Note: Descriptions are shown in the official language in which they were submitted.
~ 6~37
The present invention relates to certain new biphenylylazolyl-ethane
compounds, to a process for their production and to their use as antimycotic
agents.
It has already been disclosed that biphenylylazolyl-methane derivatives
have good antimycotic properties (see DE-OS (German Published Specification)
2,461,406 and United States Patent Specification 4,118,487). However, their
action is not always completely satisfactory against all species of fungi.
According to the present invention we provide compounds which are
biphenylylazolyl-ethanederivatives of the general formula
1 o ~ f ~, I
Xm C~l2 n
N 11
or a salt thereof, in which A represents the -CH-group or a nitrogen atom; X
represents a halogen atom or an alkyl, halogenoalkyl, alkoxy, alkylthio, nitro
or cyano radical; Y represents a halogen atom or an alkyl, halogenoalkyl, alkoxy,
alkylthio, nitro, cyano or a phenyl radical which is unsubstituted or is substi-
tuted by a halogen atom or an alkyl, halogenoalkyl, alkoxy, alkylthio, nitro or
cyano radical; and _ and n are independently 0, 1, 2 or 3.
According to the present invention we further provide a process for
the production of a compound of the present invention in which a biphenylylazolyl-
ethylene derivative of the general formula
~ ~
m CH n
~ N
N-
' i - 1 -
3Z37
-- 2 --
in which
A, X, Y, m and n have the abovementioned meaning, '
is hydrogenate~ in the presence of a catalyst and
optionally in the presence of a diluent.
The new.biphenylyl-azolylethane derivati.ves have .
powerful antimycotic pDope.rties. Surprisingly, the
. compounds accordinL to the invention exhibit a more
powerful action than the biphenylyl-azolylmethane
derivatives which are known from the state of the art
and are closely related compounds chemically ~nd from the
point o~. view of their action. The substances according
to the invention thus represent an enrichment of pha~macy.
Preferred compounds of the presenk invention are
those in which X represents a halogen atom, a straight-
15 . chain or branched alkyl radical with 1 to 4 carbon atoms,a halogenoalkyl radical with 1 to 4 carbon atoms and 1 to
5 identical or different halo.~en.atoms,. halogens being,
preferably, fluorine and chlorine, an alkoxy or alkylthio
radical with in each case 1 to 4. carbon atomsg. or a nitro
or cyano radical, and Y, independently of X, represents
any of the radicals which have been mentioned immediately
above for X~ or represents a phenyl radical which is
optionally substituted by a radical specified immediately
above for X3 and A, m and n have the meanings given in the
.25. definition of compounds of formula (I).
Very particularly preferred ccmpounds of the
present invelltion are those in which X repre.s.ents a
fluorine, chlorine or bromine atom or a methyl, ethyl,
isopropyl, tert -butyl, trifluoromethyl, methoxy, ethoxy,
methylthio, ethylthio, nitro or cyano radical, Y independ-
ently of X represents the radicals mentioned immediately
above for X, or represents a phenyl radical which is
opticnally substituted by ~.luorine, chlorine, methyl, tert-
butyl, trifluoromethyl, nitrc or cyano, and A, n and m have
35. the meanings ~iven in the definition.of compounds of formula
(I).
The followin~ comp.ounds of the present inve.n.ti.o~
.. .... .... ....
' L'e 'A''2G''~'30
.
37
may be mentioned specifically, in addition to the
. compounds mentioned in the preparative Exa~.ples:
X '~ CH2 ~ Yn
~ N
N
__ . _ _
2-Cl ~~~`~~~~ N
3-F N
3-Cl N
- CH
4-CI CH
3-CH3 CH
4-C(CH3 )3 CH
4-C1 3-Cl CH
4-C1 2-C} CH
3-CF3 CH
2~5-Cl2 CH
44~> CH
4-Br CH
4-Cl, 3-N02 CH
3-N02 CH
- N
4-Cl N
3-CH3 N
4-C(CH3 )3 N
:Le A 2 0 2 ~0
~61~23
-- 4 --
X~i ~n . ..
.. . . . .. ..
4-C1 ~-Cl N
4-C1 2-Cl N
~ 3-CF3 N
2,5-Cl2 N
_ 4 ~ N
- 4-Br N
4-Cl,3-N02 N
3-N02 N
If, for example 1-(4-biphenylyl)-1-~2-chloro-
phenyl-)-2-(imidazol-1-yl)-ethylene and hydrogen are used
as starting substances, the course of the reaction according
to the present invention is illustrated by the following
. equation:
CH ~ C~t~ ~t ~ -C\H
C ~ ~N~
Pre.ferred biphenylyl-azolylethylene derivatives of
formula (II) to be used as starting substances for the
process according to the invention are those in which A, X~
Y, m and n h.ave those meanings which have already been
given in connection with the description of the preferred
and particularly preferred compounds of the present invent-
ion.
