Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
The present invention relates -to new triazolylalkanols,
a process for their preparation and their use as antimycotics.
It has already been disclosed that hydroxypropyl-
imidazoles, such as, for example, 2-(4-biphenylyl~ (2,~-
dichlorophenyl)-3-(imidazol-1-yl) 2-propanol, or l-hydroxyethyl-
azole derivatives, such às, for example, 2-(4-chlorophenoxymethyl)-
3,3-dimethyl-1-imidazol-1-yl)-2-butanol or 2-(2-methylphenoxymethyl)
-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-and (imidazol-1-yl)-2-butanol,
exhibit good antimycotic prcperties (compare DE-OS [German
Published Specification] 2,820,489 and DE-OS [German Published
Specification] 3,018,865~. ~owever, the action of these compounds
is not always completely satisfactory, in particular in vivo.
New triaæolylalkanols of ~he general formula
OH
~ ~ - CH2 - C - CH2 - N ¦ (I)
have been found in which R represents alkenyl, alkynyl, phenyl-
alkynyl, which is optionally substituted in the phenyl ring by
one to three identical or different substituents selected from
halogen, alkyl having 1 to 4 carbon atoms, alkoxy and alkylthio
each having 1 to 2 carbon atoms, alkoxyalkyl having 1 to 2 carbon
atoms in each alkyl part and phenyl which is optionally sub-
stituted by halogen and their physiologically tolerated acid
addition salts.
In addition, it has been found that the triazolylalkanols
of the formula (I) are obtained when dihalogenoalkanols of the
formula ~
~3~7
OH
2 ~ 2 (II)
in which R has the above-mentioned meaning and Hal' represents
halogen, are reacted with azoles of the formula
/N-~
M - ~ ¦ ~III)
in which M represents hydrogen or an alkali metal, in the presence
of a diluent and optionally in the presence of an acid binding
agent.
If appropriate, an acid can s~lbsequently be added to the
comp~unds of the formula (I) thus obtained.
The new triazolylalkanols of the formula (I~ exhibit
strong antimycotic properties. Inthis context, the compounds
according to the invention, surprisingly, show a better thera-
peutically useful in vivo eEfectiveness than -the compounds known
from the state of the art 2-(4-biphenylyl)-1-(2,4-dichlorophenyl)-
3-(imidazol-1-yl)-2-propanol; 2-(4-chlorophenoxymethyl)-3,3-
dimethyl.-l-(imidazol-l-yl)-2-butanol and 2-(2-methylphenoxymethyl)-
3,3-dimethyl-1-(1,2,4-triazol-1-yl)- and (imidazol-1-yl)-2-
butanol, which are closely related chemical compounds. The sub-
stances according to the invention thus represent an enrichment
of pharmacy.
In addition, the new triazolylalkanols are interesting
intermediate products. Thus, for example, the compounds of the
general formula (I) can be converted at the hydroxyl yroup in
a customary manner lnto the corresponding ethers. Furthermore,
-- 2
acyl or carbamoyl derivatives of the compounds of the general
formula (I) can be obtained by reaction with, for example, acetyl
halides or carbamoyl halides in a manner which is known in
principle.
The triazolylalkanols according to the invention are
generally defined by the formula (I~. In this formula ~ pre-
ferably represents alkenyl and alkynyl, each having 2 to 6 carbon
atoms, and represents phenylalkynyl, having 2 to 4 carbon atoms
in the alkynyl part, and phenylalkenyl, having 2 to 4 carbon atoms
in the alkenyl part, each is optionally substituted in the phenyl
ring by one to three identical or different substituentsselected from
halogen, alkyl having 1 to 4 carbon aioms, alkoxy and alkylthio
each having 1 to 2 carbon atoms, alkoxyalkyl having 1 to 2 carbon
atoms in each alkyl part and phenyl which is optionally sub-
stituted by halogen. If, for example, 4-chloro-3-chloromethyl-3-
hydroxy~l-phenyl-l butyne and 1,2,4-triazole are used as the
starting materials and potassium carbonate as the acid binding
agent, the course of reaction of the process according to the
invention can be represented by the following equation:
I ~ I K CO
ClCH -C-CH Cl + 2 H-N I 2 3
C
C ~ N -CH2-C-CH2-W
C
~J
The dihalogenoalkanols to be used as starting materials
for the process according to the invention are generally defined
by the formula (II~. In this formula, R preferably represents
those radicals which have already been preferably mentioned Eor
these substituents in connection with the description of the
substances of the formula (I) according to the in~ention. Hal'
preferably represents chlorine.
