e~ample 2,2,2-trichloroethoxycarbonyl
or 2-iodoethoxycarbonyl, optionally sub~tituted l-phenyl-
lower alko~ycarbonyl; for example benzyloxycarbonyl or
diphenylmethoxyearbonyl, or aroylmethoxycarbonyl, for
i575
- 29 -
example phenacyloxycarbonyl, or optionally substituted 1-
polyphenyl-lower alkyl groups, in which the substituents,
especially of the phenyl moiety, have, for example, the
meaning given above and are especially trityl.
A radical that can be split off and is formed by X2
and X and/or X and X together is especially a
bivalen~ group that can be split oEf by hydrogenolysis,
such as optionally substituted l-phenyl-lower alkylidene,
in which the substituents, especially of the phenyl moiety,
may be, for example, lower alkyl or lower alkoxy, and
especially benzylidene, or group~ that can be split
off by solvolysis, especially by hydrolysis, such as lower
alkylidene, for example methylene or isopropylidene, or
1-phenyl-lower alkylidene in which the phenyl moiety is
optionally substituted by lower alkyl, such as methyl, or
lower alkoxy, such as methoxy, especially benzylidene, or
cycloalkylidene, for example cyclopentylidene or
cyclohexylidene.
Starting materials ~hat can be used in the form of
salts are especially in the form of acid addition salts,
for example with ~ineral acids, and also with organic
acids.
Radicals X2, X and/or X that can be split off
by hydrogenolysis, especially optionally substitu~ed 1-
phenyl-lower alkyl groups, and sui~able acyl groups, such as
optionally substituted l-phenyl-lower alkoxycarbonyl, and
optionally substituted l-pbenyl-lower alkylidene groups
formed by X2 and X3 and also by X4 and X5 together,
and hydroxy- and/or amino-protecting groups of this kind
present in the radical Arl can be split off by treating
~ith catalytically activated hydrogen, for example with
hydrogen in the presence of a nickel catalyst, such as Raney
nickel, or of a suitable noble metal catalyst.
Groups X2, X3 and/or X4 that can be split off by
hydrolysis, such as acyl radicals of organic carboxylic
acids, for example lower alkanoyl, and of semiesters of
carbonic acid, for example lower alkoxycarbonyl, and also,
7S
- 30 -
for example, trityl radicals, and lower alkylidene, 1-
phenyl-lower alkyI~dene ~r cycloalkylidene groups formed
by the radicals X2 and X3 and/or X4 and X5 together,
and hydroxy- and/or amino-protecting groups of this kind
present in a radical Ar can be split off, depending on
the kind of such radicals, 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 hydroxide
or carbonate or of an amine, such as isopropylamine.
By aminolysis it is possible to split off, for
example, acyl radicals present as protecting groups of
hydroxy groups, and especially lower alkylidene, l-phenyl-
lower alkylidene or cycloalkylidene groups formed by X
and X5 together, such as, for example, the l-methylethyli-
dene group, for example by reacting with ammonia or, espe-
cially in the case of the above-mentioned bivalent protect-
ing groups, with primary amines, such as, for example, i80-
propyla~ine or benzylamine, in a suitable reaction medium,
such as, for example, isopropanol or dioxan. A starting
material of the formula II for the first-mentioned manu-
facturing process for compounds of the formula I may also
function as a pri~ary amine. For that reason, in the reac-
tion of compounds of the formula IVe given below, in which
X and X together represent one of the above-mentioned
bivalent protecting groups, such as, for example, isopropyl-
idene, with double the molar amount of corresponding start-
ing materials of the formula II, which for their part also
come under the formula IVa, in which reaction the protecting
group formed by X4 and X5 is split off, end products
of the for~ula I are obtained directly; on the other hand,
the protecting group mentioned remains in existence and
the corresponding starting material of the formula IV is
produced if, for example, instead of an excess of the com-
pound of the formula ~I or IVa, certain inorganic bases,
6uch as alkali metal carbonates, are used as agents for
binding hydrogen halide.
~6575
- 31 -
Radicals X2, X3 and/or X4 and/or hydroxy- and/or
amino-protecting groups~ln- a radical Arl which can be
split off by acidolysis are especially certain acyl radicals
of semiesters of carbonic acid, such as, for example, tert.-
lower alkoxycarbonyl or optionally substituted diphenyl-
methoxycarbonyl radicals, and also the tert.-butyl radical;
such radicals can be split off by treating with suitable
strong organic carboxylic acids, such as lower alkanecarb-
oxylic acids optionally substituted by halogen, especially
fluorine, especially trifluoroacetic acid (if necessary,
in the presence of an activating agent, such a5 anisolei,
and also with formic acid.
B~ radical 8 X2, X3 and/or X4 and/or hydroxy-
and/or amino-protecting groups in a radical Ar which
can be split off by reduction there is to be understood
also thoYe radicals which can be split off by ~reating with
a chemical reducing agent (especially with a reducing metal
or a reducing metal compound). Such radicals are especially
2-halo-1-lower alkoxycarbonyl or arylmethoxycarbonyl, which
can be spli~ off, for exa~ple, by treating with a reducing
heavy metal, such as zinc, or with a reducin~ heavy metal
salt, such as a chromium(II) salt, for example chromium(II)
chloride or acetate, usually in the presence of an organic
carboxylic acid, such as for~ic acid or acetic acid, and
of water.
Protecting groups of hydroxy and/or amino groups that
are optionally present in a radical Arl correspond to
the groups mentioned above 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
simultaneously with other groups or subsequently in a
separate process step.
The above reactions are usually carried out in the
presence of a solvent or ~olvent mixture, it being possible
for suitable reactants to function ~imultaneously as such,
and, if necessary, while cooling or heating, for e~ample
in an open or clo~ed vessel and/or in the atmosphere of
- 32 -
an inert gas, for example nitrogen.
The starting materla-ls of the formula IV can be
obtained in a manner known ~ e as follows: for the
manufacture of a stzrting material in which m is 0, for
example, a compound of the formula Ar1-H is reacted,
according to the Friedel-Crafts process, with a haloacetyl
halide, for example chloroacetyl chloride, in the presence
cf a suitable Lewis acid, for example aluminium chloride,
the carbonyl group in the Ar -haloacetyl compound obtained
in this manner or in another usual manner is reduced, for
example by means of sodium borohydride, to the carbinol
group~ and the resulting compound is reacted with an amine
of the formula
O - X4 X
~N - alk - (O) ~ CON / (rVa)
in which X3 has the meaning given, and X4 or X4 and
X5 together are different from hydrogen.
Starting materials of the formula IV in which m has
the meaning given above can be obtained by reacting a
compound of the formula II described above with a compound
of the formula IVa. This reaction is carried out in a
manner known per se.
The Schiff's base formed, for example, by reacting
a compound of the formula
Ar -(CH ) -CH - CH - NH
1 2 m 1 2 2
X2 (IVb)
with a carbonyl compound of the formula
~6~7~
3~ -
O _ ~4
__ .
_ ~ ~-- CON / (IVc)
in which R represents an alkyl radical corresponding to
the alkylene radical alk and containing a carbonyl group
which i-~ separated from the oxygen atom or the phenyl
radical by ~t least one carbon atom, and X or X and
X together denote one of the mentioned protecting groups,
can be reduced with a borohydride, for example sodium
borohydride, to a compound of the formula IV. The reduction
can also be effected by means of activated hydrogen in the
presence of a hydrogenation catalyst, for example a platinum-
on-carbon catalyst.
Amines of the formula IVb, in which X represents
hydrogen or a group that can be split off by reduction,
including hydrogenolysis, and replaced by hydrogen, can
be manufactured, for example, by reacting a compound of
~he formula
~1
I
1 2 m 2 1 (IVd),
in which X and Z have She meaning given under formula
~II), with ammonia or with an amine, for example
benzylamine, tha~ contains a radical which can be split
off by means of reduction, includin~ hydrogenolysis, for
example as stated, and replaced by hydroyen.
Carbonyl compounds of the formula (IVc) in which n
represents the value 1 can be obtained in the usual manner
by reacting a compound of the formula
O _ ~4
CO~ / (IVe)
- 34 -
with a compound of the formula R-~al ~IVf), in which R has
the meaning given above and represents a compound (IVf),
for example a haloketone, for example chloroacetone.
It is also possible to manufacture from the above-
~entioned compounds of the formula (IVe), by reaction with
non-geminal, especially vicinal, dihalo-lower alkane~,
more especially dibromo- or bromo-chloro~lower alkanes,
compounds of the formula
O _ ~4
Hal-alk-O ~ CO ~ \ tIV9)
in which Bal denotes a bromine or chlorine atom and R ,
alk, X and X have the meanings given above, and these
compounds can be reacted with compounds of the formula IVb
to form starting materials of the formula IV, wherein, as
already described, end products of the formula I may
optionally be produced directly.
The novel compounds of ~he formula I can also be
obtained as follows: in a compound of the formula
~X8
Ar -(CH ) -Y - X - ~O) ~ ~ Rl
2 2 m 6 n ~ - R (V),
in which X is a reducible group of the formula
-CH = N - alk - (Va~ or -CH2 - N = alkl- (Vb),
or -C (-X7) - N (X8~ - alk - (Vc) or
- C~ - N (X ) - C (-X ) - alk - (Vd)
or is a group -CH2 - N (X ) - alk - (Ve),
wherein alk represents the alkyl-ylidene radical corres-
ponding ~o a radical alk, and alk corresponds to a radi-
cal alk that is shorter by a methylene group bonded to the
nitrogen atom, X represents the oxo or thioxo radical
and X represents hydrogen or a radical that can be
replaced by hydrogen under the conditions for the reduction
i7
-- 35 --
of X and/or Y, and Y represents a radical of the formula
-CO- ~Vf~ or -C~(OX )- tvg), in which X has the meaning
given abo~e, Ar corresponds to a radical Ar but option-
ally carries, in place of one or two hydroxy and/or amino
groups in each case, one or two groups -OX8 and~or
N(X8~-, in which X has the meaning given above, m and
n have t:he meanings given above, wherein, at all times,
X is a reducible group Va to Vd and/or Y is a carbonyl
group Vf, this group or these groups isfare reduced and,
in the same operation, the groups X that are different
from hydrogen are replaced by hydrogen, and, if desired,
the additional process steps mentioned in connection with
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
the substituents may be, for example, lower alkoxy, such
as methoxy, and more especially benzyl.
~ rotecting groups which are present a~ the hydroxy
and/or amino groups optionally substituting the radical
Ar correspond to those groups mentioned hereinbefore
for X which can be split off by means of the described
methods and replaced by hydrogen, such groups being split
off in the course of the described process simultaneously
with other groups or subsequently in a separate process
step.
Starting materials of the formula V having a group
X of the formula Vb may also be in the isomeric form
of ring tautomers of the formula
Ar2-(CH2)~-~H ~H~ --X8
~alk3 ()n ~ ~ Rl (Vh)
in which alk corresponds to the meaning of alk and
the oxygen atom and the nitrogen atom of the ring are bonded
to the same carbon atom.
S~S
- 36 -
An alkyl-ylidene group alk is, for example,
ethylylidene or ~-propanyl-2-ylidene, whilst an alkylidene
group alk represents, for example, methylene, ethylidene
or isopropylidene.
The reduction of the nitrogen-carbon double bond in
starting materials of the formula V which contain, as the
radical:X , a group Va or Vb, while Ar2, Y, X and n
have the meaninqs given under formula V, (or, in the
isomeric compounds of the formula Vg, the reduction of the
oxygen-carbon-nitrogen bond) to form a nitrogen-carbon
single bond can be effected in a manner known per se, for
example by treating with catalytically activated hydrogen,
such as hydrogen in the presence of a suitable hydrogenation
catalyst, for example a nickel, platinum or palladium
catalyst, the groups X8 that can be split off by
hydrogenolysis at the same time being split off and replaced
by hydrogen; or a suitable hydride reducing agent is used,
such as an alkali metal borohyride, for example sodium
borohydride. In all cases, a carbonyl radical Y, if
present, is reduced to form the hydroxymethylene radical
simultaneously with the reduction of the group Va or Yb
and, if a hydride reducing agent is used, also acyl radicals
of carboxylic acids, for example aeetic acid, may be present
as radicals X8 and may be split off in the same
operation.
The reduction of the carbonyl group Y in starting
compounds of the general formula V which contain, as the
radical X , a group Ve, while Ar2, X8 and n have the
meanings given under formula V, can be effected in the
manner given above for the reduction of the groups Va and
Vb, wherein, once again, in the case of catalytic
hydrogenation, corresponding radicals X can be ~plit
off by hydrogenolysisO
Especially suitable for the reduction of compounds
of the formula V having a group of the formula Ve or Vd
and the meanings of Ar , Y and n defined under the formula
V are hydride reducing agents, such as, for example, sodium
~6575
borohydride or diborane.
Simultaneously with the reduction of a group Vc or
Vd, the reduction of a carbonyl group Y, if present, and
also the splitting off of acyl radicals of carboxylic acids,
for example acetic acid, bonded to oxygen as radicals X8
also takes place. On the other hand, it must be ensured,
by limiting the amount of reducing agent and suitable
selection of the reduction conditions, that the aromatically
bonded carboxamide group is not reduced. Groups of the
formulae Ve and Vdr in which X7 represents, in each case,
a thioxo group, are converted into the group of the formula
-cH2-NH-alk- by reductive desulphuration, for example
by treating with a hydrogenation catalyst, such as Raney
nickel. The above reduction reactions are carried out in
a manner known E~ se, usually in the presence of an inert
solvent and, if necessary, while cooling or heating, for
example within a temperature range of from approximately
-20 to approximately 150 , and/or in a closed vessel
under pressure and/or in an inert gas atmosphere, for
example a nitrogen atmosphere.