The biphenylyl-azolylethylene derivatives of the
formula (Il) are novel. They are obtained by a process
in which a hydroxyethyl-azole of the general formula
0~
~ ~ - C ~ (III)
Xm CH2 ~n
~ N~
.~ N
. .
.Le ~ 20 230
23~
in which A, X, Y, m and n have the above-mentioned meanlng, is reacted with a
water-binding agent, optionally in the presence of a diluent.
Water-binding agents which may be mentioned are, as preferences, acid
anhydrides, such as acetic anhydride; halides of oxyacids, such as thionyl
chloridei and isocyanates, such as methyl isocyanate.
Preferred diluents Eor this reaction are inert organic solvents. These
include, as preferences, chlorinated hydrocarbons, such as chloroform or
methylene chloride.
The reaction temperatures can be varied within a substantial range in
carrying out this reaction. In general, this reaction is carried out between 0
and 120 C, preferably between 20 and 100 C.
This reaction is preferably carried out in molar amounts or wi-th an
excess of water-binding agent. The compounds of the formula II are isolated by
customary methods (see also the preparative examples).
The hydroxyethy]azoles of the formula III are likewise novel; however,
they are the subject of our earlier copending Application 340,547. They can be
obtained by reacting the corresponding hydroxyethyl halides with imidazole or
triazole, if appropriate in the presence of an acid-binding agent, such as,
preferably, an excess of azole, or in the form of one of their alkali metal
salts, such as are obtained, for example, by treatment with sodium methylate in
a suitable solvent, and if appropriate in the presence of an inert organic sol-
vent, such as, for example, dimethylformamide, at temperatures between 30 and
120C
The hydroxyethylazoles of the formula III can also be ob-tained by
reacting oxiranes of -the general formula
~:~6~Z37
~ C ~ ~ IV
Xm 2 n
in which X, Y, m and n have the above-men-tioned meaning, with imidazole or tri-
azole in the presence of an alkali metal alcoholate, such as sodium methylate,
and in the presence of an inert organic solvent, such as, dimethylformamide, at
a temperature between 30 and 100 C (see also the preparative examples).
The oxiranes of the formula IV are novel. They can be obtained by
reacting appropriate ketones either with dimethyloxosulphonium methylide in a
manner which is in itself known in the presence of a diluent, such as dimethyl
sulphoxide, at a temperature between 20 and 80 C; or with trimethylsulphonium
methyl-sulphate in a manner which is in itself known in the presence of a two-
phase system and if appropriate in the presence of a phase transfer catalyst,
at a temperature between 0 and 100 C (see also the preparative examples).
The hydrogenation according to the invention is carried out in the
presence of a catalyst. Noble metal satalysts, noble metal oxide (or noble
metal hydroxide) catalysts or Raney catalysts, such as platinum, platinum oxide,
Raney nickel and palladium oxide, are preferably used.
Preferred possible diluents for the hydrogenation according to the
invention are inert organic solvents. These include, as preferences, alcohols
(such as methanol and ethanol), nitriles (such as acetonitrile), esters (such
as ethyl acetate) and glacial acetic acid.
The reaction temperatures can be varied within a substantial range in
the hydrogenation according to the
. .-. - 6 -
,
Z37
irve.ntion. In general~ the reaction is carried out at
a temperature between 20 and 200 C, preferably at a
. temperature between 40 and 150C.
The hydrogenation according to the invention is
preferably carried out under increased pressure. In
general, it is carried out under between l and 200 atmos-
p.heres gauge, preferably under l to 150 ~mospheres gauge.
In the hydrogen~tion according to the invention,
about l mole of hydrogen and about 0.1 mole of catalyst
are preferably employed per mole of the co~pound of the
formula (II). The end products of the formula (I)
are isolated in the customary manner.
The following acids can pre~erably be used for
the preparation of physiologically acceptable acid addition
salts of the compounds of the formula (I): hydrogen halide
acids (such as hydrobromic acid and, preferably, hydro-
chloric acid) phosphoric acid, nitric acid, sulphuric acid,.
monofunctional and bifunctional carboxylic acids and
hydroxycarboxylic acids (such as acetic acid, maleic acid~
succinic acid, fumaric acid, tartaric acid, citric acidg
salicylic ac.id, sorbic acid and lactic acid), and sulphonic
acids (such as p-toluenesulphonlc acld and 1,5-nap~thalene-
disulphonic acid).
