PROCESS FOR THE PREPARATION OF O-ALKYLATED HYDROXYLAMINES

PROCEDE POUR LA PREPARATION D'HYDROXYLAMINES ALKYLEES EN O

English Abstract

ABSTRACT OF THE DISCLOSURE
A process for the preparation of 0-alkylated hydroxylamines of
general formula
(I)
<IMG>
wherein X represents -OR', -SR' or <IMG>; R1 represents hydrogen or, if X
is -OR1, an amino group, or alkyl or a mono- or binuclear optionally substi-
tuted aryl radical; R2 and R3 which may be the same or different each repre-
sents hydrogen, optionally substituted alkyl or cycloalkyl, aralkyl or di-
aralkyl or aryl, hydroxyl, if the other of R2 and R3 is hydrogen; or R2 and
R3 together with the nitrogen atom to which they are attached represent an
optionally substituted 5- to 7-membered saturated ring optionally interrupted
by A further hetero atom or a 5-membered heteroaromatic ring optionally anel-
lated with a benzene or uracil ring; together with their physiologically com-
patible acid addition salts with those organic or inorganic acids which per-
mit the preparation of non-toxic salts, in which in a first state a hydroxyl-
amine compound of formula (VII)
<IMG> (VII)
is reacted with a compound of formula U-R6 (VIII) to form compounds of
formula
<IMG> (IX)

protecting groups <IMG> are separated therefrom
as <IMG> by hydrolysis and the product of formula (I)
is isolated in the form of a free base or is converted
with a suitable acid into a physiologically compatible
acid addition salt,
wherein in the above formulae;
R4 represents optionally substituted alkyl or aryl;
R5' represents hydrogen, optionally substituted alkyl or
aryl or halogen;
R6 has the meanings specified above for y or additionally
represents the radical
<IMG> ;
T represents a hydrogen atom, if U has a different
meaning from hydrogen, or the group <IMG> or
<IMG>
U represents a hydrogen atom, if T has a different
meaning from hydrogen, or the group <IMG>
or <IMG> and
Z represents a halogen atom, or a reactive sulphonic
acid ester group, whereby in each case T or U is
hydrogen.

Claims

- 18 -
The embodiments of the invention for which an
exclusive right or privilege are claimed are as follows:
1. A process for the preparation of 0-alkylated
hydroxylamines of general formula
<IMG> (I)
in which
X represents - OR1, -SR1 or <IMG>
(wherein R1 represents
a) a hydrogen atom
b) when X represents -OR1, an amino group
c) an alkyl group having 1 to 6 carbon atoms, or
d) a mononuclear or binuclear aryl radical which is
optionally substituted up to three times with one
or more groups selected from halogen atoms, alkyl,
alkoxy, and/or halogenoalkyl groups each having
up to 4 carbon atoms, cycloalkyl groups having
3 to 6 carbon atoms, and nitro and/or cyano groups;
R2 and R3, which may be the same or different,
each represents
a) a hydrogen atom,
b) an alkyl group having 1 to 6 carbon atoms or a
cycloalkyl group having 3 to 7 carbon atoms each
of which may be optionally substituted with one

- -
19
or more hydroxyl groups or alkoxycarbonyl groups
having 1 to 4 carbon atoms,
c) an aralkyl or diaralkyl group, the alkyl moieties
of which having 4 carbon atoms and are optionally
substituted with one or more hydroxyl groups, and
the mononuclear or binuclear aryl moieties of which
may be optionally substituted up to three times
with one or more groups selected from alkoxy groups
having 1 to 4 carbon atoms and halogen atoms,
d) an aryl group, which may be optionally substituted
up to three times with one or more groups selected
from alkyl, alkoxy, and halogenoalkyl groups each
with up to 4 carbon atoms and halogen atoms, and
which contains up to 10 carbon atoms in the aryl
moiety,
e) hydroxyl, if the other of R2 and R3 is hydrogen;
or R2 and R3, together with the nitrogen atom to
which they are attached represent,
f) a 5-membered to 7-membered saturated ring which
may be optionally substituted up to 4 times with
alkyl groups having 1 to 4 carbon atoms, and may
be optionally interrupted by a further heteroatom
selected from oxygen, sulphur and nitrogen, which
nitrogen may be optionally substituted, by an
alkyl or hydroxyalkyl group (each having up to 4
carbon atoms), an aralkyl or diarylalkyl group
(each having up to 4 carbon atoms in the alkyl

