CA1110642A - Process for the preparation of o-alkylated hydroxylamines - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A process for the preparation of 0-alkylated hydroxylamines of general formula (I) wherein X represents -OR', -SR' or ; 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) (VII) is reacted with a compound of formula U-R6 (VIII) to form compounds of formula (IX) protecting groups are separated therefrom as 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 ;

T represents a hydrogen atom, if U has a different meaning from hydrogen, or the group or U represents a hydrogen atom, if T has a different meaning from hydrogen, or the group or

Description

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;

:

. ~'.

.
.

-. 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 ~ , . ' 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 ~ 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,,, .. . . . . ... ., ' ' : . , , ' :' ' ' .

. -.:

-- 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 -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 ~ 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) \ 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 ~

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.

.

- ., ~. . - . ,~
. .

- 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 \ 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) ;~' , .
. ' .

.
', ' '.

- . ~ . . , .

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--,.: . , - 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 ~ ' .

: , , . , :

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~

- 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 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~ ' ' '' .; . , .

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.

.

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%

~ .

., : .
.

.; . . . .

., ,. .
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 .

.. . .

. .

.

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 ' ': . ' ' - . .

, , .

: -. ~ .

,., `~' ' ' ` .

: . . ..

Claims (9)

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 (I) in which X represents - OR1, -SR1 or (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 - -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 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) (VII) is reacted with a compound of formula (VIII) U-R6 (VIII) to form compounds of formula (IX) (IX) , protecting groups are separated therefrom as 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 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 ;

T represents a hydrogen atom, if U has a different meaning from hydrogen, or the group or ;
U represents a hydrogen atom, if T has a different meaning from hydrogen, or the group or and Z represents a halogen atom, or a reactive sulphonic acid ester group, whereby in each case T or U is hydrogen.

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 (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 (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 is reacted with a compound of formula VIII in which U is hydrogen and R6 is a group 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 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, followed by hydrolysis with hydrochloric acid to form the trihydrochloride salt and, if required, converting the trihydrochloride salt to the free base.