4,5-Diphenyltriazol-3-ones: Openers of large-conductance Ca2+-activated potassium (maxi-K) channels

Article abstract of DOI:10.1021/jm010569q

A series of diphenyl-substituted heterocycles were synthesized and evaluated by electrophysiological techniques as openers of the cloned mammalian large-conductance, Ca²⁺-activated potassium (maxi-K) channel. The series was designed from deannu

Full text of DOI:10.1021/jm010569q

2942
J . Med. Chem. 2002, 45, 2942-2952
4,5-Dip h en yltr ia zol-3-on es: Op en er s of La r ge-Con d u cta n ce Ca 2+-Activa ted
P ota ssiu m (Ma xi-K) Ch a n n els
J effrey L. Romine,*,† Scott W. Martin,† Valentin K. Gribkoff,‡ Christopher G. Boissard,‡ Steven I. Dworetzky,‡
J oanne Natale,‡ Yi Li,§ Qi Gao,| Nicholas A. Meanwell,† and J ohn E. Starrett, J r.†
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, Connecticut 06492
Received December 17, 2001
A series of diphenyl-substituted heterocycles were synthesized and evaluated by electrophysi-
ological techniques as openers of the cloned mammalian large-conductance, Ca2+-activated
potassium (maxi-K) channel. The series was designed from deannulation of known benzimi-
dazolone maxi-K opener NS-004 (2) thereby providing an effective template for obtaining
structure-activity-related information. The triazolone ring system was the most studied
wherein 4,5-diphenyltriazol-3-one 6d (maxi-K ) 158%) was identified as the optimal maxi-K
channel opener.
In tr od u ction
heterocycle were important to the pharmacophore and
revealed that the inserted methylene unit was well-
tolerated.19 Similarly, electron deficient 3-hydroxyox-
indoles have also demonstrated significant increases in
maxi-K current expressed in ooyctes,22 and the develop-
ment of a pharmacophore model has led to identification
of flavanoids as maxi-K openers.23
In an effort to further explore and develop maxi-K
opener chemotypes, we sought to deannulate the ben-
zimidazolone ring system (Figure 1) to the 4,5-diphenyl
heterocyclic system 5 (n ) 0), and homologue (n ) 1),
and examine this area of the pharmacophore by sys-
tematic variation of the heterocyclic nucleus.
Potassium (K+) channels are a widely distributed and
structurally diverse family of membrane-spanning pro-
teins that play important roles in cell function.1-3 In
nerve and muscle, these channels serve to modulate
cellular excitability through the regulation of K+ ion
homeostasis and its effects on membrane potential and
membrane resistance.4-7 Large-conductance, Ca2+-de-
pendent K+ channels (maxi-K or BK channels) shorten
the duration of action potentials and block Ca2+ entry
thereby repolarizing excitable cells after excitation.7-9
Additionally, they are associated with presynaptic ele-
ments where they may regulate transmitter release.10
Hyperpolarization of cell membrane potential leading
to reduction of transmitter release and Ca2+-mediated
excitotoxic cascades by maxi-K channel opening has
been postulated to confer neuroprotection during stroke
and has attracted attention as a means for therapeutic
intervention in asthma, hypertension, convulsions, and
traumatic brain injury among others.7,9,11 Recently, the
fluorooxindole 1 (MaxiPost, Figure 1), a Ca2+-sensitive
opener of maxi-K channels, has demonstrated signifi-
cant neuroprotection in a rat model of permanent
stroke.12
Prototypical maxi-K channel openers, NS-004 (2)13
and NS-16193 (3)14 (Figure 1), were reported to selec-
tively shift the maxi-K channel activation curve toward
less positive membrane potentials in a dose-dependent
manner.15-18 On the basis of the benzimidazolone
template, a series of N-benzylated benzimidazolones 4
(Figure 1) were assessed for their ability to increase
maxi-K-mediated outward K+ current.19 Standard two
electrode voltage clamp recordings were made using
Xenopus laevis oocytes injected with cloned mouse
maxi-K channel mSlo.20,21 Elucidation of structure-
activity relationships (SAR) indicated that electron
deficient substituents on the aromatic ring fused to the
Ch em istr y
A series of triazolones (Table 1) were synthesized as
shown in Scheme 1. Benzanilides, obtained from coup-
ling benzoyl chlorides with anilines, were treated with
phosphorus pentachloride in benzene at reflux to gener-
ate iminoyl chlorides. The iminoyl chlorides were trans-
ferred to a solution of anhydrous hydrazine in tetrahy-
drofuran (THF), and the resultant amidrazones were
cyclized to triazolones after they were stirred with
carbonyldiimidazole.24-26 Subjecting the anisoles to neat
pyridine hydrochloride heated at 225 °C for 1 h liberated
the target phenols 6a -h .27 A regioisomeric triazolone
was secured from the corresponding regioisomeric ben-
zanilide upon exposure to the same reaction sequence
to give 7.
Scheme 2 depicts synthesis of four “methylene-
inserted” triazolone systems 8-11. Although compounds
9-11 were secured via the method above (Scheme 1),
triazolone 8 was more efficiently prepared upon coupling
5-chloro-2-methoxybenzylamine with 5-[4-(trifluoro-
methyl)phenyl]-1,3,4-oxadiazol-2(3H)one28 followed by
cyclization in 1 N sodium hydroxide at reflux.29 An
alternate method of demethylation, boron tribromide in
methylene chloride at 0 °C, was employed in this case
due to instability at the higher temperature.30
* To whom correspondence should be addressed. Tel.: (203)677-
6694. Fax: (203)677-6984. E-mail: rominej@bms.com.
† Department of Chemistry.
The intermediate amidrazone of Scheme 1 above was
readily converted to a series of heterocycles as shown
in Scheme 3. The triazolothione 12 was obtained upon
‡ Department of Neuroscience.
§ Computer-Assisted Drug Discovery.
| Department of Analytical Research and Development.
10.1021/jm010569q CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/24/2002

4,5-Diphenyltriazol-3-ones
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 2943
F igu r e 1. Reference compounds and deannulation concept.
treatment with 1,1′-thiocarbonyldiimidazole in THF,
followed by pyridine hydrochloride, and aminotriazole
13 by reaction with cyanogen bromide in the presence
of sodium bicarbonate prior to boron tribromide de-
methylation. Cyclization with N,N-dimethylformamide
dimethyl acetal gave the triazole ring system 14 after
exposure to pyridine hydrochloride. Alkylation of the
triazolone from 6a with methyl iodide and demethyla-
tion gave N-methylated triazolone 15.
Imidazoles 16 and 17 were synthesized by addition
of dimethylaminoacetaldehyde diethyl acetal to iminoyl
chlorides (Scheme 4). Heating the resultant acetals at
reflux in benzene under Dean-Stark conditions caused
cyclization to the imidazole rings.31 The regioisomeric
imidazole 18 (Scheme 5) was prepared through conden-
sation of 4-trifluoromethylbenzaldehyde with 2-amino-
4-chloroanisole and trapping the resultant imine with
tosylmethylisocyanide (TosMIC) under basic condi-
tions.32,33 Metalation of commercially available 1-(4-
trifluoromethylphenyl)imidazole (BuLi/DMPU) followed
by quenching with 5-chloro-2-methoxybenzaldehyde
gave an alcohol, which was reductively cleaved (trieth-
ylsilane/trifluoroacetyl (TFA)) to provide the homolo-
gated imidazole 19.34
lones. Both 4-hydroxy derivative 6g (maxi-K ) 99%) and
transposed 2-chloro-5-hydroxy analogue 6h (101%) were
found inactive, whereas triazolones 6a ,b,d ,e, with the
appropriately placed ortho phenol, showed channel-
opening properties.