- 20 -
moiety thereof and the mononuclear or binuclear aryl
moieties may be optionally substituted with halogen),
or by an aryl group which may be optionally
substituted once or several times with a group
selected from alkyl, alkoxy, and halogenoalkyl groups
each with up to 4 carbon atoms, and halogen atoms
and hydroxyl groups, or it may also be substituted
by a 3-aminooxy-2-hydroxypropyl group, or
g) a 5-membered heteroaromatic ring which is optionally
anellated with a benzene or uracil ring and which
may contain up to 4 nitrogen atoms),
together with their physiologically compatible acid
addition salts with those organic or inorganic acids
which permit the preparation of non-toxic salts,
in which in a first state a hydroxylamine compound
of formula (VII)
<IMG> (VII)
is reacted with a compound of formula (VIII)
U-R6 (VIII)
to form compounds of formula (IX)
<IMG> (IX) ,
protecting groups <IMG> are separated therefrom
as <IMG> by hydrolysis and the product of formula

- 21 -
(I) is isolated in the form of a free base or is
converted with a suitable acid into a physiologically
compatible acid addition salt,
wherein in the above formulae;
R4 represents an alkyl group having 1 to 6
carbon atoms or an aryl group optionally substituted
up to three times with an alkyl or alkoxy group each
with up to 2 carbon atoms or a halogen atom;
R5' represents a hydrogen atom, an alkyl group
having 1 to 6 carbon atoms or an aryl group optionally
substituted up to three times with an alkyl or alkoxy
group each with up to 2 carbon atoms, or a halogen
atom;
R6 has the meanings specified above for X
or additionally represents the radical
<IMG> ;
T represents a hydrogen atom, if U has a different
meaning from hydrogen, or the group
<IMG> or <IMG>;
U represents a hydrogen atom, if T has a different
meaning from hydrogen, or the group
<IMG> or <IMG> and Z represents a
halogen atom, or a reactive sulphonic acid ester group,
whereby in each case T or U is hydrogen.

- 22 -
2. A process according to claim 1 in which in the
case of R2 and R3 being as defined under f), the
second heteroatom of the 5- to 7-membered ring is
nitrogen which carries an alkyl or hydroxyalkyl group
each with up to 4 carbon atoms;
an aralkyl or diarylalkyl group each with up to
4 carbon atoms in the alkyl part and wherein the aryl
portion is mononuclear or binuclear and may be
substituted once or twice with a halogen atoms,
or an aryl group which is optionally substituted
up to three times with an alkyl, alkoxy, or haloalkyl
group each with up to 4 carbon atoms, a halogen atom
or a hydroxyl, or a 3-aminooxy-2-hydroxypropyl group.
3. A process according to claim 1 or 2 wherein in a
first stage a hydroxylamine derivative of general
formula
<IMG> (X)
is reacted with a compound of formula U2-R6 (XIII),
whereby R4, R5' and U are as defined in claim 1
except that U is not hydrogen.
4. A process according to claim 1 wherein in a first
stage an 0-alkylated hydroxylamine derivative of
formula

<IMG>
(VII)
is reacted with nucleophilic compounds of formula H-R6 (XI), whereby R4, R5'
and T are as defined in claim 1 except that T is not hydrogen.
5. A process according to claim 1, wherein 0-(2,3-epoxypropyl)-
acetoxime of formula (VII) is reacted with morpholine of formula (XI).
6. A process according to claim 1 wherein a compound of formula VII
in which R4 and R5' are both methyl groups and T is a group of formula
<IMG>
is reacted with a compound of formula VIII in which U is hydrogen and R6 is
a group <IMG> in which R2 and R3, together with the nitrogen atom,
form a morpholine ring.
7. A process for preparing 0-[3-(4-morpholinyl)-2-hydroxypropyl]-
hydroxylamine or its hydrochloride salt which comprises reacting 0-(2,3-
epoxypropyl)-acetoxime and morpholine, followed by hydrolysis with hydro-
chloric acid to form the hydrochloride salt and, if required, converting the
hydrochloride salt to the free base.
8. A process according to claim 1 wherein a compound of formula VII in
which R4 and R5' are both methyl groups and T is hydrogen is reacted with a
compound of formula VIII in which U is a group of formula
<IMG>
and R6 is a 4-(2-methoxyphenyl)-piperazinyl group.
9. A process for preparing 0-[3-{4-(2-methoxyphenyl)-1-piperazinyl}-2-
hydroxypropyl]-hydroxylamine or its trihydrochloride salt which comprises
reacting acetoxime with 1-(2,3-epoxypropyl)-4-(2-methoxyphenyl)-piperazine,
23

followed by hydrolysis with hydrochloric acid to form the trihydrochloride
salt and, if required, converting the trihydrochloride salt to the free
base.
24

