2-[3,4-DISUBSTITUTED-PHENYLIMINO]-IMIDAZOLIDINES

2-[PHENYLIMINO DISUBSTITUE EN 3,4] IMIDAZOLIDINES

English Abstract

ABSTRACT
Novel 2- [3,4-disubstituted-phenylimino] -imidazolidines
This invention related to 2- [ 3,4-disubstituted-phenyli-
mino ] -imidazolidine compounds of general formula (I)
<IMG> I
[ wherein Z represents a phenyl group substituted in one
of the 3- and 4- positions by a fluorine atom and in the
remaining 3- or 4- position by a chlorine atom or a
methyl, nitro or amino group] and acid addition salts
thereof, their preparation and pharmaceutical compositions
containing such compounds or salts. In that the compounds
of general formula (I) and their acid addition salts
possess presynaptic and .alpha.-adrenergic activity they are
suitable for use in the treatment of migraine.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing 2-[3,4-disubstituted-phenylimino]-imida-
zolidine compounds of general formula (I)
<IMG> I
[wherein Z represents a phenyl group substituted in one of the 3- and 4-
positions by a fluorine atom and in the remaining 3- or 4- position by a
chlorine atom or a methyl, nitro or amino group] and pharmaceutically accept-
able acid addition salts thereof, which process comprises:
(a) reacting ethylene diamine with a compound of formula (II)
<IMG> II
[wherein Z is as defined above and X and Y, which may be the same or different,
each represents a halogen atom or a hydrothio, hydroxy, amino or nitroamino
group or an alkylthio or alkoxy group containing 1 to 4 carbon atoms];
(b) reacting an aniline of formula (III)
Z -NH2 III
[wherein Z is defined above] with a compound of formula (IV)
<IMG> IV
[wherein R1 represents a group susceptible to nucleophilic exchange and R2
represents a hydrogen atom or an aliphatic acyl group] and, when R2 represents
other than a hydrogen atom, subsequently splitting off the acyl group hydro-
13

lytically; or
(c) for the preparation of 2-[4-fluoro-3-aminophenylamino]-imida-
zolidine, reducing 2-[4-fluoro-3-nitrophenylimino]-imidazolidine and, if
required, converting a compound of formula I into a pharmaceutically accept-
able acid addition salt.
2. A process as claimed in claim 1, wherein process (a) is used and
the compound (II) is an isocyanide dihalide, thiourea, carbaminic acid ester,
thiocarbaminic acid chloride, guanidine (or acid addition salt thereof) or
nitroguanidine or an O-alkylurea (or acid addition salt thereof), S- alkyl-
thiourea (or acid addition salt thereof) or alkyl thiocarbaminic acid chloride
in which the said alkyl groups contain 1 to 4 carbon atoms.
3. A process as claimed in claim 2, wherein the compound (II) is an
isocyanide dichloride.
4. A process as claimed in claim 1 when process (a) is used, 2 or 3
wherein the reaction is effected at a temperature between 0 and 200°C.
5. A process as claimed in claim 1 when process (a) is used, 2 or 3
wherein a compound of formula (II) is used in which X and Y both represent
halogen atoms and the reaction is effected in the presence of an acid binding
agent.
6. A process as claimed in claim 1, wherein process (b) is used and
in the compound of formula (IV) R1 represents a halogen atom or a methylthio,
methoxy or hydroxyl group.
7 A process as claimed in claim 6, wherein in the compound of formula
(IV) R1 represents a chlorine atom.
8. A process as claimed in claim 6, wherein in the compound of formula
14

(IV) R1 represents a hydroxyl group and R2 represents an aliphatic acyl group.
9. A process as claimed in claim 8, wherein the reaction is effected
in the presence of phosphorous oxychloride at a temperature of 50 to 100°C.
10. A process as claimed in claim 1 when process (b) is used, 6 or 7
wherein a compound of formula (IV) is used in which R2 represents an acetyl
group.
11. A process as claimed in claim 1 when process (b) is used, in the
compound of formula IV R2 represents an aliphatic acyl group and subsequent
deacylation is effected by refluxing with a lower alcohol.
12. A process as claimed in claim 11, wherein the said lower alcohol
is methanol.
13. A process as claimed in claim 1, wherein process (c) is used and
the reduction is carried out by hydrogenation in the presence of a metal
catalyst.
14. A process as claimed in claim 13, wherein the said metal catalyst
comprises palladium, platinum or Raney-nickel.
15. A compound of formula I as defined in claim 1 when prepared by a
process according to claim 1 or an obvious chemical equivalent thereof.
16. A process according to claim 1 wherein Z is a phenyl group sub-
stituted in the 3-position by a fluorine atom and in the 4-position by a
methyl group.
17. A process for preparing 2-[3-fluoro-4-methylphenylimino]-imida-
zolidine which comprises reacting N-(3-fluoro-4-methylphenyl)-5-methyl-thio-
uronium iodide with ethylene diamine.

