AMINOPROPANES SUBSTITUES, LEURS PROCEDES D'OBTENTION ET LEUR UTILISATION

SUBSTITUTED AMINOPROPANES, PROCESSES FOR THEIR PREPARATION, AND THEIR USE

Abrégé anglais

HOE 91/F 287
Abstract of the disclosure
Substituted aminopropanes, processes for their
preparation, and their use
Compounds of the formula I
<IMG>
can be used for the treatment and for the prophylaxis of
fungal diseases. They are obtained by reacting II
<IMG>
II
with III
<IMG> III
to give IV

<IMG>
(IV)
and by reaction with a nucleophile M-NR(2)R(3),

Revendications

- 49 - HOE 91/F 287
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Substituted aminopropanes of the formula I
<IMG>
I
in which
R(1) is H, (C1-C10)-alkyl, (C2-C10)-alkenyl,
benzyl, [unsubstituted or monosubstituted
or polysubstituted by F, Cl, Br, CF3,
(C1-C4)-alkyl, OCH3, O-phenyl or phenyl],
C(O)-( C1-C8)-alkyl, C(O)-phenyl
R(2) is H, (C1-C18)-alkyl, (C1-C6)-alkyl-oxy-
(C1-C6)-alkyl, (C1-C6)-alkyl-thio-phenyl,
(C1-C6)-alkyl-oxy-phenyl, (C2-C18)-alkenyl,
(C3-C12)-cycloalkyl (mono-, bi- or
multicyclic), phenyl-(C1-C6)-alkyl, the
alkyl chain being unsubstituted or
monosubstituted or disubstituted by OH, or
is phenyl-(C2-C6)-alkenyl, diphenyl-
(C1-C6)-alkyl, phenyl, the phenyl systems
being unsubstituted or monosubstituted or
polysubstituted by substituents selected
from the group comprising F, Cl, Br,
(C1-C10)-alkyl, (C3-C10)-cycloalkyl, OH, SH,
(C1-C10)-alkoxy, (C1-C4)-alkylenedioxy,
(C1-C10)-alkylthio, dimethylaminoethoxy,
(C1-C4)-alkoxycarbonylmethoxy, phenoxy,
phenyl, benzyl, phenethyl, thiophenyl,
CaF2a+1 (where a equals 1 - 6),

- 50 -
or
R(2) is an indol-3-yl-(C1-C4)-alkyl, thienyl or
thienylmethyl radical, the thienyl ring
being unsubstituted or substituted by F,
Cl, (C1-C4)-alkyl, O(C1-C4)-alkyl,
or
R(2) is piperidin-4-yl, unsubstituted or
substituted by 1 to 4 methyl groups and
having a hydrogen, an acetyl group, a
phenyl group or a benzyl group on the N
atom of the piperidine,
R(3) is defined as R(2), the meanings of R(2)
and R(3) in each case being identical or
different, or
R(2) together with R(3) forms a chain -(CH2)m-
where m equals 4 - 6 and in which a CH2
group can be replaced by oxygen or sulfur,
A is (C1-C18)-alkyl, (C2-C18)-alkenyl or a group
<IMG>
,
in which the radicals R(4), R(5) and R(6) have the
following meaning:

- 51 -
R(4) is H, (C1-C18)-alkyl, (C2-C18)-alkenyl,
(C3-C20)-cycloalkyl (mono-, bi- or
multicyclic), Y-(C1-C20)-alkyl, Y-(C2-C18)-
alkenyl, Y-(C3-C20)-cycloalkyl (mono-, bi-
or multicyclic), phenyl, Y-phenyl, phenyl-
(C1-C6)-alkyl, phenyl-(C1-C4)-alkoxy,
biphenylyl, F, Cl, Br, CaF2a+1 (where a
equals 1 to 8), CCl3, YH, naphthyl, CN,
NO2, the phenyl systems being unsubstituted
or monosubstituted or disubstituted by F,
Cl, CF3, (C1-C4)-alkyl, (C1-C4)-alkoxy, CN,
-O-(CH2)1-2-O-,
where Y equals oxygen or sulfur, SO, SO2,
R(5) is defined as R(4), R(4) and R(5) being
identical or different, or
if the substituents are bonded to the phenyl
ring in adjacent positions,
R(4) together with R(5) forms a (CH2)r chain
where r equals 3 or 4, or an O(CH2)1-2-O-
chain,
R(6) is H, (C1-C15)-alkyl, (C2-C15)-alkenyl, Y-
(C1-C15)-alkyl, Y-(C2-C15)-alkenyl, phenyl,
Y-phenyl, benzyl, biphenylyl, F, Cl, Br,
I, CaF2a+1 (where a equals 1 - 8), CCl3,
naphthyl, YH,
X is oxygen or sulfur,
R(7) is (C1-C12)-alkyl, (C3-C12)-cycloalkyl
(mono-, bi- or multicyclic, such as
norbornyl or adamantyl), (C3-C12)-alkenyl,
phenyl-thio-phenyl, phenyl-oxy-phenyl,
biphenylyl, phenyl-methyl-phenyl, naph-
thyl, phenyl, thienyl, pyridyl, the

- 52 -
aromatic and heteroaromatic ring systems
mentioned being unsubstituted or
monosubstituted or polysubstituted by F,
Cl, Br, (C1-C18)-alkyl, (C1-C18)-alkoxy,
(C2-C18)-alkenyloxy, CF3, C2F5, CN,
(C1-C18)-alkylthio.
2. A compound of the formula I as claimed in claim 1,
in which
R(1) is H, (C1-C6)-alkyl, benzyl, [unsubstituted
or monosubstituted or disubstituted by F,
Cl, Br, CF3, (C1-C4)-alkyl, OCH3, O-phenyl
orphenyl],C(O)-(C1-C8)-alkyl,C(O)-phenyl
R(2) is H, (C1-C18)-alkyl, (C1-C6)-alkyl-oxy-
(C1-C6)-alkyl, (C1-C6)-alkyl-thio-phenyl,
(C1-C6)-alkyl-oxy-phenyl, (C2-C18)-alkenyl,
(C3-C12)-cycloalkyl (mono-, bi- or
multicyclic), phenyl-(C1-C6)-alkyl, the
alkyl chain being unsubstituted or
monosubstituted or disubstituted by OH, or
is phenyl-(C2-C6)-alkenyl, diphenyl-(C1-C6)-
alkyl, phenyl, the phenyl systems being
unsubstituted or monosubstituted or
polysubstituted by substituents selected
from the group comprising F, Cl, Br,
(C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C1-C10)-
alkoxy, (C1-C4)-alkylenedioxy, (C1-C4)-
alkoxycarbonylmethoxy, phenoxy, phenyl,
benzyl, phenethyl, thiophenyl, CF3,
or
R(2) is an indol-3-yl-(C1-C4)-alkyl, thienyl or
thienylmethyl radical, the thienyl ring
being unsubstituted or substituted by Cl,
(C1-C4)-alkyl, O(C1-C4)-alkyl,
or

- 53 -
R(2) is piperidin-4-yl, unsubstituted or
substituted by 1 to 4 methyl groups and
having a hydrogen, an acetyl group, a
phenyl group or 21 benzyl group on the N
atom of the piperidine,
R(3) is defined as R(2), the meanings of R(2)
and R(3) in each case being identical or
different, or
A is (C1-C18)-alkyl, (C2-C18)-alkenyl or a group
<IMG>
,
in which the radicals R(4), R(5) and R(6) have the
following meaning:
R(4) is H, (C1-C16)-alkyl, (C3-C16)-alkenyl,
(C3-C12)-cycloalkyl (mono-, bi- or
multicyclic), Y-(C1-C16)-alkyl, Y-(C3-C16)-
alkenyl, Y-(C3-C12)-cycloalkyl (mono-, bi-
or multicyclic), phenyl, Y-phenyl, phenyl-
(C1-C6)-alkyl, phenyl-(C1-C4)-alkoxy,
biphenylyl, F, Cl, CF3, naphthyl, CN, the
phenyl systems being unsubstituted or
monosubstituted or disubstituted by F, Cl,
CF3, (C1-C4)-alkyl, (C1-C4)-alkoxy,

