Phenoxyphenyl sulfone N-formylhydroxylamines (Retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors

Article abstract of DOI:10.1021/jm0103920

A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1′ substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a.highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.

Full text of DOI:10.1021/jm0103920

J . Med. Chem. 2002, 45, 219-232
219
P h en oxyp h en yl Su lfon e N-F or m ylh yd r oxyla m in es (Retr oh yd r oxa m a tes) a s
P oten t, Selective, Or a lly Bioa va ila ble Ma tr ix Meta llop r otein a se In h ibitor s
Carol K. Wada,* J ames H. Holms, Michael L. Curtin, Yujia Dai, Alan S. Florjancic, Robert B. Garland, Yan Guo,
H. Robin Heyman, J amie R. Stacey, Douglas H. Steinman, Daniel H. Albert, J ennifer J . Bouska,
Ildiko N. Elmore, Carole L. Goodfellow, Patrick A. Marcotte, Paul Tapang, Douglas W. Morgan,
Michael R. Michaelides, and Steven K. Davidsen
Cancer Research Area, Abbott Laboratories, Department 47J , Building AP10, 100 Abbott Park Road,
Abbott Park, Illinois 60064-6100
Received August 17, 2001
A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated
as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-
770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but
was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and
diminished oral exposure. Replacement of the biphenyl P1′ substituent with a phenoxyphenyl
group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-
1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led
to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP
inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.
Ch a r t 1. MMP Inhibitors
In tr od u ction
The matrix metalloproteinases (MMPs) are a family
of zinc-dependent endopeptidases that are involved in
the degradation of all components of the extracellular
matrix. This family of enzymes plays an important role
in remodeling and maintenance of normal tissue. It is
the inappropriate activity of MMPs that has been
implicated in a variety of pathologies such as arthritis,
tumor metastasis, periodontal diseases, and multiple
sclerosis, although the role of each MMP is not known
for certain.1-4
MMP inhibitors possessing a range of potencies and
selectivities have been evaluated in clinical studies
(Chart 1).5 They include hydroxamate-based compounds
such as marimastat (1) and prinomastat (2) as well as
compounds bearing thiol (BMS-275291, 3) and carboxy-
late (BAY 12-9566, 4) zinc binding groups. One of the
findings from some of these studies was the onset of
joint toxicity occurring predominantly in the upper
limbs. In severe cases, upper limb range of motion was
dramatically reduced (“frozen shoulder”) requiring a
dosing “holiday”.6 As a means of avoiding these effects,
our efforts have focused on the discovery of subtype
selective MMP inhibitors as antitumor agents. We
targeted gelatinases A and B (MMP-2 and -9) since they
have been consistently associated with tumor progres-
sion.1,2 The substrate specificity of MMP-2 and -9 for
type IV collagen, a major component of basement
membranes, also supports their role in tumor progres-
sion. Significantly, MMP-2 and -9 deficient mice exhibit
suppression of tumor growth and metastasis without
gross developmental abnormalities.7,8
analysis and homology modeling, the MMPs may be
classified into two broad structural classes, those with
a relatively deep S1′ pocket (MMP-2, -3, -8, -9, and -13)
and those with a shallow S1′ pocket (MMP-1 and -7).9,10
Consequently, incorporation of an extended P1′ group
(e.g., biphenyl) leads to selective inhibition, whereas the
presence of smaller P1′ groups generally leads to broad
spectrum inhibition.
Previously, we have disclosed the N-formylhydroxyl-
amine (retrohydroxamate) 5 (Chart 2, ABT-770) as a
potent MMP inhibitor with selectivity for inhibition of
MMP-2 over MMP-1.11,12 The replacement of the more
typical hydroxamic acid zinc binding group with the
retrohydroxamate and optimization of the R′ substituent
(adjacent to the retrohydroxamate center) with a hy-
dantoin group led to potent, long-lived, orally bioavail-
able MMP inhibitors.
Selective inhibition of MMPs is possible due to dif-
ferences in the depth of the S1′ pocket. From X-ray
crystallographic and nuclear magnetic resonance (NMR)
To further probe the structure-activity relationship
(SAR) of the retrohydroxamates as MMP inhibitors, we
* To whom correspondence should be addressed. Tel: (847)935-4795.
Fax: (847)935-5165. E-mail: carol.wada@abbott.com.
10.1021/jm0103920 CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/06/2001

220 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1
Ch a r t 2. Ether and Sulfone Retrohydroxamates
Wada et al.
able MMP inhibitors leading to the clinical candidate
ABT-518 (6).13
Ch em istr y
The sulfone retrohydroxamates were synthesized by
three general methods as shown in Schemes 1 and 2.
Method A (Scheme 1) involves alkylation of an arylthiol
with an R-bromo ketone (7) or an epoxide (8). The P1′
biaryl group may be installed from the onset by prepa-
ration of the appropriate biarylthiol via standard lit-
erature methods,14-16 or it may be installed stepwise
by alkylation of 4-bromothiophenol followed by a Suzuki
coupling with the aryl bromide 9 (R′ ) Br).17 Reaction
of the thiol with the R-bromo ketone in the presence of
K2CO3 proceeded rapidly in dimethylformamide (DMF)
at -5 °C (75-90% yield). In the case of ring opening of
the epoxide, the reaction was heated at 100 °C. The
resultant alcohol was then oxidized to the ketone by
treatment with Dess-Martin periodinane.18
To install the retrohydroxamate group, a three step
sequence was utilized, in most cases with purification
only at the third step (50-80% overall yield). The
ketones 9 and 12 were converted to the oximes by
treatment with hydroxylamine hydrochloride in the
presence of pyridine. The oxime was then reduced to
the hydroxylamine using borane‚pyridine/4 N HCl-
have investigated various replacements for the biaryl
ether and hydantoin groups. Although 5 exhibits selec-
tive inhibition of MMP-2 over MMP-1, it is only mod-
erately active against MMP-9. In our efforts to improve
the inhibition of MMP-9, we have found that replace-
ment of the ether linkage of 5 with a sulfone group
(OfSO2) led to a substantial increase in activity against
MMP-9. Herein, we report the discovery of sulfone
retrohydroxamates as potent, selective, orally bioavail-
Sch em e 1. Synthesis of Sulfone Retrohydroxamates via Arylthiolsa
a
Reagents: (a) K2CO3, HSAryl, DMF. (b) Dess-Martin. (c) ArylB(OR)2, Pd(PPh3)4, NaOH. (d) HONH2‚HCl, pyridine, THF, EtOH. (e)
BH3‚pyr. (f) Acetic formic anhydride, THF. (g) OXONE, MeOH, H2O.
Sch em e 2. Syntheses of Sulfone Retrohydroxamates via Aryl Methyl Sulfones
a
Reagents: (a) nBuLi, H3CSO2Aryl, THF, -78 °C. (b) NaBH4, MeOH, THF. (c) MsCl, Et3N, CH2Cl2. (d) PPh3, DEAD, THF. (e) HONH2,
THF. (f) Acetic formic anhydride. (g) Trifluoroethyl formate. Reagents: (a) nBuLi, THF, -78 °C. (b) NaBH4, MeOH, THF. (c) OXONE.
(d) MsCl, Et3N, CH2Cl2. (e) HONH2, THF. (f) Trifluoroethyl formate.
b

Phenoxyphenyl Sulfone N-Formylhydroxylamines
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1 221
Sch em e 3. Synthesis of Sulfone Retrohydroxamate 6a
a
Reagents: (a) 4-Trifluoromethoxyphenol, KOtBu, DMSO. (b) nBuLi, THF. (c) NaBH4, EtOH. (d) MsCl, Et3N, CH2Cl2. (e) HONH2,
THF. (f) Trifluoroethyl formate.
dioxane. We observed that using HCl in dioxane over
aqueous HCl19 gave consistently shorter reaction times
for the reduction. Formylation of the hydroxylamine 10
was carried out with acetic formic anhydride at 0 °C in
tetrahydrofuran (THF).20 The final step of the synthesis
was oxidation of the sulfide to the sulfone 11 or 13,
which was accomplished cleanly by treatment with
OXONE in methanol/H2O.
Method B (Scheme 2) involves addition of the lithium
anion of a methyl sulfone to an aldehyde 14 or ester
15. The biaryl methyl sulfones are readily prepared by
nucleophilic aromatic substitution on 4-fluorophenyl
methyl sulfone21 or by Suzuki coupling between an
arylboronic acid and a 4-bromophenyl methyl sulfone.17
The lithium anion of the methyl sulfone was generated
by treatment with n-butyllithium at -78 °C in THF to
which was added the aldehyde at -78 °C to give the
alcohol adduct 16. Reaction of the methyl sulfone anion
with the ester also proceeded at -78 °C. The resultant
ketone was then reduced to the alcohol by treatment
with sodium borohydride.
To install the retrohydroxamate, the â-hydroxy sul-
fone 16 was first converted to the R,â-unsaturated
sulfone 17 by either of two routes, formation of the
mesylate followed by elimination or direct elimination
of the alcohol under Mitsunobu conditions. Treatment
of the R,â-unsaturated sulfone with aqueous hydroxy-
lamine in THF gave the 1,4-Michael adduct 18 in good
yield. Previous literature examples of the conjugate
addition have used HONH2‚HCl and base.22 Under
those conditions, we observed substantial amounts of
the bis-Michael adduct. The N-formylation was initially
carried out by treatment with acetic formic anhydride
at 0 °C in THF.19 However, for certain substrates,
substantial amounts of the N,O-bis formyl or O-formyl
products were obtained. Investigation of several formy-
lating reagents led to the use of trifluoroethyl formate23
in refluxing THF or MTBE to give high yields of the
desired N-formyl product 19.24
sentially reverses the functionality with respect to the
addition of the methyl sulfone anion to the ester. In
method C (Scheme 2), the ester functionality resides
with the biaryl group 21, and the R′ substituent resides
with the methyl sulfone 22.
Synthesis of 6 was carried out using method B and is
detailed in Scheme 3. The phenoxyphenyl methyl sul-
fone 26 was easily prepared by nucleophilic aromatic
substitution between 4-fluoro-1-nitrobenzene and 4-tri-
fluoromethoxyphenol. Treatment of the methyl sulfone
26 with n-butyllithium generated the lithium anion, to
which was added the optically active methyl ester 27
at -78 °C in THF to give the ketone 28 in 79% yield
(>99% ee). The ketone was then reduced with sodium
borohydride to the alcohol 29. Treatment of the alcohol
with methanesulfonyl chloride and triethylamine led to
elimination of the mesylate to give the R,â-unsaturated
sulfone 30 as a 1:10 mixture of cis and trans isomers.
The 1,4-addition of hydroxylamine to the olefin mixture
proceeded with 4:1 selectivity in favor of the desired
stereochemistry. The pure diastereomer 31 can be
obtained by recrystallization and silica gel chromatog-
raphy. Selective N-formylation of the hydroxylamine
was accomplished by treatment with trifluoroethyl
formate in refluxing MTBE to give 6 in 42% yield
overall. Analysis of the final product by chiral high-
performance liquid chromatography established the
enantiomeric excess of 6 as >99%. This six step se-
quence has been optimized to give multikilogram quan-
tities of 6 in 50% overall yield with >99% enantiomeric
excess.25
Resu lts a n d Discu ssion
Although the retrohydroxamate 5 (Table 1) is a potent
and selective inhibitor of MMP-2 (IC50 ) 3.7 nM), it is
only moderately active against MMP-9 (IC50 ) 120 nM).
Replacement of the ether linkage of 5 with a sulfone
group (OfSO2) (13a , Table 1) led to a substantial
increase in activity against MMP-9 (IC50 ) 0.86 nM).
Unfortunately, this small change led to nearly complete
loss of selectivity for inhibition of MMP-2 and -9 over
For compounds with ultimately two sulfone groups,
a modification of method B was utilized, which es-

222 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1
Ta ble 1. Ether vs Sulfone Biaryl Retrohydroxamates
Wada et al.
with either a deep or a shallow S1′ pocket. It was then
proposed that introduction of another change in angle
or increase in size of the P1′ group could alter the
interaction with the enzyme to once again take advan-
tage of the differences in size of the S1′ pocket. This
was found to be the case when insertion of an ether
linkage between the two aryl rings of the biphenyl group
led to an improvement in selectivity (11b-g, Table 2).
The direct phenoxyphenyl analogue 11b containing a
5,5-dimethylhydantoin group and a p-trifluoromethoxy
substituent had an IC50 ratio for MMP-1/MMP-2 of
>600. Methylation of the 1N of the hydantoin group led
to a further increase in selectivity (11e-g, Table 2) with
the p-trifluoromethoxy compound 11e being the most
selective (>27 000-fold). In contrast to the studies in the
5 ether series, we observed no N-dealkylation of the
trimethylhydantoin in vivo.26 Unfortunately, this series
of hydantoin sulfone retrohydroxamates exhibited poor
oral exposure (3 mpk in cynomolgous monkey, n ) 2);
the greatest exposure was obtained for the least selec-
tive p-Cl compounds 11d and 11g.
a
( standard deviation (number of determinations). b Three mpk
in cynomolgous monkey; n ) 1 iv; n ) 2 po. c S stereochemistry
at * center.
MMP-1 (IC50 MMP-1/MMP-2 < 10-fold) in addition to
a significant decrease in exposure after oral dosing
(AUC ) 17.8 vs 5 µM‚h, dose ) 3 mpk).
Varying the substituent on the biphenyl sulfone had
virtually no effect on the selectivity (13b-d , 19a , 11a ;
Table 2). Even a large p-butoxy group (13b) only
increased the selectivity to 100-fold. One possible ex-
planation is that the larger sulfone group perturbed the
interaction of the P1′ substituent with the enzyme such
that a large P1′ group could be accommodated by MMPs
We continued to explore the SAR of the sulfone
phenoxyphenyl retrohydroxamates with the intent of
improving the oral exposure while maintaining the
desired selectivity profile. The effect of substituting an
aryl group for the hydantoin of 11b is summarized in
Table 3. In entries 19b-e, the aryl group has a direct
attachment with no alkyl or other spacer group. Selec-
tivity was maintained. These compounds had no activity
Ta ble 2. Hydantoin Sulfone Retrohydroxamates
a
b
( standard deviation (number of determinations). Three mpk in cynomolgous monkey; n ) 1 iv; n ) 2 po.

