New azole antifungals. 3. Synthesis and antifungal activity of 3- substituted-4(3H)-quinazolinones

Article abstract of DOI:10.1021/jm9707277

A series of azole antifungal agents featuring a quinazolinone nucleus have been subjected to studies of structure - activity relationships. In general, these compounds displayed higher in vitro activities against filamentous fungi and shorter half-lives t

Full text of DOI:10.1021/jm9707277

J . Med. Chem. 1998, 41, 1869-1882
1869
New Azole An tifu n ga ls. 3. Syn th esis a n d An tifu n ga l Activity of
3-Su bstitu ted -4(3H)-qu in a zolin on es1,2
J avier Bartroli,* Enric Turmo, Mo`nica Alguero´, Eula`lia Boncompte, Maria L. Vericat, Lourdes Conte,
J oaquim Ramis, Manuel Merlos, J ulia´n Garc´ıa-Rafanell, and J avier Forn
Research Center, J . Uriach & Cı´a. S.A., Dega` Bahı´ 59-67, 08026 Barcelona, Spain
Received October 24, 1997
A series of azole antifungal agents featuring a quinazolinone nucleus have been subjected to
studies of structure-activity relationships. In general, these compounds displayed higher in
vitro activities against filamentous fungi and shorter half-lives than the structures described
in our preceding paper. The most potent products in vitro carried a halogen (or an isostere) at
the 7-position of the quinazolinone ring. Using a murine model of systemic candidosis, oral
activity was found to be dependent on hydrophobicity, which, in turn, modulated the compound’s
half-life. The 7-Cl derivative, (1R,2R)-7-chloro-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-
3-(1H-1,2,4-triazol-1-yl)propyl]quinazolin-4(3H)-one (20, UR-9825), was selected for further
testing due to its high in vitro activity, low toxicity, good pharmacokinetic profile, and ease of
obtention. Compound 20 is the (1R,2R) isomer of four possible stereoisomers. The other three
isomers were also prepared and tested. The enantiomer (1S,2S) and the (1R,2S) epimer were
inactive, whereas the (1S,2R) epimer retained some activity. In vitro 20 was superior to
fluconazole, itraconazole, SCH-42427, and TAK-187 and roughly similar to voriconazole and
ER-30346. In vivo, 20 was only moderately active in a mouse model of systemic candidosis
when administration was limited to the first day. This was attributed to its short half-life in
that species (t1/2 ) 1 h po). Protection levels comparable to or higher than those of fluconazole,
however, were observed in systemic candidosis models in rat and rabbit, where the half-life of
the compound was found to be 6 and 9 h, respectively. Finally, 20 showed excellent protection
levels in an immunocompromised rat model of disseminated aspergillosis. The compound
showed low toxicity signs when administered to rats at 250 mg/kg qd or at 100 mg/kg bid
during 28 days.
In tr od u ction
phenyl ring specifically oriented in the space could be
responsible for the improved activity and spectrum.
However, a tendency to display long plasma elimination
half-lives in animal species was clearly observed for
those and related structures. Attempts to decrease that
pharmacokinetic parameter in the rat by means of
increasing the compound’s polarity generally resulted
in diminished activity.
During the course of that study, a very active class
of compounds containing a quinazolinone unit caught
our interest, as their structure lacked the phenyl
substituent. The new products were less hydrophobic,
a characteristic that might potentially facilitate body
clearance. But most importantly, they were particularly
active against A. fumigatus. The present paper de-
scribes the synthesis and SARs found in this new family
of antifungal agents and the selection of compound 20
(UR-9825) for preclinical development.
Since the launching of fluconazole (1) and itraconazole
(2) for the treatment of systemic mycoses a decade ago,
the race to market a new azole continues. Although new
structures in this class are frequently reported in the
patent3 and the scientific4 literature (Figure 1), an-
nouncements about their clinical discontinuation are
unfortunately also common. The medical need for new,
more effective azole antifungal drugs persists.
Clinically, candidosis and aspergillosis account for
between 80% and 90% of systemic fungal infections in
immunocompromised patients, yet the difficulties in
dealing with each of these two diseases are quite
different. Whereas many drugs have proven effective
against candidosis, only two, amphotericin B and itra-
conazole, are currently available to treat infections due
to Aspergillus fumigatus, and both have only moderate
response rates. A drug active against those two clini-
cally important pathogens would thus be highly desir-
able.
Our accompanying paper2b described the development
of a series of carboxamides with high potency against
both yeasts and filamentous fungi based on Sankyo’s
benzamide 8.5 Two compounds, 9 and 10, representing,
respectively, the open and conformationally constrained
versions of these amide derivatives, were selected and
studied further (Figure 2). It was suggested that a
heterocyclecarboxamide unit carrying a substituted
Ch em istr y
Quinazolinones were readily synthesized from enan-
tiomerically pure amines 11-145,6 by a two-step proce-
dure (Scheme 1) consisting of a DCC coupling with the
corresponding anthranilic acid, followed by heating the
resulting intermediate with triethylorthoformate or
formamidine acetate in NMP. Final compounds carry-
ing a NR1R2, OR, or SR substituent at the 7-position
were obtained by nucleophile aromatic substitution of
the 7-F derivative 24. All of the screened compounds
S0022-2623(97)00727-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/29/1998

1870 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Bartroli et al.
F igu r e 2. Structure evolution.
Sch em e 1. Synthesis of Quinazolinonesa
F igu r e 1. Azole antifungals (names and laboratory codes refer
to single enantiomers, except itraconazole which is racemic).
were prepared as the enantiomerically pure (1R,2R)
isomers. The four stereoisomers of structure 20 were
synthesized from the corresponding stereoisomeric
amines6 and their activity tested. The total synthesis
of 20 is outlined in Scheme 2. The process does not
require chromatographic purifications and presently
produces 20 in the kilogram scale with high enantio-
meric purity (>99.9% ee, chiral HPLC) and chemical
yield (35% overall).
Biologica l Tests
Compounds were tested in vitro by the agar dilution
method against an assortment of 10 yeast and 6
filamentous fungi. The individual minimum inhibitory
concentrations (MICs, µg/mL) obtained for each product
are presented in Table 10 (Supporting Information).
Two geometric means of the MICs were calculated to
facilitate SARs, one for yeasts and another for filamen-
tous fungi. Fluconazole (1), itraconazole (2), voricona-
zole (4),7 SCH-42427 (5),8 TAK-187 (6),9 ER-30346 (7),10
and 85 were also included for comparison purposes (see
Figure 1 for structures). With the exception of the
compounds with low in vitro activity, all of the products
were also tested in vivo in a murine systemic candidosis
model. In these studies, the compounds were admin-
istered orally three times over the 24 h following
a
Reagents: (a) DCC, HOBT, NEt3, DMF, room temperature,
18 h; (b) (EtO)3CH, NMP, 110 °C, 18 h; (c) HNu, NaH, NMP, heat.
infection. Each study consisted of 10 groups, one of
which was always a control group (infected but un-
treated), and another consisted of animals treated with
fluconazole at the same dose as the test compound.
Complete mortality in the control group was attained
within 3 days, whereas in the fluconazole-treated group,
100% mortality was reached toward the end of each
study, the exact day depending on the dose. Due to
slight variations in the inocule virulence from study to
study, comparison of the absolute in vivo protection

New Azole Antifungals. 3
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11 1871
Ta ble 1. Effect of Benzo Substitution
Sch em e 2. Synthesis of 20a (ref 6)
in vivo
(1 mg/kg po)c
% protection
in vitro
MICa MICb
compd R5 R6
R7
R8
yst
ff
(dC)d (dFlu)e
15
16
43
>80
0f
30
0f
0
0
0
0
0.4
1.2
3.1
1.0
0.3
2.5
4.3
45
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
H
Cl
H
H
H
F
H
H
Cl
H
H
H
F
H
Br
H
H
H
H
Cl
H
H
H
F
H
H
H
H
Cl
H
H
H
H
H
H
Cl
Br
H
8.9 10
71
50
0.7
45
57
0
40
0
0
0f
0
0f
0
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
2.4 >80
0
0
100
0
0
0
0
0
0
0
0
0.9
1.6
0.4
1.7
2.5
45
0.8 30
70
H
Br
F
F
10
100
10
0
40
10
0
Cl
Br
H
Me
H
Me
Me
H
H
H
H
H
H
H
H
H
1.7 >80
2.6 >80
2.6
1.4
2.3
3.8 >80
2.1 >80
40
45
80
H
0
0
0
Me
Me
Br
0
0
OMe 10
>80
80
22
50
80
0f
0f
0f
0
OMe OMe
H
H
H
H
7.6
0f
F
F
F
NMe2
NH2
NHCOCF3
1.4
8.7
8.1
0
NT
NT
NT
NT
a
Reagents: (a) (i) NaHMDS, THF-Et2O, -78 °C, 30 min; (ii)
2,4-diF-C6H3-COCH2Br, -78 °C, 1 h; (b) LiOH, H2O2, THF, H2O,
0 °C, 30 min; (c) (EtCO)2O, LiCl, TEA, THF, 25 °C; (d) triazole,
NaH, DMF, 60 °C, 3 h; (e) DPPA, pyr, 80 °C, 10 h; (f) 10 N HCl,
refl, 7 days; (g) 2-NH2-4-Cl-C6H3CO2H, DCC, HOBT, room tem-
perature, 18 h; (h) HC(OEt)3, HCl (cat.), dioxane-NMP, 110 °C,
18 h.
a
Geometric mean of MIC values (µg/mL) against 10 yeasts (see
b
Experimental Section). Geometric mean of MIC values (µg/mL)
against 6 filamentous fungi (see Experimental Section). c Murine
systemic candidosis: three identical doses at 1, 4, and 24 h
d
postinfection. Percent protection the day that 100% mortality was
attained in the untreated group (n ) 10). e Percent protection the
day that 100% mortality was attained in the fluconazole-treated
group (n ) 10). f Dose: 2.5 mg/kg po. NT ) not tested.
levels was not possible for all the products. We thus
report two figures for the in vivo activities. The first
shows the intrinsic activity of the compound, and it is
expressed as the percent survival observed in the
treated group when all the untreated animals were dead
(ca. day 3). The second reflects the potency of the
compound compared to that of fluconazole, and it is
given as the percentage of surviving animals the day
the group treated with fluconazole succumbed. These
values, together with their mean in vitro activities, are
presented in Tables 1-5, 8, and 9. Using the same
model of infection, compound 20 was also administered
once or twice daily during 5 days and compared to
different standards (Table 5).
Compound 20 was further tested in vivo in a model
of systemic candidosis in the rabbit and compared to
fluconazole (Table 6), and in an immunocompromised
rat model of disseminated aspergillosis in comparison
with amphotericin B (Table 7).
For selected compounds, the plasma half-life in the
rat was calculated following iv administration of a single
dose of 15 mg/kg (n ) 2 per point).
Str u ctu r e-Activity Stu d ies
In Vitr o. Pyrimidones fused with three different
types of ring (15, 16, and 17) were first evaluated for
antifungal activity. Of these, 15 ([b]pyridine) was
essentially inactive, 16 ([b]naphthyl) showed activity
against yeasts only, and 17 (phenyl) was active against
both yeasts and filamentous fungi (Table 1). Given this
result, and the ready availability of a wide range of
starting anthranilic acids, we decided to fully explore
the benzo nucleus of 17. The effect of positional
substitution was first investigated by preparing all four
possible chloro regioisomers. The products gave good
potency against yeasts, but only the 7-derivative (20)
showed high activity against filamentous fungi. The
same trend was found within the Br and F derivatives.
Disubstitution (27-29), methyl substitution (30-34),
and introduction of electron-donating groups (35-36)
all resulted in poorer compounds.
In view of the activities shown in Table 1, we focused
on the 7-position for further optimization (Table 2).
Thus, all four halogens were tested and found to be
For compound 20, a preliminary 28-day toxicology
profile was obtained in the rat (n ) 10) after oral qd or
bid administration.

1872 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Ta ble 2. Effect of Substitution at the 7-Position
Bartroli et al.
Ta ble 3. Phenylpiperazine Analogues
in vivo
(0.5 mg/kg po)c
% protection
in vitro
MICa MICb
in vivo
(0.5 mg/kg po)c
% protection
in vitro
MICa MICb
compd
R7
yst
ff
(dC)d
(dFlu)e
24
20
26
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
F
0.9
0.3
0.4
0.3
0.8
0.7
1.4
1.4
1.0
0.4
0.5
2.5
0f
0
30
0f
0
0
compd position
X
R
yst ff
(dC)d
(dFlu)e
Cl
Br
I
CN
CF3
0.7
0.8
0.9
3.5
2.2
62
63
64
65
66
7
7
7
6
7
NO2
Cl
T
7.9 >80
NT
60
20
0
NT
0
0
0
NT
100
10f
100
0
100
100
100
100
100
0
0
100
70
NT
NT
20
0
0.2
2.8
0f
H
H
2.3 >80
60
0
0
100
100
40
80
0
T
T
3.7
28
OCH2CH2F
OCH2CHF2
OCH2CF3
OCH2CF2CHF2
SMe
SO2Me
SPh
SO2Ph
O-(p-ClPh)
1-triazolyl
2-tetrazolyl
3-oxazolidin-2-one
morpholine
N-methylpiperazine
NHNH2
NHBn
NMe2
CONH2
C(dNSO2NH2)NH2
28
OH 32
>80
NT
25
15
18
3.8
>80
2.0
8.7
7.1
80
57
80
35
>80
>80
11
a,b,c,d,e See the corresponding footnotes in Table 1.
Ta ble 4. In Vivo Activity-Polarity Relationships in the
7-Halo Series
11
0.7
1.2
0.7
6.6
1.5
8.7
1.9
19
15
1.2
1.3
25
40
0
80
e50
NT
NT
0
20
0
NT
40
NT
0
in vivo
(0.5 mg/kg po)c
71
>80
>80
0f
0f
% protection
in vitro
MIC
NT
0
NT
0
g
c log HPLC
t1/2
compd R7 Pa tR (min)b C. albicansf (dC)d (dFlu)e iv (h)
a,b,c,d,e See the corresponding footnotes in Table 1. f Dose: 1 mg/
kg po.
24
20
26
40
F
2.16
6.44
9.44
10.61
11.96
e0.03
e0.03
e0.03
e0.03
0
0
0
0
0
0
1.4
2.9
-
Cl 2.50
Br 2.82
I
30
100
mostly equipotent, except for the F derivative 24 which
was slightly poorer. Similar impaired activity was seen
for the CN, SMe, SPh, O-p-ClPh, and CF3 derivatives.
This was more pronounced in the polyfluoroalkoxy
series (43-46), where the compounds showed only
moderate activity against filamentous fungi. More
deleterious was the introduction of polarity-enhancing
substituents, such as C(dNSO2NH2)NH2, CONH2,
NHNH2, SO2Me, amine derivatives, 3-oxazolidin-2-one,
tetrazole, or triazole, which resulted in compounds with
diminished or complete loss of in vitro activity against
filamentous fungi.
3.31
>48
a
b
Calculated using Molecular Design’s Chem-X. HPLC reten-
tion time in a Lichrospher 100 RP-18e 220 × 4 mm column using
MeOH:H2O, 2:1. c,d,e See the corresponding footnotes in Table 1.
f Strain of C. albicans used in the in vivo test. Rat.
g
Quantitative estimates of lipophilicity have proven to
be useful parameters of biological behavior in several
systems. Table 4 shows the calculated log P values of
the 7-halo-substituted quinazolinones together with
their in vivo anticandidal activity in mice and their half-
lives in rat. The retention times recorded for these
compounds using a reverse phase HPLC column are also
included for comparison purposes. Since the four
compounds had similar in vitro activities against C.
albicans we hypothesize that the differences in the in
vivo efficacies are due to their different half-lives, which,
in turn, seem to be related to the compound’s polarity.
For nonmetabolizable compounds, long half-lives in
mice tend to convert into even longer half-lives in larger
species, including humans. We therefore sought to
select a derivative with high in vitro activity and a
relatively short half-life in the rat to ensure clinical
viability. A compound that seemed to fulfill these
conditions was the 7-chloro derivative, compound 20.
Compound 20 further featured an expeditious and low-
cost synthesis (4-chloroanthranilic acid is inexpensive),
excellent oral bioavailability (nearly 80% in rats and
100% in dogs), and lack of toxicity in preliminary
repeated-dose tests (vide infra).
Finally, a small series of compounds carrying a
phenylpiperazine substituent of the general type found
in the structure of itraconazole (2) and SCH-56592 (3)11
(see Figure 1) was prepared (Table 3). Compound 63,
featuring a p-chlorophenylpiperazine ring pendent from
the 7-position, displayed high and broad activity, but
low oral absorption in the rat. The nitro equivalent (62)
had lower in vitro activity. Three pentyltriazolone
derivatives of the type found in Schering’s newest series
were also tested, one of them at the 6-position of the
quinazolinone nucleus. None of these products dis-
played interesting activity levels.
In Vivo. Although we were quite pleased with the
levels of in vitro activity obtained with some of the above
compounds, the preliminary in vivo results using our
previous murine candidosis model2 were in general
disappointing.

