Synthesis and in vitro and in vivo structure-activity relationships of novel antifungal triazoles for dermatology

Article abstract of DOI:10.1021/jm0494772

In search for new compounds with potential for clinical use as antifungal agents in dermatology, a series of 12 azole compounds were synthesized stereospecifically and investigated specifically for their activity against dermatophyte fungal infections in

Full text of DOI:10.1021/jm0494772

2184
J. Med. Chem. 2005, 48, 2184-2193
Synthesis and in Vitro and in Vivo Structure-Activity Relationships of Novel
Antifungal Triazoles for Dermatology
Lieven Meerpoel,*,† Leo J. J. Backx,† Louis J. E. Van der Veken,† Jan Heeres,‡ David Corens,† Alex De Groot,†
Frank C. Odds,§ Frans Van Gerven,† Filip A. A. Woestenborghs,† Andre Van Breda,† Michel Oris,†
Pascal van Dorsselaer,† Gustaaf H. M. Willemsens,† Karen J. P. Vermuyten,† Patrick J. M. G. Marichal,†
Hugo F. Vanden Bossche,† Jannie Ausma,*,| and Marcel Borgers|
Johnson & Johnson Pharmaceutical Research & Development, a division of Janssen Pharmaceutica N.V., Turnhoutseweg 30,
B-2340 Beerse, Belgium, Center for Molecular Design, a division of Janssen Pharmaceutica N.V., Beerse, Belgium,
University of Aberdeen, Aberdeen, United Kingdom, and Barrier Therapeutics N.V., Cipalstraat 3, B-2440 Geel, Belgium
Received June 30, 2004
In search for new compounds with potential for clinical use as antifungal agents in dermatology,
a series of 12 azole compounds were synthesized stereospecifically and investigated specifically
for their activity against dermatophyte fungal infections in animal models. This panel of azoles
was studied in vitro and compared with itraconazole and terbinafine for their antifungal activity
using a panel of 24 Candida spp. and 182 dermatophyte isolates. Three azoles (1c, 2c, and 4c)
showed in vitro antifungal potency equivalent to itraconazole, but superior to terbinafine,
against a panel of 24 Candida spp. with comparable or lower activity than that of itraconazole
and terbinafine against 182 dermatophyte isolates and only rare activity against other
pathogenic fungi. However, in vivo 1c and 4c, both given orally, demonstrated antifungal
activity at least three times greater than itraconazole and were superior compared to terbinafine
in M. canis infected guinea pigs. In a mouse model infected by T. mentagrophytes, again 4c,
but not 1c, showed 5-fold superior activity over itraconazole and terbinafine. Compound 2c
was effective in both models but less effective than itraconazole in these models. On the basis
of these promising results, 4c is currently being clinically investigated for its potential as a
novel antifungal agent against dermatophytosis.
Introduction
way have been proven to be clinically effective. These
are azoles7,8 such as ketoconazole,9 itraconazole,10 and
fluconazole,11 which act as 14-R-demethylase inhibitors;
allylamines such as terbinafine,12 which act as a squalene
epoxidase inhibitor; and morpholines such as amorol-
fine,13 a ∆14-reductase and ∆8-7-isomerase inhibitor.
However, extensive use and prolonged therapy with
azoles have led to resistance.14 Hence, more effective
antifungal azoles with fewer adverse effects and short-
term action are deemed necessary to treat dermatophy-
tosis. The second-generation antifungal azoles such as
voriconazole,15,16 posaconazole,17 and ravuconazole18
have shown broad spectrum antifungal activity compa-
rable or slightly superior to itraconazole (Sporanox)
against Candida species. These agents are marketed or
currently in late stage clinical trials against life threat-
ening systemic fungal infections. Voriconazole19 and
ravuconazole20 have MIC values against dermatophytes
comparable or lower than that of itraconazole, whereas
antidermatophyte acitivity for posaconazole has not yet
been reported.21
In the search for new compounds with potential for
clinical use as antifungal agents in dermatology, a huge
compound database was scanned for antifungal com-
pounds with impressive activity against dermatophytes
but not necessarily against Candida. Moreover, the
overriding selection criterion was excellent activity
against experimental guinea pig dermatophytosis mod-
els in vivo. This search was nominally structure-
activity relationship (SAR)-basedsstructures support-
ing activity versus one fungal group without regard to
Traditionally, mycotic diseases have been divided into
three broad categories including: cutaneous and mu-
cocutaneous, subcutaneous, and systemic fungal infec-
tions. Although today’s antifungal research is mainly
focused on systemic fungal infections,1 dermatomycoses
are among the most widespread and common human
superficial and cutaneous fungal infections.2,3,4 These
typically nonfatal conditions are difficult to treat,
especially infections of toenails. Dermatomycoses are
caused by filamentous fungi such as Trichophyton,
Microsporum, or Epidermophyton species. For instance,
tinea pedis, commonly known as “athlete’s foot”, is most
frequently caused by either Trichophyton or Epidermo-
phyton species. These filamentous fungi have a high
affinity for keratin, an important component of hair,
skin, and nails, which are the primary areas of infection
by dermatophytes.
The antifungal agents currently marketed for der-
matomycoses are mainly inhibitors of ergosterol bio-
synthesis,5 except for griseofulvin, which interferes with
mitotic separation of chromosomes.6 Three different
types of inhibitors of the ergosterol biosynthetic path-
* Authors to whom correspondence should be addressed. Phone:
+32 14 60 56 94 (L.M.). Fax. +32 14 60 53 44 (L.M.). E-mail:
lmeerpoe@prdbe.jnj.com. Barrier Therapeutics N. V., Cipalstraat 3,
B-2440 Geel., Belgium (J.A.). Phone: +32 14 57 05 24 (J.A.). Fax: +32
14 57 05 15 (J.A.). E-mail: jausma@barriertherapeutics.com.
† Johnson & Johnson Pharmaceutical Research & Development.
‡ Center for Molecular Design.
§ University of Aberdeen.
| Barrier Therapeutics N.V.
10.1021/jm0494772 CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/28/2005

Antifungal Triazoles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 2185
Figure 1.
another. Having found prototype molecules, we designed
new versions of them that incorporated the best modi-
fications science has given us for azole antifungals over
the years: 2,4-difluorophenyl substituted dioxolanes,
triazole in place of imidazoles, and replacement of the
triazolone moiety by other lypophilic heterocyclic moi-
eties. In times of high-throughput screening and com-
binatorial chemistry, it might be surprising that only
12 combinations were needed to discover 4c, a novel
triazole for dermatomycoses.22 In this paper, we report
the synthesis and limited structure-activity relation-
ships of derivatives and other antifungal compounds
related to 4c, which were tested for in vitro antifungal
activity and against in vivo models for superficial
mycoses and compared with itraconazole and terbin-
afine as drug standards.
difluorophenyl ring, which was found to possess a cis
configuration. The diol 7, the precursor for intermedi-
ates 8a and 8b, has been documented in the literature
to be a key intermediate in the synthesis of azole
antifungals, and both racemic and enantioselective
syntheses have been described.30-35 In our hands, the
diol 7 was obtained via two routes starting with 1-(2,4-
difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone. In the
first approach, the cyanohydrine of the ketone was
formed. Hydrolysis of the nitrile and reduction of the
carboxylic acid gave the diol compound 7 in 60% overall
yield for the three-step synthesis. Alternatively, we used
trimethylsulfoxonium iodide to form the epoxide, which
was hydrolyzed with aqueous sulfuric acid at 60 °C to
give the diol 7 with 50% overall yield for the two-step
synthesis (Scheme 1). Acetalization of 7 with 1-bromo-
2,2-diethoxyethane in the presence of methanesulfonic
acid in dichloromethane at room temperature gave a
mixture of cis- and trans-1,3-dioxolane-2-yl in a 1:1.9
ratio. Separation of the cis enantiomers on a Daicel
Chiralcel OD HPLC column gave both enantiomers 8a
and 8b in poor yield. The trans isomer was reclycled
into a diasteroisomeric 1.3:1 cis and trans mixture under
thermodynamic conditions in dichloromethane and meth-
anesulfonic acid at reflux temperature for 2 days.
NOESY experiments with compound 8a revealed a clear
correlation between the 2-H dioxolane proton and the
ortho proton of the 2,4-difluorophenyl ring, confirming
the cis configuration. In addition, X-ray diffraction
measurements established the absolute configuration
of 8a as 2S-cis-1,3-dioxolane-2-yl.
