Note: Descriptions are shown in the official language in which they were submitted.
~s~
:
The present invention relates to novel 2,6-disub-
stituted 2-phenylimino-imidazolidines, their acid addition
salts and processes for their preparation. The novel compounds
possess in~eres~ing physiological activity.
2-Phenylamino-imidazolidines have been regarded with
interest over a long neriod due to their pharmacological
and therapeutic properties. Compounds of this type have
often been described in the literature and have been disclosed,
for example, in Belgian Patents Nos. 623305, 65393~, 6~7656,
lo 687657 and 705944O In these references processes for the
production of the 2-phenylamino-imida~zolidines have also been ;~
described.
As a result of recent examinations, we have found that
conformation is of critical importance among the structural
characteristics of 2-phenyl-imida~olidines required for - -central,~ -adrenergic stimulation. Following investigations
into structure-action it has been found that only those
derivatives in which the phenyl and imidazolidine rings
are in aplanar conformation to one another, possess good
blood-pressure decreasing action.
, ., . , .. . -....
Where the phenyl and imidazolidine rings are in
aplanar conformation free rotation of the phenyl ring - -
around the C-N single bond is hampered and the two rings
remain perpendicular or substantial]y perpendicular to one
another.
-2-
Aplanarity may be achieved with 2-phenylimino-imidazo_
lidines by subs~ituting the ortho-positions of the aromatic :
part of molecule: R
/ H
~N = <~
H :
Bully atoms or groups of atoms in these positions hinder
free rotation of the phenyl ring around the C-N single bond
and~ thus~ reduce the possibility of coplanarity~
The present invention is based upon the discovery
that novel 2-phenylimino-imida~olidines substituted in both
the ortho and ortho~ position and the physiologically
compatible acid addition salts thereof possess interesting
physiological activity and in particular antihypertensive
properties~ ~ :
Thus according to one feature of the present
invention there are provided compounds of the formula~
H
Z-N = ~
H
(wherein Z represents a 2-ethyl-6-methylphenyl, 2~6-difluoro-
phenyl, 2-chloro-6-fluorophenyl, 2,6-dimethoxyphenyl, ~ - -
-3-
)5~
2,6-ditrifluoromethyl-phenyl~ 2-bromo-6-methylphenyl, 2-bromo-6-chloro-
phenyl, 2-chloro-6-trifluoromethylphenyl or 2-fluoro-6-trifluoromethylphenyl
group) and acid addition salts thereof.
According to the present invention there is also provided a
process for preparation of compounds of the formula:
N
Z - N ~ 1
N J
(wherein Z represents a 2-ethyl-6-methylphenyl, 2,6-difluorophenyl, 2-chloro-
6-fluorophenyl,2,6-dimethoxyphenylJ 2,6-ditrifluoromethylphenyl, 2-bromo-6-
methylphenyl, 2-bromo-6-chlorophenyl, 2\-chloro-6-trifluoromethylphenyl or
2-fluoro-6-trifluoromethylphenyl group) and pharmaceutically acceptable
acid addition salts thereof, which comprises reacting a compound of the
formula:-
/x ~
Z - N = C (II)
(wherein Z is as defined above and X and Y, which may be the same or dif-
ferent, each represents a halogen atom, an amino- or an alkylthio group with
1 to 4 carbon atoms or a salt thereof with ethylene diamine or a salt
thereo* and if desired, converting a compound of formula I obtained into a
pharmace~tically acceptable acid addition salt thereof.
The acid addition salts for incorporation in pharmaceutical
compositions are the physiologically compatible acid addition salts. Other
acid addition salts may, however, be useful in the preparation of compounds
of formula I and the physiologically compatible acid addition salts thereof.
As stated above the compounds of formula I and their physiological-
ly compatible acid addition salts thereof possess interesting physiological
properties and in particular blood pressure decEeasing properties. The
compounds of formula I and their physiologically compatible acid addition
salts thereof are thus potentially of lnterest in the treatment of various
forms of hypertonia.
. . . .