New Azole Antifungals. 3
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11 1873
Ta ble 5. Comparison with Standards
Ta ble 6. In Vivo Activity of 20 in a Rabbit Systemic
Candidosis Modela
in vivo
in vitro
(% protection, mice)
dose
(mg/kg, qd, po)
log cfu/g
(kidney)
log cfu/g
(lung)
compd
model 1f
model 2g
MICa MICb
20
0.5
2.5
12.5
12.5
vehicle
0.68
0.30
0.35
1.29
4.48
0.39
0.12
0.0
1.44
3.04
compd
yst
ff
(dC)d (dFlu)e (dC)d (dFlu)e
20
0.3
0.7
0
0
90h
100h
NT
20
100
20
0h
-
NT
0
20
0
fluconazole
itraconazole
voriconazole
SCH-42427
ER-30346
TAK-187
8
30
>80
100
-
fluconazole
control
5.2
0.6
8.7
0.3
2.6
4.6
63
0i
0i
0.5
25
0.8
8.9
22
0
100
50
100
100
0
100
0
a
See the Experimental Section for details.
Ta ble 7. In Vivo Activity of 20 in an Immunocompromised
100
100
NT
NT
NT
NT
Rat Model of Disseminated Aspergillosisa
dose
(mg/kg, bid, po)
log cfu/g
(liver)
a,b,d,e See the corresponding footnotes in Table 1. f Dose: 0.5 mg/
compd
g
kg (1, 4, 24 h) po. Dose: 1 mg/kg/day (days 1 through 5) qd po.
h
i
Dose: 5 mg/kg/day (days 1 through 5) bid po. In PEG 400.
20
1
5
25
1.59
1.22
0.48
0.0
0.10
2.27
Com p a r ison w ith Refer en ce Com p ou n d s. Table
50
5 shows the in vitro and anti-Candida, in vivo activities
of 20 compared to those of fluconazole, itraconazole,
voriconazole, SCH-42427, ER-30346, TAK-187, and 8.
In vitro, voriconazole, ER-30346, and 20 had comparable
low MICs and broad spectra of activity. In vivo, two
dose regimens were tested. Under the conditions used
for the in vivo screening (three single doses over the first
24 h after infection), SCH-42427, TAK-187, and San-
kyo’s 8 showed 100% survival the day that the last of
the fluconazole-treated animals died, ER-30346 showed
an incipient activity, and compound 20, itraconazole,
and voriconazole14 showed no protection at all. In the
second model, where the products were administered
qd or bid throughout the 5 days following infection,
compound 20 (5 mg/kg, bid), fluconazole (5 mg/kg, bid),
and SCH-42427 (1 mg/kg, qd) had comparably good
levels of protection, whereas voriconazole and ER-30346
(both at 1 mg/kg qd) were mostly inactive.
P h a r m a cok in etics. A pharmacokinetic study in the
mouse indicated that drug levels of 20 declined very
rapidly in that species and that they were already
undetectable 6 h postadministration. The half-life was
calculated to be 1 h. Such fast kinetics certainly
precluded maintaining drug levels effective for overcom-
ing infection. We were therefore quite happy to observe
that when the dose regime was changed to bid admin-
istration of 5 mg/kg over 5 days, 20 showed activity
comparable to that of fluconazole.
As expected, excellent levels of activity started to
appear when 20 was tested in species in which the
compound’s half-life was longer. Thus, in a systemic
candidosis model in the rat (t1/2 ) 3 h iv; 6 h po)
compound 20 administered at 1 mg/kg bid po (5 days)
gave 100% survival at the end of the study (day 45) in
an experiment where all the control (untreated) animals
were dead by day 6. Fluconazole under the same regime
was equally effective. In the rabbit, where the com-
pound’s half-life was found 9 h (po), once a day admin-
istration was sufficient to observe high levels of activity.
Thus, the group treated with 0.5 mg/kg of 20 gave
significantly lower cfu counts in the lung and kidneys
than the control group or the group treated with 12.5
mg/kg of fluconazole (Table 6).
AmB
control
2b
vehicle
a
b
See the Experimental Section for details. qd, iv.
agents, emphasis must be placed on observing the
pharmacokinetics of compounds so selected. Indeed,
due to the fungistatic nature of azoles against C.
albicans, long-term protection might not be merely
indicative of high activity but rather a consequence of
persistently high drug levels. Products with fast elimi-
nation rates in mice, on the other hand, but with
potentially acceptable half-lives in humans (such as 20)
would show little in vivo activity in murine models and
could be incorrectly rejected in a screening program.
System ic Asp er gillosis. Compound 20 was also
tested in an immunocompromised rat model of dis-
seminated aspergillosis and compared to amphotericin
B. Activity was measured by reduction of fungal loads
(cfu counts) in the liver 24 h after the last administra-
tion. Table 7 shows that compound 20 protected rats
infected with conidia of A. fumigatus in a dose-related
fashion. At 50 mg/kg bid po, compound 20 gave 100%
protection (log cfu/g ) 0), whereas amphotericin B at 2
mg/kg qd iv gave a mean log cfu/g of 0.10.
Toxicity Tests. Repeated dose toxicity tests per-
formed with compound 20 in rats indicated a low
incidence of toxic effects. Thus, when compound 20 was
administered orally to rats for 28 consecutive days at
100 mg/kg bid or at 250 mg/kg qd, no mortality or even
external signs of toxicity were observed. Slight hepa-
tomegaly and a mild increase in alanine aminotrans-
ferase (females, 250 mg/kg) suggested that the liver is
the main target organ.
Oth er Mod ifica tion s. After the selection of product
20, an attempt to further optimize its structure was
undertaken (Table 8). Some features proved critical for
maintenance of the antifungal profile while others were
more flexible. Thus, different substitution patterns of
the phenyl unit (2-F and 2,4-diCl) afforded equally
active compounds (69 and 70). Chemical reduction to
the dihydro analogue (68) also maintained the in vitro
activity. However, amide 72 was 1 order of magnitude
less active than the parent compound 20, proving that
conformational restraint to the quinazolinone nucleus
enhances potency. Introduction of a methyl group at
the pyrimidone ring (67) had a deleterious effect. The
imidazole counterpart (73) also showed impaired activ-
In summary, it was not until the end of this study
that we realized that the mouse might not have been
the ideal species for screening this type of compounds.
Since mouse models are widely used in the study of new

1874 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Ta ble 8. Derivatives of 20
Bartroli et al.
Ta ble 9. Stereochemistry
in vivo
(2.5 mg/kg po)c
% protection
in vitro
MICa MICb
abs
compd
config
yst ff
(dC)d
(dFlu)e
20
74
75
76
77
(1R,2R)
(1S,2S)
(1R*,2R*)
(1R,2S)
(1S,2R)
0.3 0.7
40
1.0
>80
7.4
60
0
NT
0
0
0
NT
0
0
>80
33
>80
65
0
a,b,c,d,e See the corresponding footnotes in Table 1.
the high insolubility of racemate 75 (mp 242 °C)
compared to that of the pure enantiomer 20 (amorphous
solid) was physically impairing membrane penetration.
In the syn series, comparison of the MIC values
obtained for epimers 76 and 77 indicated that the
impact of the absolute stereochemistry of the carbinol
center (C-2) is greater than that of the methine carbon
(C-1). All of the above findings support the assumption
that this type of structure fits in the same chiral pocket
as the lanosterol D ring in the target enzyme, cyto-
chrome P45014DM.5
in vivo
(2.5 mg/kg po)c
% protection
in vitro
MICa
yst
MICb
ff
compd
(dC)d
(dFlu)e
20
67
68
69
70
71f
72
73
0.3
6.6
0.8
0.7
0.2
0.3
3.7
2.0
0.7
36
60
NT
30
20
80
0
0
NT
0
0
0
2.8
1.1
1.6
0.9
8.9
28
Con for m a tion a l Stu d ies. Right from the beginning
of the study we observed the presence of a set of small
0
20
0
0
0
1
(5-10%) parallel signals in the H NMR spectra of all
the anti quinazolinones. We first thought that they
might be due to an impurity, but the signals failed to
disappear upon product recrystallization. Nor did the
HPLC analyses show the presence of other peaks. This
effect was most evident in the syn quinazolinone 77,
where the two set of signals approached a 1:1 ratio.
A 2D EXSY (exchange spectroscopy) experiment in
CDCl3 was performed on 20 and 77. This method shows
chemical exchange before line broadening occurs, with
the particular advantage that cross signals for all
exchanging species can be seen. Examination of the
resulting 2D NMR map clearly indicated that the
duplicity of the signals were due to rotaisomerism.
CPK model analysis of 20 showed that rotation about
the C-N bond that links the propanol unit to the
quinazolinone is severely restricted. Parallel MM cal-
culations13 further indicated conformer m to be 2.1 kcal/
mol higher in energy than M (Figure 3). Contrarily, no
difference in energy was found for the two corresponding
conformers of the syn isomer (77). These findings were
in full accordance with the above-mentioned ratios
observed in the NMR spectra of the two isomers.
For further investigation of the dynamic process,
GROESY (1D-ROE with pulse field gradients) spectra
were recorded at different temperatures. Thus, irradia-
tion of each methyl signal of 77 at -50 °C produced
a,b,c,d,e See the corresponding footnotes in Table 1. f Dehydrates
to 20 upon standing in organic solutions.
ity. Finally, the partially hydrolyzed derivative 71 was
also prepared. The in vitro activity of this compound
was strikingly similar to that of 20. However, we later
found (HPLC) that this compound reverts to 20 upon
standing in organic solutions or in the culture medium,
for which reason these values should be interpreted with
care.
Ster eoch em istr y. We2a and others12 have previ-
ously demonstrated that for antifungal azoles carrying
a 3-triazolyl-2-aryl-1-methyl-2-propanol unit, the (1R,2R)
stereoisomer has the highest activity. To further prove
this rule in our series and examine the influence of each
center’s absolute configuration upon activity, the three
stereoisomers of compound 20 (i.e., (1S,2S) 74, (1R,2S)
76, and (1S,2R) 77), and its racemate (1R*,2R*) 75 were
synthesized and tested in vitro and in vivo (Table 9).
In the anti series, only the (1R,2R) enantiomer (20)
showed high activity, whereas the (1S,2S) (74) was
virtually inactive. The racemic compound (75) showed
the expected MIC values against yeasts (i.e., nearly
2-fold those of 20) but it proved suprisingly poor against
molds. At this point, it is unknown if this was due to
deleterious, active participation of the enantiomer or if

New Azole Antifungals. 3
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11 1875
active. After thorough evaluation that included studies
of in vitro and in vivo activity in different species
(including Aspergillus fumigatus), pharmacokinetics,
and ease of synthesis, compound 20 was selected for
further development.
Exp er im en ta l Section
Ch em istr y. Tetrahydrofuran (THF) and ether (Et2O) were
dried by distillation under argon from sodium metal. Flash
chromatography was performed on SDS silica gel 60 (230-
400 mesh). 1H NMR spectra were recorded on AC-80 (80 MHz)
or an Avance DPX (300 MHz) Bruker spectrometer and are
reported in ppm on the δ scale from TMS (unless otherwise
indicated). Coupling constants are reported in hertz. NMR
interpretations are provided for representative compounds. All
the (R,R) quinazolinone derivatives appeared as a ca. 95:5-
90:10 mixture of rotamers in the 1H NMR spectrum. For
simplicity, we will describe the signals of the major rotamer
only, except for compound 20 where a full description is
reported. Melting points were recorded on Mettler FP-80, FP-
81, and FP-82 apparatuses by heating a capillary tube
containing the sample at a rate of 3 °C/min. IR spectra were
recorded on a Perkin-Elmer 983 instrument. Optical rotations
were determined with a Perkin-Elmer 241 polarimeter at room
temperature and at 589 nm using a sodium lamp and a 1 mL
cell. Data are reported as follows: [R]D (concentration g/100
mL, solvent). Elemental analysis was performed with a Carlo
Erba EA-1108 instrument, and the results are within 0.4% of
the theoretical values, except where noted. Analytical HPLC
was performed on a Hewlett-Packard HP 1050 chromatograph
coupled to a UV detector (210 nm). For routine HPLC
analyses, a 4 mm × 25 cm Lichrospher 100RP18e 5 µm silica
gel column was used. HPLC-MS analyses were performed
using the same HPLC system coupled through a Hewlett-
Packard Particle-Beam Interface 59980 to a Hewlett-Packard
5988 mass spectrometer. GC-MS spectra were performed
using a Hewlett-Packard 5980 chromatograph coupled to the
mentioned mass spectrometer. For routine GC-MS analyses,
a 12 m HP-5 column with an injector temperature of 275 °C
and a gradient oven temperature from 100 to 290 °C (25 °C/
min) was used.
F igu r e 3. Conformational analysis of the anti (20) and syn
(77) stereoisomers.13
Water-sensitive reactions were performed under an argon
atmosphere using oven-dried glassware. Fluconazole (1) was
synthesized in our research center with 1,3-dichloroacetone
and 2,4-difluorophenylmagnesium bromide as starting materi-
als, and the resulting mixture was reacted with sodium
triazolate, following a published procedure.15 SCH-42427 (5)
and itraconazole (2) were kindly provided by Schering-Plough
and J anssen, respectively. Voriconazole (4) was generously
provided by Pfizer. Ketoconazole was purchased from Sigma.
Compounds 6,9 7,10 and 85 were synthesized in our center
according to the published procedures. Amine 13 was obtained
as described in the literature.5 Amines 11, 12, and 14 were
prepared according to our previous procedure.6
enhancement of the quinazolinone methine in one
rotamer but not in the other (Figure 3), proving that
there is no rotamer interconversion at this temperature.
In 20, where the conformer ratio approached 97:3,
irradiation of the methyl signal of the major rotamer
M at -50 °C produced methine enhancement, proving
in this way the assigned conformations depicted in
Figure 3.
Con clu sion s
All final products were assayed for homogeneity on analyti-
cal thin-layer chromatography (TLC) using Macherey-Nagel
0.25 mm silica gel SIL G-25 plates. The majority of the
chemical yields reported below are not optimized and cor-
respond to reactions ran only one time.
The acyl moiety of (1R,2R)-3-azole-2-aryl-1-methyl-
2-butanol-1-acylamino antifungal agents possess enough
structural flexibility to allow product optimization. In
the preceding paper we demonstrated that the antifun-
gal spectrum can be broadened by introducing a specif-
ically oriented phenyl substituent in a five-member ring
acyl unit. The resulting compounds, however, suffered
from extremely long plasma half-lives. In the present
paper we demonstrate that the quinazolinones, which
lack the phenyl substituent, have both a broader
spectrum of activity and faster elimination rates. Sum-
marizing the findings of Tables 1-9, we can conclude
that the best-suited quinazolinone derivatives are those
carrying a halogen or an isostere at the 7-position and
no substituent at the pyrimidone unit. Diastereomers
with a stereochemistry other than (R,R) are far less
P r ep a r a tion of Qu in a zolin on es: Gen er a l Meth od . To
a cooled (0 °C) solution of amine 11-14 in DMF (1 M) were
added the corresponding anthranilic acid (1.05 equiv), HOBT
(containing 17% H2O, 1.05 equiv), and DCC (1.05 equiv). The
cooling bath was removed and the solution stirred at room
temperature for 18 h. The solid formed (dicyclohexylurea,
DCU) was filtered off and washed with CHCl3. The filtrate
was concentrated (oil pump). The residue was taken off with
EtOAc and washed with aqueous 5% NaHCO3. The product
was extracted from the organic phase with aqueous 2 N HCl.
The aqueous phase was then brought to pH 7 with aqueous
20% NaOH, and the emulsion formed was extracted with
CHCl3, washed with water and brine, dried over anhydrous
Na2SO4, filtered, and concentrated to a colored foam containing

