Methods for treating mycoses

Antimycotics containing a compound of the formula ##STR1## where .dbd.Y is .dbd.CH--OCH.sub.3, .dbd.CH--CH.sub.3, .dbd.CH--CH.sub.2 --CH.sub.3, .dbd.CH--SCH.sub.3 or .dbd.N--OCH.sub.3, and X is oxygen, or X may also be NH if Y is .dbd.N--OCH.sub.3, PA1 Z is halogen, nitro, cyano, unsubstituted or substituted organic radicals, OR.sup.12, SR.sup.13, SOR.sup.14, SO.sub.2 R.sup.15, --COOR.sup.16, --CONR.sup.17 R.sup.18, --COR.sup.19, --CR.sup.20 .dbd.NR.sup.21, --N.dbd.CR.sup.22 R.sup.23, --CR.sup.24 .dbd.N--OR.sup.25, --CR.sup.25 R.sup.26 --O--N.dbd.CR.sup.27 R.sup.28 and PA1 U, V, W can be hydrogen or one of the meanings given for Z, or where two of Z, U, V and W in adjacent positions on the phenyl ring can form an unsubstituted or substituted five- or six-membered, aromatic or aliphatic ring which may contain one to three hetero atoms (N, S, O), and R.sup.12 to R.sup.26 are identical or different and are hydrogen, unsubstituted or substituted organic radicals, are used for controlling mycoses.

The present invention relates to antimycotics which contain phenylacetic 
acid derivatives and to the use of these derivatives as antimycotics. 
The use of phenylacetic acid derivatives as fungicides in crop protection 
has been disclosed (EP 178 826, 203 606, 203 608, 226 917, 229 974, 242 
070, 242 081, 244 077, 251 082, 253 213, 254 426, 256 667, 260 794, 267 
734, 270 252, 278 595, 280 185, 291 196, 299 694, 307 103, 310 954, 336 
211, 337 211, 341 845, 342 459, 350 691, 354 571, 363 818, 370 629, 374 
811, 378 308, 378 755, 379 098, 382 375, 385 224, 385 357, 386 561, 393 
428, 393 861, 398 692, 400 417, 405 782, 422 597, 426 460, 459 285, 460 
575, 463 488, 468 684, 468 695 and 468 775). There is no indication of an 
antimycotic action therein. 
We have now found that compounds of the formula 
##STR2## 
where 
.dbd.Y is .dbd.CH--OCH.sub.3, .dbd.CH--CH.sub.3, .dbd.CH--CH.sub.2 
--CH.sub.3, .dbd.CH--SCH.sub.3 or .dbd.N--OCH.sub.3, 
X is oxygen or, if Y is .dbd.N--OCH.sub.3, also NH, 
Z is halogen (F, Cl, Br, I), nitro, cyano, unsubstituted or substituted 
alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or 
substituted aralkyl, unsubstituted or substituted aryloxyalkyl, 
unsubstituted or substituted arylthioalkyl, unsubstituted or substituted 
hetarylalkyl, unsubstituted or substituted hetaryloxyalkyl, unsubstituted 
or substituted hetarylthioalkyl, unsubstituted or substituted alkenyl, 
unsubstituted or substituted aralkenyl, unsubstituted or substituted 
aryloxyalkenyl, unsubstituted or substituted arylthioalkenyl, 
unsubstituted or substituted hetarylalkenyl, unsubstituted or substituted 
hetaryloxyalkenyl, unsubstituted or substituted hetarylthioalkenyl, 
unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, 
unsubstituted or substituted hetaryl, unsubstituted or substituted amino, 
unsubstituted or substituted arylazo, unsubstituted or substituted 
acylamino, OR.sup.12, SR.sup.13, SOR.sup.14, SO.sub.2 R.sup.15, 
--COOR.sup.16, --CONR.sup.17 R.sup.18, --COR.sup.19, --CR.sup.20 
.dbd.NR.sup.21, --N.dbd.CR.sup.22 R.sup.23, --CR.sup.24 .dbd.N--OR.sup.25, 
--CR.sup.25 R.sup.26 --O--N.dbd.CR.sup.27 R.sup.28 and 
U, V, W are identical or different and can be hydrogen or one of the 
meanings given for Z, or where two of Z, U, V and W in adjacent positions 
on the phenyl ring can form an unsubstituted or substituted five- or 
six-membered, aromatic or aliphatic ring which may contain one to three 
