Synthesis of novel triazole derivatives as inhibitors of cytochrome P450 14α-demethylase (CYP51)

Article abstract of DOI:10.1016/j.ejmech.2007.01.006

A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[(4-substitutedphenyl)-piperazin-1-yl]-propan-2-ols have been designed and synthesized on the basis of the structure-activity relationships and antimycotic mechanism of azole antifungal agents

Full text of DOI:10.1016/j.ejmech.2007.01.006

European Journal of Medicinal Chemistry 42 (2007) 1226e1233
http://www.elsevier.com/locate/ejmech
Preliminary communication
Synthesis of novel triazole derivatives as inhibitors of cytochrome
P450 14a-demethylase (CYP51)
a,*
a
Qing-Yan Sun , Jian-Ming Xu , Yong-Bing Cao , Wan-Nian Zhang , Qiu-Ye Wu ,
b
c
a
a
a
a
Da-Zhi Zhang , Jun Zhang , Hui-Qing Zhao , Yuan-Ying Jiang
b
a
Department of Organic Chemistry, College of Pharmacy, Second Military Medical University, Guohe Road 325,
Shanghai 200433, People’s Republic of China
b
Department of Pharmacology, College of Pharmacy, Second Military Medical University, Guohe Road 325,
Shanghai 200433, People’s Republic of China
c
Department of Medicinal Chemistry, College of Pharmacy, Second Military Medical University, Guohe Road 325,
Shanghai 200433, People’s Republic of China
Received 4 December 2006; received in revised form 8 January 2007; accepted 9 January 2007
Available online 24 January 2007
Abstract
A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[(4-substitutedphenyl)-piperazin-1-yl]-propan-2-ols have been designed and
synthesized on the basis of the structureeactivity relationships and antimycotic mechanism of azole antifungal agents. Their structures were
1
confirmed by elemental analysis, IR, MS and H NMR. Results of preliminary antifungal tests against eight human pathogenic fungi (Candida
albicans, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton rubrum, Fonsecaea com-
pacta, and Microsporum gypseum) in vitro showed that all title compounds exhibited activity against fungi tested to some extent. Among
the compounds tested, all compounds showed higher activity against C. albicans than fluconazole in vitro. Compounds 3, 6e8, 28, 29, and
3
2 exhibited the same activities against C. albicans as voriconazole (with the MIC value of 0.0152 mg/mL). Compounds 3, 6, and 7 showed
higher activity against C. parapsilosis than all five positive controls.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Triazole; Synthesis; Antifungal activity; CYP51
1
. Introduction
resistance, pharmacokinetic deficiencies, and/or insufficiencies
in their antifungal activities. Despite recent developments [3e
6], there is still a need for a genuinely broad-spectrum and low-
toxicity antifungal agents.
Fungal infections have become an important complication
and a major cause of morbidity and mortality in immunocom-
promised individuals suffering from tuberculosis, cancer or
AIDS and in organ transplant cases [1,2]. Triazole antifungals
CYP51 is a member of the cytochrome P450 superfamily,
which catalyzes the oxidative removal of the 14a-methyl group
1
4,15
(
e.g. fluconazole and voriconazole) which act by inhibiting lan-
of lanosterol to give D
-desaturated intermediates in ergos-
osterol cytochrome P450 14a-demethylase (CYP51) have now
become the most rapidly expanding group of antifungal com-
pounds. However, their clinical value has been limited by their
relatively high risk of toxicity, the emergence of drug
terol biosynthesis. During the catalytic cycle, a substrate
undergoes three successive monooxygenation reactions result-
ing in the formation of 14-hydroxymethyl, 14-carboxaldehyde
and 14-formyl derivatives followed by elimination of formic
acid with concomitant introduction of a C14, C15 double
bond. Ji et al. [7] built a homologous 3D model of CYP51
from C. albicans based on the crystal coordinates of all four
known prokaryotic P450s. With this model they identified the
*
Corresponding author. Tel.: þ86 21 25070382; fax: þ86 21 25070381.
E-mail address: sqy_2000@163.com (Q.-Y. Sun).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.01.006

Q.-Y. Sun et al. / European Journal of Medicinal Chemistry 42 (2007) 1226e1233
1227
structurally and functionally important residues such as the
heme binding residues, the residue interacting with the redox
partner protein and/or involved in electron transfer, the residues
lining the substrate access channel, and the substrate and inhib-
itor binding residues. Another 3D molecular model constructed
by Lewis et al. [8] also showed that typical azole inhibitors were
able to fit the putative active site of CYP51 by a combination of
heme ligation, hydrogen bonding, pep stacking and hydropho-
bic interactions within the heme environment of the enzymes.
Ji’s study indicated that the triazole ring in the scaffold of
triazole antifungals was positioned perpendicularly to the por-
phyrin plane with a ring nitrogen atom coordinated to the
heme iron of CYP51 and was of key importance for the anti-
fungal activity. The halogenated phenyl group was deep in the
same hydrophobic binding cleft in the active site of the target
enzyme CYP51 and long chains of some antifungals such as
itraconazole and ketoconazole surpassed the active site and in-
teracted with residues in the substrate access channel.
of azole antifungals, we herein designed a novel series of 1-
(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[(4-substituted
phenyl)-piperazin-1-yl]-propan-2-ols containing a triazole
ring, a difluorogenated phenyl group and a long side chain,
to find potent systemic antifungal agents that have a broad an-
tifungal spectrum but with less potential to develop resistance.
The N3 atom of triazole was designed to be coordinated to
iron atom of the heme, the 2,4-difluorophenyl group could
be located into the hydrophobic pocket and the 4-(4-substitu-
tedphenyl)piperazine was chosen as side chains to interact
with the residues of the narrow hydrophobic cleft and adjust
the physico-chemical properties of the whole molecule to
avoid the dissatisfying side effects and/or improve the pharma-
cokinetic and pharmacodynamic behavior. The structures of
this series of compounds are shown in Scheme 1.
2. Chemistry
Based on the structure of the active site of CYP51 and the
extensive investigation of the structureeactivity relationships
The general synthetic route of title compounds 1-(1H-1,2,4-
triazol-1-yl)-2-(2,4-difluoro-phenyl)-3-[(4-substitutedphenyl)-
F
O
N
OH
N
N
F
N
N
F
N
NO2
N
F
a
N
CH SO H
+
H
N
N
NO2
3
3
F
1
F
2
3
O
F
F
R
OH
OH
F
N
N
N
N
F
N
NH2
c
N
N
F
N
NH
b
N
N
NH NH2 H O
R
2
2
HOOC
F
4
5~33
Conditions: (a)CH CH OH,Et N,80°C, 5h; (b)Ranney Ni,NH NH H O,CH CH OH,80°C, 3.5h; (c)DMAP,EDCI,CH Cl ,8h.