-54-
-O-(CH2)1-2-O-,
where Y equals oxygen or sulfur,
R(5) is defined as R(4), R(4) and R(5) being
identical or different, or
if the substituents are bonded on the phenyl
ring in adjacent positions,
R(4) together with R(5) forms a (CH2)r chain
where r equals 3 or 4,
R(6) is H, (C1-C6)-alkyl, Y-(C1-C6)-alkyl, F, Cl,
CF3,
X is oxygen or sulfur,
R(7) is (C1-C12)-alkyl, (C3-C12)-cycloalkyl
(mono-, bi- or multicyclic, such as
norbornyl or adamantyl), (C3-C12)-alkenyl,
phenyl-thio-phenyl, phenyl-oxy-phenyl,
biphenylyl, phenyl-methyl-phenyl, phenyl,
thienyl, the aromatic ring systems
mentioned and the heteroaromatic ring
system mentioned being unsubstituted or
monosubstituted or polysubstituted by F,
Cl, Br, (C1-C18)-alkyl, (C1-C18)-alkoxy,
(C2-C18)-alkenyloxy, CF3, C2F5,
(C1-C18)-alkylthio.
3. A compound of the formula I as claimed in claim 1,
in which
R(1) is H, C(O)-(C1-C4)-alkyl, C(O)-phenyl
R(2) is H, (Cl-C15)-alkyl, (C1-C6)-alkyl-oxy-
(C1-C6)-alkyl, (C1-C6)-alkyl-thio-phenyl,
(C1-C6)-alkyl-oxy-phenyl, (C2-C15)-alkenyl,

-55-
(C3-C12)-cycloalkyl (mono-, bi- or
multicyclic), phenyl-(C1-C5)-alkyl,
diphenyl-(C1-C6)-alkyl, phenyl, the phenyl
systems being unsubstituted or
monosubstituted or disubstituted by
substituents selected from the group
comprising F, Cl, (C1-C8) -alkyl, (C3-C6)-
cycloalkyl, (C1-C10)-alkoxy, (C1-C4)-
alkylenedioxy, phenoxy, phenyl, benzyl,
phenethyl, thiophenyl, CF3,
or
R(2) is an indol-3-yl-(C1-C4)-alkyl, thienyl or
thienylmethyl radical, the thienyl ring
being unsubstituted,
or
R(2) is piperidin-4-yl, substituted by 1 to
4 methyl groups and having a hydrogen, an
acetyl group, a phenyl group or a benzyl
group on the N atom of the piperidine,
R(3) is hydrogen,
A is (C1-C18)-alkyl, (C2-C18)-alkenyl or a group
<IMG>
,
in which the radicals R(4), R(5) and R(6) have the
following meaning:

- 56 -
R(4) is H, (C1-C12)-alkyl, (C3-C12)-alkenyl,
(C3-C12)-cycloalkyl (mono-, bi- or
multicyclic), Y-(C1-C12)-alkyl, Y-(C3-C12)-
alkenyl, Y-(C3-C12)-cycloalkyl (mono-, bi-
or multicyclic), phenyl, Y-phenyl, phenyl-
(C1-C6)-alkyl, phenyl-(C1-C4)-alkoxy,
biphenylyl, F, Cl, CF3, the phenyl systems
being unsubstituted or monosubstituted or
disubstituted by F, Cl, CF3, (C1-C4)-alkyl,
(C1-C4)-alkoxy,
where Y equals oxygen or sulfur,
R(5) is defined as R(4), R(4) and R(5) being
identical or different, or
R(6) is H, (C1-C4)-alkyl, Y-(C1-C4)-alkyl, F, Cl,
X is oxygen or sulfur,
R(7) is (C1-C10)-alkyl, (C3-C12)-cycloalkyl
(mono-, bi- or multicyclic, such as
norbornyl or adamantyl), phenyl-thio-
phenyl, phenyl-oxy-phenyl, biphenylyl,
phenyl-methyl-phenyl, phenyl, the aromatic
ring systems mentioned being unsubstituted
or monosubstituted or polysubstituted by
F, Cl, (C1-C4)-alkyl, (C1-C4)-alkoxy, CF3,
(C1-C4)-alkylthio.
4. A compound of the formula I as claimed in claim 1,
in which
R(1) is H,
R(2) is H, (C1-C15)-alkyl, (C1-C6)-alkyl-oxy-
(C1-C6)-alkyl, (C1-C6)-alkyl-thio-phenyl,

- 57 -
(C1-C6)-alkyl-oxy-phenyl, (C3-C12)-alkenyl,
(C3-C10)-cycloalkyl (mono-, bi- or
multicyclic), phenyl-(C1-C4)-alkyl,
diphenyl-(C1-C6)-alkyl, the phenyl systems
being unsubstituted or monosubstituted or
disubstituted by substituents selected
from the group comprising F, Cl, (C1-C8)-
alkyl, (C3-C6)-cycloalkyl, (C1-C10)-alkoxy,
(C1-C2)-alkylenedioxy, phenoxy, phenyl,
benzyl, phenethyl, thiophenyl, CF3,
or
R(2) is an indol-3-yl-(C1-C4)-alkyl, thienyl or
thienylmethyl radical, the thienyl ring
being unsubstituted,
or
R(2) is piperidin-4-yl, substituted by 1 to
4 methyl groups and having a hydrogen, an
acetyl group or a benzyl group on the
N atom of the piperidine,
R(3) is hydrogen,
A is a group

- 58 -
<IMG>
,
in which the radicals R(4), R(5) and R(6) have the
following meaning:
R(4) is H, (C1-C12)-alkyl, (C3-C12)-alkenyl,
(C3-C12)-cycloalkyl (mono-, bi- or
multicyclic), Y-(C1-C12)-alkyl, Y-(C3-C12)-
alkenyl, Y-(C3-C12)-cycloalkyl (mono-, bi-
or multicyclic), phenyl, Y-phenyl, phenyl-
(C1-C6)-alkyl,phenyl-(C1-C4)-alkoxy,F,Cl,
the phenyl systems being unsubstituted or
monosubstituted or disubstituted by F, Cl,
CF3, (C1-C4)-alkyl, (C1-C4)-alkoxy,
where Y equals oxygen or sulfur,
R(5) is defined as R(4), R(4) and R(5) being
identical or different,
R(6) is H, (C1-C4)-alkyl, Y-(C1-C4)-alkyl,
X is oxygen,
R(7) is (C1-C4)-alkyl, (C3-C12)-cycloalkyl
(mono-, bi- or multicyclic, such as

- 59 -
norbornyl or adamantyl), phenyl-thio-
phenyl, phenyl-oxy-phenyl, biphenylyl,
phenyl, the aromatic ring systems
mentioned being unsubstituted or
monosubstituted or disubstituted by F, Cl,
(C1-C4)-alkyl, (C1-C4)-alkoxy, CF3,
(C1-C4)-alkylthio.
5. A process for the preparation of a compound of the
formula (I) as claimed in claim 1, which comprises
reacting a compound of the formula (II)
(II)
<IMG>
in which R(7), A and X have the meanings mentioned
in claim 1, with a sulfur ylide of the formula III
<IMG> (III)
in which p is zero or 1,
to give a compound of the formula IV

- 60 -
<IMG> (IV),
and subsequently reacting the compound IV with a
nucleophile of the formula M-NR(2)R(3) in which R(2)
and R(3) have the meanings mentioned and M is
hydrogen or a metal equivalent, giving a compound I
where R(1) = H, which is isolated in the form of the
free base, of an acid addition salt or of a
physiologically hydrolyzable derivative.
6. A compound I as claimed in claim 1 for use in the
treatment and prophylaxis of fungal diseases.
7. The use of a compound I as claimed in claim 1 for
the preparation of a pharmaceutical for the treatment and
for the prophylaxis of fungal diseases.

Description

2~780S7
I~OECHST A~TIENGESE~LLSCW'T HOE 91/F 287 Dr.vF/PL
Description
Substituted aminopropanes, proco~ses for their prepara-
tion, and their use
The invention relates to ~ubstituted ~;nopropane~ of the
formula I, to processes for th~ir preparation, and to
pharmaceutical compositions containing ~uch compounds,
and to their use a8 pharmaceuticals, in particular as
growth inhibitors of the pathogenic pha~e of dimorphic
yeast cells and as anti-ycoties, it being poesible for
the compound~ according to the invention to be u~ed in
prophylaxis as well a~ in therapy.
German Offenlegungsschrift DE 3,330,005 Al mentions
compounds of the formula A
R ( 3 )~ R ( ~ )
R ( 2 ) ~ C ~ ( CH2 ) n ~ CH
\ N ~ R ( S )
R ( 1 )R ( 6 )
In this Offenlegungsschrift, R(3) i~ generally defined as
aryl, alkyl or cycloalkyl, it being possible for each of
these radicals to be substituted, and hydrogen. ~owever,
nothing iB mentioned in the description and in the
examples about compounds where R(3) is aryl, alkyl or
cycloalkyl, and only tartaric acid derivatives of those
compounds in which R(3) is hydrogen are described.
In contrast, compounds of the formula I in which the
amine component has aliphatic, cycloaliphatic or aromatic
radicals and the substituent R(7) in formula I is simul-
taneously a group bonded via carbon, as well as the use

