4'-NITRO-ACETOPHENONE-O-AMINOETHYLOXIMES AS ANTIDEPRESSIVE COMPOUNDS

4'-NITRO-ACETOPHENONE-O-AMINOETHYLOXIMES FORMANT DES COMPOSES A PROPRIETES ANTIDEPRESSIVES

English Abstract

ABSTRACT
The novel compounds of formula I
<IMG>
wherein R is hydrogen, methyl or chlorine, R1 is oxygen or sulphur, R2 is
OCH2, CH20CH2, OC2H40CH2, R3 is hydrogen or methyl, n and p are 0 or 1 and
n + p is 0 or 1 and salts thereof have a very powerful anti-depressive
activity which for a considerable part, and in some substances even entirely,
is based on serotonine potentiation. Monoamino oxidase inhibition does not
contribute to the anti-depressive effect. The substances have a low toxicity
and are substantially free from side effects. The compounds can be synthesiz-
ed and processed to compositions according to known methods.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of compounds of the general formula
I
<IMG> (I)
and the pharmaceutically acceptable acid addition salts thereof, wherein R
is hydrogen, methyl or chlorine, R1 is oxygen or sulphur, R2 is OCH2, CH20CH2
or OC2H40CH2, R3 is hydrogen or methyl, n and p are 0 or 1 and n + p is 0 or
1, which comprises
(a) reacting a corresponding compound of the general formula II
(II)
<IMG>
and the pharmaceutically acceptable acid addition salts thereof, wherein R4
is an oxygen atom, an oxime group or an alkylenedioxy group, with a compound
of the general formula III
H2N-0-CH2-CHR3-NH (III)
or an acid addition salt thereof; or
(b) reacting a corresponding compound of the general formula IV
<IMG>
(IV)
wherein M is hydrogen or an alkali metal, with a compound of the general
formula V
Hal-CH2-CHR3-NH2 (V)
or an acid addition salt thereof, wherein Hal is halogen; or
(c) reacting a corresponding compound of the general formula VI
<IMG> (VI)
16

wherein R5 is a leaving group, with ammonia; or
(d) removing the protective group R6 from a corresponding compound
of the general formula VII
<IMG> (VII)
wherein R6 is trityl, by hydrolysis; or
(e) converting the para amino (aromatic) group in a corresponding
compound of the general formula VIII
<IMG> (VIII)
or acid addition salt thereof, into a nitro group; or
(f) for the preparation of compounds of formula I wherein n + p =
1, reacting a corresponding compound of the general formula IX
<IMG>
(IX)
and the pharmaceutically acceptable acid addition salts thereof, wherein q
is 1, 4 or 5 and Hal is halogen, with a compound of the general formula X
M'R7 (X)
wherein M' is an alkali metal and R7 is propoxy, propylthio, methoxy or
methoxyethoxy; or
(g) for the preparation of compounds of formula I wherein n + p = 1
reacting a corresponding compound of general formula XI
<IMG> (XI)
wherein R8 is oxygen or sulphur, with a compound of the general formula XII
<IMG> (XII)
wherein R? is methyl, propyl or methoxyethyl;
and where required converting any free base of formula I so produced into a
pharmaceutically acceptable acid addition salt thereof.
17

2. Compounds of the general formula I
<IMG>
(I)
and their pharmaceutically acceptable acid addition salts, wherein R, R1,
R2, R3, n and p are as defined in claim 1, when prepared by the process of
claim 1, or by an obvious chemical equivalent thereof.
3. A process according to claim 1, wherein reaction (d) or (e) is
employed and in the starting materials R is hydrogen, R3 is hydrogen, n is
O and p is 0.
4. A process according to claim 1, wherein reaction (f) is employed
and in the starting materials R is hydrogen, R3 is hydrogen, R7 is propyl-
thio and q is 1.
5. A process according to claim 1, wherein reaction (b) or (c) is
employed and in the starting materials R is hydrogen, R1 is oxygen, R3 is
hydrogen, n is 1 and p is 0; or wherein reaction (g) is employed and in the
starting materials R is hydrogen, R3 is hydrogen, R7 is propyl, R8 is
oxygen and q is 1.
6. A process according to claim 1, wherein reaction (a) is employed
and in the starting materials R is hydrogen, R2 is OCH2, R3 is hydrogen,
n is O and p is 1.
7. A process according to claim 1, wherein reaction (a) is employed
and in the starting materials R is hydrogen, R2 is OC2H40CH2, R3 is hydrogen
n is O and p is 1.
8. A process according to claim 1, wherein reaction (a) is employed
and in the starting materials R is hydrogen, R2 is CH2 OCH2, R3 is hydrogen
n is o and p is 1.
9. A process according to claim 1, wherein reaction (a) is employed
and in the starting materials R is methyl, R3 is hydrogen, n is O and p is Q.
18