~s~
The compounds of the present invention thus include the following:
2-~2-Ethyl-6-me~hylphenylimino)-imidazolidine and physiologically compatible
acid addition salts thereof;
2-(2,6-Difluorophenylimino)-imida~olidine and physiologically compatible
acid addition salts thereof;
2-(2-Chloro-6-fluorophenylimino)-imida~olidine and physiolog-
- 4a -
,
ically compatible acid addition salts thereof;
2-(2~6-Dimethoxyphenylimino~-imida301idine and physiologi- :~
cally compatible acid addition salts thereof; ~-
2-(296~Ditrifluoromethylphenylimino)-imidazolidine and
physiologically compatible acid addition salts thereof;
2-(~-Bromo-6-chlorophenylimino)-imida~olidine and physiologi- .
cally compatible acid addition salts thereof;
2-(2-~romo-6-methylphenylimino)~imidazolidine and physiologi-
cally compatible acid addition salts thereof; .
2-(2-Chloro-6-trifluoromethylphenylimino)-imidazolidine
and physiologically compatible acid addition salts thereof; and
2(2-Fluoro-6-trifluoromethylphenylimi~o)-imida~olidine
and physiologically compatible acid addition salts thereofO
The compounds of the present invention may, for
example, be prepared by one of the following processes (a)
to (j) which processes constitute further features of the
present invention~
a) the reaction of a compound of the formula: .
/X
Z-N=C \ II
Y
: :~
¦wherein ~ is as hereinbefore defined and ~ and Y, which
may be the same or different, each represents an atom or
: - . . .
1, , ,, :.
-5- : ~
.:' . .
'' :' .". :'
, . . .
group removable as an anion), or a salt thereof with ethyl-
ene diamine or a salt thereof and, if desired, converting
a compound of formula I obtained, into an acid addition
salt thereof.
A compound of formula II is preferably used in which
X and Y, which may be the same or di~ferent, each represents
a halogen, atomg preferably a chlorine atom, a sulfhydryl,
hydroxy, amino or nitroamino group or an alkylthio or
alkoxy group with 1 to 4 carbon atoms.
1~ The starting compounds of formula II may, for example,
be the isocyanide dihalides, especially the isocyanide
dichlorides~ thioureas~ 0-alkylureas or their acid addition
salts~ S-alkylthioureas or th~ir acid addition salts,
(the 0-alkylureas and the S-alkylthioureas ha~ing alkyl
groups with 1 to 4 carbon atoms) guanidines (also in the form
sf acid addition salts), carbamic acid esters, thiocarbamic
acid chlorides, alkylthiocarba~ic acid chlorides or nitro-
guanidines. ~ -
The reaction is preferably effected at a temperature
of from 0 to 200 C depending upon the radicals X and Y.
~ . .
The reaction may~ if desired, be effected in the presence of -~
polar protic~ polar aprotic or apolar solvents. Depending -~
upon the radicals X and Y~ the reaction may also, if desired,
be effected in the absence of a solvent at an elevated temp-
.
erature. If one or both radicals ~ and Y represent a
halogen atom, it is advantageous to use an acid-binding
agent for the reac~ion. The reaction time depends upon
the reactivity of the reactants used and varies~from
several minutes to several hours.
b) the reaction of a compo~d of the formula
Z-NH-C=-N III
(wherein Z is as hereinbefore defined) with ethylene
diamine or a salt thereof and if desired converting a
compound of formula I obtained into an acid addition salt
thereof.
The reaction is preferably effected at an elevated
temperature e.gD from 60 to 180 C. It is not necessary
to use a solvent. It is advantageous, however3 to use the `
ethylene diamine or its acid addition salt in excess.
c) the reaction of a compound of the formula: -
Z-NH2 IV ~ `
~wherein Z is as hereinbefore defined~ with a compound of
the formula
y CL ~ V
O O .` ' .
and if desired converting the compound of formula I obtained
into an acid addition salt thereof~
-7- ,
`: .
.