18. 2-[3-Fluoro-4-methylphenylimino]-imidazolidine when prepared by a
process according to claim 17 or an obvious chemical equivalent thereof.
19. A process according to claim 1 wherein Z is a phenyl group sub-
stituted in the 3-position by a methyl group and in the 4-position by a
fluorine atom.
20. A process for preparing 2-[4-fluoro-3-methylphenylimino]-imida-
zolidine which comprises reacting N-(4-fluoro-3-methylphenyl)-S-methylthio-
uronium iodide with ethylene diamine.
21. 2-[4-Fluoro-3-methylphenylimino]-imidazolidine when prepared by
a process according to claim 20 or an obvious chemical equivalent thereof.
22. A process according to claim 1 wherein Z is a phenyl group sub-
stituted in the 3-position by a nitro group and in the 4-position by a
fluorine atom.
23. A process for preparing 2-[4-fluoro-3-nitrophenylimino]-imida-
zolidine which comprises deacetylating 1-acetyl-2-(4-fluoro-3-nitrophenyl-
imino]-imidazolidine.
24. A process according to claim 23 wherein the 1-acetyl-2-(4-
fluoro-3-nitrophenylimino)-imidazolidine is obtained by reacting 4-fluoro-
3-nitro-aniline with 1-acetyl-imidazolidin-2-one to obtain 1-acetyl-(4-
fluoro-3-nitrophenyl-imino)imidazolidine and subsequently deacetylating
to obtain the required compound.
25. 2-[4-Fluoro-3-nitrophenylimino]-imidazolidine when prepared by a
process according to claim 23 or 24 or by an obvious chemical equivalent
thereof.
16

26. A process according to claim 1 wherein Z is a phenyl group sub-
stituted in the 3-position by a chlorine atom and in the 4-position by a
fluorine atom.
27. A process for preparing 2-[4-fluoro-3-chlorophenylimino]-imida-
zolidine which comprises reacting N-(3-chloro-4-fluorophenyl)-5-methylthio-
uronium iodide with ethylene diamine.
28. 2-[4-Fluoro-3-chlorophenylimino]-imidazolidine when prepared by a
process according to claim 27 or an obvious chemical equivalent thereof.
29. A process according to claim 1 wherein Z is a phenyl group sub-
stituted in the 3-position by an amino group and in the 4-position by a
fluorine atom.
30. A process for preparing 2-[4-fluoro-3-aminophenylimino]-imida-
zolidine which comprises reducing 2-(4-fluoro-3-nitrophenylimino)-imidazol-
idine.
31. A process according to claim 1 wherein the reduction is carried
out by hydrogenation in the presence of a Raney-nickel catalyst.
32, A process according to claim 30 wherein the 2-[4-fluoro-3-nitro-
phenylimino]-imidazolidine is obtained by a process according to claim 22.
33. 2-[4-Fluoro-3-aminophenylimino]-imidazolidine when prepared by a
process according to claim 30 or 31 or an obvious chemical equivalent thereof.
17

Description

NOVEL 2-~3,4-DISUBSTITUTED-PHENYLIMINO~ IDAZOLIDINES
This invention relates to noYel 2-[3,4-disubstituted-
phenylimino~-imidazolidine compounds and their acid
addition salts, their preparation and pharmaceutical
compositions thereof.
As a result of their pharmacological and therapeutic
properties, 2-phenylimino-imida701idines have long been
of interest. Conse~uently, compounds of this type have
frequently been described in the literature and have
been disclosed in, for example, Belgian Patent Specifi-
cations Nos.623 305,653 933, 687 656, 687 657 and 705
944. In these references the essential processes for
the production of 2-phenylimino-imidazolidines have also
been described.
Previously the major interest has been in the 2-[2,6-
disubstituted-phenylimino]- imidazolidines and their
action upon the central nervous system.
However, it has now been found that a number of 2-[3,4-
disubstituted - phenylimln~-imida~olidines surprisingly
effect practically no central stimulation , instead
predominantly effecting a peripheral pre-synaptic
~-adrenergic stimulation.
According to one aspect of the present invention we
therefore provide 2- E 3,4-disubstituted-phenylimino]-imi-
dazolidine compounds of general formu]a (I)
H
/~ - ,
Z -N ~
N
H
[wherein Z represents a phenyl grou~ substituted in one
of the 3- and 4- positions by a Eluorine atom and in the
,. ..
,, ~; ...
~:,
~ ' : " .
~,''