10. A process according to claim 1, wherein reaction (a) is employed
and in the starting materials R is chlorine, R2 is OCH2, R3 is hydrogen,
n is 0 and p is 1.
11. A process according to claim 1, wherein reaction (a) is employed
and in the starting materials R is hydrogen, R3 is methyl, n is 0 and p is 0.
12. A process according to claim 1, wherein reaction (a) is employed
and in the starting materials R is hydrogen, R1 is oxygen, R3 is methyl, n
is 1 and p is 0.
13. A process according to claim 1, wherein reaction (a) is employed
and in the starting materials R is chlorine, R2 is OCH2, R3 is methyl, n is
0 and p is 1.
14. A process for the preparation of 4'-nitrobalerophenone-0-(2-
aminoethyl) oxime and its hydrochloride, which comprises removing the pro-
tective trityl group from 4'-nitrovalerophenone O-(2-tritylaminoethyl) oxime
by hydrolysis with aqueous acetic acid, and where required converting the
free amine so formed into its hydrochloride by reaction with hydrochloric
acid.
15. A process for the preparation of 4'-nitrovalerophenone 0-(2-amino-
ethyl) oxime and its hydrochloride, which comprises coverting the para amino
(aromatic) group in 4'-aminovalerophenone 0-(2-aminoethyl) oxime dihydro-
chloride into a nitro group by reaction with m-chloroperbenzoic acid in
methylene chloride, and where required converting the free amine so formed
into its hydrochloride by reaction with hydrochloric acid.
16. 4'-Nitrovalerophenone 0-(2-aminoethyl) oxime and its hydrochloride
when prepared by the process of claim 14 or 15, or by an obvious chemical
equivalent thereof.
17. A process for the preparation of 4'-nitro-2-propylthioacetophenone
0-(2-aminoethyl) oxime and its hydrochloride, which comprises reacting 2-
19

bromo-4'-nitroacetophenone 0-(2-aminoethyl) oxime hydrochloride with
propylmercaptan, and where required converting the free amine so formed into
its hydrochoride by reaction with hydrochloric acid.
18. 4'-Nitro-2-propylthioacetophenone 0-(2-aminoethyl) oxime and its
hydrochloride when prepared by the process of claim 17, or by an obvious
chemical equivalent thereof.
19. A process for the preparation of 4'-nitro-2-propoxyacetophenone
0-(2-aminoethyl) oxime and its hydrochloride, which comprises reacting 4'-
nitro-2-propoxyacetophenone oxime with 2-chloroethyl amine hydrochloride,
and where required converting the free amine so formed into its hydrochloride
by reaction with hydrochloric acid.
20. A process for the preparation of 4'-nitro-2-propoxyacetophenone
0-(2-aminoethyl) oxime and its hydrochloride, which comprises reacting 4'-
nitro-2-propoxyacetophenone 0-(2-mesyloxyethyl) oxime with ammonia, and where
required converting the free amine so formed into its hydrochloride by
reaction with hydrochloric acid.
21. A process for the preparation of 4'-nitro-2-propoxyacetophenone
0-(2-aminoethyl) oxime and its hydrochloride, which comprises reacting 2-
hydroxy-4'-nitroacetophenone 0-(2-aminoethyl) oxime with sodium hydride and
then propyl bromide, and where required converting the free amine so formed
into its hydrochloride by reaction with hydrochloric acid.
22. 4'-Nitro-2-propoxyacetophenone 0-(2-aminoethyl) oxime and its
hydrochloride when prepared by the process of claims 19, 20 or 21, or by
an obvious chemical equivalent thereof.
23. A process for the preparation of 5-methoxy-4'-nitrovalerophenone
0-(2-aminoethyl) oxime and its hydrochloride, which comprises reacting 5-
methoxy-4'-nitrovalerophenone with 2-aminooxyethylamine dihydrochloride, and
where required converting the free amine so formed into its hydrochloride
by reaction with hydrochloric acid.

24. 5-Methoxy-4'-nitrovalerophenone 0-(2-aminoethyl) oxime and its
hydrochloride when prepared by the process of claim 23, or by an obvious
chemical equivalent thereof.
25. A process for the preparation of 5-(2-methoxyethoxy)-4'-nitro-
valerophenone 0-(2-aminoethyl) oxime and its fumarate (1:1), which comprises
reacting 5-(2-methoxyethoxy)-4'-nitrovalerophenone ethylene ketal with 2-
aminooxyethylamine dihydrochloride, and where required converting the
free amine so formed into its fumarate (1:1) by reaction with fumaric acid.
26. 5-(2-Methoxyethoxy)-4'-nitrovalerophenone 0-(2-aminoethyl) oxime
and its fumarate (1:1) when prepared by the process of claim 25, or by an
obvious chemical equivalent thereof.
27. A process for the preparation of 6-methoxy-4'-nitrohexanophenone
0-(2-aminoethyl) oxime and its hydrochloride, which comprises reacting 6-
methoxy-4'-nitrohexanophenone with 2-aminooxyethylamine dihydrochloride,
and where required converting the free amine so formed into its hydrochloride
by reaction with hydrochloric acid.
28. 6-Methoxy-4'-nitrohexanophenone 0-(2-aminoethyl) oxime and its
hydrochloride when prepared by the process of claim 27, or by an obvious
chemical equivalent thereof.
29. A process for the preparation of 3'-methyl-4'-nitrovalerophenone
0-(2-aminoethyl) oxime and its fumarate (1:1) which comprises reacting 3'-
methyl-4'-nitrovalerophenone with 2-aminooxyethylamine dihydrochloride,
and where required converting the free amine so formed into its fumarate
(1:1) by reaction with fumaric acid.
30. 3'-Methyl-4'-nitrovalerophenone 0-(2-aminoethyl) oxime and its
fumarate (1:1) when prepared by the process of claim 29, or by an obvious
chemical equivalent thereof.
31. A process for the preparation of 3'-chloro-5-methoxy-4'-nitro-
valerophenone 0-(2-aminoethyl) oxime and its fumarate (1:1), which comprises
21