1876 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Bartroli et al.
EtOAc. The mixture was then dissolved in CHCl3 and passed
through a short column of silica using EtOAc as the eluent to
afford the corresponding anthranylamide as a cream-colored
foam in 90-100% yield.
MHz, CDCl3) 8.58 (s, 1H, NdCH-N), 8.26 (d, J ) 8.6, 1H,
arom), 8.11 (d, J ) 5.7, trace rotamer), 7.76 (s, 2H, triazol),
7.74 (d, J ) 5.3, 1H, arom), 7.5 (m, 2H, arom), 7.10 (s, trace
rotamer), 6.9-6.7 (m, 2H, arom), 5.91 (dq, J d ) 2, J q ) 7, 1H,
MeCH), 5.54 (d, J ) 2, 1H, OH), 5.15 (d, J ) 14.2 1H, CH(H)),
4.9-4.7 (m, trace rotamer), 4.30 (d, trace rotamer), 3.99 (d, J
) 14.2, 1H, CH(H)), 1.46 (d, J ) 6.9, trace rotamer), 1.29 (d,
J ) 7, 3H, CHMe); GC-MS 224 (Tr-CH2COHAr, C10H8F2N3O),
208 (group N-ethylheterocycle, C10H9ClN2O); [R]D -8.0° (c 1,
CHCl3). Chiral HPLC (column, CicloBond SN 1; eluent,
MeOH: Et3NHOAc in H2O at pH7 1:1; retention times: (S,S)
(74) tR 12.6 min; (R,R) (20) tR 13.7 min). Area ratio: 0.01:
99.99. Anal. (C20H16ClF2N5O2) C, H, N.
(1R,2R)-8-Ch lor o-3-[2-(2,4-d iflu or op h en yl)-2-h yd r oxy-
1-m eth yl-3-(1H-1,2,4-tr iazol-1-yl)pr opyl]qu in azolin -4(3H)-
on e (21): white solid; mp 110-113 °C; 1H NMR (80 MHz,
CDCl3) 8.73 (s, 1H), 8.27 (dd, J ) 1.5, J ) 8, 1H), 7.84 (dt, J d
) 1.5, J t ) 7.7, 1H), 7.74 (broad s, 2H), 7.7-7.3 (m, 2H), 7.0-
6.6 (m, 2H), 5.90 (dq, J d ) 1.5, J q ) 7.3, 1H), 5.55 (d, J ) 1.5,
1H), 5.15 (d, J ) 14, 1H), 4.00 (d, J ) 14, 1H), 1.30 (d, J )
7.3, 3H); GC-MS 224 (C10H8F2N3O), 208 (C10H9ClN2O); [R]D
-21.8° (c 1, CHCl3). Anal. (C20H16ClF2N5O2‚H2O) C, H, N.
To a solution of the above intermediate in N-methylpyrroli-
done (NMP, 1 M) were added triethyl orthoformate (3 equiv)
and 5 N HCl in 1,4-dioxane (ca. 0.5 equiv). The solution was
heated at 110 °C for 18 h or until TLC analysis indicated
completion. After the mixture was cooled to room tempera-
ture, water (75 mL) was added and the pH brought to 5.5 with
saturated NaHCO3. The mixture was extracted with EtOAc
(4×). The collected organic fractions were washed with water
(4×) and brine, (1×) and dried over Na2SO4 and the drying
agent filtered. The filtrate was concentrated under reduced
pressure and the residue purified by flash chromatography
(hex:EtOAc, 1:5) and recrystallized from an EtOAc:hexane:
ether mixture (50-90% yield). In general, the quinazolinones
tended to form crystalline solvates with the solvent of recrys-
tallization. A free of solvent, amorphous solid could be
obtained by adding water to a solution of the product in EtOH.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H -1,2,4-t r ia zol-1-yl)p r op yl]p yr id o[2,3-d ]p yr im id in -
4(3H)-on e (15): white solid; mp 210-211 °C; 1H NMR (80
MHz, CDCl3) 9.03 (dd, J ) 2, J ) 4.5, 1H, ar), 8.81 (s, 1H,
NdCH-N), 8.67 (dd, J ) 2, J ) 8.7, 1H, ar), 7.77 (s, 1H,
triazole), 7.73 (s, 1H, triazole), 7.6-7.3 (m, 2H, arom), 6.9-
6.7 (m, 2H, ar), 5.90 (dq, J d ) 1.6, J q ) 7, 1H, MeCH), 5.61 (d,
J ) 1.6, 1H, OH), 5.14 (d, J ) 14, 1H, CH(H)), 4.05 (d, J ) 14,
1H, CH(H)), 1.32 (d, J ) 7, 3H, CHMe); GC/MS 224 (C10H8-
F2N3O), 175 (C19H9N3O); [R]D +0.8° (c 1, CHCl3). Anal.
(C19H16F2N6O2) C, H, N.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]ben zo[g]qu in a zolin -4(3H)-
on e (16): yellowish solid; mp 200-202 °C; 1H NMR (300 MHz,
CDCl3) 8.95 (s, 1H, arom), 8.57 (s, 1H, NdCH-N), 8.24 (s, 1H,
arom), 8.2-7.9 (m, 2H, arom), 7.77 (s, 1H, triazole), 7.72 (s,
1H, triazole), 7.7-7.3 (m, 3H, arom), 6.9-6.8 (m, 2H, arom),
5.98 (dq, J d ) 1.2, J q ) 7.3, 1H, MeCH), 5.51 (d, J ) 1.6, 1H,
OH), 5.21 (d, J ) 14.1, 1H, CH(H)), 4.08 (d, J ) 14.1, 1H,
CH(H)), 1.32 (d, J ) 7.3, 3H, CHMe); HPLC-MS 224
(C14H12N2O and C10H8F2N3O); [R]D +3.6° (c 1, CHCl3). Anal.
(C24H19F2N5O2‚1/2H2O) C, H, N.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]-5-flu or oqu in a zolin -4(3H)-
on e (22): white amorphous solid; mp 94-122 °C; 1H NMR (300
MHz, CDCl3) 8.57 (s, 1H), 7.78 (s, 1H), 7.75 (s, 1H), 7.73 (dd,
J ) 8.2, J ) 1.5, 1H), 7.8-7.5 (m, 1H), 7.49 (dt, J d ) 6.4, J t
)
8.8, 1H), 7.20 (ddd, J ) 1.0, J ) 8.0, J ) 10.7, 1H), 6.9-6.7
(m, 2H), 5.96 (dq, J d ) 1.7, J q ) 7.3, 1H), 5.57 (d, J ) 1.7, 1H),
5.23 (d, J ) 14.2, 1H), 4.07 (d, J ) 14.2, 1H), 1.30 (d, J ) 7.3,
3H); GC-MS 224 (C10H8F2N3O), 192 (C10H9FN2O); [R]D +18.1°
(c 1, CHCl3). Anal. (C20H16F3N5O2‚H2O) C, H, N.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]-6-flu or oqu in a zolin -4(3H)-
on e (23): white solid; mp 192-193 °C; 1H NMR (300 MHz,
CDCl3) 8.57 (s, 1H), 7.98 (dd, J ) 2.9, J ) 8.4, 1H), 7.8-7.7
(m, 3H), 7.6-7.4 (m, 3H), 6.9-6.7 (m, 2H), 5.95 (dq, J d ) 1.6,
J q ) 7.3, 1H), 5.54 (d, J ) 1.7, 1H), 5.18 (d, J ) 14.2, 1H),
4.02 (d, J ) 14.2, 1H), 1.32 (d, J ) 7.3, 3H); GC-MS 224
(C10H8F2N3O), 192 (C10H9FN2O); [R]D -2.3° (c 1, CHCl3). Anal.
(C20H16F3N5O2) C, H, N.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]-7-flu or oqu in a zolin -4(3H)-
on e (24): white solid; mp 139-146 °C; 1H NMR (300 MHz,
CDCl3) 8.60 (s, 1H), 8.37 (dd, J ) 6.0, J ) 8.9, 1H), 7.78 (s,
1H), 7.75 (s, 1H), 7.49 (dt, J d ) 6.5, J t ) 8.7, 1H), 7.42 (dd, J
) 2.4, J ) 9.4, 1H), 7.27 (dt, J d ) 2.5, J t ) 8.7, 1H), 6.9-6.7
(m, 2H), 5.94 (dq, J d ) 1.7, J q ) 7.3, 1H), 5.54 (d, J ) 1.7, 1H),
5.17 (d, J ) 14.1, 1H), 4.03 (d, J ) 14.1, 1H), 1.31 (d, J ) 7.3,
3H); GC-MS 224 (C10H8F2N3O), 192 (C10H9FN2O); [R]D -4.1°
(c 1, CHCl3). Anal. (C20H16F3N5O2‚1/2EtOAc) C, H, N.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr ia zol-1-yl)p r op yl] qu in a zolin -4(3H)-on e (17).
Precipitated from EtOH/water: white solid; mp 164-165 °C;
1H NMR (80 MHz, CDCl3) 8.59 (s, 1H), 8.35 (d, J ) 8.5, 1H),
8.0-7.4 (m, 6H, arom), 6.9-6.7 (m, 2H), 5.95 (dq, J d ) 1.6, J q
) 7, 1H), 5.50 (d, J ) 1.6, 1H), 5.18 (d, J ) 14, 1H), 4.02 (d, J
) 14, 1H), 1.31 (d, J ) 7, 3H); GC-MS 224 (C10H8F2N3O), 174
(C10H10N2O); [R]D -3.36° (c 1, CHCl3). Anal. (C20H17F2N5O2)
C, H, N.
(1R,2R)-5-Ch lor o-3-[2-(2,4-d iflu or op h en yl)-2-h yd r oxy-
1-m eth yl-3-(1H-1,2,4-tr iazol-1-yl)pr opyl]qu in azolin -4(3H)-
on e (18): white solid; mp 114-119 °C; 1H NMR (300 MHz,
CDCl3) 8.59 (s, 1H), 7.79 (s, 1H), 7.76 (s, 1H), 7.8-7.5 (m, 3H),
7.50 (dt, J d ) 6.4, J t ) 8.8, 1H), 6.9-6.7 (m, 2H), 5.95 (dq, J d
) 1.7, J q ) 7.3, 1H), 5.58 (d, J ) 1.7, 1H), 5.23 (d, J ) 14.2,
1H), 4.08 (d, J ) 14.2, 1H), 1.29 (d, J ) 7.3, 3H); GC/MS 224
(C10H8F2N3O), 208 (C10H9ClN2O); [R]D +39.5° (CHCl3, c 1).
Anal. (C20H16ClF2N5O2‚1/3H2O) C, H, N.
(1R,2R)-6-Ch lor o-3-[2-(2,4-d iflu or op h en yl)-2-h yd r oxy-
1-m eth yl-3-(1H-1,2,4-tr iazol-1-yl)pr opyl]qu in azolin -4(3H)-
on e (19): white solid; mp 188-189 °C; 1H NMR (80 MHz,
CDCl3) 8.56 (s, 1H), 8.30 (t, J ) 1.3, 1H), 7.75-7.70 (m, 3H),
7.7-7.3 (m, 2H), 7.0-6.6 (m, 2H), 5.93 (dq, J d ) 1.5, J q ) 7.3,
1H), 5.52 (d, J ) 1.5, 1H), 5.15 (d, J ) 14, 1H), 3.98 (d, J )
14, 1H), 1.30 (d, J ) 7.3, 3H); GC-MS 224 (C10H8F2N3O), 208
(C10H9ClN2O); [R]D +14.6° (c 1, CHCl3). Anal. (C20H16ClF2-
N5O2) C, H, N.
(1R,2R)-6-Br om o-3-[2-(2,4-d iflu or op h en yl)-2-h yd r oxy-
1-m eth yl-3-(1H-1,2,4-tr iazol-1-yl)pr opyl]qu in azolin -4(3H)-
on e (25): white solid; mp 198-199 °C; 1H NMR (300 MHz,
CDCl3) 8.59 (s, 1H), 8.47 (d, J ) 2.2, 1H), 7.88 (dd, J ) 2.2, J
) 8.6, 1H), 7.78 (s, 1H), 7.74 (s, 1H), 7.64 (d, J ) 8.6, 1H),
7.48 (dt, J d ) 6.5, J t ) 8.8, 1H), 6.9-6.7 (m, 2H), 5.93 (dq, J d
) 1.7, J q ) 7.3, 1H), 5.54 (d, J ) 1.7, 1H), 5.16 (d, J ) 14.1,
1H), 4.01 (d, J ) 14.1, 1H), 1.31 (d, J ) 7.3, 3H); GC-MS 252
and 254 (C10H9BrN2O), 224 (C10H8F2N3O); [R]D +17.6° (c 1,
CHCl3). Anal. (C20H16BrF2N5O2) C, H, N.
(1R,2R)-7-Ben zyla m in o-3-[2-(2,4-d iflu or op h en yl)-2-h y-
d r oxy-1-m eth yl-3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]qu in a zo-
lin -4(3H)-on e (58). A solution of 24 (1.85 g, 4.4 mmol) and
benzylamine (1.45 g, 13.4 mmol) in 40 mL of NMP was heated
at 120 °C for 4 days. Once the reaction was completed, water
and EtOAc were added. The aqueous phase was separated
and reextracted with additional EtOAc. The combined ex-
tracts were washed with water and brine and dried over Na2-
SO4, the drying agent was filtered, and the filtrate was
concentrated to an oil which was purified by flash chromatog-
raphy to give the title compound as an amorphous white solid
(1.45 g, 66%): mp 100-107 °C; 1H NMR (300 MHz, CDCl3)
8.45 (s, 1H), 8.09 (d, J ) 8.5, 1H), 7.76 (s, 1H), 7.73 (s, 1H),
(1R,2R)-7-Ch lor o-3-[2-(2,4-d iflu or op h en yl)-2-h yd r oxy-
1-m eth yl-3-(1H-1,2,4-tr iazol-1-yl)pr opyl]qu in azolin -4(3H)-
on e (20, UR-9825). Precipitated from EtOH/H2O (66% yield
from amine 11): white amorphous solid; mp 93-110 °C (wide
range); IR (KBr) ν 1675, 1601, 1554, 1498 cm-1; 1H NMR (300