The dihalogenoalkanols of the formula (II) have not yet
been disclosed; they can be obtained in a generally known manner
by reacting 1,3-dihalogenoacetone, such as, in particular, 1,3-
dichloroa~etone, with an appropriate Grignard reagent (in this
context also compare J.Org.Chem. 27, 2242 (1961) and the pre-
paration examples).
The azoles which are also to be used as starting materials
for the process according to the invention are generally defined
by the formula ~III). In thls formula, M preferably represents
hydrogen, sodium or potassium.
The azoles of the formula (III) are generally ]cnown
compounds in organic chemistry. The alkali metal salts are
obtalned by reaction of imidazole or 1,2,4-triazole with sodium
methylate or potassium methylate or by reaction of imidazole or
1,2,4-trizole with the equivalent amount of corresponding alkali
metal hydride.
Suitable diluents for the process according to the
invention are preferably inert organic solvents. These include
preferably ketones, such as1 in particular, acetone and methyl
ethyl ketone; nitriles, such as, in particular, acetonitrile;
-- 4
l'7
aleohols, such as, in particular, ethanol and isopropanol; ethers,
such as, in particular, tetrahydrofuran or dioxan; formamides,
such as, in partlcular, dimethylformamide; and aromatic and
halogenated hydroearbons.
The proeess according to the inventlon i5 optionally
carried out in the presenee of an aeid binding agent. ~11
eustomarily usable inorganic or organic aeid binders ean be
added, sueh as alkali metal carbonates, for example sodium carbon-
ate and potassium earbonate; or sueh as lower tertiary alkylamines,
eyeloalkylamines or aralkylamines, for example triethylamine,
N,N-dime-thylcyelohexylamine, dieyelohexylamine, N,N-dimethylbenzyl-
amine, also pyridine and diazabicyelooaetane and also an
appropriate exeess of imidazole or triazole.
In carrying out the proeess aeeording to the invention,
the reaetion temperatures ean be varied within a wide range.
In general, the process is earried out between about 20 and about
150C, preferably at 20 to 120C.
In earrying out the proeess aeeording to the invention,
2 to 4 mols of azole of the formula (III) and optionally 2 to 4
2Q mols of acid binder are employed for 1 mol of the dihalogeno-
alkanols of the formula (II~. The isolation of the compounds of
the formula (I) is earried out in a customary manner.
For the preparation of aeid addition salts of the
eompounds of the formula (I), all physiologieally tolera-ted salts
are suitable. These preferably include the hydrogen halide acids,
sueh as, for example, hydrochlorie aeid and hydrobromie aeid, in
partieular
-- 5
.~ ,
~"3~
- 6 -
hydrochlor;c ac;d, ;n addition phosphor;c acid, n;tr;c
acid, sulphuric acid, monobasic and dibasic carboxyl;c
acids and hydroxycarboxylic acids, such as, for example,
acetic acid, maleic acid, succinic ac;d, fumaric acid,
tartar;c acid, citric acid, salicyl;c acid, sorbic acid
and lactic acid and sulphonic acids~ such as, for example,
p-toluenesulphonic acid and 1,5-naphthalenedisulphonic
acid.
The salts of the compounds of the formula (I)
can be obtained in a simple manner by customary methods
of salt formation, for example by dissolving a compound
of the formula ~I) in a suitable inert solvent and adding
the acid, for example, hydrochloric acid, and can be
purified in a known manner, for example~ by filtering
off, isolating and if necessary, washing with an inert
organ;c solvent.
The compounds of the formula (I) and their acid
addition salts which can be used according to the
invention exhibit antimicrobial and, in particular,
strong antimycotic effects. They nave a very wide soec-
trum of antimycotic action, especially against dermato-
phytes and blastomyces as well as biphasic fungi, for
example, against Candida species, such as Candida albi-
cans, Epidermophyton species, such as Epidermophyton floc~
cosum, Aspergillus species, such as Aspergillus niger
and Aspergillus fumigatus~ Trichophyton species, such
as Trichophyton mentagrophytes, M;crosporon species,
such as Microsporon felineum and Torulopsis species,
such as Torulopsis glabrata. The listing of these micro-
organisms does not in any way represent a restriction
of the organisms which can be controlled, but only has
an illustrative character.
