Note: Descriptions are shown in the official language in which they were submitted.
104851Z
Detailed Description
The present invention relates to l-(imidazol-l-yl)-
2-[4-(4-chlorophenyl)phenoxy]-4,4-dimethylpentan-3-one and
its salts, to a process for their preparation and to their
antimicrobial ùse.
It ~s known that some N-tritylimidazoles exhibit
an antimycotic effect; see e.g., Belgian Patent Specification
No. 720,801. Antimycotically active imidazolyl-(l)-ether-
ketones have also already been disclosed; see e.g., German
Offenlegungsschrift 2,105,490 and Belgian Patent No. 804,092.
However, these compounds are not always satisfactory particu-
larly when administered orally at very low doses. Furthermore
their antimycotic spectrum is not very broad.
The present invention provides an imidazol-l-yl-
ether-ketone of the formula:
; Cl~ O-fH-CO-C(CH3)3
fH2 (I)
.. ~
a~d to its pharmaceutically acceptable s~lts.
` The compounds of the invention exhibit powerful
antimycotic effects.
The compounds of the invention may be prepared by
reactin~ a compound of the formula:
,
,, ' .
1~4~S~2
C~- I -CO-c(cH3)3 (Il)
OH
with imidazole in the presence of a dehydrating agent, and,
optionally converting the resulting base into a salt. The
interconversion o~ ~he compound of Formula I and its salts is
accomplished by convent~onal techniques.
. Surprisingly, the imidazol-l-yl-ether-ketone accord-
ing to the invention, and its salts, exhibit a substantially
greater antimycotic effect, particularly on oral administra-
tion, and also on parenteral administration and local applica- :
tion, than known antimycotic imidazole derivatives and known
and comm~rcially available products such as, for example,
griseofulvin, tolnaftate and nystatin.
l-Hydroxy-2-[4-(4-chlorophenyl)pheno~y]-4,4-dimethyl-
.. . .
pentan-3-one and imidazole are employed as starting materials
and the course of the reaction can be represented by the follow-
ing eq~ation: .
- .'
~ ~ ~ O-cu-co-c(cH3)3
''' ' CH ,
1H
. . .
-~2 > ~ ~ - O-CH-CO-c(cH3)3
, CH2
,. I
. ~ .
. . .
-- 2 --
. .
;.. - . ~ ,,.
~a~48512
The above hydroxy derivative of Formula II has
not previously been disclosed but can be prepared according
to known processes. For example, it is obtained when 4-(4-
chlorophenyl)phenol and a compound of the formula:
Hal-CH2-C0-C(C~3)3 (III)
in which Hal is a halogen atom, are condensed to give 1-[4-
(4-chlorophenyl)phenoxy1-3,3-dimethylbutan-2-one which is
reacted in accordance with conventional techniques, in the
presence of alkali, for example of aqueous sodium hydroxide
solution, with formaldehyde or form ldehyde donors, for exam-
.
ple a 40% strength aqueous formaldehyde solution, in an inertorganic solvent, such as ethanol, at an elevated temperature,
for example at the boiling point of the reaction mixture.
In the reaction leading to the free base of the
present illvention, diluents ean be used. These include all
inert higher-boiling water-immiscible organic solvents, pre-
ferably aliphatic and aromatic hydrocarbons which boil from
approximately 50C upwards, such as ligroin, benzene and
toluene. The reaction is carried out in the presence of a
dehydrating agent, such as calcined calcium carbonate or dry
sodium sulphate, or using a water separator. The reaction
temperature can be varied within a substantial range but in
general is carried out at from about 50C to about 180C,
preferably from 80C to 140C.
In carrying out thP process according to the in-
vention, preferably about l to about 5, especially l to 1.5,
mols of imida20le and about 0.5 to about 20, especially l to
- 3 -
.
10485~:Z
S, mols of the dehydrating agent are employed per mol of
the compound of Formula II.