The position of the trifluoromethyl group on the
electron deficient aromatic ring appears less critical for
activity as the meta derivative 6b (maxi-K ) 138% at
30 µmol) retains similar activity. Sensitivity, however,
to this region of the molecule was still somewhat
important as further transposition to the ortho deriva-
tive 6c (maxi-K ) 107%) caused a loss in channel-
opening ability. Substitution of fluorine in place of CF3,
to give the less electron deficient 6e (maxi-K ) 118%),
falls within the standard error for this evaluation, but
removal of electron-withdrawing substituent altogether,
phenyl analogue 6f (maxi-K ) 101%), eliminated chan-
nel opening. Moreover, an increase in electron defi-
ciency, as in bis CF3-substituted compound 6d (maxi-K
) 159%), provided the most effective opener of the series
(Table 1), and a more complete concentration-response
relationship was generated for this compound and is
presented in Figure 2.
Figure 2A depicts current families generated by
voltage steps from a holding potential of -60 to +140
mV in an oocyte expressing cloned maxi-K channels and
shows the large increase in current produced by 6d (50
µM). Compound 6d produced concentration-dependent
increases in maxi-K current (Figure 2B), with an
estimated EC50 of 43 µM (one site logistic fit).
As shown in Scheme 5, trapping the iminoyl chloride
of Scheme 4 with hydroxylamine and exposure to CDI
cyclization gave the oxadiazolone ring system 20.35
Alkylation of 3-[4-(trifluoro)phenyl]-1,2,4-oxzdiazol-
5(4H)one with 5-chloro-2-methoxybenzylbromide (so-
dium hydride/dimethylformamide (DMF)) and subse-
quent demethylation afforded 21.
Thus far, SAR described above parallels that reported
for the N-benzylated analogue 4.19 On the basis of the
observation that the methylene unit was well-tolerated,
the activity observed for the N-benzylated series sug-
gests that some flexibility exists in the binding region
of the channel.19 However, this observation does not
transfer to the deannulated series as seen in compound
8 (maxi-K ) 109%) with the corresponding pattern of
“methylene” insertion. Similarly, neither its regioiso-
meric counterpart 9 (maxi-K ) 84%) nor two other
methylene-inserted analogues, imidazole 19 and oxa-
diazolone 21, were found to possess channel-opening
ability (although the nature of the heterocycle may be
influencing the loss of channel-opening activity for the
latter compounds). Noteworthy, maintaining the origi-
nal spatial distance of the phenolic ring to the hetero-
cycle and inserting the methylene spacer to the electron
deficient phenyl ring causes no decrease in activity for
triazolone 10 (maxi-K ) 125%) or its regioisomeric
counterpart 11 (maxi-K ) 128%). Assuming that both
series of compounds interact at the same site on the
maxi-K channel, these data suggest that it is not
electron deficiency of the heterocyclic ring as imparted
by the aromatic system that is important but rather a
Resu lts a n d Discu ssion
Target compounds of Table 1 were evaluated for their
maxi-K channel opening properties at a concentration
of 20 µM via two-electrode voltage clamp techniques
using Xenopus laevis oocytes with mSlo cRNA injected
2-6 days prior to recording.20,21 The increase in iberi-
otoxin-sensitive outward current (i.e., maxi-K current)
in the presence of the compound is reported as an
average of at least five experiments conducted in
different oocytes.
The viability of deannulation was first evident in the
triazolone 6a (maxi-K ) 121%), which showed compa-
rable channel-opening activity to NS-004 (2; maxi-K )
132%) and NS-1619 (3; maxi-K ) 116%). A study of SAR
about 6a brings out several important relationships
with regard to the phenol, electron deficient aromatic
ring, and heterocycle.
In a discussion on small molecule maxi-K openers by
Starrett et al.,9 a common trend observed among small
molecule openers is that the position of the phenol
relative to the heteroatom portion of the molecule is
important. This also holds true for 4,5-diphenyltriazo-

2944 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Ta ble 1. Analogues of Chemotype and Percent Maxi-K Opening
Romine et al.

4,5-Diphenyltriazol-3-ones
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 2945
Ta ble 1 (Continued)
a
Except where indicated, all compounds were analyzed within (0.4% for C, H, and N. b Outward current in the presence of test compound
(20 µM) as percent of control current. c Evaluated at 30 µM. The poor solubility in the MBS buffer system required for evaluation in
oocytes precluded evaluation.
d
Sch em e 1. Synthesis of 4,5-Diphenyl Triazolones
binding pocket exists, which readily receives the lipo-
philic trifluoromethylated aromatic ring.
of the triazolone openers; compound 6a adopts two
possible conformations as shown in Figure 3. Flanked
by the phenyl ring in two different fashions, the phenol
ring is perpendicular to the heterocycle, giving a dis-
tance of 4.0 Å between the phenol and the carbonyl
oxygens. Structural optimization using Sybyl force field
with the Gasteiger-Hu¨ckel charges resulted in a dif-
ferent conformation for 6a , in which the phenol and
carbonyl oxygens are 4.6 Å apart. Nevertheless, the
energy barrier was found to be small from the energy-
minimized structure to the X-ray conformations. Mo-
lecular modeling studies on regioisomer 7 indicate a
distance of 4.9 Å between the phenol and the carbonyl
oxygens. Although it is possible for the two isomers 6a
and 7 to maintain a similar relationship between the
phenol and the carbonyl groups, a more exact spatial
relationship exists between the oxygen of phenol and
the hydrogen of the “N-H” (5.5 and 5.6 Å) for 6a and 7
Structural recognition elements of the pharmacophore
necessary for maxi-K channel opening may be somewhat
different between the two series (N-benzylation vs 4,5-
diphenyls); however, we were intrigued by the equiva-
lent behavior of compounds 10 and 11. Previous SAR
discussions have placed an emphasis on the relationship
between the phenol and the carbonyl group of the
benzimidazolone ring.9 In this series, however, trans-
position of the carbonyl group as in the regioisomeric
analogues 10 and 11 would suggest that the carbonyl
does not play a critical role. This is also corroborated
by the des-methylene analogues 6a (maxi-K ) 121%)
and regioisomer 7 (maxi-K ) 123%), which also dem-
onstrate equivalent activity.
X-ray analysis and molecular modeling studies pro-
vide further insights into the pharmacophore features

2946 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Sch em e 2. Synthesis of Methylene-Inserted Triazolones
Romine et al.
Sch em e 3. Synthesis of Heterocyclic Analogues
Sch em e 4. Imidazole Synthesis
(maxi-K ) 91%), gives compounds found devoid of
channel-opening activity; thus, it is revealed that a
hydrogen donor on the heterocycle is important to the
pharmacophore.
The triazolothione 12 (maxi-K ) 128%) bearing the
N-H did show good activity as expected; however, two
other compounds, aminotriazole 13 (maxi-K ) 117%)
and imidazole 18 (maxi-K ) 126%), which do not bear
N-H, were also active. We attribute the activity of
compound 13 to a tautomeric resonance contribution,
which places a hydrogen in the critical position on the
heterocycle. Similarly, a small percentage of protonation
at physiological pH due to the increased basicity of the
imidazole ring may account for channel opening in 18.
(Figure 4). These data, in combination with the following
SAR, indicate that the latter relationship is more
important. For instance, removal of both the carbonyl
group and the N-H gives an inactive triazole 14
(maxi-K ) 102%). However, removal of the N-H while
retaining the carbonyl, as in N-methyl derivative 15
(maxi-K ) 93%) or bistrifluoromethyl oxadiazolone 21
Con clu sion
Maxi-K channel-opening activity for a series of 4,5-
diphenyltriazolones is reported. SAR studies suggest a
lipophilic pocket exists adjacent to the binding region
of the channel. Although the 4,5-diphenyl heterocyclic
series follows general SAR trends for small molecule

4,5-Diphenyltriazol-3-ones
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 2947
F igu r e 3. Conformations of 6a determined by X-ray crystal-
lography (CCDC 182907).
F igu r e 4. Overlay of 6a and 7. Molecular modeling studies
were carried out using the Sybyl software from Tripos. Two
regioisomers of the triazolones were energy-minimized with
the Sybyl force fields including the Gasteiger-Hu¨ckel charges.