Description

64Z
- 1
This invention relates to novel O-alkylated
hydroxylamines having interesting pharmacological
properties.
A~pli~;oo
Canadian Patent ~p~ci~icatio~ No. 290 477
~~~ S (corresponding to German Patent ~pplication No.
P 26 51 083.8) discloses and claims a process for the
preparation of novel O-alkylated hydroxylamines of
formula
,
.~ H2N-O-CH2-cH-cH2 x (I)
OH
in which , R2
X repPesents -ORl, -SRl or -N ~ 3
: (wherein R represents
a) a hydrogen atom
b) when X represents -OR , an amino group,
:
c) an alkyl group having 1 to 6 carbon atoms, or
d) a mononuclear or binuclear:aryl radical which
is~optionally substituted up:to three times
with one or more groups selected from halogen
atoms, alkyl, alkoxy andlor halogenoalkyl
groups each having up to 4 carbon atoms,
cycloalkyl groups having 3 to 6 carbon atoms~
~ and nitro andlor cyano groups;
:
. ~'.
.
.

642
-- 2 --
-. R2 and R , which may be the same or different~
each represents
a) a hydrogen atom
b) an alkyl group having 1 to 6 carbon atoms or
a cycloalkyl group having 3 to 7 carbon atoms
each of which may be optionally substituted
with one or more hydroxyl groups or alkoxy-
carbonyl groups having 1 to 4 carbon atoms;
c) an aralkyl or diaralkyl group~ the alkyl
moieties of which having up to 4 carbon atoms
and are optionally substituted with one or
more hydroxyl groups, and the mononuclear or
binuclear aryl moieties of which may be
: optionally substituted up to three times with
lS one or more groups selected from alkoxy `
groups having 1 to 4 carbon atoms and
halogen atoms,
d) an aryl group~ which may be optionally
substituted up to three times with one or more
: groups selected from alkyl, alkoxy~ and
halogenoalkyl groups each with up to 4
` carbon atoms and halogen atoms, and which
contains up to 10 carbon atoms in the aryl
moiety~
e) hydroxyl~ if the other of R2 and R3 ls hydrogen;
: . or R2 and R3 together with the nitrogen atom
.to which they are attached represent,
. .f) a 5-membered to 7-membered saturated ring
which may be optionally substituted up to 4
, , .
~ 30 ~ times with alkyl groups having 1 Lo 4 carbon
~ , . '

4Z
3 --
atoms, and may be optionally interrupted by
a further heteroatom selected from oxygen,
sulphur and nitrogen, which nitrogen may be
optionally substituted, by an alkyl or
hydroxyalkyl group (each having up to 4
carbon atoms), an aralkyl or diarylalkyl
group (each having up to 4 carbon atoms in
the alkyl moiety thereof and the mononuclear
or binuclear aryl moieties may be optionally
substituted with halog~n)~ or by an aryl
group which may be optionally substituted
once or several times with a group selected
from alkyl, alkoxy, and halogenoalkyl groups
each with up to 4 carbon aSoms, and halogen
atoms and hydroxyl groups, or it may also be
substituted by a 3-aminooxy-2-hydroxypropyl
group~ or
g) a 5-membered heteroaromatic ring which is
~ - optionally anellated with a benzene or
uracil ring and which may contain up to 4
nitrogen atoms) .
. ~DDJl,~t,On
A - Canadian Patent~or~ 2~0 477 also describes a
, . : .
process~for the preparation of these compounds and
their physiologically compatible acid addition salts
of these baces with thoce organic or inor~anic
- . acids which permit the preparation of non-toxic
salts.
:~ ~ This process generally consists of linking the
: group X with the oxygen atom of a hydroxylamine compound~
with the insertion of the structural element
~ ' ' .
.
, , .
, , ' ' '

l~lQ64Z
~ 4 -
-CH2-CH(OH)-CH2-, by reacting in a first stage
A) a hydroxylamine derivative of formula
R\
/.C=N-OH (II)
R O
with a compound of general formula
Y-CH2-R (III)
: or
B) reacting an O-alkylated hydroxylamine derivative
of formula
R4
~ C=N-O-cH2-Y (IV)
R O
with a nucleophilic compound of formula
HR (V)
to form the common intermediate product of formula
=N-O-CH2-CH-CH2-R (VI)
. R O OH
splitting from the reaction products, the protecting
. . R4
group~ RsO ~ C= as R4-CooR by hydrolysls and isoIating