Phenoxyphenyl Sulfone N-Formylhydroxylamines
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1 223
Ta ble 4. Acyclic Sulfone Retrohydroxamates
Ta ble 3. Aryl Sulfone Retrohydroxamates
a
( standard deviation (number of determinations). b Three mpk
in cynomolgous monkey; n ) 1 iv; n ) 2 po. c S stereochemistry
at * center.
side chains varying from amines and sulfonamides to
alcohols and ethers. All were potent (several sub-
nanomolar) and selective (>1 000-fold), although some
subtle differences were observed. Reversing the sul-
fonamide side chain (19j vs 24a ) leads to a reversal of
potency against MMP-2 and -9. Compounds with ether
side chains (19l and 19m ) and diol side chains (19n and
19o) were the most selective for the inhibition of MMP-2
and -9 over MMP-1 with virtually no activity against
MMP-1 (>50 µM). Also, within this series were several
compounds (alcohols 19k , 19m , and 19o) that possessed
sub-nanomolar IC50s against both MMP-2 and MMP-9.
Unfortunately, no improvement in the pharmacokinetic
properties was observed.
Cyclic variants of polar groups are summarized in
Table 5. This series was found to be the most potent
with the majority of compounds having sub-nanomolar
IC50s against MMP-2 and -9. The selectivity was also
maintained (>2 900-fold). It was also in this series that
we observed a marked improvement in the pharmaco-
kinetic properties. Several compounds had oral AUCs
greater than 20 µM‚h (6, 19q, and 19s-u ). In particular,
the acetonide 6 dosed in cynomolgous monkeys had an
oral AUC of 53 µM‚h and an iv half-life of 16.8 h. The
a
( standard deviation (number of determinations). b Three mpk
in cynomolgous monkey; n ) 2.
against MMP-1 (IC50 > 50 µM), but a slight decrease in
potency against MMP-2 and -9 was observed (1.7-62
nM). The addition of a one or two methylene spacer
group (19f-h , 11h ) resulted in a shift back to micro-
molar inhibition of MMP-1 and <10 nM inhibition of
MMP-2 and -9. Overall, the exposure after oral (3 mpk
in cynomolgous monkey, n ) 2) or intravenous (iv, n )
1) dosing of this series of compounds showed no im-
provement, which may be attributed to their low
solubility. This led to the investigation of the effect of
basic or acidic functional groups. A pyridyl group (19c)
had no effect on the oral exposure. A carboxylic acid
group (19h ) led to a highly potent (<1 nM) and selective
(>10 000-fold) MMP inhibitor with a marginal increase
in oral exposure. The corresponding methyl ester 19g
was nearly 100-fold less active against MMP-2.
Various polar groups were incorporated in hopes of
improving the pharmacokinetics of the sulfone retro-
hydroxamates. Table 4 summarizes the effect of acyclic

224 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1
Ta ble 5. Heterocyclic Sulfone Retrohydroxamates
Wada et al.
Ta ble 6. Acetonide Sulfone Retrohydroxamates
a
( standard deviation (number of determinations). b Three mpk
in cynomolgous monkey; n ) 1 iv; n ) 2 po.
a metal chelating group, the ability of 6 to inhibit other
metalloproteinases was also evaluated. Retrohydrox-
amate 6 does not inhibit LPS-stimulated TNFR (tumor
necrosis factor) release from THP-1 cells suggesting a
lack of functional inhibition of the ADAM class of
metalloproteinases (Table 7). It also does not inhibit
thermolysin, rat neprilysin, or leucine aminopeptidase
(IC50 > 100 µM).
The retrohydroxamate 6 was also evaluated in in vivo
animal tumor models. The compound demonstrated
antitumor activity when administered orally as a mono-
therapy in a murine syngenetic tumor growth model
(B16 melanoma implanted subcutaneously in the flank
of mice) (Figure 1). The compound or vehicle was
administered orally twice daily on days 7-21. The
inhibition of tumor growth was found to be dose-
dependent with 48% inhibition of tumor growth to 2 g
relative to control at 30 mpk.
a
( standard deviation (number of determinations). b Three mpk
in cynomolgous monkey; n ) 1 iv; n ) 2 po. c S stereochemistry
at * center.
bioavailability of 6 was further evaluated in several
species and was found to be >70% in rat, dog, and
monkey. Compound 6 has excellent activity against
MMP-2 and -9 (IC50s ) 0.78 and 0.50, respectively) and
greater than 11 000-fold selectivity for the inhibition of
MMP-2 and -9 over MMP-1 (IC50 ) 8900 nM).
Derivatives of acetonide 6 were also synthesized and
tested as summarized in Table 6. The epimers 19v-x
were less potent inhibitors of MMP-2 and -9 (1.4-480
nM). Surprisingly, even small changes to the acetonide
such as adding a methyl substituent (19y,z) or insertion
of a methylene linker (19a a ) also led to decreased
activity and diminished oral exposure.
The retrohydroxamate 6 was judged as the most
promising candidate for further development due to its
favorable combination of potency, selectivity, and bio-
availability. Its activities against other MMPs are listed
in Table 7. It is a potent inhibitor of MMP-3 (strome-
lysin), -8 (neutrophil collagenase), and -13 (collagenase-
3) but does not inhibit MMP-7 (matrilysin). Retrohy-
droxamate 6 is a more potent inhibitor of MMP-2 and
-9 than 4. It is also more selective for the inhibition of
MMP-2 and -9 over MMP-1 than 2. Because 6 possesses
Con clu sion
We have reported that the replacement of the ether
linkage of 5 with a sulfone group leads to increased
inhibition of MMP-2 and -9 within a series of retrohy-
droxamates. Further exploration of the SAR of the
sulfone retrohydroxamates led to orally bioavailable
phenoxyphenyl sulfone retrohydroxamates, which are
highly selective for the inhibition of MMP-2 and -9 over

Phenoxyphenyl Sulfone N-Formylhydroxylamines
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1 225
Ta ble 7. Inhibition of MMPs and Cellular TNFR Release
MMP IC50 (nM)a
cmpd
MMP-1
MMP-2
MMP-1/MMP-2
MMP-3
MMP-7 MMP-8 MMP-9 MMP-13 cellular TNFR releaseb
1
2
0.78
5.7
25
0.41
0.048
41
0.41
119
0.61
>455
11,400
14
3.5
157
134
4.1
72
0.47
0.54
0.79
0.048
25
301
0.50
1.2
0.20
2100
8600
3c
4c
6
>5000
11
8900 ( 4700 (2) 0.78 ( 0.20 (2)
12 ( 3.0 (3) 11 000
5.0
3.3
>50 000
a
b
( standard deviation (number of determinations). Release of TNFR from LPS-stimulated THP-1 cells. c Ki literature values (ref 5).
product was precipitated out by addition of ether and hexanes
and collected by vacuum filtration. After purification by silica
gel chromatography (10% hexanes/CH2Cl2 to 20% EtOAc/CH2-
Cl2) (96% yield), 1.5 g (5.3 mmol) of the rearranged material
was dissolved in 40 mL of methanol. NaOH(aq) (3 N, 3.5 mL,
10.6 mmol) was added, and the mixture was heated at reflux
for 1.5 h. After the mixture was cooled to room temperature,
some of the methanol was removed by rotary evaporation and
the mixture was adjusted to pH 7 using 1 N HCl. The crude
mixture was partitioned between EtOAc and H2O, dried over
MgSO4, filtered, and concentrated to give the thiol, 4′-mer-
1
captobiphenyl-4-carbonitrile, (0.98 g, 87%). H NMR (DMSO-
d6): δ 7.92-7.84 (m, 4H), 7.66-7.63 (m, 2H), 7.44-7.40 (m,
2H), 5.65 (br, SH).
To a solution of the thiol (1.04 g, 4.9 mmol) in 50 mL of
DMF at -5 °C were added K2CO3 (612 mg, 4.41 mmol) and
the R-bromoketone, 3-(3-bromo-2-oxopropyl)-5,5-dimethylimi-
dazolidine-2,4-dione (7a )12 (1.3 g, 4.9 mmol). After 1 h at -5
°C, the reaction was quenched in H2O, extracted with EtOAc,
washed with H2O and brine, dried over Na2SO4, filtered, and
concentrated. Purification by silica gel flash chromatography
(1:1 EtOAc/hexanes) gave the ketone 9a in 86% yield (1.68 g).
F igu r e 1. Effects of 6 on the growth of B16 melanoma cells
1H NMR (DMSO-d6): δ 8.38 (br, NH), 7.94-7.87 (m, 4H),
implanted subcutaneously in the flank of mice (po, bid, d
7.73-7.69 (m, 2H), 7.45-7.41 (m, 2H), 4.51 (s, 2H), 4.26 (s,
7-21). Percent inhibition of control (2 g) in parentheses of
2H), 1.30 (s, 6H). MS (ESI) m/z: 394 (M + H), 411 (M + NH4),
legend.
416 (M + Na).
4′-[3-(4,4-Dim et h yl-2,5-d ioxoim id a zolid in -1-yl)-2-h y-
dr oxyam in opr opylsu lfan yl]biph en yl-4-car bon itr ile (10a).
MMP-1. Our research culminates in the discovery of the
highly potent and selective MMP inhibitor 6. Compound
6 possesses greater potency against MMP-2 and -9 than
our previous biphenyl ether retrohydroxamate 5 and is
more selective than the clinical candidate 2. Compound
6 has pharmacokinetics consistent with once a day
dosing. Additionally, 6 exhibits significant inhibition of
tumor growth in animal cancer models and is currently
undergoing phase I clinical trials in cancer patients.
A solution of the ketone 9a (1.67 g, 4.24 mmol) in 40 mL of
1:1 ethanol/THF was treated with hydroxylamine‚hydrochloride
(324 mg, 4.66 mmol) and pyridine (378 µL, 4.66 mmol), stirred
at 23 °C for 16 h, and partitioned between EtOAc and
saturated NaHCO3. The organic layer was washed sequentially
with water and brine, dried (Na2SO4), and concentrated to
provide the oxime, (4′-[3-(4,4-dimethyl-2,5-dioxoimidazolidin-
1-yl)-2-hydroxyiminopropylsulfanyl]biphenyl-4-carbonitrile,
which was used without further purification. 1H NMR (DMSO-
d6): δ 11.28 (s, 0.5H), 11.25 (s, 0.5H), 8.42 (s, 0.5H), 8.30 (s,
0.5H), 7.94-7.87 (m, 4H), 7.74-7.70 (m, 2H), 7.51-7.45 (m,
2H), 4.30 (s, 1H), 4.20 (s, 1H), 3.90 (s, 1H), 3.72 (s, 1H), 1.30
(s, 3H), 1.27 (s, 3H). MS (ESI) m/z: 409 (M + H), 431 (M +
Na).
A solution of the oxime (4.16 mmol) in 40 mL of 1:1 ethanol/
THF was treated sequentially with borane‚pyridine (1.26 mL,
12.48 mmol) and then dropwise with hydrochloric acid (6.25
mL, 25 mmol, 4 N in dioxane), stirred for 5 h at ambient
temperature, poured into saturated NaHCO3, and extracted
with EtOAc. The combined organic extracts were washed with
brine, dried (Na2SO4), and concentrated. Purification on silica
gel (2% methanol/CH2Cl2) provided the hydroxylamine 10a in
65% yield (1.1 g). 1H NMR (DMSO-d6): δ 8.30 (br, NH), 7.93-
7.86 (m, 4H), 7.72-7.69 (m, 2H), 7.45-7.41 (m, 2H), 7.23 (d,
J ) 3.0 Hz, OH), 5.81 (t, J ) 3.0 Hz, NH), 3.57-3.54 (m, 2H),
3.24-3.13 (m, 2H), 2.98-2.91 (m, 1H), 1.27 (s, 6H). MS (ESI)
m/z: 410 (M + H).
Exp er im en ta l Section
Ch em istr y. Melting points are uncorrected. 1H NMR
spectra were recorded on a GE QE300 spectrometer, and
chemical shifts are reported in parts per million (ppm, δ)
relative to tetramethylsilane as an internal standard. Mass
spectra were obtained on a Finnigan MAT SSQ700 instrument.
Optical rotations were obtained on a Perkin-Elmer 241 pola-
rimeter with a continuous Na lamp (569 nM). Elemental
analyses (C, H, N) were performed by Robertson Microlit
Laboratories, Inc., Madison, NJ . Silica gel 60 (E. Merck, 230-
400 mesh) was used for preparative column chromatrography.
THF was freshly distilled from sodium benzophenone ketyl.
Meth od A. P r ep a r a tion of 11a .
4′-[3-(4,4-Dim et h yl-2,5-d ioxoim id a zolid in -1-yl)-2-oxo-
p r op ylsu lfa n yl]bip h en yl-4-ca r bon itr ile (9a ). To a solution
of 4′-hydroxybiphenyl-4-carbonitrile (10 g, 51.2 mmol) in 100
mL of DMF were added cesium carbonate (20 g, 61.4 mmol)
and dimethylthiocarbamoyl chloride (7.6 g, 61.4 mmol). The
reaction mixture was stirred at 23 °C for 16 h, partitioned
between H2O and EtOAc, extracted with EtOAc, washed with
brine, dried over MgSO4, filtered, and concentrated. The crude
thiocarbamate was melted at 210 °C under argon for 10 min
to effect the rearrangement. After the mixture was cooled to
room temperature and the solid was dissolved in CH2Cl2, the
N -[1-(4′-Cya n ob ip h e n yl-4-su lfon ylm e t h yl)-2-(4,4-d i-
m eth yl-2,5-dioxoim idazolidin -1-yl)eth yl]-N-h ydr oxyfor m -
a m id e (11a ). A solution of the hydroxylamine 10a (1.1 g, 2.7
mmol) in 25 mL of THF was cooled to 0 °C and treated with
formic acetic anhydride (2.7 mL, 2.7 mmol, 1 M in THF),
stirred for 30 min, and partitioned between saturated NaHCO3
and EtOAc. The organic extracts were washed with H2O and