Amon~ the new.biphenylyl-azolylethane derivative
.25. salts of the invention, those salts that are pharmaceut
ically acceptable are particularly important and are
preferred.
The new free biphenylyl-azolylethane derivatives
of the general formula (I) and their salts can be inter-
converted in any suitable manner; methods for such inter-
conversion are known in the art.
The acid addition salts of the compounds of the
formula (I) may be obtained, for example, by dissolving a
compound of the formula (I) in a suitable irert solvent and
3~ adding the acid, for example hydrochloric acid, and
they can be isolated in a ~.nown manner, for example by
filtration~ and if appropriate purified by ~ashin~ with an
.. ... .. ..
Le A 20`230
23
-- 8 --
inert organic solvent.
Possible anions o~ the salts are, preferably,
those which are derived from the following acids: hydrogen
halide acids, such as hydrochIoric acld and hydrobromic
acid, and furthermore phosphoric acid, nitric acid and
sulphuric acid.
The compounds of the formula (I) according to
the invention and their acid addition salts display anti-
microbial actions, in particular powerful antim~cotic
actions. They have a very broad action spectrum'in
itro, which comprises dermatophytes, yeasts,''
o~a~le, moulds and biphase fungi. They can therefore be
success~ully employed against fungal infections in humans
and animals.
Examples which may be mentioned of fields of
indication in human medicine are: dermatomycoses and
systemic mycoses caused by Trich'o'ph'y't'on _'n't'a'groph~'t'es and
other species o~ ~ichophyt'on, species of'Mi'cr'osp'or'on,
Epi~ermophyt~on ~locco9um~ blas~omyces and biphase fungi
as well as moulds.
Examples which may be mentioned of fields of
indication in veterir.ary medicina are: -all dermatomycoses
and systemic mycoses, in particular those caused by the
abovementioned pathogens.
The active compounds according to the invention
are active against a very broad spectrum o~ micro-organisms.
With their aid, it is possible, for example, for Gram-
negative and Gram-positive bacteria and bacteria-like
micro-organisms to be combated and for the illnesses caused
by these pathogens to ~e prever.ted, alleviated and/or cured.
As stated above, the invention also relates to
the use in human and veterinary medicine of the compounds
of the invention.
The present invention prcvides a pharmaceutical
composition containing as active ingredient a compound
of the invention in admixture with a solid or liquefied
gaseous diluent, or in admixture with a liquid diluent
other than a solvent of a molecular weight less than
' Le' A''?'0''2'30
~6~237
g
200 (preferably less than 350) except in the presence
of a surface active agent.
The invention further provides a pharmaceutical
co~osition containing as active ingredient a compound
o~ the invention in the form of a sterile and/or physio-
logically isotonic aqueous solution.
The invention also provides a medicament in dosage
unit form comprising a compound of the invention.
The invention also provides a medicament in the
form o~ tablets (including lozenges and granules), dragees,
capsules, pills, ampoules or suppositories comprising
a compound of the invention.
"Medicament" as used in this Specification means
physically discrete coherent portions suitable ~or medical
administration. "Medica~.ent in dosage unit form" as
used in this Specification means physically discrete
coherent units suitable for medical administration each
containing a daily dose or a multiple tup to four times)
or submultiple (down to a fortieth) of a daily dose
of the compound of the invention in association with
a carrier and/or enclosed within an envelope. Whether
the medicament contains a daily dose or, for exampleg
a half~ a third or a quarter of a daily dose will depend
on whether the medicament is to be administered once
or, for example~ twice, three times or ~our times a
day respectively.
The pharmaceutical composition according to the
invention may, for exampleg take the form o~ oint~ents,
gels, pastes, creams, sprays ~including aerosols)g lotions,
suspensions, solutions and emulsions o~ the active
ingredient in aqueous or non-aqueous diluents, syrups 3
granulates or powders.
The diluents to be used in pharmaceutical compositions
te.g. granulates) adapted to be ~ormed into tablets,
dragees? capsules and pills include the following:
(a) fillers and extenders, e.g. starch, sugars, mannitol,
and silicic acid; (b) binding agents, e.g. carboxymethyl
cellulose and other cellulose derivatives, alg1nates,
.. .. .. .... .. ..