The free base of Formula I can be isolated in
accordance with customary methods. For e~xample, the solvent
can be removed by distillation in vacuo, the residue taken up
w~th methylene chloride and the organic phase separated. After
drying as over sodium sulphate, the solvent is removed by dis-
tillation in vacuo. The resulting residue is purified by re-
crystallization one or more times. One can also prepare the
salt after the first distillation of solvent and purify the
salt by recrystallization. The compound of Formula I, in the
form of the free base, can then be libera~ed from the salt
through trea~ment with a base.
The preferred salts of the imidazol-l-yl-ether-
.
ketone of Formula I are those of physiologically tolerable
acids. Examples of such acids are the hydrogen halide acids,
.especially hydrochloric ac~d, phosphorus acids, sulphuric
1 . ~
acit, nitric acid, monofunctional and bifunctional carboxylic
scids and hydroxycarboxylic acids such as, for example, acetic
acid, maleic acid, succinic acid, fumaric acid, tartaric acid,
Ioltric acid, salicylic acidD sorbic acid ant lactic acid, and
l~S-naphthalenedisulphonic acid.
The new compound of Formula I and its salts exhibit
very powerful ant~microbial effects. They display a broad
8pectrumiof action, for example against dermatophytes and
yeasts and also against biphase fungi and moulds, as well as
against staphylococci and trichomonades, and can thus be
;, . .
; - 4
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. .
- ~4851'~
successfully employed in combatting fungal infections in man
and animals, such as dermatomycoses and systemic mycoses caused
by Trichophyton mentagrophytes and other species of Tr~chophY-
ton, species of Microsp~ron, EpidermophYton floccosum, blasto-
mycetes and biphase fungi as well as moulds
The compounds of the present invention are administered
parenterally or orally in any of the usual pharmaceutical forms.
These include solid and liquid oral unit dosage forms such as
tablets, capsules~ powders, suspensions, solutions, sy,~ps and
the like, including sustained release preparations, and fluid
in~ecta~le forms such as sterile solutions and suspensions;
The term unit dosage form as used in this specificatlon and the
claims refer to physically discrete units to be administered in
single or multiple dosage to animals, each unit containing a
predetermined quantity of active material in association with
i the required diluent, carrier or vehicle. The quantity of
active material is that calculated to produce the desired thera-
J peutic effect upon administration of one or more of such units.
Powders are prepared by comminuting the compound to
a suitable fine size and mixing with a similarly comminuted
diluent pharmaceutical carrier such as an edible carbohydrate
material as for example, starch. Sweetening, flavoring, pre-
servative, dispersing and coloring agents can also be present.
;i Capsules are mad~ by preparing a powder mixture as
described above and filling formed gelatin sheaths. A lubricant
such as talc, magnesLum stearate and calcium stearate can be
:,
~ .
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` 1~)48S12
added to the powder mixture as an adjuvant before the filling
operat~on; a glidant such as colloidal silica may be added to
improve flow properties; a disintegrating or solubilizing agent
may be added to impro~e the availability of the medlcament when
the capsule is ingested.
- Tablets are made by preparing a powder mixture,
granulating or slugging, adding a lubricant and disintegrant
and pressing into tablets. A powder mixture is prepared by
mixing the compound, suitably comminuted, sith a diluent or
base such as starch, sucrose, kaolin, dicalcium phosphate and
the like. The powder mixture can be granulated by wetting
with a binder such as syrup, starch paste, acacia mucilage or
solutions of cellulosic or polymeric materials and forcing
through a screen. As an alternative to granulating, the powder
mixture can be run through the tablet machine and the resulting
imperfectly formed slugs braken into granules. The granules
can be lubricated to prevent sticking to the tablet forming
dies by means of the addition of stearic acid, a stearate salt,
'
talc or mineral oil. The lubricated mix~ re is then compressed
into tablets. The medicaments can also be combined with free
flowing inert carriers and compressed into tablets directly
without going through the granulating or slugging steps. A
protective coating consisting of a sealing coat of shellac, a
coa~ing of sugar or polymeric material and a polish coating of
wax can be provided. Dyestuffs can be added to these coat~lgs
to distinguish different unit dosages.
~ - 6 - .