reacting 3'-chloro-5-methoxy-4'-nitrovalerophenone with 2-aminooxyethylamine
dihydrochloride, and where required converting the free amine so formed into
its fumarate (1:1) by reaction with fumaric acid.
32. 3'-Chloro-5-methoxy-4'-nitrovalerophenone 0-(2-aminoethyl)oxime and
its fumarate (1:1) when prepared by the process of claim 31, or by an
obvious chemical equivalent thereof.
33. A process for the preparation of 4'-nitrovalerophenone 0-(2-
aminopropyl) oxime and its hydrochloride, which comprises reacting 4'-
nitrovalerophenone with 2-aminooxy-1-methylethylamine dihydrochloride, and
where required converting the free amine so formed into its hydrochloride
by reaction with hydrochloric acid.
34. 4'-Nitrovalerophenone 0-(2-aminopropyl) oxime and its hydrochloride
when prepared by the process of claim 33, or by an obvious chemical equi-
valent thereof.
35. A process for the preparation of 4'-nitro-2-propoxyacetophenone
0-(2-aminopropyl) oxime and its fumarate (1:1), which comprises reacting
4'-nitro-2-propoxyacetophenone with 2-aminooxy-1-methylethylamine, and where
required converting the free amine so formed into its fumarate (1:1) by
reaction with fumaric acid.
36. 4'-Nitro-2-propoxyacetophenone 0-(2-aminopropyl) oxime and its
fumarate (1:1) when prepared by the process of claim 35, or by an obvious
chemical equivalent thereof.
37. A process for the preparation of 3'-chloro-5-methoxy-4'-nitro-
valerophenone 0-(2-aminopropyl) oxime and its fumarate (1:1), which comprises
reacting 3'-chloro-5-methoxy-4'-nitrovalerophenone with 2-aminooxy-1-
methylethylamine dihydrochloride and where required converting the free amine
so formed into its fumarate (1:1) by reaction with fumaric acid.
38. 3'-Chloro-5-methoxy-4'-nitrovalerophenone 0-(2-aminopropyl) oxime
and its fumarate (1:1) when prepared by the process of claim 37, or by an
22

obvious chemical equivalent thereof.
23

Description

1~77gf~
The invention relates to novel anti-depressive compounds.
~ ritish Patent Specification 1,205,665 discloses a large group of
oxiTne ether compounds having anti-depressive activity, which compounds are
derived from alkylphenyl-ketone. The compounds have in a phenyl group one
or more substituents which are selected from a very large group. Each of
the possible substituents may be bound in any position of the phenyl group,
but according to said patent specification substitutions with nitro groups
are restricted to the meta-positions.
This suggests that oxime ether compounds which are derived from
alkylphenone and which have a nitro-group in a position other than a meta-
position, have no anti-depressive activity. The anti-depressive activity of
the known compounds is based on monoamino oxidase (MAO) inhibition and/or
noradrenaline potentiation.
However, compounds which inhibit monoamino oxidase are particular-
ly difficult to administer. They often have serious side effects and are
often incompatible with other medicines and with some nutrients.
Since the regulations governing the use of medicines have become
more srtingent, only those compounds which are substantially free from
side effects can be considered for adminstration to human beings.
, . .
The present invention pro~id~s compounds having a powerful
anti-depressive activity which is expressed inter alia in an elevation of
mood of the treated patient but which have no component based on MA0 in
hibition. The compounds in view are substantially free from side effects.
In one aspect the present invention relates to a process for the
preparation of compounds of the general formula I
02N ~ C N 0 CH2 CHR3 NH2
. . I
R CH2-(Rl~n-(cH2)3-(R2)p
- and the pharmaceutically acceptable acid addition salts thereof, wherein R
is hydrogen, methyl or chlorlne, Rl is oxygen or sulphur, R2 is OCH2, CH20CH2
or OC2H40CH2, R3 is hydrogen or methyl, n and p are 0 or 1 and n + p is 0 or
1, which colT,prises
~. .
,

~07796~
(a) reacting a corresponding compound of the general formula II
O2N ~ _ f--R4 (II)
R CH2-(Rl)n-(CH2)3 ( 2)p
and the pharmaceutically acceptable acid addition salts thereof, wherein R4
is an oxygen atom, an oxime group or an alkylenedioxy group, with a compound
of the general formula III
H2N-0-CH2-CHR3-NH2 (III)
or an acid addition salt thereof; or
(b) reacting a corresponding compound of the general formula IV
=N-0-M (IV)
R CH2-(Rl)n-(CH2)3-(R2)p
wherein M is hydrogen or an alkali metal, with a compound of the general
for~la V
Hal-CH2-CHR3-NH2 (V)
or an acid addition salt thereof, wherein Hal is halogen; or
; (c) reacting a corresponding compound of the general formula VI
~ '
O2N ~ IC N 0 CH2 CHR3 R5 (VI)
R CH2-(Rl)n-(CH2)3 (R2)p
wherein R5 is a leaving group, with ammonia; or
(d) removing the protective group R6 from a corresponding compound
of the general formula VII
02N ~ C=N-O-CH2-CHR3-NHR6 (VII)
R CH2-(Rl)n-(CH2)3 (R2)p
wherein R6 is trityl, by hydrolysis; or
(e) converting the para amino (aromatic) group in a corresponding
compound of the general formula ~III
B - 2 -
:
.