~e A 20 230
- 10 - ~l~S~23~
- gelatine and polyvinyl pyrrolidone; (c) moisturizing
age~ts, e.g. glycerol; (d) disintegrating agents, e.g.
agar-agar, calcium carbonate and sodium bicarbonate;
(e) agents for retarding dissolution e.g. paraffin;
(f) resorption accelerators3 e.g. quaternary ammonium
compounds; (g) surface active agents, e.g. cetyl alcohol~
glycerol monostearate; (h) adsorptive carriers, e.g.
kaolin and bentonite; ~i) lubricants, e.g. talc, calcium
and magnesium stearate and solid polyethyl glycols
or mixtures of these above-mentioned substances.
The tablets, dragees, capsules and pills formed
from the pharmaceutical compositions of the invention
can have the customary coatings, envelopes and protective
matrices, ~hich may contain opacifiers. They can be
so constituted that they release the active ingredient
only or preferably in a particular part of the intestinal
tract, possibly over a period o~ time. The coatings,
envelopes and protective matrices may be made, for example~
of polymeric substances or waxès.
The ingredient can also be made up in microencapsulated
form together with one or several of the abo~e-mentioned
diluents.
The diluents to be used in pharmaceutical compositions
adapted to be formed into suppositories can, for example,
be the usual water-soluble or water-insoluble diluents, such
as polyethylene glycols and ~ats (e.g.cocoa oil and high esters
(e.g. C14-alcohol with C16-fatty acid)) or mixtures o~ these
diluents.
The pharmaceutical compositions which are ointments~
pastes, creams and gels can, for example3 contain the
usual diluents, e.g. animal and vegetable fats, waxes,
paraffins, starch, tragacanth, cellulose derivatives,
polyethylene glycols, silicones, bentonites, silicic
acid, talc and zinc oxide or mixtures o~ these substances.
The pharmaceutical compositions which are powders
and sprays can, for example, contain the usual diluents,
e.g. lactose, talc, silicic acid, aluminium hydroxide,
calcium silicate~ and polyamide powder or mixtures o~
these substances. Aerosol sprays can, for example,
Le A 20 230
237
. contain the usual propellants, e.'g. chlorofluorohydro-
carbons.
The pharmaceutical compositions which are solutions
and emulsicns can, for example,' contain the customary
diluerts (with, of course, the above-mentioned exclusion
of solvents having a molecular weight below 200 except
in the presence o~ a surface-active agent) 3 such as
solvents.~ dissolving agents and emulsifiers; specific
examples of such diluents are water, ethyl alcohol,
isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene
glycol,. di~ethylformamide, oils (for example ground
nut oil), glycerol,. tetrahydro~urfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitol or mixtures
thereof.
For parenteral administration, solutions and emulsions
should be sterile, and, if appropriate, blood-isotonic.
The pharmaceutical compositi.ons which are suspensions
can co.ntain the usual diluents, such as liquid diluents,.
e.g.. water, ethyl alcohol, propylene glycol, surface-
acti.ve agents. (e g. ethoxylated isostearyl alcohols,
polyoxyethylene sorbite and sorbitane esters), micro-
crystalline cellulose~ aluminium .metahydroxide, bentonite,
agar-agar and tragacanth or mixtures thereo~.
All the pharmaceutical compositions according to
the invention can also contain colouring agents and
preservatives as well as perfumes and flavouring additions
(e.g. peppermint oil and eucalyptus cil) and sweetening
agents (e.g. saccharin).
~he pharmaceutical compositions according to the
invention generall~J contain from 0.1 to 99.5% usually
from 0.5 to95% o~ the active ingredient by welght
of the total composition.
In addition to a comound of the invention, the
pharmaceutical compositions and medicaments according
to the invention can also canta.in other pharmaceutically
active compo~mds. They may also contain a plurality
. of compounds of the lnvention.
.. . .. .... ....
' Le A Z0 230
. . _ .
~ L6~Z37
Any diluent in the medicaments of the presenk invention
may be any of those mentioned above in relation to the
pharmaceutical compositions of the present invention.
Such medicaments may include solvents of molecular ~Teight
less than 200 as sole diluent.
The discrete coherent portions constituting the
medicament according to the invention will generally
be adapted by virtue of their shape or packa~ing for
medical administration and may be, for example, any
Of the followin~: tablets (including lozenges and
~ranulates), pills, dragees, capsules, sùppositories
and ampoules. Some of these forms may be made up for
delayed release of the active ingredient. Some, such
as capsules~ include a protective envelope which renders
the portions of the medicament physically discrete and
coherent.