the products of formula (I) in the form of the free
: bases or converting them with suitable acids into
their physiologically compatible acid addition salts.
. - .In.the above formulae:- - .
.~ 20 R4 represents a straight or branched-chain alkyl
group having 1 to 6 carbon atoms or an aryl group
optionally substituted.with an alkyl or~alkoxy group
.
, . ~ . .
i,,, .. . . . . ... ., ' ' : . , , ' :' ' ' .

642
. -.:
--5 -
-- each with up to 2 carbon atoms or with a halogen atom.
R5 represen~s a straight or branched-chain alkyl -
group with 1 to 6 carbon atoms;
R is as defined above for X or represents a
group of formula
/ R4
-O-N=C
- ' \ oR5
(wherein R4 and R are as defined above)
Y represents the group CH2-CH- or Z-CH2-CH-
O OH
(in which
Z represents a halogen atom, preferably a chlorine
or bromine atom, or a reactive sulphonic acid ester
group).
The synthesis of the pharmacologically active,
7multi-functional O-alkyl hydroxylamines of formula (I)
has therefore been achieved by linking a 2-hydroxypropyl
group functionally substituted in a 3-position with the
oxygen atom of~ a hydroxylamine compound. In this
process, the starting materials are therefore alkyl
hydroximates or alkyl 0-(2,3-epoxypropyl)- or 0-(3-
halogeno-2-hydroxypropyl)-hydroximates in the form of
N-protected hydroxylamine derivatives. This process
has proved useful,
It has now been found in a development of a
~ process according to the above mentioned patent that
`~ 25 aldoximes and ketoximes~ also~ guarantee reversible
~ protection of the amino function. This mode of action
;~ prQceeds vi~ compounds in which RSO- is ~eplaced by R5
, .
" ~ .
, . .
. . .
-~ . . . .
.. . .,~ . .

~06~2
- 6 -
~ and a carbon atom from R is bound directly to the
carbon atom of the group R4-C=N-o-.
The object of the invention is therefore a
process for ~he preparation of an 0-alkylated
hydroxylamine of general formula (I) (in which X, Rl,
R2 and R3 are as hereinbefore defined) whereby the
group X is linked to the oxygen atom of a hydroxylamine
compound, with the insertion of the structural element
-CH2-CH(OH)-CH2- , wherein in a first stage a
hydroxylamine compound of formula (VII)
\ C=N-0-T (VII)
. - R5
is reacted with a compound of formula (VIII~
u_R6 (VIII)
to form the common intermediate compounds o~ fo~a (IX)
R4
\ C=N-0-CH2-CH-CH2-R (IX)
protecting groups R -C-R are separated therefrom
as R4-C-R by hydrolysis and the product of formula
(I) is isolated in the form of a free base or is
; converted with a suitable acid into a physiologically
compatible acid addition salt,
wherein in the above formulae;
R4 represents an alkyl group having 1 to 6
. carbon atoms or an aryl group optionally substituted
up to three times with an alkyl or alkoxy group each
~; 25 with up to 2 carbon atoms or a halogen atom;
.~ ' ' '
. ~ ' '

- ' ~llQ6~Z
R5 represents a hydrogen atom, an alkyl group
having 1 to 6 carbon atoms or an aryl group optionally
substituted up to three times with an alkyl or alkoxy
group each with up to 2 carbon atoms, or a halogen
atom;
R6 has the meanings specified above for X
or additionally represe.nts the radical
~R
-O-N=C ~
- R5
T represents a hydrogen atom, if U has a different
meaning from hydrogen, or.the group
CH2-/H-CH2- or Z-CH2-CH-CH2;
O ~H
U represents a hydrogen atom, if T has a different
meaning from hydrogen, or the group
~H2-CH-CH2- or Z-CH2-lH_CH2- and
O OH
Z represents a halogen atom preferably chlorine
or bromine, or a reactive sulphonic acid ester group,
whereby in each case T or U is hydrogen.
In.the foregoing definitions when R to R are
alkyl radicals,:these may each be straight or branched;
, ~ 1 ') ~
. 20 ~when R , R- and R represent aryl radicals or an aryl
substituent is present on the second nitrogen atom in
the saturated ring -l ; R according to meaning f),
. . R,
.
each of these groups may be substituted once or
several timesj for example up to three times.
.
- ., ~. . - . ,~
. .

642
-- 8 --