26~
remaining 3- or 4- position by a chlorine atom or a methyl, nitro or amino
group and acid addition salts thereof.
According to a further aspect of the present invention there are
provided processes for the preparation of compounds of general formula (I)
(as hereinbefore defined) which comprise reacting ethylene diamine with a
compound of formula Il:
/x
Z N _ C II
\Y
[wherein Z is as hereinbefore defined and X and Y, which may be the same or
diEferent, each represents a halogen atom or a hydrothio, hydroxy, amino or
nitroamino group or an alkylthio or alkoxy group containing 1 to 4 carbon
atoms], or
~b) reacting an aniline of formula (III)
Z - NH2 III
Lwherein Z is as hereinbefore defined] with a compound of formula (IV)
:
;
:`, N
:~ R ~ IV
f.' ~,~ R2
[wherein Rl represents a group susceptible to nucleophilic exchange and R2
represents a hydrogen atom or an aliphatic acyl group~ and, when R2 represents :~
.
:; ~ other than a hydrogen atom, subsequently splitting off the acyl group hydro-
lytically; and
- 2 -
~ ~,
,. . .
,. . .
' :' `' , '

(c) ~for the preparation of 2-I~-fluoro-3-aminophenylimino]-imida-
zolidine hydrogenating 2-14-fluoro-3-nitro phenylimino]-imidazolidine.
Compounds of formula ~II) used in process ~a) according to the
invention are preferably isocyanide dihalides ~more preerably the dichlorides),thioureas, carbaminic acid esters, thiocarbaminic acid chlorides, guanidines
(or acid addition salts thereof) or nitroguanidines or 0-alkylureas (or acid
addition salts thereof), S-alkyl thioureas (or acid addition salts thereof) or
alkyl thiocarbaminic acid chlorides in which the said alkyl groups contain
1 to 4 carbon atoms.
The reaction (a) is conveniently effected at temperatures between
0 and 200C, the precise temperature depending upon the groups X and Y. Polar
protic, polar aprotic and non-polar solvents may be used. Depending upon
groups X and Y, the reaction may also be effected at an elevated temperature
without a solvent. Where one or both of groups X and Y represents a halogen
atom, it is recommended to use an acid-binding agent for the reaction. The
~ .
; reaction time is determined by the reactivity of the reagents used and ranges
from several minutes to several hours.
In process (b) according to the invention, a compound of formula
,,
~;~ (IV) is preferably used in which the nucleophilically exchangeable group re-
presented by Rl is a halogen atom ~more preferably a chlorine atom) or a methyl-; ~
thio, methoxy or hydroxyl group. When R' is a hydroxyl group the compound of
formul IV may be present in the tautomeric keto-form.
- In the case where R represents a hydroxyl group, R is advant-
ageously an acyl group such as, for example, an acetyl group. The reaction
~: taking place in this case between an aniline of formula (III~ and an 1-
acylimidazolidin-2-one is appropriately effected in the presence of phosphorus
oxychloride at a temperature of from 50 to
_ 3 -
" ~ , . :
.. , : ~