A starting material of the formula V, in which m is
0, can be manufactured in a manner known per se, optionally
in situ, i.e. under the conditions of the described pro-
cess. Thus, a compound of the formula Ar2 ~ H (Vi) can
be acetylated with an acetic acld halide or anhydride in
the presence of a Lewis acid ~nd, in the resulting inter-
mediate, the acetyl group can then be converted into the
glyoxyloyl group, for example by treating with a suitable
oxidising agent, such as selenium dioxide. A glyoxyl com-
pound of this kind, or, if desired, a suitable derivative
thereof, for exa~ple an acetal, can then be reacted with
an amine of the formula
o - ~8
~2N - alk - () ~ 0~ ~ ~ (V~
575
- 38 -
to form a starting material of the formula V having the
group X of the formula Va, in which Y represents the
carbonyl group. A compound of the formula (Vi) can also
be haloacetylated, acccrding to the Friedel-Crafts method,
with a haloacetyl halide, fc- example chloroacetyl chloride,
in the presence of a suitable Lewis acid, for example
aluminium chloride, to form the corresponding Ar2-
chloroacetyl compound, and, in the haloacetyl compound
obtained in this manner or in another usual manner, the
carbonyl group can be reduced to the carbinol group by
treating with a suitable hydride reducing agent, and the
halogen atom can be converted into the primary amino group
by treating with ammonia or a suitable derivative thereof,
such as hexamethylenetetramine, and decomposing the
resulting reac~ion product with a dilute acid, for example - --
aqueous hydrochloric acid, whereupon an intermediate of
the formula
Ar -(C~ ) - CH - CH - NH
OEI
is obtained, in which m is 0. Amines of the formula Vk,
in which m has the above meaning, can, in their turn, be
obtained in known manner, for example by reacting a compound
of the formula
It
Ar -(CH ) - CH - C~ - Z (Vl~,
in which X and Z have the meaning given under the
formula (II), with ammonia or a compound that yields
ammonia, for example hexamethylenetetramine, it being
possible to obtain compounds of the formula (Vl) analogously
to the pro-ess described for the manufacture of starting
materials of the formula (II).
- 39 ~
Amines of the formula Vk in which m has the meaning
given above can also be o~tained by reacting an aldehyde .
of the formula
2 m (Vm~
-
or a sultable derivative thereof, Quch as an acetal, for
example dimethyl acetal, cr a bisulphite addition compound,
with a suitable organosilicon cyano compound, such as a
tri-lower alkylsilyl cyanide, for example trimethylsilyl
cyanide, in the usual manner in the presence of a catalyst,
such as zinc iodide, to form a compound of the for~ula
~C~
2 m ~ (Vn)
O-~i(CH3)~
and converting the latter into a compound of the formula
Vk, in which m has the meaning given above, by means of
a suitable reducing agent, for example a di-light metal
hydride, for e~ample lithium aluminium hydride, in a
solvent, this usually being an ethereal liquid, for example
diethyl ether or tetrahydrofuran.
By reacting an intermediate of the formula Vk with
a carbonyl compound of the formula
~ ~8
O - alk - (O) ~ 0~ (Vo)
it is possible to obtain star~ing materials of the formula
V having a group X6 of the formula (Vb). A modification
of these reactions is, instead of exchanging the halogen
atom in the intermediate described above for the primary
amino group by treating with ammonia etc., to exchange it,
s~
- 40 -
by reaction with a l-aryl-lower alkylamine, for example
benzylamine or a di~ aryl-lower alkyl)-amine, for example
dibenzylamine, for the corresponding l-aryl-lower alkylamino
or di-~l-aryl-lower alkyl)-amino group and to react the
resulting compound, for example tbe corresponding dibenzyl-
amino compound, with the oxo compound of the formula (Vl)
under the reducing conditions of the process. In so doing,
there is used as the reducing agent especially catalytically
activated hydrogen, for example hydrogen in the presence of
a heavy metal hydrogenation catalyst or a mixture thereof,
such as a palladiu~ and/or platinum catalyst. Under such
reaction conditions, groups X8, for example benzyl groups,
that can be split off by hydroqenolysis are split off, and
the optionally present carbonyl group is reduced to the
carbinol group and, at the same time, the nitrogen-carbon
double bond is reduced to the corresponding nitrogen-carbon
single bond.
Oxo compounds of the formula Vo in which n is 1
can, in their turn, be obtained by reacting a dihydroxy
compound of the formula
~0 O-X
\R2
with a haloalkanone compound of the above-described formula
R - Hal ~IVf), for example chloroacetone, in the presence
of an alkaline condensation agent, for example potassium
carbonate, or of an organic base, such as triethylamine.
Starting ~aterials of the formula V having a ~roup
X6 f the formula Vc or Vd can be manufactured in a manner
known per se, for example, by reacting a formyl compound of
the formula Ar2-(CH2) -CHO (Vq) with hydrocyanic
acid and, in the cyanohydrin intermediate obtained in this
~anner, hydrolysing the cyano group to form the carboxyl
group, for example under acidic conditions. The Ar2-2-
iS'~5
- 41 -
hydroxyacetic acid obtained in this manner or via the inter-
mediate stages imide chlo~ide, imido-lower alkyl ester and
lower alkyl ester is then reacted in the presence of a suit-
able condensation a~ent, for example a carbodiimide, such
as dicyclohexylcarbodiimi~e, with an amine of the formula
(Vj), whereupon a starting material of the formula V having
the group X of the formula (Vc) is obtained.
A star~ing material of the formula (V) having the
group X6 of the formula (Vd) can be obtained also by reac-
ting a compound of the formula Vk with a compound of the
ormula
~ ~8
Hal - C (-O) - alk2 - (O) ~ 0~ / 1 (Vr)
\R2
in which ~al represents halogen and especially chlorine.
Furthermore, in the above-given Ar -chloroacetyl compound,
the chlorine atom can be exchanged for the primary amino
group, for example by reaction with hexamethylenetetramine,
and a compound so obtained can be reacted with a halogen
compound of the formula Vr. In a resulting starting
material of the formula V having a group X of the formula
Yd and in which Y represents the carbonyl group, the car-
bonyl group can be reduced to the carbinol group and, at
the same time, the aliphatically bonded carbamoyl group can
be reduced to the group of the formula -CH2 ~ 1 ~ alk,
for example by means of a hydride reducing agent, especially
diborane.
The novel compounds of the formula I can also be
obtained by reacting a compound of the formula
0-~9
Ar -(CH ) - CH - C~ - N - alk - (O) ~
3 2 m 1 2 I n ~400~I (VI)
5~5
- 42 -
in which Ar has the meaning of Ar or represents a radi-
cal Ar that is substituted by 1 or 2 groups that can be
converted into hydroxy and/or amino by means of aminolysi~,
and/or by groups of the formula -COOH, Xg represents
hydrogen or a group tha~ can be split off by aminolysis, and
m and n have the meanings given above, or a reactive deri-
vative bf one of the carboxylic acids defined in formula VI,
with a compound of the formula HNRlR2 (VII) and, at the
same time, converting into hydroxy and/or amino optionally
present radicals that can be converted into hydroxy and/or
amino by aminolysis, and/or splitting off optionally present
radicals X and replacing them by hydrogenr and, if
desired, carrying out the additional process steps mentioned
in connection with the first process. Radicals that can be
converted into hydroxy and/or amino by hydrolysis and espe-
cially by aminolysis, and radicals X that can be split
off in this manner are acyl radicals of organic carboxylic
acids, for example aroyl, such as benzoyl, or lower
alkanoyl, such as acetyl.
Reactive derivatives of the carboxylic acids defined
in the formula VI are, for example, the halides, such as the
chlorides or bromides, and the azides, and also the acid
anhydrides, especially mixed acid anhydrides with, for
example, lower alkanecarboxylic acids, such as acetic acid
or propionic acid, ar.d lower alkoxyalkanecarboxylic acids,
such as 2-methoxyacetic acid. Reactive derivatives of car-
boxylic acids of the formula VI are especially esters, for
example with lower alkanols, such as methanol, ethanol,
isopropanol and tert.-butanol, or with aryl-lower alkanols,
such as benzyl alcohol optionally substituted by lower
alkyl, for example methyl, or by lower alkoxy, for example
methoxy, or phenols which are optionally activated by suit-
able substituents, 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, such as,
for example, 4-chlorophenol, 4-methoxyphenol, 4-nitro- or
2,4-dinitrophenol, also esters ~ith cycloalkanols, such as,
iS75
- 43 -
for example, cyclopentanol or cyclohexanol which may option-
ally be substi~uted by lower alkyl, for example methyl.
The reaction is carried out in a manner known 2~ se,
usually in the presence of an inert solvent, for example
within a temperature range of from approximately -10
to 50 C in a closed vessel.
The starting materials of the formula VI in which m
is O can be obtained in a manner known Per se by brominat-
inq a compound of the formula Ar - COCH , reducing the
carbonyl group in the resulting Ar3-haloacetyl compound
to the carbinol group, for example by means of diborane, and
reacting the resulting compound with an amine of the formula
O-Xg
H N - alk - (O~ ~ ~VIa),
2 n ~ ~-COO~
in which X has the meaning given, or with a reactive
derivative thereof. The Ar3-haloacetyl compound can also
be reacted with the amine of the Pormula VIa and the car-
bonyl group converted into the carbinol group subsequently.
For the ~anufacture of ~tarting materials of the
formula VI in which m has the meaning given above, it is
also possible to reduce the Schiff's base formed by reacting
a compound of the formula
3 2 m 2 2
l (VIb)
OH
with a carbonyl compound of the formula
O-Xg
~ ~OOH (VIc),
in which R represents an Dlkyl group containing a carbonyl
- 44 -
group and corresponding to the alkylene radical alk, i.e. R
corresponds to an oxaalkyl radical, with a borohydride, for
example sodium borohydride.
The reduction can also be effected by means of activa-
ted hydrogen in the presence of a hydrogenation catalyst,
for example a pla~inum-on-carbon catalyst.
Compounds of the formula VIb can, for their part, be
obtained, for example, by reacting a compound of the formula
Xl
Ar - (CH ) - CH - CH - Z ~VId),
3 2 m 2
in which Xl and Zl tQsether represent epoxy, or Xl
represents hydroxy and Z represents a reactive esterified
hydroxy group, for example halogen, such as chlorine, with
ammonia, or, i~ X represents hydroxy and Zl represents,
for example, chlorine, with hexamethylenetetramine, and
decomposing the resulting adduct with a dilute mineral acid,
such as dilute hydrochloric acid, it being possible to manu-
facture starting materials of the formula VId analogously
to the process described for the manufacture of starting
materials of the formula II.
Carbonyl compounds of the formula (VIc) in which n
is 1 can, in their turn, be obtained in a manner known
se by reacting a compound of the formula
~OOH (VIe)
with a compound of the formula R-Hal (IVf), in which Hal
represents halogen, especially chlorine.
The novel compounds of the formula I in which R
and R each represents hydrogen can also be obtained as
follows:
in a compound of the formula
s~
- 45 -
OH
Ar-(CH ) - CH - C~ - Nr -- alk-(0) - ~ ~ (VII)
OH
in which one or both hydroxy groups, and/or hydroxy and/or
amino groups present in the radical Ar are optionally
protected by those groups that can be split off by hydro~
lysis and replaced by hydrogen and which are split off and
replaced by hydrogen under the conditions of the process,
or the group -CN is present in the radical Ar optionally
together with the mentioned protected hydroxy and/or amino
groups, the groups -CN are converted by hydrolysis into the
group -CONH2 and, at the same time, optionally protected
hydroxy and/or amino groups are converted into free hydroxy
and/or amino groups and, if desired, the additional process
steps mentioned in connection with the first process are
carried out.
The starting materials of the formula VII can be manu-
factured in the usual manner by reacting a compound of the
formula
Ar - (C~ J - CH - C~ - NH ~VIIa)
OH
with a compound of the formula
OH
Hal-alk-()n ~ CN ~VIIb)
in which ~al represents chlorine, bromine or iodine. The
reaction is carried out in a manner known per se, advantage-
ously in the presence of a basic agent.
Starting materials of the formula (VIIa), in which m
has the meaning given above, can, in their turn, be obtained
by reacting a compound of the formula (II), in which X
and Z together represent the epoxy group, with ammonia,
or, if Xl represents hydroxy and Zl' as a reactive
~ 46 -
esterified hydroxy group, represents, for example, halogen,
such as chlorine~ for example with hexamethylenetetramine,
and subsequently converting the resulting adduct with a
dilute mineral acid, such as dilute hydrochloric acid.
Starting materials of the formula (VII), in which m is
0 can also be manufactured in the usual manner, for example,
by halogenating, for exampe brominating, a compound of the
formula Ar-COCH (VIIc), for example by means of bromine
in an inert solvent, such as chloroform, and, in the
resulting Ar-haloacetyl, for example bromoacetyl, compound,
replacing the halogen by the amino group, for example, by
reacting with hexamethylenetetramine in a solvent, for
example a chlorinated hydrocarbon, such as chloroform,
decomposing the resulting adduct with a dilute mineral acid,
for example hydrochloric acid, reducing the carbonyl group
in the resulting compound of the formula Ar-CO-CH2-NH
(VIId) ~o the carbinol group, for example by means of
diborane, and reacting the resulting compound of the formula
Ar - CH - C~ - NH
¦ (VIIe)
OH
with a compound of the above-described formula VIIb in the
manner there described.
A compound of the formula VIIb can, in its turn, be
obtained by the action of acetic anhydride on the oxime
corresponding to the cyanide. This takes place advantage-
ously by boiling under reflux. The oxime can, for its part,
be manufactured from the correspondinq aldehyde by boiling
under reflux with hydroxylamine hydrochloride in the
presence of an alcoholic sodium carbonate solution. The
corresponding aldehyde can, in its turn, be manufactured
by reacting 2,4-dihydroxybenzaldehyde with an a, ~-, a,y-
or a~-dihalo-lower alkane, preferably in the presence of
a basic agent. In an analogous manner, a hydroxysalicylo-
nitrile, for example 2,4-dihydroxybenzonitrile [Chem. Ber.