- All the above-mentioned haloalkyl radicals have
-- preferably 1 to 2 carbon atoms.
In one embodiment of the invention, (A), a
hydroxylamine derivative of general formula
R4
\ C=N-OH (X)
R5~
is reacted in a first s~age with a compound of formula
U-R6 (VIII), wherein R4, R5 and U are as defined above
except that U is not hydrogen.
In a second embodiment of the invention, (B), an
10 O-alkylated hydroxylamine derivative of formula t
R4 '
~ C=N-O-T (VII)
R
,
is reacted in a first stage with nucleophilic compounds
~ of formula
: ~ 6
H - R (XI)
;~ : 15 wherein R4, R$ and T are as defined above except
that T is not hydrogen.
The synthesis of the compound according to
formula (I) in which X represents the group -O-NH2
proceeds via the protected intermediate product of
:~ ~ 20 formula (XII)
;~' , .
. ' .
.
', ' '.
- . ~ . . ,
.

64
- R4 R4
5, / C N 0 C 2 , 2 5' (XII)
In this special case, N-protected hydroxylamine
derivatives of the group -0-N= ~4 will generally be
R
used as starting materials (VIII) or (IX) for R
Preferred compounds of formula (VII) are
aldoximes and ketoximes which are readily accessible
in preparation, or freely available, such as, for
example, benzaldoxime or acetoxime.
The starting compounds of formula (VIII) in
which U is not hydrogen are preferably 2,3-epoxypropyl
derivatives. These are for the most part known in
literature or can easily be prepared by processes
known in the literature, for example from epihalogeno-
hydrins, especially epichlorohydrin, and the nucelophilic
compounds of formula (XI) in the presence of bases.
The 2-propanols Z-C~2-CH(OH) CH2-R which are also
suitable as starting compounds can be prepared, in
principle, in the same way, but with the exclusion of
basic condensation agents, from epoxides such as
2~0 epichlorohydrin, epibromohydrin and 2,3-epoxypropyl-
benzene sulphonate, -toluene sulphonate, -4-bromo-
benzene sulphonate or -methane sulphonate.
~ Suitable compounds of formula (VII) in which T
-~ ~ is not hydrogen are, primarily, 0-(2,3-epoxypropyl)-
;; 25 oximes known in the literature such as 0-(2,3-epoxy-
-
,.: . ,

0642
- 10 -
- propyl)-acetaldoxime, -benzaldoxime or -acetoxime, which
can be reacted according to embodiment (B) with
alcohols, thiols, phenols, thiophenols, amines or
5-membered aromatic nitrogen heterocycles of formula
(XI)-
Among the suitable amines corresponding to
formula (XI) as saturated cyclic compound are preferably
included pyrrolidine, 2;5-dimethyl pyrrolidine,
piperidine, 2,6-dimethyl piperidine, 2,2,6-tetramethyl
piperidine, hexamethyleneimine, morpholine, thiomorpholine
and piperazine optionally substituted in 4-position.
Suitable 5-membered, aromatic, optionally anellated
nitrogen heterocycles are pyrrole, indole, pyrazole,
indazole, imidazole, benzimidazole, triazole, benzo-
triazole, tetrazole, carbazole and xanthines such astheophylline.
The alkylation reactions according to embodiments
(A) and (B) are preferably effected in a solvent or
distributing agent inert towards the reagents at a
temperature between 0 and 200C, preferably between
50C and the boiling temperature of the solvent used,
either in the presence of a base (e.g. an alkaline
earth metal hydroxide, carbonate, hydride or alcoholate
or an organic base such as tr~ethylamine, pyridine,
picoline and quinoline) or else with the use of alkali
metal or alkaline earth metal salts prepared separately
from the oximes according to formula (X) or the
alcohols, thiols, phenols, thiophenols and nitrogen
heteroaromatics according to formula (XI). In this
3~ case, the reaction time may range from one hour to a
~ ' .
: , , . , :

111064Z
few days.
Suitable solvents inert towards the reagents
include, for example, anhydrous alcohols such as
methanol, ethanol, propanol, isopropanol, butanol or
isobutanol; ethers such as diethyl ether, dii,sopropyl
ether, tetrahydrofuran, dioxan or diethylene glycol
dimethyl ether; hydrocarbons such as cyclohexane,
petroleum ether, benze~e, toluene or xylene;