100C. The reaction lasts advantageously ~rom several
hours to several days~ In order to produce compounds
of formula (I~, hydrolytic deacylation is required, which
may be achieved by, for example, refluxiny with lower
alcohols such as, for exa~ple, methanol.
The reaction of anilines of formula (III) with 2-methylt-
hioimidazol-2-ines or 2-chloroimidazol-2-ines re~uires
the use of elevated temperatures (100 to 180C). Solvents,
though not required, may,if desired, be used. Preferable
as solvents are those of polar protic or polar aprotic
character.
The reduction of process (c~ above may be effected by
hydrogenation in the presence of finely dispersed metal
catalysts such as, for example, palladium, platinum,
Raney-nickel at normal or excess pressure or by means of
"nascent" hydrogen, for example produced by hydrazine in
the presence of Raney-nickel.
:~ .
The starting products of the processes (a) and (b) above
can all be derived from anilines of fo~mula (III) and,
as such, are readily accessible followin~ methods des-
cribed in the literature.
.
The 2-phenyl-iminoimidazolidines of formula (I) according
to theinvention may be converted into their physiologi-
cally acceptable acid addition salts in a conventional
manner. Acids suitable for salt formation are, for
example, hydrochloric acid, hydrobromic acid, hydriodic
acid, hydrofluoric acid, sulfuric acid, phosphoric acid,
nitric acid, acetic acid, propionic acid, butyric acid,
caproic acid, valeric acid, oxalic acid, malonic acid,
succinic acid, maleic acid, fumaric acid, lactic acid,
tartaric acid, citric acid, malic acid, benzoic acid,

-
_-hydroxybenzoic acid, p-amino~enzoic acid, phthalic acid,
cinnamic acid, salicylic acid, ascorbic acid, methane-
sulfonic acid, ethanephosphonic acid and 8-chlorotheo-
phylline.
I-t should be noted that acid addition salts of compounds
of general formula (I) (as hereinbefore defined) other
than those classified as physiologically acceptable may
be useful in the preparation of compounds of general
formula (I~ and the physiologically acceptible acid
addition salts thereof.
The novel compounds as well as their acid addition salts
possess valuable therapeutic properties. In pharmacolog-
ical examinations of rats and cats it was found that they
effect a pre-synaptic stimulation of the peripheral
~ --adreno~receptors and thus exert a peripheral neuros-
ympathic and ~vagal transmission inhibition. As there
are practically no central activities, an influence on
blood pressure is not observed. The novel compounds may
be used, for example, for the treatment of migraine.
Preferred compounds of general formula (I) by virtue of
~heirespecially favourable pharmacological properties
are the following:
2- [3-fluoro-4-methylphenylimino] -imidazolidine,
2- [4-fluoro-3-methylphenylimino] -imidazolidine,
2- [4-fluoro 3-chlorophenylimino] -imidazolidine,
2 ¦4-fluoro--3~nitrophenylimino ] -imidazolidine and
2- [4-fluoro-3-aminophenylimino ] -imidazolidine and
acid addition salts of the aforesaid compounds.
According to a still further aspect of the present inven-
tion we therefore provide pharmaceutical compositions
comprising at least one compound of formula (I) (as here-
inbefore defined) or a physiologically acceptable acid

6~
--6--
addition salt thereof as active ingredient in association
with a pharmaceutical carrier or excipient.
The compounds of genQral formula (I) and the physiologi-
cally accepta~le acid addition salts thereof may be used
either enterally or else parenterally. Pharmaceutical
compositions in dosage unit form, for example for oral
administration, conveniently contain from 0.5 -to 50 mg,
preferably from 1 to lO mg, of the active ingredient acc-
ording -to the invention.
The compounds of formula (I) and their physiologically
acceptable acid addition salts may also be used together
with other physiologically active substances. Suitable
forms for pharmaceutical preparations are, for example,
tablets (including coated tablets), capsules, supposit-
ories, solutions, aerosol sprays or powders; together
with conventional adjuvants, excipients, carriers,
disintergrants or lùbricants or substances for obtain-
ing sustained release.
The following Examples serve to illustrate the invention
without restricting its scope.
xample l
2-(3~Fluoro-4-methylphenylimino)-imidazolidine
14.33 g (o.043 mol) of N-(3- luoro-4-methylphenyl)-S-methyl-
thiouronium-iodide are refluxed together with 4.35 ml
(~150%) of ethylenediamine in 58 ml of methanol for 8 hours
while stirring. The solvent is then distilled off in vacuo
and the residue is dissolved in 1 N hydrochloric acid. The
hydrochloric acid solution is buffered to pH 7 with 5N KOH
and extracted twice with ether (the ether extracts being
abandoned) and subsequently made alkaline with 50~ potas-
sium hydro~ide solution. This causes the precipitation
of an oil, which crystallizes within a short time. After
vacuum filtration, the residue, the title compound, is washed
:: ;
'~ :
,