Examples which may be mentioned of fields of
;ndicat;on in human medicine are:
Dermatomycoses and system;c mycoses caused by
Trichophyton mentagrophytes and other species of
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Trichophyton, species of Microsporon, Epidermophytonfloccosum, Blastomyces and biphasic fungi as well as
moulds~
Examples which may be mentioned oF field of
indication in veterinary medicine are:
All dermatomycoses and systemic mycoses,
especially those caused by the abovementioned pathogens.
The present invention includes pharmaceutical
formulations which, in addition to non-toxic, inert
pharmaceutically suitable vehicles, contain one or more
active compounds according to the invention, or which
consist of one or more active compounds according to
the invention, as well as processes for the preparation
of these formulations~
The present invention also includes pharma-
ceutical formulations in dosage units. This means that
the formulations are in the form of individual parts,
for example~ tablets, coated tablets, capsules, pills,
suppositories and ampoules, in which the content of
active compound corresponds to a fraction or a multiple
of an ;ndividual dose. The dosage units can contain,
for example, 1, 2, 3 or 4 individuaL doses or 1/2, 1/3
or 1/4 of an individual dose. An individual dose pre~
ferably contains the amount of active compound which is
given in one administration and which usually corres-
ponds to a whole, a half, a third or a quarter of a daily
dose.
By non-toxic, inert pharmaceutically suitable
vehicles there are to be understood sol;d~ semi-solid
or liquid diluents, fillers and formulation auxiliaries
of every kind.
Tablets, coated tablets, capsules, pills, gran-
ules, suppositories, solutions, suspensions and emulsions,
pastes, ointments, gels, creams, lotions, powders and sprays
may be mentioned as preferred pharmaceutical formulations.
Tablets, coated tablets, capsules, pills and
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- 8 -
granules can contain the active compound or compounds
alongside the customary vehicles, such as (a) fillers
and extenders, for example starches, lactose, sucrose~
glucose, mann;tol and sil;ca, (b) binders, for example
carboxymethylcelluLose, alginates, gelatin and polyvinyl-
pyrrolidone, (c) humectants, for example glycerol, (d)
disintegrating agents, for example agar~agar~ calcium
carbonate and sodium bicarbonate, (e) solution retarders,
for example paraffin, and (f) absorption a~ccelerators,
for example quaternary ammonium compounds, (9) wetting
agents~ for example cetyl alcohol and glycerol mono
stearate, (h) adsorbents, for example kaol;n and bento-
nite, and (i) lubricants, for example talc, calcium
stearate and magnesium stearate and solid polyethylene
glycols~ or mixtures of the substances listed under (a)
to (i).
The tablets, coated tablets~ capsules, pills and
granules can be provided with the customary coatings and
shells, optionally containing opacifying agents, and can
ZO also be of such composition that they release the act;ve
compound or compounds only, or preferentially, in a
certain part of the intestinal tract, optionally in a
delayed manner, examples of embedding compositions which
can be used being polymeric substances and waxes~
The active compound or compounds, optic,nally
together with one or more of the abovementioned vehicles,
can also be in a micro encapsulated form.
Suppositories can contain, in addition to the
active compound or compounds, the customary water~
soluble or water-insoluble veh;cles~ for example poly-
ethylene glycols, fats, for example, càcao fat, and
h;gher esters (for example C14-alcohol w;th C16-fatty ac;d),
or mixtures of these substances.
Ointments, pastes, creams and gels can contain,
in addit;on to the act;ve compound or compounds, the
customary vehicles, for example animal and vegetable
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fats, waxes, paraffins~ starches, tragacanth, cellulose
derivat;ves, polyethylene glycols~ s;l;cones, bentonites,
silica, talc and zinc oxide~ or mixtures of these
substances.
Powders and sprays can contain, in addition to
the active compound or compounds, the customary vehicles,
for example lactose, talc, silica, aluminium hydroxide,
calcium silicate and polyamide powders or mixtures of
these substances~ Sprays can additionally contain the
customary propellants, for example chlorofluorohydro-
carbons.