2078~
-- 2 --
of such compounds as inhibitors of the exoenzymes (fac-
tors of pathogenicity) of fungi and as antimycotics, are
as yet unknown.
The invention therefore relates to substituted aminoprop-
anes of the formula I
o ( R I ) ~ R ( 2 )
- X - C ~ ~ - C -- C ~
( 7 ~ R ( 3 )
to their preparation and to their use as antimycotics as
well as growth inhibitors of the pathogenic phase of
dimorphic yeast cells. The compounds can therefore be
used for the prophylaxis and treatment of fungal dis-
eases. The invention furthermore relates to pharmaceuti-
cal preparations containing these compounds and to their
salts with pharmaceutically acceptable acids and to their
physiologically hydrolyzable derivatives.
Unless specifically mentioned otherwise, alkyl, alkoxy,
alkylthio, alkylene and alkenyl groups in any form are
straight-chain or branched; alkenyl chains are monoun-
saturated or polyunsaturated. Aryl is phenyl or naphthyl.
However, phenanthryl, fluorenyl and anthracenyl can also
act as aryl radicals.
In formula I:
R(1) is H, (Cl-Cl0)-alkyl, (C2-Cl0)-alkenyl, benzyl,
[unsubstituted or monosubstituted or polysubsti-
tuted by F, Cl, Br, CF3, (C1-C4)-alkyl, OCH3, O-
phenyl or phenyl], C(O)-(Cl-C3)-alkyl, C(O)-phenyl

2~78a~7
-- 3 --
R(2) is H, (cl-cla)-alkyll ~C1-C6)-alkyl-oxy-(C1-c8)
alkyl, (cl-c6)-alkyl-thio-phen
(C1-C6)-alkyl-oxy-phenyl, (c2-c~s)-alkenyll
(C3-C12)-cycloalkyl (mono-, bi- or multicyclic,
such as norbornyl, adamantyl, decahydronaPhthyl),
phenyl-(C1-C6)-alkyl, the alkyl chain being
unsubstituted or monosubstituted or di~ubstituted
by OH, or is phenyl-(C2-C6)-alkenyl, diphenyl-
(C1-C6)-alkyl, phenyl, the phenyl systems being
unsubstituted or monosubstituted or polysubsti-
tuted by substituents selected from the group
comprising F, Cl, Br, (Cl-Cl0)-alkyl~ (C3-C10)-
cycloalkyl, OH, SH, (C,-C10)-alkoxy, (C1-C4)-
alkylenedioxy, (C1-C~0)-alkylthio, dimethylamino-
ethoxy, ( Cl-C4 ) -alkoxycarbonylmethoxy, phenoxy,
phenyl, benzyl, phenethyl, thiophenyl, C~F2~,
(where a equals 1 - 6),
or
R(2) is an indol-3-yl-(C1-C4)-alkyl, thienyl or
thienylmethyl radical, the thienyl ring being
unsubstituted or substituted by F, Cl, (C1-C4)-
alkyl, O( Cl-C4 ) -alkyl,
or
R(2) is piperidin-4-yl, unsubstituted or substituted
by 1 to 4 methyl groups and having a hydrogen, an
acetyl group, a phenyl group or a benzyl group on
the N atom of the piperidine,
R(3) is defined as R(2), the meanings of R(2) and R(3)
in each case being identical or different, or
R(2) together with R(3) forms a chain -(CH2)~- where m
equals 4 - 6 and in which a CH2 group can be
replaced by oxygen or sulfur,
A is (C1-C18)-alkyl, (c2-cl8)-alkenyl or a group

2078~5~
R ( 4 )
,~,
R(5)
R ( 6 )
in which the radicals R(4), R(5) Pnd R(6) have the
following meaning:
R(4) is H, ( C1-C1B ) -alkyl, (c2-cl8)-alkenyl/ (C3-C20)~
cycloalkyl (mono-, bi- or multicyclic), Y-
(C1-C20)-alkyl, Y-(C2-ClB)-alkenyl, Y-(C3-C20)-
cycloalkyl (mono-, bi- or multicyclic), phenyl,
Y-phenyl, phenyl-(C~-C~)-alkyl, phenyl-( C~-C4 ) -
alkoxy, biphenylyl, F, Cl, Br, C~F2~t~ (where a
equals 1 to 8), CC13, YH, naphthyl, CN, NO2, the
phenyl systems being unsubstituted or monosubsti-
tuted or disubstituted by F, Cl, CF3, ( C~-C4 ) -
alkyl, ( C~-c4 ) -alkoxy, CN, -O-(CH2) 1-2--
where Y equals oxygen or sulfur, SO, SO2,
R(5) is defined as R(4), R(4) and R(5) being identical
or different, or
if the substituents are bonded to the phenyl ring
in adjacent positions,
R(4) together with R(5) forms a (CH2)r chain where r
equals 3 or 4, or an O(CH2)~2-O- chain,
20 R(6) is H, (C1-C15)-alkyl, (C2-C~5)-alkenyl, Y-( C,-C,5)-
alkyl, Y-(C2-C~5)-alkenyl, phenyl, Y-phenyl,

207~
-- 5 --
benzyl, biphenylyl, F, C.l, Br, I, C~F2~t1 (where a
equals 1 - 8), CCl3, naphthyl, YH,
X is oxygen or sulfur,
R(7) is (Cl-C12J-alkyl, (C3-C12)-cycloalkyl (mono-, bi-
or multicyclic, such as norbornyl or adamantyl),
(C3-C12)-alkenyl, phenyl-thio-phenyl, phenyl-oxy-
phenyl, biphenylyl, phenyl-methyl-phenyl, naph-
thyl, phenyl, thienyl, pyridyl, the aromatic and
heteroaromatic ring systems mentioned being
unsubstituted or monosubstituted or polysubsti-
tuted by F, Cl, Br, (C1-C1B)-alkyl, (C1-C18)-alkoxy,
(C2-C1a)-alkenyloxy, CF3, C2F5~ CN,
(C1-C18)-alkylthio.
Preferred compounds of the formula I are those in which
15 R( 1 ) is H, (Cl-C6) -alkyl, benzyl, [unsubstituted or
monosubstituted or disubstituted by F, Cl, Br,
CF3 , ( cl-c4 ) -alkyl ~ OCH3 , O-phenyl or phenyl],
C(O)-(C1-C3)-alkyl, C(O)-phenyl
R(2) is H, ( Cl-Cl9 ) -alkyl, (C1-C6)-alkyl-oxy-(C1-C6)-
alkyl, (C1-C6)-alkyl-thio-phenyl, (Cl-C6)-alkyl-
oxy-phenyl, (C2-Cl~)-alkenyl, (C3-C12)-cycloalkyl
(mono-, bi or multicyclic, such as norbornyl,
adamantyl, decahydronaphthyl), phenyl-(C1-C6)-
alkyl, the alkyl chain being unsubstituted or
monosubstituted or disubstituted by OH, or is
phenyl-(C2-C6)-alkenyl, diphenyl-(C1-C6)-alkyl,
phenyl, the phenyl systems being unsubstituted or
monosubstituted or polysubstituted by
substituents selected from the group comprising
F, Cl, Br, (C1-C1O)-alkyl, (C3-C10)-cycloalkyl,
(Cl-C10)-alkoxy, (Cl-C4)-alkylenedioxy, (Cl-C4)-
alkoxycarbonylmethoxy, phenoxy, phenyl, benzyl,
phenethyl, thiophenyl, CF3,

~ 207~57
-- 6 --
or
R(2) is an indol-3-yl-(Cl-C4)-alkyl, thienyl or
thienylmethyl radical, the thienyl ring being
unsubstituted or substituted by Cl, (C1-C4)-alkyl,
O( Cl-C4 ) -alkyl,
or
R(2) is piperidin-4-yl, unsubstituted or substituted by
1 to 4 methyl groups and having a hydrogen, an
acetyl group, a phenyl group or a benzyl group on
the N atom of the piperidine,
R(3) is defined as R(2), the meanings of R(2) and R(3)
in each case being identical or different, or
A is (Cl-Cl3)-alkyl, (C2-C16)-alkenyl or a group
R ( 4 )
~,
/= '
R(5)
R ( 6 )
in which the radicals R(4), R(5) and R(6) have the
following meaning:
R(4) is H, (Cl-C16)-alkyl, tc3-cl6)-alkenyl~ (C3~cl2)~
cycloalkyl (mono-, bi- or multicyclic), Y-
(C1-C16)-alkyl, Y-(C3-Cl6)-alkenyl, Y-(C3-C12)-
cycloalkyl (mono-, bi- or multicyclic)~ phenyl,
Y -p he ny l, ph eny l - (Cl- C 6 ) - al ky l,