3
2
3
2
2
2
3
2
2
2
Scheme 1. Synthetic route to the title compounds.

1228
Q.-Y. Sun et al. / European Journal of Medicinal Chemistry 42 (2007) 1226e1233
piperazin-1-yl]-propan-2-ols (5e33) is outlined in Scheme 1.
The important intermediate oxirane 1 and compound 2 were
synthesized with known procedures [9e12]. The title com-
pound 3 was synthesized by ring-open reaction of oxirane 1
with compound 2. The good yield was obtained when the
reaction was performed in a protic solvent ethanol in the
showed higher activity against C. parapsilosis than all five
positive controls. Compounds 5 and 30 showed higher activ-
ity against C. tropicalis than all five positive controls (with
the MIC value of 0.0039 mg/mL). Compounds 3, 4, 6, 7,
and 27 exhibited the same activities against C. neoformans
as voriconazole (with the MIC value of 0.0152 mg/mL).
Compounds 10, 11, and 28 exhibited higher activities against
A. fumigatus than itraconazole and ketoconazole (with the
MIC value of 0.25 mg/mL). The MIC values of compounds
10, 11, and 28 are four times lower than that of itraconazole
and ketoconazole against A. fumigatus in vitro. Compound 12
exhibited the same activities against T. rubrum as voricona-
zole (with the MIC value of 0.0039 mg/mL). Compound 11
showed the same activity against M. gypseum as ketocona-
zole, voriconazole and amphotericin B (with the MIC value
of 0.0039 mg/mL).
ꢀ
presence of triethylamine as a base at 80 C. Then the nitro
group on the phenyl ring of compound 3 was reduced to an
amino group in the presence of Raney Ni and hydrazine
hydrate. In the presence of DMAP and EDCI in dichlorome-
thane at room temperature, the aniline 4 was converted to title
compounds 5e33 by reacting with various benzoic acids.
3
. Bioassays of antifungal activities
The in vitro minimal inhibitory concentrations (MICs) of
the title compounds were determined by the micro-broth di-
lution method according to the methods defined by the Na-
tional Committee for Clinical Laboratory Standards [13].
Fungi strains for testing Candida albicans, Candida parapsi-
losis, Candida tropicalis, Cryptococcus neoformans, Aspergil-
lus fumigatus, Trichophyton rubrum, Fonsecaea compacta,
and Microsporum gypseum were provided through Shanghai
Changhai Hospital. C. albicans, C. neoformans and C. para-
psilosis are ATCC standard strains, others are clinic isolates.
C. albicans (ATCCY0109), C. neoformans (ATCCBLS108)
and C. parapsilosis (ATCC0306392) were quality controlled
strains, and tested in each assay. Fluconazole (FCZ), itraco-
nazole (ICZ), ketoconazole (KCZ), voriconazole (VCZ) and
amphotericin B (AMB) obtained from their respective manu-
facturers served as the positive control. The drug MIC80 was
defined as the first well with an approximate 80% reduction
in growth compared to the growth of the drug-free well. The
title compounds to be tested were dissolved in dimethyl sulf-
oxide (DMSO), serially diluted in growth medium, inocu-
5. Conclusion
In conclusion, we have demonstrated the design and syn-
thesis of a series of novel 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-
difluoro-phenyl)-3-[(4-substitutedphenyl)-piperazin-1-yl]-pro-
pan-2-ols. All the title compounds showed antifungal
activities against all fungi tested to some extent. Some of
the compounds were found to have excellent potency against
a broad range of fungal pathogens including A. fumigatus in
vitro. The obtained results indicated that for antifungal
activity of these novel triazole derivatives it is very helpful
to introduce the 4-(4-substitutedphenyl)piperazine as side
chains to interact with the residues of the narrow hydropho-
bic cleft of CYP51 and adjust the physico-chemical proper-
ties of the whole title molecules. Further evaluations are
necessary to determine the antifungal spectrum of these title
compounds in vivo and help us to optimize these new lead-
ing compounds.
ꢀ
lated and incubated at 35 C. Growth MIC was determined
at 24 h for C. albicans, 72 h for C. neoformans and at 7
days for filamentous fungi.
6. Experimental part
Melting points were measured on a Yamato MP-21 melt-
ing-point apparatus and are uncorrected. Infrared spectra
were recorded in potassium bromide disks on a HITACHI
4
. Results and discussion
1
The in vitro antifungal activities of all title compounds 3e
3 were evaluated against eight human pathogenic fungi (C.
270-50 spectrophotometer. H NMR spectra were recorded
3
in CDCl3 or DMSO-d6 unless otherwise indicated with
a Bruker AC-300P spectrometer, using TMS as internal stan-
dard. Elemental analysis was undertaken with an Italian
MOD 1106 analyzer at the Analysis Center of Shanghai
Institute of Pharmaceutical Industry. Mass spectra were re-
corded on an Agilent 1100 HPLCeMS. The solvents and re-
agents were used as received or were dried prior to use as
needed.
albicans, C. parapsilosis, C. tropicalis, C. neoformans, A. fu-
migatus, T. rubrum, F. compacta, and M. gypseum) which
are often encountered clinically and are summarized in Table 1.
The MIC80 values (in mg/mL) against different pathogenic
fungi, in comparison with fluconazole (FCZ), itraconazole
(ICZ), ketoconazole (KCZ), voriconazole (VCZ) and ampho-
tericin B (AMB) are given.