`` 1~7796i~
H2N ~ f 2 H 3 NH2 (VIII)
R CH2-(Rl)n-(CH2)3-(R2)p-H
or acid addition salt thereof, into a nitro group; or
(f) for the preparation of compounds of formula I wherein n + p =
1, reacting a corresponding compound of the general formula IX
O2N ~ C=N-0-CH2-CHR3-NH2 (IX)
: R (CH2)q-Hal
and the pharmaceutically acceptable acid addition salts thereof, wherein q
is 1, 4 or 5 and Hal is halogen, with a compound of the general formula X
. M'R7 (X)
wherein M' is an aIkali metal and R7 is propoxy, propylthio, methoxy or :
methoxyethoxy; or
~; (g) for the preparation of compounds of formula I wherein n + p
= 1, reacting a corresponding compound of general formula XI
NO2 ~ f=N--CH2-CHR3-NH2 (XI)
2 q 8
- wherein R8 is oxygen or sulphur, with a compound of the general formula XII
; Hal R7 (XII) -
~ wherein ~ is methyl, propyl or methoxyethyl;
~ and where required converting any free base of formula I so produced into a
pharmaceutically acceptable acid addition salt thereof.
In another aspect, the present invention relates to compounds of
the general formula I
02N~ f 2 3 2 (I)
CH2-(Rl)n-(CH2)3 (R2)p
and their pharmaceutically acceptable acid addition salts, wherein R, Rl, R2,
. R3, n and p are as defined above, when prepared by the process described above
or, by an obvious chemical equivalent thereof.
'
: ,~
~*
'' ' ' '~ , . ' : ~
, . . .

1~3177~6~
It hassurprisingly been found that the anti-depressive activity
of these compounds is based for a considerable part, and in some compounds
even exclusively, on serotonine potentiation, an activity which in a
depressive patient results in an elevation of mood. However, most compounds
show, in addition to serotonine potentiation, a very powerful noradrenaline
potentiation as an anti-depressive activity component.
~ he absence of an activity based on MAO inhibition is surprising
especially as the compounds proved to be substantially free from side
effects, for example, stomach ulceration and broncho constriction, and have
a low toxicity.
In the following table properties of the compounds according to
the invention are compared with those of the closest related known compounds
from British patent specification 1,205,665.
- 3a _

lQ77~6`~a
~ ~ ..
~ I~IIIIIIIII
h O
~.
o h l l l l l l l l l l l +
tn3
. :-
oo
~1 U~ ~ 00 L~
C~ ,C ~ ~ _~ _I
5 ~ N N N N N N N N N N N N
~rl A A A A A A A A A A A A
.......
o Oo o~ a~ oo ~ ~ ,
t`l h ~ ~ ~ ~ ~ ~o N 00 e~ ~ t~ ~ t~
0 0~ _I _I ~I N ~ I 00
. . _
.
t_~ ~ a~ 0 ~1 1~ ~I N N O 00
~ ~ ~ N L~
~N ~o O A A
~ ~ ~,:
Z
~ ~ C X
~ N
_~
U~
~ t~ ~ N t~
O C~ xN ~ t~
~, c~ x ~ o o o ~ o a ~ O a
~ ~ ~ ~, ~ ~ U, ~ ~ ~ ~ C~ ~ ~
N~ONNNNNNON ~N
~ ~ N CN a ~ a X a a sN a ~N ~N a ~
. tn ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
. _ _ NNN
~N ~ 3 a ~ ~ z ~ ~
~ h
NNNNNNNNNNN
U)~ ZO ~ ~ ~ ZO ZO ~ ~ ZO ~ ZO ~ O ~ ~
~N~O~ ~N~ *
-- 4 --
~ . .

~77g6a~
The numbers in this table are ED50 values expressed in mg/kg.
It is remarkable that the compounds 9 and 10 neither potentiate
noradrenaline nor inhibit MAO. The anti-depressive activity of these
co~pounds is based entirely on serotonine potentiation.
These compounds therefore and in particular, compound 9 are
to be preferred if a very specific serotonine potentiation is endeavoured.
Noradrenaline potentiation and serotonine potentiation in com-
pounds 7 and 8 are of the same order of magnitude. Moreover, the ac-
tivity is at a high level.
Both noradrenaline potentiation and serotonine potentiation in
compound 5 are at a high level but the noradrenaline potentiation is
stronger by well over a factor 4.
It appears from the table that the compounds according to the
invention are substantially free from undesired side effects.
Although the known compounds 81 and B2 have a strong
noradrenaline and serotonine potentiating effect, they also have a powerful
MAO inhibition. In compound B3 not only both the noradrenaline potentia-
,
tion and the serotonine potentiation is of quite a different level, in
addition the compound gives stomach ulceration. Therefore, none of the
known compounds satisfy the object of the invention.
The data recorded in the table were determined by means of the
following tests.
The noradrenaline potentiation was determined in the tetra- -
.
benazine test. In this test a quantity of the compound to be tested was
. .
administered orally to five male albino mice. After 45 minutes the
animals were injected subcutaneously with 80 mg/kg of tetrabenazine. After
another 45 minutes the ptosis was determined and compared with the ptosis
of animals which had received tetrabenazine alone. The ED50 was determined
from the results.
The serotonine potentiation was determined in the 5-hydroxytrypto-
phan test. ~or this purpose the compounds to be tested were administered
orally in a series of dosages to isolated male albino mice (5 mice per
-- 5 --
.,
i .
~. .