226 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1
Wada et al.
brine, dried (Na2SO4), and concentrated. Purification on silica
gel (2% methanol/CH2Cl2) provided the sulfide retrohydrox-
amate, N-[1-(4′-cyanobiphenyl-4-sulfanylmethyl)-2-(4,4-di-
methyl-2,5-dioxoimidazolidin-1-yl)ethyl]-N-hydroxyformamide,
3.91-3.77 (m, 3H), 3.37-3.33 (m, 2H), 1.21 (s, 3H), 1.21 (s,
3H). MS (ESI) m/z: 463 (M + 1), 480 (M + NH4), 485 (M +
Na).
(4S)-2,2-Dim et h yl-4-((E/Z)-2-(4-(4-t r iflu or om et h oxy-
ph en oxy)ph en ylsu lfon yl)eth en yl)-[1,3]dioxolan e (30). The
alcohol 29 was dissolved in CH2Cl2 (250 mL), treated with
triethylamine (31.1 mL, 222 mmol), cooled to 0 °C, and treated
with methanesulfonyl chloride (8.0 mL, 103 mmol) over 40
min. The mixture was stirred for 15 min, warmed to room
temperature, stirred for 1 h, washed sequentially with water,
1 M HCl, water, 1 M NaHCO3, water, and brine, dried (Na2-
SO4), and filtered. The concentrate was purified by flash
column chromatography on silica gel using 98:2 CH2Cl2/EtOAc.
The purified concentrate was recrystallized from MTBE/
hexanes to provide the desired product as a mixture of cis and
trans isomers (1:10) in 91% yield from 28. Trans 1H NMR
(DMSO-d6): δ 7.91-7.86 (m, 2H), 7.49-7.46 (m, 2H), 7.32-
7.26 (m, 2H), 7.24-7.18 (m, 2H), 6.88 (m, 2H), 4.77-4.71 (m,
1H), 4.15 (dd, J ) 8.5, 6.8 Hz, 1H), 3.70 (dd, J ) 8.5, 6.5 Hz,
1H), 1.33 (s, 3H), 1.29 (s, 3H). MS (ESI): 445 (M + 1), 462 (M
1
in 74% yield (877 mg). H NMR (DMSO-d6): δ 9.75 (s, 0.5H),
9.51 (s, 0.5H), 8.37 (s, 0.5H), 8.33 (s, 0.5H), 8.27 (s, 0.5H), 8.25
(s, 0.5H), 7.94-7.86 (m, 4H), 7.75-7.70 (m, 2H), 7.51-7.43
(m, 2H), 4.69-4.55 (m, 0.5H), 4.14-4.04 (m, 0.5H), 3.76-3.50
(m, 2H), 3.28-2.97 (m, 2H), 1.29 (s, 3H), 1.23 (s, 3H). MS (ESI)
m/z: 437 (M - H)-.
A solution of the sulfide (840 mg, 1.9 mmol) in 20 mL of 4:1
methanol/H2O at 0 °C was treated with NaHCO3 (399 mg, 4.75
mmol) and OXONE (489 mg, 4.75 mmol active O), stirred at
23 °C for 1 h, and partitioned between H2O and EtOAc. The
organic extracts were washed with brine, dried over Na2SO4,
filtered, and concentrated. The crude material was purified
on silica gel (1-10% methanol/CH2Cl2) to give the sulfone
retrohydroxamate 11a in 54% yield (450 mg). 1H NMR (DMSO-
d6): δ 9.66 (s, 0.5H), 9.51 (s, 0.5H), 8.38 (s, 0.5H), 8.34 (s, 0.5H),
8.10 (s, 0.5H), 8.07-7.96 (s, 8H), 7.74 (s, 0.5H), 4.94-4.86 (m,
0.5H), 4.58-4.50 (m, 0.5H), 3.80-3.37 (m, 4H), 1.23-1.20 (m,
6H). MS (ESI) m/z: 488 (M + NH4). Anal. (C22H22N4O6S) C,
H, N.
1
+ NH4), 467 (M + Na). Cis H NMR (DMSO-d6): δ 7.95-7.90
(m, 2H), 7.50-7.47 (m, 2H), 7.34-7.28 (m, 2H), 7.25-7.20 (m,
2H), 6.71 (dd, J ) 11.4, 1.4 Hz, 1H), 6.41 (dd, J ) 11.4, 7.7
Hz, 1H), 5.53-5.46 (m, 1H), 4.23 (dd, J ) 8.4, 7.0 Hz, 1H),
3.66 (dd, J ) 8.4, 6.2 Hz, 1H), 1.36 (s, 3H), 1.32 (s, 3H).
Meth od B. P r ep a r a tion of 6.
4-(4′-Tr iflu or om eth oxyp h en oxy)p h en yl Meth yl Su l-
fon e (26). A mixture of anhydrous potassium carbonate (159.0
g, 1.15 mol), 4-trifluoromethoxyphenol (150 mL, 1.16 mol), and
4-fluorophenyl methyl sulfone (200.0 g, 1.15 mol) in DMSO
(1.5 L) was heated to 120 °C and stirred vigorously for 18 h.
The mixture was cooled to room temperature, filtered through
a glass wool plug with MTBE, and concentrated. The concen-
trate was diluted with water (1 L) and cooled to 0 °C. The
resulting precipitate was collected by filtration, washed with
water, and dried under vacuum at 50 °C. Recrystallization
from MTBE/hexanes provided 26 in 89% yield; mp 71.5-72
°C. 1H NMR (DMSO-d6): δ 7.96-7.91 (m, 2H), 7.49-7.44 (9M,
2H), 7.31-7.26 (m, 2H), 7.24-7.19 (m, 2H), 3.20 (s, 3H). MS
(ESI) m/z: 350 (M + 1).
1-((4R)-2,2-Dim eth yl-[1,3]d ioxola n -4-yl)-2-(4-(4-tr iflu o-
r om eth oxyp h en oxy)p h en ylsu lfon yl)eth a n on e (28). A so-
lution of 26 (36.6 g, 0.11 mol) in THF (600 mL) at -78 °C was
treated with n-butyllithium (2.5 M in hexanes, 48.0 mL, 0.12
mol) over 5 min and stirred for 1 h. The solution was
transferred by cannula to a -78 °C solution of methyl (4R)-
2,2-dimethyl-[1,3]dioxolane-4-carboxylate (27, 19.6 g, 0.12 mol)
in THF (400 mL) over 30 min, stirred for 3 h, treated with 1
M H2SO4 (75 mL), and warmed to 0 °C. The aqueous phase
was extracted with MTBE (500 mL), and the combined organic
phases were washed with water and brine, dried (Na2SO4),
and filtered. The solution was passed through a pad of silica
gel (100 g), the pad was washed with MTBE, and the resulting
solution was concentrated to one-fifth of the original volume,
treated with hexanes (300 mL), and cooled to room tempera-
ture. The resulting precipitate was collected by filtration,
washed with MTBE/hexanes, and dried to provide the desired
product in 79% yield; mp 80-81 °C; [R]D25 + 49.9° (c 4.1, CH2-
Cl2). 1H NMR (CDCl3): δ 7.91-7.87 (m, 2H), 7.29-7.26 (m,
2H), 7.13-7.07 (m, 4H), 4.60 (d, J ) 14.8 Hz, 1H), 4.54 (dd, J
) 7.2, 5.1 Hz, 1H), 4.32 (d, J ) 14.8 Hz, 1H), 4.16 (dd, J )
8.9, 7.2 Hz, 1H), 4.11 (dd, J ) 8.9, 5.1 Hz, 1H), 1.45 (s, 3H),
1.38 (s, 3H). MS (ESI) m/z: 478 (M + NH4), 483 (M + Na).
(4S)-4-((1S)-1-(H yd r oxya m in o)-2-(4-(4-t r iflu or om et h -
oxyphenoxy)phenylsulfonyl)ethyl)-2,2-dimethyl-[1,3]dioxo-
la n e (31). A solution of 30 (28.6 g, 64.3 mmol) in THF (800
mL) at -35 °C was treated with 50% aqueous hydroxylamine
(6.4 g, 193 mmol), held at -10 °C for 5 h, and concentrated.
The concentrate was dissolved in MTBE, washed with water
and brine, dried (Na2SO4), filtered, and concentrated. The
concentrate was recrystallized from MTBE/hexanes to provide
a 9:1 mixture of two diastereomers, which were separated by
flash column chromatography on silica gel using 70:30 hex-
anes/EtOAc to provide the desired product in 69% yield. 1H
NMR (DMSO-d6): δ 7.94-7.89 (m, 2H), 7.50-7.46 (m, 2H),
7.41 (d, J ) 3.0 Hz, OH), 7.31-7.26 (m, 2H), 7.25-7.20 (m,
2H), 5.60 (t, J ) 3.0 Hz, NH), 4.27-4.21 (m, 1H), 3.92 (dd, J
) 8.8, 6.8 Hz, 1H), 3.68 (dd, J ) 8.8, 6.4 Hz, 1H), 3.56-3.49
(m, 1H), 3.25-3.17 (m, 2H), 1.27 (s, 3H), 1.22 (s, 3H). MS (ESI)
m/z: 478 (M + 1), 500 (M + Na).
N-[(1S)-1-((4S)-2,2-Dim eth yl-[1,3]d ioxola n -4-yl)-2-(4-(4-
(tr iflu or om eth oxyp h en oxy)p h en ylsu lfon yl)eth yl]-N-h y-
d r oxyfor m a m id e (6). A solution of 31 (21.6 g, 45.2 mmol) in
MTBE (200 mL) was treated with trifluoroethyl formate
reagent (8.9 M, 50 mL, 443 mmol), heated to reflux, stirred
for 20 h, and slowly cooled to room temperature. The mixture
was cooled to 0 °C, and the resulting precipitate was collected
by filtration, washed with cold MTBE, and dried to provide
25
the desired product in 96% yield; mp 127.5-128.5 °C; [R]D
+
1
4.85° (c 2.14, CH2Cl2). H NMR (DMSO-d6): δ 1.20 (s, 1.2H),
1.23 (s, 1.8H), 1.26 (s, 1.2H), 1.30 (s, 1.8H), 3.32 (t, J ) 7.5
Hz, 0.6H), 3.59-3.76 (m, 2.1H), 3.92-4.15 (m, 3H), 4.57 (t, J
) 8.4 Hz, 0.4H), 7.18-7.32 (m, 4H), 7.48 (d, J ) 9.6 Hz, 2H),
7.82 (s, 0.6H), 7.88 (d, J ) 9.6 Hz, 0.8H), 7.94 (d, J ) 9.6 Hz,
1.2H), 8.13 (s, 0.4H), 9.63 (s, 0.6H), 10.00 (s, 0.4 H). MS (APCI)
m/z: 506 (M + H). Anal. (C21H22F3NO8S) C, H, N.
Meth od C. P r ep a r a tion of 24a .
Methyl(4-(4-Tr ifluor om ethoxyphenoxy)phen ylsu lfan yl)-
a ceta te (21a ). A solution of the intermediate xanthate,
dithiocarbonic acid O-ethyl ester S-(4-(4-trifluoromethoxyphe-
noxy)phenyl)ester, (5.0 g, 13.95 mmol, see 11b), and powdered
KOH (2.0 g, 35.71 mmol) in 50 mL of ethanol was heated at
80 °C for 2 h and cooled to room temperature. Another 1.0 g
of KOH and bromo acetate (1.94 g, 13.95 mmol) were added.
The reaction mixture was stirred for 16 h at 23 °C, heated at
80 °C for 3 h, cooled to 0 °C, acidified to pH 2-3 using 1 N
HCl, partitioned between H2O and EtOAc, extracted with
EtOAc, washed with H2O and brine, dried over MgSO4,
filtered, and concentrated. The oil was dissolved in 50 mL of
methanol, and the solution was cooled to 0 °C. Thionyl chloride
(1.5 mL, 20.9 mmol) was added. The reaction mixture was
stirred for 16 h at 23 °C, quenched with H2O, extracted with
(4S)-2,2-Dim et h yl-4-((E/Z)-2-(4-(4-t r iflu or om et h oxy-
p h en oxy)p h en ylsu lfon yl)eth en yl)-[1,3]d ioxola n e (29). A
suspension of 28 (37.3 g, 81 mmol) in ethanol (250 mL) at 23
°C was treated with sodium borohydride (1.40 g, 37 mmol),
stirred for 30 min, treated dropwise with acetic acid (1 mL),
and concentrated. The concentrate was partitioned between
EtOAc and water, and the organic phase was washed sequen-
tially with 1 M NaHCO3, water, and brine, dried (Na2SO4),
and filtered. The solution was passed through a pad of silica
gel (200 g) using 3:2 hexanes/EtOAc, concentrated. The crude
alcohol was carried on to the next reaction without further
purification. 1H NMR (DMSO-d6): δ 7.93-7.87 (m, 2H), 7.50-
7.46 (m, 2H), 7.28-7.18 (m, 4H), 5.39 (d, J ) 6.5 Hz, OH),