2 ~ 7 ~ 7
-- 7
phenyl-( C~-C4 ) -alkoxy, biphenylyl, F, Cl, CF3,
naphthyl, CN, the phenyl systems being unsubsti-
tuted or monosubstituted or disubstituted by F,
Cl, CF3, (C1-C4)-alkyl, ( Cl-C4 ) -alkoxy,
-O-(CH2)1-2--,
where Y equals oxygen or sulfur,
R(5) is defined as R(4), R(4) and R(5) being identical
or different, or
if the substituents are bonded on the phenyl ring
in adjacent positions,
R(4) together with R(5) forms a (CH2) r chain where r
equals 3 or 4,
R(6) is H, (C1-C6)-alkyl, Y-(C1-C6)-alkyl, F, Cl, CF3,
X is oxygen or sulfur,
R(7) is (C~-C12)-alkyl, (C3-C~2)-cycloalkyl (mono-, bi-
or multicyclic, such a~ norbornyl or adamantyl),
(C3-C~2)-alkenyl, phenyl-thio-phenyl, phenyl-oxy-
phenyl, biphenylyl, phenyl-methyl-phenyl,phenyl,
thienyl, the aromatic ring systems mentioned and
the heteroaromatic ring 6ystem mentioned being
unsubstituted or monosubstituted or polysubsti-
tuted by F, Cl, Br, (C,-C1B)-alkyl, (C1-C1B)-alkoxy,
(C2-C18)-alkenyloxy, CF3, C2F5, (C1-C1a)-alkylthio.
Particularly preferred compounds of the formula I are
those in which
R(l) is H, C(O)-(C1-C4)-alkyl, C(O)-phenyl
R(2) is H, (C1-C15)-alkyl, (C1-C6)-alkyl-oxy-(C~-C6)-
alkyl, (C~-C6)-alkyl-thio-phenyl, (C1-C6)-alkyl-

2~780~7
-- 8 --
oxy-phenyl, (C2-Cls)-alkenyl, (C3-Cl2)-cycloalkyl
(mono-, bi- or multicyclic, such as norbornyl,
adamantyl, decahydronaphthyl), phenyl-(Cl-C6)-
alkyl, diphenyl-(Cl-C6)-alkyl, phenyl, the phenyl
systems being unsub~tituted or monosubstituted or
disubstituted by substituents selected from the
group comprising F, Cl, (Cl-C6)-alkyl, (C3-C6)-
cycloalkyl,(Cl-C~O)-alkoxy,(Cl-C4)-alkylenedioxy,
phenoxy, phenyl, benzyl, phenethyl, thiophenyl,
CF3,
or
R(2) is an indol-3-yl-(Cl-C4)-alkyl, thienyl or thien-
ylmethyl radical, the thienyl ring being
unsubstituted,
or
R(2) is piperidin-4-yl, substituted by 1 to 4 methyl
groups and having a hydrogen, an acetyl group, a
phenyl group or a benzyl group on the N atom of
the piperidine,
R(3) is hydrogen,
A is (Cl-Cl8)-alkyl, (C2-ClB)-alkenyl or a group
R ( 4 )
,~
R(5)
R ( 6 )
in which the radicals R(4), R(5) and R(6) have the
following meaning:

207~7
g
R(4) is H, (Cl-Cl2)-alkyl, (C3-Cl2)-alkenyl, (C3~Cl2)~
cycloalkyl (mono-, bi- or multicyclic), Y-
(Cl-Cl2)-alkyl, Y-(c3-cl2)-alkenyll Y-(C3-C~2)-
cycloalkyl (mono-, bi- or multicyclic), phenyl,
Y-phenyl, phenyl-(Cl-C6)-alkyl, phenyl-(Cl-C4)-
alkoxy, biphenylyl, F, Cl, CF3, the phenyl systems
being unsubstituted or monosubstituted or
disubstituted by F, Cl, CF3, (C,-C4)-alkyl,
(Cl-C4)-alkoxy,
where Y equals oxygen or sulfur,
R(5) i 6 defined as R(4), R(4) and R(5) being identical
or different, or
R(6) is ~ ( Cl-C4 ) -alkyl, Y-( Cl-c4 ) -alkyl, F, Cl,
X is oxygen or sulfur,
R(7) is (Cl-C~O)-alkyl, (C3-C~2)-cycloalkyl (mono-, bi-
or multicyclic, such as norbornyl or adamantyl),
phenyl-thio-phenyl, phenyl-oxy-phenyl, biphenyl-
yl, phenyl-methyl-phenyl, phenyl, the aromatic
ring systems mentioned being unsubstituted or
monosubstituted or polysubstituted by F, Cl,
(Cl-C4)-alkyl, (Cl-C4)-alkoxy, CF3,
( C~-C4 ) -alkylthio.
Very particularly preferred compounds of the formula I
are those in which
25 R(l) is H,
R(2) is H, (C,-C,5)-alkyl, (C,-C6)-alkyl-oxy-(C,-C6)-
alkyl, (C,-C6)-alkyl-thio-phenyl, (Cl-C6)-alkyl-
oxy-phenyl, (C3-Cl2)-alkenyl, (c3-clo)-cycloalk
(mono-, bi- or multicyclic, such as norbornyl,
adamantyl, decahydronaphthyl), phenyl-(Cl-C4)-

2078a~7
-- 10 --
alkyl, diphenyl-(Cl-C6)-alkyl, the phenyl systems
being unsubstituted or monosubstituted or disub-
stituted by substituents selected from the group
comprising F, Cl, (C,-C6)-alkyl, (C3-C6)-cycloal-
kyl, (C1-C1O)-alkoxy, (C1-Cz)-alkylenedioxy~
phenoxy, phenyl, benzyl, phenethyl, thiophenyl,
CF3,
or
R(2) is an indol-3-yl-(C1-C4)-alkyl, thienyl or thien-
ylmethyl radical, the thienyl ring being
unsubstituted,
or
R(2) is piperidin-4-yl, substituted by 1 to 4 methyl
groups and having a hydrogen, an acetyl group or
a benzyl group on the N atom of the piperidine,
R(3) is hydrogen,
A is a group
R ~ 4 )
,~,
R(5)
R ( 6 )
in which the radicals R(4), R(5) and R(6) have the
following meaning:

2 ~ 7 ~ 7
-- 11 --
R(4) is H~ (Cl-Cl2)-alkyl~ (C3-C12)-alkenyl, ~C3-C12)-
cycloalkyl (mono-, bi- or multicyclic), Y-
(Cl-C12)-alkyl, Y-(C3-C12)-alkenyl, Y-~C3-cl2)
cycloalkyl (mono-, bi- or multicycliC), phenyl,
Y-phenyl, phenyl-(C1-C6)-alkyl, phenyl-~Cl-C4)-
alkoxy, F, Cl, the phenyl systems being unsubsti-
tuted or monosubstitutecl or disubstituted by F,
Cl, CF3, (C1-C4)-alkyl, (C1-C4)-alkoxy,
where Y ecluals oxygen or sulfur,
0 R(5) is defined as R(4), R(4) and R(5) being identical
or different,
R(6) is H, (C1-C4)-alkyl, Y-( C~-C4 ) -alkyl,
X is oxygen,
R(7) is (C,-C4)-alkyl, (C3-Cl2)-cycloalkyl (mono-, bi-
or multicyclic, such as norbornyl or adamantyl),
phenyl-thio-phenyl, phenyl-oxy-phenyl, biphenyl-
yl, phenyl, the aromatic ring 6ystems mentioned
being unsubstituted or monosubstituted or disub-
stituted by F, Cl, (Cl-C4)-alkyl, (Cl-C4)-alkoxy,
CF3, ( C~-C4 ) -alkylthio.
Racemates can be resolved into the enantiomers by custom-
ary methods, for example by salt formation with an
optically active acid, separation of the diastereomeric
salts and liberation of the pure enantiomers by means of
a base. Moreover, the enantiomers can also be resolved by
means of chromatography on chiral phases or
enzymatically.
The invention furthermore relates to a process for the
preparation of compounds of the formula (I), which
comprises reacting a compound of the formula (II)

2078~7
- 12 -
// (II)
A - X - CH2 -'~
R ( 7 )
in which R(7), A and x have the meanings mentioned, with
a sulfur ylide of the formula III
(H3C)2S = CHi~
ll (III)
(O)p
in which p is zero or 1,
to give a compound of the formula IV
07
A - X - CH2 V R ( 7 ) (IV),
and subsequently reacting the compound IV with a
nucleophile of the formula M~R(2)R(3) in which R(2) and
R(3) have the meanings mentioned and M i8 hydrogen or a
metal equivalent, giving a compound I where R(1) = H,
which is isolated in the form of the free base, of an
acid addition salt or of a physiologically hydrolyzable
derivative.