~077964
dosage) 1 hour prior to intraperitoneal administration of 150 mg/kg
of dl-5-hydroxytryptopban. 30 minutes after this threshold dosage the
mice were observed individually and the following parameters were scored:
stereotypical shaking of the head, spreading of the hindlegs, tremor,
tendency to flee, lordosis and clonic stamping with the frontlegs. The
ED50 value was calculated from the results.
The monoamino oxydase (MAO) inhibiting effect was determined in
experiments in which a quantity of the compound to be tested was ad-
ministered orally to fiYe male albino mice. One hour later the animals
were injected subcutaneously with tryptamine hydrochloride in a quantity
of 250 mg/kg. This quantity does not cause mortality in animals which did
not receive the compound to be tested, but did cause mortality in animals
to which an active substance had been administered. Eighteen hours after
the administration of tryptamine hydrochloride it was determined how many
treated animals had died. The ED50 was determined from the results.
By means of the method by Metysova, Arzneimittelforschung 13
1039 (1963) it was determined whether the oral administration of 200 mg of
a compo~nd to be tested causes stomach ulceration.
By means of the method by Konzett-R~ssler, Arch. Esp. Path.
pharmakol, 195 71 (1940) it was investigated whether a compound to be
tested causes bronchoconstriction after intravenous administration of
3 mg/kg. Reduction of the breathing function as a result of broncho-
constriction is expressed in this method in a smaller volume of air taken
in.
On the basis of their properties the compounds of formula I and
their salts are particularly suitable for use in the treatment of depres-
sive patients. This applies in particular to the compounds: 5-(2-meth-
oxyethoxy)-4'-nitrovalerophenone 0-~2-aminoethyl)oxime, 4'-nitro-3'-
methyl-valerophenone 0-(2-aminoethyl)oxime, 3'-chloro-5-methoxy-4'-
nitrovalerophenone 0-(2-aminoethyl)oxime, 4'-nitrovalerophenone
0-~2-aminopropyl)oxime and 3'-chloro-4'-nitro-5-methoxyvalerophenone
0-(2-aminopropyl) oxime and their salts.
-- 6 --
,

7796~
The quantity, the frequency, and the way in which the compounds
according to the invention are administered may differ for each individual
patient and also in accordance with the severity of the disturbance to be
treated. In general, an oral daily quantity of 25-500 mg will be chosen,
as a rule 50-200 mg.
The compounds are preferably used in the form of tablets,
coated tablets, capsules, pills, powders, injection liquids and the like.
They can be processed to such compositions according to methods which are
known per se.
The invention also relates to compositions having a compound
of formula I or a salt thereof formed with a pharmaceutically acceptable
acid as an active constituent, and to methods to bring the compounds and
their salts in a form suitable for administration, for example, by mixing
an active substance with or dissolving it in solid or liquid pharmaceutical
carrier materials.
As examples of pharmaceutically acceptable acids with which the
bases of formula I can form salts may be mentioned: inorganic acids, for
example hydrochloric acid, nitric acid, sulphuric acid and organic acids,
for example, malic acid, citric acid, fumaric acid, maleic acid, tartaric
acid, benzoic acid and the like.
The compounds of formula I and their salts can be prepared
; according to methods which are known for the preparation of this type of
compounds and according to methods analogous thereto.
The invention also relates to the preparation of the compounds.
The compounds can be prepared inter alia by converting a compound
of formula II with a compound of formula III or a salt thereof. In this
case R4 is an oxygen atom, an oxime group or an alkylene dioxygroup, for
' example ethylenedioxy.
The reaction is preferably carried out in an inert solvent,
.
for example an alcohol, dioxan, dimethyl formamide, tetrahydrofuran
. . ~
or a mixture thereof, at temperatures between room temperature and the
boiling point of the mixture and possibly in the presence of an acid
~ - 7 -
.