Phenoxyphenyl Sulfone N-Formylhydroxylamines
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1 227
EtOAc, washed with H2O and brine, dried over MgSO4,
filtered, and concentrated. Purification by silica gel chroma-
tography (8:1 hexanes/EtOAc) gave 2.93 g (59%) of the methyl
2H), 3.83-3.56 (m, 2H), 4.51 (m, 0.5H), 5.04 (m, 0.5H), 7.30-
7.20 (m, 4H), 7.48 (d, 2H, J ) 9.0 Hz), 7.85 (s, 0.5H), 7.91 (dd,
2H, J ) 9.0, 3.0 Hz), 8.10 (s, 0.5H), 9.89 (s, br, 0.5H), 10.08 (s,
br, 0.5H). MS (ESI) m/z: 527 (M + H), 544 (M + NH4). Anal.
(C19H21F3N2O8S2) C, H, N.
1
ester. H NMR (CDCl3): δ 7.46-7.41 (m, 2H), 7.21-7.18 (m,
2H), 7.03-6.98 (m, 2H), 6.97-6.92 (m, 2H), 3.72 (s, 3H), 3.60
(s, 2H).
Com p ou n d s P r ep a r ed by Meth od A.
2-Oxo-3-(4-(4-tr iflu or om eth oxyp h en oxy)p h en ylsu lfa n -
yl)p r op a n e-1-su lfon ic Acid Dim eth yl Am id e (22a ). To a
solution of N,N-dimethylmethanesulfonamide (20a , 560 mg,
4.47 mmol) in 25 mL of THF at -25 °C was added n-
butyllithium (2.0 mL, 4.92 mmol, 2.5 M in hexanes). The
reaction mixture was stirred at -25 °C for 1.5 h and then
cooled to -78 °C. A solution of 21a (1.6 g, 4.47 mmol) in 15
mL of THF was added. The reaction mixture was stirred for
16 h, quenched with saturated NH4Cl and H2O, extracted with
EtOAc, washed with brine, dried over MgSO4, filtered, and
concentrated. Purification by silica gel chromatography (2:1
hexanes/EtOAc) gave 0.917 g (46%) of the ketone. 1H NMR
(CDCl3): δ 7.37 (d, J ) 6.6 Hz, 2H), 7.20 (d, J ) 9.0 Hz, 2H),
7.01 (d, J ) 6.6 Hz, 2H), 6.94 (d, J ) 8.7 Hz, 2H), 4.22 (s, 2H),
3.90 (s, 2H), 2.88 (s, 6H). MS (ESI) m/z: 450 (M + H), 450 (M
+ Na).
N-[2-(4,4-Dim eth yl-2,5-d ioxoim id a zolid in -1-yl)-2-(4-(4-
tr iflu or om eth oxyp h en oxy)p h en ylsu lfon ylm eth yl)eth yl]-
N-h yd r oxyfor m a m id e (11b ). To a solution of 4-trifluoro-
methoxyphenol (5 g, 28 mmol) in 75 mL of DMSO were added
potassium t-butoxide (3.36 g, 30 mmol) and a solution of
1-fluoro-4-nitrobenzene (2 mL, 19 mmol) in 25 mL of DMSO.
The reaction mixture was heated at 100 °C for 1 h, cooled to
room temperature, partitioned between CH2Cl2 and 1 N
NaOH, washed with 1 N NaOH and brine, dried over MgSO4,
filtered, and concentrated. The nitro group was then reduced
to the amine by treatment of the crude material with 840 mg
of 10% Pd-C under 4 atm of H2 in 200 mL of methanol for 3
h followed by filtration and concentration. To a cooled (ice bath)
mixture of concentrated HCl (3.4 mL) and ice (4.9 g) was added
the amine. A solution of NaNO2 (1.3 g, 19 mmol) in 7.4 mL of
H2O was added dropwise. After 30 min, the mixture was added
slowly to a solution of potassium ethyl xanthate (6 g, 38 mmol)
in 7.4 mL of H2O at 70 °C. The reaction mixture was heated
for 1 h at 70 °C, cooled to room temperature, adjusted to pH
8 using 1 N HCl, extracted with EtOAc, dried over MgSO4,
filtered, and concentrated. The crude dithiocarbonate was
dissolved in 30 mL of ethanol and treated with KOH (4.7 g,
85 mmol) and heated at reflux for 2 h. The reaction mixture
was cooled to room temperature, adjusted to pH 7 using 1 N
HCl, extracted with EtOAc, dried over MgSO4, filtered, and
concentrated to give the thiol, 4-(4-trifluoromethoxyphenoxy)-
benzenethiol. 1H NMR (DMSO-d6): δ 7.39-7.32 (m, 4H), 7.09-
7.06 (m, 2H), 7.00-6.97 (m, 2H), 5.49 (br, SH).
The thiol was carried on to the title compound 11b as
described for the conversion of 7a to 11a . 1H NMR (DMSO-
d6): δ 9.64 (s, 0.5H), 9.45 (s, 0.5H), 8.35 (d, 1H, J ) 12.2 Hz),
8.10 (s, 0.5H), 7.91 (dd, 2H, J ) 8.9, 2.8 Hz), 7.68 (s, 0.5H),
7.47 (d, 2H, J ) 9.2 Hz), 7.30-7.21 (m, 4H), 4.88-4.77 (m,
0.5H), 4.51-4.40 (m, 0.5H), 3.73-3.38 (m, 4H), 1.24 (s, 3H),
1.22 (s, 3H). MS (ESI) m/z: 546 (M + H), 568 (M + Na), 544
(M - H). Anal. (C22H22N3O8SF3) C, H, N.
N-[1-(4-(4-Cyan oph en oxy)ph en ylsu lfon ylm eth yl)-2-(4,4-
d im et h yl-2,5-d ioxoim id a zolid in -1-yl)et h yl]-N-h yd r oxy-
for m a m id e (11c). Compound 11c was prepared as described
for 11b, except the thiol was prepared using 4-cyanophenol
and Fe/NH4Cl in methanol/H2O for the reduction of the nitro
group to the amine. 1H NMR (DMSO-d6): δ 9.70 (s, 0.5H), 9.50
(s, 0.5H), 8.39 (s, 0.5H), 8.34 (s, 0.5H), 8.10 (s, 0.5H), 7.98-
7.91 (m, 4H), 7.68 (s, 0.5H), 7.37-7.27 (m, 4H), 4.88-4.77 (m,
0.5H), 4.52-4.41 (m, 0.5H), 3.78-3.39 (m, 4H), 1.24-1.22 (m,
6H). MS (ESI) m/z: 487 (M + 1). Anal. (C22H22N4O7S) C, H,
N.
2-H yd r oxy-3-(4-(4-t r iflu or om et h oxyp h en oxy)p h en yl-
su lfon yl)p r op a n e-1-su lfon ic Acid Dim eth yl Am id e (23a ).
To a solution of 22a (888 mg, 1.98 mmol) in 20 mL of methanol
at 0 °C was added portionwise NaBH4 (90 mg, 2.38 mmol).
The reaction mixture was stirred at 0 °C for 1 h, quenched
with acetone, concentrated, diluted with H2O, extracted with
EtOAc, washed with brine, dried over MgSO4, filtered, and
concentrated to give the crude alcohol, 2-hydroxy-3-(4-(4-
trifluoromethoxyphenoxy)phenylsulfanyl)propane-1-sulfonic acid
1
dimethyl amide. H NMR (DMSO-d6): δ 7.44 (d, J ) 9.0 Hz,
2H), 7.39 (d, J ) 9.0 Hz, 2H), 7.11 (d, J ) 9.0 Hz, 2H), 7.04 (d,
J ) 9.0 Hz, 2H), 5.55 (d, J ) 5.7 Hz, 1H), 4.02 (m, 1H), 3.30-
3.02 (m, 4H), 2.74 (s, 6H).
To a solution of the alcohol (880 mg, 1.95 mmol) in 50 mL
of methanol were added 25 mL of H2O, NaHCO3 (410 mg, 4.88
mmol), and OXONE (3.0 g, 4.88 mmol). The suspension was
stirred at 23 °C for 16 h, diluted with H2O, extracted with
EtOAc, washed with brine, dried over MgSO4, filtered, and
1
concentrated to give the crude sulfone. H NMR (DMSO-d6):
δ 7.91 (d, J ) 9.3 Hz, 2H), 7.49 (d, J ) 9.3 Hz, 2H), 7.28 (d, J
) 9.3 Hz, 2H), 7.22 (d, J ) 9.3 Hz, 2H), 5.58 (d, J ) 6.6 Hz,
1H), 4.36 (m, 1H), 3.61 (dd, J ) 14.4, 4.5 Hz, 1H), 3.50 (dd, J
) 14.4, 7.5 Hz, 1H), 3.28 (dd, J ) 14.4, 4.5 Hz, 1H), 3.19 (dd,
J ) 14.4, 7.5 Hz, 1H), 2.73 (s, 6H). MS (ESI) m/z: 484 (M +
H), 501 (M + NH4).
2-(F or m ylh yd r oxya m in o)-3-(4-(4-t r iflu or om e t h oxy-
p h en oxy)p h en ylsu lfon yl)p r op a n e-1-su lfon ic Acid Di-
m eth yla m id e (24a ). To a solution of the â-hydroxy sulfone
23a (920 mg, 1.90 mmol) in 20 mL of CH2Cl2 at 0 °C were
added triethylamine (398 µL, 2.86 mmol) and methanesulfonyl
chloride (177 µL, 2.29 mmol). The reaction mixture was stirred
at 0 °C for 1.5 h, diluted with CH2Cl2, washed with 1 N HCl
and H2O, dried over MgSO4, filtered, and concentrated to give
a mixture of the mesylate, 1-dimethylsulfamoylmethyl-2-(4-
(4-trifluoromethoxyphenoxy)phenylsulfonyl)ethyl methansul-
fonate and the corresponding elimination product alkene.
N-[1-(4-(4-Ch lor op h en oxy)p h en ylsu lfon ylm et h yl)-2-
(4,4-d im e t h yl-2,5-d ioxoim id a zolid in -1-yl)e t h yl]-N -h y-
d r oxyfor m a m id e (11d ). Compound 11d was prepared as
described for 11b, except the thiol was prepared using 4-chlo-
rophenol and Fe/NH4Cl in methanol/H2O for the reduction of
1
To a solution of the mesylate/alkene (960 mg, 1.71 mmol)
in 20 mL of THF was added aqueous hydroxylamine (1 mL,
17.1 mmol, 50 wt %). The reaction mixture was heated at
reflux for 1 h, cooled to room temperature, concentrated,
diluted with H2O, extracted with ethyl acetate, washed with
brine, dried over MgSO4, filtered, and concentrated to give the
crude hydroxylamine, 2-hydoxyamino-3-(4-(4-trifluorometh-
oxyphenoxy)phenylsulfonyl)propane-1-sulfonic acid dimethyl
the nitro group to the amine. H NMR (DMSO-d6): δ 9.67 (s,
0.5H), 9.50 (s, 0.5H), 8.36 (d, 1H, J ) 13.2 Hz), 8.10 (s, 0.5H),
7.90 (dd, 2H, J ) 8.8, 3.0 Hz), 7.68 (s, 0.5H), 7.53 (d, 2H, J )
8.8 Hz), 7.20 (d, 4H, J ) 8.8 Hz), 4.89-4.77 (m, 0.5H), 4.52-
4.40 (m, 0.5H), 3.68-3.38 (m, 4H), 1.25-1.21 (m, 6H). MS
(ESI) m/z: 496 (M + H), 513 (M + NH4), 494 (M - H). Anal.
(C21H22ClN3O7S).
N -H y d r o x y -N -[1-(4-(4-t r iflu o r o m e t h o x y p h e n o x y )-
ph en ylsu lfon ylm eth yl)-2-(3,4,4-tr im eth yl-2,5-dioxoim id a -
zolid in -1-yl)eth yl]for m a m id e (11e). Compound 11e was
prepared as described for 11b, except using 3-(3-bromo-2-
oxopropyl)-1,5,5-trimethylimidazolidine-2,4-dione (7b).12 1H
NMR (DMSO-d6): δ 9.51 (s, 0.5H), 9.70 (s, 0.5H), 8.09 (s, 0.5H),
7.91 (dd, J ) 8.9, 3.1 Hz, 2H), 7.68 (s, 0.5H), 7.47 (d, J ) 9.2
H, 2 Hz), 7.31-7.21 (m, 4H), 4.90-4.78 (m, 0.5H), 4.51-4.40
(m, 0.5H), 3.74-3.40 (m, 4H), 2.76 (d, J ) 1.7 Hz, 3H), 1.27-
1
amide. H NMR (DMSO-d6): δ 7.92 (d, J ) 9.0 Hz, 2H), 7.60
(d, J ) 3.3 Hz, 1H), 7.48 (d, J ) 9.9 Hz, 2H), 7.29 (d, J ) 9.3
Hz, 2H), 7.24 (d, J ) 9.0 Hz, 2H), 5.71 (t, J ) 3.3 Hz, 1H),
3.62-3.46 (m, 2H), 3.47-3.18 (m, 2H), 2.74 (s, 6H). MS (ESI)
m/z: 499 (M + H).
The hydroxylamine was carried on to the title compound
as described for the conversion of 31 to 6: mp 124.5-125.5
°C. 1H NMR (DMSO-d6): δ 2.74-2.69 (2 s, 6H), 3.44-3.25 (m,