New Azole Antifungals. 3
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11 1877
7.48 (dt, J d ) 6.4, J t ) 8.8, 1H), 7.5-7.3 (m, 5H), 6.9-6.7 (m,
4H), 5.90 (dq, J d ) 1.5, J q ) 7.3, 1H), 5.42 (d, J ) 1.5, 1H),
5.17 (d, J ) 14.2, 1H), 4.72 (broad t, J ) 4.8, 1H, NH), 4.47 (d,
J ) 5.5, 2H, NCH2), 4.03 (d, J ) 14.2, 1H), 1.26 (d, J ) 7.3,
3H); GC-MS 279 (C17H17N3O), 224 (C10H8F2N3O); [R]D -32.3°
(c 1, CHCl3). Anal. (C27H24F2N6O2) C, H, N.
2.95 (s, 3H, Me), 1.29 (d, J ) 7.3, 3H); GC-MS 224
(C10H8F2N3O), 188 (C11H12N2O); [R]D +10.9° (c 1, CHCl3). Anal.
(C21H19F2N5O2‚1/2H2O) C, H, N.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr iazol-1-yl)pr opyl]-6-m eth ylqu in azolin -4(3H)-
on e (31): white solid; mp 189-190 °C; 1H NMR (80 MHz,
CDCl3) 8.53 (s, 1H), 8.13 (s, 1H), 7.76 (s, 1H), 7.71 (s, 1H),
7.9-7.3 (m, 3H), 6.9-6.7 (m, 2H), 5.95 (dq, J d ) 1.7, J q ) 7.3,
1H), 5.48 (d, J ) 1.5, 1H), 5.14 (d, J ) 14.2, 1H), 3.97 (d, J )
14.2, 1H), 2.51 (s, 3H, Me), 1.30 (d, J ) 7.3, 3H); GC-MS 224
(C10H8F2N3O), 188 (C11H12N2O); [R]D -17.0° (c 1, CHCl3). Anal.
(C21H19F2N5O2) C, H, N.
(1R,2R)-7-Br om o-3-[2-(2,4-d iflu or op h en yl)-2-h yd r oxy-
1-m eth yl-3-(1H-1,2,4-tr iazol-1-yl)pr opyl]qu in azolin -4(3H)-
on e (26). (a) To a solution of 58 (1.45 g, 2.8 mmol) in MeOH
(10 mL) was added 10% Pd/C (250 mg) and a solution of
ammonium formate (700 mg, 11.2 mmol) in H2O (2.5 mL). The
mixture was refluxed for 24 h and then filtered through Celite.
The filtrate was concentrated to give (1R,2R)-7-amino-3-[2-
(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-
yl)propyl]quinazolin-4(3H)-one as an off-white solid (1.16 g,
93%): mp 103-109 °C; 1H NMR (300 MHz, MeOH-d4) δ
(MeOH) 8.39 (s, 1H), 8.17 (s, 1H), 7.98 (d, J ) 8.7, 1H), 7.63
(s, 1H), 7.5-7.2 (m, 2H), 7.03 (ddd, J d ) 2.5, J d ) 8.5, J d ) 14,
1H), 6.9-6.8 (m, 2H), 6.03 (q, J ) 7.3, 1H), 5.06 (d, J ) 14.2,
1H), 4.14 (d, J ) 14.2, 1H), 1.26 (d, J ) 7.3, 3H); GC-MS 224
(C10H8F2N3O), 189 (C10H11N3O); [R]D -11.6° (c 0.5, CHCl3).
(b) To a cooled (0 °C) solution of the product obtained above
(300 mg, 0.7 mmol) in 48% HBr (3 mL) was added a solution
of NaNO2 (48 mg, 0.7 mmol) in H2O (0.5 mL). The mixture
was poured into a mixture of CuBr (55 mg, 0.4 mmol) in 48%
HBr (1 mL). The reaction mixture was then refluxed for 2 h.
Next, H2O and EtOAc were added, the layers were separated,
and the organic phase was washed with 1 N NaOH and with
brine, dried over Na2SO4, filtered, concentrated, and purified
by flash chromatography to give the title product as a white
solid (145 mg, 43%): mp 109-112 °C; 1H NMR (300 MHz,
CDCl3) 8.58 (s, 1H), 8.19 (d, J ) 8.5, 1H), 7.94 (d, J ) 1.8,
1H), 7.76 (s, 1H), 7.74 (s, 1H), 7.64 (dd, J ) 1.8, J ) 8.5, 1H),
7.48 (dt, J d ) 6.4, J t ) 8.8, 1H), 6.9-6.7 (m, 2H), 5.91 (dq, J d
) 1.5, J q ) 7.3, 1H), 5.54 (d, J ) 1.5, 1H), 5.14 (d, J ) 14.2,
1H), 4.00 (d, J ) 14.2, 1H), 1.29 (d, J ) 7.3, 3H); GC-MS 252
and 254 (C10H9BrN2O), 224 (C10H8F2N3O); [R]D -10.8° (c 1,
CHCl3). Anal. (C20H16BrF2N5O2‚1/2H2O) C, H, N.
(1R,2R)-6,7-Diflu or o-3-[2-(2,4-diflu or oph en yl)-2-h ydr oxy-
1-m eth yl-3-(1H-1,2,4-tr iazol-1-yl)pr opyl]qu in azolin -4(3H)-
on e (27): white solid; mp 212-213 °C; 1H NMR (300 MHz,
CDCl3) 8.56 (s, 1H), 8.09 (dd, J ) 8.4, J ) 9.9, 1H), 7.77 (s,
1H), 7.74 (s, 1H), 7.54 (dd, J ) 7.0, J ) 9.9, 1H), 7.6-7.4 (m,
1H), 6.9-6.7 (m, 2H), 5.89 (dq, J d ) 1.7, J q ) 7.3, 1H), 5.55 (d,
J ) 1.6, 1H), 5.14 (d, J ) 14.2, 1H), 3.99 (d, J ) 14.2, 1H),
1.29 (d, J ) 7.3, 3H); GC-MS 224 (C10H8F2N3O), 210
(C10H8F2N2O); [R]D -4.5° (c 1, CHCl3). Anal. (C20H15F4N5O2)
C, H, N.
(1R,2R)-6,8-Dich lor o-3-[2-(2,4-d iflu or op h en yl)-2-h y-
d r oxy-1-m eth yl-3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]qu in a zo-
lin -4(3H)-on e (28): white solid; mp 158-160 °C; 1H NMR (80
MHz, CDCl3) 8.71 (s, 1H), 8.24 (d, J ) 2.2, 1H), 7.92 (d, J )
2.2, 1H), 7.75 (s, 2H), 7.6-7.1 (m, 1H), 7.0-6.6 (m, 2H), 5.90
(dq, J d ) 1.5, J q ) 7.3, 1H), 5.58 (d, J ) 1.5, 1H), 5.12 (d, J )
14, 1H), 3.99 (d, J ) 14, 1H), 1.30 (d, J ) 7.3, 3H); GC-MS
242 and 244 (C10H8Cl2N2O), 224 (C10H8F2N3O); [R]D -6.8° (c
1, CHCl3). Anal. (C20H15Cl2F2N5O2) C, H, N.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr iazol-1-yl)pr opyl]-8-m eth ylqu in azolin -4(3H)-
on e (32): white solid; mp 141-144 °C; 1H NMR (80 MHz,
CDCl3) 8.63 (s, 1H), 8.20 (dd, J ) 1.5, J ) 8, 1H), 7.76 (s, 1H),
7.72 (s, 1H), 7.8-7.3 (m, 3H), 7.0-6.5 (m, 2H), 5.95 (dq, J d
)
1.5, J q ) 7.3, 1H), 5.48 (d, J ) 1.5, 1H), 5.19 (d, J ) 14, 1H),
3.98 (d, J ) 14, 1H), 2.66 (s, 3H, Me), 1.31 (d, J ) 7.3, 3H);
GC-MS 224 (C10H8F2N3O), 188 (C11H12N2O); [R]D -49.3° (c 1,
CHCl3). Anal. (C21H19F2N5O2) H, N; C: calcd, 61.31; found,
61.72.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-t r ia zol-1-yl)p r op yl]-6,8-d im et h ylq u in a zolin -
1
4(3H)-on e (33): white amorphous solid; mp 95-105 °C; H
NMR (300 MHz, CDCl3) 8.58 (s, 1H), 7.98 (s, 1H), 7.75 (s, 1H),
7.73 (s, 1H), 7.49 (dt, J d ) 6.4, J t ) 8.8, 1H), 7.48 (s, 1H), 6.9-
6.8 (m, 2H), 5.94 (dq, J d ) 1.7, J q ) 7.3, 1H), 5.44 (d, J ) 1.6,
1H), 5.18 (d, J ) 14.2, 1H), 4.00 (d, J ) 14.2, 1H), 2.62 (s, 3H,
Me), 2.47 (s, 3H, Me), 1.29 (d, J ) 7.3, 3H); GC-MS 224
(C10H8F2N3O), 202 (C12H14N2O); [R]D -11.1° (c 1, CHCl3). Anal.
(C22H21F2N5O2‚H2O) C, H, N.
(1R,2R)-8-Br om o-3-[2-(2,4-d iflu or op h en yl)-2-h yd r oxy-
1-m eth yl-3-(1H-1,2,4-tr iazol-1-yl)pr opyl]-6-m eth ylqu in azo-
lin -4(3H)-on e (34): white solid; mp 116-123 °C; 1H NMR
(300 MHz, CDCl3) 8.71 (s, 1H), 8.11 (q, J ) 0.85, 1H), 7.93 (d,
J ) 1.88, 1H), 7.77 (s, 1H), 7.75 (s, 1H), 7.50 (dt, J d ) 6.4, J t
) 8.8, 1H), 6.9-6.7 (m, 2H), 5.92 (dq, J d ) 1.7, J q ) 7.3, 1H),
5.53 (d, J ) 1.7, 1H), 5.15 (d, J ) 14.2, 1H), 4.00 (d, J ) 14.2,
1H), 2.51 (s, 3H, Me), 1.31 (d, J ) 7.3, 3H); GC-MS 266 and
268 (C11H11BrN2O), 224 (C10H8F2N3O); [R]D -20.6° (c 1, CHCl3).
Anal. (C21H18BrF2N5O2‚1/2H2O) C, H, N.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H -1,2,4-t r ia zol-1-yl)p r op yl]-8-m e t h oxyq u in a zolin -
4(3H)-on e (35): white solid; mp 117-121 °C; 1H NMR (80
MHz, CDCl3) 8.60 (s, 1H), 7.92 (dd, J ) 1.3, J ) 7.7, 1H), 7.74
(s, 1H), 7.71 (s, 1H), 7.6-7.3 (m), 7.0-6.6 (m, 2H), 5.95 (dq, J d
) 1.5, J q ) 7.3, 1H), 5.48 (d, J ) 1.5, 1H), 5.15 (d, J ) 14, 1H),
4.05 (s, 3H, OMe), 3.98 (d, J ) 14, 1H,), 1.29 (d, J ) 7.3, 3H);
GC-MS 224 (C10H8F2N3O), 204 (C11H12N2O2); [R]D -19.7° (c
1, CHCl3). Anal. (C21H19F2N5O3‚1/2H2O) C, H, N.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]-6,7-d im eth oxyqu in a zolin -
4(3H)-on e (36): white solid; mp 144-159 °C; 1H NMR (80
MHz, CDCl3) 8.70 (s, 1H), 7.75 (s, 1H), 7.73 (s, 1H), 7.66 (s,
1H), 7.6-7.3 (m, 1H), 7.15 (s, 1H), 7.0-6.5 (m, 2H), 5.97 (dq,
J d ) 1.5, J q ) 7.3, 1H), 5.47 (d, J ) 1.5, 1H), 5.18 (d, J ) 14,
1H), 4.01 (s, 6H, 2 OMe), 3.98 (d, J ) 14, 1H), 1.30 (d, J ) 7.3,
3H); GC-MS 234 (C12H14N2O3), 224 (C10H8F2N3O); [R]D -11.7°
(c 1, CHCl3). Anal. (C22H21F2N5O4‚1/2H2O) C, H, N.
(1R,2R)-6,8-Dib r om o-3-[2-(2,4-d iflu or op h en yl)-2-h y-
d r oxy-1-m eth yl-3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]qu in a zo-
lin -4(3H)-on e (29): white solid; mp 134-135 °C; 1H NMR
(300 MHz, CDCl3) 8.75 (s, 1H), 8.46 (d, J ) 2, 1H), 8.20 (d, J
) 2, 1H), 7.78 (s, 1H), 7.76 (s, 1H), 7.49 (dt, J d ) 6.5, J t ) 8.8,
1H), 6.9-6.7 (m, 2H), 5.90 (dq, J d ) 1.7, J q ) 7.3, 1H), 5.58 (d,
J ) 1.6, 1H), 5.13 (d, J ) 14.1, 1H), 4.00 (d, J ) 14.1, 1H),
1.31 (d, J ) 7.3, 3H); GC-MS 330, 332, and 334 (C10H8Br2-
N2O), 224 (C10H8F2N3O); [R]D -10.2° (c 1, CHCl3). Anal.
(C20H15Br2F2N5O2‚H2O) C, H, N.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr iazol-1-yl)pr opyl]-5-m eth ylqu in azolin -4(3H)-
on e (30): white solid; mp 87-89 °C; 1H NMR (300 MHz,
CDCl3) 8.54 (s, 1H), 7.79 (s, 1H), 7.75 (s, 1H), 7.7-7.6 (m, 2H),
7.49 (dt, J d ) 6.4, J t ) 8.8, 1H), 7.30 (dt, J t ) 0.8, J d ) 6.7,
1H), 6.9-6.8 (m, 2H), 5.94 (dq, J d ) 1.7, J q ) 7.3, 1H), 5.49 (d,
J ) 1.7, 1H), 5.19 (d, J ) 14.2, 1H), 4.09 (d, J ) 14.2, 1H),
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]-7-(d im eth yla m in o)-6-flu o-
r oqu in a zolin -4(3H)-on e (37). This compound was obtained
as a byproduct when the preparation of compound 27 was
carried out in DMF instead of NMP (22% yield): white solid;
1
mp 197-198 °C; H NMR (80 MHz, CDCl3) 8.45 (s, 1H), 7.91
(s, 1H), 7.74 (broad s, 3H), 7.7-7.3 (m, 1H), 7.0-6.6 (m, 2H),
5.90 (dq, J d ) 1.5, J q ) 7.3, 1H), 5.46 (d, J ) 1.5, 1H), 5.16 (d,
J ) 14, 1H), 4.00 (d, J ) 14, 1H), 3.06 (s, 6H, NMe2), 1.25 (d,
J ) 7.3, 3H); MS 458 (M+); [R]D -36° (c 1, CHCl3). Anal.
(C22H21F3N6O2‚1/2 Et2O) C, H, N.
(1R,2R)-7-Am in o-3-[2-(2,4-d iflu or op h en yl)-2-h yd r oxy-
1-m eth yl-3-(1H-1,2,4-tr iazol-1-yl)pr opyl]-6-flu or oqu in azo-
lin -4(3H)-on e (38). This compound was obtained as a byprod-