Chemistry
The 12 target compounds, 1a,b,c, 2a,b,c, 3a,b,c, and
4a,b,c, are described in Table 1. Their syntheses are
straightforward combinations of two enantiomeric pairs
of cis-1,3-dioxolane-4-yl (5b and 6a) and cis-1,3-di-
oxolane-2-yl (8a and b) with three phenolic heterocyclic
substituents 12, 15, and 18. Access to the enantiomeri-
cally pure dioxolanes was key in the synthesis of these
novel azoles. Literature precedent23,24 for the stereo-
selective synthesis of ketoconazole by transketalisation
with optically pure solketal tosylates assisted us in the
synthesis of 2,4-difluorophenyl dioxolane intermediates
5 and 6. Recently, the same method was further
optimized and used in the stereoselective synthesis of
hydroxyitraconazole.25 Ketalization of 1-(2,4-difluoro-
phenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone with (R)- and
(S)-glyceryl tosylate26,27 or mesylate28,29 in a mixture of
methanesulfonic acid and dichloromethane gave cis and
trans diastereoisomers in an approximately 1.5:1 ratio,
respectively, with moderate yields. For compound 6a,
NOESY correlations were observed between the 4-H
dioxolane proton and the ortho proton of the 2,4-
The heterocyclic phenols 12, 15, and 18 were synthe-
sized starting from the aniline 936 using conventional
heterocyclic synthesis as depicted in Scheme 2. As
shown in Table 1, the target series 1, 2, 3, and 4 were
synthesized via a nucleophilic subtitution of the enan-
tiomerically pure dioxolanes 5b, 6a, 8a, and 8b in
combination with the heterocyclic phenols 12, 15, and
18. All reactions were performed in dry dimethyl for-

2186 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Table 1. Target Compounds3
Meerpoel et al.
Laboratory Standards 2002 (NCCLS) and gives compa-
rable results with the quality control yeast strains
recommended by the NCCLS.38
The imidazolidinone triazoles (c series: 1c, 2c, and
4c) demonstrated a consistently greater potency com-
pared to the pyrimidinetrione triazoles (a series) and
triazinetrione triazoles (b series) against all dermato-
phytes tested (Table 2). For the 2S-cis-1,3-dioxolane-2-
yl triazole series (4a,b,c), consistently high stereo-
selective antifungal activity against both yeasts and
molds in vitro was found as opposed to the 2R-cis series
(3a,b,c), which were almost inactive, especially for 3c
and 4c when compared with the 1,3-dioxolane-4-yl
congeners 1c and 2c the influence of stereochemistry
was striking. The in vitro activity against Epidermo-
phyton species for compounds 1c and 4c was comparable
to itraconazole and terbinafine, both compounds were
weaker against Microsporum species (Table 2). The
overall activity of 1c and 4c against Trichophyton
species was less than that of itraconazole, especially
when compared to terbinafine (Table 2). Compound 2c
showed an overall lower potency, except for Microsporum
species, when compared to itraconazole. Compounds 1c,
2c, and 4c had similar potency against Candida species
in vitro. A clearly lower effect was observed with these
compounds on A. fumigatus, and a lack of activity
against a panel of other fungi such as Cryptococcus,
Sporothrix, and Fusarium species (Table 3) was ob-
served with these compounds.
On the basis of the promising in vitro results, the
same panel of novel triazoles was tested for their efficacy
against dermatophyte infections in a guinea pig model
infected with Microsporum canis and a mouse model
infected with Trichophyton mentagrophytes (var. T.
quinckeanum) according to the method previously de-
scribed by Odds et al.22 Tables 4 and 5 show results of
various prophylactic oral treatment experiments, in
which treatment was started at day 0, in the cutaneous
infection models of M. canis in guinea pig and T.
mentagrophytes in mice, respectively. In these tables,
the effective dosages (ED50 values) of oral treatment
experiments with various novel triazoles in comparison
to itraconazole and terbinafine are given.
In the first model, it was confirmed that imidazoli-
dinones (c series) have superiority over pyrimidinetrione
and triazinetrione a and b series, respectively. In the
cutaneous M. canis infection model in guinea pigs,
compound 1c (ED50 0.33 to 0.44 mg/kg) was almost
equipotent with 4c, ED50 0.31 mg/kg at all time inter-
vals, and was at least two times more effective than its
enatiomer 2c, ED50 0.89-1.29 mg/kg. In comparison to
itraconazole, 4c showed higher antifungal activity by
at least a factor of 4. In this model, terbinafine was even
shown to be less effective than itraconazole.
1 Yields are calculated based upon mass of isolated and recrys-
talized compounds and were not optimized. 2 MeOH. 3 General
procedure: (a) stirred in the presence of NaHMDS in DMF at 60
°C; (b) stirred in the presence of NaOH pellets in DMF at 60 °C;
(c) stirred in the presence of NaH in DMF at 60 °C.
mamide in the presence of a base at 60 °C and gave
moderate to good yields. Utilizing sodium hydroxide
pellets as the base gave consistently better yields than
either sodium bis(trimethylsilyl)amide or sodium hy-
dride (Table 1).
Results and Discussion
The novel azoles series 1, 2, 3, and 4 were screened
against a panel of 182 dermatophytes consisting of
Epidermophyton, Microsporum, and Trichophyton spe-
cies (Table 2). These anamorphic genera were selected
because they are the main cause for dermatophytic
infections: tinea capitis, tinea barbae, tinea corporis,
tinea cruris, tinea pedis, and onychomycosis. In addi-
tion, their potential antifungal activity against systemic
fungal infections was determined via a panel of 24
Candida species, 8 Aspergillus species, and 13 other
fungi including Cryptococcus, Sporothrix, and Fusarium
species (Table 3). For all fungi, the susceptibility test
method used was a microplate broth dilution method
described previously.22,37 This method is based on the
recommendation of the National Committee for Clinical
To confirm the promising in vivo results, the most
active compounds were retested in the T. mentagro-
phytes mouse model (Table 5). From these experiments,
confirmatory results were obtained. Compound 4c was
the most effective azole with an ED50 of <0.63 mg/kg,
thereby showing superiority over itraconazole, ED50 2.60
mg/kg, and terbinafine, ED50 > 5.00 mg/kg. After orally
dosing for 4 days at 2.5 mg/kg in mice, evidence for the
greater in vivo activity of 4c over itraconazole was found
with 5-fold and 3-fold higher plasma and skin levels in

Antifungal Triazoles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 2187
Scheme 1. Synthesis of Dioxolane Intermediatesa
a Reagents and conditions: (a) CH3SO3H/CH2Cl2 (1.3:1 ratio), reflux, 20 h, 19% yield (for both 5a and 5b); (b) 2-hydroxy-2-
methylpropionitrile, NH4OHcat., room temperature, 50 h, 71% yield; (c) 12N HCl, reflux, 20 h, 96% yield; (d) LiAlH4, THF, 24 h, 87%
yield; or (e) Me3SO+I-, 50% w/v NaOH, toluene, N-benzyltriethylammonium chloridecat., reflux, 24 h; (f) 10% v/v H2SO4/H2O, room
temperature, 50% yield (two-step synthesis); (g) CH3SO3H/CH2Cl2 (1:10 ratio), bromoacetaldehyde diethylacetal added at 0 to 10 °C,
room temperature, 20 h; (h) Chiralcel OD 8a (9% yield), 8b (11% yield), (()-trans (38% yield).
a Carlo-Erba EA1110 analyzer. Mass spectra were obtained
with a Waters-Micromass ZQ mass spectrometer with an
electrospray ionization source operated in positive and nega-
tive ionization modes. Mass spectra were acquired by scanning
from 100 to 1000 mass units in 1 s using a dwell time of 0.1 s.
The capillary needle voltage was 3 kV, and the source
temperature was maintained at 140 °C. Nitrogen was used
as the nebulizer gas. Cone voltage was 10 V for positive
ionization mode and 20 V for negative ionization mode.