228 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1
Wada et al.
1.22 (m, 6H). MS (ESI) m/z: 558 (M - H), 560 (M + H), 577
(M + NH4), 582 (M + Na). Anal. (C23H24F3N3O8S) C, H, N.
2H), 7.31-7.26 (m, 2H), 7.22-7.18 (m, 2H), 5.64 (d, J ) 7.8
Hz, 1H), 4.99-4.90 (m, 0.5H), 4.43-4.34 (m, 0.5H), 4.03-3.87
(m, 2H), 3.75-3.63 (m, 1H), 3.52-3.41 (m, 1H), 3.17 (s, 3H).
MS (ESI): 544 (M + 1). Anal. (C22H20F3N3O8S) C, H, N.
N-[2-(4,4-Dim eth yl-2,5-d ioxoim id a zolid in -1-yl)-1-(4′-tr i-
flu or om et h oxyb ip h en yl-4-su lfon ylm et h yl)et h yl]-N-h y-
d r oxyfor m a m id e (13a ). Compound 13a was prepared as
described for the preparation of 13d , except using 4-(trifluo-
romethoxy)phenylboronic acid; mp 195-197 °C. 1H NMR
(DMSO-d6): δ 9.62 (bs, 1H), 8.29-8.43 (c, 1H), 8.10 (s, 1/2H),
7.95-8.05 (c, 4H), 7.92 (d, 1H, J ) 3 Hz), 7.88 (d, 1H, J ) 3
Hz), 7.74 (s, 1/2H), 7.54 (s, 1H), 7.49 (s, 1H), 4.87-4.99 (c,
1/2H), 4.50-4.63 (c, 1/2H), 3.43-3.80 (c, 4H), 1.22 (s, 6H). MS
(ESI) m/z: 530 (M + H), 547 (M + NH4), 552 (M + Na), 1076
(2M + NH4), 1081 (2M + Na). Anal. (C22H22F3N3O7S) C, H, N.
N-[1-(4′-Bu t oxyb ip h en yl-4-su lfon ylm et h yl)-2-(4,4-d i-
m eth yl-2,5-dioxoim idazolidin -1-yl)eth yl]-N-h ydr oxyfor m -
a m id e (13b). Compound 13b was prepared as described for
the preparation of 13d , except using 4-butoxyphenylboronic
acid. 1H NMR (DMSO-d6): δ 0.92-0.97 (t, 3H, J ) 7.5 Hz),
1.20, 1.22 (s+s, 6H), 1.42-1.52 (m, 2H), 1.68-1.77 (m, 2H),
3.41-3.72 (m, 3.5H), 4.02-4.06 (t, 2H, J ) 6.6 Hz), 4.52 (m,
0.5H), 4.89 (m, 0.5H), 7.05-7.08 (d, 2H, J ) 8.4 Hz), 7.70-
7.74 (2H), 7.91 (s, 3.5H), 8.10 (s, 0.5H), 8.32-8.35 (d, 1H, J )
9.6 Hz), 9.48 (s, 0.5H), 9.62 (s, 0.5H). MS (ESI) m/z: 518 (M +
H), 535 (M + NH4), 516 (M - H), 552 (M + Cl). Anal.
(C25H31N3O7S‚0.25H2O) C, H, N.
N-[1-(4-(4-Cya n op h en oxy)p h en ylsu lfon ylm et h yl)-2-
(3,4,4-tr im eth yl-2,5-d ioxoim id a zolid in -1-yl)eth yl]-N-h y-
d r oxyfor m a m id e (11f). Compound 11f was prepared as
described for 11b, except the thiol was prepared using 4-cy-
anophenol and Fe/NH4Cl in methanol/H2O for the reduction
of the nitro group to the amine and using 3-(3-bromo-2-
oxopropyl)-1,5,5-trimethylimidazolidine-2,4-dione (7b) in place
1
of 7a . H NMR (DMSO-d6): δ 9.74 (br, 0.5H), 9.52 (br, 0.5H),
8.10 (s, 0.5H), 7.97-7.90 (m, 4H), 7.68 (s, 0.5H), 7.36-7.28
(m, 4H), 4.89-4.79 (m, 0.5H), 4.52-4.42 (m, 0.5H), 3.76-3.37
(m, 4H), 2.76 (s, 1.5H), 2.76 (s, 1.5H), 1.26-1.23 (m, 6H). MS
(ESI) m/z: 501 (M + 1). Anal. (C23H24N4O7S) C, H, N.
N-[1-(4-(4-Ch lor op h en oxy)p h en ylsu lfon ylm et h yl)-2-
(3,4,4-tr im eth yl-2,5-d ioxoim id a zolid in -1-yl)eth yl]-N-h y-
d r oxyfor m a m id e (11g). Compound 11g was prepared as
described for 11b, except the thiol was prepared using 4-chlo-
rophenol and Fe/NH4Cl in methanol/H2O for the reduction of
the nitro group to the amine and using 3-(3-bromo-2-oxopro-
pyl)-1,5,5-trimethylimidazolidine-2,4-dione (7b) in place of 7a .
1H NMR (DMSO-d6): δ 9.78-9.71 (m, 0.5H), 9.58-9.49 (m,
0.5H), 8.09 (s, 0.5H), 7.89 (dd, J ) 5.8, 2.9 Hz, 2H), 7.68 (s,
0.5H), 7.53 (d, J ) 9.2 Hz, 2H), 7.20 (d, J ) 8.8 Hz, 4H), 4.88-
4.78 (m, 0.5H), 4.50-4.38 (m, 0.5H), 3.72-3.40 (m, 4H), 2.76
(s, 1.5H), 2.76 (s, 1.5H), 1.26-1.22 (m, 6H). MS (ESI) m/z: 510
(M + H), 527 (M + NH4), 508 (M - H). Anal. (C22H24ClN3O7S)
C, H, N.
N-H yd r oxy-N-[2-(3-m et h yl-2,6-d ioxo-3,6-d ih yd r o-2H -
p yr im id in -1-yl)-1-(4-(4-tr iflu or om eth oxyp h en oxy)p h en -
ylsu lfon ylm eth yl)eth yl]for m a m id e (11h ). To a solution of
1-methyl-1H-pyrimidine-2,4-dione (440 mg, 3.49 mmol) in 17
mL of methanol were added epibromohydrin (3 mL, 35 mmol)
and potassium carbonate (482 mg, 3.49 mmol). The reaction
mixture was stirred at room temperature for 16 h, diluted with
CH2Cl2, filtered, and concentrated to give the epoxide, 1-meth-
yl-3-oxiranylmethyl-1H-pyrimidine-2,4-dione (8a ). MS (ESI):
183 (M + 1), 200 (M + NH4). 1H NMR (DMSO-d6): δ 7.70 (dd,
J ) 7.8, 0.8 Hz, 1H), 5.69 (d, J ) 7.8, 1.4 Hz, 1H), 4.06 (dd, J
) 13.6, 4.8 Hz, 1H), 3.86 (dd, J ) 13.6, 4.8 Hz, 1H), 3.00 (s,
3H), 3.15-3.09 (m, 1H), 2.70 (t, J ) 4.6 Hz, 1H), 2.53-2.51
(m, 1H).
N-[2-(4,4-Dim eth yl-2,5-d ioxoim id a zolid in -1-yl)-1-(4′-tr i-
flu or om e t h ylb ip h e n yl-4-su lfon ylm e t h yl)e t h yl]-N -h y-
d r oxyfor m a m id e (13c). Compound 13c was prepared as
described for the preparation of 13d , except using 4-(trifluo-
romethyl)phenylboronic acid. 1H NMR (DMSO-d6): δ 1.19-
1.27 (m, 6H), 3.38-3.79 (m, 5H), 7.75 (s, 0.5H), 7.87-7.94 (m,
2H), 7.97-8.08 (m, 6H), 8.10 (s, 0.5H), 8.35 (s, 0.5H), 8.38 (s,
0.5H), 9.51 (s, 0.5H), 9.67 (s, 0.5H). MS (ESI) m/z: 514 (M +
H), 531 (M + NH4), 512 (M - H). Anal. (C22H22F3N3O6S‚
0.75H2O) C, H, N.
N-[1-(3′-Cyan om eth ylbiph en yl-4-su lfon ylm eth yl)-2-(4,4-
d im et h yl-2,5-d ioxoim id a zolid in -1-yl)et h yl]-N-h yd r oxy-
for m a m id e (13d ). The ketone, 3-(3-(4-bromophenylsulfanyl)-
2-oxopropyl)-5,5-dimethylimidazolidine-2,4-dione, was prepared
as described for 9a except using 4-bromothiophenol. The
ketone (1.0 g, 2.69 mmol) was treated with the pinacol
boronate, [3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phe-
nyl]acetonitrile (785 mg, 3.23 mmol), Pd(PPh3)4 (311 mg, 0.269
mmol), and 1 N NaOH (5.38 mL, 5.38 mmol) in 30 mL of 1,2-
dimethoxyethane at 90 °C for 3 h. The reaction mixture was
cooled to room temperature, quenched with saturated NH4Cl,
extracted with EtOAc, washed with brine, dried over Na2SO4,
filtered, and concentrated. Purification by silica gel chroma-
tography (20% EtOAc, CH2Cl2) gave 217 mg (20%) of the biaryl
ketone, [4′-(3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-oxo-
propylsulfanyl)biphenyl-3-yl]acetonitrile (12d). 1H NMR (DMSO-
d6): δ 1.49 (s, 6H), 3.75 (s, 2H), 3.81 (s, 2H), 4.55 (s, 2H), 5.30
(s, 1H), 7.29-7.34 (m, 1H), 7.42-7.55 (m 7H). MS (APCI)
m/z: 408 (M + H), 425 (M + NH4), 406 (M - H), 442 (M + Cl).
The biaryl ketone 12d was carried on to the title compound
13d as described for the conversion of 9a to 11a . 1H NMR
(DMSO-d6): δ 1.21-1.23 (6H), 3.35-3.78 (m, 5H), 4.47-4.60
(m, 0.5H), 4.86-4.96 (m, 0.5H), 7.45-7.47 (d, 1H, J ) 7.5 Hz),
7.54-7.59 (t, 1H, J ) 8.4 Hz), 7.74-7.77 (m, 2.5H), 7.94-8.02
(m, 4H), 8.09 (s, 0.5H), 8.33-8.36 (d, 1H, J ) 9.6 Hz), 9.48 (s,
0.5H), 9.63 (s, 0.5H). MS (ESI) m/z: 485 (M + H), 502 (M +
NH4), 507 (M + Na), 483 (M - H). Anal. (C23H24N4O6S‚0.4Et2O
H2O).
To a solution of the thiol, 4-(4-trifluoromethoxyphenoxy)-
benzenethiol prepared as described in 11b, (1.19 g, 4.16 mmol)
in 17 mL of DMF were added K2CO3 (478 mg, 3.46 mmol) and
the epoxide 8a (630 mg, 3.46 mmol). The reaction mixture was
heated at 100 °C for 16 h, cooled to room temperature,
partitioned between H2O and EtOAc, washed with H2O and
brine, dried over Na2SO4, filtered, and concentrated. Purifica-
tion by silica gel chromatography (1:1 to 1:4 EtOAc/hexanes)
gave 735 mg (45%) of the alcohol, 1-methyl-3-[2-hydroxy-3-(4-
(4-trifluoromethoxyphenoxy)phenylsulfonyl)propyl]-1H-pyrimi-
1
dine-2,4-dione. MS (ESI) m/z: 469 (M + 1). H NMR (DMSO-
d6): δ 7.65 (d, J ) 7.8 Hz, 1H), 7.40-7.37 (m, 4H), 7.13-7.08
(m, 2H), 7.03-6.99 (m, 2H), 5.65 (d, J ) 7.8 Hz, 1H), 5.16 (d,
J ) 5.4 Hz, OH), 4.01-3.84 (m, 3H), 3.27 (s, 3H), 3.03-2.88
(m, 2H).
The alcohol (730 mg, 1.56 mmol) was dissolved in 15 mL of
CH2Cl2. The solution was cooled to 0 °C and treated with
Dess-Martin periodinane (991 mg, 2.34 mmol). After the
solution was stirred for 3 h at 23 °C, the reaction was quenched
with 1:1 saturated NaHCO3/10% NaHSO3, extracted with
EtOAc, washed with brine, dried over Na2SO4, filtered, and
concentrated. Purification by silica gel flash chromatography
(1:1 EtOAc/hexanes) gave 625 mg (86%) of the ketone, 1-meth-
yl-3-[2-oxo-3-(4-(4-trifluoromethoxyphenoxy)phenylsulfonyl)-
propyl]-1H-pyrimidine-2,4-dione (9h ). MS (ESI) m/z: 467 (M
Com p ou n d s P r ep a r ed by Meth od B.
N-[2-(4,4-Dim et h yl-2,5-d ioxoim id a zolid in -1-yl)-1-(4′-
m et h ylsu lfa n ylb ip h en yl-4-su lfon ylm et h yl)et h yl]-N-h y-
d r oxyfor m a m id e (19a ). To a solution of 4-(thiomethyl)-
phenylboronic acid (6.72 g, 39.99 mmol) and 4-bromophenyl
methyl sulfone (9.41 g, 40.03 mmol) in 140 mL of DMF were
added PdCl2(dppf) (1.63 g, 2 mmol) and cesium carbonate (39.1
g, 120 mmol). The mixture was heated at 65 °C for 5.5 h, cooled
to room temperature, partitioned between EtOAc and 1:1
1
+ 1). H NMR (DMSO-d6): δ 7.73 (d, J ) 7.8 Hz, 1H), 7.45-
7.38 (m, 4H), 7.14-7.09 (m, 2H), 7.04-6.99 (m, 2H), 5.72 (d,
J ) 8.1 Hz, 1H), 4.87 (s, 2H), 4.11 (s, 2H), 3.29 (s, 3H).
The ketone 9h was converted to the title compound 11h as
described for the conversion of 9a to 11a . 1H NMR (DMSO-
d6): δ 9.52 (br, 0.5H), 9.42 (br, 0.5H), 8.04 (s, 0.5H), 7.89-
7.85 (m, 2H), 7.73 (s, 0.5H), 7.70-7.66 (m, 1H), 7.49-7.46 (m,