hetero atoms (N, S, O), and R.sup.12 to R.sup.28 are identical or 
different and are hydrogen, unsubstituted or substituted C.sub.1 -C.sub.8 
-alkyl, unsubstituted or substituted C.sub.2 -C.sub.8 -alkenyl, 
unsubstituted or substituted C.sub.2 -C.sub.8 -alkynyl, unsubstituted or 
substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, 
unsubstituted or substituted aryl, unsubstituted or substituted hetaryl, 
unsubstituted or substituted aralkyl, unsubstituted or substituted 
hetarylalkyl, unsubstituted or substituted aryloxyalkyl, unsubstituted or 
substituted arylthioalkyl, unsubstituted or substituted hetaryloxyalkyl or 
unsubstituted or substituted hetarylthioalkyl, 
have a good antimycotic action. The compounds and the preparation thereof 
have been disclosed (see the European Laid-Open Applications mentioned at 
the outset). 
One aspect of the invention relates to antimycotics which contain compounds 
of the formula 1 where U, V and W are identical or different and are 
hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, 
trifluoromethyl, methyl or methoxy. 
Another aspect of the invention relates to antimycotics which contain 
compounds of the formula 1 where U, V and W are hydrogen. 
Another aspect of the invention relates to antimycotics which contain 
compounds of the formula 1 where Z is OR.sup.12 or SR.sup.13, and R.sup.12 
and R.sup.13 have the abovementioned meanings. 
Another aspect of the invention relates to antimycotics which contain 
compounds of the formula 1 where R.sup.12 and R.sup.13 are unsubstituted 
or substituted alkyl, unsubstituted or substituted aryl, or unsubstituted 
or substituted five- or six-membered hetaryl with 1 to 3 hetero atoms (N, 
O, S). 
Another aspect of the invention relates to antimycotics which contain 
compounds of the formula 1a 
##STR3## 
where U, V, W, X and Y have the abovementioned meanings, and --A-- is 
--CR.sup.30 .dbd.CR.sup.31 --, --CHR.sup.+ --CHR.sup.31 --, 
--O--CHR.sup.30 --, --CHR.sup.+ --O--, --CHR.sup.30 --S--, --S--CHR.sup.30 
--, --O--N.dbd.CR.sup.30 -- or --CHR.sup.30 --, and where R.sup.29 is 
unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, 
unsubstituted or substituted aryl, unsubstituted or substituted hetaryl, 
unsubstituted or substituted aralkyl, unsubstituted or substituted 
hetarylalkyl, and R.sup.30 and R.sup.31 are identical or different and are 
hydrogen or straight-chain or branched C.sub.1 -C.sub.4 -alkyl. 
Another aspect of the invention relates to antimycotics which contain 
compounds of the formula 1a where R.sup.29 --A-- is R.sup.32 R.sup.33 
C.dbd.N--O--CHR.sup.31 -- where R.sup.31 has the abovementioned meanings, 
and R.sup.32 and R.sup.33 are, independently of one another, hydrogen, 
C.sub.1 -C.sub.12 -alkyl, C.sub.1 -C.sub.4 -haloalkyl, C.sub.1 -C.sub.4 
-alkoxy-C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.12 -alkylthio-C.sub.1 
-C.sub.4 -alkyl, aryl-C.sub.1 -C.sub.4 -alkyl, aryloxy-C.sub.1 -C.sub.4 
-alkyl, arylthio-C.sub.1 --C.sub.4 -alkyl, hetaryl-C.sub.1 -C.sub.4 
-alkyl, C.sub.2 -C.sub.12 -alkenyl, aryl-C.sub.2 -C.sub.4 -alkenyl, 
hetaryl-C.sub.2 -C.sub.4 -alkenyl, C.sub.2 -C.sub.12 -alkynyl, C.sub.3 
-C.sub.6 -cycloalkyl, aryl, hetaryl, cyano or one of (a) to (d) 
##STR4## 
or R.sup.32 and R.sup.33 form, together with the carbon atom to which they 
are bonded, a 4- to 7-membered ring which may contain an oxygen or sulfur 
atom and which may have one or two aromatic rings fused on, e.g. 