The optimized structure of 6a was in good agreement with that
of the X-crystallographic structure. The results from a simple
overlay of two structures shown in the figure suggest that the
phenolic hydroxyls of both regioisomers can achieve the same
space orientation and location relative to the acidic amide
moiety.
F igu r e 2. (A) Current families generated by voltage steps.
(B) Dose response for 6d .
Sch em e 5. Imidazoles and Oxadiazolones
Exp er im en ta l Section
Melting points were taken on a Thomas-Hoover capillary
apparatus and are uncorrected. Proton (1H NMR) nuclear
magnetic resonance spectra were recorded on a Bruker AM
FT instrument operating at 300 MHz. Infrared (IR) spectra
were obtained using a Perkin-Elmer 1800 FT IR, scanning
from 4000 to 400 cm-1 and calibrated to the 1601 cm-1
absorption of a polystyrene film. Mass spectral data were
obtained on a Finnigan model 4500 GC/MS using electrical or
chemical ionization (isobutane) procedures. Elemental analy-
ses were provided by Bristol-Myers Squibb’s Analytical Chem-
istry Department through Oneida Research Services, Whites-
boro, NY.
Gen er a l Meth od for th e P r ep a r a tion of Tr ia zolon es.
4-(5-Ch lor o-2-h ydr oxyph en yl)-5-[3,5-bis(tr iflu or om eth yl)-
p h en yl]-2,4-d ih yd r o-3H-1,2,4-tr ia zol-3-on e. (6d ). (a ) To a
solution of 5-chloroanisidine (5.6 g, 36.3 mmol) in THF (350
mL) was added dropwise 3,5-bis(trifluoromethyl)benzoyl chlo-
ride (10.1 g, 36.6 mmol) dissolved in THF (85 mL) under N2
at 0 °C followed by addition of triethylamine (5.3 mL, 38.0
mmol). The reaction mixture was stirred for 18 h at 24 °C,
filtered to remove Et3N‚HCl, and concentrated to give a white
solid (13.08 g, 90%). An analytical sample was obtained as
colorless needles after the sample was recrystallized from
ethanol/water (2:1); mp 151-153 °C. IR (KBr): 3298, 1654,
1
1534, 1292, 1276, 1188, 1136, 804 cm-1. H NMR (DMSO-d6):
δ 3.83 (3H, s), 7.13 (1H, d, J ) 8.9 Hz), 7.26 (1H, dd, J ) 8.8
Hz, 2.7 Hz), 7.76 (1H, d, J ) 2.6 Hz), 8.33 (1H, br.s), 8.56 (2H,
br.s), 10.25 (1H, br.s). MS m/z: 398 (MH+). Anal. (C16H10ClF6-
NO2) C, H, N.
(b) N-(5-Chloro-2-methoxyphenyl)-3,5-bis(trifluoromethyl)-
benzamide (8 g, 20.1 mmol) was taken up in benzene (100 mL)
under N2, and phosphorus pentachloride (4.6 g, 22.1 mmol)
was added. The solution was heated at reflux for 3 h. After it
was concentrated to remove POCl3, the residue was taken up
maxi-K openers, the presence of a hydrogen donor on
the heterocyclic ring and its spatial relationship to the
ortho phenol were found paramount for maxi-K channel
activity.

2948 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Romine et al.
in THF (165 mL) and cannulated dropwise into a stirred THF
(165 mL) solution of anhydrous hydrazine (6.4 mL) at 0 °C
under N2. The reaction mixture was stirred for 1 h at 24 °C
and poured into water (200 mL) and extracted with ethyl
acetate, and the organic phase was washed with brine and
dried (Na2SO4) to give 7.69 g (93%); mp 117-120 °C. IR
(KBr): 3339, 3252, 1591, 1510, 1384, 1284, 1255, 1182, 1128
) 2.6 Hz), 10.31 (1H, s), 12.07 (1H, s). MS m/z: 288 (MH+).
Anal. (C14H10ClN3O2) C, H, N.
4-(3-Ch lor o-4-h yd r oxyp h en yl)-5-[4-(t r iflu or om et h yl)-
p h en yl]-2,4-d ih yd r o-3H-1,2,4-tr ia zol-3-on e (6g). mp 260-
262 °C. IR (KBr): 3170, 1710, 1502, 1326, 1136 cm-1. 1H NMR
(DMSO-d6): δ 6.99 (1H, d, J ) 8.6 Hz), 7.05 (1H, dd, J ) 8.6
Hz, 2.3 Hz), 7.44 (1H, d, J ) 2.3 Hz), 7.52 (2H, d, J ) 8.1 Hz),
7.76 (2H, d, J ) 8.2 Hz), 10.66 (1H, s), 12.29 (1H, s). MS m/z:
356 (MH+). Anal. (C15H9ClF3N3O2) C, H, N.
4-(2-Ch lor o-5-h yd r oxyp h en yl)-5-[4-(t r iflu or om et h yl)-
p h en yl]-2,4-d ih yd r o-3H-1,2,4-tr ia zol-3-on e (6h ). mp 283-
284 °C. IR (KBr): 3222, 1702, 1486, 1326, 1120 cm-1. 1H NMR
(DMSO-d6): δ 6.93 (1H, dd, J ) 8.8 Hz, 2.9 Hz), 7.02 (1H, d,
J ) 2.8 Hz), 7.40 (1H, d, J ) 8.8 Hz), 7.51 (2H, d, J ) 8.3 Hz),
7.75 (2H, d, J ) 8.4 Hz), 10.20 (1H, s), 12.38 (1H, s). MS m/z:
356 (MH+). Anal. (C15H9ClF3N3O2) C, H, N.
cm-1 1H NMR (CDCl3): δ 3.93 (3H, s), 5.66 (2H, br.s), 5.94
.
(1H, br.s), 6.25-6.26 (1H, m), 6.77-6.84 (2H, m), 7.78 (1H, s),
8.01 (2H, s). MS m/z: 412 (MH+). Anal. (C16H12ClF6N3O) C,
H, N.
(c) N-(5-Chloro-2-methoxyphenyl)-3,5-bis(trifluoromethyl)-
benzene carbohydrazonamide (4 g, 9.7 mmol) was taken up in
THF (600 mL) under N2, and 1,1′-carbonyldiimidazole (1.9 g,
11.72 mmol) was added. The solution was stirred for 18 h at
24 °C. After it was concentrated, the residue was taken up in
ethyl acetate and washed with 0.1 N HCl solution, water, and
brine prior to drying (MgSO4). Recrystallization from aceto-
nitrile gave 2.92 g (68.6%); mp 205.5-207 °C. IR (KBr): 3170,
5-(5-Ch lor o-2-h yd r oxyp h en yl)-4-[4-(t r iflu or om et h yl)-
p h en yl]-2,4-d ih yd r o-3H-1,2,4-tr ia zol-3-on e (7). mp 236-
238.5 °C. IR (KBr): 3186, 3088, 2854, 1715, 1332, 1284, 1172,
1
1132, 1070 cm-1. H NMR (DMSO-d6): δ 6.72 (1H, d, J ) 8.8
3057, 1726, 1504, 1277, 1128 cm-1 1H NMR (DMSO-d6): δ
.
Hz), 7.31 (1H, dd, J ) 8.8 Hz, 2.7 Hz), 7.41 (2H, d, J ) 8.5
Hz), 7.49 (1H, d, J ) 2.7 Hz), 7.75 (2H, d, J ) 8.5 Hz), 10.10
(1H, s) 12.27 (1H, s). MS m/z: 356 (MH+). Anal. (C15H9-
ClF3N3O2) C, H, N.