24, 3657 (1891)] or 2,5-di~,ydroxybenzonitrile [~elv. Chi~.
s
- 47 -
Acta 30, 149, 153 (lg47)] can be reacted with a non-geminal
dihalo-lower alkane to--form a co~pound of the formula YIIb.
The novel compounds of the formula I in which m is l,
2 or 3 can also be obtained as follows:
in a compound of the formula
OH
I 2 n ~ \ (VIII),
OH
in which A represents the group -N-alk- or -N=alk -, in
which alk represents the group alk having one fewer
methylene group, and X represents a group that can be con-
verted into a methylene, ethylene or trimethylene group
by means of reduction, including hydrogenolysis, and one
or both hydroxy groups, and/or hydroxy and/or amino groups
that are optionally present in the radical Ar are protected
by those groups that can be split off by means of reduction!
including hydrogenolysis, and replaced by hydrogen and which
are split off and replaced by hydrogen under the conditions
of the process, the group X is converted into a methylene,
ethylene or trimethylene group by means of reduction,
including hydrogenolysis, and, at the same time, an option-
ally present unsaturated group A is converted into the satu-
ra~ed group A and, at the same time, optionally present
protected hydroxy and/or amino groups are converted into
the free hydroxy and/or amino groups, and, if desired, the
additional process steps mentioned in connection with the
first process are carried out.
A ~roup X represents especia?ly a carbonyl group
standing in place of a methylene group and which, according
to the meaning of m as 1, 2 or 3, either stands alone or
adopts each of the possible positions together with one or
two methylene groups. A group X also represents a group
having 2 or 3 carbon atoms which has a double or triple
bond, for example a vinylene, 1,2-propenylene, 2,3-pro-
5~5
- 4~ -
penylene, or ethynylene or 1,3-propynylene group.
The reduction of the group X is effected in the usual
manner, for example by means of activated hydrogen, such
as hydrogen in the presence of a hydrogenation catalyst, for
example a nickel catalyst or a noble metal catalyst, such
as platinum or palladium, optionally precipitated on a
carrier, such as active carbon, or a platinum-on-carbon or
palladium-on-carbon catalyst~ In this operation, option-
ally present hydroxy- and/or amino-protecting ~roups that
can be split off by hydrogenolysis are split off and
replaced by hydrogen. The reduction, including hydrogeno-
lysis, is carried out in a manner known per ~ usually in
the presence of an inert solvent at normal or elevated
pressure and normal or elevated temperature.
Starting materials of the formula VIII, in which X
represents a group of the formula -CO- ~VIIIa), co-ca -
~VIIIb) or -CO-CH2-CH2- (VIIIc) and, as stated above,
protected hydroxy and/or amino groups are present in the
radical Ar, can be obtained, in a manner known per se, by
epoxidising the qroup -C~SCH in a compound of the formula
Ar - X - CH = CH (IX)
/o\
to form the group -C~ - CH2, (cf. in this connection:
Cahnmann, Bull. Soc. Chim. France [5], 4, 1937, 226, 230.)
for example as described under the starting materials of
the formula (II), by reaction with a peroxy compound, such
as hydrogen peroxide, or an organic peracid, such as, for
example, an optionally substituted, such as halo~enated,
aliphatic or aromatic peracid, for example peracetic acid
or trifluoroperacetic acid, perbenzoic acid or m-chloroper-
benzoic acid, in an anhydrous solvent, for example chloro-
form or dioxan. The resul~ing compound or a compound
obtained therefrom, for example by reaction with a hydro-
halic acid, for example hydrochloric acid, in a solvent,
5~'~
- 4g -
for example dioxan, having the general formula
11 ~xj,
Ar - X - CH - CH - Z
in which Xl and Z3 together represent epoxy, or X
represents hydroxy and Z3 represents halogen, for example
chlorine, can then be converted with ammonia or, if X
and Z3 is halogen, with hexamethylenetetramine and subse-
quent decomposition of the resulting adduct with a dilute
mineral acid, for example hydrochloric acid, into a compound
of the formula
Ar X - CH - C~ - NH
1 2 2 (XI)-
OE3
From this, by reaction with a compound of the formula
., ~
~al-alk-(O) ~ COW ~ 1 (XII),
\R2
in which ~al represents halogen and especially chlorine, a
starting material of the formula VIII having the group A
of the formula -I-alk- can be manufactured or, by reaction
with a compound of the formula
1~4~;57~
- 50 -
OH
0~alk -~0) ~ CO~ / 1 ~XIII),
in which alk has the meaning given above, a starting
material of the formula VIII in which the group A corres-
ponds to the formula -N=alk - can be manufactured. These
reactions are carried out in a manner known ~r se: for
example, in the reaction with a compound of the formula
XII, an alkalin~ condensation agent is used, for example
an alkali metal or alkaline earth metal carbonate, such as
sodium or calcium carbonate.
Starting material~ of the formula VIII, in which X
represents a group having 2 or 3 carbon atoms which has
a double or triple bond, and A has the meaning given above,
can be obtained by converting a compound of the formula
Ar - X - CHO (XIV),
in whi~h X represents a group having 2 or 3 carbon atoms
which has a double or triple bond, or a suitable derivative
thereof, such as an acetal, for example the dimethyl acetal,
or a bisulphite addition compound, with a suitable organo-
silicon cyano compound, such as a tri-lower alkylsilyl
cyanide, for example trimethylsilyl cyanide, in the usual
manner in the presence of a catalyst, such as zinc iodide,
into a compound of the formula
CN
/
Ar - X - CH~ (XV)
Si~C~3)3
and, in this compound, converting the group -CN by means of .
reduction, with the simultaneous replacement of the tri-
7S
- 51 -
methylsilyl group~~y hydr~xy, into the group -C~2NH2.
As reducing agent, there can be used, for example, a di-
light metal hydride, such as lithium aluminium hydride, in ~~~
a suitable ~olvent, this usually being an ethereal liquid, ~-
for example diethyl ether or tetrahydrofuran. The compound
of the formula
Ar - X - C~ - CH - NH
_ I (XVI)
OH
obtained in this manner can then be reacted with a compound
the formula (VIII) in which A represents the group of the
formula -N-alk- ; or a compound of the formula XVI is reac-
ted with a compound of the above-described formula (XIII),
whereupon a starting material of the formula VIII is
obtained in wbich A represents the group of the formula
-N=alkl-.
These reactions are carried out in the usual manner.
When selecting the suitable above-mentioned process
for the manufacture of compounds of the formula I care must
be taken that any substituents present, especially in the
radical Ar, are not converted or split off if such conver-
sions or splitting-off operations are not desired. Thus,
especially functionally modified carboxy groups, such as
esterified or amidated carboxy groups, and cyano groups, as
substituents of the radicals Ar, may participate in the
reactivn and be converted durinq solvolysis, especially
hydrolysis, and also in the case of reduction. On the other
hand, simultaneous conversions of substituents may be
desired; for example, unsaturated substituents, such as
lower alkenyl, can be reduced, for example to lower alkyl,
under the conditions of a reduction process used according
to the invention.
In resulting compounds, it is possible within the
5~S
- 52 -
scope of the definition of compounds of the formula I to
convert resulting compounds obtained in accordance with
the process into other end products in the usual manner,
for example by modifying, introducing or splitting off sui~-
able substituents.
Thus, in resulting compounds, unsaturated substituents
in the radical Ar, such as lower alkynyl or lower alkynyl-
oxy, or lower alkenyl or lower alkenyloxy, can be reduced,
for example by treating with catalytically activated
hydrogen.
In compounds having halogen atoms as substituents of
the radical Ar, the halogen can be replaced by hydrogen, for
example by treating with hydrogen in the presence of a
customary hydrogenation catalyst, such as Raney nickel or
palladium-on-carbon.
In compounds having an esterified carboxy group as
substituent in the radical Ar, this group can be converted
in the usual manner, for example by ammonolysis or amino-
lysis with ammonia or a primary or secondary amine, into
the corresponding carbamoyl group.
Compounds having a carbamoyl group in the radical
Ar and groups R1 and R2 that are different from hydrogen
can be dehydrated in the usual manner, for example by the
action of dehydrating agents, such as phosphorus pentoxide
or phosphorus oxychloride, preferably at relatively high
temperatures, to form the corresponding cyano compounds.
In compounds having a cyano group as substituent in
the radical Ar, this group can be alcoholysed in the usual
manner, for example by the addition of alcohols in the pre-
sence of an anhydrous acid, such a~ hydrochloric acid, and
subsequent hydrolysis of the resulting imido ester to form
the corresponding compounds having esterified carboxy
groups.
In compounds having a nitro group as substituent in
the radical Ar, this group can be reduced to the amino
group, for example by means of catalytically activated
5 ~Cj
- 53 -
hydrogen, such as-hy~ro~e~ in the presence of a hydrogena-
tion catalyst, such as Raney nickel or a palladium-on-carbon
catalyst, or by means of a metal, for example iron, zinc or,
if desired, zinc amalgam, in an acid, for example a mineral
acid, such as hydrochloric acid or a carboxylic acid, such
as acetic acid or mixtures thereof.
In compounds having a primary amino group as substi-
tuent in the radical Ar, this group can be converted into
a lower alkylamino or di-lower alkylamino grou~, for example
by reaction with a corresponding suitable alkylating agent,
such as a reactive esterified lower alkanol, for example
the halide, such as the chloride, bromide or iodide, or an
ester with a strong organic sulphonic acid, for example the
methanesulphonic acid ester, advantageously in the presence
of a basic agent, such as an alkali metal hydroxide or
carbonate.
In compounds having a primary amino group in the
radical Ar, this group can be converted into the ureido,
N'-lower alkylureido or N,N'-di-lower alkylureido group,
for example by reaction with cyanic acid or a salt thereof,
such as potassium cyanate, in an acidic medium, such as
aqueous hyarochloric acid, or with a lower alkylurea or
N,N-di-lower alkylurea at elevated temperature.
In compounds having a primary amino group in the
radical Ar, this group can be converted into a lower alkyl-
sulphonylamino group, for example by reaction with a lower
alkylsulphonyl halide in the presence of a basic agent,
for example pyridine.
As in the manufacturing processes, when carrying out
the additional steps, care must be taken that undesired
side reactions which result in the conversion of additional
groupings do not occur.
The reactions described above may be carried out
simultaneously or in succession, as desired, and also in
any sequence. If necessary, they are carried out in the
presence of diluents, condensation agents and/or catalyti-
7~
- 54 ~
cally active agents, at-reduced or elevated temperature,
in a closed vessel under pressure and/or in an inert gas
atmosphere.
Depending on the process conditions and the starting
~aterials, 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 of 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 hydro~ides, carbon-
ates or bicarbonates, or ion exchangers. On the other hand,
resulting free bases with organic or inorganic acids, for
example with the mentioned acids, may form acid addition
salts, there being used for the manufacture thereof espe-
cially those acids which are suitable for the formation of
pharmaceutically acceptable salts.
These or other salts, especially acid addition salts,
of the novel compounds, such as, for example, oxalates or
perchlorates, may also be used to purify the resulting free
bases, by converting the free bases into salts, separating
and purifying these, 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 o
optical antipodes or racemates or, if they contain at least
two asymmetric carbon atoms, also as racemic mixtures.
The starting materials may also be used in the form of
specific optical antipodes.
Resulting racemic mixtures may be separated on the
basis of the physical-chemical differences between the dia-
stereoisomers, in known manner, for example by chromato-
graphy and/or fractional crystallisation, into the two
stereoisomeric (diastereoisomeric) racemates.
Resulting racemates can be resolved into the anti-
~6S7S
- 55 -
podes according to methods- known per se, for example by
recrystallisation from an optically active 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 actisn
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 acid~ Advantageously, the more active of the
two antipodes is isolated.
The invention relates also to those embodiments of
the process according to which a compound obtained as an
intermediate at any stage of the process is used as starting
material and the remaining process steps are carried out, or
the process is discontinued at any stage, or in which a
starting material 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 E~ se, as stated
above, for example analogously to the methods described
in the Examples. The invention relates also to novel start-
ing materials. The invention relates also to intermediates
that can be obtained in accordance with the process.
The novel compounds may be used, for example, in the
form of pharmaceutical preparations which contain a pharma-
cologically active amoun~ of the active substance, option-
657~
- 56 -
ally together with pharmaceutically acceptable carriers
which are ~uitable for 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, dextro~e, sucrose, mannitol,
sorbitol, cellulose and/or glycerine and/or lubricants,
fsr 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
starches, agar, alginic acid or a salt thereof, such as
sodium alginate, and~or effervescing mix~ures, or adsorb-
ents, colouring substances, flavourinqs and sweeteners.
The novel pharmacologi~ally active compounds can also be
used in the form of parenterally admini~rable 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 on its own or together with a carrier, such as manni-
tol. The pharmaceutical preparations can be sterilised
and/or contain adjuncts, for example preservatives, stabi-
lisers, wetting agents and/or emulsifiers, solubilisers,
salts for regulating the os~otic preYsure and/or buffers.
The present pharmaceutical preparations which may, if des-
ired, contain further pharmacologically active substances,
are manufactured in a manner known Per se, for example by
means of conventional mixing, granulating, coating, dissolv-
ing or lyophili~ing processes, and contain from approxim-
ately 0.1 % to 100 ~, especially from approximately 1 %
to approximately 50 %, and, in the case of lyophilisates,
up to 100 %, of the active substance.
6S7~
- 57 -
The dosage ~ay 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 anim~ls is
between 0.03 mg/kg and 3 mg/kg and for warm-blooded animals
of approximately 70 kg body weight preferably between
approximately 0.004 9 and approximately 0.08 g, and of ~-
receptor stimulators of the formula I, between 0.01 mg/kg
and 1 mg/kg and for warm-blooded animals of approximately
70 kg body weight between approximately 0.002 g and approxi-
mately 0.04 g.
The following Examples serve to illustrate the
invention; temperatures are given in degrees Centigrade.