unsubstituted or substituted benzene rings, and R.sup.34, R.sup.35, 
R.sup.36, R.sup.37, R.sup.38 and R.sup.39 are each hydrogen, C.sub.1 
-C.sub.4 -alkyl, aryl or hetaryl. 
Another aspect of the invention relates to antimycotics which contain 
compounds of the formula 1a where R.sup.29 is five- or six-membered aryl 
which is unsubstituted or substituted one or more times by halogen, 
C.sub.1 -C.sub.12 -alkyl, C.sub.1 -C.sub.12 -haloalkyl, C.sub.2 -C.sub.12 
-alkenyl, C.sub.2 -C.sub.12 -alkynyl, unsubstituted or substituted aryl, 
unsubstituted or substituted hetaryl, unsubstituted or substituted 
aralkyl, C.sub.1 -C.sub.12 -alkoxy, C.sub.1 -C.sub.12 -haloalkoxy, C.sub.2 
-C.sub.12 -alkenyloxy, C.sub.2 -C.sub.12 -alkynyloxy, unsubstituted or 
substituted aryloxy, formyl, C.sub.1 -C.sub.12 -acyl, cyano, 
trifluoromethyl, nitro or --CR.sup.34 .dbd.N--OR.sup.35 and/or may be 
fused with a benzene ring, or is benzyl or hetaryl, where R.sup.34 is 
hydrogen or C.sub.1 -C.sub.4 -alkyl and R.sup.35 is hydrogen, C.sub.1 
-C.sub.8 -alkyl, C.sub.2 -C.sub.8 -alkenyl or C.sub.2 -C.sub.8 -alkynyl. 
Supplementary reference is made, concerning the preparation of the active 
substances, to the fact that the compounds where Y has any of the 
abovementioned meanings can be prepared from the keto esters of the 
formula 2 
##STR5## 
where U, V, W, X and Z have the abovementioned meanings, by known 
processes. 
Furthermore, the preparation of the keto esters 2 is described in the 
abovementioned publications. 
Examples of compounds of the formula I which can be present in the 
antimycotics according to the invention are listed in Table 1. Other 
examples are indicated in the European patent applications mentioned. 
##STR6## 
The compounds may occur in isomeric forms in respect of the C.dbd.Y double 
bond. The E isomers are preferred. 
TABLE 1 
__________________________________________________________________________ 
No. 