1878 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Bartroli et al.
uct when the preparation of compound 27 was carried out
using formamidine acetate instead of triethyl orthoformate and
5 N HCl in 1,4-dioxane (43% yield): white solid; mp 124-125
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]-7-(2,2,3,3-tetr a flu or op r o-
p oxy)qu in a zolin -4(3H)-on e (46). A solution of 2,2,3,3-
tetrafluoropropanol (381 mg, 2.9 mmol) in anhydrous NMP
(10 mL) was treated with NaH (55% oil dispersion, 126 mg,
2.9 mmol) for 10 min at room temperature. Once H2 ceased
to evolve, compound 24 (400 mg, 0.96 mmol) was added and
the mixture was stirred at 120 °C overnight. Once the reaction
was completed, water and EtOAc were added. The aqueous
phase was separated and reextracted with additional EtOAc.
The combined organic extracts were washed with water and
brine, dried over anhydrous Na2SO4, filtered, concentrated, and
purified by flash chromatography to give the title compound
as an amorphous white solid (200 mg, 48%): 1H NMR (300
MHz, CDCl3) 8.56 (s, 1H), 8.29 (d, J ) 9.5, 1H), 7.76 (s, 1H),
7.74 (s, 1H), 7.48 (dt, J d ) 6.5, J t ) 8.8, 1H), 7.15 (m, 2H),
6.9-6.7 (m, 2H), 6.08 (tt, J ) 4.5, J ) 53, 1H, CHF2), 5.92
(dq, J d ) 2, J q ) 7.3, 1H), 5.51 (d, J ) 1.5, 1H), 5.16 (d, J )
14.3, 1H), 4.49 (tt, J ) 1.5, J ) 12, 2H, CH2), 4.01 (d, J )
14.3, 1H), 1.29 (d, J ) 7.3, 3H); GC-MS 304 (C13H12F4N2O2),
224 (C10H8F2N3O); [R]D -16.7° (c 1, CHCl3). Anal. (C23H19F6-
N5O3‚1/2H2O) C, H, N.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr iazol-1-yl)pr opyl]-7-(2-flu or oeth oxy)qu in azo-
lin -4(3H)-on e (43). Obtained in an analogous way from the
reaction of 24 and 2-fluoroethanol (23% yield): white solid;
mp 191-194 °C; 1H NMR (300 MHz, CDCl3) 8.54 (s, 1H), 8.29
(d, J ) 9.5, 1H), 7.76 (s, 1H), 7.73 (s, 1H), 7.48 (dt, J d ) 6.5, J t
) 8.8, 1H), 7.3-7.1 (m, 2H), 6.9-6.7 (m, 2H), 5.93 (dq, J d ) 2,
J q ) 7.3, 1H), 5.49 (d, J ) 1.5, 1H), 5.17 (d, J ) 14.3, 1H),
4.90 (t, J ) 4, 1H), 4.75 (t, J ) 4, 1H), 4.40 (t, J ) 4, 1H), 4.31
(t, J ) 4, 1H), 4.02 (d, J ) 14.3, 1H), 1.29 (d, J ) 7.3, 3H);
GC-MS 236 (C12H13FN2O2), 224 (C10H8F2N3O); [R]D -22.9° (c
1, CHCl3). Anal. (C22H20F3N5O3‚1/2EtOAc) C, H, N.
1
°C; H NMR (300 MHz, CDCl3) 8.45 (s, 1H), 7.86 (d, J ) 11,
1H), 7.76 (s, 1H), 7.72 (s, 1H), 7.6-7.4 (m, 1H), 6.97 (d, J )
8.0, 1H), 6.9-6.7 (m, 2H), 5.89 (dq, J d ) 1.7, J q ) 7.3, 1H),
5.46 (d, J ) 1.7, 1H), 5.15 (d, J ) 14.2, 1H), 4.43 (broad s, 2H,
NH2), 4.01 (d, J ) 14.2, 1H), 1.26 (d, J ) 7.3, 3H); GC-MS
224 (C10H8F2N3O), 207 (C10H10FN3O); [R]D -0.31° (c 1, MeOH).
Anal. (C20H17F3N6O2‚1/2H2O) C, H; N: calcd, 19.13; found,
17.42.
(1R,2R)-N-[3-[2-(2,4-Diflu or oph en yl)-2-h ydr oxy-1-m eth -
yl-3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]-6-flu or o-4-oxo-3,4-d ih y-
d r oqu in a zolin -7-yl]-2,2,2-tr iflu or oa ceta m id e (39). A so-
lution of 38 (500 mg, 1.16 mmol) in pyridine (5 mL) was treated
with trifluoroacetic anhydride (488 mg, 2.3 mmol) at 0 °C for
1 h. Next aqueous Na2CO3 solution was added, pyridine was
removed in vacuo, and the residue was partitioned between
water and CHCl3. The organic layer was separated, dried over
Na2SO4, filtered, and concentrated to an oil that was purified
by flash chromatography to give the title product as a white
solid (412 mg, 67%): mp 130-132 °C; 1H NMR (300 MHz,
CDCl3) 8.77 (d, J ) 7, 1H), 8.58 (s, 1H), 8.33 (broad s, 1H,
NH), 8.07 (d, J ) 10.6, 1H), 7.76 (s, 1H), 7.74 (s, 1H), 7.49 (dt,
J d ) 6.5, J t ) 9, 1H), 6.9-6.7 (m, 2H), 5.91 (dq, J d ) 1.5, J q
)
7.3, 1H), 5.56 (d, J ) 1.7, 1H), 5.13 (d, J ) 14.2, 1H), 4.02 (d,
J ) 14.2, 1H), 1.30 (d, J ) 7.3, 3H); GC-MS 303 (C12H9F4N3O2),
224 (C10H8F2N3O); [R]D -38.4° (c 1, CHCl3). Anal. (C22H16F6-
N6O3‚1/2H2O) C, H, N.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H -1,2,4-t r ia zol-1-yl)p r op yl]-7-iod oq u in a zolin -4(3H )-
on e (40). To a cooled (0 °C) solution of (1R,2R)-7-amino-3-
[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-
1-yl)propyl]quinazolin-4(3H)-one (see section (a) of preparation
of 26) (500 mg, 1.2 mmol) in a mixture of concentrated HCl (3
mL) and ice (4 mL) was added a solution of NaNO2 (88 mg,
1.3 mmol) in H2O (0.5 mL). After 15 min, the resulting
mixture was poured to a mixture of KI (1.9 g, 12 mmol) in
H2O (10 mL). The reaction mixture was stirred at 25 °C for
15 h. Then, H2O and EtOAc were added, the layers were
separated, and the organic phase was washed with 1 N NaOH
and with brine, dried over Na2SO4, filtered, concentrated, and
purified by flash chromatography to give the title product as
(1R,2R)-7-(2,2-Diflu or oeth oxy)-3-[2-(2,4-diflu or oph en yl)-
2-h yd r oxy-1-m eth yl-3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]qu in -
a zolin -4(3H)-on e (44). Obtained in an analogous way from
the reaction of 24 and 2,2-difluoroethanol (60% yield): white
solid; mp 96-102 °C; 1H NMR (300 MHz, CDCl3) 8.55 (s, 1H),
8.27 (d, J ) 9.5, 1H), 7.76 (s, 1H), 7.73 (s, 1H), 7.49 (dt, J d
)
6.5, J t ) 8.8, 1H), 7.15 (m, 2H), 6.9-6.7 (m, 2H), 6.16 (tt, J )
4, J ) 55, 1H, CHF2), 5.93 (dq, J d ) 2, J q ) 7.3, 1H), 5.50 (d,
J ) 1.5, 1H), 5.16 (d, J ) 14.3, 1H), 4.32 (dt, J d ) 4, J t ) 13,
2H, OCH2), 4.02 (d, J ) 14.3, 1H), 1.29 (d, J ) 7.3, 3H); GC-
MS 254 (C12H12F2N2O2), 224 (C10H8F2N3O); [R]D -25.7° (c 1,
CHCl3). Anal. (C22H19F4N5O3) C, H; N: calcd, 14.67; found,
13.21.
1
a white solid (225 mg, 35%): mp 155-156 °C; H NMR (300
MHz, CDCl3) 8.56 (s, 1H), 8.18 (d, J ) 1.5, 1H), 8.02 (d, J )
8.5, 1H), 7.85 (dd, J ) 1.5, J ) 8.5, 1H), 7.76 (s, 1H), 7.74 (s,
1H), 7.48 (dt, J d ) 6.4, J t ) 8.8, 1H), 6.9-6.7 (m, 2H), 5.91
(dq, J d ) 1.5, J q ) 7.3, 1H), 5.53 (d, J ) 1.5, 1H), 5.14 (d, J )
14.2, 1H), 4.00 (d, J ) 14.2, 1H), 1.29 (d, J ) 7.3, 3H); GC-
MS 300 (C10H9IN2O), 224 (C10H8F2N3O); [R]D -19.3° (c 1,
CHCl3). Anal. (C20H16IF2N5O2‚H2O) C, H; N: calcd, 12.94;
found, 12.23.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]-7-(2,2,2-tr iflu or oeth oxy)-
qu in a zolin -4(3H)-on e (45). Obtained in an analogous way
from the reaction of 24 and 2,2,2-trifluoroethanol (21% yield):
white amorphous solid, contaminated with ca. 15% of the
product resulting from substitution of the 2,4-difluorophenyl
ring; 1H NMR (300 MHz, CDCl3) 8.56 (s, 1H), 8.29 (d, J ) 8.8,
1H), 7.76 (s, 1H), 7.74 (s, 1H), 7.4-7.1 (m, 3H), 6.9-6.7 (m,
2H), 5.93 (dq, J d ) 2, J q ) 7.3, 1H), 5.51 (d, J ) 1.5, 1H), 5.16
(d, J ) 14.3, 1H), 4.49 (q, J ) 7.9, 2H, CH2), 4.02 (d, J ) 14.3,
1H), 1.29 (d, J ) 7.3, 3H); GC-MS 272 (C12H11F3N2O2), 224
(C10H8F2N3O).
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]-7-(m eth ylth io)qu in a zolin -
4(3H)-on e (47). Obtained in an analogous way from the
reaction of 24 and sodium thiomethoxide (89% yield): white
solid; mp 152-153 °C; 1H NMR (300 MHz, CDCl3) 8.55 (s, 1H),
8.17 (d, J ) 8.9, 1H), 7.76 (s, 1H), 7.74 (s, 1H), 7.6-7.4 (m,
2H), 7.36 (dd, J ) 1.7, J ) 8.5, 1H), 6.9-6.7 (m, 2H), 5.92 (dq,
J d ) 1.5, J q ) 7.3, 1H), 5.50 (d, J ) 1.5, 1H), 5.17 (d, J ) 14.2,
1H), 4.02 (d, J ) 14.2, 1H), 2.59 (s, 3H, SMe), 1.29 (d, J ) 7.3,
3H); GC-MS 224 (C10H8F2N3O), 220 (C11H12N2OS); [R]D -53.6°
(c 1, CHCl3). Anal. (C21H19F2N5O2S) C, H, N.
(1R,2R)-7-Cya n o-3-[2-(2,4-d iflu or op h en yl)-2-h yd r oxy-
1-m eth yl-3-(1H-1,2,4-tr iazol-1-yl)pr opyl]qu in azolin -4(3H)-
on e (41). 4-Cyanoanthranilic acid was prepared as described
in the literature:16 white solid; mp 168-169 °C; 1H NMR (300
MHz, CDCl3) 8.64 (s, 1H), 8.43 (d, J ) 8.2, 1H), 8.08 (d, J )
1.1, 1H), 7.76 (s, 1H), 7.74 (s, 1H), 7.73 (dd, J ) 1.5, J ) 8.2,
1H), 7.47 (dt, J d ) 6.4, J t ) 8.8, 1H), 6.9-6.8 (m, 2H), 5.91
(dq, J d ) 1.2, J q ) 7.3, 1H), 5.60 (d, J ) 1.3, 1H), 5.13 (d, J )
14.1, 1H), 4.00 (d, J ) 14.1, 1H), 1.31 (d, J ) 7.3, 3H); GC-
MS 423 (M+ + 1), 224 (C10H8F2N3O), 198 (C11H8N3O); [R]D
-0.95° (c 1, CHCl3). Anal. (C21H16F2N6O2‚H2O) C, H, N.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr iazol-1-yl)pr opyl]-7-tr iflu or om eth ylqu in azo-
lin -4(3H)-on e (42): white solid; mp 142-143 °C (MeCN); 1H
NMR (300 MHz, CDCl3) 8.65 (s, 1H), 8.46 (d, J ) 8.3, 1H),
8.04 (s, 1H), 7.76 (s, 1H), 7.74 (d, J ) 8.6, 1H), 7.73 (s, 1H),
7.48 (q, J ) 8.5, 1H), 6.9-6.7 (m, 2H), 5.94 (dq, J d ) 1.5, J q
)
7.3, 1H), 5.57 (d, J ) 1.5, 1H), 5.15 (d, J ) 14.1, 1H), 4.00 (d,
J ) 14.2, 1H), 1.31 (d, J ) 7.3, 3H); GC-MS 242 (C11H9F3N2O),
224 (C10H8F2N3O); [R]D +4.2° (c 1, CHCl3). Anal. (C21H16F5-
N5O2) C, H, N.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr iazol-1-yl)pr opyl]-7-(m eth ylsu lfon yl)qu in azo-
lin -4(3H)-on e (48). A solution of compound 47 (0.22 g, 0.49
mmol) in CH2Cl2 (10 mL) was treated with a dried (Na2SO4)