~%~
with water a~d dried.
Yield: 6.1 g = 73.41% o theory
Melting point: 109.5 - 110.5 C
Rf: 0.1 system: benzene 50, dioxan 40, ethanol 5, conc.
NH~O~ 5
Carrier: silicagel G ~ luminous pigmen-t,made visihle by:
UV and potassium iodoplatinate
Elemental analysis:
C H F ~l
Calcn 62.16 6.26 9.8321.75 %
~ound: 62.44 ~.44 9.8422.04 %
Example 2
2-(4-Fluoro-3-methylphen~limino1-imi~azolidine
. .
46 g (0.141 mol~ of N-(4-fluoro-3-methylphenyl?-S-methylth-
iouronium iodiae are refluxed together with 14.1 ml
(~150%) of ethylenediamine in 190 ml of methanol for 5
hours while stirring. The solvent is then distilled off
in vacuo and the residue is dissolved in lN hydrochloric
acid. The hydrochloric acid solution is buffered to pH 7
with 5N KOH and extracted twice with ether (the ether
extracts being abandoned1. ~fter admixing with active
charcoal and subsequent filtration, the filtrate is made
alkaline with 50% KOX. At first, the base precipiates
as an oil, then, after covering with petroleum-ether at
at a temperature of from 40 to 80C and with vigourous
stirring it crystallizes. After vacuum filtration the
residue, the title compound, is washed with water and
dried.
Yield: 9.4 g = 34.50% of theory
Melting point: 113-114 C
Rf: 0.3 system: benzene 50, dioxan 40, ethanol 5, conc.
NH40H 5
Carrier: silicagel G ~ luminous pigment, made visible by
UV and potassium iodoplatinate.
.. . .

~2~
Elemental Analysis:
C H F N
Calc: 62.16 6.26 9.83 21.75 %
Found 62.04 6.13 9.85 21.78 %
_xample 3
2-(4-Fluoro-3-nitrophenylimino~-imidazolidine
A mixture consis~ing of 16.6 g (0.1 mol) of 4-fluoro-3-nitroaniline
and 12.54 g (0.11 mol) of l-acetyl-imidazolidin-~-one in 145 ml of phosphorus
oxychloride are heated for 70 hours at 50 degr. C while stirring. The excess
of phosphorus oxychloride is then removed by distillation in vacuo. The
residue is treated with ice/water until complete solution. The solution is
made alkaline with 4N NaOH while cooling with ice and then extracted four
.- times with ethylacetate. The organic layer is dried over anhydrous sodium
sulfate and evaporated. The crude material is recrystallized from toluene to
~ ,;~, ,
yield 23.1 g (88.1 % of theory) 1-acetyl-(4-fluor-3-nitrophenyl-imino)-imida-
zolidine having a melting point of 150 to 151 degr. C.
, .
4.5 g (0.0173 mol) of 1-acetyl-2-(4-fluoro-3-nitrophenylimino)-
imidazolidine, m.p. 150 - 151C, are refluxed for lO hours in 66 ml of methanol
while stirring. After cooling, the insoluble remnant is filtered off, the
- 20 solvent is distilled off in vacuo and the residue remaining is dissolved in 1
N hydrochloric acid. The hydrochloric acid solution is extracted at rising
pH-values (made alkaline by the stepwise addition of 2 N sodium hydroxide
solution) with ether, fractionated from pH 8.5, precipitated and vacuum fil-
tered. The solid fractions, the title compound, are united and dried.
Yicld: 1.7 g = 43.81% of theory
Melting point: 146 - 147C
Rf: 0.4 system: benzene 50, dioxan 40, ethanol 5, conc.
NH4OH 5. Carrier: silicagel G + luminous pigment,
- 8 -
.," -, . . .
.. ,: : . . .; .
: , . , . . ~ . . ,, :

~2~
Detector: W; potassium iodoplatinate.
Elemental Analysis:
C H F N
Calc.: 48.21 4.05 8.48 24.99 %
Found: 47.55 4.02 8.71 24.41 %
Example 4
2-(4-Fluoro-3-chloroph nylimino)-imidazolidine
,~` 20.8 g ~0.06 mol~ of N-(3-chloro~4-fluorophenyl)-S-methyl-thio-
`~ uronium iodide are refluxed together with 6 ml (nv150%) of ethylenediamine
~ ~ ,
~ ' 10 in 82 ml of methanol for 4 hours, while
s~,
~:~
~,~, ,",~
. :~
; .
.~ .
- 8a -
, :, - :-'
..