Z U, V, W 
Y X 
__________________________________________________________________________ 
1 
##STR7## H, H, H 
CHOCH.sub.3 (E) 
O 
2 
##STR8## " NOCH.sub.3 (E) 
O 
3 " " CHCH.sub.3 (E) 
O 
4 " " CHCH.sub.2CH.sub.3 (E) 
O 
5 " " CHSCH.sub.3 (E) 
O 
6 " " NOCH.sub.3 (E) 
NH 
7 
##STR9## " CHOCH.sub.3 (E) 
O 
8 
##STR10## " NOCH.sub.3 (E) 
O 
9 
##STR11## " NOCH.sub.3 (E) 
O 
10 " " CHOCH.sub.3 (E) 
O 
11 
##STR12## " NOCH.sub.3 (E) 
O 
12 " " CHOCH.sub.3 (E) 
O 
13 
##STR13## " CHOCH.sub.3 (E) 
O 
14 
##STR14## H, H, H 
CHOCH.sub.3 (E) 
O 
15 " " NOCH.sub.3 (E) 
O 
16 
##STR15## " CHOCH.sub.3 (E) 
O 
17 
##STR16## " CHOCH.sub.3 (E) 
O 
18 
##STR17## " NOCH.sub.3 (E) 
O 
19 " " CHOCH.sub.3 (E) 
O 
20 
##STR18## " NOCH.sub.3 (E) 
O 
21 " " " NH 
22 
##STR19## " " O 
23 " " " NH 
24 
##STR20## " CHOCH.sub.3 (E) 
O 
25 " " CHCH.sub.3 (E) 
O 
26 " " CHCH.sub.2CH.sub.3 (E) 
O 
27 " " NOCH.sub.3 (E) 
O 
28 
##STR21## " CHOCH.sub.3 (E) 
O 
29 " " NOCH.sub.3 (E) 
O 
30 
##STR22## " CHOCH.sub.3 (E) 
O 
31 " " NOCH.sub.3 (E) 
O 
32 
##STR23## " CHOCH.sub.3 (E) 
O 
33 
##STR24## " NOCH.sub.3 (E) 
O 
34 
##STR25## " NOCH.sub.3 (E) 
O 
35 
##STR26## " NOCH.sub.3 (E) 
O 
36 
##STR27## " CHOCH.sub.3 (E) 
O 
37 
##STR28## " NOCH.sub.3 (E) 
O 
__________________________________________________________________________ 
Surprisingly, the phenylacetic acid derivatives not only have a very good 
in vitro antimycotic activity but also a good in vivo activity which can 
be used therapeutically, especially for dermatophytes, but also for other 
microorganisms. They also have antibacterial activity. The active 
substances thus represent a valuable enrichment of pharmacy. 
The action on dermatophytes, bacteria and protozoa can be demonstrated by 
methods as are described, for example, in P. Klein, Bakteriologische 
Grundlagen der chemotherapeutischen Laboratoriumspraxis, SpringerVerlag, 
Berlin, 1957. The action on yeasts can be demonstrated in the test on the 
pseudomycelium or mycelium phase (cf. DE-A 30 20 093). 
The minimum inhibitory concentration (MIC) was determined by the agar 
dilution method of DIN 58 940/ICS. 
For this, Petri dishes with a diameter of 9 cm were charged under sterile 
conditions with 20 ml of freshly prepared Muller-Hinton agar (Merck, Cat. 
No 5337), which was kept liquid at 50.degree. C., and to which 10% by 
volume of the particular active substance solution was added. The samples 
are readily soluble in DMSO. In each case 10.0 mg were dissolved in 10.0 
ml of DMSO and further diluted with sterile double-distilled water. The 
final concentrations after mixing with the test agar are to be found in 
Table 2. Plates with the highest solvent concentration in each case 
(control C 1) and with 10% double-distilled water (control C 2) without 
active substance were used to check growth by comparison. 
After solidification and drying (about 1 h at 37.degree. C.) the test 
plates were inoculated by dotting with 10 .mu.l of the test organism 
suspensions (inoculum) in each case. 
The inocula were prepared in accordance with NCCLS/FDA recommendations. 
After culturing on solid media and checking purity and identity, some 
colonies were transferred into sterile Muller-Hinton broth (Merck, Cat. 
No. 10293) and incubated until turbidity was visible. These cultures were 
diluted by adding sterile broth until the turbidity corresponded to 0.5 of 
the McFarland standard (=about 10(8) CFU/ml). A further 1:10 dilution was 
used as inoculum, and its organism concentration was determined in 
parallel once again by spiralometer. 
The inoculated plates were incubated at 36.degree..+-.1.degree. C. 