Analytical results were within (0.4% of the theoretical values,
except when noted otherwise. Silica gel thin-layer chromatog-
raphy was performed on precoated plates Kieselgel 60F254
(E. Merck, AG Darmstadt, Germany). Silica gel column chro-
matography was performed with Kiesel gel 60 (0.063-0.200
mm) (E. Merck, AG Darmstadt, Germany). Chiral HPLC
purifications were performed on a Daicel cellulose normal
phase Chiracel OD HPLC column purchased from Chiral
Technologies Europe. Sensitive reactions were performed
under nitrogen. Commercial solvents were used without any
pretreatment. Brine is a saturated solution of sodium chloride
in water. DMF (N,N-dimethylformamide), THF (tetrahydro-
furane), MIK (4-methyl-2-pentanone), DIPE (diisopropyl ether),
and 80% NaH (Sigma Aldrich) were washed free of oil with
hexane prior to use.
(-)-(2S-cis)-1-Ethyl-3-[4-[4-[4-[[4-(2,4-diflurorophenyl)-
4-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]meth-
oxy]phenyl]-1-piperazinyl]phenyl]-5,5-dimethyl-
2,4,6(1H,3H,5H)-pyrimidinetrione (1a). Sodium bis(tri-
methylsilyl)amide (24 mL, 0.024 mol) was added dropwise to
a stirred mixture of 12 (5 g, 0.011 mol) in dry DMF (50 mL) at
room temperature under inert nitrogen flow. The mixture was
stirred for 10 min, and 6a (5 g, 0.011 mol) was added. The
mixture was stirred at 60 °C for 18 h in an oil bath, then
cooled, poured out into H2O, and extracted with CH2Cl2 (3 ×
100 mL). The combined organic layers were washed with H2O,
dried over anhydrous MgSO4, and filtered, and the solvent was
evaporated at reduced pressure. The residue was purified by
silica gel column chromatography gradient elution, CH2Cl2/
CH3OH/EtOAc/hexane 49/1/30/20 toward 48/2/30/20, to give
mice, 0.158 µg/mL and 0.093 µg/g, respectively. For
itraconazole, plasma and skin levels were 0.0371 µg/
mL and 0.032 µg/g, respectively.
Triazole 4c was compared in vitro with itraconazole
for their inhibitory effects on growth and ergosterol
biosynthesis in C. albicans and T. mentagrophytes
species and Microsporum canis.39 In all species, inhibi-
tion of ergosterol synthesis coincided with the ac-
cumulation of 14-methylsterols, indicative for the P450
14R-demethylase, CYP51, as the target enzyme.
Conclusion
Twelve novel triazoles were compared in vitro and in
vivo with itraconazole and terbinafine for their anti-
fungal activity. The imidazolidinone series 1c, 2c, and
4c showed antifungal potency equivalent to or slightly
less than itraconazole against a panel of 24 Candida
species, 2-fold or more lower activity against 182 der-
matophyte isolates, and only rare activity against other
pathogenic fungi. In animal models, 4c consistently
showed antifungal efficacy at least 4 times higher than
that of itraconazole. These data indicate that if effects
of 4c, R126638, seen when it is used to treat animals
can be extrapolated in humans, then it might be
expected to show effects at doses lower than those used
for existing drugs and, hence, present a lower risk for
side effects.
Experimental Section
Chemistry. General Methods. Melting points were mea-
sured in open capillaries on a Buchi B545 instrument and are
uncorrected. 1H NMR spectra were recorded with Bruker
Avance DPX 400 and 360 spectrometers, and chemical shifts
(δ) are expressed in parts per million (ppm) with TMS as
internal standard. Elemental analyses were performed with

2188 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Scheme 2. Synthesis of Phenol Precursorsa
Meerpoel et al.
a Reagents and conditions: (a) KOCN, HCl, 4 h, room temperature, 100% yield; (b) 2,2-dimethylmalonyl chloride, sulfolane, 5 h, 50 °C,
83% yield; (c) NaH, EtI, DMF, 3 h, 85 °C, 40% yield; (d) 48% aqueous HBr, HBr/AcOH, NaHSO3, 5 h, reflux; (e) n-PrNCO, CH2Cl2,
overnight, room temperature, 86% yield; (f) chlorocarbonylisocyanate, 1,2-dichloroethane, 1 h, reflux, 88% yield; (g) EtBr, KOH, DMF,
room temperature, overnight, 70% yield; (h) phenylchloroformate, Et3N, CH2Cl2, overnight, room temperature, 100% yield; (i) N-(2,2-
dimethoxyethyl)-2-propaneamine, DMAP, dioxane, reflux, 4 h; followed by HCOOH, 3 h, 70 °C, 75% yield; (j) H2, AcOH, 10% Pd/C.
a solid which was crystallized from ethanol yielding 1a (4.98
g, 61%): mp 155-157 °C. [R]20D -10.69° (c 1.0, DMF). MS (ESI)
MHz, CDCl3): δ 11.1, 13.1, 21.1, 38.5, 44.7, 48.9, 50.6, 54.5
(d, J ) 3 Hz), 67.6 (d, J ) 3 Hz), 74.9, 105.1 (t, J ) 26 Hz),
106.7 (d, J ) 4 Hz), 111.2 (dd, J ) 21, 3 Hz), 115.2, 116.3,
118.4, 121.7 (dd, J ) 13, 3 Hz), 125.2, 128.8, 129.2 (dd, J )
10, 5 Hz), 144.8, 146.0, 148.9, 149.0, 149.2, 151.3, 151.4, 152.5,
160.4 (dd, J ) 252, 12 Hz), 163.7 (dd, J ) 252, 12 Hz). Anal.
(C37H40F2N8O6.‚H2O) C,H,N.
1
m/z: 716 (MH+). H NMR (360 MHz, CDCl3): δ 1.24 (t, J )
7.0 Hz, 3 H), 1.64 (s, 6 H), 3.23 (dd, J ) 6.3, 3.8 Hz, 4 H), 3.39
(dd, J ) 6.3, 3.8 Hz, 4 H), 3.49 (dd, J ) 9.7, 6.3 Hz, 1 H), 3.79
(dd, J ) 9.7, 4.7 Hz, 1 H), 3.82 (dd, J ) 8.5, 5.2 Hz, 1 H), 3.98
(q, J ) 7.0 Hz, 2 H), 3.98 (dd, J ) 8.4, 6.5 Hz, 1 H), 4.41 (tt,
J ) 6.3, 5.1 Hz, 1 H), 4.68 (d, J ) 14.7 Hz, 1 H), 4.74 (d, J )
14.7 Hz, 1 H), 6.80 (m, 2 H), 6.87 (m, 2 H), 6.94 (m, 2 H), 7.03
(m, 2 H), 7.07 (m, 2 H), 7.50 (td, J ) 8.8, 6.5 Hz, 1 H), 7.89 (s,
1 H), 8.22 (s, 1 H). 13C NMR (101 MHz, CDCl3): δ 13.2, 24.8,
37.7, 47.8, 49.0, 50.6, 54.5 (d, J ) 4 Hz), 67.6, 74.9, 105.2 (t, J
) 26 Hz), 106.7 (d, J ) 4 Hz), 111.2 (dd, J ) 21, 4 Hz), 115.2,
116.4, 118.4, 121.7 (dd, J ) 13, 4 Hz), 125.8, 128.8, 129.2 (dd,
J ) 10, 5 Hz), 144.9, 146.1, 150.7, 151.3, 151.3, 152.6, 160.4
(dd, J ) 252, 12 Hz), 163.7 (dd, J ) 252, 12 Hz), 172.2, 172.8.
Anal. (C37H39F2N7O6) H, N; C calcd, 62.09; found, 61.23.
The synthetic methods for the following compounds 1b, 2a,
2b, and 3a-c were similar to the synthesis of compound 1a.