In the case of compounds that have two centres of
asymmetry and, therefore, may be in the form of diastereo-
isomeric mixtures, the relative content of the two lia-
stereoisomers (enantiomer pairs) was determined by C-NMR
spectroscopy on the basis of the relative intensity of the
two C-methyl signals at 13.3 ~ 0.1 ppm and 13.6 + 0.1 ppm,
respectively. The C spectra were recorded in ~SMO-d
on a Varian-XL-100 instrument at 25.16 MHz using tetra-
methylsilane as the internal standard. (Digital resolution
0.8 points/Hz). Salts were investigated as such. Bases
have to be neutralised with acids (for example, 1 equivalent
of fumaric acid) to obtain a separation of the methyl
signals.
1.~ '1~5~5
-- 58 --
Example 1
2~4 g of 2,4-dichloro-1-(epoxyethyl)-benzene are added
to a solution of 1.96 9 of 5-(2-aminoethoxy~-salicylamide
in 15 ml of anhydrous dimethyl sulphoxide and the mixture
is stirred for 30 minutes in a bath at 80 . The reaction
mixture is poured onto 30 ml of ice-water and extracted
with 100 ml of ethyl acetate. The or~anic phase is sepa-
rated off, dried over magnesium sulphate and concentrated
by evaporation. The evaporation residue is stirred with
20 ml of petroleum ether and the resulting crystals are
filtered with suction and recrystallised from methanol,
yielding a~- [N ~2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-
aminomethyl]-2,4-dichloroben~yl alcohol having a melting
point of 139-140 .
The 5-(2-aminoethoxy)-salicylamide required as
starting material can be produced as follows:
a) According to the method described by Irvine et
al., Synthe~is 1972, 568, 2,5-dihydroxybenzamide is con-
verted, using an excess of acetone, into 2,3-dihydro-2,2-
dimethyl-6-hydroxy-4~-1,3-benzoxazin-4-one having a melt-
ing point of 215-216
b) A mixture of 70 9 of 2r3-dihydro-2,2-dimethyl-6-
hydroxy-4~-1,3-benzoxazin-4-one, 75 9 of dried potassium
carbonate and 400 ml of 1,2-dibromoethane is boiled under
reflux for 14 hours while stirring. The mixture is cooled
and filtered, the residue is stirred thoroughly with 400 ml
of water and flltered with suction, and the residue is dried
in vacuo at 80 . Crude 6-~2-bromoethoxy~ 2,3-dihydro-2,2-
dimethyl-4H-1,3-benzoxazin-4-one having a melting point of
190-200, which is adequately pure for further reactions,
i8 obtained. A pure product having a melting poin~c of
205-208 i8 obtained by recrystallisation from methanol.
c) A mixture of 60 g of 6-~bromoethoxy)-2,3-dihydro-
2,2-dimethyl-4H-1,3-benzoxazin-4-one and 110 ml of benzyl
amine is stirred for 30 minutes in a bath at 80 . The
reaction mixture is then, while cooling with ice, adjusted
5~75
- 59 -
to a pH of 3-4 wit-h-conc-entrated hydrochloric acid and
left to crystallise. After 2-4 hours the crystals are
filtered with suction, washed with 50 ml each of water and
ethyl acetate, and dried. The resulting 5-1(2-benzylamino)-
ethoxy]-salicylamide hydrochloride has a melting point of
214-216 . The base liberated therefrom has a melting
point of 107-108 (from ethyl acetate/ether).
d) Catalytic debenzylation of 5-[(2-benzylamino)-
ethoxy]-salicylamide in methanol by means of a palladium-
on-carbon catalyst (5 ~ strength) results in 5-(2-amino-
ethoxy)-salicylamide having a melting point of 140 .
Example 2
a-[N-12-(~-carbamoyl-4-hydroxyphenoxy)-ethyl]-amino-
methyl~-4-chloro-3-nitrobenzyl alcohol having a melting
point of 16~-163 (from eShyl acetate) is ob~ained analo-
gously to Example 1 from 17.4 g of ~-chloro-l-lepoxyethyl)-
3-nitrobenzene and 11.4 g of 5-(2-a~inoe~hoxy)-salicylamide
in 50 ml of dimethyl sulphoxide.
Example 3
8 9 of ~-chloro-S-(epoxyethyl)-benzenesulphonamide
and 5 g of 5-(2-aminoethoxy)-salicylamide are dissolved
in 40 ml of dimethyl sulphoxide and the ~olution is heated
for 65 minutes at 90 while stirring. The reaction
mixture is then cooled, poured onto ice-water and extracted
with ethyl acetate. The organic phase is then extracted
with lN aqueous methanesulphonic acid solution, and the
acidic phase is rendered alkaline with ammonia and extracted
repeatedly with ethyl acetate. After drying the organic
phase over sodiu~ sulphate, the solvent is removed in a
rotary evaporator and the residue is recrystallised from
isopropanol. ~fter recrystalli~ing again from methanol,
a-[N-l2-~3-carbamoyl-4-hydroxyphenoxy1-ethyll-a~inomethyl]~
3-sulphamoyl-4-chlorobenzyl alcohol having a melting point
of 193-195 is obtained.
575
- 60 -
The 2-chloro-5-(epoxyethyl)-benzenesulphonamide re-
quired as starting material can be produced as follows:
a) 13.5 9 of sodium borohydride are added in portions
at 0-5 , in the course of 1~ hours, to a solution of 20 9
of 5-(bromoacetyl)-2-chlorobenzenesulphonamide (DE-OS
26 01 59B) in BOO ml of methanol. S~irring is continued
for a further 3 hours at room te~perature, the solvent is
removed in a rotary evaporator~ and the residue i5 parti-
tioned between water and ethyl acetate. The organic phase
is dried and concentsated by evaporation, and the residue
is recrystallised from ethyl acetate/ether, yielding 2-
chloro-5-(epoxyethyl)-benzenesulphonamide having a melting
poin~ of 126-129 .
Example 4
After adding 20 g of potassium bicarbonate, a solution
of 21.9 g of 4-t2-aminoethoxy)-salicylamide and 30.3 g of
a-tblomomethyl)-4-nitrobenzyl alcohol in 250 ml of ethanol
is boiled under reflux for 12 hours while stirring. After
oooling and filtering, the filtrate i~ concentrated by eva-
poration and the residue is partitioned between 50 ml of
2N hydrochloric acid and lOQ ml of ethyl acetate. The
aqueou~ phase is concentrated by evaporation and the residue
is recrystallised from methanol. a-~N-[2-(4-carbamoyl-3-
hydroxyphenoxy)-ethyl]-aminomethyl]-4-nitrobenzyl alcohol
i8 obtained in the form of the hydrochloride having a melt-
ing point of 231-233 (from methanol).
The 4-(2-a~inoethoxy)-salicylamide re~uired as -ctart-
ing ~aterial is obtained as follow~:
a) 16.2 g of the 2,3-dihydro-2,2-di~ethyl-7-hydroxy-
4H-1,3-benzoxazin-4-one obtained according to Example 8b)
are reacted analogsusly to Exa~ple lb) with 84 ~1 of 1,2-
dibromoethane and yield 2,3-dihydro-2,2-di~ethyl-7 (2-bromo-
ethoxy)-4~-1,3-benzoxazin-4-one having a ~elting point of
156-158 (from i~opropanol).
57S
- 61 -
b) 53 g of -273-dihydro 2,2~dimethyl-7-(2-bromo-
ethoxy)-4~-1,3-benzoxazin-4-one and 94 g of benzyla~ine are
boiled for 3 hours while stirring. The reaction mi~ture is
rendered alkaline with concentrated ammonia and the organic
phase is concentrated by evaporation at a maximum of 50 .
The resu~ting 4-[2-(benzylamino)-ethoxy]-salicylamide forms
an oil, the hydrochloride of which melts at 252-254 (from
methanol).
c) Catalytic debenzylation of 4-l(2-benzylamino)-
ethoxy]-salicylamide analogously to Example 1 yield~ 4-~2-
aminoethoxy)-salicylamide having a melting point of
126-130 ~from isopropanol).
Example 5
A mi~ture of 16.4 g of N-[5-(2-bromo-1-hydroxyethyl)-
2-chlorophenyl~-methanesulphonamide, 1~.7 g of 5-(2-amino-
ethoxy)-salicyla~ide and 5 9 of potassium bicarbonate in
100 ml of isopropanol is boiled under reflux for 25 hours
while stirring. The reaction mi~ture is filtered, and the
filtrate is concentrated by evaporation and partitioned
between ether and 2N hydrochloric acid. The aqueous phase
is rendered alkaline with solid potassium bicarbonate and
the ~ixture is extracted with ethyl acetate. By concentra-
ting by evaporation a foam is formed, and from this a-~N-[2-
(3-carbamoyl-4-hydroxyphenoxy)-ethyll-a~inomethyl]-3-
(methylsulphonylamino)-4-chlorobenzyl alcohol ha~ing a melt-
ing point of 139-141 gradually crystallises from a little
ethyl acetate. It form~ a neutral fumarate having a mel~ing
point of 190-192 (from methanol3.
The N-[5-~2-bromo-1-hydroxyethyl)-2-chlorophenyl]-
~e~hanesulphonamide required as s~arting material i8 pro-
duced in the following manner:
a) While cooling with iC2~ 110 9 of methanesulphonic
acid chloride are added dropwise to a solution of 162.5 g of
3-amino-4-chloroacetophenone is 900 ml of pyridine. After
stirring further at room temperature for 3 hours, the
- 62 ~
resulting precipitate is filtered oEf and the filtrate is
concentrated by evaporatio~n. The residue crystallises when
water is added. The resulting crude N-~2-chloro-5-
acetylphenyl)-methanesulphonamide is recrystallised from
ethanol, melting point 112-114 .
b) By brominating the compound obtained according to
Example 5a) with the equivalent amount of bromine in chloro-
form, N-(5-bromoacetyl-2-chlorophenyl)-methaneSulphonamide
having a melting point of 120-123 is obtained.
c) By reducing the compound obtained according to
Example 5b) with the equivalent molar amount of sodium boro-
hydride in dioxan/water t9~ N-[5-(2-bromo-1-hydroxy-
ethyl~-2-chlorophenyl]-methanesulphonamide having a melting
point of 130-134 is obtained.
Example 6
4.7 9 of 4-amino-a-(aminomethyl~-3,5-dichlorobenzyl
alcohol, 6.0 9 of 5-(2-bromoethoxy)-salicylamide and 12.9 9
of N,N-diisopropylethylamine are boiled under reflux for 3
hours in a mixture of 20 ml of dimethylformamide and 50 ml
of dioxan. After evaporatinq off the solvent, the residue
is worked up analogously to ~xample 5. ~-[N-[2-(3-
carbamoyl-4-hydroxyphenoxy)-ethyll-aminomethyl]-3,5-
dichloro-4-aminobenzyl alcohol is obtained as brownish
crystals having a melting point of 196~201 .
The 5-(2-bromoethoxy)-salicylamide required as
starting material can be obtained as follows:
a) 30.0 9 of the 6-(2-bromoethoxy)-2,3~dihydro-2,2-
dimethyl-4~-1,3-benzoxazin-4-one obtained according to
Example lb) are boiled under reflux for 1~ hours, while
stirring, in a mixture of 100 ml of dioxan and 100 ml of
6N hydrochloric acid. The crystals obtained after concen-
trating the reaction mi~ture by evaporation are washed with
50 ml of water and dried in vacuo. The resulting 5~(2-
o
bromoethoxy)-salicylamide melts at 141-143 .
iS~5
- 63 _
The 4-amino-~-(aminomethyl)-3,5-dichlorobenzyl alcohol
required as s~arting material is produced as follows:
b) 6.5 9 of sodium hydride suspension (55 % in
paraffin oil) are added in portions, while stirring, to
a suspension of 17.9 g of phthalimide in 70 ml of dimethyl-
formamide. After one hour, wi~h further stirring and cool
ing at 10-20 , a solution of 34.5 9 of 4-amino-~-bromo-
3,5-dichloroacetophenone in 50 ~1 of dimethylformamide is
added dropwise, and the reaction mixture is then stirred
for a fur~her 3-4 hours and then poured into 1200 ml of
water. The precipitated crystals are filteted with suction
and dried in vaouo at 100 . Crude N-[2-(4-amino-3,5-
dichlorophenyl)-2-oxoethyl~-phthalimide having a melting
point of 255-260 is obtained.
c) 5~2 9 of sodium borohydride are added in portions
to a suspension of 2~.6 9 of N-[2-(4-amino-3,5-dichl~ro-
phenyl)-2-oxoethyll-phthalimide in a mixture of 150 ml of
dioxan and 20 ml of water, and the mixture is then stirred
for 48 hours at 80-90 . After 24 hours another 5.2 9
of sodium borohydride are added.
Th~ excess sodium borohydride is decomposed by 2N
hydrochloric acid while cooling with ice and the reaction
~ixture is concentrated by evaporation. The residue is
rendered alkaline with concentrated ammonia solution and
extracted with ethyl acetate. After removing the solvent,
crude 4-amino-3,5-dichloro-a-[N-(2-hydroxymethylbenzoyl~-
aminome~hyl]-benzyl alcohol having a melting point of
165-170 is obtained, which can be further processed
without further purification.
d) 19 . 4 q of the crude product according to Example
6c) and 4.8 9 of sodium hydroxide are boiled under reflux
for 5 hour~ in 200 ml of ethanol. By partitioning the
evaporation residue between 200 ml of ethyl acetate and
30 ml of water, and working up in a customary manner, 4-
amino-~-(aminomethyl)-3,5-dichlorobenzyl alcohol having
a ~elt$ng point of 124-127 i8 obtained.
~1L.~6S 75
Exam~le 7 __ _
A mixture of 8.7 9 of ~-13-(2-amino-1-hydroxyethyl)-
phenyl]-methanesulphonamide and 9.0 9 of 5-~2-broooethoxy~-
salicylamide in 50 ml of dioxan and 20 ml of triethylamine
is boiled under reflux for 4 hours while stirring. The
foam obt~ined by concentrating by evaporation is stirred
with 100 ml of caturated potassium bicarbonate solution and
500 ml of ethyl acetate until it has dissolved completely.