New Azole Antifungals. 3
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11 1879
solution of MCPBA (55%, 0.62 g, 1.98 mmol) in CH2Cl2 (10
mL) at 25 °C for 18 h. The solid formed was filtered, and the
filtrate was then washed with 10% aqueous Na2S2O3 solution,
1 N NaOH, and brine. The organic phase was dried over
anhydrous Na2SO4, filtered, concentrated, purified by flash
chromatography, and recrystallized from EtOAc:ether to give
the title product as a white solid (141 mg, 56%): mp 223-224
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]-7-(2-oxa zolid in on e-3-yl)-
qu in a zolin -4(3H)-on e (54). Obtained from the reaction of
compound 24 and the sodium salt of 2-oxazolidinone (10%
yield): white solid; mp 294-295 °C; 1H NMR (300 MHz,
DMSO-d6) 8.38 (s, 1H), 8.21 (d, J ) 8.9, 1H), 8.18 (s, 1H), 7.85
(dd, J ) 2.0, J ) 8.8, 1H), 7.79 (d, J ) 8.9, 1H), 7.54 (s, 1H),
7.3-7.2 (m, 2H), 6.94 (dt, J d ) 2.3, J t ) 8.4, 1H), 6.33 (s, 1H),
5.84 (q, J ) 7.2, 1H), 4.84 (d, J ) 14.4, 1H), 4.96 (t, J ) 7.7,
2H), 4.2-4.1 (m, 3H), 1.17 (d, J ) 7.2, 3H); [R]D +32.4° (c 0.5,
DMSO). Anal. (C23H20F2N6O4‚1/2EtOAc) C, H, N.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr iazol-1-yl)pr opyl]-7-(4-m or ph olin yl)qu in azo-
lin -4(3H)-on e (55). Obtained from the reaction of compound
24 and morpholine (64% yield): white solid; mp 196-197 °C;
1H NMR (300 MHz, CDCl3) 8.49 (s, 1H), 8.18 (d, J ) 9.0, 1H),
7.75 (s, 1H), 7.73 (s, 1H), 7.5-7.4 (m, 1H), 7.09 (dd, J ) 2.4, J
) 9.0, 1H), 7.02 (d, J ) 2.4, 1H), 6.9-6.6 (m, 2H), 5.91 (dq, J d
) 1.6, J q ) 7.3, 1H), 5.45 (d, J ) 1.6, 1H), 5.17 (d, J ) 14.2,
1H), 4.03 (d, J ) 14.2, 1H), 3.88 (m, 4H, morph), 3.38 (m, 4H,
morph), 1.27 (d, J ) 7.3, 3H); GC-MS 259 (C14H17N3O2), 224
(C10H8F2N3O); [R]D -37.9° (c 1, CHCl3). Anal. (C24H24F2N6O3)
C, H, N.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr iazol-1-yl)pr opyl]-7-(4-m eth yl-1-piper azin yl)-
qu in a zolin -4(3H)-on e (56). Obtained from the reaction of
compound 24 and N-methylpiperazine (55% yield): white solid;
mp 121-131 °C; 1H NMR (300 MHz, CDCl3) 8.47 (s, 1H), 8.15
(d, J ) 9.0, 1H), 7.75 (s, 1H), 7.72 (s, 1H), 7.5-7.4 (m, 1H),
7.10 (dd, J ) 2.4, J ) 9.0, 1H), 7.02 (d, J ) 2.3, 1H), 6.9-6.6
(m, 2H), 5.91 (dq, J d ) 1.6, J q ) 7.3, 1H), 5.44 (d, J ) 1.6, 1H),
5.17 (d, J ) 14.2, 1H), 4.02 (d, J ) 14.2, 1H), 3.45 (m, 4H,
pip), 2.58 (m, 4H, pip), 2.36 (s, 3H, NMe), 1.27 (d, J ) 7.3,
3H); GC-MS 271 and 272 (C15H20N4O), 224 (C10H8F2N3O); [R]D
-14.3° (c 1, CHCl3). Anal. (C25H27F2N7O2‚1/2EtOAc) C, H, N.
1
°C; H NMR (300 MHz, CDCl3) 8.68 (s, 1H), 8.53 (d, J ) 8.4,
1H), 8.36 (d, J ) 1.6, 1H), 8.03 (dd, J ) 1.6, J ) 8.3, 1H), 7.77
(s, 1H), 7.74 (s, 1H), 7.48 (dt, J d ) 6.4, J t ) 8.8, 1H), 6.9-6.7
(m, 2H), 5.92 (dq, J d ) 1.5, J q ) 7.3, 1H), 5.59 (d, J ) 1.5, 1H),
5.15 (d, J ) 14.2, 1H), 4.00 (d, J ) 14.2, 1H), 3.13 (s, 3H,
SO2Me), 1.32 (d, J ) 7.3, 3H); GC-MS 252 (C11H12N2O3S), 224
(C10H8F2N3O); [R]D +2.1° (c 0.5, CHCl3). Anal. (C21H19F2N5-
O4S‚1/2H2O) C, H, N, S.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]-7-(p h en ylth io)qu in a zolin -
4(3H)-on e (49). Obtained from the reaction of 24 and sodium
thiophenoxide (66% yield): white solid, contaminated with ca.
20% of the product resulting from substitution of the 2,4-
difluorophenyl ring: 1H NMR (300 MHz, CDCl3) 8.50 (s, 1H),
8.17 (d, J ) 8.5, 1H), 7.75 (s, 1H), 7.76 (s, 1H), 7.6-7.3 (m,
8H), 6.9-6.7 (m, 2H), 5.90 (dq, J d ) 1.5, J q ) 7.3, 1H), 5.48 (d,
J ) 1.5, 1H), 5.15 (d, J ) 14.2, 1H), 3.99 (d, J ) 14.2, 1H),
1.27 (d, J ) 7.3, 3H); GC-MS 282 (C16H14N2OS), 224
(C10H8F2N3O). Anal. (C26H21F2N5O2S) C, H, S; N: calcd, 13.85;
found, 13.04.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]-7-p h en ylsu lfon ylqu in a zo-
lin -4(3H)-on e (50). Same oxidation procedure as for 48 (29%
yield): white solid; mp 125-130 °C; 1H NMR (300 MHz,
CDCl3) 8.63 (s, 1H), 8.44 (d, J ) 8.4, 1H), 8.35 (d, J ) 1.6,
1H), 8.02 (d, J ) 8.3, 3H), 7.77 (s, 1H), 7.73 (s, 1H), 7.6-7.4
(m, 4H), 6.9-6.7 (m, 2H), 5.90 (dq, J d ) 1.5, J q ) 7.3, 1H),
5.55 (d, J ) 1.5, 1H), 5.12 (d, J ) 14.2, 1H), 3.94 (d, J ) 14.2,
1H), 1.28 (d, J ) 7.3, 3H); GC-MS 314 (C16H14N2O3S), 224
(C10H8F2N3O); [R]D +7.0° (c 1, CHCl3).
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H -1,2,4-t r ia zol-1-yl)p r op yl]-7-h yd r a zin oq u in a zolin -
4(3H)-on e (57). This compound was obtained as a byproduct
in the preparation of compound 53 (22% yield): white solid;
(1R,2R)-7-(4-Ch lor op h en oxy)-3-[2-(2,4-d iflu or op h en yl)-
2-h yd r oxy-1-m eth yl-3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]qu in -
a zolin -4(3H)-on e (51). Obtained from the reaction of com-
pound 24 and sodium 4-chlorophenoxide (40% yield): white
solid; mp 198-199 °C; 1H NMR (300 MHz, CDCl3) 8.50 (s, 1H),
1
mp 227-230 °C; H NMR (300 MHz, MeOH-d4) 8.52 (s, 1H),
8.28 (d, J ) 8.6, 1H), 8.18 (s, 1H), 7.64 (s, 1H), 7.40 (dt, J d
6.5, J t ) 8.9, 1H), 7.3-7.2 (m, 2H), 7.04 (ddd, J d ) 2.5, J d
)
)
8.5, J d ) 14, 1H), 6.88 (dt, J d ) 2.5, J t ) 8.5, 1H), 6.04 (q, J )
7.2, 1H), 5.05 (d, J ) 14.4, 1H), 4.17 (d, J ) 14.4, 1H), 1.29 (d,
J ) 7.2, 3H); [R]D +2.4° (c 0.2, DMSO). Anal. (C20H19F2N7O2‚1/
4EtOAc) C, H, N.
8.26 (d, J ) 8.7, 1H), 7.75 (s, 1H), 7.68 (s, 1H), 7.47 (dt, J d
)
6.5, J t ) 9, 1H), 7.34 (d, J ) 8.6, 2H), 7.15 (dd, J ) 2.4, J )
8.6, 1H), 7.13 (d, J ) 2.2, 1H), 7.03 (d, J ) 8.6, 2H), 6.9-6.7
(m, 2H), 5.97 (dq, J d ) 1.5, J q ) 7.3, 1H), 5.58 (d, J ) 1.5, 1H),
5.17 (d, J ) 14.2, 1H), 3.96 (d, J ) 14.2, 1H), 1.30 (d, J ) 7.3,
3H); GC-MS 300 and 302 (C16H13ClN2O2), 224 (C10H8F2N3O);
[R]D -22° (c 0.1, CHCl3). Anal. (C26H20ClF2N5O3) C, H, N.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]-7-d im eth yla m in oqu in a zo-
lin -4(3H)-on e (59). This compound was obtained as a byprod-
uct when the preparation of compound 24 was carried out in
DMF instead of NMP (44% yield): white solid; mp 201-201
°C; 1H NMR (80 MHz, CDCl3) 8.45 (s, 1H), 8.15 (d, J ) 8, 1H),
7.75 (s, 1H), 7.72 (s, 1H), 7.7-7.3 (m), 7.1-6.5 (m), 5.92 (dq,
J d ) 2, J q ) 7.3, 1H), 5.43 (d, J ) 2, 1H), 5.18 (d, J ) 14, 1H),
4.05 (d, J ) 14, 1H), 3.11 (s, 6H, NMe2), 1.27 (d, J ) 7.3, 3H);
GC-MS 440 (M+), 216 (C12H14N3O), 224 (C10H8F2N3O); [R]D
-43° (c 1, CHCl3). Anal. (C22H22F2N6O2) C, H, N.
(1R,2R)-7-Ca r b a m oyl-3-[2-(2,4-d iflu or op h en yl)-2-h y-
d r oxy-1-m eth yl-3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]qu in a zo-
lin -4(3H)-on e (60). A solution of compound 41 (500 mg, 1.2
mmol) in MeOH (5 mL) and CHCl3 (5 mL) was cooled to 0 °C,
and HCl gas was bubbled until saturation (1.5 h). The mixture
was allowed to stand at 0 °C overnight and was then
concentrated, and the residue was slowly added to aqueous
K2CO3 solution (2.5 g). The yellowish precipitate formed was
filtered, dried, taken up in methanol, and allowed to react with
sulfamide (350 mg, 3.6 mmol) at reflux for 3 h. The reaction
mixture was then concentrated and partitioned between water
and CHCl3. The organic layer was separated, dried over Na2-
SO4, filtered, and concentrated, and the resulting residue (a
mixture of three spots on the TLC plate) was chromatographed
on silica. The first compound to elute was identified as the
methyl imidate and was discarded. The second compound was
identified as the amide (12 mg, 2%, title compound): off-white
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H -1,2,4-t r ia zol-1-yl)p r op yl]-7-(1H -1,2,4-t r ia zol-1-yl)-
qu in a zolin -4(3H)-on e (52). Obtained from the reaction of
compound 24 and the sodium salt of 1,2,4-triazole (52%
yield): white solid; mp 236-237 °C; 1H NMR (300 MHz,
DMSO-d6) δ (DMSO) 9.58 (s, 1H, triazole), 8.46 (s, 1H), 8.38
(d, J ) 8.7, 1H), 8.34 (s, 1H, triazole), 8.24 (d, J ) 1,5, 1H),
8.19 (s, 1H, triazole), 8.11 (dd, J ) 2, J ) 8.5, 1H), 7.55 (s, 1H,
triazole), 7.3-7.2 (m, 2H), 6.95 (dt, J d ) 2.3, J t ) 8.4, 1H),
6.35 (s, 1H), 5.86 (q, J ) 7.3, 1H), 4.84 (d, J ) 14.5, 1H), 4.22
(d, J ) 14.5, 1H), 1.20 (d, J ) 7.3, 3H); GC-MS 240
(C12H11N5O), 224 (C10H8F2N3O); [R]D +61.7° (c 1, DMF). Anal.
(C22H18F2N8O2‚1/2H2O) C, H, N.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr iazol-1-yl)pr opyl]-7-(2-tetr azolyl)qu in azolin -
4(3H)-on e (53). Obtained from the reaction of compound 24
and sodium tetrazolate (9% yield): white solid; mp 198-201
°C; 1H NMR (300 MHz, CDCl3) 8.74 (s, 1H), 8.67 (s, 1H), 8.57
(s, 1H), 8.54 (d, J ) 9.4, 1H), 8.36 (dd, J ) 2.0, J ) 8.7, 1H),
7.78 (s, 1H), 7.75 (s, 1H), 7.47 (dt, J d ) 6.5, J t ) 9, 1H), 6.9-
6.7 (m, 2H), 5.95 (dq, J d ) 1.5, J q ) 7.3, 1H), 5.60 (d, J ) 1.5,
1H), 5.17 (d, J ) 14.2, 1H), 4.05 (d, J ) 14.2, 1H), 1.33 (d, J )
7.3, 3H); DIP-MS 242 (C11H10N6O), 224 (C10H8F2N3O); [R]D
-16.9° (c 0.2, CHCl3). Anal. (C21H17F2N9O2‚1/2H2O) C, H, N.