(bacteria) or 20.degree..+-.1.degree. C. (fungi) for 24 (bacteria) or 72 
(fungi) h and then evaluated. 
The complete test was repeated in an independent experiment. The results 
were reproducible in all cases. 
The reported MIC was that concentration of active substance at which no 
growth was visible on inspection. Minimal, scarcely visible growth or a 
few small colonies were not counted. On the growth controls without active 
substance all the test organisms had grown as a spot about 0.5 cm.sup.2 in 
size (precondition for evaluation). The following test organisms were 
tested as examples (concentration in CFU/ml): 
Staphylococcus (S.) aureus ATCC 6538 (1.2.times.10.sup.6) 
Pseudomonas (Ps.) aeruginosa ATCC 27853 (1.0.times.10.sup.6) 
Escherichia (E.) coli ATCC 8739 (1.4.times.10.sup.6) 
Candida (C.) tropicalis DSM 4238 (0.8.times.10.sup.6) 
Aspergillus (A.) niger ATCC 16404 (0.9.times.10.sup.6) 
Microsporum (M.) canis CBS 38564 (1.0.times.10.sup.6) 
Trichophyton (T.) mentagrophytes CBS 26379 (0.9.times.10.sup.6) 
T. rubrum DSM 4167 (1.3.times.10.sup.6) 
Epidermophyton (E.) floccosum CBS 55384 (1.4.times.10.sup.6) 
TABLE 2 
__________________________________________________________________________ 
Results of the agar dilution tests 
Growth of test organisms: + MIC in .mu.g/ml 
No growth of test organisms: - 
C = controls without active substance 
Compound of Example No. 
Example No. 
Test organisms 
C 1 
C 2 
1 2 3 7 8 9 10 11 12 13 14 15 16 17 18 19 
__________________________________________________________________________ 
S. aureus 
+ + &gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
Ps. aeruginosa 
+ + &gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
E. coli + + &gt;5.0 
&gt;5.0 
&gt; 5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
&gt;5.0 
C. tropicalis 
+ + 0.1 
0.1 
0.5 
0.1 
0.5 
0.1 
0.1 
0.1 
0.1 
0.5 
0.1 
0.5 
0.5 
0.5 
0.1 
0.1 
A. niger + + 0.1 
0.1 
0.1 
0.1 
0.5 
0.5 
0.5 
1.0 
0.5 
0.5 
0.1 
0.5 
0.5 
0.5 
1.0 
0.5 
M. canis + + 5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
&gt;5.0 
5.0 
5.0 
5.0 
5.0 
T. mentagrophytes 
+ + 5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
&gt;5.0 
5.0 
5.0 
5.0 
5.0 
T. rubrum 
+ + 5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
&gt;5.0 
5.0 
5.0 
5.0 
5.0 
E. floccosum 
+ + 5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
5.0 
&gt;5.0 
5.0 
5.0 
5.0 
5.0 
__________________________________________________________________________ 
The compounds of the present invention also have good inhibitory effects on 
the test organisms Exophiola jennselmei. 
For example: 
______________________________________ 
Compound of 
Example No. MIC [.mu.g/ml] 
______________________________________ 
1 10 
3 30 
8 10 
10 10 
16 3 
17 3 
19 10 
______________________________________ 
In the model of guinea pig trichophytosis (Trichophyton mentagrophytes), 
cf. Heffter-Heubner: Handbuch der exp. Pharmakologie, Vol. XVI/II A, the 
novel compounds are highly effective on external use without recurrence. 
The actions of the test substances on topical use against Exophiola 
jennselmei as the cause of subcutaneous mycoses and in a model of 
experimental C. albicans vaginitis were likewise good. 
The novel compounds also have oral activity. Good cure rates for infections 
were obtained after oral administration of low therapeutic doses of the 
test substances in the model of experimental generalized candidiasis in 
mice and in the model of experimental vaginitis with Candida albicans in 
rats. 