The organic phase is dried over magnesium sulphate and con-
centrated by evaporation, yielding 12 9 of a greenish foam
from which ~-IN-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-
aminomethyl]-3-(methylsulphonylamino)-benzyl alcohol having
a melting point of 135-137 is crystallised by dissolving
in a mixture of methanol and isopropanol (approximately
1:10~ .
23 q of crude ~-[N-12-(2,3-dihydro-2,2-dimethyl-4-
oxo-4~-1,3-benzoxazin-7-yloxy)-1-methylethyl]-aminomethyl]-
4-(~ethylsulphonylamino)-benzyl alcohol are boiled under
reflux for 2 hours in a mi~ture of 50 ml of isopropylamine
and 200 ml of isopropanol and then concentrated by evapora-
tion, and the residue is ~tirred with 5 ml of isopropanol
and 20 ml of ether. The crystals which gradually form are
filtered with suction and comprise a-[N-[2-(4-carbamoyl-3-
hydroxyphenoxy)-l-methylethyl]-aminomethyl]-4-~methylsul-
phonylamino)-benzyl alcohol in the form of a diastereoiso-
meric mixture. A 1:1 mixture of the diastereoisomers ~elts
at 140-145 .
The starting ~aterial i8 produced in the following
manner:
a~ After adding 0.13 9 of conrentrated ~ulphuric
acid, a solution of 11.5 9 of N-14-(2-amino-1-hydroxyethyl)-
phenyl]-methanesulphonamide and 1~.4 9 of 2,3-dihydro-2,2-
dimethyl-7-~2-oxopropoxy)-4~-1,3-ben~oxazin-4-one in 250 ml
of methanol is hydrogenated under nor~al conditions over 1 g
~6st75
- 65 -
of platinum-on-car~on ca~alyst until the calculated amount
of hydrogen has been absorbed. After filtering off the
catalyst, the solution is concentrated by evaporation,
yielding crude ~-lN-[2-(2,3-dihydro-2,2-dimethyl-4-oxo-4H-
1,3-benzoxazin-7-yloxy)-1-methylethyl]-aminomethyll-4-
methylsulphonylamins)-benzyl alcohol as an oil, which is
further processed in ~hat form.
The 2,3-dihydro-2,2-dimethyl-7-(2-oxopropoxy)-4H-1,3-
benzoxazin-4-one required as the further starting material
can be obtained as follows:
b) 2,3-dihydro-2~2-dimethyl-7-hydroxy-4H-1,3-benz-
oxazin-4-one having a melting point of 24g-251 is
obtained from 2,4-dihydroxybenzamide analogously to ~xample
la).
c) 16B g of 2,3-dihydro-2,2-dimethyl-7-hydroxy-4~-
1,3-benzoxazin-4-one, 305 g of potassium carbonate and ~8 ml
of chloroacetone in 1.2 litres of acetonitrile-are-boiled
for 28 hours and then worked up to yisld 2,3 dihydro-2,2-
dimethyl-7-(2-o~opropoxy)-4H~1,3-benzoxazin-4-one having a
melting point of 160-162 (from isopropanol).
Example 9
~ -[N-[2- (3-carbamoyl-4-hydroxyphenoxy) -l-methylethyl]-
a~inomethyl]-3,4-methylenedioxybenzyl alcohol is obtained
as a diastereoisomeric mixture from ~-(aminomethyl)-304-
methylenedioxybenzyl alcohol ~melting point 75-78 ; cf.
~. Tatsuno et al.r J. Med. Chem. ~L 394- 1977) and 2,3-
dihydro-2,2-dimethyl-6-(2-oxopropoxy)-4~-1,3-benzoxazin-4-
one analogously to Exa~ple 8 and 8a). A pure enantio~er
p~ir having a melting point of 211-212 is obtained by
fractional crystallisation of the hydrochloride from
methanol/water (~
The 2,3-dihydro-2,2-dimethyl-5-(2-oxopropoxy)-4~-
1,3-benzoxazin-4-one required as starting material can be
obtained as follows:
a) 70 g of the 2,3-dihydro-2,2-dimethyl-6-hydroxy-
i5'7~i
- 66 -
4H-1,3-benzoxazin-4-one obtained according to Example la)
are stirred under reflux for 30 hours in 400 ml of aceto-
nitrile with 100 9 of potassium carbonate and 32 ml of
chloroacetone. After adding a Eurther 32 ml of chloro-
acetone, the reaction mixture is heated for a further 15-20
hours. The reaction mixture, still warm, is filtered, 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-oxopropoxyJ-4H-1,3-benzoxazin-4-
one having a melting point of 125-126 .
Exa~nPle 10
~ -[N-[2-14-carbamoyl-3-hydroxyphenoxy)-1-methylethylj-
aminomethyl]-3,4-methylenedioxybenzyl alcohol in ~he form of
a diastereoisomeric mixture (approximately 1:1) having a
melting point of 164-174 is obtained analogously to
Example 9 using 2,3-dihydro-2,2-di~ethyl-7-~2-oxopropoxy)-
4H-1,3-benzoxazin-4-one. It forms a neutral fumarate having
a melting point of 193-204 (from methanol/wa'erJ, which
is identified by means of its C nuclear magnetic
resonance spectrum as a mixture of the diastereoisomers
(approximately 1:1). ~
ExamPle 11
2 9 of molecular sieve (3 ~) and 0.44 9 of sodium
cyanoborohydride are added to a solution of 0~795 9 of 1-
(3-sulphamoyl-4-chlorophenyl)-2-aminoethanol and 0.707 g of
(2v3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-on-6-yloxy3-
acetaldehyde in 20 ml of methanol and the suspension is
stirred ~t room temperature. The pH is ~aintained at 6-7
by the dropwise additisn of methanolic hydrochloric acid.
After 12 hours the mixture is filtered, 1 ml of concentrated
hydrochloric acid is added ~o the filtrate to decompose the
cyanoborohydride, stirring is carried out for 10 minutes and
then the pH is adjusted to 9 with concentrated ammonia.
~5
- 67 -
The solvent is remQved from the suspension and the residue
is made into a ~lurry with a mixture of chloroform/methanol/
ammonia (40:10:1), filtered and the filtrate concentrated
again. The residue is chromatographed over 150 9 of silica
gel with a mixture of chloroform/methanol/ammonia (40:10:1),
the main fraction is concentrated by evaporation and the
residue heated at 80 for 15 minutes in a mixture of 20 ~1
of dioxan and 1 ml of concentrated hydrochloric acid. After
removing the solvent, the residue is taken up in ethyl
acetate and extracted with 2N ammonia. The organic phase is
dried, concentrated by evapora~ion, and the residue is re-
crystallised from isopropanol/ethyl acetate, yielding x-lN-
l2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-aminomethyl}-3-
sulphamoyl-4-chlorobenzyl alcohol having a melting point of
193-195 .
The (2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-on-
6-yloxy)-acetaldehyde required as starting ~aterial can be
obtained as follows: -
a) A solution of 9.65 g of the 2,3-dihydro-2,2-
dimethyl-6-hydroxy-4~-1,3-benzoxazin-4-one obtained accor-
ding to Example la) and 9.1 g of allyl bromide in 150 ml
of acetonitrile is stirred under reflux for 5 hours with
the addition of 10.3 9 of dry potassium carbonate. The
seaction mixture is filtered whilst still warm, the fil-
~rate is concentrated by evapora~ion and ~he re~ainin~
crystals are filtered with suction after triturating with
ether, yielding crude 2,3-dihydro-2,2-dimethyl-6-allyloxy-
4~-1,3-benzoxazin-4-one having a melting point o
137-138 .
b) Approximately 20 mg of osmium tetroxide are added,
while stirring, to a ~olution of 4.7 9 of 2,3-dihydro-2,2-
dimethyl-6-allyloxy-4H-1,3-benzoxazin-4-one in a mixture of
50 ml of dioxan and 15 ml of ~ater. After 15 minutes, 8.6 9
of ~odium metaperiodate are added in portions, the tempera-
ture rising to 45 . After 2 hours the reaction miYture
is filtered, the filtrate is concentrated by evaporation
5'75
- 68 -
and the residue is ~artitioned between 20 ml of water and
200 ml of ethyl acetate. The organic phase is separated
off, dried and concentrated by evaporation. The remaining
oil is chrsmatographed o~er 100 g of silica gel. By elu-
tion with ethyl acetate and evaporating to dryness, (2,3-
dihydro-~,2-dimethyl-4X-1,3-benzoxazin-4-on-6-yloxy)-
acetaldehyde having a melting point of 153-163 is
obtained.
A solution of 9.2 g of ~-(aminomethyl)-4-(methylsul-
phonylamino)-benzyl alcohol and 8.5 g of 4-(2-oxopropoxy)-
salicyl2~ide in 180 ml of methanol i~ hydrogenated over
1 g of platinum-on-carbon catalyst (5 ~) with the addition
of 0.1 9 of concentrated ~ulphuric acid. After filtering
and concentrating the filtrate by evaporation, a foam is
obtained which, after standing for several days, yieldq
from isopropanol ~-[N-[2-~4-carbamoyl-3-hydroxyphenoxy)-1-
methylethyl]-aminomethyl]-4-(methyl~ulphonylamino)-benzyl
alcohol in the form of a diastereoi~Qmeric mixture (appro~
mately 1:1) having a melting point of 141-152 . The iso-
lation of the pure diastereoiso~ers i5 described in Example
28.
The 4-(2-oxopropoxy)-salicylamide required as ~tarting
~terial can be produced as follows:
a) 66 9 of crude 2,3-dihydro-2,2-di~ethyl-6-(2-oxo-
propoxy)-4B-1,3-benzoxazin-4-one obtained according to
8sample 9a) is hydrolysed in a mixture of 150 ml of dioxan
and 400 ml of 2N hydrochloric acid for one hour on a boiling
water bathO After evaporating off the solvent and tri~ura-
ting the residue with water, crude 4-(2-o~opropoxy)-salicyl-
amide having a melting point of 126-140 is obtained.
After recrystallising from ethanol, the product has a
melting point of 145-148 .
S75
- 69 -
Example 13
Analogously to Example 12, using the equivalent amount
of the 5-t2-oxopropoxy)-salicylamide obtained according to
Example lOa), a-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-
methylethyl]-aminomethyl]-4-(methylsulphonylamino)-benzyl
alcohol is obtained as an oil, which forms a neutral
fumarate as a mi~.ture of the diastereoisomers in a ratio
of approximately 6:4 according to C spectroscopic exami-
nation, having a melting point of 210-215 .
Example 14
A solution of 24.1 9 of 5-(2-amino-1-hydroxyethyl)-
salicylamide and 25.6 9 of 5-(2-oxopropoxy)-salicylamide
is hydrogenated, analogously to Example 12, over 2 g of
platinum-on-carbon ca~alys~ (5 ~) which is added in 2
portions, until the calculated amount of hydrogen has been
absorbed. The evaporation residue of the filtered solu-
tion is dissolved in water with the addition of fumaric -
acid, the solution is extracted with ethyl acetate and the
aqueous phase is separated off. This is rendered alkaline
wi~h saturated potassium bicarbonate solution and the resul-
ting precipitate is extracted with a large amount of ethyl
acetate by stirring for 1 hour. After drying the ethyl
acetate solution over ~aynesium sulphate and concentrating
by evaporation, a-[N-[2-(3-caebamoyl-4-hydroxyphenoxy)-1-
methylethyl]-aminomethyl]-3-carbamoyl-4-hydroxybenzyl
alcohol is obtained which, after recrystallisation from
ethyl acetate, melts at 143-148 with decomposition and
is a mixture of the dia4tereoisomers in a ratio of approxi-
mately 1:1.
Example 15
A solution of lU.0 9 of e-(aminomethyl)-4-(2-methoxy-
ethoxy)-benzyl alcohol and 9.9 9 of 5-(2-oxopropoxy)-sali-
cylamide is hydrogenated in 200 ml of methanol analogously
to Example 12 and worked up analogou~ly to Example 14.
5~7S
- 70 -
a-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl~-
aminomethyl]-4-(2-methoxyethoxy)~-benzyl alcohol is obtained
which, after recrystallisation from ethyl acetate, melts at
100-106 and is a diastereoisomeric mixture in a ra~io of
approximately 1:1.
The a-~aminomethyl)-4-(2-methoxyethoxy)-benzyl alcohol
used as starting material can be produced in the following
manner:
a) A suspension of 21 g of 2-methoxyethyl bromide,
13.6 g of 4-hydroxyacetophenone and 27.6 g of potassium
carbonate in 250 ml of acetone is boiled under reflux for
20 hours while stirring. Customary working up and distil-
lation of the crude product at 0.001 torr yields 4-(2-
methoxyethoxy)-acetophenone, having a boiling point of
113-116 /0.001 torr, in the form of a colourless oil which
solidifies into crystals.
b) Bromination of the compound obtained according to
example a) witb the eguivalent amount of bro~ine in chloro-
for~ at 20-30 for 2 hours yields wrbromo-4-(2-methoxy-
ethoxy)-acetophenone, which is further usad in that form.
c) A ~olution of 53 g of the crude compound obtained
according to example b) in 350 ml of dimethylformamide is
cooled to 0-S and 15.4 g of ~odium azide are added in
portions while stirring. When the exothermic reaction has
subsided, cooling with ice is discontinued and the reaction
mixture is then stirred for 3 hours. The solution is sub-
sequently poured onto 3 litres of ice-wa~er and the yellow
oil which separates is ex~racted wi~h ether. Tbe ether
solution (500 ml) i8 washed twice with 10Q ml of water,
then with 100 ml of saturated sodiuffl chloride solution, is
thoroughly dried over magnesium sulphate and filtered and
the filtrate is reduced with a ~uspension of 35 g of lithium
aluminium hydride in 500 ml of ether for 2 hours at 10-
12. Customary working up yields crude a-(aminomethyl~-4-
(2-methoxyethoxy~-benzyl alcohol in the form of a yellowish
oil, which can be further used in its crude form. On
575
- 71 -
distillation in a--bulb tube it boils at 130-140 /0.08
torr.