3.48 (3H, s), 7.15 (1H, d, J ) 9.0 Hz), 7.55 (1H, dd, J ) 8.9
Hz, 2.6 Hz), 7.69 (1H, d, J ) 2.6 Hz), 7.87 (2H, br.s), 8.17 (1H,
br.s), 12.50 (1H, br.s). MS m/z: 438 (MH+). Anal. (C17H10
-
ClF6N3O2) C, H, N.
4-[(5-Ch lor o-2-h yd r oxyp h en yl)m eth yl]-5-[4-(tr iflu or o-
m eth yl)p h en yl]-2,4-d ih yd r o-3H-1,2,4-tr ia zol-3-on e (8). (a )
5-[4-(Trifluoromethyl)phenyl]-1,2,4-oxadiazol-3(3H)one (2 g,
8.7 mmol) and 5-chloro-2-methoxybenzylamine hydrochloride
(1.5 g, 8.7 mmol) were heated at reflux in toluene for 18 h.
Concentration to one-fourth volume caused precipitation of a
solid, which was isolated by filtration. The solid, identified as
a mixture of product and symmetrical urea of 5-chloro-2-
methoxybenzylamine (1:1), was not further purified but di-
rectly taken up in 100 mL of 1 N sodium hydroxide solution.
An additional 4 mL of 10 N sodium hydroxide solution was
added, and the reaction mixture was heated at reflux for 24 h
before neutralization with HCl solution. The aqueous solution
was extracted with ethyl acetate, and the organic phase was
washed with brine and dried (Na2SO4). Flash chromatography
(15% THF/benzene) gave 800 mg (25%), which was recrystal-
lized from diethyl ether/acetonitrile (5:1); mp 190-191 °C. IR
(d ) 4-(5-Chloro-2-methoxyphenyl)-5-[3,5-bis(trifluorometh-
yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (1.6 g, 3.6 mmol)
was admixed with pyridine hydrochloride (6.7 g, 58 mmol) and
heated at 225 °C for 1 h under N2. After it was cooled, the
resultant solid was covered with ethyl acetate (25 mL) and
water (15 mL) and subjected to ultrasonication (bath) for
several minutes until the solid was suspended in solution. The
organic suspension was diluted with ethyl acetate and washed
with water, saturated sodium carbonate solution, and brine
before drying. Concentration gave a solid 1.46 g (95%), which
was recrystallized from acetonitrile to give a sample for
elemental analysis; mp 275-278 °C. IR (KBr): 3166, 1681,
1314, 1275, 1180, 1140 cm-1. 1H NMR (DMSO-d6): δ 6.92 (1H,
d, J ) 8.8 Hz), 7.38 (1H, dd, J ) 8.8 Hz, 2.6 Hz), 7.58 (1H, d,
J ) 2.0 Hz), 7.91 (2H, s), 8.17 (1H, s), 10.45 (1H, s), 12.44 (1H,
s). MS m/z: 424 (MH+). Anal. (C16H8ClF6N3O2) C, H, N.
The following triazolones were prepared as above.
1
(KBr): 3068, 1706, 1326, 1252, 1120 cm-1. H NMR (DMSO-
4-(5-Ch lor o-2-h yd r oxyp h en yl)-5-[4-(t r iflu or om et h yl)-
p h en yl]-2,4-d ih yd r o-3H-1,2,4-tr ia zol-3-on e (6a ). mp 293-
295 °C. IR (KBr): 3268, 1730, 1688, 1324, 1286, 1166, 1132
d6): δ 3.60 (3H, s), 4.84 (2H, s), 6.93-6.97 (2H, m), 7.27 (1H,
dd, J ) 8.8 Hz, 2.7 Hz), 7.72 (2H, d, J ) 8.3 Hz), 7.82 (2H, d,
J ) 8.4 Hz), 12.21 (1H, s). MS m/z: 384 (MH+).
cm-1 1H NMR (DMSO-d6): δ 6.91 (1H, d, J ) 8.8 Hz), 7.34
.
(b ) 4-[(5-Chloro-2-methoxyphenyl)methyl]-5-[4-(trifluoro-
methyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (540 mg, 1.4
mmol) was suspended in dichloromethane (50 mL) at 0 °C
under N2. Boron tribromide (4.2 mL, 1 M in CH2Cl2) was added
dropwise, and the reaction mixture was stirred for 18 h at 24
°C. A solution of 1 N sodium hydroxide (50 mL) was slowly
added and stirred for 10 min. The two phase solution was
concentrated to remove solvent, and the aqueous phase was
acidified with HCl solution and extracted with ethyl acetate.
A brine wash and drying with Na2SO4 prior to concentration
gave 500 mg (96%); mp 213-214 °C. IR (KBr): 3142, 1686,
(1H, dd, J ) 8.8 Hz, 2.6 Hz), 7.52-7.57 (3H, m), 7.74 (2H, d,
J ) 8.3 Hz), 10.32 (1H, br. s), 12.28 (1H, br. s). MS m/z: 356
(MH+). Anal. (C15H9ClF3N3O2) C, H, N.
4-(5-Ch lor o-2-h yd r oxyp h en yl)-5-[3-(t r iflu or om et h yl)-
ph en yl]-2,4-dih ydr o-3H-1,2,4-tr iazol-3-on e (6b). mp 232.5-
233.5 °C. IR (KBr): 3294, 3068, 3000, 1619, 1312, 1276, 1170,
1
1120 cm-1. H NMR (DMSO-d6): δ 6.92 (1H, d, J ) 8.8 Hz),
7.35 (1H, dd, J ) 8.8 Hz, 2.6 Hz), 7.54 (1H, d, J ) 2.6 Hz),
7.57-7.66 (3H, m), 7.75 (1H, d, J ) 7.2 Hz), 10.37 (1H, s),
12.25 (1H, s). MS m/z: 356 (MH+). Anal. (C15H9ClF3N3O2) C,
H, N.
1324, 1168, 1108 cm-1 1H NMR (DMSO-d6): δ 4.81 (2H, s),
.
4-(5-Ch lor o-2-h yd r oxyp h en yl)-5-[2-(t r iflu or om et h yl)-
p h en yl]-2,4-d ih yd r o-3H-1,2,4-tr ia zol-3-on e (6c). mp 248-
6.76 (1H, d, J ) 8.7 Hz), 6.78 (1H, d, J ) 2.7 Hz), 7.09 (1H,
dd, J ) 8.6 Hz, 2.6 Hz), 7.71 (2H, d, J ) 8.3 Hz), 7.80 (2H, d,
J ) 8.4 Hz), 10.01 (1H, br. s), 12.23 (1H, br. s). MS m/z: 370
(MH+). Anal. (C16H11ClF3N3O2) C, H, N.
1
249 °C. IR (KBr): 3182, 1686, 1316, 1174, 1136, 776 cm-1. H
NMR (DMSO-d6): δ 6.82-6.85 (1H, m), 7.20-7.24 (2H, m),
7.46-7.52 (1H, m), 7.60-7.66 (2H, m), 7.78-7.84 (1H, m),
10.36 (1H, s), 12.19 (1H, s). MS m/z: 356 (MH+). Anal. (C15H9-
ClF3N3O2) C, H, N.
5-[(5-Ch lor o-2-h yd r oxyp h en yl)m eth yl]-4-[4-(tr iflu or o-
m et h yl)p h en yl]-2,4-d ih yd r o-3H -1,2,4-t r ia zol-3-on e (9).
Starting with N-(4-trifluoromethylphenyl)-4-chloro-2-meth-
oxybenzeneacetamide, triazolone 9 was prepared using the
procedure as described in the preparation of 6d ; mp 224-225
4-(5-Ch lor o-2-h yd r oxyp h en yl)-5-(4-flu or op h en yl)-2,4-
d ih yd r o-3H-1,2,4-tr ia zol-3-on e (6e). mp 270.5-272.5 °C. IR
(KBr): 3322, 3096, 1716, 1510, 1424, 1234, 1224, 826 cm-1
.
°C. IR (KBr): 3330, 1716, 1692, 1426, 1324, 1174, 1120 cm-1
.