2a78~
- 13 -
To prepare the compounds of the formula (I), a ketone of
the formula (II) in which R(7), .A and X have the above-
mentioned meanings is reacted, in a first reaction step
for the preparation of the compou,nds of the formula (IV),
with a sulfur ylide of the formula (III) in an inert
solvent, preferably dimethyl sulfoxide or tetrahydrofur-
an, or in mixtures of dimethyl sulfoxide with other inert
solvents, for example tetrahydrofuran. A temperature
range of from -10 to 50C, preferably from 0 to 30C,
is expedient if a sulfur ylide of the formula (III) is
used where p = zero; if a sulfur ylide of the form-
ula (III) is used where p = 1, then a temperature range
of from 0 to 80C, preferably from 20 to 60C, is
expedient.
The intermediates of the formula IV are converted into
the end products of the formula I where R(1) = H in a
second reaction step by reaction with a compound of the
formula MNR(2)R(3) in which R(2), R(3) and M have the
abovementioned meanings.
This reaction is effected in a temperature range of from
20 - 160C, if appropriate in an inert solvent.
Examples of suitable solvents are N,N-dimethylformamide,
N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, N-
methyl-2-pyrrolidone, dioxane, tetrahydrofuran, acetoni-
trile, 4-methyl-2-pentanone, methanol, ethanol, isopropyl
alcohol, propanol, butanol, pentanol, tert-butyl alcohol,
methyl glycol, methylene chloride or an aromatic hydro-
carbon such as benzene, chlorobenzene, nitrobenzene,
toluene or xylene, or water. Mixtures of the solvents
which have been mentioned by way of example can also be
used.
The reaction of the compounds of the formula II with the
compounds of the formula III to give the intermediates of
the formula IV, and their reaction with compounds of the

2078~.57
- 14 -
formula MNR(2)R(3) to give compounds of the formula I
where R(l) = H can also be carried out in the form of a
one-pot process.
To this end, a solution of a compound of the formula IV
in one of the abovementioned inert solvents is first
prepared as indicated above by reacting a compound of the
formula II with a compound of the formula III. At least
an equivalent amount of a compound of the formula
HNR(2)R(3) is subsequently added to this solution.
Compounds of the formula I in which R(l) has the meanings
mentioned and is not hydrogen, are prepared by reacting
a compound of the formula where R(l) = H with a
corresponding alkyl halide, alkenyl halide or henzyl
halide, preferably a chloride, bromide or a tosylate or
mesylate, in the presence of a base, in an inert solvent,
in a temperature range of from 0 - 100C. The solvents
used are preferably those which are indicated for the
reaction of compounds of the formula IV with M-NR(2)R(3),
and bases which are suitable are, for example, inorganic
bases such as carbonates, hydrogen carbonates, hydrox-
ides, alcoholates or hydrides of alkali metals or alkal-
ine earth metals, for example sodium carbonate, sodium
hydrogen carbonate, potassium carbonate, sodium hydrox-
ide, sodium methylate or sodium hydride, or organic bases
such as tert-amines, such as triethylamine, ethylmor-
pholine or, for example, DBU, imidazole or pyridine.
Compounds of the formula I in which R(l) has the meaning
of C(0)-(Cl-C8)-alkyl or -C(0)-phenyl are prepared by
reacting a compound of the formula I where R(l) equals H
with a compound of the formula Va or Vb
R(l)-Q R(l)-0-R(l)
Va Vb

2078~)~7
- 15 -
where Q equals hydroxyl, halogen, such as chlorine or
bromine, or an imidazolide. To do so, a procedure is best
followed in which equimolar amountg or an up to 50-fold
excess of a compound of the formula I where R(l)
equals H, if appropriate in an inert, aprotic solvent
such as chloroform, dichloromethane,
tetrahydrofuran (THF) or dioxane, are reacted with a
compound of the formula Va until the reaction is
complete, if appropriate in the presence of a base,
preferably pyridine or triethylamine. If a compound of
the formula Va where Q equals OH is employed, then it is
recommended that dicyclohexylcarbodiimide (DCC), if
appropriate in the presence of a catalyst such as N,N-
dimethylaminopyridine (DMAP) is added. If Vb tan acid
anhydride) is used,
R(l)-O-R(1) Vb
then the process can be carried out without or with a
catalyst such as DMAP or 4-pyrrolidinopyridine (PPY). The
reaction temperatures here are between -70C and +120C,
preferably, if a solvent is used, between the melting
point and the boiling point of the solvent, in particular
between -30 and +60C. The reaction times are 1 to
180 hours, preferably 1 to 48 hours, particularly prefer-
ably 1 to 8 hours.
Compounds of the formula I which contain a thioether
group can be oxidized on the sulfur to give a sulfoxide
or sulfone. To this end, such compounds of the formula I
are reacted in an inert solvent and in a temperature
range of from -10 to 80C with an oxidant, for example
hydrogen peroxide or m-chloroperbenzoic acid. To prepare
sulfoxides, one mole equivalent of oxidant is employed
for this purpose, and for the preparation of sulfones two
mole equivalents, or, if appropriate, an excess.

2378a~7
- 16 -
Solvents which are preferably uied are tho~e indicated
for the reaction of compounds of the formula IV with
M-NR(2)R(3).
The invention furthermore relates to a process for the
preparation of the compounds of the formula I, in which
a compound of the formula II
ll (II)
A-X-CH2-C-R(7)
in which R(7), X and A have the meanings mentioned, is
reacted with a phosphorus ylide to give a compound of the
formula VI
C H 2
A - X - CH2 - ~ (VI)
R ( 7 )
and the compound VI is subsequently reacted with a
peroxide to give a compound of the formula IV
07
A - X - CH2 V R ( 7 ) (IV)
and IV is reacted further as already mentioned above with
a nucleophile of the formula M-NR(2)R(3) in which R(2)
and R(3) have the meanings mentioned and M is hydrogen or
a metal equivalent, giving a compound I where R(1) equals

207~57
hydrogen, and, if desired, this compound I is alkylated,
alkenylated, benzylated or esterified and, if
appropriate, oxidized on the sulfur of a thioether group
to give the sulfoxide or sulfone,
and, if appropriate, the product iB converted into the
salt with a physiologically acceptable acid, or into a
physiologically hydrolyzable derivative.
To prepare the compound~ of the formula I, a ketone of
the formula II in which A, X and R(7) have the
abovementioned meanings i8 reacted, in a first reaction
step to prepare compounds of the formula V, with a
phosphorus ylide in an inert solvent at a temperature of
from -60 to +80C.
The phosphorus ylide used here is prepared by reacting a
methyltriarylphosphonium salt, preferably
methyltriphenylphosphonium chloride, methyltriphenyl-
phosphonium bromide or methyltriphenylphosphonium iodide,
with a strong base in an inert solvent. Examples of
suitable bases are alkali metal hydrides, alkali metal
amides, alkali metal alcoholates, alkaline earth metal
hydrides, alkaline earth metal amides or alkaline earth
metal alcoholates, sodium bistrimethylsilylamide or
lithium organyls such as n-butyllithium or phenyllithium.
The solvents used are those indicated for the reaction of
compounds of the formula IV with M-NR(2)R(3).
In a second reaction step for the preparation of com-
pounds of the formula IV, a compound of the formula VI is
reacted with an oxidant in an inert solvent at a tempera-
ture of from -10 to +80C, if appropriate in the presence
of a base and of a nitrile, for example benzonitrile, or
thionylbisimidazole or -triazole.
Examples of suitable oxidants are HzO2 or percarboxylic
acids such as, for example, peracetic acid, trifluoroper-

2~78a~r~
- 18 -
acetic acid, perbenzoic acid or m-chloroperbenzoiC acid.
The solvents used are those indicated for the reaction of
compounds of the formula IV with M-NR(2)R(3).
In a third reaction step for the preparation of compounds
of the formula I where R(1) c ~I from compounds of the
formula IV, the procedure is as indicated in the process
above.
These compounds of the formula I where R(1) ~ H can, if
desired, be alkylated, alkenylated, benzylated or esteri-
fied and oxidized to give compounds where R(1) isnot equal to H, and, if appropriate, converted with a
physiologically acceptable acid into the salt as
indicated in the process above.
Preparation of the starting substances
The preparation of compounds of the formula II i8 known
from the literature. For example, an ~-haloketone of the
formula VII:
,1~
¦ R(7) (VII)
Hsl
is reacted with a phenol or thiophenol in an inert
solvent such as acetone, using a base (for example X2CO3).
Examples of suitable bases are carbonates, hydrogen
carbonates, hydroxides or hydrides of alkali metals or
alkaline earth metals such as, for example, sodium
carbonate, sodium hydrogen carbonate, potassium carbon-
ate, sodium hydroxide or sodium hydride.