(-)-(2S-cis)-1-Ethyl-3-[4-[4-[4-[[4-(2,4-difluorophenyl)-
4-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]meth-
oxy]phenyl]-1-piperazinyl]phenyl]-5-propyl-1,3,5-tri-
azine-2,4,6(1H,3H,5H)-trione hydrate (1:1) (1b). Yield 51%,
(-)-(2S-cis)-1-[4-[4-[4-[[4-(2,4-Difluorophenyl)-4-(1H-
1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phen-
yl]-1-piperazinyl]phenyl]-3-(1-methylethyl)-2-imid-
azolidinone (1c). A mixture of 6a (20 g, 0.053 mol), 18 (25 g,
0.053 mol), and NaOH pellets (5.3 g, 0.13 mol) in DMF (500
mL) was stirred at 60 °C under nitrogen flow for 24 h. The
solvent was evaporated under reduced pressure. The residue
was triturated with H2O (250 mL) and extracted with CH2Cl2
(3 × 300 mL). The combined organic layers were washed with
H2O (3 × 250 mL) and brine, dried over anhydrous MgSO4,
and filtered, and the solvent was evaporated at reduced
pressure. The residue was purified by silica gel column
chromatography (CH2Cl2/hexane/EtOAc 50/20/30) to give an
oil that was crystallized from EtOAc to give 1c (26.2 g, 75.5%)
as a white solid: mp 186.5-188.5 °C. [R]20D -14.23° (c 0.506,
DMF). MS (ESI) m/z: 660 (MH+). 1H NMR (400 MHz, DMSO-
d6): δ 1.11 (d, J ) 7.0 Hz, 6 H), 3.18 (m, 8 H), 3.36 (m, 2 H),
3.72 (m, 5 H), 4.01 (m, 2 H), 4.40 (m, 1 H), 4.71 (m, 2 H), 6.84
(d, J ) 9.1 Hz, 2 H), 6.96 (m, 4 H), 7.07 (td, J ) 8.5, 2.6 Hz, 1
H), 7.32 (ddd, J ) 11.4, 9.1, 2.5 Hz, 1 H), 7.44 (m, 3 H), 7.86
(s, 1 H), 8.41 (s, 1 H). 13C NMR (101 MHz, DMSO-d6): δ 19.2,
36.0, 42.3, 43.1, 49.1, 49.6, 54.0 (d, J ) 3 Hz), 66.6, 67.7, 74.9,
104.9 (t, J ) 26 Hz), 106.3 (d, J ) 4 Hz), 111.1 (dd, J ) 21, 3
Hz), 115.1, 116.2, 117.5, 118.2, 122.5 (dd, J ) 13, 3 Hz), 129.3
(dd, J ) 10, 5 Hz), 133.4, 145.4, 145.7, 146.1, 150.7, 151.8,
crystallized from ethanol: mp 111-113 °C. [R]20 -10.69° (c
D
1
1.01, MeOH). MS (ESI) m/z: 731 (MH+). H NMR (360 MHz,
CDCl3): δ 0.96 (t, J ) 7.5 Hz, 3 H), 1.29 (t, J ) 7.1 Hz, 3 H),
1.72 (m, 2 H), 3.22 (dd, J ) 6.1, 3.9 Hz, 4 H), 3.39 (dd, J ) 6.3,
3.7 Hz, 4 H), 3.49 (dd, J ) 9.7, 6.3 Hz, 1 H), 3.79 (dd, J ) 9.7,
4.7 Hz, 1 H), 3.82 (dd, J ) 8.5, 5.2 Hz, 1 H), 3.89 (m, 2 H),
3.99 (m, 3 H), 4.41 (tt, J ) 6.3, 5.1 Hz, 1 H), 4.68 (d, J ) 14.7
Hz, 1 H), 4.73 (d, J ) 14.7 Hz, 1 H), 6.80 (m, 2 H), 6.88 (m, 2
H), 6.94 (m, 2 H), 7.03 (m, 2 H), 7.15 (m, 2 H), 7.50 (td, J )
8.8, 6.5 Hz, 1 H), 7.89 (s, 1 H), 8.22 (s, 1 H). 13C NMR (91

Antifungal Triazoles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 2189
Microsporum spp (38)a Trichophyton mentagrophytes (20)a
Table 2. MIC Values of Test Substances for Panels of Dermatophytes
Epidermophyton floccosum (12)a
entry
rangeb
50%c
90%c
range
50%
90%
>20
>20
range
50%
90%
1a
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
4c
0.32-1
1
1
1
0.032->20
0.01->20d
0.0032-1
0.032->20
0.032->20
0.0005-1
1->20
3.2
1
0.1
10
1
0.1->20
0.32-3.2
0.0005-0.1
0.1->20
1
1
>20
0.32-3.2
0.01-0.1
0.32->20
0.32-3.2
0.032-3.2
0.32->20
10->20
0.01->20
1-3.2
3.2
0.093
3.2
0.032
0.032
3.2
1
0.32
0.032
1
0.32
0.021
>20
>20
13
>20
3.2
2.98
0.032-3.2
0.0032-0.1
>20->20
>20->20
0.32->20
1-10
1
0.406
0.032
>20
>20
0.524
0.032
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
1->20
>20
1
1
1
0.1->20
2.1
1
2.98
3.2
0.093
0.093
0.093
0.1->20
3.2
3.2
3.2
3.2
0.032
0.1288
0.01
1-3.2
0.0032->20
0.0005->20
0.0005-1
0.01-0.32
3.2
0.32-3.2
1
0.01-0.1
0.01-0.32
0.01-0.1
0.032
0.032
0.032
0.032
0.032
0.032
0.524
0.524
0.032
0.0032-0.032
0.0032-1
0.0032-0.01
0.01
0.01
0.01
itraconazole
terbinafine
Trichophyton rubrum (14)a
Trichophyton tonsurans (18)a
Other Trichophyton spp. (80)a
entry
rangeb
50%c
90%c
range
50%
90%
range
50%
>20
15
0.32
>20
3.2
0.32
90%
1a
1->20
11.6
3.2
0.32
11.6
3.2
0.21
>20
>20
>20
>20
>20
3.2->20
0.32->20
0.1-1
>20
>20
>20
1
0.1->20
0.1->20
>20
>20
1
1b
0.32->20
0.0032-1
1->20
>20
1
1c
0.934
0.0032-0.32
0.32->20
0.32->20
0.0005->20
1->20
2a
>20
3.2
1->20
>20
>20
10
>20
>20
1
>20
>20
>20
>20
>20
2b
1-3.2
0.01-1
0.32->20
0.032-1
>20->20
3.2->20
1->20
3.2
0.32
2c
1
>20
>20
>20
10
1
3a
>20->20
>20->20
3.2->20
1-10
>20
>20
>20
>20
>20
>20
13
>20
3b
3.2->20
>20
>20
3c
0.1->20
4a
3.2
3.2
0.32
0.1
0.01
1->20
3.2
10
0.1->20
3.2
3.2
0.1
0.1
0.01
4b
1-10
10
0.32->20
0.01-1
>20
1
0.0005->20
0.0032->20
0.0005->20
0.0005->20
4c
0.0032-1
0.01-1
0.796
0.32
1.22
itraconazole
terbinafine
0.32
0.01-1
0.01-3.2
0.32
0.524
0.0524
1
0.0032-0.1
0.0254
0.032
0.032
a Number of species tested. b MICs in µg/mL as the lowest concentrations of test compounds that reduced growth below 50% of the
level of the control growth. c MICs at which 50% and 90% of the isolate in the test panel, respectively, are inhibited. d Number of
Microsporum species tested is 37.
Table 3. MIC Values of Test Substances for Panels of Other Fungi
Candida spp. (24)a
rangeb 50%c
0.32
Aspergillus spp. (8)a
other fungi (13)a
50%
entry
90%c
range
50%
90%
>20
>20
1.66
>20
>20
range
90%
1a
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
4c
0.01->20
0.01->20
0.01->20
0.032->20
0.01->20
0.01->20
0.32->20
1->20
>20
>20
>20
>20
10
>20->20
10->20
>20
>20
0.1->20
0.1->20
0.1->20
0.1->20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
3.2
0.32
0.66
1
0.1
15
0.32-3.2
>20->20
3.2->20
0.1-1
>20->20
>20->20
>20->20
>20->20
10->20
0.66
>20
10
0.32->20
0.032->20
1->20
>20->20
>20->20
0.32->20
0.01->20
0.1->20
0.032-20
0.1-3.2
>20
10
>20
>20
>20
>20
>20
>20
>20
17
0.32
0.524
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
1
10
>20
0.1->20
0.01->20
0.01->20
0.01->20
0.01->20
0.1->20
0.66
3.2
0.1
0.1
0.32->20
0.032-3.2
0.032-3.2
itraconazole
terbinafine
0.32
0.32
1.184
1.66
>20
>20
0.32
3.2
a Number of species tested. b MICs in µg/mL as the lowest concentrations of test compounds that reduced growth below 50% of the
level of the control growth. c MICs at which 50% and 90% of the isolate in the test panel, respectively, are inhibited.
156.8, 159.9 (dd, J ) 251, 12 Hz), 162.8 (dd, J ) 247, 12 Hz).