1H NMR (DMSO-d6): δ 6.92 (1H, d, J ) 8.8 Hz), 7.16-7.24
(2H, m), 7.31-7.43 (3H, m), 7.48 (1H, d, J ) 2.7 Hz), 10.30
(1H, s), 12.08 (1H, s). MS m/z: 306 (MH+). Anal. (C14H9-
ClFN3O2) C, H, N.
1H NMR (DMSO-d6): δ 3.74 (2H, s), 6.69 (1H, d, J ) 8.6 Hz),
6.92 (1H, d, J ) 2.1 Hz), 7.03 (1H, dd, J ) 8.5 Hz, 2.3 Hz),
7.57 (2H, d, J ) 8.1 Hz), 7.85 (2H, d, J ) 8.2 Hz), 9.74 (1H, s),
11.80 (1H, s). MS m/z: 370 (MH+). Anal. (C16H11ClF3N3O2) C,
H, N.
4-(5-Ch lor o-2-h yd r oxyp h en yl)-5-p h en yl-2,4-d ih yd r o-
3H-1,2,4-tr ia zol-3-on e (6f). mp 262-265 °C. IR (KBr): 3240,
4-(5-Ch lor o-2-h yd r oxyp h en yl)-5-[[4-(tr iflu or om eth yl)-
p h en yl]m et h yl]-2,4-d ih yd r o-3H -1,2,4-t r ia zol-3-on e (10).
Starting with N-(4-chloro-2-methoxyphenyl)-4-trifluorometh-
1
1708, 1674, 1504, 1450, 1290, 690 cm-1. H NMR (DMSO-d6):
δ 6.91 (1H, d, J ) 8.8 Hz), 7.31-7.39 (6H, m), 7.47 (1H, d, J

4,5-Diphenyltriazol-3-ones
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 2949
ylbenzeneacetamide, triazolone 10 was prepared using the
procedure as described in the preparation of 6d ; mp 235-236
°C. IR (KBr): 3336, 1690, 1658, 1506, 1428, 1328, 1286, 1160,
1112, 1068 cm-1. 1H NMR (DMSO-d6): δ 3.78 (2H, d, J ) 18.2
Hz), 6.94 (1H, d, J ) 8.8 Hz), 7.05 (1H, d, J ) 2.6 Hz), 7.20-
7.30 (3H, m), 7.55 (1H, d, J ) 8.1 Hz), 10.44 (1H, br. s), 11.69
(1H, br. s). MS m/z: 370 (MH+). Anal. (C16H11ClF3N3O2) C, H,
N.
formed as described above in 8 part b; mp 147-155 °C. IR
(KBr): 3076, 1622, 1506, 1326, 1284, 1128, 1068 cm-1. 1H NMR
(DMSO-d6): δ 5.88 (2H, s) 6.99 (1H, d, J ) 8.8 Hz), 7.39 (1H,
dd, J ) 8.8 Hz, 2.6 Hz), 7.48 (1H, d, J ) 2.5 Hz), 7.53 (2H, d,
J ) 8.2 Hz), 7.68 (2H, d, J ) 8.3 Hz), 10.55 (1H, br. s). MS
m/z: 355 (MH+). HRMS calcd for C15H10ClF3N4O, 355.0574;
found, 355.0566; Dev: 2.3 ppm.
4-Ch lor o-2-[3-[4-(tr iflu or om eth yl)p h en yl]-4H-d ih yd r o-
1,2,4-t r ia zol-4-yl]p h en ol (14). (a ) N-(5-Chloro-2-meth-
oxyphenyl)-4-(trifluoromethyl)benzene carbohydrazonamide
(3.5 g, 10.18 mmol) and N,N-dimethylformamide dimethyl
acetal (1.8 mL, 13.55 mmol) were taken up in benzene (250
mL), and catalytic p-TsOH (212 mg) was added. The solution
was heated under Dean-Stark conditions for 18 h. After it
was concentrated, the residue was dissolved in ethyl acetate
and washed with saturated NaHCO3 solution and brine before
drying (MgSO4). Flash chromatography (1% AcOH, 1% MeOH,
CH2Cl2) gave 2.4 g (67%); mp 154-156 °C. IR (KBr): 1508,
5-(5-Ch lor o-2-h yd r oxyp h en yl)-4-[[4-(tr iflu or om eth yl)-
p h en yl]m eth yl]-2,4-d ih yd r o-3H-1,2,4-tr ia zol-3-on e (11).
Starting with N-[(4-trifluoromethylphenyl)methyl]-4-chloro-2-
methoxybenzamide, triazolone 11 was prepared using the
procedure as described in the preparation of 6d ; mp 217-219
°C. IR (KBr): 3184, 1720, 1470, 1324, 1260, 1166 cm-1 1H
.
NMR (DMSO-d6): δ 4.80 (2H, s), 6.94 (1H, d, J ) 8.8 Hz), 7.17
(1H, d, J ) 2.6 Hz), 7.21 (2H, d, J ) 8.1 Hz), 7.35 (1H, dd, J
) 8.8 Hz, 2.7 Hz), 7.60 (2H, d, J ) 8.2 Hz), 10.57 (1H, s), 12.05
(1H, s). MS m/z: 370 (MH+). Anal. (C16H11ClF3N3O2) C, H, N.
4-(5-Ch lor o-2-h yd r oxyp h en yl)-5-[4-(t r iflu or om et h yl)-
ph en yl]-2,4-dih ydr o-3H-1,2,4-tr iazol-3-th ion e (12). (a) N-(5-
Chloro-2-methoxyphenyl)-4-(trifluoromethyl)benzamide was
prepared as described above in 6d part a ; mp 113-115 °C. IR
1328, 1258, 1120 cm-1 1H NMR (DMSO-d6): δ 3.50 (3H, s),
.
7.22 (1H, d, J ) 9.0 Hz), 7.57-7.62 (3H, m), 7.76-7.79 (3H,
m), 8.83 (1H, s). MS m/z: 354 (MH+). Anal. (C16H11ClF3N3O)
C, H, N.
(KBr): 3404, 1670, 1596, 1532, 1326, 1258, 1174, 1130 cm-1
.
(b) Demethylation of 4-(5-chloro-2-methoxyphenyl)-5-[4-
(trifluoromethyl)-phenyl]-4H-dihydro-3H-1,2,4-triazole was per-
formed as described above in 6d part d ; mp 223-225.5 °C. IR
1H NMR (DMSO-d6): δ 3.48 (3H, s), 7.12 (1H, d, J ) 8.8 Hz),
7.24 (1H, dd, J ) 8.8 Hz, 2.6 Hz), 7.88-7.90 (3H, m), 8.13 (2H,
(KBr): 3094, 1508, 1328, 1296, 1136, 1064 cm-1 1H NMR
.
d, J ) 8.3 Hz), 9.84 (1H, s). MS m/z: 330 (MH+). Anal. (C15H11
ClF3NO2) C, H, N.
-
(DMSO-d6): δ 6.97 (1H, d, J ) 8.8 Hz), 7.41 (1H, dd, J ) 8.8
Hz, 2.6 Hz), 7.65 (1H, d, J ) 2.7 Hz), 7.66 (2H, d, J ) 8.1 Hz),
7.78 (2H, d, J ) 8.4 Hz), 8.80 (1H, s), 10.60 (1H, s). MS m/z:
340 (MH+). Anal. (C15H9ClF3N3O) C, H, N.
(b) N-(5-Chloro-2-methoxyphenyl)-4-(trifluoromethyl)ben-
zene carbo-hydrazonamide was prepared as described above
in 6d part b; mp 94-95 °C. IR (KBr): 3328, 3252, 3190, 1590,
1326, 1218, 1162, 1120 cm-1. 1H NMR (DMSO-d6): δ 3.84 (3H,
s), 6.01 (1H, d, J ) 2.4 Hz), 6.71 (1H, dd, J ) 8.6 Hz, 2.4 Hz),
6.75 (2H, br. s), 6.92 (1H, d, J ) 8.6 Hz), 7.26 (1H, br. s), 7.62-
4-(5-Ch lor o-2-h yd r oxyp h en yl)-5-[4-(t r iflu or om et h yl)-
p h en yl]-2,4-d ih yd r o-2-m eth yl-3H-1,2,4-tr ia zol-3-on e (15).