~3~
The reaction is advantageously effected at an ele- .
vated temperature, e.gO of from 80 to 180 C and conven~èntly
in the presence of an apolar, inert solventO
d) the cyclization of a compound of the formula
Z-NH-C~ \ VI
NH-CH2-CH2-NH2
lwherein Z is as hereinbefore defined and W represents an :
oxygen or sulfur atom) and if desired converting the
compound of formula I obtained into an acid addition
salt thereof. ~ -
The cyclization is preferably effected at a temp- .
erature of from 120 to 160 CO However, no solvents need ~ -~
to be usedO
e) the deacylation of a compound of the formula:
-
N
Z-N ~ VIIa
N - : -:
Acyl
~wherein Z is as hereinbefore defined and Acyl represents
an aliphatic acyl group) and if desired converting the :~
compound of formula I obtained into an acid addition salt
thereof O ' ': "
The compound of formula VIIa is preferably first
prepared by reacting a compound of the formula~
,.......
A 8
:, :
; .:
~ . ,, . ; . ~ . . :: . .
2 IV
(wherein Z is as her0inbefore defined3 with a compound of
the formula:-
~_ , .
R" - N
\ VIIb
N
Acyl
(wherein Rl~ represents an atom or group removable as an
anion and Acyl represents an aliphatic acyl group) whereby
a compound of formula VIIa is obtained.
A compound of formula VIIb is preferably used in which
R~ represen~s a nucleophilically exchangeable group, for
example a halogen atom~ preferably chlorine, or a methylthio,
methoxy or hydroxy group.
~here Rl' represents a hydroxy group, it is advantageous - ;~
if R"lrepresents an acyl group, e.gO an acetyl group. The
reaction between an aniline of formula IV and a l-acylimi- :
da~olidin-2-one is conveniently effected at a moderate
temperature e.g. approximately 50 C. Advantageously~ the
reaction lasts from several hours to daysO In order to e~fect ~ ~-
deacylation of the compounds of formula VIIa and/or YIIb
these compounds are subjected to hydrolysis. The deacylation
is preferably effected in the presence of a lower alcohol,
E.g. methanol~ the l-acyl compounds are advantageously refluxed.
6~
f) the reaction of a compound of the formula:
2 IV
(wherein Z is as hereinbefore defined) with a compound of
the formula:
/ N ~
R~ VIIc
N
H
(wherein R~' represents an atom or group removable as an -
anion) and if desired converting the compound of formula I
obtained into an acid addition salt thereof.
The reaction of anilines of formula IV with 2-methyl-
1~ thioimidazolidines-(2~ or 2-chloroimidazolidines-(2) is preferably
effected at an elevated temperature te.g. 100 to 180C). No
solvents are required~ but they may be used if desired.
Polar protic and polar aprotic solvents are advantageously
used where it is desired to use a solvent.
g) the reaction of a carbodiimide of formula
Z-~=G=~Z VIII
j (wherein Z is as hereinbefore defined) with ethylene
diamine or a salt thereof3 and if desired con~erting a
compound of formula I obtained into an acid addition salt
thereof.
The reaction is preferably effected in the presence
of an inert solvent~ such as ben3ene~ conveniently at room
--10-- '
'~
temperature and advantageously after distilling off the
solvent at an elevated temperature of e.g. approximately
10~ to 220C.
h) for the preparation of compounds of the invention
(wherein Z represents a 2,6-difluorophenyl, 2-chloro-6-
fluorophenyl, 2-bromo-6-methylphenyl, 2-bromo-6-chlorophenyl~
2-chloro-6-~rifluoromethyl or 2-fluoro-6-trifluoromethylphenyl
group) which process comprises reacting a compound of the
formula:
2 ~1
R1
,
(wherein R1 represents a fluorine, chlorine, or bromine atom
or a methyl or trifluoromethyl group) by methods known per se
whereby a compound of formula I as hereinbefore defined is
obtained and if desired converting the said compound of
formula I into an acid addition salt thereof.
A compound of formula I~ is preferably used in which
R1 represents a fluorine~ chlorine, or bromine atom or a
methyl group. The reaction is preferably effected according
to the Sand~eyer reaction. Thus the reaction may, for
example be effected by dia~otisation and halogenation of the
diazonium compound thus foImed.
" ' ; ' I
~, .. . .
3~:~
i) for the preparation of compounds of the invention
(wherein Z represents a 2,6-difluorophenyl group)
the reaction of a compound of the formula~
/ 2 H
N ~ ~ IXa
H :.