2078~7
-- 19 --
The compounds of the formula VII are either commercially
available or can be synthesized by halogenating the
corresponding aryl methyl ketones by processes known from
the literature.
The compounds of the formula I, their acid addition salts
and their physiologically hydrolyzable derivatives are
valuable pharmaceuticals. They have, in particular, an
antimicrobial action and are suitable for preventing and
treating fungal infections in humans and in various
mammalian specie6.
The invention also relates to the preparation and the use
of the compounds of the type I in the form of the free
bases or of an acid addition salt as potent inhibitors of
the exoenzymes of fungi, or as antimycotics.
Examples of pharmaceutically acceptable salt-forming
acids are inorganic acids such as hydrochloric acid,
hydrobromic acid, hydroiodic acid, ~ulfuric acid, phos-
phoric acid or nitric acid, or organic acids such as
malonic acid, oxalic acid, gluconic acid, camphorsulfonic
acid, benzenesulfonic acid, acetic acid, propionic acid,
p-toluenesulfonic acid or salicylic acid.
The compounds I have at least one asymmetrical C atom and
can therefore exist in the form of enantiomers and
diastereomers. The invention embraces the preparation and
the use of the pure isomers as well as their mixtures.
Mixtures of diastereomers can be resolved into the
components by customary methods, for example by selective
crystallization from suitable solvents or by chromato-
graphy on silica gel or aluminum oxide.
The compounds of the formula I, their acid addition salts
and their physiologically hydrolyzable derivatives are
valuable pharmaceuticals. They have, in particular, an
antimicrobial action and are suitable for preventing and

2~781~
- 20 -
treating fungal infections in humans and in various
mammallan specles.
The compounds have a very good in vitro activity against
dermatomycetes such as, for example, Trichophyton
mentagrophytes, Microsporum canis, Epidermophyton
floccosum; against molds such as, for example,
Aspergillus niger, or against yeasts such as, for
example, Candida albicans, C. tropicalis, Torulopsis
glabrata and Trichosporon cutanuem or against Protozoa
such as Trichomonas vaginalis or T. fetus, or else
against Gram-positive and Gram-negative bacteria.
After oral or parenteral administration, the compounds
also have a very good systemic effect in vitro, for
example against Candida albicans, for example in experi-
mental renal candidosis in mice. In this case, in parti-
cular the exoenzyme system of the yeast Candida albicans
is affected in such a way that the pathogenicity of the
pathogens is markedly reduced. There is also a very good
effect against various pathogens of dermatomycoses (for
example Trichophyton mentagrophytes) in guinea-pigs after
oral, parenteral or local administration.
- Examples of indication areas in human medicine which may
be mentioned are: dermatomycoses and systemic mycoses
caused by Trichophyton mentagrophytes and other
Trichophyton species, Microsporon species, Epidermophyton
floccosum, and biphasic fungi, as well as molds.
In particular, deep mycoses caused by Candida albicans
are affected favorably since penetration of the fungi
into the host cell is prevented or hindered.
Examples of indication areas in veterinary medicine which
- may be mentioned are:

2~78~7
- 21 -
All dermatomycoses and systemic mycoses, in particular
those caused by the abovementioned pathogens.
The present invention includes pharmaceutical prepara-
tions which contain one or more active ~ubstances in
addition to non-toxic, inert pharmaceutically suitable
carriers, or which are composed of one or more active
substances used according to the invention, and processe~
for manufacturing these preparations.
Non-toxic, ~nert pharmaceutically suitable carriers are
to be understood as meaning solid, semi-solid or liquid
diluents, fillers and formulation auxiliaries of any
type.
An inhibitor for the various phospholipases of Candida
albicans must be present in adequate concentrations in
the patient in all regions where the fungus can colonize
the parenchyma. A precondition for this is the fact that
the appropriate substances must be administered in a
concentration which has previously proven effective in
animal experiments.
When patients show severe symptoms of deep candidosis,
they are frequently in a very poor general state. ~igh
temperature and other diseases can frequently be found.
When deciding on the dosage rate, a difference must be
made between prophylactic administration and therapy in
the case where an infection has been established. In
prophylaxis, it can be assumed that the general state of
the patients is better, which allows oral administration.
Tablets, solutions, gels or inspissated juice can be
used. In forms where deep candidoses have been estab-
lished, it must frequently be assumed that controlledoral resorption of the active substances is not always
guaranteed. In this case, parenteral administration forms
are suitable. In exceptional cases, subcutaneous
administration may also be considered.

207~a57
- 22 -
Candidates for prophylaxis are mainly immunocompressed
patients who are in this situation due to strain caused
by medicaments or due to endogenous immunity problems.
These are, in particular, transplant patients, diabetics
and/or patients suffering from adiposis, AIDS patients,
patients under chemotherapy, long-term ventilation
patients, and others.
Some of the compounds inhibit the phospholipase of
Candida albicans to an extent which is far below the
minimum inhibitory concentrations of the active substanc-
es to Candida albicans which have been determined in
vitro. The dosage rate can therefore in many cases be
below the rate which would be necessary for a purely
antimycotic therapy.
The action within the patient is based on the fact that
the active substances have two different effects on the
Candida cells in the vicinity of the parenchyms. On the
one hand, adhesion of the yeast cells to the somatic
cells is prevented and, on the other hand, Candida
albicans is prevented from penetrating the somatic cells
with germination tubes.
This dual concept of action prevents the yeast from fully
exploiting its pathogenicity. However, it must be men-
tioned that in addition to the phospholipases Candida
albicans also has other pathogenicity mechanisms such as,
for example, the protease. Adhesion to endogenous cells
is, however, the first step towards penetration. Since
this adhesion is prevented by phospholipase inhibitors,
the other pathogenicity mechanisms cannot be utilized
fully.
Suitable formulations are, for example, tablets, coated
tablets, capsules, pills, aqueous solutions, suspensions
and emulsions, optionally sterile solutions for injec-
tion, non-aqueous emulsions, suspensions and solutions,

2~7~.57
- 23 -
ointments, creams, pastes, lotions, gprays etc.
The abovementioned pharmaceutical preparations should
contain the prophylactically ancl therapeutiCallY active
compounds preferably in a concentration of about 0.1
to 99.5, preferably approximately 0.5 to 95, % by weight
of the total mixture.
The abovementioned pharmaceutical preparations can also
contain other pharmaceutical active substances in addi-
tion to the active substances used according to the
lQ invention.
The abovementioned pharmaceutical preparations are
prepared in the customary manner by known methods, for
example by mixing the active substance, or active sub-
stances, with the carrier, or carriers.
The present invention includes the use of the active
substances according to the invention and the pharmaceut-
ical preparations which contain one or more active
substances according to the invention in human and
veterinary medicine for preventing, alleviating and/or
curing the abovementioned diseases.
The active substances or the pharmaceutical preparations
can be aclministered locally, orally, parenterally,
intraparenterally and/or rectally.
In general, it has proved advantageous in both human and
veterinary medicine to administer the active substance,
or active substances, used according to the invention in
total amounts of from at least about 0.05, preferably
0.1, in particular 0.5, mg/kg of body weight up to not
more than about 200, preferably up to 100, in particular
up to 10, mg/kg of body weight per 24 hours, if
appropriate in the form of several individual doses, to
achieve the desired results. The total amount is

2~78~.~7
- 24 -
administered in 1 to 8, preferabLy in 1 to 3, individual
doses, but over considerably longer period~ (up to
6 weeks) in the case of deep mycoses.
However, it may be necessary to deviate from the dosage
rates mentioned, namely as a function of the species and
the body weight of the subject to be treated, the nature
and severity of the disea~e, the nature of the prepara-
tion and administration of the pharmaceutical, and the
period or interval within which the administration is
effected. Thus, in some cases it may suffice to make do
with less than the abovementioned amount of active
-- substance, while in other cases the abovementioned amount
of active substance must be exceeded. The decision with
regard to optimum dosage rate and type of application of
the active substances which are necessary in each case
can be made easily by anyone skilled in the art due to
his expert knowledge.
Example 1
Synthesisof2-t-butyl-1-(2,4-dichlorophenoxy)-3-isoprop-
yl-amino-2-propanol (I.7)
C i o Cl
~~ V~ (CH~)~5 (O) I, NaH ~~
/~ ! DVSO, 25 'C ~J
I . 7 IV.7
ClOH
isopropylamine o ~ NH
ethanol, H20
Cl l 7
(2 steps)