1880 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Bartroli et al.
solid; mp 235-236 °C; 1H NMR (300 MHz, CDCl3) 8.63 (s, 1H),
8.42 (d, J ) 8.2, 1H), 8.13 (d, J ) 1.5, 1H), 7.98 (dd, J ) 8.2,
14.2, 1H), 3.6-3.5 (m, 4H, pip), 3.4-3.3 (m, 4H, pip), 1.28 (d,
J ) 7.3, 3H); [R]D +6.0° (c 0.2, MeOH).
J ) 1.5, 1H), 7.77 (s, 1H), 7.74 (s, 1H), 7.48 (dt, J d ) 6.4, J t
8.8, 1H), 6.9-6.8 (m, 2H), 6.3 (br s, 2H, NH2), 5.92 (dq, J d
)
)
(c) The above product (1.2 g, 1.7 mmol) was dissolved in 1,2-
dimethoxyethane (25 mL) and was treated with hydrazine
hydrate (693 mg, 14 mmol) at 80 °C for 3 h. Solvents were
removed in vacuo, and the resulting yellowish residue was
recrystallized from MeOH-H2O to give the corresponding
semicarbazide as an off-white solid (900 mg, 84%): mp 190-
193 °C; 1H NMR (300 MHz, MeOH-d4) δ (MeOH) 8.45 (s, 1H),
8.17 (s, 1H), 8.12 (d, J ) 9.0, 1H), 7.64 (s, 1H), 7.5-7.2 (m),
7.2-6.7 (m), 6.04 (q, J q ) 7.3, 1H), 5.07 (d, J ) 14.2, 1H), 4.13
(d, J ) 14.2, 1H), 3.6-3.5 (m, 4H, pip), 3.4-3.3 (m, 4H, pip),
1.27 (d, J ) 7.3, 3H); [R]D +5.2° (c 0.2, MeOH).
(d) The compound obtained above (900 mg) was dissolved
in DMF (10 mL) and treated with formamidine acetate (665
mg, 6.3 mmol) at 80 °C for 3 h. The resulting product was
isolated in a manner similar to that described in section (c),
and finally it was flash chromatographed to give the title
product as an off-white solid (450 mg, 49%): 1H NMR (300
MHz, CDCl3) 10.4 (br s, 1H, NH), 8.50 (s, 1H), 8.19 (d, J )
8.9, 1H), 7.77 (s, 1H), 7.72 (s, 1H), 7.63 (s, 1H, triazolone), 7.44
(d, J ) 9, 2H), 7.5-7.4 (m, 1H), 7.14 (dd, J ) 2.3, J ) 9.0,
1H), 7.07 (d, J ) 2.3, 1H), 7.00 (d, J ) 9, 2H), 6.9-6.7 (m,
2H), 5.90 (q, J ) 7.3, 1H), 5.46 (br s, 1H), 5.18 (d, J ) 14.2,
1H), 4.03 (d, J ) 14.2, 1H), 3.60 (m, 4H, pip), 3.40 (m, 4H,
pip), 1.27 (d, J ) 7.3, 3H).
1.2, J q ) 7.3, 1H), 5.56 (d, J ) 1.3, 1H), 5.16 (d, J ) 14.1, 1H),
4.03 (d, J ) 14.1, 1H), 1.32 (d, J ) 7.3, 3H); GC-MS 224
(C10H8F2N3O), 216 (C11H11N3O2).
(1R,2R)-7-[(Am in osu lfon yla m in o)im in om et h yl]-3-[2-
(2,4-d iflu or op h en yl)-2-h yd r oxy-1-m eth yl-3-(1H-1,2,4-tr ia -
zol-1-yl)pr opyl]qu in azolin -4(3H)-on e (61). Proceeding with
the above flash chromatography the title product eluted in the
third place (80 mg, 13%): white solid; mp 203-206 °C; 1H
NMR (300 MHz, MeOH-d4) 8.59 (s, 1H), 8.39 (d, J ) 8.4, 1H),
8.19 (dd, J ) 1.5, J ) 8.5, 1H), 8.17 (s, 1H), 8.02 (dd, J ) 1.7,
J ) 8.4, 1H), 7.63 (s, 1H), 7.42 (dt, J t ) 6.5, J d ) 9, 1H), 7.05
(ddd, J d ) 2.5, J d ) 8.5, J d ) 14, 1H), 6.89 (dt, J d ) 2.5, J t
)
8.5, 1H), 6.06 (q, J ) 7.3, 1H), 5.06 (d, J ) 14.2, 1H), 4.22 (d,
J ) 14.2, 1H), 1.31 (d, J ) 7.3, 3H); GC-MS 224 (C10H8F2N3O),
199 (C11H9N3O); [R]D +35.5° (c 0.2, MeOH). Anal. (C21H20F2-
N8O4S) C, H; N: calcd, 21.61; found, 20.19; S: calcd, 6.18; S,
5.49.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]-7-[4-(4-n itr op h en yl)-1-p i-
p er a zin yl]qu in a zolin -4(3H)-on e (62). Obtained from the
reaction of compound 24 and 4-(4-nitrophenyl)piperazine (57%
yield): orange-colored solid; mp 287-289 °C; 1H NMR (300
MHz, CDCl3) 8.50 (s, 1H), 8.3-8.1 (m, 3H), 7.76 (s, 1H), 7.73
(s, 1H), 7.47 (dt, J d ) 6.5, J t ) 9, 1H), 7.10 (dd, J ) 2.3, J )
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]-7-[4-[4-[2,4-d ih yd r o-2-(3-
pen tyl)-3H-1,2,4-tr iazol-3-on e-4-yl]ph en yl]-1-piper azin yl]-
qu in azolin -4(3H)-on e (64). A solution of the product obtained
above (100 mg) in DMF (5 mL) was treated with Cs2CO3 (50
mg, 0.16 mmol) and 3-bromopentane (47 mg, 0.32 mmol) at
65 °C for 18 h. The mixture was partitioned between EtOAc
and H2O, and the organic phase was separated, dried, con-
centrated, and purified by flash chromatography to give the
title compound as a cream-colored solid (70 mg, 27%): mp
206-211 °C; 1H NMR (300 MHz, CDCl3) 8.49 (s, 1H), 8.18 (d,
J ) 8.9, 1H), 7.76 (s, 1H), 7.72 (s, 1H), 7.64 (s, 1H, triazolone),
7.44 (d, J ) 9, 2H), 7.5-7.4 (m, 1H), 7.14 (dd, J ) 2.3, J ) 9.0,
1H), 7.06 (d, J ) 2.3, 1H), 7.02 (d, J ) 9, 2H), 6.9-6.7 (m,
2H), 5.91 (dq, J d ) 1.5, J q ) 7.3, 1H), 5.46 (d, J ) 1.5, 1H),
5.17 (d, J ) 14.2, 1H), 4.1-3.9 (m, 1H, CHEt2), 4.03 (d, J )
14.2, 1H), 3.60 (m, 4H, pip), 3.39 (m, 4H, pip), 1.9-1.6 (m, 4H,
CH(CH2CH3)2), 1.27 (d, J ) 7.3, 3H), 0.88 (t, J ) 7.3, 6H, CH-
9.0, 1H), 7.03 (d, J ) 2.3, 1H), 6.9-6.7 (m, 4H), 5.92 (dq, J d
)
1.5, J q ) 7.3, 1H), 5.46 (d, J ) 1.5, 1H), 5.17 (d, J ) 14.2, 1H),
4.03 (d, J ) 14.2, 1H), 3.67 (s, 8H, pip), 1.28 (d, J ) 7.3, 3H);
[R]D -41° (c 0.2, CHCl3). Anal. (C30H28F2N8O4) C, H, N.
(1R,2R)-7-[4-(4-Ch lor op h en yl)-1-p ip er a zin yl]-3-[2-(2,4-
d iflu or op h en yl)-2-h yd r oxy-1-m eth yl-3-(1H-1,2,4-tr ia zol-
1-yl)p r op yl]qu in a zolin -4(3H)-on e (63). Obtained from the
reaction of compound 24 and 4-(4-chlorophenyl)piperazine
(61% yield): white solid; mp 218-219 °C; 1H NMR (300 MHz,
CDCl3) 8.49 (s, 1H), 8.19 (d, J ) 8.9, 1H), 7.76 (s, 1H), 7.73 (s,
1H), 7.47 (dt, J d ) 6.5, J t ) 9, 1H), 7.24 (dt, J t ) 2.8, J d ) 9.6,
2H), 7.14 (dd, J ) 2.4, J ) 9.0, 1H), 7.06 (d, J ) 2.3, 1H), 6.89
(dt, J t ) 2.8, J d ) 9.6, 2H), 6.9-6.7 (m, 2H), 5.91 (dq, J d ) 1.5,
J q ) 7.3, 1H), 5.46 (d, J ) 1.5, 1H), 5.17 (d, J ) 14.2, 1H),
4.03 (d, J ) 14.2, 1H), 3.6-3.5 (m, 4H, pip), 3.4-3.3 (m, 4H,
pip), 1.28 (d, J ) 7.3, 3H); MS (DIP) 367 (C20H20ClN4O), 224
(C10H8F2N3O); [R]D -34.1° (c 1, CHCl3). Anal. (C30H28ClF2-
N7O2‚1/2EtOAc) C, H, N.
(CH2CH3)2); MS (DIP) 711 (M+), 486 (C27H32N7O2), 224 (C10
-
H8F2N3O); [R]D -30.3° (c 1, CHCl3). Anal. (C37H40F2N10O3)
C, H, N.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H -1,2,4-t r ia zol-1-yl)p r op yl]-7-[4-[4-(2,4-d ih yd r o-3H -
1,2,4-tr iazol-3-on e-4-yl)ph en yl]-1-piper azin yl] qu in azolin -
4(3H)-on e. (a) A solution of 62 (1.3 g, 2.1 mmol) in EtOH
(200 mL) and CHCl3 (5 mL) was treated with Pd/C (5%, 1 g)
and H2 at 1 atm for 24 h. The catalyst was filtered off, and
the resulting solution was evaporated to dryness to give the
amino derivative as a slighly greenish solid (1.2 g, 100%): mp
170-173 °C; 1H NMR (300 MHz, MeOH-d4) 8.57 (s, 1H,
NdCH-N), 8.2-8.0 (m, 2H), 7.90 (s, 1H), 7.39 (dt, J d ) 6.5, J t
) 9, 1H), 7.4-7.0 (m), 7.29 (dt, J t ) 2.2, J d ) 9.3, 1H), 7.15
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]-6-[4-[4-[2,4-d ih yd r o-2-(3-
pen tyl)-3H-1,2,4-tr iazol-3-on e-4-yl]ph en yl]-1-piper azin yl]-
qu in a zolin -4(3H)-on e (65). Obtained by reaction of 4-[4-[2,4-
dihydro-2-(3-pentyl)-3H-1,2,4-triazol-3-one-4-yl]phenyl]-1-pi-
perazine and 23 (31% yield): cream-colored solid; 81-109 °C;
1H NMR (300 MHz, CDCl3) 8.46 (s, 1H), 7.76 (s, 1H), 7.72 (s,
1H), 7.7 (m, 2H), 7.64 (s, 1H, triazolone), 7.46 (d, J ) 9, 2H),
7.5-7.4 (m, 2H), 7.05 (d,J ) 9.0, 2H), 6.9-6.7 (m, 2H), 5.96
(dq, J d ) 1.5, J q ) 7.3, 1H), 5.46 (d, J ) 1.5, 1H), 5.19 (d, J )
14.2, 1H), 4.1-3.9 (m, 1H, CHEt2), 4.01 (d, J ) 14.2, 1H), 3.60
(m, 4H, pip), 3.39 (m, 4H, pip), 1.9-1.6 (m, 4H, CH(CH2CH3)2),
1.30 (d, J ) 7.3, 3H), 0.89 (t, J ) 7.3, 6H, CH(CH2CH3)2); GC-
MS 486 (C27H32N7O2), 224 (C10H8F2N3O); [R]D +20.3° (c 1,
CHCl3). Anal. (C37H40F2N10O3‚3/2H2O) C, H, N.
(1R,2R)-3-[2-(2,4-Diflu or op h en yl)-2-h yd r oxy-1-m eth yl-
3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]-7-[4-[4-[2,4-d ih yd r o-2-[(S)-
1-eth yl-2(S)-h yd r oxyp r op yl]-3H-1,2,4-tr ia zol-3-on e-4-yl]-
ph en yl]-1-piper azin yl]qu in azolin -4(3H)-on e (66). Obtained
as 64 but using (3R,2S)-3-brosyloxy-2-pentanol17 (23% yield):
cream-colored solid; mp 249-252 °C; 1H NMR (300 MHz,
CDCl3) 8.49 (s, 1H), 8.19 (d, J ) 8.9, 1H), 7.76 (s, 1H), 7.73 (s,
1H), 7.67 (s, 1H, triazolone), 7.45 (d, J ) 9, 2H), 7.5-7.4 (m,
1H), 7.14 (dd, J ) 2.3, J ) 9.0, 1H), 7.06 (d, J ) 2.3, 1H), 7.02
(d, J ) 9, 2H), 6.9-6.7 (m, 2H), 5.92 (dq, J d ) 1.5, J q ) 7.3,
1H), 5.46 (d, J ) 1.5, 1H), 5.17 (d, J ) 14.2, 1H), 4.1-3.9 (m,
2H, CHOH and CHN), 4.03 (d, J ) 14.2, 1H), 3.60 (m, 4H,
(ddd, J ) 2.4, J ) 8.7, J ) 11.5, 1H), 6.89 (dt, J d ) 2.5, J t
)
8.5, 1H), 6.05 (q, J q ) 7.3, 1H), 5.06 (d, J ) 14.2, 1H), 4.18 (d,
J ) 14.2, 1H), 3.7-3.5 (m, 4H), 3.5-3.3 (m, 4H), 1.29 (d, J )
7.3, 3H).
(b) A solution of the above product (1.2 g, 2.1 mmol) in
pyridine (75 mL) was treated with phenyl chloroformate (393
mg, 2.5 mmol) at 25 °C for 3 h. The reaction was quenched
by the addition of 10% aqueous NaHCO3 solution. Next, most
of the pyridine was removed in vacuo, and the residue was
partitioned between CHCl3 and H2O. The layers were sepa-
rated, and the organic phase was dried over Na2SO4, filtered,
concentrated, and purified by flash chromatography to give
the corresponding phenyl carbamate as a yellowish solid (1.2
g, 83%): mp 137-143 °C; 1H NMR (300 MHz, CDCl3) δ (CDCl3)
8.49 (s, 1H), 8.19 (d, J ) 8.9, 1H), 7.76 (s, 1H), 7.73 (s, 1H),
7.47 (dt, J d ) 6.5, J t ) 9, 1H), 7.4-6.5 (m), 5.92 (q, J q ) 7.3,
1H), 5.45 (d, J ) 1.5, 1H), 5.17 (d, J ) 14.2, 1H), 4.03 (d, J )