,. NH2
by methods known per se whereby a compound of formula I
(wherein Z represents a 2,6-difluorophenyl group) is obtained
.l and if desired converting the compound of formula I thus
obtained into an acid addition salt thereof. Similarly
the reaction is preferably effected according to the -
` 10 Sandmeyer reaction thus the compound of formula IXa is
diazotised and the diazonium compound thus formed is
: fluorinated. : :
,, .
i i~ for the preparation of compounds of the invention
;l (wherein Z represents a 2,6-dihydroxyphenyl group), the ~ -~
;~ ether clea~age of a compound of the form~lla~
/ OR2 H
H : ::
(wherein R2 and R2l~ which may be the same or different, each ~:
represents an alkyl group with 1 to 4 carbon atoms3 and if
.~ , . . .
-12-
' ..
''' ''"
.. ,, , , .. ~
3~
desired converting the compound of formula I thus obtained
into an acid addition salt thereof.
The ether cleavage is con~eniently effected in
the presence of concentrated hydrobromic acid preferably
at an elevated temperature. The ether cleavage may also
- be effected by the use of a Lewis acid according to methods
known ~ se~ as known from the literature.
The novel 2g6-disubstituted anilines of formula IV
used as starting products may, for example, be produced~
according to one of the following reaction schemes:
Reaction Scheme 1:
B~tv1 Lithiu~ / ~ L
R~ L ¦ -60 to -70 C
'`,: ;' .
~ R ~ 2 L~ ~
COOH ~ ¦ or R
R' ~ ~ C
Rl - Z-NH2 IV
., ~.
'
-13-
.
:~- . ' ' ' , . .: . .
~56~
Reaction Scheme 2:
2 ~ ~--N2
COOH C
NH
1~ ~
~ ,
2 ~N2
C NH :
2 t
; ,,
. .
R
~N2
R ' - .
: ' :' .:
R -:
2-NH2 -- ~ NH2
IV) R 7 ~ ;
'..,: '
, - .....
~, . . .
.
.. . . .
~.~3~
When sy~thetic route 1 is employed the desired benzoic acid as well as the
isomers thereof are obtained~ The desired isomer may, for example, be
separated by column chromatography (silica gel).
The synthesis of 2,6-ditrifluoromethylphenyl lithium, an inter-
mediate step in the production of 2,6-ditrifluoromethylaniline has been
describedg for example, by Go Hallas et al in J. Soc. Dyers and Colourists~
1970~ 86 200.
The intermediates or starting products of the individual processes
are derived from the anilines of formula IV thus produced and may, for ~- -
lQ example, be obtained according to methods known from the literature. For -~
example, the carbodiimides of formula VIII or the isocyanide dichlorides
of formula II may be produced from the anilines of formula IV as follows;-
l. + H~O~H / Cl
Z-NH ~ > Z-N=C~
2 2. + S2Cl2/SC12 \ Cl
IV
+ Z-NH2 . HCl
> Z-N~-Z
VIII
The 2-phenyl-iminoimidazolidines of formula I according to the
invention may, if desired, be converted into their physiologically compat-
bile acid addition salts in the conventional manner. Acids suitable for
salt formation include, for example, hydrochloric acid, hydrobromic acid,
hydriodic acid~ hydrofluoric acid, sulfuric acid, phosphoric acid, nitric
acid~ acetic acid~ propionic acid~ butyric acid, capronic acid~ valeric
acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid,
lac~ic acid, tartaric acid, citric acid, malic acid~ benzoic acid, p-hydroxy-
benzoic acid, E-aminobenzoic acid7 phthalic acid, cinnamic acid, salicyclic
acid~ ascorbic acid, methane-sulfonic acid, ethanephosphoric acid and 8-
chlorotheophylline.
--15--
. .
~ ~3~
According to a yet still -further feature of the present invention
there are provided pharmaceutical compositiGns comprising as active ingred-
ient at least one compound of formula I as hereinbefore defined or a phy-
siologically compatible salt thereof in association with a pharmaceutical
carrier or excipient.