The results of antifungal activities in vitro showed that all
the title compounds were active against all fungi tested to
some extent. Among the compounds tested, all compounds
showed higher activity against C. albicans than fluconazole
in vitro. Compounds 3, 6e8, 28, 29, and 32 exhibited the
same activities against C. albicans as voriconazole (with
the MIC value of 0.0152 mg/mL). Compounds 3, 6, and 7
6.1. Preparation of 1-(1H-1,2,4-triazol-1-yl)-2-
(2,4-difluorophenyl)-3-[4-(2-fluoro-4-nitro-phenyl)-
piperazin-1-yl]-propan-2-ol (3)
To a stirred mixture of 1-[2-(2,4-difluorophenyl)-2,3-ep-
oxypropyl]-1H-1,2,4-triazole methanesulfonate (1) (1.65 g,

Q.-Y. Sun et al. / European Journal of Medicinal Chemistry 42 (2007) 1226e1233
1229
Table 1
Antifungal activities of the title compounds in vitro (MIC80 mg/mL)
a
Compound
C. alb.
C. par.
C. tro.
C. neo.
A. fum.
T. rub.
0.0152
0.25
F. com.
M. gyp.
3
4
5
6
7
8
9
0.0152
0.25
0.0039
0.25
0.0152
4
0.0152
0.0152
0.0625
0.0152
0.0152
0.25
1
4
0.0625
0.25
0.25
0.0152
0.0625
0.0152
0.0625
0.0152
0.0152
0.0625
0.25
0.0625
0.0152
0.0152
0.0152
0.25
0.0152
<0.0039
0.0039
0.0152
0.0152
0.0152
0.0152
0.0152
0.0625
0.0152
0.0152
0.0152
0.0152
0.25
0.0039
0.0152
0.0152
0.0152
0.0625
0.0152
0.0625
0.0152
0.0625
0.0152
0.0152
0.0152
0.25
1
0.0152
0.0152
0.25
4
0.0625
0.0625
0.0625
0.25
1
1
0.0152
0.0625
0.0625
0.0625
0.0039
0.0625
0.0625
0.0625
0.0625
0.0625
0.0625
0.0625
0.0625
0.25
0.25
0.25
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
0.0625
0.25
0.25
0.25
1
0.0625
0.25
0.25
0.0625
0.0625
0.25
0.0039
0.0625
0.25
0.0625
0.0625
0.0625
0.0625
0.0625
0.25
4
0.25
0.25
0.0625
0.0625
0.0625
0.25
1
0.0152
0.0152
1
1
0.25
1
0.0625
0.25
0.25
4
0.0625
0.0152
0.0152
0.25
0.25
0.25
0.0625
0.0625
0.0625
1
0.0625
0.25
1
0.0152
4
1
0.25
0.25
1
0.0625
1
1
0.0625
0.25
0.25
0.0625
0.25
4
0.25
0.25
1
0.25
0.0625
1
0.25
4
0.25
1
1
1
1
0.25
16
4
0.0625
0.25
0.0625
0.25
1
0.25
0.0625
0.25
0.25
4
4
0.25
4
1
1
0.25
1
0.0625
0.0625
0.0152
0.0152
0.0625
0.25
0.0152
0.0152
0.0152
0.0625
0.0039
0.0625
0.0625
4
0.0625
0.0152
0.0625
0.25
1
0.0625
0.0152
0.25
0.0625
0.25
0.25
0.0152
0.0152
0.0625
0.0625
0.0625
0.0625
1
1
0.25
0.25
0.25
1
0.0625
0.25
0.0625
0.25
0.0625
0.25
0.25
1
1
4
>64
4
1
0.0152
0.25
1
0.25
1
0.0152
0.25
0.25
1
0.0625
0.0625
0.25
4
0.0625
16
0.25
FCZ
ICZ
KCZ
VCZ
AMB
a
4
1
0.25
1
0.25
1
64
1
1
1
0.0152
0.0625
0.0039
1
0.0152
0.0039
0.0039
0.0039
0.0625
0.0152
1
0.0625
1
0.0152
0.0625
0.25
0.0625
0.0625
0.0152
1
1
0.0625
0.0152
16
>64
4
Abbreviations: C. alb., Candida albicans; C. par., Candida parapsilosis; C. tro., Candida tropicalis; C. neo., Cryptococcus neoformans; A. fum., Aspergillus
fumigatus; T. rub., Trichophyton rubrum; F. com., Fonsecaea compacta; M. gyp., Microsporum gypseum; FCZ, fluconazole; ICZ, itraconazole; KCZ, ketoconazole;
VCZ, voriconazole; AMB, amphotericin B.
0.005 mol), CH CH OH (30 mL) and N(C H ) (3 mL), 1-(2-
fluoro-4-nitro-phenyl)-piperazine (2) (1.35 g, 0.006 mol) was
added and was heated at 70e80 C for 5 h. The reaction
6.2. Preparation of 1-(1H-1,2,4-triazol-1-yl)-2-
(2,4-difluorophenyl)-3-[4-(2-fluoro-4-amino-phenyl)-
piperazin-1-yl]-propan-2-ol (4)
3
2
2 5 3
ꢀ
was monitored by TLC. After filtration, the filtrate was evap-
orated under reduced pressure. Water (30 mL) was added to
the residue, which was then extracted with ethyl acetate
To a stirred mixture of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-
difluorophenyl)-3-[4-(2-fluoro-4-nitro-phenyl)-piperazin-1-yl]-
propan-2-ol (3) (2.31 g, 0.005 mol), CH CH OH (20 mL) and
(
80 mL ꢁ 3). The extract was washed with saturated NaCl
3
2
solution (20 mL ꢁ 3), dried over anhydrous Na SO and
85% hydrazine hydrate (8 mL), freshly prepared Raney Ni
ꢀ
2
4
evaporated. The residue was crystallized from DMF/H O to
2
(0.5 g) was added and was heated at 70e80 C for 3 h. The re-
ꢀ
1
afford a white solid 3 in 78% yield: m.p. 165e167 C. H
action was monitored by TLC. After filtration, the filtrate was
evaporated under reduced pressure. Water (20 mL) was added
to the residue, which was then extracted with ethyl acetate
(60 mL ꢁ 3). The extract was washed with saturated NaCl so-
lution (20 mL ꢁ 3), dried over anhydrous Na SO and evapo-
NMR (DMSO-d ): 6.80e7.96 (6H, m, AreH), 7.93, 8.13
6
(
leeCH e), 2.50e3.18 (8H, m, piperazineeH), 2.73e3.16
2H, ss, triazoleeH), 4.52e4.61 (2H, dd, J ¼ 15 Hz, triazo-
2
(
2H, dd, J ¼ 15 Hz, CH epiperazinee), 5.05 (1H, s, OH).