The preferred daily dose for administration of
the medicaments of the invention is 2.5g to lO g
o~ active ingredient.
The production of the above-mentioned pharmaceuticaI
compositions and medicaments is carried out by any method
known in the art, for example, by mixing the active
ingredient(s) with the diluent(s) to form a pharmaceutical
composition (e.g. a granulate) and then forming the
composition into the medicament (e.g. tablets3.
This invention further provides a method of combating
(including prevention, relief and cure of) the above~
mentioned diseases in human and non-human animals, which
comprises administering to the animals a compound of
the invention alone or in admixture with a diluent or
in the form of a medicament according to the invention.
It is envisaged that these active compounds will
be administered perorally, parenterally (for example
intramuscularly, intraperitoneally, subcutaneously ar.d
intravenously), rectally or locally, preferably parenterally,
especially intravenously. Preferred pharmaceutical
ccmpositions and medicaments are therefore those adapted
.. .. .. ..
Le A 20 230
.. . .
37
1~
.~or administration such as parenteral administration.
Administration in the ~.ethod of the invention is pre.ferably
parenteral administration.
In general it has proved advantageous to adminis.ter
amounts.of from lOmg to 300mg/kg, preferably from 50mg to
200mg/kg, of body weight per day to achieve effective
results. Neverthe.less, it can at times be necessary
to deviate from those dosage rates, and in particular
to do so as a function of the nature and body weight
of the human or animal subject to be treated, the
individual reaction of this subje.ct to the treatment,
the ty.pe of formulation in which the active ingredient
is administered and the mode in which the administration
is carried out,. and the point in the progress o~ the
disease or interval at which it is. to be administered.
Thus it may in some case suffice to use less than the
above-mentioned minimum dosage rate, whilst other cases
. the upper limit me.ntioned must.be exce.eded to achi.eve
the desired results.. Where larger amounts are administered
it can be advisab.le to divide these into several individual
.administrations. over the. course of the day.
The following Examples 1 to 8 illustrate processes for
the production of compounds of the present invention.
E'ga'mpl'e' 1 Cl
~ ~ IH -
. fH2
L~
4.0 g of 1-(4-biphenylyl)-1-(2-chlorophenylj-2-
(imidazol-I-yl)-ethylene were dissolved in 100 ml of
glacial aceticacid and were hydrogenated at 60C under 40
bars of H2 for ~ hours, using platinum oxide as the
catalyst. The solvent was then distilled off and the.
syrupy residue was chromatographed over Merck Silica gel
60 ~mobile phase: chloroform/methanol = 10/0.5).
.... .. .. ..
L'e' A' 2'0' 2'30
.
3~7
- 14 --
3.4 g (85% of theory) of 1-(4-biphenylyl)-1-(2-chloro~
phenyl)-2-(imidazol-1-yl)-ethane of melting point 86C
were. obtained.
Preparat'ion'o'f'th'e pre'curs'o'rs
Cl
(II-l) ~ e ~
CH
N ~
Il N
1.9 g of 1-(4-biphenylyl)-1-( ~chlorophenyl)-2-
timidazol-l-yl)-ethan-l-ol were suspended in 30 ml of
. chloroform, and 1.4 ml of thionyl chloride were added.
The mixture was stirred at 60C for 18 hours. The clear
.solution was then .evaporated`'in''v'ac'uo, the residue was
taken up in 30 ml of chloroform and, after adding another
1.4 ml of thionyl chloride, the mixture was stirred again
.at 60C for 18 hours. The crystalline crude product
which remained after stripping off the solvent was
1.5 recrystallised from isopropanol. 16 g (89% o~ theory)
. of 1-(4-biphenylyl~-1-(2-:chlorophenyl)-2-(imidazol-1-yl)-
ethylene of melting point 196C were obtained.
OHcl
H2
._....N
3.5 g (o.o65 mole) of sodium methylate were diss-
olved in 20 ml of methanol, and 7.5 ~ (0.11 mole) of
imidazole were added. A solution of 15 g (0.05 mole) of
2-(4-biphenylyl)-2-(2-chlorophenyl)-oxirane in 75 ml of
dimethylformamide was added dropwise and the reaction mix-
. ture was heated to 80C for 1.5 hours. Thereafter, the
reaction mixture was poured onto w.ater and the crystals
formed were filtered off and dried. 14.7 g (79%. o~
~ Le A'2'0''2'30
.