The compounds are therefore particularly suitable for external as well as 
oral treatment of fungal infections in humans and animals. Examples of 
indications for humans and animals are: subcutaneous mycoses and 
dermatomycoses, especially caused by dermatophytes such as species of the 
genera Epidermophyton, Microsporum or Trichophyton, yeasts such as species 
of the genera Candida and molds such as species of the genera Aspergillus, 
Mucor or Absidia. 
The compounds can be used alone or together with other known active 
substances, especially antibiotics. 
The chemotherapeutic agents or formulations are produced with conventional 
solid, semi-solid or liquid excipients or diluents and the conventional 
pharmaceutical auxiliaries appropriate for the required mode of 
administration in a dosage suitable for use in a conventional manner, 
especially by mixing (cf. H. Sucker et al., Pharmazeutische Technologie, 
Thieme-Verlag, Stuttgart, 1978). 
Examples of suitable dosage forms are uncoated and coated tablets, 
capsules, pills, aqueous solutions, suspensions and emulsions, sterile 
injectable solutions, non-aqueous emulsions, suspensions and solutions, 
ointments, creams, pastes, lotions etc. 
The therapeutically active compound is preferably present in pharmaceutical 
formulations in a concentration of 0.01 to 90% by weight of the complete 
mixture. 
In general, on oral administration both in human and in veterinary 
medicine, the active substance or substances can be administered in 
amounts of from about 1.0 to about 50.0, preferably from 2 to 10, mg/kg of 
body weight per day, preferably in the form of several individual doses to 
achieve the required results. However, it may be necessary to deviate from 
the stated dosages, specifically depending on the nature and severity of 
the disease, the nature of the formulation and of the administration of 
the drug, and the time or interval over which administration takes place. 
Thus, in some cases less than the abovementioned amounts of active 
substances may suffice, whereas in other cases these amounts must be 
exceeded. Examples of pharmaceutical formulations:

EXAMPLE A 
Tablet containing 250 mg of active substance Composition for 1,000 tablets: 
______________________________________ 
Active substance 250 g 
Potato starch 100 g 
Lactose 50 g 
4% gelatin solution 45 g 
Talc 10 g 
______________________________________ 
Production: 
The finely powdered active substance, potato starch and lactose are mixed. 
The mixture is moistened with about 45 g of 4% gelatin solution, 
granulated and dried. The dried granules are screened, mixed with 10 g of 
talc and compressed to tablets in a rotary tableting machine. The tablets 
are packed in tightly closing polypropylene containers. 
EXAMPLE B 
Cream containing 1% active substance 
______________________________________ 
Active substance 1.0 g 
Glycerol monostearate 10.0 g 
Cetyl alcohol 4.0 g 
Polyethylene glycol 400 stearate 
10.0 g 
Polyethylene glycol sorbitan monostearate 
10.0 g 
Propylene glycol 6.0 g 
Methyl p-hydroxybenzoate 0.2 g 
Demineralized water to 100.0 g 
______________________________________ 
Production: 
The very finely powdered active substance is suspended in propylene glycol, 
and the suspension is stirred into a melt of glycerol monostearate, cetyl 
alcohol, polyethylene glycol 400 stearate and polyethylene glycol sorbitan 
monostearate at 65.degree. C. A solution of the methyl p-hydroxybenzoate 
in water at 70.degree. C. is emulsified in this mixture. After cooling, 
the cream is homogenized in a colloid mill and packed into tubes. 
EXAMPLE C 
Dusting powder containing 1% active substance 
______________________________________ 
Active substance 1.0 g 
Zinc oxide 10.0 g 
Magnesium oxide 10.0 g 
Highly disperse silica 2.5 g 
Magnesium stearate 1.0 g 
Talc 75.5 g 
______________________________________ 
Production: 
The active substance is micronized in an air jet mill and mixed 
homogeneously with the other ingredients. The mixture is passed through a 
screen (mesh No. 7) and packed in polyethylene containers with perforated 
cap.