Exam~le 16
Analogously to the method of operation deccribed in
Example 12, using 7.5 g of a-(aminomethyl)-4-methylbenzyl
alcohol and 10.45 g of 5-(2-oxopropoxy)-salicylamide, a-lN-
[2-~3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl~-amino-
methyl]-4-methylbenzyl alcohol having a melting point of
120-134 (from ethyl acetate) is obtained, which is in the
form of a mixture of the diastereoisomers in a ratio of
approximately 1:1.
A solution of 6.1 9 of ~-aminomethyl-4-methoxybenzyl
alcohol (S~ M. Albonico et al., J. Chem. Soc. 1967, 1327)
and 7.7 9 of 5-(2-oxopropoxy)-salicylamide in 130 ml of
methanol ic hydrogenated analogously to Example 12 with
the addition of 0.09 9 of concentrated sulphuric acid and
1.2 9 of platinum-on-carbon catalyst (5 ~). The crude
product is recrystallised from 700 ml of ethyl acetate,
then from acetonitrile. The higher-melting enantiomer pair
of ~-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl]-
aminomethyl]-4-methoxybenzyl alcohol is obtained; melting
point 144-146 . By concentration, the other enantiomer
pair is obtained from the ethyl acetate ~other liquor and
is purified by crystallisation from acetonitrile; melting
point 129-131 .
Example 18
70 mg of concentrated sulphuric acid are added to
a solution of ~ g of ~-laminomethyl)-3-sulphamoyl-~-chloro-
benzyl alcohol and 5.8 9 of 5-(2-oxopropoxy)-salicylamide
in 130 ml of methanol and the mixture is ~hen shaken for
~wo hours at room temperature under nitrogen. O.7 ~ of
platinum-on-carbon catalyst 15 %) is then added and the
S
- 72 -
mixture is hydrogenated under normal pressure until the
absorption of hydrogen has ceased. The catalyst is filtered
off, the filtrate is freed of solvent and the remaining
foam is recrystallised from isopropanol and then from
methanol/isopropanol, resulting in a-lN-[2-(3-carbamoy-~-4-
hydroxyphenoxy)-l-methylethyl]-aminomethyl]-3-sulphamoyl-4-
chlorobenzyl alcohol in the form of an approximately 1:1
diastereoisomeric ~ixture with 0.5 mole of isopropanol of
crystallisation,having a melting point of 103-106 .
The a-~aminomethyl)-3-sulphamoyl-4-chlorobenzyl
alcohol required as starting material can be obtained as
follows:
a) 8 g of sodium azide are added in portions at
0-5 in the course of 30 minutes to a solution of 28 g
of 5-(bromoacetyl)-2-chlorobenzenesulphonamid~-(DE-~S
26 01 598) in 40 ml of dimethylformamide. The reaction -
mixture is stirred for a further 2 hours at this temperature
and then poured onto an ice/water mixture. The 5-(azido-
acetyl)-2-chlorobenzenesulphonamide which crystallises out
decomposes from 152 ; it is filtered with suction, washed
with a large amount of water and dried in a high vacuum.
The resulting crude product is used directly in the next
stage.
b) A solution of 29.5 g of crude 5-(azidoacetyl)-2-
chlorobenzenesulphonamide in 800 ml of methanol and 46.4
ml of hydrochloric acid i9 hydrogenated in the presence
of 3 g of a platinum-on-carbon catalyst (5 %) at room
temperature and normal pressure until absorption of hydrogen
i8 complete. The catalyst i5 filtered off, the filtrate
concentrated by evaporation and the residue made into 3
slurry in acetone. The resulting 5-(aminoacetyl)-2-chloro-
benzenesulphonamide hydrochloride is filtered off and used
as a crude product in the next stage.
c) 1.6 g of sodium borohydride is added in portions
to 5 9 of 5-(aminoacetyl)-2-chlorobenzenesulphonamide
hydrochloride made into a slurry in 100 ml of methanol.
6575
The solution is stirred at room temperature for 1/2 hour,
concentrated by evaporation in a rotary evaporator, and
water and etbyl acetate are added to the residue. The
organic phase is dried ov~r sodium sulphate, concentrated
by evap~ration; and the residue is recrystallised from ethyl
acetate, yielding a-(aminomethyl)-3-sulphamoyl-4-chloro-
benzyl alcohol having a melting point of 179-182 .
Example 19
a-[N-[2~3-hydroxy-4-carbamoylphenoxy)-1-methyle~hyl]-
aminomethyl]-3-sulphamoyl-4-chlorobenzyl alcohol having
a melting point of 112-116 is obtained in the form of
a dias~ereoisomeric mixture (approximately 1:1) analogously
to the method described in Example 18 from a-(aminomethyl)-
3-sulpha~oyl-g-chlorobenzyl alcohol and 4-(2-oxopropoxy)-
salicylamide.
Example 20
A solution of 20 g of crude ~-1N-[2-(3-carbamoyl-4-
hydroxyphenoxy)-ethyl]-benzylaminomethyl]-3-sulphamoyl-4-
methoxybenzyl alcohol in 200 ml of methanol is hydrogenated,
after the addition of 2 9 of palladium-on-carbon catalyst
(5 %), until the calculated amount of hydrogen has been
absorbed. Filtration and concentration by evaporation of
the filtrate yields a viscous residue, from which ~-[N-[2-
(3-carbamoyl-4-hydroxyphenoxy)-ethyll-aminomethyl]-3-sulph-
amoyl-4-methoxybenzyl alcohol crystallises by dissolving
in a mixture of methanol and isopropanol and has a melting
point of 160-162 after recrystallisation from methanol.
A crystal modification having a melting point of 191-194
results if ~he compound is recrystallised from acetonitrile.
The starting material can be produced in the following
manner:
a) 2-Methoxy-5-(bromoacetyl)-benzenesulpbonamide is
reduced in methanol with S times the molar amount of sodium
borohydride to yield S-(epoxyethyl)-2-methoxybenzenesulphon-
575
- 74 -
3~ide ~melting point 158-160 from methanol).
b~ A solution f ?.7 9 of 5-(epoxyethyl)-2-methoxy-
benzenesulphonamide and 8.6 g of the 5-[~2-benzylamino)-
ethoxy]-salicylamide obtained according to Example lc) in
150 ~1 of isopropanol is boiled under reflux for 2a hours.
By concentrating the solution by evaporation, a-lN [2-(3-
carbamoyl-4-hydroxyphenoxy)-ethyl]-benzylaminomethyl]-3-
sulphamoyl-4-methoxybenzyl alcohol is obtained as an orange-
coloured resin, which is further processed without further
purification.
Example 21
A solution of 5.5 g of 1-[N-benzyl-2-(3-carbamoyl-4-
hydroxyphenoxy)-ethylamino]-4-(2-methoxyphenyl)-2-butanol
in-60 ml of methanol i~ hydrogenated under normal conditions
with the addition of 0.6 g of palladium-on-carbon catalyst
(5 %) until the absorption of hydrogen is complete, the
reduction product partly precipitating from the solution.
The suspension is diluted with 400 ml of methanol, warmed
and filtered through a filter aid. Methanolic hydrochloric -
acid is added in excess to the filtrate and solvent is
removed in a rotary evaporator. The residue is recrystal-
lised from acetonitrile/ethyl acetate, yielding 1-[2-(3-
carbamoyl-4-hydroxyphenoxy)-ethylamino]-4-(2-methoxyphenyl)-
2-hutanol hydrochloride having a melting point of
124-126 .
The l-[N-benzyl-2-(3-carbamoyl-4-hydroxyphenoxy~-
ethyl-amino]-4-l2-methoxyphenyl)-2-butanol required as
starting material can be produced as follows:
a~ A solution of 7.3 9 of m-chloroperbenzoic acid
in 60 ml of methylene ohloride is slowly added dropwise
at room temperature, while stirring, to a solution of 5 9
of 1-(3-butenyl)-2-metho~ybenzene (cf. Wa S~ Johnson: JACS
86, 1975, (1964)) in 25 ml of methylene chloride. After 2
hours, filtration is carried out, the filtrate i8 washed
with 10 4 strength ~odium sulphite solution, dried over
S~i
sodium sulphate and concentrated. The remaining crude
1 (3,4-epoxybutyl)-2-methoxybenzene is further processed
in that form.
b) 2.45 9 of crude 1- (3,4~ epoxybutyl)-2-methoxy-
benzene and 3.9 g of the 4 [2-(benzylamino)-ethoxyl-salicyl-
amide obtained according to Example 4b) are dissolved in
65 ml of isopropanol and the solution is heated under reflux
for 80 hours. The solvent is then removed and the residue
i8 cbromatographed over 300 g of silica gel with a mixture
of chloroform/methanol/ammonia of 350:50:1, resulting in 1-
[N-benzyl-2-(4-hydroxy-3-carbamsylphenoxy)-ethylamino]-4-
(2-methoxyphenyl)-2-butanol in the form of a yellowish oil,
whicb is further processed in that form.
Example 22
2.7 g of (2,3-epoxypropyl)-benzene are added to a
solution of 2.9 9 of 5-(2-aminoethoxy)-s21icylamide in 10
ml of dimethyl sulphoxide and tbe ~olution i6 then heated
for 40 ~inutes, while stirring, in a bath at approximately
90 . The solution i3 cooled and diluted with 40 ml of
water. The precipita~ed crystals are filtered with suction,
washed with a little water and dried in vacuo. In this
manner 1-[2-~3-carba~oyl-4-hydroxyphenoxy)-ethyla~ino]-3-
phenyl-2-propanol having a melting point of 142-143 (from
a little isopropanol) is obtained.
Examp~le 23
A solution of 11.4 g of 1-[2-(3-carbamoyl-4-hydroxy-
phenoxy)-N-benzylethylamino]-3-[2-methoxyphenyl)-2~propanol
in 130 ml of methanol i8 hydrogenated at room temperature
in the presence of 1.2 9 of palladium-on-rarbon catalyst
until absorption of hydrogen i3 co~plete. The catalyst is
filtered off and the filter residue is washed with a large
amount of ~ethanol, the filtrate is evapora~ed to dryne~s
under reduced preScure, the residue is recrystallised from
~ethanol, the resulting crystals are suspended in ~ethanol
~6575
- 76 -
and methanolic hydrochlorie acid is added to the suspension,
the solution is evaporated to dryness under reduced pressure
and the residue is recrystallised from acetonitrile. 1-12-
(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-(2-methoxy-
phenyl~-2-propanol is obtained as a hydrochloride having a
mel~ing point of 152-154 .
The starting ~aterial can be produced as follows:
A solution of 5 9 of 2-methoxy-1-(2,3-epoxypropyl)-
benzene (cf. Compt. rendues, 219, 163-64 ~1944)) and 8.7 9
of 5-(2-N-benzylaminoethoxy)-salicylamide in 130 ~1 of
isopropanol is boiled under reflux for 20 hours. The sol-
vent is then removed in a rotary evaporator, and the residue
i~ chromatographed over 500 9 of silica gel and eluted with
a mixture of chloroform/methanol/ammonia 350:50:1. The
fractions 4-20 are collected, combined and evap~E-a-ted--to
dryness, yielding 1-12-(3-carb~moyl-4-bydroxyphenoxy)-N-
benzylethylamino] 3-12-methoxyphenyl)-2-propanol in the form
of an oily residue.
Exa~ple 24
4.18 9 of a-aminomethyl-2-methoxybenzyl alcohol are
stirred in 250 ml of methanol and 4.28 ml of 5.9N methanolic
hydrochloric acid (~^pH 6). 0.59 9 of potassium hydroxide
~solid) is added to the reaction solution (~ p~ 9). After
adding 25 g of molecular sieve 3 R and 5.60 9 of (2,3-
dihydro-2,2-dimethyl-4~-1,3-benzoxazin-4-on-6-yloxy)-
acetaldehyde, a solution of 0.59 g of ~odium cyanoboro-
hydride in 60 ml of methanol ~s added dropwise. The reac-
tion mixture i~ stirred for 24 hours at room temperature,
filt~red and boiled under reflux for 1 hour with 50 ml of
5.9N methanolic hydrochloric acid. The reaction solution
i5 freed of solvent and the residue is chromatographed over
500 9 of ~ilica gel with a ~ixture of chloroform/methanol/
ammonia (40:5:0.5). The main fraction is coneentrated by
evaporation. a-~M-[2-(3-carba~oyl-4-bydroxyphenoxy)-ethyl]-
aminonethyl~-2-methoxybenzyl alcohol having a melting point
575
- 77 -
of 167-168 is obtained by crystallisation from isopro-
panol.
The a-a~inomethyl-2-methoxybenzyl alcohol required
as starting material can be obtained as follows:
a) So85 g of sodium azide are added in the course
sf 30 ~nutes at 0-5 , while stirring, to a solution of
13.8 g of a-bromo-2-methoxyacetophenone in 30 ml of
dimethylformamide. After stirring for 2 hours at 0 ,
the reaction mixture i~ poured onto 100 ml of ice/water
and the crystalline a-azido-2-methoxyacetophenone is
filtered with suction. The filter residue is dissolved
in 300 ml of toluene, the solution is dried (~gS04) and
added dropwise at 0-5 , in the course of 1 hour, to a
suspension of 10 g of lithium aluminium hydride in 200 ml
of tetrahydrofuran. The reaction mixture is ~tirred for
1~ hours at 0-5 and ~en, at 0-5 , 10 ml of water,
10 ml of concentrated sodium hydroxide solution and then
30 ml of water are added dropwise. The precipitate is
filtered off and the filtrate is concentrated by evapora-
tion. The residue is crystallised from ethyl a_etate _
resulting in ~-aminomethyl-2-methoxybenzyl alcohol having
a melting point of 122-123 .