The compositions according to the invention may be presented, for
example, in a form suitable for oral, parenteral or rectal administrationO
The compounds according to the invention may be presented in the
conventional pharmacological forms of administration, such as tablets,
coated tablets~ pills solutions~ suspensions~ emulsions, powders~ capsules~ -
tinctures, injection solutions or sustained release forms~ Conventional
pharmaceutical excipients as well as the usual methods of production may
be employed for the preparation of these forms~ Tablets may be produced,
for example, by mixing the active ingredient or ingredients with known
excipients, such as for example with diluents, such as calcium carbonate,
calcium phosphate or lactose, disintegrants such as corn starch or alginic
acid, binders such as starch or gelatin, lubricants such as magnesium
stearate or talcum, and/or agents for obtaining sustained release, such as
carboxypolymethylene, carboxymethyl cellulose, cellulose cellulose phthalate
or polyvinylacetate~
The tablets may if desired consist of several layers. Coated
tablets may be produced by coating cores~ obtained in a similar manner to
the tablets~ with agents commonly used for tablets coatings for example ~ -
polyvinyl pyrrolidone or shellac, gum arabic, talcum, titanium dioxide or
sugar. In order to obtain sustained release or to avoid imcompatibilities
the core may also consist of several layers. The tablet-coat may also
consist of several layers in order to obtain sustained release~ in which
case the excipients mentioned above in relation to tablets may be used.
Syrups of the active ingredient according to the invention or combinations
~16_
5~
of active ingredients may additionally contain a sweetener~ such as saccharin
cyclamate7 glycerin or sugar, and/or taste improving agents such as flavour-
ings, e~g. vanillin or orange extract~ They may also contain suspension
agents or thickeners, such as sodium carboxymethyl cellulose, wetting agents,
such as for example condensation products of fatty alcohols with ethylene
oxide, or preservatives, such as ~_hydrox~benzoates~
Injection solutions may, for example, be produced in the conven-
tional manner, such as by the addition of preservatives~ such as ~-hydroxy-
benzoates, or stabilizers, such as Complexons, e.g. ethylenediamine tetra -
acetic acid. The solutions are then filled into injection vials or
ampoules.
Capsules containing one or several active ingredients may be
produced for example by mixing the active ingredients with inert carriers,
such as lactose or sorbitol, and filling the mixture into gelatin
capsules.
Suitable suppositories may, for example~ be produced by mixing
the active ingredient or active ingredient coml~inations with the conventional
carriers envisaged for this purpose, such as neutral fats or polyethylene-
glycol or derivatives thereo~.
Advantageously~ the compositions may be formulated as dosage
units3 each unit being adapted to supply a fixed dose of active ingredient~
Tablets, coated tablets, capsules~ suppositories and ampoules are examples
of suitable dosage unit forms~ Each dosage unit preferably contains 0.1 to
80 mg. especially 0.5 to 30 mg of the said active ingredient.
According to a still further feature of the present invention
there is provided a method of treating a patient to reduce blood pressure
which method comprises administering to the patient an effective amount of
a pha~maceutical composition as hereinbefore defined
The following examples lllustrate the preparation of compounds
- 17 ~
~3~ ~ ~a~
according to the invention, and also pharmaceutical compositions containing
such compounds as active ingredients:
Production Examples
.. ~. ~.
322 g (o.96 mol) of N_(2-ethyl-6-methylphenyl)-S-methylisothiouronium
hydriodide are heated while stirring with 96 ml of ethylene diamine in an
oil bath at 150C for 20 minutes. Excess ethylene diamine is then evap-
orated in vacuo. The viscous residue is taken up in a little methanol and
the crude base precipitated by the simultaneous addition of 5G% potassium
hydroxide solution and water~ This latter step is effected while ice- ~
cooling. When the aqueous phase has been decanted off~ the oily base is ~ -
dissolved in chloroform, the chloroform solution is dried over anhydrous
magnesium sulfate and evaporated in vacuoO
The residue is dissolved in dilute hydrochloric acid and the
solution thus obtained extracted with ether in fractions at various pH-
values (addition of dilute sodium hydroxide ~olution~. The thin-layer
chromatographically pure fractions are combined and evaporated in vacuo
... .... . .
to dryness. For further purification the product is chromatographed on
Al203 (chloroform is used as the eluant3. 3204 g of highly pure imidazoline
base of mOp. 134 to 136C (corresponding ko 1606% of theory~ are obtained.