10779~;4
.
binder, for example pyridine.
The compounds are also prepared by converting a compound of
formula IV wherein N is a hydrogen atom or an alkali metal atom with a
compound of formula v or a salt thereof wherein Hal is a halogen atom,
preferably a chlorine atom or a bromine atom.
The reaction is preferably carried out in an inert solvent,
for example alcohols, ethers or dimethyl formamide. When M is a hydrogen
atom, an acid binder for example an alcoholate is preferably added as
well. As a rule the reaction temperature is between 0 and 50C.
The compounds can also be prepared by converting a compound of
formula VI wherein R5 is a leaving group, for example a mesyloxy group
or a tosyloxy group, with ammonia. The reaction is preferably carried out
in an inert solvent, for example an alcohol, as a rule at temperatures
between room temperature and 150C.
The compounds of formula VI are prepared by converting a com-
pound of formula IV in ethanol and in the presence of an alcoholate at
temperatures up to 60C with ethylene oxide or propylene oxide. The
reaction product is then converted with mesylchloride or tosylchloride
dissolved in methylene chloride.
The compounds can also be obtained by removingthe protective
group R6 by means of hydrolysis from a compound of formula VII. As
a protective group may be mentioned, for example, the trityl group. The
reaction is carried out, for example, in a water-miscible solvent in acid
conditions at a temperature between room temperature and 100 C.
The compounds can also be obtained by converting the para
amino taromatic) group in a compound of formula VIII into a nitro group.
The conversion can be carried out by a reaction with nitrous
; acid at -10 to +50C, followed by decomposition of the resulting
diazonium compound in the reaction mixture at 20-75C in the presence of
copper. The conversion of compounds wherein Rl does not represent sulphur
may also be carried out with a peroxide, for example hydrogen peroxide
or m-chloroperbenzoic acid, in an inert solvent, for example methylene
- 8 -