2
2
4
EIMS, m/z: 463 (M þ 1). IR (KBr): 3200, 2940, 2893,
rated. The residue was crystallized from ethyl acetate to afford
ꢂ1
ꢀ
1
a white solid 4 in 75% yield: m.p. 134e135 C. H NMR
1605, 1514, 1338, 1257, 1136, 918 cm . Anal. calcd for
C H F N O : C, 54.54; H, 4.58; N, 18.17. Found: C,
(DMSO-d ): 6.35e7.56 (6H, m, AreH), 7.79, 8.15 (2H, ss, tri-
6
2
1
21
3
6
3
5
4.04; H, 4.55; N, 17.97.
azoleeH), 4.52e4.54 (2H, dd, J ¼ 15 Hz, triazoleeCH e),
2

1230
Q.-Y. Sun et al. / European Journal of Medicinal Chemistry 42 (2007) 1226e1233
2
.49e2.84 (8H, m, piperazineeH), 2.69e3.14 (2H, dd,
CH epiperazinee), 5.22 (1H, s, OH). EIMS, m/z: 555
2
J ¼ 15 Hz, CH epiperazinee), 5.28 (1H, s, OH), 3.52 (2H,
(M þ 1). IR (KBr): 3327, 3126, 2946, 2828, 1662, 1603,
2
ꢂ1
s, NH ). EIMS, m/z: 433 (M þ 1). IR (KBr): 3404, 3212,
1512, 1426, 1272, 1236, 1138, 1012, 966 cm . Anal. calcd
for C H F N O : C, 60.64; H, 4.73; N, 15.15. Found: C,
60.66; H, 4.79; N, 14.98.
2
ꢂ1
3
Anal. calcd for C H F N O: C, 58.33; H, 5.36; N, 19.43.
117, 3053, 2950, 2835, 1616, 1514, 1274, 1139, 965 cm
.
2
8 26 4 6 2
2
1 23 3 6
Found: C, 58.17; H, 5.36; N, 19.19.
6.3.4. Data for 2-chloro-N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
6
.3. General procedure for the preparation of title
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-3-
compounds 5e33
fluoro-phenyl)-benzamide (8)
Yield: 85.5%; m.p. 87e89 C; H NMR (DMSO-d6):
6.81e7.92 (10H, m, AreH), 7.78, 8.14 (2H, ss, triazoleeH),
ꢀ
1
To a stirred mixture of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-di-
fluorophenyl)-3-[4-(2-fluoro-4-amino-phenyl)-piperazin-1-yl]-
4.50e4.58 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.52e2.95
2
propan-2-ol (4) (0.001 mol) DMAP (100 mg) and EDCI
ꢀ
(8H, m, piperazineeH), 2.71e3.16 (2H, dd, J ¼ 15 Hz,
(
200 mg) in 50 mL dichloromethane under 0 C and
CH epiperazinee), 5.23 (1H, s, OH). EIMS, m/z: 571
2
substituted benzoic acid (0.001 mol) were added and stirred
for 8e12 h. The reaction was monitored by TLC. After filtra-
tion, the filtrate was evaporated under reduced pressure. The
residue was then extracted with ethyl acetate (60 mL ꢁ 3).
The extract was washed with saturated NaCl solution
(M þ 1). IR (KBr): 3311, 3070, 2954, 2833, 1704, 1673,
ꢂ1
1601, 1513, 1324, 1139, 964 cm . Anal. calcd for
C H ClF N O : C, 58.90; H, 4.59; N, 14.72. Found: C,
58.82; H, 4.67; N, 14.81.
2
8
26
3 6 2
(
20 mL ꢁ 3), dried over anhydrous Na SO and evaporated.
6.3.5. Data for 3-chloro-N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-3-
fluoro-phenyl)-benzamide (9)
2
4
The residue was crystallized from ethyl acetate to afford the
title compounds 5e33.
The title compounds 5e33 were characterized as follows.
ꢀ
1
Yield: 82.8%; m.p. 102e104 C; H NMR (DMSO-d ):
6
6.81e7.82 (10H, m, AreH), 7.79, 8.15 (2H, ss, triazoleeH),
6
3
.3.1. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-hydroxy-
-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-3-fluoro-
4.51e4.59 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.54e2.96
2
(8H, m, piperazineeH), 2.76e3.17 (2H, dd, J ¼ 15 Hz,
phenyl)-benzamide (5)
CH epiperazinee). EIMS, m/z: 571 (M þ 1). IR (KBr):
2
ꢀ
1
Yield: 85.6%; m.p. 157e158 C; H NMR (DMSO-d ):
3310, 3070, 2953, 2882, 2822, 1703, 1673, 1601, 1513,
.
6
ꢂ1
6
4
.83e7.84 (11H, m, AreH), 7.80, 8.15 (2H, ss, triazoleeH),
.50e4.58 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.52e2.95
1324, 1224, 1139, 964 cm
Anal. calcd for
C H ClF N O : C, 58.90; H, 4.59; N, 14.72. Found: C,
28 26 3 6 2
58.74; H, 4.72; N, 14.85.
2
(
8H, m, piperazineeH), 2.71e3.16 (2H, dd, J ¼ 15 Hz,
CH epiperazinee), 5.23 (1H, s, OH). EIMS, m/z: 537
2
(
M þ 1). IR (KBr): 3375, 3122, 2949, 2820, 1655, 1527,
6.3.6. Data for 4-chloro-N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-3-
fluoro-phenyl)-benzamide (10)
ꢂ1
1
C, 62.68; H, 5.07; N, 15.66. Found: C, 62.68; H, 5.08; N,
1
425, 1272, 1139, 965 cm . Anal. calcd for C H F N O :
2
8 27 3 6 2
ꢀ
1
5.54.
Yield: 87.5%; m.p. 188e190 C; H NMR (DMSO-d ):
6
6.82e7.79 (10H, m, AreH), 7.80, 8.15 (2H, ss, triazoleeH),
6
3
.3.2. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-hydroxy-
-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-3-fluoro-
4.53e4.56 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.52e2.95
2
(8H, m, piperazineeH), 2.71e3.13 (2H, dd, J ¼ 15 Hz,
phenyl)-2-fluoro-benzamide (6)
CH epiperazinee), 5.23 (1H, s, OH). EIMS, m/z: 571
2
ꢀ
1
Yield: 87.4%; m.p. 179e180 C; H NMR (DMSO-d ):
(M þ 1). IR (KBr): 3336, 3132, 2950, 2830, 1645, 1594,
6
ꢂ1
6
4
.80e8.31 (10H, m, AreH), 7.77, 8.16 (2H, ss, triazoleeH),
.54e4.62 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.62e3.01
1511, 1414, 1269, 1140, 1015, 966 cm . Anal. calcd for
C H ClF N O : C, 58.90; H, 4.59; N, 14.72. Found:
C, 58.78; H, 4.59; N, 14.67.