2~78i~.57
- 25 -
a) Preparation of the oxirane :rv. 7
1.5 g of trimethylsulfoxonium iodide (6.8 mmol) are
dissolved in 30 ml of ab~olute ~MSO, 0.195 g (6.5 mmol)
of sodium hydride ~80 % suspens:ion in mineral oil) are
added, and the mixture iB stirred until the evolution of
gas has ceased (approx. 30 minutes). 1.51 g (5.8 mmol) of
1-(2,4-dichlorophenoxy)-~,3-dimethyl-2-butanone~ di~-
solved in 5 mi of absolute DMSO, are subsequently added
at 25C, and the reaction mixture is stirred for 1 hour
at 25C and for 2 hours at 40C.
For work-up, the reaction mixture is poured into water
(400 ml), and the aqueous phase i9 extracted four times
using 100 ml portions of dichloromethane. The combined
organic phases are washed four times with 100 ml portions
of water and dried over Na2SO4, the drying agent is
filtered off, and the mixture is concentrated on a rotary
evaporator under reduced pressure.
Yield: 1.24 g (78 %, 4.5 mmol, colorless oil).
The crude product is reacted directly, without further
purification steps.
b) Reaction with isopropylamine
1 g of the oxirane prepared under a) t3.63 mmol) are
dissolved in 30 ml of ethanol, and 6.38 ml (4.43 g,
75 mmol) of isopropylamine and l ml of water are added.
The reaction mixture is refluxed for 12 hours. The course
of the reaction is monitored by thin-layer chromatography
(silica gel plates, mobile phase: dichloromethane/ethyl
acetate = 1/1).
For work-up, the solvent is removed on a rotary evaporat-
or under reduced pressure, and the crude product obtained
is chromatographed over silica gel (Silica Gel 60,
manufactured by Merck 0.043 - 0.060 mm, mobile phase:
CH2Cl2/methanol z 19/1).

2~78~7
- 26 -
Yield: 0.972 g (2.9 mmol, 80 % of theory), colorless oil.
RF (CHzCl2/ethyl acetate = 1:1 silica gel glass plates)
= 0.18.
Example 2
Synthesis of 3-N-benzylamino-2-t-butyl-l-(4-hept
phenyloxy)-2-propanol (I.l9)
(2 steps)
C H 3 - ( C H 2 ) 6 - ~ ~( C H ~ S ( O ) I
I I .19
7 benzylamine
CH~-(CH2)6-0 ~ ~ l20C
IV.l9
O H
CH3- ( CH~ ) 6- ~ O ~NH,J3
I . 19

2~78~57
- 27 -
a) Preparation of the oxirane IV.l9
7.37 g (33.5 mmol) of trimethylsulfoxonium iodide are
introduced into 150 ml of absolute tetrahydrofuran, and
0.88 g (29 mmol) of sodium hydride (80 % ~uspension in
paraffin oil) i8 added in portion6 under an N2 protective
gas atmosphere. To deprotonate the mixture completely, it
is refluxed for 2 hours, with stirring. 7.67 g (25 mol)
of 3~3-dimethyl-l-(4-heptyloxy-phenyloxy)-2-butanone~
dissolved in 40 ml of absolute THF, are subseguently
added, and the reaction solution i~ heated for 6 hours at
40C.
For work-up, the reaction mixture is poured into 400 ml
of ice-water, and, after phase separation, the aqueous
phase is extracted using 4 x 100 ml of ethyl acetate. The
combined organic phases are washed with 4 x 100 ml of
water and dried over Na2S04. After the drying agent has
been removed by filtration, the solvent is removed under
reduced pressure.
According to lH NMR spectra, the yellow solid residue has
the structure indicated and a purity of approx. 96 %.
Yield 6.9 g (87 ~), yellow solid
RF (silica gel glass plates, mobile phase CH2Cl2): 0.42
b) Reaction of the oxirane IV.19 with benzylamine
1 g (3.14 mmol) of the oxirane from a) is dissolved in
6 ml of benzylamine and heated for 2 hours at 120C.
After most of the benzylamine has been removed by means
of bulb tube distillation under an oil pump vacuum
(0.1 mbar), the product is chromatographed over a silica
gel column (mobile phase: CH2Cl2/MeOH = 40:1).
The reaction product is subsequently recrystallized from
heptane.

2 0 7 ~
- 28 -
Yield: 1.002 g (2.3 mmol, 75 ~)
Melting point: 52C
Other compounds of the formula I where R(l) - H which
were prepared analogously to Examples 1 and 2, but using
corresponding compounds of the formula IV and MNR(2)R(3),
are those listed in Table 1. ExampleQ 1 and 2 are con-
tained in ~able 1 under I.7 and I.l9.

2~78~7
-- 29 --
M.p.: oil
OH CH, EA: calc . f ound:
Cl--~3 ~`'~ CH3 C 66.06% C 6 5 0
H 8.99% H8 9
J Cl 11.30%
N 4.46% N4 . 5
O 10.19%
H C
M . p .: oil
OH CH3 EA: calc .: f ound :
--CH3 C 684 79% 8 8
HN Cl 11.82%
N 4 67% 4 . 8
O 1067%
H3C\ CH3
M.p.: oil
OH CH, EA: calc .: f ound :
3 ~ CH3
Cl= o HN CH3 C66.06% 6 5 . 2
H8.99% 9.1
H3C ~ Cl11 30/O 4 . 6
\~ O 10.19%
H,C

2~7~7
- 30 --
M.p, oil
OH CH~ calc .: f ound :
1 . 4 ~ ~ CH~
C74.77%74 7
H9.15% 9 3
\~CH, N3i63-/;3 . 7
M . p . resin
1 - OH CH~ calc .: f ound :
~ '/~ C74 77%7 4 . 82
H9.15% 9-
H3C C~3 N3.63%3 . 8
~=9 ,H3 012.45%
M.p.: oil
OH CH3 EA: calc .: f ound :
1 . 6 ~ /~CH~
HN C 74.36% 7 4 5
H3C 1 CH3 N3.77% 3 7

2~78~
- 31 -
M.p-: oil
1 . 7Cl OH CH~ EA: calc.: found:
Cl= ~/ T CH~
CH~ C 57.49%5 7 . 4
\=/ HN Cl 21 210;o 7 . 6
N 4.19%4 3
O 9.57%
H~C ~ CH~
M.p.: oil
Cl OH CH~ EA: calc. found-
= CH~
HN C 58.62%58 . 6
Cl 2~086O/;D 79
H~C I--CH~ N 4.02% 4 1
CH~
M.p.: oil
1 9 Cl OH CH~ EA: calc.: found:
Cl ~ O~ CH~
C 58.62%58. 6
\ Cl 27 86o/; 7 . 9
. N 4.02%4 . 2
O 9.19%
CH~

- 32 - 207~7
M.p.: oil
EA: calc.: found:
1.10 OH CH~
H~C ~ O ~ CH3 C 75.19% 74.2
HN N 4.38-/ 40 64
CH~ ¦ O 10.02%
,~ /\
M.p.: oil
EA:calc.: found:
OH CH~
1.,, 1 1
~ CH3
H~r \ ~ O ~ CH~C 75.17% 7;.2
j ~ HN H 11.12% 11 3
CH~ ~ N 417% 4 3
CH~
M.p.: oil
EA: calc.: found:
1.12 OH CH~
H~C ~ O ~ CH~ C 74.72% 74.8
HN H 10.97% 10.8
CH~ l N 4360/; 4.4
H~C CH~

2~78~
- 33 -
M.p.: oil
OH CH, EA:calc.: found:
H,C ~)_ /~ CH,
CH HN C 78.00% 78 . 2
3 H9.55% 9 6
\~ 03 660/3 8
M.p.: oil
1 ~ OH CH, EA: calc.: found:
H,~o ~CH, C76.34%76.4
3 H1 1 .48% 11 6
H3C~ ~,CH3 N3 71% 3 9
CH, CH,
M.p.: oil
1 .1; HO EA: calc .: found:
CH
C80.70%8 0 . 8
\~ H8.64% 8 . 6
~ / N3.25%
H C~CH, O741%
CH,

- 34 - 2~78~7
M.p.: oil
1.16 ~ EA: calc.: found:
~0
C81 .~2%8 1 . 7
~ ~ CH H9.82/~9: 9
$ O 5.88-/
H~C + CH~
CH3
A M.p.: oil
17 ~ EA:calc.: found:
~N J
C 76.58% 7 6.6
H 9.38Yo 9 5
I CH3Cl 6 11%
H Cl~ N 241% 2.7
O 551%
H3C - ~ CH~
CH~
M.p. oil
EA: calc.: found:
1 . 18 OH CH~
o ~ o/;~,
_/ I C73.24% 7 3 3
~ N3.56-Jo 3 5 8
H3C H~C