iO77964
chloride or chloroform, at temperatures between room temperature and the
boiling point of the mixture.
Compounds of formula I wherein n + p = 1 can furthermore be
prepared by reacting a compound of formula IX with a compound of formula
X. In these formulae q has the value of 1, 4 or 5, M' is an alkali
metal atom and R7 is a propoxy group, a propylthio group, a methoxy group
or a methoxyethoxy group. Hal is a halogen atom, preferably a chlorine
atcm or a bromine atom. The reaction may be carried out, for example,
in aqueous alcohol at ternperatures of 0C or possibly lower, to room tem-
perature.
Compounds of formula I wherein n + p = 1 can also be obtained
by reacting a compound of formula XI with a compound of formula XII. In
these foxmulae q has the value 1, 4 or 5, R8 is an oxygen atom or a
sulphur atom, M' is an alkali metal atom, R'7 is a methyl group, a propyl
group or a methoxy ethyl group, and Hal is a halogen atom, preferably a
chlorine atom or a bromine atom. The reaction may be carried out in a
polar aprotic solYent, for example hexamethylphosphortriamide, at a
temperature between 0C and room temperature. In all formulae the symbols
not described haye the same meaning as in formula I.
The invention will be described in greater detail with refe-
rence to the ensuing specific examples
1) 5-Methoxy-4'-nitrovalerophenone 0-(2-aminoethyl) oxime hydrochloride.
5.35 Mmol (1.27 g) of 5-methoxy-4'-nitrovalerophenone (melting point
64.5-65.5C), 5.35 mmol (0.80 g) of 2-aminooxyethylamine dihydrochloride
and 0.34 ml of pyridine were refluxed for 2 hours in 5 ml of absolute
ethanol. After evaporating the reaction mixtuxe to dryness in vacuo, 25 ml
of water and 10 ml of 2N sodium hydroxide solution were added and extrac-
ted with 25 and 10 ml, respectively, of methylene chloride. The extracts
were dried over sodium sulphate and then evaporated to dryness in
3Q ~acuo. Toluene was added anothex two ti~es to the resulting base which
was evaporated in vacuo. The residue was dissolved in absolute ethanol
and an equi~olar quantity of alcoholic hydrochloric acid was added. After
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1~77964
the addition of diethyl ether, the title compound crystallized. Melting
point 121.5-122.5C.
2) 6-Methoxy-4'-nitrohexanophenone 0-(2-aminoethyl)oxime hydrochloride.
135 Mmol (33.7g) of 6-methoxy-4'-nitrohexanophenone (melting point 50C),
135 mmol (20.1g) of 2-aminooxyethylamine dihydrochloride and 100 ml of pyri-
dine were refluxed for 5 hours in 300 ml of absolute ethanol. The reaction
mixture was evaporated to dryness in vacuo and the residue, after having been
dissolved in 200 ml of water, was washed twice with lOOml of petroleum ether
40-60. The aqueous solution was rendered alkaline Wit}l 200 ml of 2N sodium
hydroxide solution and then extracted four times with 100 ml of ether. The
combined ether extracts were washed with 100 ml of waterJ dried on sodium
sulphate and then evaporated to dryness in vacuo. The resulting oil, after
the addition of toluene, was evaporated to dryness in vacuo another three
times and then dissolved in absolute ethanol. After the addition of an equiv-
alent quantity of alcoholic hydrochloric acid it was evaporated to dryness in
vacuo again. The residue was crystallized from alcohol/ether. The resulting
`; crystals were recrystallized twice from acetonitrile and alcohol/ether,
respectively. Meltlng point 92-93C.
3) 3'-Methyl-4'-nitrovalerophenone 0-(2-aminoethyl)oxime fumarate (1 : 1).
20 5.7 Mmol of 3'-methyl-4'-nitrovalerophenone, 5.7 mmol of 2-aminooxyethylamine
dihydrochloride and 0.9 ml of pyridine were refluxed for three hours in 15 ml
of absolute ethanol. The base was isolated from the reaction mixture as de-
scribed in example 2. It was dissolved in an equimolar quantity of ethanolic
-fumaric acid. Melting point after recrystallization from ethanol 152.5-154
O
4) 3'-Chloro-5-methoxy-4'-nitrovalerophenone 0-(2-aminoethyl)oxime fumarate
.' (1: 1).
In the same manner as described in example 3, the title compound was obtained
from 3'-chloro-5-methoxy-4'-nitrovalerophenone (melting point 54.5-56C) and
2-aminooxyethylamine dihydrochloride. After crystallization from ethanol the
melting point was 148-148.5C.
5) 4'-Nitrovalerophenone-0-(2-aminopropyl)oxime hydrochloride.
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In the same manner as described in Example 2 the title compound was obtained
from 4'-nitrovalerophenone (boiling point at 0.03 mm: 128-132C) and 2-
aminooxy-l-methylethylamine dihydrochloride. The melting point after recrys-
tallization from acetonitrile/ether was 148-149C.
6) 4'-Nitro-2-propoxyacetophenone 0-(2-aminopropyl)oxime fumarate ~1 : 1).
In the same manner as described in Example 3 the title compound was obtained
from 4'-nitro-2-propoxyacetophenone (melting point 49-50C) and 2-aminooxy-1-
methylethylamine dihydrochloride. The melting point after recrystallization
from ethanol was 141-142 C.
7) 3'-Chloro-5-methoxy-4'-nitrovalerophenone 0-(2-aminopropyl)oxime fumarate
(1: 1).
In the same manner as described in Example 3 the title compound was obtained
from 3'-chloro-5-methoxy-4'-nitrovalerophenone (melting point 54.5-56C) and
2-aminooxy-1-methylethylamine dihydrochloride. After crystallization from
ethanol/acetonitrile the melting point was 140-142C.
8) 4'-Nitrovalerophenone 0-(2-aminoethyl)oxime hydrochloride.
10 Mmol of 4'-nitrovalerophenone 0-(2-tritylaminoethyl)oxime were dissolved
in 50 ml of 90% acetic acid. After standing for three days at room tempera-
ture, this reaction mixture was evaporated to dryness in vacuo after which
the residue was dissolved in 50 ml of ether. The resulting solution was ex-
tracted with 50 ml of 0.2N hydrochloric acid and the extract, after being
rendered alkaline with 10 ml of 2N sodium hydroxide solution, was extracted
with 50 and 25 ml, respectively, of methylene chloride. After drying on sodi-
um sulphate and evaporating in vacuo the resulting base was converted into
the title compound with alcoholic hydrochloric acid. After crystallization
and recrystallization from ethanol/ether the melting point was 107-108 C.
9) 4'-Nitro-2-propoxyacetophenone 0-(2-aminoethyl)oxime hydrochloride.
10 Mmol of 4'-nitro-2-propoxyac0tophenone oxime, 10.4 mmol of 2-chloroethyl
amine hydrochloride and 1.4 g of powdered potassium hydroxide were added to
25 ml of dimethyl formamide while stirring at 10C. Afte-r stirring for two
days at room temperature the dimethyl formamide was evaporated in vacuo, the
residue was brought in water and then 2N hydrochloric acid was added until
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1~77964
pH 3. The remaining oxime was removed by means of ether, after which 30 ml
of 2N sodium hydroxide solution were added. Then three extractions with
ether were carried out. The collected ether layers were washed twice with a
5% sodium bicarbonate solution and then dried on sodium sulphate. After