Exam~le 2
~ ' .
5.8 g of the thiourea prepared from 2,6-difluoroaniline (literature: J0 of
~edicinal Chemistry 11/4, 814(1968~ (m.p. 148 149 C) are heated in 30 ml
of absolute methanol together with 208 ml of methyl iodide at reflux
tamperature ~or 3 hoursO The N~~2~6-difluorophenyl~ methyl-isothio-
uronium hydriodide of m.p7 150 C resulting therefrom ~quantitative yield)
is heated with 301 ml of ethylene diamine (150%) to 155 - 160 C on an oil
-18-
' . ''
. : .: ' ', , , . ......... , ............. , . . ~
. ,, . , . :, . ., . :
bath while stirring. During this process methyl mercaptan and ammonia escape
from the reaction mixture as gases. After 15 minutes, the reaction product
is taken up in 20 cc of methanol and purified with activated charcoal. After
filtration the clear3 light yellow solution is made aIkaline with 50% pota-
ssium hydroxide solution and the separated solid imidazoline base filtered
off with suction. After washing with water and drying, 1.3 g ~corresponding
to 21.4% of ~heory3 of thin-layer chromatographically pure base of mOp.
169 to l70C are obtained. The hydrochloride of 2~(2,6-difluorophenylimino)-
imidazolidine melts at 248 to 250C~ This product is whi~e in colour and
readily dissolves in water and alcohols.
~ ' .
_ ~chloro 6-fluor~ehenylimino)-imida olidine
The 2-chloro-6-fluoro-aniline hydrochloride of m.p. 179-180 C produced
according to reaction scheme 1 is reacted with ammonium rhodanide in chloro-
benzene to give N-(2-chloro-6-fluorophenyl)-thiourea (m.p. 135 C) which is
further reacted with methyl iodide to give N-2-chloro-6-fluorophenyl)-S-
methyl isothiouronium hydriodideO 13.2 g of 1the isothiouronium hyd~iodide
are hea~ed with 3.8 ml of ethylene diamine (15~) on an oil bath to 150 to
160 G for 15 minutes while stirring The clear, homogeneous melt is dis-
solved after cooling~ in approximately 30 ml of methanol and the solution
purified wit~ activated charcoal. The imidazoline base is then precipitated
with 50% potassium hydroxide solution (ice cooling), filtered off with suc- ~`
tion, washed with water and dried.
Yield: 1.8 g corresponding to 22~2~ of theory.
Melting Point 139 - 142 C
The hydrochloride produced in the conventional way melts at 260 to
262 C. ~he substance is thin-layer chromatographically pure.
6 ~
.: . ... . :. ~ . . . . , . . ~ .
. .
~ia~
1.77 g of N-(2,6-dimethoxyphenyl)-S-methyl isothiouronium hydriodide of
m.p. 193-195 C are refluxed together with 0.5 ml of ethylene diamine in
10 ml of n-butanol for 1 hour. 0.5 g of 2-(2,6-dimethoxyphenylimino)-imid-
azolidine hydriodide of m.p. 207 to 208 C are obtainedO This product is
difficultly soluble in water, but readily soluble in ethanol and dimethyl-
sulfoxide.
Production of the imida~olidine base:
105 g of the hydriodide obtained above are dissolved in 75 ml of water and
the imida~olidine base is liberated with 5 N sodium hydroxide solution.
This product initially remains dissolved and only separates out in solid
form after salting with common salt. The product is taken up in chloro-
form~ the chloroform phase is separated out, dried over anhydrous magnesium
sulfate and evaporated in vacuo to give a small volume~ After addition of
absolute ether the base crystalli7es out.
Yield: 0.5 g, m.p. 155 to 157 C.