~2~
g
stirring. The solvent is then distilled off in vacuo
and the residue dissolved in 1 N hydrochloric acid. The
hydrochloric acid solution is extracted twice with ether
(the ether phases being abandoned1 and subsequently made
alkaline with 50% KOH~ This results in the precipitation
of an oil, which crystallizes within a short time. After
vacuum filtration the residue, the title compound, is
washed with water and dried.
Yield: 7.2 g = 56.17% of theory
Melting point: 118.5 - 119.5 C
Rf: 0.5, system: benzene 50, dioxan 40, ethanol 5, conc.
NH40H 5
Carrier: silicagel G + luminous pigment
Detector: UV, potassium iodoplatinate
Elemental Analysis:
C H Cl F N
Calc.: 50.59 4.2516.60 8.89 19~67 %
Found: 49.80 4.6416.57 ~.25 19.42 %
Example 5
2-(4-Fluoro-3-aminophenylimino)-imidazolidine
~ . .
5.5 g (0.0225 mol) of 2-(4-fluoro-3-nitrophenylimino)-
imidaæolidine are dissolved in 40 ml of methanol and
hydrogenated under normal pressure over Raney-nickel until
the theoretical uptake of h~ydrogen is reached. Then the
Raney-nickel is removed by vacuum filtration over active
charcoal and the filtrate is evaporated in vacuo. For
purification the residue is eluted in fractions over a
400 g silicagel column. (Mixture of eluents: ethylacetate
7, isopropanol 3, conc. NH~OH 1). The thin-layer chromato-
graphically uniform fractions are united and evaporated
in vacuo up to constant weight. The remaining thick oil
is dissolved in a little methanol and admixed with etheric
hydrochloric acid to form the acid salt of the title
compound. Subsequently, it is precipated with ether and
:

--10--
the precipitated salt is vacuum filtered, washed with
ether and dried.
Yield: 3.7 g = 61.56% of theory
Melting point: 222 C
Rf: 0.08; system: benzene 50, dioxan 40, ethanol 5,
conc. NH40H 5.
Carrier: silicagel G ~ luminous pigment,
Detectox: UV, potassium iodoplatinate
Elemental Analysis:
C H Cl F N
Calc.: 40.46 ~.90 26.55 7.11 20.57 %
Found: 39.53 5.18 26.26 6.5S 20.37
~ :;
: ~
,
,,

Example 6: Tablets
Active ingredient according to the invention 5 mg
corn starch 160 mg
sec. calcium phosphate 250 mg
magnesium stearate 5 mg
total 420 mg
Production:
The individual components are admixed intensely and the
mixture is granulated in the conventional manner and sub-
.
sequently pressed to form tablets,each o F which weighs
420 mg and contains S mg of the active ingredient accor-
ding to the invention.
Example 7: Gelatin Capsules
The content of each capsule is as follows:
Active ingredient according to the invention 3 mg
corn starch 172 mg
total 175 mg
Production:
__ .
The components are admixed intensely and portions of 175
mg of the mixture are filled into gelatin capsules of
suitable size. Each capsule thus contains 3 mg of the
active ingredient according to the invention.
Example 8: Inje_tible Soultion
The solution is produced of the following components:
Active ingredient according to capsule is as follows:
the invention l.0 part by weight
sodium salt o~ ethylene-
dia~ine tetra-acetic acid 0.2 parts by weight
distilled water ad l000.0 parts by weight
. ,
.

-12-
Production:
The active ingredient according to the invention and the
sodium salt of ethylene-diamine tetra-acetic acid are
dissolved in sufficient distilled water and made up with
distilled water to the desired volume. The solution is
filtered free from suspended particles and 2 ml fractions
are filled into ampoules under aseptic conditions. ~ubs-
equently the ampoules are sterilized and sealed. Each
ampoule thus contains 2 mg of the active substance.
Exam~le 9: Drops
L
Active ingredient according to the invention 0.20 g
methyl p-hydroxybenzoate 0.07 g
propyl ~-hydroxybenzoate 0.03 g
demineralized water ad lO0 ml
The active ingredient according to the invention and the
methyl p-hydroxybenzoate and propyl p-hydroxybenzoate are
dissolved in sufficient demineralized water and made up
with demineralized water to the desired volume.