Anal. (C35H39F2N7O4.) C,H,N.
The synthetic methods for 2c and 4c were similar to the
synthesis of compound 1c.
combined organic layers were washed with H2O and brine,
dried over anhydrous MgSO4, and filtered, and the filtrate was
evaporated at reduced pressure. The residue was purified by
silica gel column chromatography (gradient elution CH2Cl2/
CH3OH/EtOAc/n-hexane 49/1/30/20 toward 48/2/30/20). The
residue was crystallized from methanol to give 4a (1 g, 14%):
(+)-(2S-cis)-1-Ethyl-3-[4-[4-[4-[[4-(2,4-diflurorophen-
yl)-4-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-2-yl]meth-
oxy]phenyl]-1-piperazinyl]phenyl]-5,5-dimethyl-2,4,6-
(1H,3H,5H)-pyrimidinetrione (4a). Under nitrogen flow,
sodium hydride (0.4 g, 0.01 mol) was added to a stirred solution
of compound 12 (4.4 g, 0.01 mol) in dry DMF (60 mL) and dry
toluene (10 mL). After addition, the reaction was heated for
30 min at 50 °C, then a solution of 8a (5.4 g, 0.015 mol) in dry
DMF (20 mL) was added dropwise at 60 °C. After the reaction
was stirred for 6 h at 60 °C, it was cooled, poured into an ice-
water mixture, and extracted with CH2Cl2 (3 × 100 mL). The
mp 115-117 °C. [R]20 +14.73° (c 1.0, DMF). MS (ESI) m/z:
D
716 (MH+). 1H NMR (360 MHz, CDCl3) δ: 1.24 (t, J ) 7.0 Hz,
3 H), 1.64 (s, 6 H), 3.24 (m, 4 H), 3.39 (m, 4 H), 3.98 (q, J )
7.0 Hz, 2 H), 4.03 (dd, J ) 9.3, 1.4 Hz, 1 H), 4.11 (d, J ) 3.1
Hz, 2 H), 4.54 (d, J ) 14.3 Hz, 1 H), 4.67 (d, J ) 14.4 Hz, 1 H),
4.71 (dd, J ) 9.4, 3.4 Hz, 1 H), 5.31 (t, J ) 3.1 Hz, 1 H), 6.85
(m, 2 H), 6.93 (m, 2 H), 6.97 (m, 2 H), 7.03 (m, 2 H), 7.07 (m,
2 H), 7.35 (td, J ) 8.6, 6.4 Hz, 1 H), 7.78 (s, 1 H), 8.17 (s, 1 H).
Anal. (C37H39F2N7O6.) H, N; C calcd, 62.09; found, 61.22.

2190 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Table 4. ED50 Values in Guinea Pigs Infected with M. Canisa
Meerpoel et al.
ED50 (mg/kg)
assessed on day
doses tested (mg/kg)
(number of animals)b,c
entry
7
14
21
1a
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
4c
1.18
1.18
3.28
1.94
2.35
1.94
0.31; 0.63; 1.25 (n ) 8); 2.5 (n ) 12); 5
0.31; 0.63; 1.25 (n ) 8); 2.5 (n ) 8)
0.31; 0.63; 1.25 (n ) 8); 2.5 (n ) 8)
1.25; 2.5; 5
0.33
0.44
0.33
>5.00
>2.50
0.89
>5.00
>2.50
1.29
>5.00
>2.50
1.21
>2.50
>2.50
>2.50
2.35
1.25; 2.5
0.31; 0.63; 1.25 (n ) 8); 2.5 (n ) 12); 5
1.25; 2.5
>2.50
>2.50
>2.50
2.35
>2.50
>2.50
>2.50
2.35
1.25; 2.5
1.25; 2.5
1.25; 2.5
1.25
2.35
>2.50
<0.31
1.18
0.31; 0.63; 1.25 (n ) 8); 2.5 (n ) 8)
0.31; 0.63; 1.25 (n ) 8); 2.5 (n ) 12)
0.31; 0.63; 1.25 (n ) 8); 2.5 (n ) 12); 5; 10
2.5; 5 (n ) 8); 10
<0.31
0.84
<0.31
1.20
itraconazole
terbinafine
>10
>10
>10
a Response was defined as a lesion score of less than 2; treatment started on day 0 and continued daily for 12 days. b The test groups
comprised six animals each unless indicated otherwise in parentheses. c Untreated control group contained 18 animals.
Table 5. ED50 Values in Mice Infected with T.
(-)-(2S, cis)-2-(2,4-Difluorophenyl)-2-(1H-1,2,4-triazol-
1-ylmethyl)-1,3-dioxolane-4-methanol 4-Methylbenzene-
solfonate Ester 4-Methylbenzensulfonate Salt (1:1) (5a).
In a two-neck flask provided with a Dean-Stark trap, meth-
anesulfonic acid (200 mL) was added slowly to a solution of
1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone40 (44.6
g, 0.2 mol) and (2S)-1,2,3-propanetriol-1-(4- methylbenzene-
sulfonate) ester27 (56 g, 0.227 mol) in CH2Cl2 (150 mL) at room
temperature. After addition, the solution was heated to reflux
for 24 h, cooled to room temperature, and slowly poured into
a mixture of ice (500 g), water (800 mL), K2CO3 (400 g), and
CH2Cl2 (500 mL). The organic layer was separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 250 mL). The
combined CH2Cl2 layers were dried over anhydrous MgSO4 and
filtered, and the filtrate was evaporated under reduced pres-
sure. The residue was purified by column chromatography
(silica gel, CHCl3), and fractions containing the cis isomer were
evaporated at reduced pressure and converted to its 4-meth-
ylbenzenesulfonate salt in MIK. The salt was crystallized from
MIK to give 5a (20.5 g, 16.4%): mp 182-184 °C. [R]20D -13.79°
(c 1.0, MeOH). 1H NMR (200 MHz, CDCl3): δ 3.12 (s, 3H),
4.44 (dd, 1H), 4.65 (dd, 1H), 4.84 (m, 2H), 5.40 (m, 1H), 5.81
(s, 2H), 8.59 (m, 2H), 9.21 (m, 3H), 9.75 (m, 3H), 10.15 (s, 1H).
Anal. (C20H19F2N3O5S‚C7H8O3S) C, H, N.
Mentagrophytesa
ED50 (mg/kg)
assessed on day
doses tested (mg/kg)
entry
day 7
(number of animals)b,c
1a
1b
1c
2a
2c
4b
4c
>2.50
2.86
>2.50
3.10
2.60
0.63; 1.25 (n ) 12); 2.5 (n ) 12)
0.63; 1.25 (n ) 12); 2.5
0.63; 1.25 (n ) 12); 2.5
2.5; 5
0.63; 1.25 (n ) 12); 2.5 (n ) 12); 5
0.63; 1.25
0.63; 1.25 (n ) 12); 2.5 (n ) 12); 5
0.63; 1.25 (n ) 12); 2.5 (n ) 12); 5
2.5; 5
>1.25
<0.63
2.60
itraconazole
terbinafine
>5.00
a Response was defined as a lesion score of less than 2;
treatment started on day 0 and continued daily for 5 days. b The
test groups comprised six animals each unless indicated otherwise
in parentheses. c Untreated control group contained 18 animals.
(+)-(2S-cis)-1-Ethyl-3-[4-[4-[4-[[4-(2,4-difluorophenyl)-
4-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-2-yl]meth-
oxy]phenyl]-1-piperazinyl]phenyl]-5-propyl-1,3,5-tri-
azine-2,4,6(1H,3H,5H)-trione (4b) was synthesized accord-
ing to the method described for 4a to give 4b (40%) crystallized
from ethanol: mp 159-161 °C. [R]20D +15.73° (c 0.099, DMF).
MS (ESI) m/z: 731 (MH+). 1H NMR (360 MHz, CDCl3): δ 0.96
(t, J ) 7.5 Hz, 3 H), 1.29 (t, J ) 7.0 Hz, 3 H), 1.72 (m, 2 H),
3.24 (m, 4 H), 3.39 (m, 4 H), 3.89 (m, 2 H), 4.00 (q, J ) 7.0 Hz,
2 H), 4.03 (dd, J ) 9.4, 1.5 Hz, 1 H), 4.11 (d, J ) 3.1 Hz, 2 H),
4.54 (d, J ) 14.3 Hz, 1 H), 4.67 (d, J ) 14.4 Hz, 1 H), 4.71 (dd,
J ) 9. 5, 3.5 Hz, 1 H), 5.31 (t, J ) 3.0 Hz, 1 H), 6.85 (m, 2 H),
6.95 (m, 4 H), 7.03 (m, 2 H), 7.15 (m, 2 H), 7.35 (td, J ) 8.6,
6.3 Hz, 1 H), 7.78 (s, 1 H), 8.18 (s, 1 H). Anal. (C37H40F2N8O6.)
C, H, N.