(a ) Cyclization of N-(5-Chloro-2-methoxyphenyl)-4-(trifluo-
romethyl)benzene carbohydrazonamide was performed as
described above in 6d part c; mp 250-253 °C. IR (KBr): 3188,
7.68 (4H, m). MS m/z: 344 (MH+). HRMS calcd for C15H14
-
ClF3N3O, 344.0777 (MH+); found, 344.0770; Dev: 2.2 ppm.
1706, 1322, 1244, 1164, 1138 cm-1 1H NMR (DMSO-d6): δ
.
(c) N-(5-Chloro-2-methoxyphenyl)-4-(trifluoromethyl)ben-
zene carbohydrazonamide (2.5 g, 7.27 mmol) was dissolved in
THF (450 mL) under N2, and 1,1′-thiocarbonyldiimidazole (1.95
g, 11.0 mmol) was added. The solution was stirred at reflux
for 18 h, and solvent was removed by rotary evaporation. The
residue was taken up in ethyl acetate and washed with 0.1 N
HCl solution, water, and brine prior to drying over MgSO4.
Recrystallization from acetonitrile gave 1.91 g (68%); mp 277-
280 °C. IR (KBr): 3080, 3058, 3020, 2916, 1506, 1488, 1322,
1288, 1174, 1130, 1110 cm-1. 1H NMR (DMSO-d6): δ 3.51 (3H,
s), 7.17 (1H, d, J ) 9.0 Hz), 7.53-7.57 (3H, m), 7.69 (1H, d, J
) 2.6 Hz), 7.77 (2H, d, J ) 8.4 Hz), 14.29 (1H, s). MS m/z:
386 (MH+). Anal. (C16H11ClF3N3OS) C, H, N.
3.49 (3H, s), 7.14 (1H, d, J ) 9.0 Hz), 7.50-7.53 (3H, m), 7.64
(1H, d, J ) 2.7 Hz), 7.73 (2H, d, J ) 8.3 Hz), 12.34 (1H, s). MS
m/z: 370 (MH+). Anal. (C16H11ClF3N3O2) C, H, N.
(b) 4-(5-Chloro-2-methoxyphenyl)-5-[4-(trifluoromethyl)phen-
yl]-2,4-dihydro-3H-1,2,4-triazol-3-one (2.6 g, 7.0 mmol) and
methyl iodide (0.53 mL, 8.5 mmol) were taken up in anhydrous
DMF (20 mL) and treated with sodium hydride (290 mg, 80%,
9.7 mmol) under N2. After it was stirred for 18 h, the reaction
mixture was poured onto 1 N HCl solution (200 mL) while
stirring, and the resulting precipitate was filtered and washed
with water. Recrystallization from benzene gave 1.96 g (73%);
mp 158-160 °C. IR (KBr): 1719, 1412, 1252, 1110 cm-1 1H
.
NMR (DMSO-d6): δ 3.44 (3H, s), 3.50 (3H, s), 7.16 (1H, d, J )
9.0 Hz), 7.49-7.56 (3H, m), 7.66 (1H, d, J ) 2.7 Hz), 7.74 (2H,
d, J ) 8.4 Hz). MS m/z: 384 (MH+). Anal. (C17H13ClF3N3O2)
C, H, N.
(d ) Demethylation of 4-(5-chloro-2-methoxyphenyl)-5-[4-
(trifluoromethyl)-phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-thi-
one was performed as described above in 6d part d ; mp 274-
276 °C. IR (KBr): 3420, 3300, 3158, 1326, 1280, 1164, 1134
(c) Demethylation of 4-(5-Chloro-2-methoxyphenyl)-5-[4-
(trifluoromethyl)phenyl]-2,4-dihydro-2-methyl-3H-1,2,4-tri-
azol-3-one was performed as described above in 6d part d ; mp
246-251 °C. IR (KBr): 3076, 1680, 1422, 1332, 1282, 1172,
1112 cm-1. 1H NMR (DMSO-d6): δ 3.49 (3H, s), 6.93 (1H, d, J
) 8.8 Hz), 7.36 (1H, dd, J ) 8.8 Hz, 2.6 Hz), 7.54-7.57 (3H,
m), 7.75 (2H, d, J ) 8.3 Hz), 10.38 (1H, s). MS m/z: 370 (MH+).
Anal. (C16H11ClF3N3O2) C, H, N.
4-Ch lor o-2-[2-[4-(tr iflu or om eth yl)ph en yl]-1H-im id a zol-
1-yl]p h en ol (16). (a ) N-(5-Chloro-2-methoxyphenyl)-4-(tri-
fluoromethyl)benzamide (5.17 g, 15.7 mmol) was dissolved in
benzene (100 mL) under N2, and phosphorus pentachloride
(3.61 g, 17.3 mmol) was added. The solution was heated at
reflux for 2.5 h before distillation in vacuo to remove solvent
and phosphorus oxychloride. The residue was taken up in THF
(55 mL) and cannulated dropwise into a solution of aminoac-
etaldehyde diethyl acetal (5 mL, 34.4 mmol) in THF (50 mL)
at 0 °C under N2. After it was stirred for 18 h at 24 °C, the
reaction mixture was diluted with diethyl ether (1.5 vol) and
filtered. The filtrate was concentrated by rotary evaporation
to give an oil (7.63 g), which was dissolved in 500 mL of
benzene. Two equivalents of p-TsOH‚H2O (6 g, 30 mmol) were
added, and the solution was heated at reflux for 2 h under
cm-1 1H NMR (DMSO-d6): δ 6.92 (1H, d, J ) 8.8 Hz), 7.37
.
(1H, dd, J ) 8.8 Hz, 2.6 Hz), 7.57 (1H, d, J ) 2.6 Hz), 7.60
(2H, d, J ) 8.2 Hz), 7.78 (2H, d, J ) 8.4 Hz), 10.40 (1H, s),
14.24 (1H, s). MS m/z: 372 (MH+). HRMS calcd for C15H9-
ClF3N3OS, 372.0185; found, 372.0197; Dev: 3.2 ppm.
4-Ch lor o-2-[3-a m in o[5-[4-(t r iflu or om et h yl)p h en yl]]-
4H-1,2,4-tr ia zol-4-yl] p h en ol. (13). (a ) N-(5-Chloro-2-meth-
oxyphenyl)-4-(trifluoromethyl)benzene carbohydrazonamide
(1.5 g, 4.36 mmol) was dissolved in 1,4-dioxane (7 mL), and
cyanogen bromide (475 mg, 4.48 mmol) was added. A solution
of sodium bicarbonate (380 mg in 7 mL of water) was added
dropwise, and the reaction mixture was stirred for 3 h.
Additional water (7 mL) was added, and the heterogeneous
reaction mixture was filtered, and the filtrate was rinsed with
water; recrystallization from acetonitrile gave 922 mg (57.3%);
mp 247-248 °C. IR (KBr): 3416, 3076, 3052, 1652, 1561, 1504,
1322, 1136, 1110 cm-1 1H NMR (DMSO-d6): δ 3.60 (3H, s),
.
5.92 (2H, s), 7.22 (1H, d, J ) 9.5 Hz), 7.47 (2H, d, 8.3 Hz),
7.54-7.57 (2H, m), 7.67 (2H, d, J ) 8.4 Hz). MS m/z: 369
(MH+). Anal. (C16H12ClF3N4O) C, H, N.
(b) Demethylation of 4-(5-Chloro-2-methoxyphenyl)-5-[4-
(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-amine was per-

2950 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Romine et al.