removing the ether in vacuo the residue was dissolved in absolute ethanol and
-- converted into the title compound by means of alcoholic hydrochloric acid.
After recrystallization from alcohol/ether the melting point was 128-130C.
10) 4'-Nitro-2-propoxyacetophenone 0-~2-aminoethyl)oxime hydrochloride.
a) 2.3 g of ethylene oxide were led into 30 mmol of 4'-nitro-2-propoxyace-
10tophenone oxime in 50 ml of absolute ethanol in which 0.007 g of lithium had
been previously dissolved while stirring and at 45C by means of a flow of
nitrogen, after which stirring at 60C was continued for another hour. After
the addition of 0.6 ml of acetic acid it was evaporated to dryness in vacuo.
The residue was taken up in ether and washed with water. After drying on
sodium sulphate and evaporating the ether a residue was obtained which was
purified by means of a silica gel column using methylene chloride as an
eluent. After evaporation of the solvent the 0-(2-hydroxyethyl)oxime was
obtained as an oil.
b) To a solution of 22 mmol hereof in 120 ml of methylene chloride 4.5 ml of
triethylamine were added while stirring at -5 to -10C, and then 24 mmol ~1.9
iml) of mesyl-chloride were added dropwise in 20 minutes. Stirring was con-
tinued for another 30 minutes at 0C and the reaction mixture was then washed
with water, as sodium bicarbonate solution and a saturated sodium chloride
solution. After drying on sodium sulphate the methylene chloride was evapo-
rated in vacuo. In this manner the 0-(2-mesyloxyethyl)oxime was obtained.
c) A mixture of 26 mmol thereof in 100 ml of methanol which contained 12 g
of ammonia was kept in an autoclave at 80C for 16 hours. After cooling, the
methanol was removed in vacuo. The residue was stirred with 50 ml of 2N sodi-
um hydroxide solution and extracted ~ times with ether. The ether layer was
washed twice with a 5% sodium bicarbonate solution. After drying on sodium
;sulphate and distilling off the other under reduced pressure the resulting
oil was converted into the title compound by means of alcoholic hydrochloric
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acid. After two crystallizations from alcohol/ether the melting point was
128-130C.
11) 5-(2-Methoxyethoxy)-4'-nitrovalerophenone 0-(2-aminoethyl)oxime fumarate
-
(1: 1).
10 M~lol (3.25 g) of 5-(2-methoxyethoxy)-4'-nitrovalerophenone ethylene ketal,
10 mmol ~1.49 g) of 2-aminooxyethylamine dihydrochloride and lO ml of meth-
anol were refluxed for 6 hours. The resulting residue, after evaporating the
methanol, was washed three times with ether after having been dissolved in
water. The aqueous solution was extracted three times with methylene chlo-
ride after previously being rendered alkaline with a sodium hydroxide solu-
tion. The combined extracts were washed with a 5% sodium bicarbonate solu-
tion and then with water. After drying on sodium sulphate and evaporating
the methylene chloride, the free base was obtained, which was converted into
': the title compound by means of an equimolar quantity of fumaric acid. After
crystallization from alcohol the melting point was 134.5-135.5 C.
12) 4'-Nitrovalerophenone 0-(2-aminoethyl)oxime hydrochloride.
4 Mmol (1.23 g) of 4'-aminovalerophenone 0-(2-aminoethyl)oxime dihydrochlo-
ride (melting point 175-177C) were converted into the free base by means of
1 2N sodium hydroxide solution. A solution hereof in 5 ml of methylene chlo-
ride was added dropwise while stirring at 25 to 40C to 12.3 mmol ~2.5 g) of
m-chloroperbenzoic acid (85%) in lO ml of methylene chloride. Stirring at 30
to 35C was then continued for another three hours. The precipitate was
sucked off and washed with methylene chloride. After the addition of 50 ml
of ether to the filtrate and the washing liquid, the mixture was washed three
times with 2N sodium hydroxide solution and finally twice with a 5% sodium
bicarbonate solution. After drying on sodium sulphate and removing the ether
under reduced pressure, the residue was chromatographed over silical gel with
methylene chloride as an eluent. The methylene chloride was distilled off
from the eluate, after which the residue was converted into the title com-
; 30 pound by means of alcoholic hydrochloride acid. After crystallization from
alcohol/ether the melting point was 107-108C.
13) 4'-Nitro-2-propylthioacetophenone 0-(2-aminoethyl)oxime hydrochloride.
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6 Mmol (0.54 g) of propylmercaptan were added while stirring to a solution
of 6 mmol (0.24 g) of sodium hydroxide in 10 ml of 50% alcohol cooled with
ice-water. Stirring was continued for another 10 minutes after which 3 mmol
(1.02 g) of 2-bromo-4'-nitroacetophenone 0-(2-aminoethyl)oxime hydrochloride
(melting point 197C) were added within 30 minutes while stirring at a tem-
perature between 0 and 5C. Stirring was continued for another hour at 5C
and then one hour at room temperature. The reaction mixture was evaporated
in vacuo and the residue was washed with water and dissolved in methylene
chloride. The solution was washed with water and dried over sodium sulphate.
After evaporation, a base was obtained which was converted into the title
compound by means of alcoholic hydrochloric acid. After recrystallization
from acetonitrile/ether the melting point was 122.5-123.5C.
14) 4'-Nitro-2-propoxyacetophenone 0-(2-aminoethyl)oxime hydrochloride.
0.09 g of 55-60% sodium hydride in mineral oil was added to a solution of 2.0
mmol (0.48 g) of 2-hydroxy-4'-nitroacetophenone 0-(2-aminoethyl)oxime (melt-
ing point 97-98C) in 5 ml of hexamethyl phosphoric acid triamide while stir-
ring at room temperature. After 4 minutes, 0.20 ml of propyl bromide was
added while stirring. The reaction mixture was then stirred at room tempera-
ture for another 4 hours, diluted with 50 ml of water and extracted two times
with 25 ml of ether. The combined ether extracts were dried on sodium sul-
phate and evaporated to dryness in vacuo. The residue was chromatographed by
means of ethanol/ammonia 95/5 over 15 g of silica gel. The eluate was evap-
orated to dryness in vacuo and then converted into the title compound by
means of alcoholic hydrochloric acid. After crystallization from alcohol/
ether the melting point was 128-130C.
15) Tablet
50 mg of 4'-nitro-3'-methylvalerophenone 0-(2-aminoethyl)oxime HCl
335 mg of lactose
60 mg of potato starch
25 mg of talc
5 mg of magnesium stearate
5 mg of gelatin.
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16) Suppository
50 mg of 4'-nitrovalerophenone 0-(2-aminopropyl)oxime HCl
1500 mg of suppository mass.
17) Injection liquid
25 g of 3'-chloro-4'-nitro-5-methoxyvalerophenone 0-(2-aminopropyl)oxime HCl
1.80 g of methyl-p-hydroxybenzoate
0.20 g of propyl-p-hydroxybenzoate
9.0 g of sodium chloride
: 4.0 g of poly-~oxyethylene)20 sorbitan monooleate water to 1000 ml.
.j,
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