Solutions and emulsions can contain, in addition
to the active compound or compounds, the customary
vehicles, such as solvents, solubilis;ng agents and
emulsifiers, for exampLe ~ater, ethyl alcohol, isopropyl
alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,
benzyl benzoate~ propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils, especially cottonseed oil,
groundnut oil, maize germ oil~ olive oil, caster oil
and sesame oil, glycerol, glycerol-formal, te~rahydro~
furfuryl alcohol, polyethylene glycols and fa~ty acid
esters of sorbitan, or mixtures of these substances.
For parenteraL administration, the solutions
and emulsions can also be in a sterile form which is
isotonic with blood.
Suspensions can contain~ in addition to the
active compound or compounds~ the customary vehicles,
such as liquid diluents~ for example water, ethyl alcohol
or propylene glycolO suspending agents, for example
ethoxylated isostearyl alcohols, polyoxyethylene sorbitol
esters and sorbitan esters, micro-crystalline cellulose,
aluminium metahydroxide, bentonite, agar-agar and traga-
canth, or mixtures of these substances~
The formulation forms mentioned can also contain
colorants, preservati~es and additives which improve the
odour and flavour, for example peppermint oil and
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3~ 7
- 10 -
eucalyptus oil, and sweeteners, for example saccharin.
The therapeutically active compounds should pre-
ferably be present in the abovementioned pharmaceutical
formulations in a concentration of about 0.1 to 99.5,
preferably of about 0.5 to 95~ by weight of the total
mixture.
The abovementioned pharmaceutical formulations
can also contain o~her pharmaceutical active compounds
in add;tion to the active compounds according to the
invention.
The abovementioned pharmaceutical formulations
are prepared in the customary manner according to known
methods, for example by mixing the active compound or
compounds with the vehicle or vehicles.
The present invention also includes the use of
the active compounds according to the invention, and of
pharmaceutical for0ulations which contain one or more
active compounds according to the invention, in human
and veterinary medicine, for the prevention, alleviation
and/or cure of the abovementioned diseases.
The active compounds or the pharmaceutical for-
mulations c3n be administered locally~ crally~ paren-
terally, intraperitoneally and/or rectally, preferably
parenterally, and in particular intravenously~
In general, it has proved advantageous both in
human medicine and in veterinary medicine, to administer
the active compound or compounds according to the
invention in total amounts of about 10 to about 300,
preferably 50 to 200, mg/kg of body weight every 24
hours~ optionally in the form of several individual
administrations, in order to achieve the desired results.
However, it may be necessary to deviate from the
dosages mentioned, and in particular to do so as a
function of the species and the body weight of the sub
ject to be treated, the nature and sPverity of the dis-
ease, the nature of the formulation and of the
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'7
administration of the medicament and the time or ;nter-
val over which the administration takes place. Thus it
can in some cases suffice to manage with less than the
abovementioned amount of active compound, whilst in
S other cases the abovementioned amount of active compound
must be exceeded. The particular optimum dosage required
and the type of administration of the active compounds
can easily be determined by anyone skilled in the art on
the basis of his expert knowledge.
Preparation examples
Example 1
OH /== N
¦ N - CH2 ~ - CH2
~,
22.9 9 (0.1 mol) of 4-chloro-3-chloromethyl-3-
hydroxy-1-phenyl-1-butine are added dropwise to a mixture
15 of 27.6 9 (0.4 mol~ of 1,2,4-triazole and 55.2 9 (OD4
mol) of potassium carbonate in 300 ml of acetor,e. The
reaction mixture is allowed to stand for 12 hours under
reflux. After cooling down, it is filtered. The fil-
trate is evaporated in vacuo and the oily residue is
i~ 20 purified by chromatography (silica gel 60 Merck, chloro-
form). 8 9 (27X of theory) of 3-hydroxy~1~phenyl-4~
(1,2,4-triazol-1-yl) 3-~1,2,4-triazol 1-ylmethyl)-1-
butine of melting point 140C are obtained.