Dean-Stark conditions. Concentration gave a residue, which
was partitioned between ethyl acetate and water. The aqueous
phase was extracted with ethyl acetate, and combined organic
layers were washed with water and brine before drying over
MgSO4. Flash chromatography and elution with 10% ethyl
acetate/methylene chloride gave 4.15 g (75%); mp 151-152.5
°C. IR (KBr): 1504, 1464, 1324, 1284, 1246, 1176, 1122, 1108,
acetic acid (1 mL), triethylsilane (2.2 mL) was added, and the
solution was heated at 100 °C in a sealed tube for 18 h. The
volatiles were removed in vacuo, and the residue was taken
up in ethyl acetate and washed with saturated NaHCO3
solution, water, and brine and dried with MgSO4 prior to
concentration to give 1.2 g (94%); mp 78-81 °C. IR (KBr):
1326, 1256, 1172, 1122, 1068 cm-1 1H NMR (DMSO-d6): δ
.
1074, 846 cm-1
.
1H NMR (DMSO-d6): δ 3.48 (3H, s), 7.17-
3.57 (3H, s), 3.95 (2H, s), 6.87 (1H, d, J ) 8.8 Hz), 6.99 (1H, d,
J ) 1.3 Hz), 7.01 (1H, d, J ) 2.7 Hz), 7.19 (1H, dd, J ) 8.8 Hz,
2.7 Hz), 7.38 (1H, d, J ) 1.4 Hz), 7.59 (2H, d, J ) 8.2 Hz),
7.21 (2H, m), 7.43 (1H, d, J ) 1.3 Hz), 7.51-7.59 (4H, m), 7.66
(2H, d, J ) 8.4 Hz). MS m/z: 353 (MH+). Anal. (C17H12
ClF3N2O) C, H, N.
-
7.87 (2H, d, J ) 8.4 Hz). MS m/z: 367 (MH+). Anal. (C18H14
-
ClF3N2O) C, H, N.
(b) Demethylation of 1-(5-Chloro-2-methoxyphenyl)-2-[4-
(trifluoromethyl)phenyl]-1H-imidazole was performed as de-
scribed above in 6d part d ; mp 252-254 °C. IR (KBr): 3000-
2500, 1506, 1174, 1130 cm-1. 1H NMR (DMSO-d6): δ 6.97 (1H,
d, J ) 8.8 Hz), 7.20 (1H, d, J ) 1.2 Hz), 7.37 (1H, dd, J ) 8.8
Hz, 2.6 Hz), 7.40 (1H, d, J ) 1.2 Hz), 7.47 (1H, d, J ) 2.6 Hz),
7.59 (2H, d, J ) 8.4 Hz), 7.67 (2H, d, J ) 8.5 Hz), 10.40 (1H,
s). MS m/z: 339 (MH+). Anal. (C16H10ClF3N2O) C, H, N.
(b) Demethylation of 2-[(5-chloro-2-methoxyphenyl)methyl]-
1-[4-(trifluoromethyl)phenyl]-1H-imidazole was performed as
described above in 6d part d ; mp 183.5-185 °C. IR (KBr):
2904, 1484, 1426, 1326, 1284, 1180, 1126 cm-1 1H NMR
.
(DMSO-d6): δ 3.93 (2H, s), 6.73 (1H, d, J ) 8.6 Hz), 6.92 (1H,
d, J ) 2.7 Hz), 7.01-7.05 (2H, m), 7.40 (1H, d, J ) 1.3 Hz),
7.61 (2H, d, J ) 8.3 Hz), 7.87 (2H, d, J ) 8.4 Hz), 9.88 (1H, s).
MS m/z: 353 (MH+). Anal. (C17H12ClF3N2O) C, H, N.
4-Ch lor o-2-[1-[4-(tr iflu or om eth yl)p h en yl]-1H-im id a zol-
2-yl]p h en ol (17). (a ) Preparation of 2-(5-chloro-2-methoxy-
phenyl)-1-[4-(trifluoromethyl)phenyl]-1H-imidazole was per-
formed as above in 16 part a ; mp 95-106 °C. IR (KBr): 3104,
1616, 1522, 1496, 1436, 1324, 1304, 1288, 1254, 1166, 1120
3-[(3,5-Bis(t r iflu or om et h yl)p h en yl]-4-(5-ch lor o-2-h y-
d r oxyp h en yl)-1,2,4-oxa d ia zol-5-(4H)-on e (20). (a ) N-(5-
Chloro-2-methoxyphenyl)-3,5-bis(trifluoromethyl) benzamide
(3 g, 7.5 mmol) was suspended in benzene (40 mL) under N2,
phosphorus pentachloride (1.7 g, 8.3 mmol) was added, and
the solution was heated at reflux for 2.5 h. After it was
concentrated to remove solvent and POCl3, the residue was
taken up in diethyl ether (45 mL) and cannulated dropwise
into a stirred ethanolic solution (130 mL) of anhydrous
hydroxylamine (75.4 mmol, obtained by admixture of HCl salt
(5.2 g) with 1 equiv EtONa (1.7 g, 75.4 mmol) in hot EtOH
and filtration to remove NaCl) at 0 °C under N2. The reaction
mixture was stirred for 18 h at 24 °C, concentrated, and
partitioned between ethyl acetate and water. Saturated NaH-
CO3 was added, and the organic phase was washed with brine
and dried (Na2SO4) to give 1.8 g (59%). The amidoxime (1.6 g,
3.9 mmol) was taken up in THF (130 mL) and stirred with
1,1′-carbonyldiimidazole (762 mg, 4.7 mmol) at reflux for 2 h.
After it was concentrated, the residue was taken up in ethyl
acetate and washed with water and brine prior to drying
(MgSO4) to give 1.7 g (97%); mp 145.5-147.5 °C. IR (KBr):
1792, 1278, 1196, 1136 cm-1. 1H NMR (DMSO-d6): δ 3.54 (3H,
s), 7.16 (1H, d, J ) 9.0 Hz), 7.59 (1H, dd, J ) 8.9 Hz, 2.6 Hz),
7.82 (1H, d, J ) 2.6 Hz), 8.07 (2H, s), 8.37 (1H, s). MS m/z:
439 (MH+). Anal. (C17H9ClF6N2O3) C, H, N.
cm-1 1H NMR (CDCl3): δ 3.18 (3H, s), 6.61 (1H, d, J ) 8.9
.
Hz), 7.22-7.32 (5H, m), 7.56-7.61 (3H, m). MS m/z: 353
(MH+). Anal. (C17H12ClF3N2O) C, H, N.
(b) Demethylation of 2-(5-chloro-2-methoxyphenyl)-1-[4-
(trifluoromethyl)phenyl]-1H-imidazole was performed as de-
scribed above in 6d part d ; mp 110-112.5 °C. IR (KBr): 3200-
2800, 1488, 1326, 1256, 1172, 1134 cm-1 1H NMR (DMSO-
.
d6): δ 6.81 (1H, d, J ) 8.7 Hz), 7.13 (1H, d, J ) 2.6 Hz), 7.22-
7.26 (2H, m), 7.54 (2H, d, J ) 8.3 Hz), 7.63 (1H, d, J ) 1.4
Hz), 7.84 (2H, d, J ) 8.4 Hz), 10.84 (1H, s). MS m/z: 339
(MH+). Anal. (C16H10ClF3N2O) C, H, N.