2
28 26
3 6 2
(
8H, m, piperazineeH), 2.77e3.21 (2H, dd, J ¼ 15 Hz,
CH epiperazinee). EIMS, m/z: 555 (M þ 1). IR (KBr):
2
3
1
393, 3117, 2958, 2828, 1655, 1532, 1423, 1382, 1238,
138, 1012, 965, 752 cm . Anal. calcd for C H F N O :
6.3.7. Data for 2,4-dichloro-N-(4-{4-[2-(2,4-difluoro-phe-
nyl)-2-hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-
1-yl}-3-fluoro-phenyl)-benzamide (11)
ꢂ1
2
8 26 4 6 2
C, 60.64; H, 4.73; N, 15.15. Found: C, 60.72; H, 4.73; N,
1
ꢀ
1
5.04.
Yield: 88.4%; m.p. 99e101 C; H NMR (DMSO-d6):
.81e7.82 (9H, m, AreH), 7.80, 8.14 (2H, ss, triazoleeH),
6
6
3
.3.3. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-hydroxy-
-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-3-fluoro-
4.50e4.58 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.52e3.01
2
(8H, m, piperazineeH), 2.71e3.16 (2H, dd, J ¼ 15 Hz,
phenyl)-4-fluoro-benzamide (7)
Yield: 86.2%; m.p. 158e159 C; H NMR (DMSO-d ):
CH epiperazinee), 5.21 (1H, s, OH). EIMS, m/z: 605
2
ꢀ
1
(M þ 1). IR (KBr): 3204, 3100, 2942, 2825, 1651, 1586,
6
ꢂ1
6
4
.81e7.86 (10H, m, AreH), 7.80, 8.15 (2H, ss, triazoleeH),
.51e4.58 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.52e2.95
1512, 1382, 1252, 1137, 965 cm
.
Anal. calcd for
C H Cl F N O : C, 55.55; H, 4.16; N, 13.88. Found:
28 25 2 3 6 2
C, 55.38; H, 4.19; N, 13.74.
2
(
8H, m, piperazineeH), 2.71e3.16 (2H, dd, J ¼ 15 Hz,

Q.-Y. Sun et al. / European Journal of Medicinal Chemistry 42 (2007) 1226e1233
1231
6
.3.8. Data for 2-bromo-N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
4.54e4.55 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.52e2.95
2
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-3-
fluoro-phenyl)-benzamide (12)
(8H, m, piperazineeH), 2.74e3.16 (2H, dd, J ¼ 15 Hz,
CH epiperazinee), 5.23 (1H, s, OH), 2.42 (3H, s, eCH ).
2
3
ꢀ
1
Yield: 81.2%; m.p. 94e96 C; H NMR (DMSO-d6):
.81e7.70 (10H, m, AreH), 7.78, 8.14 (2H, ss, triazoleeH),
EIMS, m/z: 551 (M þ 1). IR (KBr): 3355, 3137, 2947, 2822,
ꢂ1
6
4
1655, 1513, 1269, 1140, 967 cm
.
Anal. calcd for
.50e4.58 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.52e2.95
C H F N O : C, 63.26; H, 5.31; N, 15.26. Found: C,
29 29 3 6 2
63.22; H, 5.29; N, 15.20.
2
(
8H, m, piperazineeH), 2.71e3.16 (2H, dd, J ¼ 15 Hz,
CH epiperazinee), 5.22 (1H, s, OH). EIMS, m/z: 615
2
(
M þ 1). IR (KBr): 3309, 3070, 2953, 2881, 2835, 1703,
6.3.13. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-3-
fluoro-phenyl)-3-trifluoromethyl-benzamide (17)
ꢂ1
1
C H BrF N O : C, 54.64; H, 4.26; N, 13.66. Found: C,
5
673, 1601, 1514, 1324, 1139, 964 cm . Anal. calcd for
2
8
26
3 6 2
ꢀ
1
4.47; H, 4.35; N, 13.48.
Yield: 82.8%; m.p. 128e130 C; H NMR (DMSO-d ):
6
6.83e8.09 (10H, m, AreH), 7.79, 8.15 (2H, ss, triazoleeH),
6
.3.9. Data for 3-bromo-N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
4.51e4.59 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.54e2.96
2
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-3-
fluoro-phenyl)-benzamide (13)
(8H, m, piperazineeH), 2.72e3.17 (2H, dd, J ¼ 15 Hz,
CH epiperazinee), 5.22 (1H, s, OH). EIMS, m/z: 605
2
ꢀ
1
Yield: 83.6%; m.p. 126e128 C; H NMR (DMSO-d ):
(M þ 1). IR (KBr): 3279, 3109, 2952, 2826, 1741, 1659,
6
ꢂ1
6
4
.81e7.97 (10H, m, AreH), 7.79, 8.15 (2H, ss, triazoleeH),
.51e4.59 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.53e2.96
1616, 1512, 1426, 1335, 1250, 1139, 966 cm . Anal. calcd
for C H F N O : C, 57.62; H, 4.33; N, 13.90. Found: C,
57.51; H, 4.41; N, 13.89.
2
29 26 6 6 2
(
8H, m, piperazineeH), 2.72e3.17 (2H, dd, J ¼ 15 Hz,
CH epiperazinee), 5.23 (1H, s, OH). EIMS, m/z: 615
2
(
M þ 1). IR (KBr): 3276, 3108, 2946, 2821, 1655, 1601,
6.3.14. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-
3-fluoro-phenyl)-2,4-dimethyl-benzamide (18)
ꢂ1
1
C H BrF N O : C, 54.64; H, 4.26; N, 13.66. Found: C,
5
511, 1428, 1249, 1139, 1011, 966 cm . Anal. calcd for
2
8
26
3 6 2
ꢀ
1
4.40; H, 4.29; N, 13.52.
Yield: 76.8%; m.p. 92e93 C; H NMR (DMSO-d6):
.83e7.58 (9H, m, AreH), 7.79, 8.15 (2H, ss, triazoleeH),
6
6
3
.3.10. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-hydroxy-
-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-3-fluoro-
4.51e4.55 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.52e2.94
2
(8H, m, piperazineeH), 2.71e3.16 (2H, dd, J ¼ 15 Hz,
CH epiperazinee), 5.23 (1H, s, OH), 2.35 (6H, s, eCH ),
phenyl)-2-methyl-benzamide (14)
2
3
ꢀ
1
Yield: 79.3%; m.p. 74e76 C; H NMR (DMSO-d6):
.83e7.57 (10H, m, AreH), 7.79, 8.15 (2H, ss, triazoleeH),
2.46 (6H, s, eCH ). EIMS, m/z: 565 (M þ 1). IR (KBr):
3
6
4
3311, 3069, 2932, 2836, 1705, 1674, 1596, 1513, 1318,
1252, 1141, 966 cm . Anal. calcd for C H F N O : C,
63.82; H, 5.53; N, 14.88. Found: C, 63.74; H, 5.62; N, 14.74.