37
-- 15 --
. theo.ry). of 1-(4-biphenylyl)~1-(2-chlorophenyl)-2-imidazol
-l-yl-ethan-l-ol of melting pcint 222C were obtained.
C1
/C\~
CH2--O
90 ml of dimethyl sulphoxide were added to 2.7 g
(0.09 mole) of 80% strength sodium hydride and 19.8 g
(0.09 mole) of trimethyloxosulphonium iodide in the course
of 20 minutes. When the evolution of hydrogen had ended,
a solution of 22 g (0.075 mole)' of 2'-chloro-4'-phenyl-
. benzophenone in 60 ml of dimethyl sulphoxide was added
dropwise and the mixture was sub.sequently stirred at 50C
for 1 hour. 200 ml of water were added to the cooled
reaction mi.xture and the mixture was extracted by shaking
with ether. The ether solution ~as washed with water,
. dri.ed.over s.odium sulphate and. concentrated by distilling
off the solvent in''~acuo. The residue was recr~stallised
from diisopropyl ether. 15 g (65% of theory) of 2-(4-
. biphenylyl)-2-(2-chlorophenyl)-oxirane of melting point
'70C were o.btained.
The compounds of the formula (I) listed in Table 1
which follows. c.ould be obtained by the process as described
Lxample 1 using corresponding starting materials.
- Ta~le 1
~ ~ CH
Xm CH2 Yn
I
N
N
- Le A 20 230
.
37
-
Ex-
. N.o.~.. m .......... Yn - - A Meit n(O
2 4-C1 2-Cl CH 188
3 - 2-F CH resin
4 - 3-Cl CH oil
- 2-Cl CH 282(xl/2 NDS).
6 ~ 2-F CH 297(xl/2 NDS)
7 - 3 Cl CH 265(xl/2 N3S.)
8 4-C1 2-Cl N 152
NDS = 1,5-naphthalenedisulphonic acid
The starting materials. o~ the ~ormula (II) listed in
Table 2 which follows could be obtained by the process
described Example 1 for the prepa~ation of precurso:rs using
corresponding starting materials for that process.
X~ 11 ~Y
m CH n (II)
~N~A
N_
Ex-
ample X Y A Melting
. 15 . No... m ........... n................ p.o.in.t. (.C.)
(II-2)4-C1 2-Cl CH 174
(II-3) - 2-F CH oil
(II~4) - 3-Cl CH 211
(II-5) - 2-F CH 325 (decompo-
sition)(xl/2 NDS)
(II-6)4-C1 2-C1 N 17Q
(II-7) - 4-Cl CH n20 = 1.6350
Le A 20 230
_ .
~ 3
- 17 - , ... .
' The', following Example illustrates the' in'''i't'ro
activity, of compounds of the present invention. In
this Example, the compour.ds according to the present invent-
ion are each identified by the number ~given in brackets)
of the corresponding preparative Example~ which will be
found earlier in this specification.
The known comparison compounds are identified as
follows:
Cl
(A) Cl ~ - ~ - CH
Cl
(B) Cl- ~ ~ ~ CH ~
CH3
(c) ~-f~
~N~
N
(D) ~ ~ - CH
~ N~N
N 11
,
I0' Example A
Antimy'c'oti'c'i'n''v'i't'r'o''a'c't'i'v'it'y
. .
D'e-sc'rip'ti'on''o'f'the'-e'xpe'ri'men't:
The in ~itro test was carried out as a series
dilution test using germ inocula of an average 5 x 10
&erms/ml of substrate, The nutrient medium used was:
Le A 2~ 230
__
- 18 -
a) fcr dermatophytes and moulds: Sabouraud's milieu
. d'ep.re.uve, and
. b) .for yeasts: isotonic sensi.test broth from Oxid,
~he incubation temperature was 28C; the
.5 incubation time was 24 hours in the case of yeasts and
96 hours in the case of dermatophytes and moulds.
In this test, for example, the compounds (5),
(6)~ (7) and (8) exhibited a very good action which is
superior to. that of the compounds (A), (B), (C) and (D)
- lO known from the prior art.
The present invention also comprises pharmaceutic-
ally acceptab.Ie bioprecursors of thè active compounds of
. the present inventi.on.
For the purposes of this specification the term
'pharmaceutica~ly acceptable bioprecursor' of an active
compound of the invention means a compound h.aving a
structural formula differe.nt from the active compound but
wh.i.ch nonetheless, upon administration to an animal or
human being is. converted in the patient's body to the
active compound.
Le A 20 2~0
_ _