1~)4851Z
Oral fluids such as syrups and elixirs can be prepared
in unit dosage form so that a glven quantity, e.g., a teaspoon-
ful, contains a predetermined amount of the compound. Syrups
can be prepared by dissolving the compound in a suitably flavored
aqueous sucrose solution while elixirs are prepared through the
use o a non-toxic alcoholic vehicle. Suspensions can be form~-
lated by dispersing the compound in a non-toxic vehicle in which
it is insoluble.
Fluid unit dosage forms for parenteral administration
can be prepared by suspending or dissolving a measured amount
of the compound in a non-toxic liquid vehicle suitable for
injection such as an aqueous or oleaginous medium and steriliz-
ing the suspension or solution. Alternatively a measured amount
of the compound is placed in a vial and the vial and its con-
tents are sterilized and sealed. An accompanying vial or
vehicle can be provided for mixing prior to administration
In general it has proved advantageous to administer
amounts of fro~ about 10 mg to about 300, preferably from
50 to 20~, mg/kg of body weight per day to achieve effective
results. Nevertheless, it is at times necessary to deviate
from these dosage ra~es, and in particular to do so as a
;', '
function of the nature and body weight of the human or animal
sub~ect being treated, the individual's response, the formu-
lation, the stage of the disease, and the interval at which
it is administered. Thus in some cases, it suffices to use
less than the above-mentioned minimum dosage while in other
. :
_ 7 _
lV48SlZ
cases the upper limit must be exceeded to achieve the desired
results. Where lar~er amounts are administered it is often
desirable to divide these into several indi.vidual administra-
tions over the course of the day.
The microbiological activity of the active com-
pounds usable according to the invention can be conveniently
observed in vitro and in vivo models. As will be seen from
; these data, the compounds are well-tolerated and very effect- ;
ive antimycotics having a broad spectrum of action on oral,
parenteral and local administration. They are superior to
clotrimazol, miconazol and all other azole derivatives by
virtue of their effectiveness at very low doses on oral ad-
ministration, superior to griseofulvin, tolnaftate, nystatin
; and pimaricin by virtue of their very mNch broader spectrum
of action, and superior to amphotericin B by virtue of their
substantially lower toxicity.
1.) in vitro activity.
The preparations according to the invention show a
broad activity, in vitro, against fungi which are pathogenic
to humans and animals, Gram positive bacteria and tricho-
monades. The table which follows lists MIC values of the
preparations in comparison with representative species of
fungi, Staph. aureus and Trichomonas va~inalis
The activity was tested in the series dilution test
on Sabouraud's milieu d'epreuve, meat broth-glucose, bouillon,
Fr-ncis blood agar and Kimmig malt extract-peptone medium.
.
. . .
~48Sl~
The incubation temperatures were 28 and 37C and the
incubation time wa~ 24, 48 and 96 hours. The inoculum wasr
~n every case S x 103 germs/ml of substrate. The results
are summarized in Table A and compared with two commercially
available preparations while the effects of some previously
known imidazol-l-yl-ether derivatives are shown in Table B.
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The antimyoo~ic type of effect is primarily fungi-
static; a fungicidal a~tion, with a reduction of the inoculum
by more than 99%, is achievable with 2 to 4 times th~ m~nlmum
inhibitory concentrations in vitro and in vivo.
Development of resistance o~ initially sensitive germs
could not be found by the passage method and by the Szibalsky
technique. This makes it possible to state that development
of resistance, if it occurs at all, takes place slowly and
... .
in accordance with the multiple-step schème.
2.) in vivo activitY.
The preparations claimed also have a curative effect
in vivo in the case of dermatophytoses and systemic mycoses
when administered orally or parenterally or applied locally
to the infected test animal,
a) Effect on oral administration.
,
I) on condidosis in mice.
;~ White mice of the CFlSPF strain are infected with
1-3 x 106 Candida albicans cells intravenously by puncture
of the tail vein. Untreated control animals die from the 3rd
to the 6th day after infection as a result of the candidosis
of the organs which develops. If the preparations claimed
are given orally in doses of 2 x 6.25 - 2 x 150 mg/kg of body
weight, starting from the day of infection and up to the 5th
day after infection, the following survival rates are observed:
,. . .
- 13 -
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1~48512
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bO 0 hVO ~C 0
a ~
o m . u~ u~ o o o o
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;~ ~ .... ___
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- 14 - .