(+)-(2R, cis)-2-(2,4-Difluorophenyl)-2-(1H-1,2,4-triazol-
1-ylmethyl)-1,3-dioxolane-4-methanol 4-Methylbenzene-
solfonate Ester 4-Methylbenzensulfonate Salt (1:1) (5b).
The title compound was prepared from (2R)-1,2,3-propanetriol-
1-(4-methylbenzenesulfonate) ester as a 4-methylbenzene-
sulfonate salt following the procedure described for compound
5a. The salt was crystallized from MIK to give 5b (20.6%):
mp 183-185 °C. [R]20 +14.43° (c 1.0, MeOH).
D
(-)-(2S-cis)-2-(2,4-Difluorophenyl)-2-(1H-1,2,4-triazol-
1-ylmethyl)-1,3-dioxolane-4-methanol Methanesulfonate
Ester (6a). The title compound was prepared from (2S)-1,2,3-
propanetriol-1-(methylsulfonate) ester following the procedure
described for compound 5a to give 6a (22%) crystallized from
MIK: mp 114.1-114.7 °C. [R]20D ) -14.50 (c 0.2, CH3OH). 1H
NMR (400 MHz, DMSO-d6): δ 3.26 (s, 3 H), 3.76 (dd, J ) 8.8,
5.7 Hz, 1 H), 3.96 (dd, J ) 8.7, 6.8 Hz, 1 H), 4.02 (dd, J )
11.0, 6.2 Hz, 1 H), 4.20 (dd, J ) 11.0, 3.7 Hz, 1 H), 4.41 (dd, J
) 6.2, 3.7 Hz, 1 H), 4.74 (m, 2 H), 7.05 (td, J ) 8.5, 2.6 Hz, 1
H), 7.28 (dd, J ) 11.4, 9.1, 2.5 Hz, 1 H), 7.41 (td, J ) 8.8, 6.6
Hz, 1 H), 7.86 (s, 1 H), 8.42 (s, 1 H). 13C NMR (101 MHz,
DMSO-d6): δ 36.8, 54.1 (d, J ) 3 Hz), 66.0, 68.9, 74.2, 104.9
(t, J ) 26 Hz), 106.7 (d, J ) 4 Hz), 111.1 (dd, J ) 21, 3 Hz),
122.1 (dd, J ) 13, 3 Hz), 129.3 (dd, J ) 10, 5 Hz), 145.3, 150.8,
159.9 (dd, J ) 252, 13 Hz), 162.8 (dd, J ) 250, 15 Hz). Anal.
(+)-(2S-cis)-1-[4-[4-[4-[[4-(2,4-Difluorophenyl)-4-(1H-
1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]-
phenyl]-1-piperazinyl]phenyl]-3-(1-methylethyl)-2-imid-
azolidinone (4c) (63%) was crystallized from DIPE/EtOAc:
mp 178-180 °C. [R]20 +17.54° (c 0.05, DMF). H NMR (400
1
D
MHz, DMSO-d6): δ 1.11 (d, J ) 7.0 Hz, 6 H), 3.19 (m, 8 H),
3.36 (m, 2 H), 3.72 (m, 2 H), 4.02 (m, 3 H), 4.12 (dd, J ) 11.0,
3.3 Hz, 1 H), 4.59 (m, 2 H), 4.68 (dd, J ) 9.1, 3.3 Hz, 1 H),
5.28 (t, J ) 3.5 Hz, 1 H), 6.92 (d, J ) 9.1 Hz, 2 H), 6.97 (m, 4
H), 7.06 (td, J ) 8.6, 2.2 Hz, 1 H), 7.34 (m, 2 H), 7.42 (d, J )
9.1 Hz, 2 H), 7.83 (s, 1 H), 8.36 (s, 1 H). 13C NMR (101 MHz,
DMSO-d6): δ 19.2, 36.0, 42.3, 43.1, 49.1, 49.6, 55.0, 67.8, 72.4
(d, J ) 6 Hz), 80.9 (d, J ) 4 Hz), 102.3, 104.3 (t, J ) 26 Hz),
111.5 (dd, J ) 21, 3 Hz), 115.1, 116.2, 117.5, 118.2, 123.6 (dd,
J ) 15, 3 Hz), 128.6 (dd, J ) 10, 7 Hz), 133.5, 145.1, 145.8,
146.1, 150.9, 151.8, 156.8, 158.8 (dd, J ) 247, 13 Hz), 162.2
(dd, J ) 247, 12 Hz). Anal. (C35H39F2N7O4.) C, H, N.
(C
14H15F2N3O5S) C, H, N.
(2S-cis)-1-[[2-(Bromomethyl)-4-(2,4-difluorophenyl)-
1,3-dioxolan-4-yl]methyl]-1H-1,2,4-triazole (8a) and (2R-
cis)-1-[[2-(Bromomethyl)-4-(2,4-difluorophenyl)-1,3-diox-
olan-4-yl]methyl]-1H-1,2,4-triazole (8b). 1-Bromo-2,2-di-

Antifungal Triazoles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 2191
ethoxyethane (40 g, 0.2 mmol) was added dropwise to a stirred
solution of 2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)1,2-
propanediol30-35 (40.3 g, 0.16 mmol) in methanesulfonic acid
(100 mL) and CH2Cl2 (1000 mL) at 10 °C. After addition, the
mixture was allowed to warm at room temperature, stirred
overnight, poured into a mixture of ice, H2O (750 mL), NaHCO3
(160 g), and extracted with CH2Cl2 (3 × 750 mL). The combined
organic layers were dried over anhydrous MgSO4 and filtered,
and the filtrate was evaporated at reduced pressure. The
residue was purified over silica gel (CH2Cl2/CH3OH gradient
elution from 100/0 to 98/2). The desired fractions were col-
lected, and the solvent was evaporated under reduced pres-
sure. The residue (cis and trans isomers) was purified by chiral
column chromatography (Chiralcel OD, 20 µm, 1000 Å, hexane/
ethanol 75/25) to give 8a (5.1 g, 9%), 8b (6.3 g, 11%), and trans
isomer (21.8 g, 38%). 8a: mp 165-167 °C. [R]20D +5.83° (c 0.94,
evaporated at reduced pressure, and aqueous K2CO3 was
added to adjust the pH to 8. The mixture was extracted with
CH2Cl2 (3 × 300 mL), and the combined organic layers were
washed with H2O (100 mL) and brine (100 mL), dried over
anhydrous MgSO4, and evaporated at reduced pressure. The
residue was chromatographed on silica gel (2% MeOH in CH2-
Cl2). The desired fraction was recrystallized from CH3CN to
give 12 (1.2 g, 40%): mp 253-254 °C. 1H NMR (400 MHz,
DMSO-d6): δ 1.12 (t, J ) 7.1 Hz, 3 H), 1.49 (s, 6 H), 3.06-
3.15 (m, 4 H), 3.27-3.35 (m, 4 H), 3.80 (q, J ) 7.0 Hz, 2 H),
6.68 (d, J ) 8.8 Hz, 2 H), 6.86 (d, J ) 8.8 Hz, 2 H), 7.03 (d, J
) 9.1 Hz, 2 H), 7.10 (d, J ) 9.1 Hz, 2 H), 8.86 (s, 1 H). 13C
NMR (101 MHz, DMSO-d6): δ 12.9, 24.4, 36.6, 47.1, 48.3, 50.2,
115.3, 115.5, 118.1, 126.5, 129.2, 144.0, 150.6, 150.6, 151.2,
172.4, 172.7. Anal. (C24H28N4O4) C, H, N.
1-[4-[4-(4-Methoxyphenyl)-1-piperazinyl]phenyl]-3-pro-
pyl-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione (13). Propyliso-
cyanate (38.4 mL, 0.4 mol) was added to a solution of
compound 9 (100 g, 0.35 mol) in CH2Cl2 (1 L), stirred overnight
at room temperature, and evaporated under reduced pressure.