2~78a~
-- 35 --
M.p-: oil
EA: calc .: f ound :
OH CH,
~ /~' C 75.84% 7 5 . 9
H,C ~ N 3 28/; 3 3
M . p .: re6in
EA: calc .: f ound:
' OH CH,
/--/ ~ H~
~ ~H~C--LCH C 75.55% 7; . 3
H~C ~ N 5 51% 5 6
M.p.: oil
1 . 21 ~o OH CH, EA: calc.: found:
/--/ \~ CH,
-- H,C CH,
H,C O ~J H 9 300/o 9 3
o~J O 1268470/~ 3 . o
CH,

2~78~57
-- 36 --
M.p.: oil
1 . 2 2
EA calc .: f ound :
~ O OH CH,
H~C ~ H 9.29 / 9 1
~3 0 9.03% . 6
M.p.: oil
<~ \~CH, EA: calc .: f ound :
~_~ HN
/--/ J C75.99%7 5 7
H~C ~/ N2 77 ~o 1 2 8
O 9.49%
H~C
M . p .: oil
EA: calc .: found :
O ~ O OH CH~
/--/ \~ CH~
-- CH~ C72.78%7 3 . O
~ HN N3.69% 3 6
H,C H,C CH, O12.64%

207~57
-- 37 --
M. p : oil
1 . 2 5
EA: calc .: f ound :
--J~ N 2.51.Y 2.6
H,C
M.p.: oil
EA: calc .: f ound :
1.25
O ,HN J~3
11 H3C T CH3 C 78.94% 7 8 . 9
CH3 N 3 54% 3
O 8.09% '
M . p .: oil
1 . 27 OH EA: calc.: found:
[~ ~3 CH, H 190.. 2713% 10 9

- 38 - 2~78a5~
M.p.: oil
1.28 EA:calc.: found:
OH
CH ~ C 78.S9%78.7
H 11.70%11.6
~_~,H,C~ ~_~_~ N 296%3 0
M.p.: resin
1.29 ~ EA: calc.: found:
OH ~
O~HNJ C79.17~o 79 . 2
H~C ~ CH3 H9.60% 9 8
CH, O7 81C~o 3 4
~f
M.p.: oil
EA:calc.: found:
1.30 OH
,- ~ CH, CH, H :037% 0 9
8.85% 3. 9

- 39 - 2~7~7
H,C CHl 28 42 2 3
>~ N found: -alc.:
~H CH, H9'4 769'967
~-t C CH, O 10,56
CH,
1.32 C23H33N3
~ found: calc:
H C74,1 74,36
~O ~, CH, H3 8 3,77
C26H31N3
Oh ~ found calc.:
~O~N~J~ C76 ~3 77 01
'',~ . c~, N3,4 3,45
-CH, O11,84
. C31H49~03
Oh H found: calc.:
C77,1 76,97
~,c
1.3, C38H65N3
found: calc.:
~=a C78,4 78,16
~,, ~ o~o/~ ~ N2 6 t82,222
~,c ,~r

2 ~ 7
- 40 -
1.36 C27H40CLN2
c~ found: calc.
~,c~ ~,c ,_~ C72,5 72,70
r~ \~ OH H 9,0 9,04
- N3,2 3,14
Cl~ H l7 17
C26H38ClN2
c~ found: calc
r - / ~ r C72~4 72,28
, Cl3 8 3.24
29H44CLN2
f ound: calc
o o~ c~ C73 3 73 4,
c~, N3,0 6 75
Cl ~C CH, Cl 7,48
32H4 9ClN22
f ound: calc
O O H C759'3 72,63
Cl6,70
CH,

2~7~7
- 41 -
C33H46CIN2
found: calc.:
c~ C75,8 75,61
H,C ~ OH N 2 5 2 67
u,c ~c ~ O 6,10
~ ~ ~N H Cl 6,76
1 41 C25H29C12N02
found: calc.:
C67,4 67,26
OH H63 2 63 154
~ ~ O 7,17
I Cl 15,88
NH ~ ~Cl
C~ gH23C12N02
found: calc
- C61,8 61,96
H 6,4 6.29
~ Cl 3,80
r, Cl
CH,
C~ 8H21C12N02
found: calc
c ~ C60.8 61,03
o O 3 9 3,95
N H ~CI C1 20.01
H,C--~

2~78~7
- 42 -
1 44 C21H27Cl2N2
found: calc.:
~' C 6'.5 6:i,64
H 6 8 638,,85077
Cl 17,89
~7C
c27~37Cl2No2
found: calc.:
C 67,9 67,78
H 7,8 7,79
Cl 124~682
'~ 'r, Cl
~ C30H39N5
found calc.
O~ H C72,9 72,99
~,o ~ N ~ ~ H7,8 7,96
1.47 C31H51 2
found: calc.:
OH ~ C 80,0 7~26
H ~ H 10,9 10,94
~3C~H C~ ~CH, - ~ N3,12 98
Cli,
~,,

2~7~7
- 43 -
C28 41 2 2
Oh H ~cl found: calc.:
~-~ C68 48 68 306
~ ,C ~ CH Cl ~ 2,8 2,83
h~ I CH, C, 6,47
H,C ~
Ch,
C33H61N2
,~ ~ found: calc :
-3-~ ~,C CH, ~ H2 9 12 728
A~ X ~ O6,35
~A,C
~ C30H47 4
Ch H ~5~CH, found: calc.:
C 74 1 74 19
H,C~CH, H,C N2,8 2,88
h~ Ch~ H,C 13,18
CH,
1._ C33H47N3
OH ~ found: calc.:
o~30/~ 99,2 9 37
~q

2~78~7
- 44 -
1.5~ C30H49N3
O~ ~ found: calc.:
C76,6~6,39
o ~ ~Y H10,610,47
o ~ `NH '--' N3,1 2,97
O 10,17
CH,
34H55NO3
found: calc.:
C!~ C77,477,66
h H ~ H 10 4 12 646
J
~/ ~ ~
rl~C

2~780~7
- 45 -
To determine the enzyme inhibition, a suspension of
Candida albicans blastoconidia (~itrain 200/175), in which
the cell density had been adjusted photometriCallY to an
absorption of 0.5 (500 nm), was mixed with solution of
preparations, or with solvent ~olution as a control,
namely
a) 100 ~l solution of preparation (suspension)
+900 ~1 cell suspension
b) 100 ~1 solvent
+900 ~l cell suspension
5 ~l aliquots of the blastoconidia suspension which had
been incubated for 30 minutes at 21C were added dropwise
onto an agar plate (Sabouraud agar with an addition of
8 ~ egg yolk, 1 mM NaCl, 5 mM CaCl2).
The plate which had been inoculated in this manner was
incubated for 3 days at 37C.
The evaluation was carried out in such a way that
1. the diameter (mm) of the Candida albicans colony
(treated and untreated) and0 2. the total diameter of colony and zone of turbidity
caused by exoenzymes (treated and untreated) was
determined.
Determination of the quotient of treated group and
control group gave a value which was to be regarded as a
measure for enzyme activity.
As can be seen from Table 2, the compound5 used according
to the invention inhibit the exoenzymes freed to a
considerably greater extent than propranolol.
Propranolol is described in the literature (Pappu A.S. et
al. in Biochem. Pharmacol. 34, 521-24, 1985) as the most

2~7~7
- 46 -
effective substance which showed an inhibitory action to
phospholipase from liver cells in a suitable in vitro
test.
The compounds I used according to the invention clearly
outperform the prior art.
Table 2
Percentage inhibition of the freed exoenzymes of Candida
albicans in vitro
PreparationConcentration% Inhibition of
(~m/ml) the phospholipase
1 . 5 100 100
100
1.7 100 100
100 100
lS 10 20
1. 11 100 100
100 100
1. 15 100 100
100
100
100
1.17 100 100
100
100
S 100
1.18 100 100
100
100

2078~7
-- 47 --
100
1 . 19 100 100
100
100
100
1.21 100 100
100
100
1 . 22 100 100
100
1.23 100 100
100
100
100
1 . 24 100 100
100
100
100
20 1.31 100 100
100
100
7.7
1 . 34 100 100
100
100
33.3
6 .3
1.48 100 100
100

2~78~5~
- 48 -
100
100
1 14.3
1.53 100 100
100
100
100
Propranolol 100 30
The fungus-destroying, antimycotic activity of the
compounds was verified with the aid of a few examples
(see Table 3) with reference to the percentage destruc-
tion of Trichophyton mentagrophytes in vitro (~tandard
preparation Rilopirox as comparison 6ubstance).
Table 3
15 Compound ~g/ml
1.17 100 97.8
Rilopirox 100 100
(Values in ~ destruction of Trichophyton mentagrophytes
after 14 hours in distilled water)~

Dessin représentatif