New Azole Antifungals. 3
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11 1881
pip), 3.39 (m, 4H, pip), 3.08 (d, J ) 8.7, 1H, OH), 2.1-1.8 (m,
2H, CHCH2CH3), 1.28 (d, J ) 7.3, 3H), 1.22 (d, J ) 6.2, 3H,
HOCHCH3), 0.94 (t, J ) 7.4, 3H, CHCH2CH3); [R]D -26.7° (c
0.5, CHCl3). Anal. (C37H40F2N10O4) C, H, N.
(C10H8F2N3O), 208 (C10H9ClN2O); [R]D -99.8° (c 1, CHCl3).
Anal. (C20H18ClF2N5O3) C, H, N.
(1R,2R)-2-Am in o-4-ch lor o-N-[2-(2,4-d iflu or op h en yl)-2-
h yd r oxy-1-m et h yl-3-(1H -1,2,4-t r ia zol-1-yl)p r op yl]b en z-
a m id e (72). Obtained from the reaction of amine 11 and
4-chloroanthranilic acid, following the general procedure (first
step) (ca. 100% yield): white foam; 1H NMR (300 MHz, CDCl3)
7.78 (s, 1H), 7.77 (s, 1H), 7.37 (dt, J d ) 6.5, J t ) 9, 1H), 7.33
(d, J ) 8.4, 1H), 6.8-6.6 (m, 4H), 6.59 (br d, J ) 9.3, 1H, NH),
5.74 (br s, 2H, NH2), 5.32 (d, J ) 1.3, 1H), 5.02 (d, J ) 14.2,
1H), 4.94 (quint, J ) 6.9, 1H), 4.48 (d, J ) 14.2, 1H), 0.99 (d,
J ) 6.9, 3H); GC-MS 224 (C10H8F2N3O), 197 (C9H10ClN2O),
154 (C7H5ClNO); [R]D -90.8° (c 1, CHCl3). Anal. (C19H18Cl-
F2N5O2) C, H, N.
(1R,2R)-7-Ch lor o-3-[2-(2,4-d iflu or op h en yl)-2-h yd r oxy-
1-m eth yl-3-(1H-1,2,4-tr iazol-1-yl)pr opyl]-2-m eth ylqu in azo-
lin -4(3H)-on e (67). Obtained following the general quinazo-
linone ring formation procedure but using triethyl orthoacetate
(59%): white solid; mp 200-201 °C (EtOH/H2O); 1H NMR (300
MHz, CDCl3) 8.20 (d, J ) 8.6, 1H), 8.17 (s, 1H), 7.8-7.6 (m,
2H), 7.68 (s, 1H), 7.47 (dd, J ) 1.9, J ) 8.6, 1H), 7.45 (s, 1H),
6.9-6.7 (m, 2H), 5.18 (q, J ) 6.9, 1H), 4.80 (dd, J ) 1.1, J )
14.0, 1H), 4.32 (d, J ) 14.0, 1H), 2.87 (s, 3H, CH3), 1.39 (d, J
) 6.9, 3H); GC/MS 224 (C10H8F2N3O), 221 (C11H10ClN2O); [R]D
-59.2° (c 1, CHCl3). Anal. (C21H18ClF2N5O2) C, H, N.
(1R,2R)-7-Ch lor o-3-[2-(2,4-d iflu or op h en yl)-2-h yd r oxy-
1-m et h yl-3-(1H -im id a zol-1-yl)p r op yl]q u in a zolin -4(3H )-
on e (73). Obtained following the general procedure using
(1R,2R)-7-Ch lor o-3-[2-(2,4-d iflu or op h en yl)-2-h yd r oxy-
1-m eth yl-3-(1H-1,2,4-tr iazol-1-yl)pr opyl]-2,3-dih ydr oqu in -
a zolin -4(1H)-on e (68). The procedure described in the
literature for a similar reaction was followed.18 To a solution
of compound 20 (250 mg, 0.59 mmol) in EtOH (3 mL) was
added aqueous formaldehyde (46 mcL, 0.59 mmol), and the
solution was heated at reflux for 4 h. An 80% NaOH aqueous
solution (0.2 mL) was added, and the solution was stirred at
reflux for 20 min. The cooled mixture was concentrated and
partitioned between CHCl3 and water. The organic solution
was dried over Na2SO4, filtered, concentrated, and purified by
flash chromatography to a white amorphous solid (190 mg,
74%); mp 62-75 °C (wide range); 1H RMN (300 MHz, CDCl3)
1
amine 14:6 white solid; mp 142-146 °C; H NMR (300 MHz,
CDCl3) (ca. 1:1 mixture of two rotamers) 8.50 (s, 1/2H), 8.32
1
1
1
(d, J ) 8.6, /2H), 8.27 (d, J ) 8.6, /2H), 8.12 (s, /2H), 7.8-7.5
1
1
(m), 7.28 (s), 7.04 (s, /2H), 7.0-6.7 (m), 6.32 (s, /2H), 6.07 (s,
1/2H), 5.89 (q, J ) 7.3, /2H), 4.83 (d, J ) 14.5, /2H), 4.68 (q, J
1
1
) 6.9, 1/2H) 4.48 (dd, J ) 2.4, J ) 14.2, 1/2H), 3.92 (d, J ) 14.2,
1/2H), 3.72 (d, J ) 14.5, /2H), 1.44 (d, J ) 6.9, /2H), 1.27 (d, J
1
3
) 7.2, 3/2H); GC-MS 430 (M+), 223 (C11H9F2N2O), 207 (C10
H8ClN2O); [R]D +72.5° (c 1, CHCl3). Anal. (C21H17ClF2N4O2‚
1/2EtOAc) C, H, N.
-
(1S,2S)-7-Ch lor o-3-[2-(2,4-d iflu or op h en yl)-2-h yd r oxy-
1-m eth yl-3-(1H-1,2,4-tr iazol-1-yl)pr opyl]qu in azolin -4(3H)-
on e (74). Obtained as a white amorphous solid, from the
diastereomer (1S,2S) of amine 11:6 GC-MS 224 (C10H8F2N3O),
208 (C10H9ClN2O); [R]D +8.8° (c 1, CHCl3). Anal. (C20H16Cl-
F2N5O2) C, H, N.
(1R*,2R*)-7-Ch lor o-3-[2-(2,4-diflu or oph en yl)-2-h ydr oxy-
1-m eth yl-3-(1H-1,2,4-tr iazol-1-yl)pr opyl]qu in azolin -4(3H)-
on e (75). Obtained as a white solid, from racemic amine 11:5
mp 242-243 °C; GC-MS 224 (C10H8F2N3O), 208 (C10H9ClN2O).
Anal. (C20H16ClF2N5O2) C, H, N.
7.9 (d, J ) 8.4, 1H), 7.78 (s, 1H), 7.75 (s, 1H), 7.38 (dt, J d
)
6.5, J t ) 9, 1H), 6.89 (dd, J ) 1.6, J ) 8.4, 1H), 6.9-6.7 (m,
3H), 5.44 (q, J ) 6.9, 1H), 5.3-5.1 (m, 3H), 4.75 (dd, J ) 1.7,
J ) 9.9, 1H), 4.50 (s, 1H), 4.48 (d, J ) 14.2, 1H), 1.00 (d, J )
6.9, 3H); GC-MS 224 (C10H8F2N3O), 209 (C10H10ClN2O); [R]D
-134.0° (c 0.5, CHCl3). Anal. (C20H18ClF2N5O2) C, H, N.
(1R,2R)-7-Ch lor o-3-[2-(2-flu or op h en yl)-2-h yd r oxy-1-
m eth yl-3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]qu in a zolin -4(3H)-
on e (69). Obtained following the general procedure using
1
amine 12:6 white solid; mp 124-129 °C; H NMR (300 MHz,
(1R,2S)-7-Ch lor o-3-[2-(2,4-d iflu or op h en yl)-2-h yd r oxy-
1-m eth yl-3-(1H-1,2,4-tr iazol-1-yl)pr opyl]qu in azolin -4(3H)-
on e (76). Obtained as a white, amorphous solid, from the
diastereomer (1R,2S) of amine 11:6 mp 85-89 °C (EtOH/H2O);
1H NMR (300 MHz, CDCl3) (ca. 1:1 mixture of two rotamers)
8.41 (s, 1/2H), 8.17 (s, 1/2H), 8.02 (d, J ) 8.6, 1/2H), 7.9-7.8 (m),
CDCl3) 8.65 (s, 1H), 8.31 (d, J ) 8.5, 1H), 7.80 (d, J ) 1.9,
1H), 7.77 (s, 1H), 7.76 (s, 1H), 7.6-7.4 (m, 2H), 7.3-7.2 (m,
1H), 7.2-7.0 (m, 2H), 6.02 (dq, J d ) 1.2, J q ) 7.3, 1H), 5.47 (d,
J ) 1.3, 1H), 5.24 (d, J ) 14.1, 1H), 4.05 (d, J ) 14.1, 1H),
1.31 (d, J ) 7.3, 3H); GC-MS 207 (C10H9ClN2O), 206 (C10H9-
FN3O); [R]D -9.0° (c 0.5, CHCl3). Anal. (C20H17ClFN5O2) C,
H, N.
1
1
7.79 (s, /2H), 7.75 (s, /2H), 7.60 (s, 1H), 7.5-7.2 (m), 7.12 (q,
J ) 8.8, 1/2H), 6.89 (s, 1/2H), 6.8-6.6 (m, 3/2H), 6.43 (t, J ) 7.4,
1/2H), 5.85 (q, J ) 6.8, 1/2H), 5.47 (s, 1/2H), 5.15 (d, J ) 14,
1/2H), 4.85 (q, J ) 6.9, 1/2H), 4.65 (s, 1/2H), 4.60 (d, J ) 14,
1/2H), 1.74 (d, J ) 7.1, 3/2H), 1.51 (d, J ) 6.9, 3/2H); GC-MS
224 (C10H8F2N3O), 208 (C10H9ClN2O); [R]D +45.0° (c 1, CHCl3).
Anal. (C20H16ClF2N5O2‚1/2H2O) C, H, N.
(1R,2R)-7-Ch lor o-3-[2-(2,4-d ich lor op h en yl)-2-h yd r oxy-
1-m eth yl-3-(1H-1,2,4-tr iazol-1-yl)pr opyl]qu in azolin -4(3H)-
on e (70). Obtained following the general procedure using
1
amine 13:5 white solid; mp 144-146 °C; H NMR (300 MHz,
CDCl3) 8.57 (s, 1H), 8.26 (d, J ) 8.6, 1H), 7.81 (s, 1H), 7.76 (d,
J ) 2, 1H), 7.73 (s, 1H), 7.62 (d, J ) 8.6, 1H), 7.49 (dd, J ) 2,
J ) 8.6, 1H), 7.38 (d, J ) 2.2, 1H), 7.17 (dd, J ) 2.2, J ) 8.6,
1H), 6.40 (dq, J d)1.7, J q)7.3, 1H), 5.74 (d, J ) 14.3, 1H) 5.64
(d, J ) 1.8, 1H), 3.96 (d, J ) 14.3, 1H), 1.26 (d, J ) 7.3, 3H);
GC-MS 208 and 210 (C10H9ClN2O), 256 and 258 (C10H8-
Cl2N3O); [R]D) -46.6° (c 0.12, CHCl3). Anal. (C20H16Cl3N5O2)
C, H, N.
(1S,2R)-7-Ch lor o-3-[2-(2,4-d iflu or op h en yl)-2-h yd r oxy-
1-m eth yl-3-(1H-1,2,4-tr iazol-1-yl)pr opyl]qu in azolin -4(3H)-
on e (77). Obtained as a white amorphous solid from the
diastereomer (1S,2R) of amine 11:6 mp 83-87 °C (EtOH/H2O);
GC-MS 224 (C10H8F2N3O), 208 (C10H9ClN2O); [R]D -46.1°
(c 1, CHCl3). Anal. (C20H16ClF2N5O2‚1/2H2O) C, H, N.
In Vitr o Activity. Test organisms were obtained from the
ATCC or were clinical isolates.
Agar dilution method: Suspensions of each microorganism
were prepared to contain 105 colony forming units (cfu)/mL.
All drugs were dissolved in ethanol 50% to obtain an stock
solution of 800 µg/mL. The agar dilution method was per-
formed using Kimmig’s agar (K.A., Merck) suplemented with
0.5% glycerol. Plates of K.A. containing 2-fold serial dilutions
(80 to 0.03 µg/mL) of the drugs were inoculated with 10 µL of
the fungal inocula and incubated at 25 °C during 48 h for
yeasts and 120 h for filamentous fungi. Following incubation,
MICs (minimal inhibitory concentrations, µg/mL) were deter-
mined. For the purpose of determining the geometric mean,
MICs of >80 µg/mL were assumed to be 160 µg/mL and MICs
of e0.03 µg/mL were assumed to be 0.03.
(1R,2R)-4-Ch lor o-2-for m am idoN-[2-(2,4-diflu or oph en yl)-
2-h yd r oxy-1-m eth yl-3-(1H-1,2,4-tr ia zol-1-yl)p r op yl]ben z-
a m id e (71). To a solution of 3.0 g of 20 (7 mmol) in 75 mL of
THF was added 150 mL of 0.1 N NaOH aqueous solution. The
mixture was stirred at room temperature for 3 h. The product
was extracted with EtOAc (×3). The collected organic fractions
were washed with 0.1 N HCl aqueous solution and brine and
dried over anhydrous Na2SO4, the drying agent was filtered,
and the filtrate was concentrated and purified by flash
chromatography to give the title compound (25% yield): white
solid; mp 160-161 °C; 1H NMR (300 MHz, CDCl3) 11.22 (br s,
1H), 8.78 (d, J ) 1.9, 1H), 8.48 (d, J ) 1.3, 1H), 7.81 (s, 1H),
7.78 (s, 1H), 7.53 (d, J ) 8.5, 1H), 7.37 (dt, J d ) 6.5, J t ) 9,
1H), 7.15 (dd, J ) 2.0, J ) 8.4, 1H), 6.8-6.7 (m, 3H), 5.40 (d,
J ) 1.3, 1H), 5.01 (d, J ) 14.2, 1H), 4.93 (quint, J ) 6.9, 1H),
4.46 (d, J ) 14.2, 1H), 1.02 (d, J ) 6.9, 3H); GC-MS 224
System ic Ca n d id osis in Mice. An in vivo murine can-
didosis model was used to monitor the antifungal activity of

1882 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Bartroli et al.
the test compounds.2 Groups of 10 male mice were inoculated
iv with 0.2 mL of a suspension containing 2 to 8 × 107 cfu/mL
of C. albicans. Compounds were administered orally as
suspensions in 1% Tween + 0.2% carboxymethylcellulose in
distilled water, at times 1, 4, and 24 h after infection. The
control group received only the vehicle. At least 90% of the
animals in the control group died by day 3 of infection. The
antifungal activity was assessed by the survival rate at days
3, 5, 7, and 9 postinfection and compared with both, that of
the control animals and that of the animals treated with
fluconazole at the same dosis.
System ic Ca n d id osis in Ra bbit. Groups of 10 male New
Zealand rabbits were inoculated iv with C. albicans (1.2 × 107
cfu/kg). Compounds were administered orally as suspensions
in 1% Tween 80 + 0.2% carboxymethylcellulose in distilled
water, 4 h after infection (day 0), qd (i.e., once a day) for 6
additional days. The control group received only the vehicle.
Rabbits were killed on day 7. Kidneys and lungs were excised
and homogenized in 1 mL saline per gram of wet tissue. An
aliquot of the homogenate was added to Sabouraud agar and
incubated for cell count (37 °C, 7 days). Results were
expressed as the log cfu per gram of wet tissue.
Syst em ic Asp er gillosis in R a t . Groups of 10 male
Sprague-Dawley rats were immunosuppressed with 1 mg/kg/
day po of dexamethasone 21-acetate, starting 4 days before
the iv inoculation of A. fumigatus (4.6 × 105 cfu/animal).
Compound 20 was administered orally as a suspension in 1%
Tween 80 + 0.2% carboxymethylcellulose in distilled water, 1
and 8 h after infection (day 0), and bid (i.e., twice daily) for 6
additional days. Amphotericin B was administered iv qd and
served as a positive standard. The control group received po,
twice daily the vehicle used with compound 20. Rats were
killed on day 7. Livers were excised and homogenized in 1
mL saline per gram of wet tissue. An aliquot of the homoge-
nate was added to Sabouraud agar and incubated for cell count
(37 °C, 7 days). Results were expressed as the log cfu per gram
of liver.
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(4) For two recent reviews on the newer triazole derivatives in the
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SCH-39304) have been terminated. For a recent review, see:
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(9) Itoh, K.; Okonogi, K.; Tasaka, A.; Hayashi, R.; Tamura, N.;
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36nd Interscience Conference on Antimicrobial Agents and
Chemotherapy (ICAAC), September 1996, New Orleans, LA.
(10) Eisai’s compound ER-30346 has been licensed to Bristol-Myers
Squibb. The new laboratory code for this compound is BMS-
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(12) (a) Tasaka, A.; Tamura, N.; Matsushita, Y.; Teranishi, K.;
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Azoles. I. Synthesis and Antifungal Activity of (2R,3R)-2-(2,4-
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Its Stereoisomers. Chem. Pharm. Bull. 1993, 41, 1035-1042.
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Ack n ow led gm en t. The authors thank Mr. Manuel
Anguita for his invaluable contribution to the syntheses
and process optimization and Mr. J ordi Belloc for the
NMR experiments and mass spectral and HPLC mea-
surements. We also thank Mrs. Consol Ferreri, Guada-
lupe Mart´ınez, Ascensio´n Palencia, Mar´ıa-J ose´ Redondo,
Carmina Ferna´ndez, and Mr. J ose´ Antonio Garc´ıa for
their expert technical assistance, Dr. Elena Carceller,
Dr. Carmen Almansa, and Mrs. Neus Virgili for helpful
discussions, and Dr. Loebenberg, Dr. Vanden Bossche,
and Dr. Pitcher for providing us with samples of SCH-
42427, itraconazole, and voriconazole, respectively.
(13) MM2 calculations were performed using Chem-X force field from
Chemical Design Ltd.
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following multiple dose administration in sensitive rodent spe-
cies and hence shows little efficacy in murine models. J ezequel,
S. G.; Clark, M.; Cole, S.; Evans, K. M.; Wastall, P. UK-109,496,
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science Conference on Antimicrobial Agents and Chemotherapy
(ICAAC), September 1995, San Francisco, CA. (b) Voriconazole
produced efficacy similar to that of fluconazole in a guinea pig
model of candidosis. Troke, P. F.; Brammer, K. W.; Hitchcock,
C. A.; Sarantis, N.; Yonren, S. A Novel. UK-109, 496, A Novel
Wide-Spectrum Triazole Derivative for the Treatment of Fungal
Infections: Activity in Systemic Candidiasis Models and Early
Efficacy in Oropharyngeal Candidiasis. 35 Interscience Confer-
ence on Antimicrobial Agents and Chemotherapy (ICAAC),
September 1995, San Francisco, CA.
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(17) Girijavallabhan, V. M.; Saksena, A. K.; Lovey, R. G.; Bennett,
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A. K. SCH 56592, A Novel Broad Spectrum Antifungal Agent.
35 Interscience Conference on Antimicrobial Agents and Che-
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(18) Baldazzi, C.; Barbanti, M.; Basaglia, R.; Benelli, A.; Bertolini,
Su p p or tin g In for m a tion Ava ila ble: Individual MIC
values for each final compound (Table 10) (3 pages). Ordering
information is given on any current masthead page.
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