Example 6
n ~ dazolidine
1.25 g (0O004 mol) of N-(2g6-di-trifluoromethylphenyl)-isocyanide dichlor-
ide [prepared from 1,3-di-~trifluoromethyl)-ben~ene via 2g6-di-(trifluoro-
methyl)-benzoic acid (m.p. 136 ~ 138 C), 2,6-di-~trifluoromethyl)-ben~amide
(m.p. 200 - 202 C)~ 2~6-di-~trifluoromethyl)-aniline and 2,6-di-(trifluor-
omethyl)- formanilide (m.pO 179 - 181 C)~ are reacted with 2.7 g of ethy-
lene diamine in 15 ml of aosolute ether at 10 C, while stirring. After
complete addition of the isocyanide dichloride the temperature of the
reaction mixture is allowed to rise to room temperature and stirring is
continued for 30 more minutes. The reaction mixture is evaporated to dry-
ness in vacuo and the residue dissolved in dilute hydrochloric acid.
Purification is effected by adding ether to the acid mixture and separating
out the ether phase at a pH-value of approximately 5.5. The ether separ-
-20- ~
.,.' :
,.. , . . . , : ::
: .,; . . . . .
~3~
ation is carried out twice. The aqueous imidazolidine hydrochloride sol-
ution is made aIkaline by the simultaneous addition of 5 N sodium hydroxida
solution and petroleum etherO The product crystallizes out. After filter-
ing off with suction3 washing with a little water and petroleum ether and
drying the crude imidazolidine base is obtained of m.p. t70 to 174C.
Yield: 360 mg corresponding to 30.2% o-f theoryO
In order to purify the crude base it is chromatographed over sil-
ica gel. A mixture of methanol: acetone: chloroform = 6 : 3 : 15 serves
as the eluant. In this manner~ substantially pure 2-~2,6-di-trifluoro-
methylphenylimino~-imida~olidine of m.p. 177 - 178 C is obtained.
2-(2-bromo-6-m_thyl~ nyllmino)-imidazolidine
The 2 bromo-6-methylaniline synthesized according to reaction scheme 2 is
reacted via the N-(~-bromo-6-methylphenyl)-thiourea (m.p. 166 to 168 C)
to gi~e N~ bromo-6-methyl-phenyl)-S-methyl isothiouronium hydriodide,
of which 1704 g (0.045 mol~ are refluxed together with 405 ml of ethylene
diamine in 50 ml of ethyleneglycol monomethylether for 10 hoursO The
reac~ion mixture is then evaporated to dryness in vacuo and the semi-solid
residue ~issolved in methanol. After treatment with activated charcoal -
the methanolic solution is made alkaline with 50% potassium hydroxide
solution. The precipitated imidazolidine base is filtered off with suc-
tionO For further purification the product is dissolved in dilute hydro-
chloric acid and the hydrochloric acid solution ethered out several timesa
The mixture is then extracted with ether in fractions at various pH-values.
The fractions which are substantially thin~layer chromatographically pure
are combined, and after drying evaporated over anhydrous magnesium sulfate~
The remaining residue is stirred with a little absolute ether following -~
which the title product crystaIlizes out.
Yield: 2.6 m.p. 140 - 145C.
-21-
.,: . . . . . .... . . . ..
Conversion into a purer form of the base is effected by column chromato-
graphy on silica gel with methanolo acetone: chloroform = 6 : 3 : 15 as
the eluant. The melting point of the compound thus purified is now 142 to
14~~
Example 8
2-(2-Bromo-6-chloro-phenyliminol-imidazolidine hydrochloride
2-bromo-6-chloroaniline was synthesized from 3-chloro-2~nitrobenzoic acid
according to reaction scheme 2 via the following steps:
3-chloro-2-nitro-benzoylchloride, m.p. 62 - 64 C; 3-chloro-2-nitro-benza-
mide of m.pO 200 - 203 C; 3-chloro-2-nitroaniline of mOp. 60 to 65 C; 3-
chloro-2~nitro-bromobenzene and reduction to the anilineO
2-bromo-6-chloro-aniline is reacted via N-(2--bromo-6-chloro-phenyl)-thiourea
(mup. 148 - 153 C)~by means of methyl iodide to give N-(2-bromo-6-chloro-
phenyl)-S-methylisothiouronium hydriodide, of which 8.3 g (00021 mol) are
reflu~ed with 20l ml of ethylene diamine in 20 ml of n-butanol, while
stirring for 16 hours. ~he reaction mixture is allowed to cool and a
precipitate separates out. This precipitate is fil~ered off with suction
and the mother liquor evaporated to dryness in vacuo. The oil remaining
as residue is dissolved in dilute hydrochloric acid and the hydrochloric
acid solution extracted with etherO The ether extracts are discardedO
The aqueous phase is then extracted in fractions with ether at various pH-
va]uesu The thin-layer chromatographically pure fractions are combined
.
and after drying over anhydrous magnesium sulfate evaporated ~LX~Q-
After dissolving the residue in ether, the hydrochloride is precipitated
. . .
with ethereal hydrochloric acid, filtered off with suction and dried.