halogenated hydrocarbons such as dichloromethane,
chloroform, carbon tetrachloride or chlorobenzene;
aprotic solvents such as dimethyl formamide, dimethyl
acetamide, N-methyl pyrrolidsne, tetramethyl urea,
hexamethyl phosphoric acid.trisamide, dimethyl
sulphoxide or acetonitrile, and also mixtures of these
solvents. Both in the reaction of the hydroxylamine
derivatives (X) with epoxides of formula (VIII) in
embodiment (A), and in the addition of thiols, phenols,
thiophenols and nitrogen heteroaromatics of formula
(XI) to the oxiranes (VII) in embodiment (B) it has
been found especially desirable to work in dimethyl
formamide with the addition of triethylamine as
catalyst at temperatures between 50 and 100C, the
reagents being used in equimolar quantities or with
a slight. excess of the alkylating agent.
In contrast thereto, alkylation of (X) is
effected with the 2-propanols of formula (VIII)
: ' advantageously with the use of alkali metal or alkaline
. earth metal oximates in alcoholic solution at boiling
temperature,
Aminolysis of the oxiranes (VII) with amines of
.~ . ' .
, , .
.
,

4~
- 12 -
- formula (XI) according to embodiment (B) is preferably
effected by boiling for 1 to 5 hours in high-boiling
alcohols such as n-propanol or isopropanol without
any further addition of base.l In the case of primary
amines it is preferred to use them in excess up to
four times the stoichiometric quantity.
In general, isolation of the intermediate
compound of formula (IX) and (XIII) which is obtained
according to embodiments (A) or (B) in a pure state is
not required for subsequent hydrolytic elimination of
the protective group in question. However, it may be
- effectedif desired by fractionated vacuum distillation
or in individual cases also by crystallisation.
Hydrolytic separation is preferably effected
under acid conditions in aqueous, aqueous-alcoholic
or aqueous ether solution at a reaction temperature
between 0 and 120C, particularly from 60 to 110C,
the reaction time ranging, as a rule, between a few
minutes and a few hours. Diluted mineral acids such
as hydrochloric acid and sulphuric acid are especially
suitable.
Isolation of the products of the novel process
may be effected either in the form of the stable free
bases or, preferably, as non-toxic acid addition
salts. ~cids suitable for the purpose are, for example
hydrohalic acids, such as hydrochloric acid, sulphuric,
phosphoric, acetic, lactic, maleic, ~umaric, oxalic,
tartaric, citric, gluconic, p-toluenesulphonic,
methanesulphonic, benzenesulphonic and cyclohexylamido
sulphonic acid.
The compounds according to the invention of
- , .
'.' '. .: - . ., ,.- ., , ~ :

~lQ642
- 13 -
formula (I~ have a chiral centre due to the propanol-
(2) structure and may thus be present in the optically
active D- or L-form. The invention relates therefore
to preparation of both the enantiomeric compounds and
racemic mixtures thereof.
To prepare the pure antipodes, it is possible
with the reactions according to embodiments (~) and
(B) to start from the enantiomeric starting compounds
of formula (VIII) or (VII~ or else to separate into
the enantiomers the racemates obtained by one of the
two process embodiments by means of processes known
se~ for example by fractional crystallisation
of the acid addition salts of an optically active
acid.
The novel hydroxylamines of formula (I) and
their physiologically compatible acid addition salts
possess valuable pharmacological properties.
Depending on the constitution of the substituent
X, compounds of the invention have been found to
display good hypotensive, but also bronchospasomolytic,
anti-convulsive, analgesic, anti-phlogistic, ch~leretic,
uric-acid-reducing, anthelmintic and anti-mycotic
activity. At the same time, they represent important
starting-materials for the synthesis of further
valuable medicaments, for example for the preparation
of substituted 0-(2-hydroxypropyl)-aldoximes by