ꢂ1
.53e4.55 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.52e2.94
2
30 31 3 6 2
(
8H, m, piperazineeH), 2.74e3.16 (2H, dd, J ¼ 15 Hz,
CH epiperazinee), 5.22 (1H, s, OH), 2.49 (3H, s, eCH ).
2
3
EIMS, m/z: 551 (M þ 1). IR (KBr): 3311, 2953, 2821, 1702,
6.3.15. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-
3-fluoro-phenyl)-3,4-dimethyl-benzamide (19)
ꢂ1
1672, 1596, 1513, 1321, 1286, 1139, 965 cm . Anal. calcd
for C H F N O : C, 63.26; H, 5.31; N, 15.26. Found: C,
2
9 29 3 6 2
ꢀ
1
6
3.21; H, 5.41; N, 15.41.
Yield: 77.2%; m.p. 73e75 C; H NMR (DMSO-d6):
.80e7.74 (9H, m, AreH), 7.80, 8.15 (2H, ss, triazoleeH),
6
6
.3.11. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
4.51e4.55 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.52e2.95
2
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-
3
(8H, m, piperazineeH), 2.71e3.16 (2H, dd, J ¼ 15 Hz,
-fluoro-phenyl)-3-methyl-benzamide (15)
CH epiperazinee), 5.23 (1H, s, OH), 2.32 (6H, s, 2CH ).
2
3
ꢀ
1
Yield: 78.5%; m.p. 167e169 C; H NMR (DMSO-d ):
EIMS, m/z: 565 (M þ 1). IR (KBr): 3331, 3071, 2938, 2821,
6
ꢂ1
6
4
.82e7.75 (10H, m, AreH), 7.79, 8.15 (2H, ss, triazoleeH),
.51e4.59 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.53e2.96
1709, 1679, 1615, 1593, 1510, 1284, 1141, 966 cm . Anal.
calcd for C H F N O : C, 63.82; H, 5.53; N, 14.88. Found:
C, 63.86; H, 5.57; N, 14.79.
2
30 31 3 6 2
(
8H, m, piperazineeH), 2.72e3.17 (2H, dd, J ¼ 15 Hz,
CH epiperazinee), 5.23 (1H, s, OH), 2.42 (3H, s, eCH ).
2
3
EIMS, m/z: 551 (M þ 1). IR (KBr): 3373, 3112, 2963, 2828,
6.3.16. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-
3-fluoro-phenyl)-4-ethyl-benzamide (20)
ꢂ1
1645, 1588, 1523, 1420, 1272, 1137, 1015, 966 cm . Anal.
calcd for C H F N O : C, 63.26; H, 5.31; N, 15.26. Found:
C, 63.23; H, 5.28; N, 15.25.
2
9 29 3 6 2
ꢀ
1
Yield: 74.5%; m.p. 165e167 C; H NMR (DMSO-d ):
6
6.81e7.76 (10H, m, AreH), 7.79,8.15 (2H, ss, triazoleeH),
6
.3.12. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
4.51e4.58 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.52e2.94
2
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-
3
(8H, m, piperazineeH), 2.72e3.16 (2H, dd, J ¼ 15 Hz,
CH epiperazinee), 1.24e1.28 (3H, t, CH ), 2.69e2.71 (2H,
-fluoro-phenyl)-4-methyl-benzamide (16)
2
3
ꢀ
1
Yield: 77.6%; m.p. 174e175 C; H NMR (DMSO-d ):
m, CH ). EIMS, m/z: 565 (M þ 1). IR (KBr): 3356, 3135,
6
2
ꢂ1
6
.81e7.74 (10H, m, AreH), 7.80, 8.15 (2H, ss, triazoleeH),
2965, 2834, 1649, 1513, 1417, 1269, 1140, 1015, 966 cm
.

1232
Q.-Y. Sun et al. / European Journal of Medicinal Chemistry 42 (2007) 1226e1233
Anal. calcd for C H F N O : C, 63.82; H, 5.53; N, 14.88.
3
Found: C, 63.94; H, 5.54; N, 14.92.
6.3.21. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-
0 31 3 6 2
3
-fluoro-phenyl)-4-pentyl-benzamide (25)
Yield: 68.5%; m.p. 174e175 C; H NMR (DMSO-d ):
ꢀ
1
6
.3.17. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
6
6
4
.81e7.75 (10H, m, AreH), 7.79, 8.15 (2H, ss, triazoleeH),
.51e4.59 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.54e2.95
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-
3
-fluoro-phenyl)-4-propyl-benzamide (21)
2
ꢀ
1
(8H, m, piperazineeH), 2.75e3.17 (2H, dd, J ¼ 15 Hz,
CH epiperazinee), 0.87e0.90 (3H, t, CH ), 2.64e2.67 (2H,
m, CH ), 1.29e1.33 (4H, m, CH ), 1.60e1.66 (2H, m,
Yield: 70.8%; m.p. 166e167 C; H NMR (DMSO-d ):
6
6
4
.81e7.75 (10H, m, AreH), 7.79, 8.15 (2H, ss, triazoleeH),
.51e4.58 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.52e2.94
2
3
2
2
2
CH ). EIMS, m/z: 607 (M þ 1). IR (KBr): 3434, 3130, 2929,
(
8H, m, piperazineeH), 2.71e3.16 (2H, dd, J ¼ 15 Hz,
2
ꢂ1
2827, 1667, 1615, 1513, 1424, 1274, 1139, 1013, 967 cm
Anal. calcd for C H F N O : C, 65.33; H, 6.15; N, 13.85.
.
CH epiperazinee), 0.93e0.96 (3H, t, CH ), 2.63e2.66 (2H,
2
3
m, CH ), 1.64e1.68 (2H, m, CH ), 5.23 (1H, s, OH). EIMS,
2
33 37 3 6 2
2
Found: C, 65.38; H, 6.19; N, 13.77.
m/z: 579 (M þ 1). IR (KBr): 3356, 3049, 2947, 2836, 1650,
ꢂ1
1511, 1417, 1269, 1138, 1015, 966 cm . Anal. calcd for
C H F N O : C, 64.35; H, 5.75; N, 14.52. Found: C,
3
1 33 3 6 2
6
4.29; H, 5.66; N, 14.41.