Yield: 1.5 g, m.p. 297 - 300 C.
.
9 g of N-(2-chloro-6~trifluoromethylphenyl)-isocyanide di-chloride [prepared
-22-
s~
from 3-chloro-benzotrifluoride according to the above-described reaction
scheme 1 via the steps:
2-chloro-6-trifluoromethyl~benzoic acid (m.p. 120 - 123 C), 2-chloro-6-
trifluoromethyl-aniline (oily) and 2-chloro-6-trifluoromethyl-formanilide
~m.p. 167 - 170C)~ are reacted with 21.6 ml of ethylene diamine (10-fold
excess~ at 10C, while stirring in 100 cc of absolute etherO After a
reaction time of 30 minutes, the reaction mixture is evaporated to dryness
in vacuo and the remaining oil is dissolved in dilute hydrochloric acidO
After two extractions with ether, the aqueous phase is separated out and
treated with activated charcoal. The product is then extracted with ether
in fractions at increasing pH-values (making alkaline with sodium hydroxide
so]ution)O The thin-layer chromatigraphically pure ether fractions are
combined, dried and in order to precipitate the imidazolidine hydrochloride
mixed with ethereal hydrochloric acid until a congo acid reaction is obtain-
edO
Yield of pure 2-~2 chloro-6-trifluoromethylphenylimino)-imidazolidine hydro-
chloride: 3.2 g corresponding to 32.9% of theory. M.p. 277 to 279 C. The
whlte~ crystalline substance dissolves in water and lower alcohols.
Example 10
As described in E;xample 9 the above identified compound is prepared accord-
ing to reaction route 1 via the intermediates 2-fluoro-6-trifluoromethyl
benzoic acid (mOp. 81 - 84 C)~ 2-fluoro-6-trifluoromethyl aniline (oil~,
2~fluoro-6-trifluoromethyl formanilide (m.p. 116 -118 C) and reaction of the
isocyanide dichloride resultin~ therefrom with ethylene diamine
Yield 44.9 % of theory, m.p. 262 to 264 C.
Pharmaceutical_ompositions Examples
Example A: Tablets
.
2-~2,6-di-trifluoromethyl-phenyl-imino)-
-23-
imidazoline 15 mg
corn starch loO mg
? .. .
sec. calcium phosphate 250 mg
magnesium stearate 5 mg
total430 mg
Production
.
The individual components are thoroughly mixed and the mixture granulated
in the usual way. The granulate is pressed into tablets each weighing 430
mg and each comprising 15 mg of active ingredient.
Example B: Gelatin Capsules
Éach capsule consists of 2-(2~6-di-trifluoromethylphenyl-imino)-
imidazolidine 25 mg
corn starch 175 mg
total200 mg -
Production:
.
The components of the capsule are thoroughly mixed and 200 mg-portions of
the mixture are filled into gelatin capsules of suitable size~ Each capsule
:
contains 25 mg of active ingredientO
: :
The solution contains the following components:
2-~2~6-di-trifluoromethyl-phenylimino)-
imidazoline 105 parts ;
sodium salt of the ethylenediamine
tetra acetic acid 0.2 parts
distilled waterad 100.0 parts
Produc~ion:
The active ingredient and the sodium salt of ethylenediamine tetra acetic
acid are dissolved in sufficient water and the solution is then made up
with water to the desired volumeO The solution is filtered free of sus-
-~4-
pended particles and filled into 2 ml ampoules under aseptic conditionsO
The ampoules are then sterilized and sealed. Each ampoule contains 20 mg
of active ingredient.