Phenoxyphenyl Sulfone N-Formylhydroxylamines
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1 229
brine/H2O, and extracted with EtOAc. The combined extracts
were washed with H2O and brine, dried over Na2SO4, filtered,
and concentrated. Purification by silica gel chromatography
(5-10% EtOAc/hexanes) gave the biphenyl methyl sulfone,
4-methanesulfonyl-4′-methylsulfanylbiphenyl, in 93% yield
(10.39 g). 1H NMR (DMSO-d6): δ 2.54 (s, 3H), 3.09 (s, 3H),
7.34-7.37 (d, J ) 8.4 Hz, 2H), 7.53-7.56 (d, J ) 8.7 Hz, 2H),
7.74-7.76 (d, J ) 8.4 Hz, 2H), 7.98-8.01 (d, J ) 8.4 Hz, 2H).
MS (APCI) m/z: 279 (M + H), 296 (M + NH4).
except using (thiophen-1-ylsulfanyl)acetic acid methyl ester in
place of 27; mp 120-122 °C. 1H NMR (DMSO-d6): δ 10.12 (bs,
1/2H), 9.80 (bs, 1/2H), 8.35 (s, 1/2H), 7.89-7.98 (m, 2.5H),
7.73-7.79 (m, 1H), 7.55-7.63 (m, 2H), 7.34-7.42 (m, 2H),
7.23-7.32 (m, 3H), 7.11-7.20 (m, 1H), 4.72-4.82 (m, 1/2H),
4.04-4.13 (m, 1/2H), 3.63-3.88 (m, 2H), 2.99-3.19 (m, 2H).
MS (ESI) m/z: 533 (M + NH4 - H2O), 550 (M + NH4), 555 (M
+ Na). Anal. (C21H18F3NO6S3) C, H, N.
Met h yl 4-[3-(F or m ylh yd r oxya m in o)-4-(4-(4-t ir flu or o-
m eth oxyp h en oxy)p h en ylsu lfon yl)bu tyl]ben zoa te (19g).
Compound 19g was prepared as described for 6, except using
4-(2-methoxycarbonylethyl)benzoic acid methyl ester in place
of 27; mp 153-154 °C. 1H NMR (DMSO-d6): δ 9.84-10.09 (m,
1/2H), 9.55-9.73 (m, 1/2H), 8.21 (s, 1/2H), 7.83-7.94 (m, 4H),
7.80 (s, 1/2H), 7.42-7.52 (m, 2H), 7.23-7.34 (m, 4H), 7.13-
7.23 (m, 2H), 4.52-4.61 (m, 1/2H), 4.04-4.15 (m, 1/2H), 3.83
(s, 3H), 3.57-3.74 (m, 1H), 3.44-3.55 (m, 1H), 2.43-2.68 (m,
2H), 1.86-2.01 (m, 1H), 1.71-1.83 (m, 1H). MS (APCI) m/z:
568 (M + H), 585 (M + NH4). Anal. (C26H24F3NO8S) C, H, N.
The methyl sulfone was treated with n-butyllithium and
methyl (4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetate and
carried on to the final product 19a as described for the
1
conversion of 28 to 6; mp 215.3-217.7 °C. H NMR (DMSO-
d6): δ 1.20-1.23 (m, 6H), 2.53 (s, 3H), 3.34-3.76 (m, 4H),
4.47-4.60 (m, 0.47H), 4.84-4.95 (m, 0.53H), 7.38-7.41 (d, J
) 8.4 Hz, 2H), 7.71-7.75 (dd+s, J ) 2.7, 8.7 Hz, 2.47H), 7.94-
7.95 (d, J ) 1.8 Hz, 4H), 8.10 (s, 0.53H), 8.26-8.32 (d, J ) 9.6
Hz, 1H), 9.50 (s, 0.47H), 9.65 (s, 0.53H). MS (ESI) m/z: 492
(M + H), 509 (M + NH4), 514 (M + Na), 490 (M - H)-. Anal.
(C22H25N3O6S) C, H, N.
4-[3-(F or m ylh yd r oxya m in o)-4-(4-(4-t r iflu or om e t h -
oxyp h en oxy)p h en ylsu lfon yl)bu tyl]ben zoic Acid (19h ). To
a solution of the methyl ester 19g (609 mg, 1.1 mmol) in 5 mL
of 1:1 THF/methanol was added KOH (73 mg, 1.3 mmol) in
1.2 mL of H2O. The reaction mixture was stirred at 23 °C for
16 h, diluted with H2O, acidified to pH 3, extracted with
EtOAc, dried over Na2SO4, filtered, and concentrated. The
crude material was recrystallized from EtOAc/hexanes to give
N-Hyd r oxy-N-[1-p h en yl-2-(4-(4-tr iflu or om eth oxyp h en -
oxy)p h en ylsu lfon yl)eth yl]-for m a m id e (19b). To a solution
of the methyl sulfone 26 (1 g, 3 mmol) in 50 mL of THF at
-78 °C was added dropwise n-butyllithium (1.2 mL, 3.6 mmol,
2.5 M in hexanes). The reaction mixture was stirred for 1.5 h
at -78 °C. Benzaldehyde (0.48 g, 4.5 mmol) was added. The
reaction mixture was stirred for 4 h at -78 °C, quenched with
saturated NH4Cl, extracted with ethyl acetate, dried over
MgSO4, filtered, and concentrated. Purification by silica gel
chromatography gave 1.9 g (90%) of the alcohol, 1-phenyl-2-
(4-(4-trifluoromethoxyphenoxy)phenylsulfonyl)ethanol (16b).
1H NMR (DMSO-d6): δ 7.91-7.86 (m, 2H), 7.51-7.46 (m, 2H),
7.32-7.24 (m, 7H), 7.18-7.12 (m, 2H), 5.64 (d, 4.8 Hz, OH),
5.02-4.96 (m, 1H), 3.71 (dd, J ) 14.7, 8.5 Hz, 1H), 3.55 (dd, J
) 14.7, 3.7 Hz, 1H).
1
the title compound (420 mg, 71%); mp 189-191 °C. H NMR
(DMSO-d6): δ 9.50-9.85 (m, 1/2H), 8.21 (s, 1/2H), 7.82-7.94
(m, 4H), 7.79 (s, 1/2H), 7.44-7.52 (m, 2H), 7.23-7.32 (m, 4H),
7.15-7.23 (m, 2H), 4.52-4.62 (m, 1/2H), 4.04-4.14 (m, 1/2H),
3.58-3.74 (m, 1H), 3.46-3.55 (m, 1H), 2.42-2.66 (m, 2H),
1.85-2.01 (m, 1H), 1.72-1.83 (m, 1H). MS (APCI) m/z: 554
(M + H), 571 (M + NH4). Anal. (C25H22F3NO8S) C, H, N.
N-[2-Dim et h yla m in o-1-(4-(4-t r iflu or om et h oxyp h en -
oxy)p h en ylsu lfon ylm eth yl)eth yl]-N-h yd r oxyfor m a m id e
(19i). Compound 19i was prepared as described for 6, except
using ethyl dimethylaminoacetate in place of 27. 1H NMR
(DMSO-d6): δ 2.04 (s, 3H), 2.10 (s, 3H), 2.21-2.39 (m, 2H),
3.40-3.48 (m, 1H), 3.53-3.63 (m, 1H), 4.05-4.17 (m, 0.5H),
4.62-4.72 (m, 0.5H), 7.19-7.30 (m, 4H), 7.47 (d, J ) 9.0 Hz,
2H), 7.86 (s, 0.5H), 7.87-7.94 (m, 2H), 8.10 (s, 0.5H), 9.45 (bs,
0.5H), 9.85 (bs, 0.5H). MS (ESI) m/z: 463 (M + H), 485 (M +
Na). Anal. (C19H21F3N2O6S) C, H, N.
The alcohol 16b was carried on to the final product 19b as
described for the conversion of 29 to 6. H NMR (DMSO-d6):
1
δ 10.06 (s, 0.5H), 9.96 (s, 0.5H), 8.18-8.11 (m, 1H), 7.87-7.85
(m, 2H), 7.50-7.47 (d, J ) 8.8 Hz, 2H), 7.30-7.24 (m, 5H),
7.15-7.13 (d, J ) 8.5 Hz, 2H), 5.78 (s, 0.5H), 5.41 (s, 0.5H),
4.24-4.04 (m, 3H). MS (ESI) m/z: M - H (480). Anal.
(C22H18F3NO6S) C, H, N.
N -H yd r oxy-N -[1-p yr id in -2-yl-2-(4-(4-t r iflu or om e t h -
oxyph en oxy)ph en ylsu lfon yl)eth yl]for m am ide (19c). Com-
pound 19c was prepared as described for 6, except using
nicotinic acid methyl ester in place of 27; mp 116.4-117.6 °C.
1H NMR (DMSO-d6): δ 3.88-4.04 (m, 1H), 4.28-4.36 (dd, J
) 4.5, 15 Hz, 1H), 5.50 (br, 0.5H), 5.84 (br, 0.5H), 7.12-7.44
(m, 6H), 7.44-7.50 (d, J ) 9 Hz, 2H), 7.74-7.95 (m, 2H), 8.18
(s, 0.5H), 8.25 (s, 0.5H), 8.47 (1H), 9.66 (s, 0.5H). MS (ESI)
m/z: 483 (M + H), 505 (M + Na), 481 (M - H), 517 (M + Cl).
Anal. (C21H17F3N2O6S).
N-Hyd r oxy-N-[2-(4-(4-tr iflu or om eth oxyp h en oxy)p h en -
ylsu lfon yl)-1-(4-tr iflu or om eth ylp h en yl)eth yl]for m a m id e
(19d ). Compound 19d was prepared as described for 19b,
except using 4-trifluoromethylbenzaldehyde in place of ben-
zaldehyde. 1H NMR (DMSO-d6): δ 10.25 (s, 0.5H), 9.70 (s,
0.5H), 8.25-8.1 (m, 1H), 7.90-7.85 (d, J ) 8.6 Hz, 2H), 7.77-
7.70 (d, J ) 8.8 Hz, 2H), 7.65 (s, 1H), 7.52-7.46 (d, J ) 8.7
Hz, 2H), 7.23-7.10 (d, J ) 8 Hz, 2H), 5.87 (s, 0,5H), 5.55 (s,
0.5H), 4.20-4.00 (m, 3H). MS (ESI) m/z: 548 (M - H). Anal.
(C23H17F6NO6S‚1.25 EtOAc) C, H, N.
N -[2-(F or m ylh yd r oxya m in o)-3-(4-(4-t r iflu or om e t h -
oxyp h en oxy)p h en ylsu lfon yl)p r op yl]-N-m eth ylm eth a n e-
su lfon a m id e (19j). The BOC-protected amino alcohol, tert-
butyl (2-hydroxy-3-(4-(4-trifluoromethoxyphenoxy)phenylsul-
fonyl)propyl)methylcarbamate, was prepared from methyl (t-
butoxycarbonylmethylamino)acetate as described for the con-
version of 26 to 29. The BOC-amine (2 g, 4 mmol) was
dissolved in 10 mL of 4 N HCl/dioxane. The reaction mixture
was stirred at 23 °C for 2 h, concentrated, taken up in
saturated NaHCO3 and EtOAc, extracted with EtOAc, dried
over Na2SO4, filtered, and concentrated to give the amino
alcohol,
1-methylamino-3-(4-(4-trifluoromethoxyphenoxy)-
1
phenylsulfonyl)propan-2-ol (16j). H NMR (CDCl3): δ 7.92 (s,
1H), 7.89 (s, 1H), 7.29 (s, 1H), 7.26 (s, 1H), 7.06-7.16 (m, 4H),
4.19-4.31 (m, 1H), 3.18-3.40 (m, 2H), 2.57-2.80 (m, 2H), 2.42
(s, 3H), 2.05 (bs, 2H). MS (DCI) m/z: 406 (M + H).
To a solution of the amino alcohol 16j (1.59 g, 3.6 mmol) in
100 mL of CH2Cl2 at 0 °C were added triethylamine (1.62 mL,
11.6 mmol) and methanesulfonyl chloride (730 µL, 9.4 mmol).
The reaction mixture was stirred at 23 °C for 1 h. DBU (934
µL, 6.25 mmol) was added. The reaction mixture was heated
at reflux 1 h, cooled to room temperature, washed with H2O,
1 N HCl, and saturated NaHCO3, dried over Na2SO4, filtered,
and concentrated. Purification by silica gel chromatography
(3-8% EtOAc/hexanes) gave 1.2 g (71%) of the alkene N-meth-
yl-N-[3-(4-(4-trifluoromethoxyphenoxy)phenylsulfonyl)allyl]-
N-Hyd r oxy-N-[1-(1-m eth yl-1H-in d ol-2-yl-2-(4-(4-tr iflu o-
romethoxyphenoxy)phenylsulfonyl)ethyl]formamide (19e).
Compound 19e was prepared as described for 6, except using
1-methyl-1H-lindole-2-carboxylic acid methyl ester in place of
1
27. H NMR (DMSO-d6): δ 9.95 (s, 0.5H), 9.56 (s, 0.5H), 8.13
(s, 0.5H), 7.90-7.85 (d, J ) 8.9 Hz, 2H), 7.50-7.40 (m, 4H),
7.2-7.0 (m, 6H), 6.53 (s, 1H), 6.1 (s, 0.5H), 5.70 (s, 0.5H), 4.15
(m, 2H), 3.7-3.65 (m, 4H). MS (ESI) m/z: 533 (M - H). Anal.
(C25H21F3N2O6S) C, H, N.
1
methanesulfonamide (17j). H NMR (CDCl3): δ 7.86 (t, J ) 3
N -H yd r oxy-N -[2-(t h iop h e n -2-ylsu lfa n yl)-1-(4-(4-t r i-
fluor om ethoxyphen oxy)ph enylsu lfonylm ethyl)ethyl]for m -
a m id e (19f). Compound 19f was prepared as described for 6,
Hz, 1H), 7.83 (t, J ) 3 Hz, 1H), 7.29 (s, 1H), 7.26 (s, 1H), 7.05-
7.15 (m, 4H), 6.90 (dt, J ) 15, 6 Hz, 1H), 6.61 (dt, J ) 12, 3