6.3.22. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-
6
.3.18. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
3
-fluoro-phenyl)-2-methoxy-benzamide (26)
Yield: 70.2%; m.p. 165e167 C; H NMR (DMSO-d ):
ꢀ
1
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-
6
3
-fluoro-phenyl)-4-isopropyl-benzamide (22)
Yield: 71.8%; m.p. 160e161 C; H NMR (DMSO-d ):
6
.83e8.27 (10H, m, AreH), 7.80, 8.15 (2H, ss, triazoleeH),
ꢀ
1
6
4.51e4.58 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.52e2.95
2
6
4
.82e7.78 (10H, m, AreH), 7.75, 8.16 (2H, ss, triazoleeH),
.54 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.54e2.98 (8H,
(
8H, m, piperazineeH), 2.71e3.16 (2H, dd, J ¼ 15 Hz,
2
CH epiperazinee), 5.24 (1H, s, OH), 4.05 (3H, s, eOCH ).
2
3
m, piperazineeH), 2.68e3.16 (2H, dd, J ¼ 15 Hz, CH epiper-
2
EIMS, m/z: 567 (M þ 1). IR (KBr): 3352, 3131, 2832, 1670,
ꢂ1
azinee), 1.26e1.27 (6H, d, CH ), 2.95e2.97 (1H, m, CH).
3
1595, 1509, 1242, 1137, 1048, 963 cm . Anal. calcd for
C H F N O : C, 61.48; H, 5.16; N, 14.83. Found: C,
EIMS, m/z: 579 (M þ 1). IR (KBr): 3375, 3139, 2960, 2829,
2
9 29 3 6 3
ꢂ1
1651, 1512, 1418, 1269, 1140, 1015, 966 cm . Anal. calcd
for C H F N O : C, 64.35; H, 5.75; N, 14.52. Found: C,
61.50; H, 5.24; N, 14.84.
3
1 33 3 6 2
6
4.34; H, 5.77; N, 14.47.
6
.3.23. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
6
.3.19. Data for 4-butyl-N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-3-
fluoro-phenyl)-benzamide (23)
3-fluoro-phenyl)-3-methoxy-benzamide (27)
ꢀ
Yield: 68.8%; m.p. 149e151 C; H NMR (DMSO-d ):
6
1
ꢀ
1
Yield: 72.5%; m.p. 139e141 C; H NMR (DMSO-d ):
6
6
4
.81e7.71 (10H, m, AreH), 7.80, 8.15 (2H, ss, triazoleeH),
.51e4.58 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.52e2.95
6
4
.81e7.75 (10H, m, AreH), 7.80, 8.15 (2H, ss, triazoleeH),
.51e4.58 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.52e2.94
2
2
(
8H, m, piperazineeH), 2.71e3.16 (2H, dd, J ¼ 15 Hz,
(
8H, m, piperazineeH), 2.71e3.16 (2H, dd, J ¼ 15 Hz,
2 3
CH epiperazinee), 5.23 (1H, s, OH), 3.86 (3H, s, eOCH ).
2
3
CH epiperazinee), 0.91e0.94 (3H, t, CH ), 2.65e2.71 (2H,
m, CH ), 1.32e1.39 (2H, m, CH ), 1.58e1.64 (2H, m,
EIMS, m/z: 567 (M þ 1). IR (KBr): 3445, 3394, 3135, 2951,
2
2
ꢂ1
2
827, 1663, 1594, 1424, 1258, 1139, 1041, 967 cm . Anal.
CH ). EIMS, m/z: 593 (M þ 1). IR (KBr): 3377, 3134, 2933,
2
ꢂ1
calcd for C29H F N O : C, 61.48; H, 5.16; N, 14.83. Found:
29 3 6 3
C, 61.61; H, 5.18; N, 14.68.
2825, 1655, 1513, 1424, 1249, 1139, 1015, 966 cm . Anal.
calcd for C H F N O : C, 64.85; H, 5.95; N, 14.18. Found:
C, 65.01; H, 5.98; N, 14.06.
3
2 35 3 6 2
6
.3.20. Data for 4-tert-butyl-N-(4-{4-[2-(2,4-difluoro-
6.3.24. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-
3-fluoro-phenyl)-4-methoxy-benzamide (28)
phenyl)-2-hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-
piperazin-1-yl}-3-fluoro-phenyl)-benzamide (24)
ꢀ
1
ꢀ
1
Yield: 71.3%; m.p. 187e188 C; H NMR (DMSO-d ):
Yield: 67.8%; m.p. 173e175 C; H NMR (DMSO-d ):
6
6
6
.81e7.78 (10H, m, AreH), 7.80, 8.15 (2H, ss, triazolee
6.81e7.81 (10H, m, AreH), 7.80, 8.15 (2H, ss, triazoleeH),
4.53e4.55 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.52e2.94
H), 4.54e4.55 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.52e
2
2
2
.95 (8H, m, piperazineeH), 2.71e3.16 (2H, dd,
(8H, m, piperazineeH), 2.71e3.16 (2H, dd, J ¼ 15 Hz,
J ¼ 15 Hz, CH epiperazinee), 1.34 (9H, s, CH ). EIMS,
CH epiperazinee), 5.23 (1H, s, OH), 3.86 (3H, s, eOCH ).
2
3
2
3
m/z: 593 (M þ 1). IR (KBr): 3283, 2961, 2828, 1663, 1607,
EIMS, m/z: 567 (M þ 1). IR (KBr): 3371, 3137, 2949, 2835,
ꢂ1
ꢂ1
1
513, 1271, 1133, 964 cm
.
C H F N O : C, 64.85; H, 5.95; N, 14.18. Found:
Anal. calcd for
1657, 1606, 1514, 1245, 1139, 968 cm . Anal. calcd for
C H F N O : C, 61.48; H, 5.16; N, 14.83. Found: C,
61.57; H, 5.16; N, 14.89.
3
2
35
3
6
2
29 29 3 6 3
C, 64.76; H, 5.99; N, 14.09.

Q.-Y. Sun et al. / European Journal of Medicinal Chemistry 42 (2007) 1226e1233
1233
6
.3.25. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
(M þ 1). IR (KBr): 3244, 3115, 2944, 2820, 1681, 1601,
ꢂ1
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-
3
1510, 1349, 1272, 1139, 1012, 965, 899 cm . Anal. calcd
for C H F N O : C, 57.83; H, 4.51; N, 16.86. Found: C,
57.86; H, 4.55; N, 16.77.