1~48512
The previously known imidazol-l-yl-ether deriva-
tives in Table B show, at a dose of SO mg/kg of body weight
to 125 mg/kg of body weight, given twice daily, survival
rates of approximately 75~ to 85Z on the 6th day after in-
fection.
II) On trichophytosis in mice and guinea pigs, caused by
Trich. mentagrophytes and Trich. Quinckean~m:
Mice (CFlSPF) and guinea pigs (Pearl brigh~ white)
are infected on the back with suspensions of spores of Trich.
ment. or Trich. Quinckeanum. In the case of the untreated
control animals, the s~mptoms of a dermatophytosis, typical
of the pathogen, developed within 12 days after infection.
Oral doses of 1 x 25 to 1 x 100 mg/kg of body weight
administered from the 3rd to the 12th day after infection en-
tirely suppress the development of the experimental dermato-
phytoses.
b) ~ffect of local application, on trichophytosis in
, guinea pigs.
White guinea pigs weighing 400-500 g are infected
~ 20 o~ the back with a suspension of spores of Trich. ment. in
`¦ the usual form. For local therapy, the compounds in a 1%
il solution in polyethylene glycol 400 are applied as a thin
layer to the infected area, once daily, from the 4th to the
13th day after ~nfection, a~d rubbed in lightly with a horn
8patula. Table D whi~h foll~ws shows the curative effects of
the preparations in comparison to the untreated control:
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, - 15 -
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1~4851Z
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c) Guideline data on the pharmacok~netic~ after oxal
administration.
The preparations claimed are resorbed well on oral
administration to mice and guinea pigs and after doses of
50 mg/kg of body weight give serwm peak concentrations of
4-6 ~/ml for the case of the hydrochloride.
The elimination half-life is approx. 4.5-5.5 hours;
approx. 20~ of the elimination take~ place renally and ~70%
faecally via the bile.
d) Acute toxicity ~nd toleration.
On oral administration to mice, rats and guinea pig~,
the preparation~ mentioned sh~wed an LD50 of between 750 and
1,200 mg~k~ of body weight. The toleration by skin, on
local application of l~/o 8trength solutions, wa8 excellent.
.. . . . . . .
E~am~le 1
o_Cc~-CO-C(CH3)3
- L ~ x HCl
, . .
i 30.3 g (0 1 mol) of 1-t~-(4-chlorophenyl)phenoxy]
:3,3-dimethylbutan-2-one were suspended in 200 ml of ethanol.
30 ml of 30% strength formalin solution and 3 ml of 10%
! strength sodium hydroxide solution were added. After heat-
ing for 4 hours ~nder reflux, the solvent was distilled off
~n vacuo. The oil wh~ch remained was taken up in 200 ml of
. ~ . . , ~
-1 toluene and, after addltion of 10 g tO-15 mol) of ~midazole
the mixture was heated overnight under reflux. The solvent
.' ' , '. ' .
- 17 - ~
. ~ .
~48S12
was then dis~illed off in vacuo, the residue was taken up
in ether and the solution was repeatedly washe(d with water
The organic phase was dried over sodium sulphate and 30 ml
of hydrochloric acid in ether was ~dded; After distilling
off the ~olvent in vacuo, 100 ml of diethyl e1:her and 50 ml
of ethyl acetate were added. The mixture was stirred until
crystallization ~tar~ed. The crystals were filtered off,
washed with an ether/ethyl acetate mixture and dried.
13.8 g (33% of theory) of 1-(imidazol-1-yl)-2-
¦4-(4-chlorophenyl)phenoxy~-4,4-dimethylpentan-3-one hydro-
chloride of melt~ng point 178-180C are obtained.
ExamPle 2
Cl~o-CH-CO-C ( CH3 j 3
CH2
- . ~
.
The free base oi E~ample 1 was obtained in accordance
with the method described there, by adding the calculated
amount of triethylamine in ethyl acetate to the hydro- -
. . . .
chloride and filtering ofi the triethylamine hydrochloride
which had precipitated, and distilling ofi the solvent in
vacuo. Th~ melting point was 122-124C.
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