4-Ch lor o-2-[5-[4-(tr iflu or om eth yl)p h en yl]-1H-im ida zol-
1-yl]p h en ol. (18). (a ) 5-Chloroanisidine (6.0 g, 38.2 mmol)
and 4-RRR-trifluorotolualdehyde (6.6 g, 38.2 mmol) were
dissolved in methanol (250 mL) and stirred for 3 h. The solvent
was removed by rotoevaporation, the residue was taken up in
benzene (200 mL), and the solution was heated under Dean-
Stark conditions to remove traces of methanol prior to distil-
lation of the benzene. The residue was taken up in DMF, and
tosylmethylisocyanide (7.46 g, 3.82 mmol) and DBU (0.5 mL,
3.82 mmol) were added under N2. The reaction mixture was
stirred at 24 °C for 48 h before it was diluted with water (1
vol) and extracted with ethyl acetate. The organic phase was
washed with water and brine and dried. Flash chromatogra-
phy, elution with 30% ethyl acetate/benzene, gave (1 g, 8%);
mp 158-159 °C. IR (KBr): 1504, 1462, 1324, 1260, 1176, 1122
(b) Demethylation of 3-[(3,5-bis(trifluoromethyl)phenyl]-4-
(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-(4H)-one was per-
formed as described above in 8 part b; mp 182-183 °C. IR
1
(KBr): 3308, 1784, 1276, 1134 cm-1. H NMR (DMSO-d6): δ
6.93 (1H, d, J ) 8.9 Hz), 7.42 (1H, dd, J ) 8.9 Hz, 2.7 Hz),
7.73 (1H, d, J ) 2.7 Hz), 8.07 (2H, s), 8.39 (1H, s), 10.86 (1H,
s). MS m/z: 425 (MH+). Anal. (C16H7ClF6N2O3) C, H, N.
cm-1 1H NMR (CDCl3): δ 3.49 (3H, s), 6.86 (1H, d, J ) 8.9
.
Hz), 7.20-7.24 (3H, m), 7.32-7.38 (2H, m), 7.48 (2H, d, J )
8.2 Hz), 7.60 (1H, s). MS m/z: 353 (MH+). Anal. (C17H12
-
4-[5-(Ch lor o-2-h yd r oxyp h en yl)m eth yl]-3-[4-(tr iflu or o-
m eth yl)p h en yl]-1,2,4-oxa d ia zol-5-(4H)-on e (21). (a ) 3-[4-
(Trifluoromethyl)phenyl]-1,2,4-oxa-diazol-5(4H)-one (2 g, 8.7
mmol) was dissolved in DMF (100 mL) under N2, and sodium
hydride (390 mg, 80% suspension) was added. The solution
was heated to 60 °C for 15 min, and 5-chloro-2-methoxyben-
zylbromide (2.0 g, 8.7 mmol) was added as a solid. The reaction
mixture was stirred for 3 h, poured into water (100 mL), and
extracted with diethyl ether. Concentration gave 1.7 g (70%);
ClF3N2O) C, H, N.
(b) Demethylation of 1-(5-Chloro-2-methoxyphenyl)-5-[4-
(trifluoromethyl)phenyl]-1H-imidazole was performed as de-
scribed above in 8 part b; mp 220-225 °C. IR (KBr): 3118,
1508, 1326, 1290, 1128 cm-1. 1H NMR (DMSO-d6): δ 6.94 (1H,
d, J ) 8.8 Hz), 7.34-7.40 (4H, m), 7.47 (1H, d, J ) 2.6 Hz),
7.65 (2H, d, J ) 8.3 Hz), 7.84 (1H, s), 10.36 (1H, s). MS m/z:
339 (MH+). Anal. (C16H10ClF3N2O‚0.23 H2O) C, H, N.
5-Ch lor o-2-[[1-[4-(tr iflu or om eth yl)ph en yl]-1H-im idazol-
2-yl]m eth yl]p h en ol (19). (a ) 1-(4-Trifluoromethylphenyl)-
imidazole (3.0 g, 14.1 mmol) was dissolved in THF (140 mL)
and cooled to -78 °C, and n-butyllithium (5.9 mL, 2.5 M in
hexanes) was added dropwise under N2. The solution was
stirred for 2 h and 2-methoxy-5-chlorobenzaldehyde (2.9 g, 17
mmol), dissolved in THF (30 mL), was added dropwise and
stirred for 2 h before slowly warming to 24 °C. The reaction
mixture was quenched with saturated ammonium chloride
solution and diluted with diethyl ether (1 vol) before it was
washed with NaHCO3 solution, water, and brine. Crystalliza-
tion from benzene/isopropyl alcohol gave 4.6 g (84%). The
resultant alcohol (1.3 g, 3.4 mmol) was taken up in trifluoro-
mp 145-147 °C. IR (KBr): 1784, 1326, 1260, 1178, 1148 cm-1
.
1H NMR (DMSO-d6): δ 3.55 (3H, s), 4.76 (2H, s), 6.91 (1H, d,
J ) 8.9 Hz), 7.10 (1H, d, J ) 2.6 Hz), 7.26 (1H, dd, J ) 8.8 Hz,
2.6 Hz), 7.81 (2H, d, J ) 8.2 Hz), 7.91 (2H, d, J ) 8.3 Hz). MS
m/z: 385 (MH+). Anal. (C17H12ClF6N2O3) C, H, N.
(b) Demethylation of 4-[5-(chloro-2-methoxyphenyl)methyl]-
3-[4-(trifluoro-methyl)phenyl]-1,2,4-oxadiazol-5-(4H)one was
performed as described above in 6d part d ; mp 243-245 °C.
1
IR (KBr): 3418, 1740, 1460, 1420, 1324, 1164, 1134 cm-1. H
NMR (DMSO-d6): δ 4.74 (2H, s), 6.69 (1H, d, J ) 8.6 Hz) 6.95
(1H, d, J ) 2.6 Hz), 7.07 (1H, dd, J ) 8.6 Hz, 2.6 Hz), 7.78
(2H, d, J ) 8.2 Hz), 7.88 (2H, d, J ) 8.3 Hz), 10.06 (1H, s). MS
m/z: 371 (MH+). Anal. (C16H10ClF3N2O3) C, H, N.

4,5-Diphenyltriazol-3-ones
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 2951
(10) Knaus, H.-G.; Schwarzer, C.; Koch, R. O. A.; Eberhart, A.;
Kaczorowski, G. J .; Glossmann, H.; Wunder, F.; Pongs, O.;
Electr op h ysiology. Frog oocytes were surgically harvested
from mature Xenopus laevis that had been anesthetized with
0.15% 3-aminobenzoic acid ethyl ester (tricaine). Only late
stage V and VI oocytes were selected for cRNA injection; the
overlying follicle cell layers were manually removed. Each
oocyte was injected with approximately 50 nL of the mSlo
cRNA. Following injection, oocytes were maintained at 17 °C
in ND96 medium consisting of (in mM): NaCl, 90; KCl, 1.0;
CaCl2, 1.0; MgCl2, 1.0; HEPES, 5.0; pH 7.5. Horse serum (5%)
and penicillin/streptomycin (5%) were added to the incubation
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Two electrode voltage clamp techniques were used to record
membrane currents; recording commenced 2-6 days following
cRNA injection. For recording and compound application,
oocytes were placed in a recording chamber and incubated in
Modified Barth’s Solution (MBS) consisting of (in mM): NaCl,
88; NaHCO3, 2.4; KCI, 1.0; HEPES, 10; MgSO4, 0.82; Ca(NO3)2,
0.33; CaCl2, 0.41; pH 7.5. Voltage clamp protocols typically
consisted of a series of voltage steps 500-750 ms duration, in
+20 mV steps from a holding potential of -60 mV to a
maximal potential of +140 mV (see Figure 2). A family of
outward currents was generated under control conditions for
comparison with currents elicited in the presence of an
experimental compound. Control and drug solutions were
introduced into the recording chamber continually using a
gravity-flow system; solutions were switched using a rotary
valve. A minimum of five oocytes was used to generate each
data point for each compound, and the compounds were
applied at a screening concentration of 20 µM, with the
exception of 6d , for which a more complete concentration-
response relationship was determined. Putative maxi-K chan-
nel openers were applied for 5 min, when steady state current
values were obtained, followed by application of 50 nM of the
specific maxi-K channel blocker IbTX (alone) to estimate the
percent of total current that was attributable to maxi-K
channel expression in the oocyte under voltage clamp. In this
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Ack n ow led gm en t. We express our thanks to Dr.
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