-fluoro-phenyl)-4-trifluoromethoxy-benzamide (29)
2
8 26 3 7 4
ꢀ
1
Yield: 80.5%; m.p. 203e205 C; H NMR (DMSO-d ):
6
6
4
.81e7.89 (10H, m, AreH), 7.80, 8.15 (2H, ss, triazoleeH),
.51e4.58 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.52e2.95
2
6.3.29. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
(
8H, m, piperazineeH), 2.71e3.16 (2H, dd, J ¼ 15 Hz,
2
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-
CH epiperazinee), 5.23 (1H, s, OH). EIMS, m/z: 621
3
-fluoro-phenyl)-4-nitro-benzamide (33)
(
1
5
M þ 1). IR (KBr): 3348, 3136, 2948, 2832, 1651, 1512,
ꢀ
Yield: 80.8%; m.p. 133e135 C; H NMR (DMSO-d ):
6
1
ꢂ1
250, 1168, 967 cm . Anal. calcd for C H F N O : C,
9 26 6 6 3
2
6
4
.35e7.56 (10H, m, AreH), 7.79, 8.15 (2H, ss, triazoleeH),
.50e4.57 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.49e2.84
6.13; H, 4.22; N, 13.54. Found: C, 56.15; H, 4.25; N, 13.43.
2
(
8H, m, piperazineeH), 2.69e3.14 (2H, dd, J ¼ 15 Hz,
6
.3.26. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
CH epiperazinee), 5.28 (1H, s, OH). EIMS, m/z: 582
2
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-
3
(
M þ 1). IR (KBr): 3403, 3211, 2951, 2835, 1616, 1514,
-fluoro-phenyl)-3,4-dimethoxy-benzamide (30)
ꢂ1
ꢀ
1
1275, 1165, 965 cm . Anal. calcd for C28
H
26
F
3
N
7
O
4
: C,
7.83; H, 4.51; N, 16.86. Found: C, 57.74; H, 4.56; N, 16.79.
Yield: 68.9%; m.p. 168e169 C; H NMR (DMSO-d ):
6
5
6
4
.83e7.72 (9H, m, AreH), 7.80, 8.15 (2H, ss, triazoleeH),
.51e4.58 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.52e2.95
2
(
8H, m, piperazineeH), 2.71e3.16 (2H, dd, J ¼ 15 Hz,
2 3
Acknowledgements
CH epiperazinee), 5.23 (1H, s, OH), 3.94 (6H, s, OCH ).
EIMS, m/z: 597 (M þ 1). IR (KBr): 3369, 3111, 2955, 2828,
We wish to express our thanks to the National Natural &
Science Foundation of China (Grant No. 30300437) for finan-
cial support.
ꢂ1
1647, 1583, 1514, 1383, 1223, 1137, 1019, 810 cm . Anal.
calcd for C H F N O : C, 60.40; H, 5.24; N, 14.09. Found:
C, 60.51; H, 5.26; N, 13.98.
3
0 31 3 6 4
References
6
.3.27. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-
[
1] S.K. Fridkin, W.R. Jarvis, Clin. Microbiol. Rev. 9 (1996) 499e511.
2] J.R. Wingard, H. Leather, Biol. Blood Marrow Transplant. 10 (2004)
3
-fluoro-phenyl)-3,4,5-trimethoxy-benzamide (31)
Yield: 65.8%; m.p. 106e108 C; H NMR (DMSO-d ):
[
ꢀ
1
6
73e90.
3] P. Kale, L.B. Johnson, Drugs Today 41 (2005) 91e105.
6
4
.81e7.76 (9H, m, AreH), 7.79, 8.15 (2H, ss, triazoleeH),
.51e4.60 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.56e2.99
[
[4] P.H. Chandrasekar, E. Manavathu, Drugs Today 37 (2001) 135e148.
[
2
5] A. Chen, J.D. Sobel, Expert Opin. Emerg. Drugs 10 (2005) 21e33.
6] S. Sundriyal, R.K. Sharma, R. Jain, Curr. Med. Chem. 13 (2006) 1321e
(
8H, m, piperazineeH), 2.74e3.19 (2H, dd, J ¼ 15 Hz,
2 3
[
CH epiperazinee), 3.89e3.91 (9H, m, OCH ). EIMS, m/z:
1335.
7] H. Ji, W. Zhang, Y. Zhou, M. Zhang, J. Zhu, Y. Song, J. Lu, J. Med.
Chem. 43 (2000) 2493e2505.
6
1
27 (M þ 1). IR (KBr): 3289, 2941, 2833, 1586, 1510, 1418,
[
ꢂ1
333, 1225, 1128, 1010, 966 cm
. Anal. calcd for
C H F N O : C, 59.42; H, 5.31; N, 13.41. Found: C,
3
[8] D.F. Lewis, A. Wiseman, M.H. Tarbit, J. Enzym. Inhib. 14 (1999)
75e192.
9] K. Richardson, USP: 4404216, 1983.
1 33 3 6 5
1
5
9.34; H, 5.37; N, 13.39.
[
[
[
[
[
10] J. Yang, L. Liu, X. Wang, J. Lu, C. Sun, H. Zhang, Y. Zhou, Z. Zhang,
Yiyao Gongye 5 (1984) 1e4.
6
.3.28. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-
hydroxy-3-[1H-1,2,4]triazol-1-yl-propyl]-piperazin-1-yl}-
3
11] D.K. Hutchinson, M.R. Barbachyn, S.J. Brickner, R.B. Gammill, M.V.
Patel, USP: 880432, 1996.
-fluoro-phenyl)-2-nitro-benzamide (32)
ꢀ
1
12] Q. Sun, C. Liu, Q. Wu, D. Zhang, Y. Cao, Y. Jiang, H. Zhao, Zhongguo
Yaowu Huaxue Zazhi 14 (2004) 14e18.
Yield: 78.6%; m.p. 167e169 C; H NMR (DMSO-d ):
6
6
4
.80e8.11 (10H, m, AreH), 7.76, 8.13 (2H, ss, triazoleeH),
.50e4.58 (2H, dd, J ¼ 15 Hz, triazoleeCH e), 2.52e2.95
13] National Committee for Clinical Laboratory Standards Approved stan-
dard, Document M27-A2, Reference Method for Broth Dilution Antifun-
gal Susceptibility Testing of Yeasts, National Committee for Clinical
Laboratory Standards, Wayne, PA, 2002.
2
(
8H, m, piperazineeH), 2.71e3.16 (2H, dd, J ¼ 15 Hz,
2
CH epiperazinee), 5.22 (1H, s, OH). EIMS, m/z: 582