The residue was triturated with MeOH (250 mL), and the
precipitate was filtered and dried under reduced pressure at
60 °C to give N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-
N′-propylurea (112 g, 86%). N-[4-[4-(4-Methoxyphenyl)-1-
piperazinyl]phenyl]-N′-propylurea (50 g, 0.136 mol) was dis-
solved in 1,2-dichloroethane (500 mL) at reflux temperature.
The mixture was cooled to room temperature, and chlorocar-
bonylisocyanate (10.9 mL, 0.136 mol) was added. The mixture
was refluxed for 1 h and cooled to room temperature, and an
aqueous saturated NaHCO3 solution (150 mL) was added and
stirred for 1 h. The precipitate was filtered, washed with H2O
(2 × 50 mL) and CH2Cl2 (50 mL), and dried to give 13 (47.5
g). Combined filtrates were separated, and the organic layer
was washed with H2O (2 × 100 mL) and brine (100 mL) and
dried over anhydrous MgSO4. The filtrate was evaporated at
reduced pressure to give another crop of 13 (12.3 g). The
combined crops were recrystallized from acetonitrile to give
13 (52.7 g, 88%): mp 233-235 °C. 1H NMR (400 MHz, DMSO-
d6): δ 0.87 (t, J ) 7.5 Hz, 3 H), 1.58 (m, 2 H), 3.16 (dd, J )
6.5, 3.6 Hz, 4 H), 3.32 (dd, J ) 6.6, 3.5 Hz, 4 H), 3.67 (dd, J )
8.3, 6.2 Hz, 2 H), 3.70 (s, 3 H), 6.85 (d, J ) 9.2 Hz, 2 H), 6.97
(d, J ) 9.2 Hz, 2 H), 7.03 (d, J ) 9.1 Hz, 2 H), 7.16 (d, J ) 9.1
Hz, 2 H), 11.71 (s, 1 H). 13C NMR (101 MHz, DMSO-d6): δ
11.0, 20.6, 42.9, 48.2, 49.7, 55.2, 114.3, 115.3, 117.7, 125.5,
129.3, 145.2, 148.8, 148.9, 150.1, 150.7, 153.2. Anal. (C23H27N5O4)
C, H, N.
1
DMF). H NMR (400 MHz, DMSO-d6): δ 3.64 (dd, J ) 11.2,
4.2 Hz, 1 H), 3.70 (dd, J ) 11.2, 3.4 Hz, 1 H), 4.03 (dd, J )
9.1, 1.5 Hz, 1 H), 4.60 (m, 2 H), 4.68 (dd, J ) 9.0, 3.1 Hz, 1 H),
5.19 (t, J ) 3.8 Hz, 1 H), 7.04 (td, J ) 8.5, 2.4 Hz, 1 H), 7.29
(m, 2 H), 7.81 (s, 1 H), 8.39 (s, 1 H). Anal. (C13H12BrF2N3O2)
C, H, N; H, 3.79. 8b: oil. [R]20D -4.26° (c 0.82, DMF). 1H NMR
(400 MHz, C6D6): δ 2.96 (dd, J ) 11.3, 3.5 Hz, 1 H), 2.99 (dd,
J ) 11.3, 3.5 Hz, 1 H), 3.57 (dd, J ) 9.2, 1.7 Hz, 1 H), 4.05 (d,
J ) 14.4 Hz, 1 H), 4.11 (d, J ) 14.4 Hz, 1 H), 4.35 (dd, J )
9.2, 3.1 Hz, 1 H), 4.56 (t, J ) 3.5 Hz, 1 H), 6.43 (m, 2 H), 6.96
(m, 1 H), 7.77 (s, 1 H), 7.91 (s, 1 H). trans isomer 1H NMR
(400 MHz, CDCl3): δ 3.35 (m, 2H), 4.25 (dd, J ) 9.3 Hz, 1.7
Hz, 1H), 4.49 (m, 2H), 4.62 (d, J ) 14.4 Hz, 1H), 5.26 (t, 1H),
6.87 (m, 2H), 7.48 (m,1H), 7.84 (s, 1H), 8.05 (s, 1H).
1-[4-[4-(4-Methoxyphenyl)-1-piperazinyl]phenyl]-5,5-
dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione (10). A solu-
tion of potassium isocyanate (11.2 g, 0.138 mol) was added
dropwise over a period of 3 h to a solution of 9 (13.02 g, 0.046
mol) in concentrated HCl (138 mL, 0.138 mol) and then stirred
for an additional 1 h. The mixture was neutralized with NaOH,
and the precipitate was filtered, washed with H2O (3 × 75 mL),
and dried in vacuo at 30 °C to give N-[4-[4-(4-methoxyphenyl)-
1-piperazinyl]phenyl]urea (15 g, 100%) as a white solid (mp
320 °C decomposition). 2,2-Dimethylmalonyl chloride (7.7 g,
0.046 mol) was added dropwise to a stirred solution of N-[4-
[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]urea (15 g, 0.046
mol) in tetrahydrothiophene-1,1-dioxide (150 mL) at room
temperature. After 15 min, the reaction was heated at 40 °C
and stirred for 3 h followed by additional stirring at 50 °C for
2 h. The reaction mixture was allowed to stand overnight at
room temperature. The product was precipitated by addition
of diethyl ether, filtered, and crystallized from 2-propanol to
give 10 (16.1 g, 83%) as a white solid: mp 218-222 °C. 1H
NMR (360 MHz, DMSO-d6): δ 1.46 (s, 6 H), 3.16 (m, 4 H),
3.32 (m, 4 H), 3.70 (s, 3 H), 6.85 (d, J ) 8.8 Hz, 2 H), 6.97 (d,
J ) 8.8 Hz, 2 H), 7.03 (d, J ) 9.1 Hz, 2 H), 7.10 (d, J ) 9.1 Hz,
2 H), 11.44 (s, 1 H). 13C NMR (91 MHz, DMSO-d6): δ 24.1,
46.7, 48.3, 49.8, 55.2, 114.3, 115.3, 117.7, 126.1, 129.3, 145.3,
150.5, 150.6, 153.2, 173.3, 173.6. Anal. (C23H26N4O4) C, H, N.
5-Ethyl-1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phen-
yl]-3-propyl-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione (14). Eth-
yl bromide (9.3 mL, 0.12 mol) was added to a mixture of
compound 13 (50 g, 0.114 mol) and KOH pellets (12.7 g, 0.228
mol) in DMF (500 mL) and was stirred overnight at room
temperature. The reaction mixture was then poured into a
mixture of ice-water (400 mL). The precipitate was filtered,
dissolved in CH2Cl2 (500 mL), washed with H2O (2 × 100 mL)
and brine (100 mL), and dried over anhydrous MgSO4, and
the filtrate was evaporated at reduced pressure. The residue
was recrystallized from 2-propanol to give 14 (37 g, 70%): mp
177-179 °C. Anal. (C23H27N5O4) C, H, N.
1-Ethyl-3-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phen-
yl]-5,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (11).
Dry DMF (70 mL) was added to a flask containing the oil free
NaH (0.52 g, 0.0174 mol) under argon. Compound 10 (7 g,
0.0166 mol) was added, after stirring for 30 min, ethyl iodide
(1.41 mL, 0.0182 mol) was added dropwise, and the mixture
was heated at 85 °C for 3 h. The mixture was cooled, poured
into H2O (100 mL), and extracted with CH2Cl2 (3 × 100 mL).
The combined organic layers were washed with H2O (50 mL)
and brine (50 mL), dried over anhydrous MgSO4, and filtered,
and the filtrate was evaporated at reduced pressure. The
residue was chromatographed on silica gel (2% MeOH in CH2-
Cl2), and the desired compound was crystallized from CH3CN
to give 11 (3 g, 40%): mp 184-185 °C.
5-Ethyl-1-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phen-
yl]-3-propyl-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione (15).