Example 25
A solution of 100 9 of crude 2-[N-benzyl-N-12-(4-
carbamoyl-3-hydroxyphenoxy)-ethyl]-amino]-4-methylsul-
phonylaminoacetophenone in 1000 ml of methanol is hydrogena-
ted at 30-40 under normal pressure, ~ith the addition of
100 ml of acetic acid and 20 g of palladium-on-carbon cata-
lyst (10 ~), until the absorption of hydrogen h~s ceased
(80 % of the theoretic~l amount). After filtration and
evaporating off the solvent an oil is obtained which, aPter
neutralising to a pH of 3-4 with 6N hydrochloric acid, cry-
stallises. The crystals are filtered with suction and
recrystallised fro~ water. In this manner a-lN-[2-(4-
carbamoyl-3-hydroxyphenoxy)-ethyl]-aminomethyl]-~-methyl-
S75
- 78
sulphonylaminobenzyl alcohol i5 obtained as a hydrochloride
having a melting point of 239-240 .
The starting material can be produced in the following
manner:
a) A mixture of 58.6 9 of 2-bromo-4-methylsulphonyl-
aminoacetophenone, 57.2 9 of 4-[2-benzylaminoethoxy]-sali-
cyla~ide and 30 9 of potassium bicarbonate is- stirred for
4 hours at 20-30 in 400 ml of dioxan, filtered and con-
centrated by evaporation. ~he evaporation residue is parti-
tioned between ethyl acetate an~ 2N potassium bicarbonate
solution, and the organic phase is separated of and
extracted three times with 2N hydrochloric acid. ~y neutra-
lising the acidic extract with potassium bicarbonate and
e~tracting with ethyl acetate, crude 2-[N-benzyl-N-[2-(4-
carbamoyl-3-hydroxyphenoxy)-ethyl]-amino]-4-methylsulphonyl-
aminoacetophenone is obtained in the form of a brown oil
which is further processed in that form.
ExamPle 26
Analogously to Examples 25 and 25a using 5-12-benzyl-
aminoethoxy]-salicylamide, ~-IN-[2-(3~carbamoyl-~-hydroxy-
phenoxy)-ethyl]-aminomethyl]-4-methylsulphonylaminobenzyl
alcohol i~ obtained as a base having a melting poiat of
172-174 (fro~ ethanol~ by renderinq the evapQrated hydro-
genation mixture alkaline wi~h 2N a~monia ~olution and
extracting the base with a large amount of ethyl acetate.
ExamPle 27
A solution of 3.5 g of a-(aminomethyl)-4-(N-methyl-
sulpha~oyl)-benzyl alcohol and 7.7 g of 4-(2-oxopropoxy)-
salicyla~ide is hydrogenated and worked up analogously to
~xample 12. Practional recrystallisation from ethanol and
ethyl acetate yields 3 crystal fractions which giYe uniform
spots in a thin layer chromatogram (syste~: ethyl acetate,
ethanol, concentrated ammonia 24:12:~), and which are
together recrystalli~ed from ethanol to yield a-[N-12-(4-
- 79 -
carbamoyl 3-hydroxyphenoxy)-1-methylethyll-aminomethyl]-4-
(N-methylsulphamoyl)-benzyl aleohol in the form of a
diastereoisomeric mixture (3:1) having a melting point of
136-150 . Further recrystallisation from etbanol yields
al~ure diastereoisomer having a melting point of 138-140
( C-N~R signal at 15.3 ppm after the addition of fumaric
acid).
The starting material can be produced in the following
manner:
a) 4-Chlorosulphonylacetophenone is reacted with
an excess of methylamine to form 4-(N-methylsulphamoyl)-
ace~ophenone; melting point 111-112 (from isopropanol)
b) 60 g of the resulting compound are reacted in
1000 ml of acetic acid, with the addition of 1 9 of
aluminium bromide, with 44.3 q of bro~ine to yield
2-bromo-4-(N methylsulphamoyl)-acetophenone, a yellowish
oil which is further used in crude form.
c) 80 9 of the resulting compound are dissolved in
760 ml of acetone and 109 g of dibenzylamine are added.
The reaction ~ixture is stirred for 16 hours at 20-30 .
The dibenzyla~ine hydrobromide which crystallises out is
filtered off and the filtrate is concentrated by
evaporation. 500 ~1 of ethee are added to the residue,
undissolved material is filtered of} and the ether solution
is concentrated by evaporation. The crude 2-benzylamino-4-
(N-methylsulphamoyl)-acetophenone thus obtained in the form
of an oil can be reduced in its crude form with sodium
borohydride. A pure product having a melting point 93-94
is obtained by recrystallisation from isopropanol.
d) 100 g of the resulting crude compound are
dissolved in a mixture of 1800 ml of isopropanol and 200
ml of methanol and 9.5 9 of sodium borohydride are added
in portions to the solution while stirring and cooling at
10-15 . After 2-3 hours the reaction mixture is adjusted
to a pH of 5-6 with acetic acid, concentrated by evaporation
under reduced pressure and partitioned between ethyl acetate
114~5~Cj
- 80 -
and water. The o~anic phase is separated off, washed with
water, dried (MgSO ) and concentrated by evaporation.
The remaining oil crystallises gradually from a little
ether. ~n this manner u-(dibenzylaminomethyl)-4-(N-methyl-
sulphamoyl)-benzyl alcohol having a melting point of 105-
106 is obtained.
e) By c~talytic debenzylation of the resulting
compound in methanol over palladium-on-carbon catalyst,
~-(aminomethyl)-4-~N-methylsulphamoyl)-benzyl alcohol having
a melting point of 130-132 (from methanol/toluene) is
obtained.
Example 28
110~0 9 of ~-(aminomethyl)-4-(methylsulphonylamino)-
benzyl alcohol are reacted with 100.0 g of 4-(2-oxopropoxy)-
salicylamide as described in Example 12. The hydrogenation
solution is concentrated to approximately 300 ml and left
to crystallise for 15-20 hours. The crys~als of the
resulting a-lN- E2- l4-carbamoyl-3-hydroxyphenoxy)-1-methyl-
ethyl]-aminomethyl]-4-(methylsulphonylamino)-benzyl alcohol
are filtered with suctlo3n and have a ~elting point of 156-
162 . According to C-NMR analysis they comprise a
~ixture of 75 % of the higher-melting enantiomer pair A
and 25 % of the lower-melting enantiomer pair B. By further
recrystallisation from methanol three times, the enantiomer
pair A having a melting point of 165-167 ( ~ 90 ~ A)
is obtained. It forms a hydrochloride having a melting
point of 219-220 (from methanol); C-NMR: C- CH 3
sign~l at 13.15 ppm.
~ y further concentration of the first mother liquor,
a further crystalline fraction having a melting point of
138-144 is obtained, the ratio of the diastereoisomers
being ~ 1:1. The mother liguor removed therefrom by
filtration does not crystallise any further. ~ccording
to C-NMR an~lysis it contains the enantiomer pair B
enriched to 60-70 ~. This mother liquor (~ 80 9 of brown
_ _ , . . , . . . _ _ . . .. _ . . _ _ ... . _ . _ _ .
i~6575
- 81 -
oil) is chromatographed over 4 kg of silica gel. With 70
fractions of ethyl acetate per 150 ml, unidentified
impurities are eluted. Further elution ~ith methanol (80
fractions per 150 ml) produces a brown oil which gradually
partly crystallises. By repeated recrystallisation from
ethanol, the enantiomer pair 8 having a melting point of
144-145 (~90 ~ B) is obtained. It forms a hydrochloride
having a melting point of 206-209 (from ethanol), which
in C-NMR analysis exhibits the siqnal of the C-methyl - -
group at 13.65 ppm (~ 95 %).
Example 29
A solution of 19.6 g of 5-(2-aminoethoxy)-salicylamide
in 100 ml of dimethyl sulphoxide is stirred with 19.0 g
of (3~4-epoxybutyl)-benzene for 1 hour in a bath at 120
and then poured onto 200 ml of ice-water. By extracting
three times with 400 ml of ethyl acetate each time, washing
the extract with water, drying (MgSO ) and concentrating
by evaporation, a semi-solid residue is obtained fro~ whi-ch - -
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-4-phenyl-2-
butanol having a melting point of 159-160 is obtained
by recrystallisation from a little methanol.
Example 30
A solution of 29 9 of crude 1-lN-benzyl-2-(3-
carbamoyl-4-hydroxyphenoxy)-ethylamino]-4-~2-methylphenyl)-
2-butanol in methanol is hydrogenated under normal condi-
tions over 3.0 9 of palladium-on-carbon catalyst (5 %) until
the absorption of hydrogen has ceased. By filtration and
concentration by evaporation, crude 1-[2-~3-carbamoyl-4-
hydroxyphenoxy)-ethylamino]-4-(2-methylphenyl)-2-butanol is
obtained which, after recrystallisation from isopropanol,
melts at 140-142 . It forms a hydrochloride having a
melting point of 155-157 (from isopropanol).
The starting materials can be obtained in the
following manner:
5t~5
- 82 -
a) A solution-of_4~.3 g of epichlorohydrin in 175 ml
of benzene i~ added drop~ise to 2-methylbenzyl magnesium
bromide (produc~d from 92.5 9 of a-bromo-o-xylene and 12~5 9
of ~agnesium turnings in 250 ml of absolute ether). The
ether is then distilled off and the reaction ~i~ture, after
reaching an internal temperature of 65 , is boiled under
reflux for a further hour. While cooling with ice, the
reaction mixture first has 50 ml of water carefully added
to it and is then rendered acidic with 125 ml of 2N sul-
phuric acid. Insoluble material is filtered off, the
aqueous phase is extrac~ed twice with 200 ml of ethyl
acetate each time, and the organic phases are combined~
washed with water, dried (MgSO ) and concentrated by eva-
poration. Crude l-chloro-4-(2-methylphenyl)-2-butanol is
obtained as a yellow oil, which is further processed in
that form.
b) 98 g of the resulting compound are dissolved in
700 ml of dichloromethane, 16.7 9 of tetrabutylammonium
hydrsgen sulphate and 700 ml of 2N sodium hydroxide solution
are added, and the mixture is stirred for 7 hours at room
temperature. Separation of the layers, drying (MgSO )
and concentration by evaporation of the dichloromethane
solution yield an oil which, on bulb tube distillation at a
bath temperature of 135-145 and 0.5 mm pressure~ roduces
two fractions. ~he more volatile component exhibits in its
H-NMR spestrum the signals expected for 2-(3,4-epoxy-
butyl)-toluene: (CDCl ; ~ in ppm~ 1.8 (m, 2~); 2.3 (s,
3H); 2.45 ~q, lH); 2.7 (m, 2H); 2.85 ~, lH); 2.95 (m, lB);
7.1 (s, 4H).
c) A solution of 15.0 g of the resulting epoxide and
18.6 9 of 5-(2-benzylaminoethoxy)-salicylamide in 130 ml of
isopropanol iP boiled under reflux for 24 hours and then
concentrated by evaporation. Crude l-[N-benzyl-2-(3-
carbamoyl-4-hydroxyphenoxy)-ethylaDino]-4-(2-methylphenyl)-
2-butanol i5 obtained as a yellow oil, which i8 further
processed in that form~
5'75
- 83 -
Example 31
20 g of cru~e~l-~N-b~nzyl-2-(3-carbamoyl-4-hydroxy-
phenoxy~-ethylamino]~4-[4-(2-methoxyethoxy)-phenyl]-2
butanol are catalytically debenzylated analogously to
Example 30. 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-
4-l4-(2-methoxYethoxY~-phenyll-2-butanol having a melting
point of 151-153 (from methanol) is obtained. It forms
a hydrochloride having a melting point of 207-208 (from
methanol).
a) 76 g of 4-hydroxybenzsic acid methyl ester are
alkylated by boiling under reflux for 18 hours with 92 g
of (2-methoxyethyl)-methanesulphonate in 1500 ml of aceto-
nitrile in the presence of 138 g of potassium carbonate,
yielding 4-(2-methoxyethoxy)-benzoic acid methyl ester
having a melting point of 35-38 .
b) 66 g of the resulting compound are reduced with
12 g of lithiu~ aluminium hydride in 700 ml of tetrahydro-
furan, yielding crude 4-(2-methoxyethoxy)-benzyl alcohol
in the form of an oil which is further used in that form.
c) ~ydrogen chloride gas is introduced in rapid
current into a solution of 49 9 of the resulting compound
in 550 ml of toluene for 1 hour at approximately -5 .
The reaction mixture is then stirred for a further hour
at approximately 0-5 , washed with saturated aqueous
sodium chloride solution, dried (MgSO ) and concentrated
by evaporation _ vacuo below 50 . The resulting crude
4-(2-methoxyethoxy)-benzyl chloride is further processed
without further purification.
d) From 45 g of the resulting compound and 6.5 g
of magnesium turnings in a mixture of 100 ~1 each of ether
and tetrahydrofuran, the Grignard compound $s produced and
then reacted with 21 g of epichlorohydrin analogously to
~xample 30a). In this manner crude l-chloro-4-[4-(2-
methoxyethoxy)-phenyll-2-butanol is obtained in the form
of an oil, which is reacted analogously to Example 30b)
to form 1-(3,4-epoxybutyl~-4-(2-methoxyethoxy)-benzene.
~6575
- ~4 -
~-NMR (CDC13): 1.6-1.8 (m1 2.45 ~q~; 2.8-3.0 (m).
In the light of t~ese ~ignals a content of epoxy compound
of 50 ~ is calculated.
~ ) Equivalent amounts of the resulting compound and
5-(2-benzylaminoethoxy)-salicylamide are reacted analogously
to Example 30c) and yield 1-[N~benzyl-2-(3-carbamoyl-4-
hydroxyphenoxy)-ethylamino]-4-[4-(2-methoxyethoxy)-phenyl]-
2-butanol in the form of an oil, which is further proces~ed
in that form.