reaction with 2-formyl-5-nitroimidazgles or 2-formyl-
, C~
5-nblt~ofurane, as described in~Patent Application
~71~84~ (corresponding to German Patent Application
P 26 51 084.9), or for the preparation of products
i~ ' ' ''
.; . ,
.

4Z
- 14 -
which are described in the eanadian Patent Appli-
cations 293.840 and 293.826.
The novel compounds of formula (I) and their
physiologically compatible salts may thus be used as
medicaments, especially those for the treatment of
hypertonic conditions, wherein they are admimistered
either alone or mixed with suitable carriers. A
further aspect of the invention relates to
medicaments which contain as active substance
at least one compound of formula (I), optionally in
the form of one of its physiologically compatible
acid addition salts. The preparations may be applied
orally and/or parenterally. Suitable solid or
liquid galenic preparations are, for example granulates,
powders, tablets, capsules, syrups, emulsions,
suspensions, drops or injectable solutions as well as
preparations which allow sustained release of the
active substance. As carriers frequently used
magnésium carbonate, various sugars, starch, cellulose
derivatives, gelatine, animal and vegetable oils,
polyethylene~glycols and solvents, are all suitable.
A particular application of the compounds of
;~ formula (I) according to the invention as well as
their salts lies in their combination with other
suitable active substances, for example diuretics,
saluretic, ~- and especially ~- sympatholytics,
tranquillisers~ vasodilating agents and other anti-
hypertensive agents.
.

64Z
- 15
Examples
The structure of the compounds described herein-
after was proved by elementary analysis and by
reference to the IR and H-NMR spectrum.
l) 0-[3-(4-morpholinyl)-2-hydroxYpropyl]-hydroxyl-
amine dihydrochloride
According to process embodiment (B), a solution
of 12.9 g (O.l mol) of 0-(2,3-epoxypropyl)-acetoxime
and 8.7 g (O.l mol) of morpholine in 60 ml of
isopropanol is refluxed for 4 hours and allowed to
cool. The alcohol is distilled off under reduced
pressure, the residue is mixed with 150 ml of 3N
hydrochloric acid and the mixture is boiled for 15
minutes with vigorous stirring. The resulting
mixture is thereàfter evaporated under reduced
pressure and the residue is recrystallised from
methanol with the addition of diethyl ether at its
~boiling point until cloudiness appears.
_ield: 23.6 g (95% of theory)
Melting point 178-180C (with decomposition).
~ -H2N-0-CH2-cbH CH2 ~ 0 . 2 HCl
; ~ c7Hl8cl2N2o3 (M.W. = 249.1)
Analysis:
Calculated: C 33.75% H 7.28% Cl 28.46% N 11.24%
Found- C 3J.61% H 7~39% Cl 28~37~/o N 11.14%
~ .
.,
: .
.
.; . . . .
.,

642
,. .
The free base of the dihydrochloride may likewise
be isolated in crystalline forms. After recrystalli-
sation from diisopropyl ether it has a melting point
of 80 81 C- C7H16 2 3 (
Analysis:
Calculated: C 47.71% H 9.15% N 15.90%
Found: C 47095% H 9~24% N 15.98%
2) 0-[3-~4-(2-methoxyphenYl)-l-piperazinyl~-2-
hydroxypropyl~-hydroxvlamine trihydrochloride mono-
hydrate
According to process embodiment (A) a solution o7.3 g (0.1 mol) of acetoxime and 24.8 g (O.l mol)
of l-(2,3-epoxypropyl~-4-(2-methoxyphenyl)-piperazine
in 150 ml of isopropanol and 2 ml of triethylamine
is refluxed for 8 hours and allowed to cool. The
alcohol is distilled off under reduced pressure,
the residue is mixed with 150 ml of 3N hydrochloric
acid and the mixture is boiled for 15 minutes with
vigorous stirring. The resulting mixture is thereafter
evaporated under reduced pressure and the residue is
recrystallised from methanol with the addition of
diethyl-ether at its boiling point until cloudiness
appears.
Yield: 29.4 8 (72% of theory).
Melting point: 142~(with decomposition).
H2N-O-CH2-CH C 2 ~ ~ x 3 HCl x H20
OCH3
.
.. . .
. .

64Z
- 17
.
C14 28 3 3 4
Analvsis:
Calculated: C 41.14 H 6.90 Cl 26.02 N 10~28
Found: C 40.91 H 6091 Cl 26.04 N 10.30
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