Compound 15 was synthesized in 95% yield according to the
method described for compound 12 and recrystallized from
1
n-propanol: mp 256-258 °C. H NMR (400 MHz, DMSO-d6):
δ 0.88 (t, J ) 7.4 Hz, 3 H), 1.16 (t, J ) 7.0 Hz, 3 H), 1.60 (m,
J ) 7.4, 7.4, 7.4, 7.4, 7.4 Hz, 2 H), 3.11 (m, 4 H), 3.32 (m, 4 H),
3.73 (t, J ) 7.3 Hz, 2 H), 3.82 (q, J ) 7.0 Hz, 2 H), 6.68 (d, J
) 8.6 Hz, 2 H), 6.86 (d, J ) 8.6 Hz, 2 H), 7.03 (d, J ) 8.7 Hz,
2 H), 7.17 (d, J ) 8.7 Hz, 2 H), 8.86 (s, 1 H). 13C NMR (101
MHz, DMSO-d6): δ 11.1, 12.8, 20.6, 37.6, 43.8, 48.2, 50.1,
115.2, 115.5, 118.1, 125.8, 129.2, 144.0, 148.9, 148.9, 149.1,
150.8, 151.2. Anal. (C24H29N5O4) C, H, N.
1-Ethyl-3-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phen-
yl]-5,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (12).
Compound 11 (3.07 g, 6.8 mmol) was heated to reflux for 5 h
in a mixture of 48% HBr (60 mL) and HBr saturated acetic
acid (30 mL) in the presence of NaHSO3 (1 g). The solvent was
1,3-Dihydro-1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]-
phenyl]-3-(1-methylethyl)-2H-imidazol-2-one (17). A mix-
ture of compound 1636 (95 g, 0.23 mol), N-(2,2-dimethoxyethyl)-

2192 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Meerpoel et al.
2-propaneamine41 (49 g, 0.23 mol), DMAP (17.6 g, 0.144 mol),
and triethylamine (66 mL) in dioxane (880 mL) was refluxed
for 4 h. The mixture was cooled to room temperature, and H2O
(880 mL) was added and stirred for 15 min. The precipitate
was filtered, washed with H2O (2 × 50 mL), and dried under
reduced pressure. The solid was stirred in formic acid (440
mL) at 70 °C for 3 h followed by evaporation of the solvent at
reduced pressure. The residue was dissolved in methylisobutyl
ketone (500 mL), washed with aqueous saturated NaHCO3 (2
× 100 mL), H2O (100 mL), and brine (100 mL), dried over
anhydrous MgSO4, and evaporated at reduced pressure. The
residue was chromatographed on silica gel (CH2Cl2/MeOH/
hexane/EtOAc, 48/2/20/30) to give an oil that was triturated
with diisopropyl ether yielding 17 (68 g, 75%): mp 186.9 °C.
MS m/z: 513 (MH+). 1H NMR (400 MHz, CDCl3): δ 1.34 (d, J
) 6.8 Hz, 6 H), 3.23 (m, 4 H), 3.33 (m, 4 H), 3.78 (s, 3 H), 4.47
(m, 1 H), 6.35 (d, J ) 3.1 Hz, 1 H), 6.51 (d, J ) 3.1 Hz, 1 H),
6.86 (d, J ) 9.1 Hz, 2 H), 6.96 (d, J ) 9.1 Hz, 2 H), 7.00 (d, J
) 9.1 Hz, 2 H), 7.48 (d, J ) 9.1 Hz, 2 H) 13C NMR (101 MHz,
CDCl3) δ 22.0, 44.5, 49.7, 50.8, 55.5, 107.3, 109.8, 114.5, 116.7,
118.5, 123.0, 130.0, 145.6, 149.3, 151.3, 154.1. Anal. (C33H28N4O2)
C, H, N.
1-[4-[4-(4-Hydroxyphenyl)-1-piperazinyl]phenyl]-3-(1-
methylethyl)-2-imidazolidinone (18). Compound 17 (67 g,
0.17 mol) was dissolved in acetic acid (2 L), 10% palladium on
charcoal (8 g) was added, and the mixture was degassed three
times. This mixture was hydrogenated overnight at atmo-
spheric pressure and filtered, and the filtrate was evaporated
at reduced pressure. The residue (47 g) was heated at reflux
temperature for 2 h in 48% HBr (300 mL) and HBr saturated
acetic acid (200 mL) in the presence of NaHSO3 (3 g). The
reaction was cooled to room temperature, and H2O (500 mL)
was added. After the reaction mixture was stirred for 30 min,
the precipitate was filtered. The precipitate was stirred in H2O
(500 mL), and the mixture was neutralized with aqueous
ammonia. The precipitate was filtered and recrystallized from
2-propanol to give 18 (52 g, 80% for the two steps): mp 234-
237 °C. 1H NMR (400 MHz, DMSO-d6): δ 1.10 (d, J ) 6.6 Hz,
6 H), 3.09 (m, 4 H), 3.18 (m, 4 H), 3.36 (m, 2 H), 3.72 (m, 2 H),
4.01 (m, 1 H), 6.67 (d, J ) 8.8 Hz, 2 H), 6.84 (d, J ) 8.8 Hz, 2
H), 6.95 (d, J ) 8.8 Hz, 2 H), 7.41 (d, J ) 8.8 Hz, 2 H), 8.83 (s,
1 H). 13C NMR (101 MHz, DMSO-d6): δ 19.1, 36.0, 42.3, 43.1,
49.2, 50.1, 115.4, 116.1, 117.9, 118.2, 133.4, 144.0, 146.1, 151.0,
156.7. Anal. (C22H28N4O2) H, N; C calcd, 69.45; found, 68.90.
In Vitro Antifungal Activities. All fungi used for testing
were originally isolated from humans or animals. They were
stored at -80 °C, as part of the collection of the Department
of Bacteriology and Mycology at the Janssen Research Foun-
dation currently known as Johnson and Johnson Pharmaceu-
tical Research and Development a division of Janssen Phar-
maceutica N.V., in dilute casein hydrolysate yeast extract/
glucose medium with 10% glycerol. The species tested and
numbers of isolates of each tested were as follows: Candida
spp. (24), (Candida albicans (5), C. famata (1), C. glabrata (4),
C. guilliermondii (1), C. kefyr (2), C. krusei (2), C. lusitaniae
(2), C. parapsilosis (3), C. tropicalis (4)), Epidermophyton
floccosum (12), Microsporum spp. (38), (Microsporum audouinii
(7), M. canis (22), M. gypseum (7), M. nanum (1), M. vanbreu-
seghemii (1)), Trichophyton spp. (132) (Trichophyton ajelloi (5),
T. concentricum (6), T. equinum (17), T. ferrugineum (2), T.
gallinae (2), T. megninii (1), T. mentagrophytes (20), T.
persicolor (2), T. quickeanum (2), T. rubrum (14), T. schoen-
leinii (2), T. soudanesis (6), T. sulfureum (1), T. terrestre (5),
T. tonsurans (18), T. verrucosum (20), T. violaceum (9)),
Aspergillus spp. (8) (Aspergillus fumigatus (6), Aspergillus
niger (1), Aspergillus flavus (1)), and other fungi (13) (Mucor
racemous (1), Rhizopus microsporum (1), Cumminghamella
elegans (1), Fusarium oxysporum (1), Cryptococcus neoformans
(2), Sporothrix schenckii (2), Exophilia dermatididis (1), Exo-
philia spinifera (1), Fonsecaea pedrosoi (1), Phialophora ver-
rucosa (2)). The test compounds were dissolved in dimethyl
sulfoxide (DMSO), and a dilution series was prepared in
DMSO to give concentrates that were stored at -20 °C.
Concentrations of the stock solutions were 100 times the final
concentration of each compound. For preparation of microdi-
lution plates, 2 µL volumes of concentrate in DMSO were
added to 100 µL volumes of sterile distilled water by means
of a computer-controlled dispenser. Addition of 100 µL of
inoculated culture medium as detailed below provided the final
dilution step, creating cultures with 1% (v/v) DMSO. Earlier
tests showed that this concentration of DMSO is not inhibitory
for species tested; all control cultures also contained 1%
DMSO.
Full experimental procedures for the in vitro and in vivo
antifungal screening have been published recently.22
Acknowledgment. We thank Professor C. J. De
Ranter of the KU-Leuven University for X-ray crystal-
lography of crystals of 8a and Luc Wouters, MSc, of
Barrier Therapeutics N.V. for statistical analyses of the
biological results. This study was supported by a grant
from the IWT-Vlaanderen (Grant 030023 to J.A.)
Supporting Information Available: Analysis data for
2a,b,c and 3a,b,c, X-ray determination of absolute configu-
ration of 4-methylbenzenesulfonate salt of compound 8a, and
elemental analysis data of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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