Example 32
A solution of 2.1 9 of crude ~-[Nl2-(4-methoxycar-
bonyl-3-hydroxyphenoxy)-1-methylethyll-aminomethyll-4-
(methylsulphonylamino)-benzyl alcohol in 20 ml of dioxan
is left to stand for 3 days at 20-30 with 40 ml of
concentrated am~onia solution. By concentrating the
solution by evaporation, a foam is obtained which gradually
crystallises from ethanol and constitutes G-[~-[2-(4-
carbamoyl-3-hydroxyphenoxy)-1-methylethyl]-aminomethyl]-4-
(methylsulphonylamino)-benzyl alcohol in the form of a
diastereoisomeric mixture (approxi~ately 1:1) having a
melting point of 141-150 .
The starting material can be produced in the following
manner:
a) A solution of 3.4 9 of 2,4-dihydroxybenzoic acid
methyl ester, 4.0 g of triethylamine and 2.8 9 of chloro- _
acetone in 40 ml of acetonitrile is boiled under reflux for
lS hours. After adding 1.4 9 of chloroacetone and 1.3 9
of triethylamine, the reaction mixture is boiled for a
further 5 hour~, then concentrated by evaporation, the resi-
due is dissolved in S0 ml of toluene, the solution is washed
with 10 ml of water, then wi~h 10 ml of saturated aqueous
sodium chloride solution, and chromatographed over 200 9
of silica gel. The fractions first eluted with toluene
contain 4-(2-oxopropoxy)-salicylic acid Methyl ester which
iq recry-tallised from isopropanol and melts at 106-108 .
~4tiS7~
b3 A solution of 203 9 of a-(aminomethyl)-4-(methyl-
sulphonylamino)-benzyl aIcohol and 1.9 g of 4-~2-o~opro-
poxy~-salicylic acid methyl ester in 50 ml of methanol is
hydrogenated analogously to ExampLe 12. By filtering and
concentrating by evaporation, crude a-[N-[2-(3-methoxycar-
bonyl-4-hydroxyphenoxy)-1-methylethyl]-aminomethyl]-4-
(methylsulphonylamino3-benzyl alcohol is obtained as a
yellowi~h oil which qradually solidifies into crystals.
It can be further processed in crude for~. By recrystalli-
~ation from ethyl aceta~e/ether, crystals having a meltinq
point of 113-121 (diastereoisomeric mixture)-~re
obtained.
1.2 g of crude a-[N-12-(4-cyano-3-hydroxyphenoxy)-
ethyl]-a~inomethyl]-4-methylsulphonylaminobenzyl alcohol
is dissolved in 15 ml of concentrated hydrochloric acid
and the solution is left to stand for 24 bour~ at 20-25 .
By concentrating by evaporation _ vacuo, a-[N-[2-(4-
carbamoyl-3-hydroxyphenoxy)-ethyll-aminomethyll-4-methylsul-
phonylaminobenzyl alcohol is obtained as its hydrochloride
which, after recrystalli~ation from water, melts at
239-24~ .
The starting material can be produced in the following
manner:
a) A mixture of 27.4 g of 2,4-dihydroxybenzonitrile,
30.8 g of potassium carbona~e, 1000 ml of 1,2-dibromoethane
and 100 ml of dimethylformamide is 80 heated in a descending
cooler, while stirring, that an internal te~perature of 127-
129 is reached. The heating is continued for 6 hours.
The distillate is rejected. The reaction mixture is
filtered and the filtrate concentrated by evaporation in
vacuo. By partitioning the residue between ethyl acetate
and water, drying ~MgS0 ~, concentrating khe organic phase
by evaporation and crys~allising, 4-(2-bromoethoxy)-2-
hydroxybenzonitrile having a ~elting point of 160~175
~4~57
-- 86 --
(from ethyl acetate) is obtained, which is sufficiently pure
for the following reaction.
b) A mixture of 2.8 9 of a-(aminomethyl)-4-methylsul-
phonylaminobenzyl alcohol, 2.4 g of 4-(2-bro~oethoxy)-2-
hydroxybenzonitrile, 4.1 9 of trie~hylamine and 20 ml of
dioxan :is heated under reflux for 3 hours whilst stirring.
The reaction product is worked up analogously to Example 7
to yield crude a-lN-[2-(4-cyano-3-hydroxyphenoxy)-ethyl~-
aminomethyl]-4-methylsulphonylaminobenzyl alcohol in the
form of a brown foam, which is urther processed in crude
form.
Example 34
A solution of 10.5 9 of crude 1-[N-benzy~--2 -t-~--
carbamoyl-4~hydroxyphenoxy)-ethylamino]-4-(4-benzyloxy-
phenyl~-2-butanol in 55 ml of methanol is catalytically
debenzylated analogously to Example 30. In this manner
1-12-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-4-(4-
hydroxypbenyl)-2-butanol is obtained.
The starting material can be produced in the following
manner:
a) 18 g of 4-benzyloxybenzyl alcohol is chlorinated
with 21 ml of thionyl chloride in 30 ml of pyridine to form
4-benzyloxybenzyl chloride; melting point of the crude sub-
stance 72-78 ;
b) 15 9 of the resulting 4-benzyloxybenzyl chloride
are reacted analogously to Example 31d) to form the Grignard
compound and this is reacted with 7 9 of epichlorohydrin
to for~ l-(3,4-epoxybutyl)-4-benzyloxybenzene.
c) Reaction of 15 9 of the resulting epoxide with
18.6 9 of 5-(2-benzylaminoethoxy)-salicylamide analogously
to Example 30c) yields crude 1-lN-benzyl-2-~3-carbamoyl-4-
hydroxyphenoxy)-ethylaminol-4-(4-benzyloxyphenyl)-2-butanol
in the form of an oil, which is further processed in that
form.
65~5
- 87 -
Example 3S
8~4 g of ~-IN-[2-(4-methoxycarbonyl-3-hydroxyphenoxy)-
l-methylethyl]-aminomethyll-4-(methylsulphonylamino)-benzyl
alcohol is dissolYed in S0 ml of dioxan and 200 ml of a
40 ~ aqueous methylamine solution is added. The solution is
left to stand at room temperature for 2-3 days. Working up
analogously to Example 32 yields ~-[N-[2-(4-methylcarbamoyl-
3-hydroxyphenoxy)-1-methylethyl]-aminomethyl]-4-(methylsul-
phonylamino)-benzyl alcohol in the form of a diastereoiso-
meric mixture.
Example 36
Tablets containing 20 mg of active sub~tance are
produced in customary manner in the following composition:
Compo6ition:
~-[N-[2-~3-carbamoyl-4-hydroxyphenoxy)- -
l-methyletbyl]-amino~ethyl3-3-sulphamoyl-
4-chlorobenzyl alcohol 20 mg
wheat starch 60 mg
lacto~e 50 mg
colloidal silica S mg
talc 9 mg
magnesium ~tearate 1 ~9
1~5 mg
~anufacture: .
~ -[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl]-
aminomethyl~-3-sulphamoyl-4-chlorobenzyl alcohol is mixed
s
- 88 -
with some of th~ ~heat s~arch, wil:h the lactose--and the
colloidal silica and the mixture is forced through a sieve.
A further portion of the wheat starch i8 made into ~ paqte
with 5 times the amount of water on a water bath and the
pulverulent mixture is kneaded with this paste until a
slightly plastic composition is formed.
The plastic composition is pressed through a sieve
having a mesh width of approximately 3 mm, dried and the
resulting dry granulate is again forced ~hrough a sieve~
~he remainder of the wheat starch, the talc and the mag-
nesium stearate are then admixed and the mixture is pressed
into tablets each weighing 145 mg and having a-br~a~-groove.
Example 37
Tablets containing 1 mg of active substance are pro-
duced in customary manner in the following composi-~i~
ComPosition~
a-[N-[2-(3-hydroxy-4-carbamoylphenoxy~- ~
l-methylethylf-aminomethyl~-3-sulphamoyl-
4-chlorobenzyl alcohol 1 mg
whe~t starch 60 mg
lactose 50 ~9
colloidal silica 5 mg
talc 9 ~9
magnesium ~tearate 1 mg
126 mg.
~3l4~5~75
- 89 -
~anufacture:
a-~N-l2~ hydrox~-4-carbamoylphenoxy)-l-methylethyl]
a~inomethyl~-3-sulphamoyl-4-chlorobenzyl alcohol is mixed
with some 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 S times the amount of water on a water bath, and the
pulverulent mixture is kneaded with this paste until a
slightly plastic composition is formed.
The plastic composition is pressed through a sieve
having a mesh width of approximately 3 mm, dried and the
resulting dry granulate is again forced through a sieve.
The remainder of the wheat starch, the talc and the
magnesium stearate are then admixed and the mixture is
pressed into tablets each weighing 145 mg and having a break
groove.
Exa~ple 38
Capsules containing 10 mg of active substance--are-~-~
produced in customary manner as follows:
Com~osition
a-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-
ethyl~-aminomethyl]-3-sulphamoyl-4-
chlorobenzyl alcohol 2500 mg
talc 200 mg
colloidal silica 50 mg
Manufacture:
The active substance is inti~ately mixed with talc and
colloidal silica, the mixture is forced through a sieve hav-
ing a mesh width of 0.5 mm, and is introduced in 11 mg por-
tions into hard gela~in capsules of suitable size.
S~t~
~- 9o -
Exam~ e 39
A sterile solution of 5.0 g of e-[N-12-(3-carbamoyl-4-
hydroxyphenoxy)-l-methylethyl]-aminomethyll-3-sulphamoyl-4-
chlorobenzyl alcohol methanesulphonate in 5000 ml o
distilled water is filled to 5 ~1 into ampoules which
contain S mg of active substance in 5 ml of solution.
Example 40
3.62 g of a-[N-[2-~3-carbamoyl-4-hydroxyphenoxy)-1-
methylethyl]-aminomethyl]-3-sulphamoyl-4-chlorobenzyl
alcohol are dissolved, with tbe addition of 100.0 ml of
O.lON hydrochloric acidr with 18000 ml of distilled water
to a volume of 18100 ml. 5.0 ml portions of the sterilised
solution each containing 1 mg of active substance are filled
into a~poules.
ExamPle 41 ~~~~~~~ ~~-~~ ~
Instead of the compounds used as active substance
in Examples 37-40, it is alternatively possible to use the
following compounds of the formula I, or their pharmaceuti-
cally acseptable non-toxic acid addition salts, as active
substances in tablets, dragees, capsules, ampoule solutions
~tc.:
a-lN-[2-~3-carba~oyl-4-hydroxyphenoxy)-ethyl]-aminomethyl]-
2,4-dichlorobenzyl alcohol,
a-[N-12-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-aminomethyl]-
4-chloro-3-nitrobenzyl alcohol,
a-[N-[2-(4-carbamoyl-3-hydroxyphenoxy)-ethyl]-aminomethyl]-
4-nitrobenzyl alcohol,
~-[N-12-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-a~inomethyl~-
3-lmethylsulphonylamino)-4-chlorobenzyl alcohol,
-- gl --
a-lN-[2-(3-car~amoyl-4-hydroxypherloxy)-ethyl3-aminomethyl]-
3,5-dichloro-4-aminobenzyl alcohol,
c-lN-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyll-aminomethyll-
3-(methylsulphonylamino)-benzyl alcohol,
~-[N-12-54-carbamoyl-3-hydroxyphenoxy)-1-methylethyl]-amino-
methyl]-4-(methylsulphonylamino)-benzyl alcohol~-- .--..
a-[N-[2-(3-carba~oyl-4-hydroxyphenoxy)-1-methylethyl]-amino-
methyl]-3,4-methylenedioxybenzyl alcohol,
a-lN-[2-~4-carbamoyl 3-hydroxyphenoxy)-1-methylethyl]-amino-
methyl]-3,4-~ethylenedioxybenzyl alcohol,
a-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl~-amino-
methyll-4-(methylQulphonylamino)-benzyl alcoh~l-r
a-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl~-amino-
methyll-3-carbamoyl-4-hydroxybenzyl alcohol,
a-[N-~2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyll-amino-
methyl]-4-(2-methcxyethoxy)-benzyl alcohol,
~-[N-[2-(3-carb2moyl-4-hydroxyphenoxy)-l-methylethyl]-amino-
methyl]-4-methylbenzyl alcohol,
a-[~-[2-(3-carbamoyl-4-hydroxyphenoxy)-l-me~hylethyll-amin
methyl]-4-~ethoxybenzyl alcohol,
~-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-aminomethyl]-
3-sulphamoyl-4-methoxybenzyl alcohol,
1-[2-(3-carba~oyl-4-hydroxyphenoxy)-ethyla~ino3-4-(2-
methoxyphenyl)-2-butanol,
5~S
- 92 ~ .
1-[2-(3-carba~oyl-4-hydroxyphenoxy)-e~hylamino]-3-phenyl-2-
propanol, or
1-[2-t3-carba~oyl-4-hydroxypheRoxy~-et~ylamino-3-(2-methoxy-
phenyl)-2-propanolO
~-[N-[2-~3-carbamoyl-~-hydroxyphenoxy)-ethyl]-amino~ethyl]-
2-~ethoxybenzyl ~lcohol,
~-[N-la-(4-c~rbamoyl-3-hydroxyph~noxy)-ethyl]-aminomethyl]-
4-~ethylsulpbonyla~ino benzyl aicohol,
N-[2-~3-c~rbamoyl-4-hydroxyphenoxy)-ethy~ noffleth
4-m-thyl~ulphonyla~ino benzyl alcohol,
~-lN-[2-~4-carbamoyl-3-hydro~yphenoxy~ ethylethyl]~amlno-
nethyll-4-methylsulphonylamino benzyl alcohol as an
enantiomer pair h~ving a meltinq point of 165-167 , aad aa
an enantiomer p~ir hav~ng a melting point o~ 144-145 ,
1- [2- ~3-carbamoyl-4-hydroxyphenoxy~ -ethylamino] -4-phenyl-2-
butanol,
1- [2- t3-carbam3yl-4-hydroxyphenoxy) -ethyl~m~nol - (2-methyl-
phenyl ) - 2-butanol,
and
1-[2-(3-carbaMoyl-4-hydroxyphenoxy)-ethylamlnol-4-[4-~2-
~ethoxyethoxy)-phenyl]-2-butanol.