230 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1
Wada et al.
Hz, 1H), 3.97 (dd, J ) 4.5, 3 Hz, 2H), 2.88 (s, 3H), 2.85 (s,
3H). MS (DCI) m/z: 483 (M + NH4).
The acetonide (598 mg, 1.22 mmol) was dissolved in 40 mL of
THF and treated with 2.3 mL of 3 N HCl at 23 °C for 2.5 h.
The reaction mixture was partitioned between EtOAc and
saturated NaHCO3, washed with brine, dried over Na2SO4,
filtered, and concentrated to give the diol hydroxylamine, 2-[1-
hydroxyamino-2-(4-(4-trifluoromethoxyphenoxy)phenylsulfonyl)-
The R,â-unsaturated sulfone 17j was carried on to the title
compound 19j as described for the conversion of 30 to 6; mp
135-138 °C. 1H NMR (CDCl3): δ 8.28 (s, 1/2H), 7.95 (s, 1/2H),
7.82-7.90 (m, 2H), 7.23-7.31 (m, 2H), 7.05-7.14 (m, 2H),
5.02-5.12 (m, 1/2H), 4.45 (bs, 1/2H), 3.42-3.75 (m, 2H), 3.23-
3.40 (m, 2H), 2.80-2.95 (m, 6H). MS (ESI) m/z: 525 (M - H)-.
Anal. (C19H21F3N2O8S2) C, H, N.
1
ethyl]propane-1,3-diol (18n , 533 mg, 97%). H NMR (DMSO-
d6): δ 7.93-7.88 (m, 2H), 7.49-7.45 (m, 2H), 7.31-7.26 (m,
2H), 7.24-7.19 (m, 2H), 5.5 (br, 1H), 4.45 (t, J ) 4.8 Hz, OH),
4.39 (t, J ) 4.8 Hz, OH), 3.51-3.42 (m, 6H). MS (APCI) m/z:
452 (M + 1), 486 (M + Cl).
The hydroxylamine 18n was treated with acetic formic
anhydride as described for the preparation of 11a to give the
title compound 19n ; mp 129.2-131.3 °C. 1H NMR (DMSO-
d6): δ 1.69-1.79 (m, 1H), 3.57-3.80 (m, 2H), 3.24-3.51 (m,
overlapped with solvent H), 4.13-4.19 (dt, J ) 1.5, 8.4 Hz,
1H), 4.64-4.70 (1H), 7.19-7.30 (m, 4H), 7.45-7.48 (d, J ) 9
Hz, 2H), 7.678 (s, 0.7H), 7.86-7.90 (m, 2H), 8.04 (s, 0.3H). MS
(ESI) m/z: 480 (M + H), 502 (M + Na), 981 (2M + Na), 478
(M - H)-, 957 (2M - H)-. Anal. (C19H20F3NO8S‚0.25 H2O) C,
H, N.
N -H yd r oxy-N -[2-h yd r oxy-1-(4-(4-t r iflu or om e t h oxy-
p h en oxy)p h en ylsu lfon ylm eth yl)eth yl]for m a m id e (19k ).
The TBDMS-protected alcohol, N-[2-(tert-butyldimethylsila-
nyloxy)-1-(4-(4-trifluoromethoxyphenoxy)phenylsulfonylmethyl)-
ethyl]-N-hydroxyformamide, was prepared as described for
19a , except using (tert-butyldimethylsilanyloxy)acetaldehyde
in place of benzaldehdye. To a solution of the silyl-protected
alcohol (250 mg, 455 µmol) in 10 mL of THF at 0 °C was added
tetrabutylammonium fluoride (910 µL, 1 M in THF, 910 µmol).
The reaction mixture was stirred at 0 °C for 1.5 h, partitioned
between ether and brine, dried over MgSO4, filtered, and
concentrated. Purification by silica gel chromatography (5%
2-propanol/CH2Cl2 to 10% methanol/CH2Cl2) followed by re-
crystallization from ether gave 69 mg (35%) of the title
compound 19k ; mp 115-117 °C. 1H NMR (DMSO-d6): δ 3.30-
3.62 (m, 4H), 3.93-4.03 (m, 0.5H), 4.51-4.61 (m, 0.5H), 4.95-
5.06 (m, 1H), 7.22 (d, J ) 9.0 Hz, 2H), 7.25-7.32 (m, 2H), 7.48
(d, J ) 9.0 Hz, 2H), 7.76 (s, 0.5H), 7.86-7.94 (m, 2H), 8.13 (s,
0.5H), 9.41 (bs, 0.5H), 9.82 (bs, 0.5H). MS (ESI) m/z: 436 (M
+ H), 453 (M + NH4), 458 (M + Na). Anal. (C17H16F3NO7S) C,
H, N.
(1S ,2S )-N -[2,3-Dih yd r oxy-1-(4-(4-t r iflu or om e t h oxy-
p h en oxy)p h en ylsu lfon ylm eth yl)p r op yl]-N-h yd r oxyfor m -
a m id e (19o). Compound 19o was prepared as described for
19n , except using methyl (4R)-2,2-dimethyl[1,3]dioxolane-4-
caboxylate; mp 137-138 °C; [R]D + 4.2° (MeOH). 1H NMR
25
(DMSO-d6): δ 3.30-3.60 (m, 4H), 3.65-3.78 (m, 1H), 3.90-
3.90 (m, 0.5H), 4.53-4.62 (m, 0.5H), 4.78 (bs, 1H), 4.94 (bs,
1H), 7.21 (d, J ) 9.0 Hz, 2H), 7.25-7.32 (m, 2H), 7.47 (d, J )
8.60 Hz, 2H), 7.70 (s, 0.5H), 7.84-7.92 (m, 2H), 8.09 (s, 0.5H),
9.30 (bs, 0.5H), 9.65 (bs, 0.5H). MS (ESI) m/z: 466 (M + H),
483 (M + NH4), 488 (M + Na). Anal. (C18H18F3NO8S) C, H,
N.
N -H yd r oxy-N -[2-m e t h oxy-1-(4-(4-t r iflu or om e t h oxy-
p h en oxy)p h en ylsu lfon ylm eth yl)eth yl]for m a m id e (19l).
The alcohol, 1-methoxy-3-(4-(4-trifluoromethoxyphenoxy)-
phenylsulfonyl)propan-2-ol, was prepared as described for 29,
except using ethyl methoxyacetate in place of 27. To a solution
of the alcohol (610 mg, 1.53 mmol) in 10 mL of THF at 23 °C
were added triphenylphosphine (482 mg, 1.84 mmol) and
DEAD (291 µL, 1.84 mmol). The reaction mixture was stirred
at 23 °C for 1 h and concentrated. Purification by silica gel
chromatography (30% EtOAc/hexanes) gave 530 mg (90%) of
a 1.8:1 trans/cis mixture of alkenes 1-methoxy-3-(4-(4-trifluo-
N-Hyd r oxy-N-[2-m or p h olin -4-yl-1-(4-(4-tr iflu or om eth -
oxyphenoxy)phenylsulfonylmethyl)ethyl]formamide (19p).
Compound 19p was prepared as described for 6, except using
methyl 3-(morpholin-4-yl)propionate in place of 27; mp 139.1-
140.5 °C. 1H NMR (DMSO-d6): δ 1.58-2.40 (m, 4H), 2.90-
3.20 (br, 2H), 3.40-3.75 (m, 4H), 3.85-4.08 (br, 0.6H), 4.60-
4.70 (br, 0.4H), 7.21-7.29 (m, 4H), 7.46-7.49 (d, J ) 8.4 Hz,
2H), 7.80 (s, 0.6H), 7.89-7.92 (d, J ) 8.7 Hz, 2H), 8.10 (s,
0.4H), 9.63 (s, 0.6H), 10.1 (br, 0.4H). MS (ESI) m/z: 519 (M +
H), 541 (M + Na), 517 (M - H)-, 553 (M + Cl). Anal.
(C22H25F3N2O7S‚H2O) C, H, N.
(1S)-N-Hyd r oxy-N-[1-(2R)-t et r a h yd r ofu r a n -2-yl)-2-(4-
(4-t r iflu or om e t h oxyp h e n oxy)p h e n ylsu lfon yl)e t h yl]-
for m a m id e (19q). Compound 19q was prepared as described
for 6, except using methyl (2R)-tetrahydrofuran-2-carboxylate
in place of 27. 1H NMR (DMSO-d6): δ 1.37-1.45 (m, 1H),
1.71-1.82 (m, 2H), 1.88-1.99 (m, 1H), 3.28 (m, 0.6H), 3.56-
3.73 (m, 4H), 3.81-3.91 (m, 2H), 4.46 (t, J ) 10.0 Hz, 0.4H),
7.22 (d, J ) 9.0 Hz, 2H), 7.25-7.29 (m, 2H), 7.46 (d, J ) 8.5
Hz, 2H), 7.77 (s, 0.6H), 7.90 (d, J ) 9.0 Hz, 2H), 7.93 (d, J )
8.5 Hz, 2H), 8.12 (S, 0.4H), 9.45 (s, br, 0.6H), 9.82 (s, br, 0.4H).
MS (ESI) m/z: 476 (M + H), 493 (M + NH4). Anal. (C20H20F3-
NO7S) C, H, N.
1
romethoxyphenoxy)phenylsulfonyl)-2-propene (17l). H NMR
(DMSO-d6): δ 7.94-7.85 (m, 2H), 7.50-7.45 (m, 2H), 7.33-
7.26 (m, 2H), 7.23-7.18 (m, 2H), 6.90 (dt, J ) 15.3, 3.5 Hz,
0.64H), 6.77 (dt, J ) 15.3, 1.9 Hz, 0.64H), 6.63 (dt, J ) 11.5,
2.2 Hz, 0.36H), 6.45 (dt, J ) 11.5, 5.3 Hz, 0.36H), 4.49 (dd, J
) 5.3, 2.2 Hz, 0.72 H), 4.12 (dd, J ) 3.5, 1.9 Hz, 1.28H), 3.28
(s, 1.92H), 3.26 (s, 1.08H).
The R,â-unsaturated sulfone 17l was converted to the title
compound 19l as described for the conversion of 30 to 6. 1H
NMR (DMSO-d6): δ 3.20 (s, 3H), 3.23-3.45 (m, 3H), 3.52-
3.65 (m, 1H), 4.16-4.27 (m, 0.5H), 4.70-5.02 (m, 0.5H), 7.21
(dd, J ) 3,9 Hz, 2H), 7.28 (dd, J ) 6,9 Hz, 2H), 7.47 (d, J ) 9
Hz, 2H), 7.81 (s, 0.5H), 7.90 (dd, J ) 3,9 Hz, 2H), 8.12 (s, 0.5H),
9.56 (bs, 0.5H), 9.91 (bs, 0.5H). MS (ESI) m/z: 448 (M - H)-.
Anal. (C18H18F3NO7S‚0.25 EtOAc) C, H, N.
N-H yd r oxy-N-[2-(2-h yd r oxyet h oxy)-1-(4-(4-t r iflu or o-
m eth oxyph en oxy)ph en ylsu lfon ylm eth yl)eth yl]for m am ide
(19m ). Compound 19m was prepared as described for 19k ,
except using (2-tert-butyldimethylsilanyloxy)ethoxy)acetaldehyde
in place of (tert-butyldimethylsilanyloxy)acetaldehyde. 1H
NMR (DMSO-d6): δ 3.4-3.63 (m, 6H), 4.13-4.26 (m, 0.5H),
4.63 (s, 1H), 4.69-4.8 (m, 0.5H), 7.23 (d, J ) 9 Hz, 2H), 7.29
(d, J ) 9 Hz, 2H), 7.48 (d, J ) 9 Hz, 2H), 7.8 (s, 0.5H), 7.91
(dd, J ) 9.1,8.8 Hz, 2H), 8.14 (s, 0.5H), 9.54 (s, 0.5H), 9.92 (s,
0.5H). MS (ESI) m/z: 478 (M - H)-. Anal. (C19H20F3NO8S) C,
H, N.
N-Hyd r oxy-N-[3-h yd r oxy-2-h yd r oxym eth yl-1-(4-(4-tr i-
flu or om eth oxyp h en oxy)p h en ylsu lfon ylm eth yl)p r op yl]-
for m a m id e (19n ). The acetonide-protected diol hydroxyl-
amine, N-[1-(2,2-dimethyl[1,3]dioxan-5-yl)-2-(4-(4-trifluoro-
methoxyphenoxy)phenylsulfonyl)ethyl]hydroxylamine, was pre-
pared as described for the conversion of 26 to 31, except using
ethyl 2,2-dimethyl[1,3]dioxane-5-carboxylate in place of 27.
N -H y d r o x y -N -[3-m o r p h o lin -4-y l-3-o x o -1-(4-(4-t r i-
flu or om eth oxyp h en oxy)p h en ylsu lfon ylm eth yl)p r op yl]-
for m a m id e (19r ). Compound 19r was prepared as described
for 6, except using methyl 4-(morpholin-4-yl)-4-oxobutyrate in
1
place of 27. H NMR (DMSO-d6): δ 1.64-1.86 (m, 2H), 2.17-
2.31 (m, 2H), 3.40-3.71 (m, 10H), 4.10-4.23 (m, 0.5H), 4.52-
4.63 (m, 0.5H), 7.22 (d, J ) 9 Hz, 2H), 7.28 (d, J ) 8.9 Hz,
2H), 7.47 (d, J ) 9.1 Hz, 2H), 7.74 (s, 0.5H), 7.85 (d, J ) 9 Hz,
2H), 8.11 (s, 0.5H), 9.48 (s, 0.5H), 9.82 (s, 0.5H). MS (ESI)
m/z: 545 (M - H)-. Anal. (C23H25F3N2O8S) C, H, N.
(1S)-N-Hyd r oxy-N-[1-(1-(2S)-m eth a n esu lfon ylp yr r oli-
d in -2-y l)-2-(4-(4-t r iflu o r o m e t h o x y p h e n o x y )p h e n y l-
su lfon yl)eth yl]for m a m id e (19s). Compound 19s was pre-
pared as described for 6, except using methyl (2S)-1-
methanesulfonylpyrrolidine-2-carboxylate in place of 27. 1H
NMR (DMSO-d6): δ 1.65-1.78 (m, 3H), 1.93-2.08 (m, 1H),
2.85 (s, 0.4H), 2.88 (s, 0.6H), 3.12-3.45 (m, 3H), 3.71-3.79
(m, 0.6H), 4.23-4.28 (m, 0.4H), 7.19-7.29 (m, 4H), 7.43-7.46