-~-r~
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- 12 -
Pre~aration of the starting ~rod~ct
___ _____ _ ______________ _.______
()I I
C
lCI
A suspension of phenylacetylenylmagnesium bromide in diethyl ether -
prepared from 12 g (0.5 mol) of magnesium, 54.5 ~ (0.5 mol) of ethyl bromide
and 51 g (0.5 mol) of phenylacetylene in 500 ml of diethyl ether - is added
dropwise at -60C to a solution of 63.5 g (0.5 mol) of 1,3-dichloroacetone in
300 ml of diethyl ether. After 2 hours, the reaction mixtuTe is allowed to
warm to 0C and 49.3 g (0.82 mol) of acetic acid are added; further warming to
about 20C taking place. After addition of 200 ml of wa-ter, the ether phase is
separated off, washed with water, d~ied over sodium sulphate and evaporated in
vacuo. 114 g (99% of theory) of 4-chloro-3-chloro-methyl-3-hydroxy-1-phenyl-1-
butine, of refractive index nD = 1.5S75, are obtained.
In a corresponding manner and according to the process according to
the invention, the following compounds of the general formula (I) are obtained
OH
N==~ I
R (I)
````:
- 13 -
Table 1
Example Melting point (C) or
No. Cl A B nD0
2 ~ C - C- N N 126
3 Cl ~ C _ C- N N 164
4 Cl ~ C _ C- N N 128
~ C -3 C N N 1.5985
6 ~ CH = CH- N N 65
The following intermediate products of the general formula (IIa~
are obtained according to Example 1:
OH
~ (IIa)
Table 2
Example
No. R Physical constants
Cl
II-2 ~ C _ C- viscous oil
II-3Cl ~ C ~ C- nD =1.5744
II-4 Cl ~ C -- C- nD =1.5818
:t:[-5 ~ C -- C- viscous oil
- ~3;~ .7
- 14 -
Use examples
In the following example, the compounds mentioned
below are employed as comparison experiments:
(A~ Cl ~ CH2-C-CH2-N
(~) r,_ ~ ~-CH2-C-CH2-N J
C(CH3)3
( C ) ~o - C H 2 - C - C H 2 - N~
C ( C H 3 ( 3
(D) ~ -C~-CH2-0~CH2~N ¦
. C(CH3)3
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'7
Example A
Antimycotic in vivo effectiveness (oral) for mouse
candidosis
Experimental_descr1ption.
Mice of type SPF-CF1 were infected intravenously
nith 1 - 2 x 106 Candida cells, growing logarithnically,
which were suspended in physiological saline. One hour
before and seven hours after infection, the animals were
each treated orally with 50 - 100 mg/kg of body weight
of the products.
Result_
Untreated an;mals died 3 to 6 days after infec-
tion. The survival rate on the 6th day after infection
was abou~ 5% in untreated control animals~ In this test,
for example, the compounds according to the invent~on
exhibited a better effect than the compounds 1 and 3
kno~n from the state of the art.
Explanation of symbols:
+++++ = very good effect = 90% survivals on 6th day
after infection
~+++ = good effect - 80~. survivals on 6th day
after infection
~+ = effect = 60% survivals on 6th day
after infection
+~ = weak effect = 40X survivals on 6th day
after infection
~ = trace effect
N.E. = no effect
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- 16
Table A
Antimycotic in vivo effectiveness (oral) for mouse
candidosis
Active compound Effect
S (A) ~known) N.E.
(B) (known) N.E.
(C) (known) N.E~
(D) (known) N.E.
Compounds accord7ng to_preparation_example
1 ++~
3 +~+~
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- 17 -
Example 8 / Formulations
1) Solution:
Active compound according to
formula tI): 10 9
Alcohol, pure ~6%): 300 9
Isopropyl myristate: 526 9
836 9
2) Cream:
Active compound according to
formula (I): 10 9
.`~ Arlacel 60: 20 9
(sorbitan-monostearate)
Tween 60: 15 9
(polyoxyethylene(20)~sorbitan
monostearate)
Artif;c;al spermaceti: 30 9
(mixture of esters of saturated C
C~8 fatty acids and C14-C18
fatty alcohols)
Lanette 0: 100 9
(mixture of cetyl alcohol and
stearyl alcohol)
Entanol ~: 135 9
(Z~octyl-dodecanol)
Benzyl alcohol: 10 9
Deminer3lised water: 680 g
1 ,000 g
~* f~ ~C7
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