Phenoxyphenyl Sulfone N-Formylhydroxylamines
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1 231
(d, J ) 8.7 Hz, 2H), 7.80 (s, 0.6H), 7.86-7.92 (m, 2H), 8.17 (s,
0.4H), 9.48 (s, 0.6H), 9.71 (s, 0.4H). MS (ESI) m/z: 553 (M +
H), 570 (M + NH4), 551 (M - H). HRMS (APCI) calcd for
Hz, 2H), 7.81 (s, 0.5H), 7.85-7.95 (m, 2H), 8.14 (s, 0.5H), 9.66
(br s, 0.5H), 10.11 (br s, 0.5H). MS (ESI) m/z: 534 (M + 1),
551 (M + NH4). Anal. (C23H26F3NO8S) C, H, N.
C
21H24F3N2O8S2 (M + 1) m/z: 553.0926; found, 553.0930.
N-Hyd r oxy-N-[3-(4-m eth a n esu lfon ylp ip er a zin -1-yl)-1-
(1S)-N-Hyd r oxy-N-[2-(4-(4-tr iflu or om eth oxyp h en oxy)-
ph en ylsu lfon yl)-1-((4S)-2,2,5-tr im eth yl[1,3]dioxolan -4-yl)-
eth yl]for m a m id e (19z). Compound 19z was prepared as
described for 6, except using methyl (4R)-2,2,5-trimethyl[1,3]-
dioxolane-4-carboxylate in place of 27. 1H NMR (DMSO-d6):
δ 1.2-1.3 (m, 9H), 3.3-3.5 (m, 2H), 3.6-3.9 (m, 3H), 4.1-4.2
(apparent t, J ) 5.0 Hz, 0.5H), 4.6-4.7 (apparent t, J ) 5.0
Hz, 0.5H), 7.2-7.3 (m, 4H), 7.48 (d, J ) 9.0 Hz, 2H), 7.85-
8.00 (m, 2.5H), 8.15 (s, 0.5H), 9.69 (s, 0.5H), 9.95 (s, 0.5H).
MS (ESI) m/z: 520 (M + 1), 537 (M + NH4). Anal. (C22H24F3-
NO8S) C, H, N.
(1S)-N-[2-((4S)-2,2-Dim eth yl[1,3]d ioxola n -4-yl)-1-(4-(4-
tr iflu or om eth oxyp h en oxy)p h en ylsu lfon ylm eth yl)eth yl]-
N-h yd r oxyfor m a m id e (19a a ). Compound 19a a was pre-
pared as described for 6, except using methyl (4S)-(2,2-
dimethyl[1,3]dioxolan-4-yl)acetate in place of 27. 1H NMR
(DMSO-d6): δ 1.18-1.27 (m, 6H), 1.56-1.74 (m, 1H), 1.74-
1.93 (m, 1H), 3.26-3.71 (m, 3H), 3.81-3.94 (m, 2H), 4.12-
4.23 (m, 0.5H), 4.66-4.76 (m, 0.5H), 7.19-7.31 (m, 4H), 7.48
(d, J ) 9.0 Hz, 2H), 7.76 (s, 0.5H), 7.87-7.94 (m, 2H), 8.12 (s,
0.5H), 9.59 (s, 0.5H), 9.88 (s, 0.5H). MS (ESI) m/z: 520 (M +
H), 537 (M + NH4). Anal. (C22H24F3NO8S) C, H, N.
(4-(4-tr iflu or om eth oxyp h en oxy)p h en ylsu lfon ylm eth yl)-
p r op yl]for m a m id e (19t ). Compound 19t was prepared as
described for 19j, except using tert-butyl 4-(2-ethoxycarbon-
ylethyl)piperazine-1-carboxylate in place of 27; mp 165.9-
167.2 °C. 1H NMR (DMSO-d6): δ 1.61-1.74 (m, 2H), 2.10-
2.46 (m, 6H), 2.87 (s, 3H), 2.94-3.13 (m, 4H), 3.44-3.72 (2H),
4.10-4.22 (m, 0.7H), 4.63-4.73 (m, 0.3H), 7.21-7.30 (m, 4H),
7.46-7.49 (d, J ) 8.4 Hz, 2H), 7.78 (s, 0.7H), 7.89-7.92 (2H),
8.10 (s, 0.3H), 9.56 (s, 0.7H), 10.09 (s, 0.3H). MS (ESI) m/z:
596 (M + H), 618 (M + Na), 594 (M - H) Anal. (C23H28F3N3-
O8S2) C, H, N.
N -[1-(1,4-D io x a s p ir o [4.5]d e c -8-y l)-2-(4-(4-t r iflu o -
r om et h oxyp h en oxy)p h en ylsu lfon yl)et h yl]-N-h yd r oxy-
for m a m id e (19u ). Compound 19u was prepared as described
for 6, except using ethyl 1,4-dioxaspiro[4.5]decane-8-carboxy-
1
late in place of 27; mp 139.5-141.2 °C. H NMR (DMSO-d6):
δ 0.93-1.70 (m, 11H), 3.51-3.65 (m, 1H), 3.81-3.82 (s+s, 4H),
4.02-4.10 (m, 0.5H), 4.57-4.67 (m, 0.5H), 7.19-7.31 (m, 4H),
7.46-7.49 (d, J ) 9.3 Hz, 2H), 7.88-7.93 (m, 2.5H), 8.11 (s,
0.5H), 9.50 (s, 0.5H), 9.85 (s, 0.5H). MS (ESI) m/z: 560 (M +
H), 577 (M + NH4), 582 (M + Na), 558 (M - H), 594 (M + Cl).
Anal. (C25H28F3NO8S) C, H, N.
Com p ou n d s P r ep a r ed by Meth od C.
N-H yd r oxy-N-[1-(m or p h olin e-4-su lfon ylm et h yl)-2-(4-
(4-t r iflu or om e t h oxyp h e n oxy)p h e n ylsu lfon yl)e t h yl]-
for m a m id e (24b). Compound 24b was prepared as described
for 24a , except using 4-methansulfonylmorpholine in place of
(1S)-N-[1-((4R)-2,2-Dim eth yl[1,3]d ioxola n -4-yl)-2-(4-(4-
t r iflu or om et h oxyp h en oxy)p h en ylsu lfon yl)et h yl]-N-h y-
d r oxyfor m a m id e (19v). Compound 19v was prepared as
described for 6, except using (4S)-2,2-dimethyl-1,3-dioxolane-
4-carboxylate in place of 27. The major product, (4R)-4-((1S)-
1-(hydroxyamino)-2-(4-(4-trifluoromethoxyphenoxy)phenyl-
sulfonyl)ethyl)-2,2-dimethyl[1,3]dioxolane (18v), from the
conjugate addition of hydroxylamine (3:1 ratio) was carried
on to the title compound. 1H NMR (DMSO-d6): δ 1.05 (s, 1.5H),
1.14 (s, 1.5H), 1.20 (s, 1.5H), 1.23 (s, 1.5H), 3.3-3.4 (m, 1H),
3.5-4.1 (m, 4.5H), 4.3-4.4 (m, 0.5H), 7.2-7.3 (m, 4H), 7.48
(d, 2H), 7.8-8.0 (m, 2.5H), 8.15 (s, 0.5H), 9.68 (br s, 0.5H),
10.10 (br s, 0.5H). MS (ESI) m/z: 506 (M + 1), 523 (M + 18).
(1R)-N-[1-((4R)-2,2-Dim eth yl[1,3]d ioxola n -4-yl)-2-(4-(4-
t r iflu or om et h oxyp h en oxy)p h en ylsu lfon yl)et h yl]-N-h y-
d r oxyfor m a m id e (19w ). Compound 19w was prepared as
described for 19v, utilizing the minor product (4R)-4-((1R)-1-
(hydroxyamino)-2-(4-(4-trifluoromethoxyphenoxy)phenyl-
sulfonyl)ethyl)-2,2-dimethyl[1,3]dioxolane (18w ) from the con-
jugate addition of hydroxylamine. 1H NMR (DMSO-d6): δ 1.21
(s, 1.5H), 1.23 (s, 1.5H), 1.26 (s, 1.5H), 1.30 (s, 1.5H), 3.3-3.4
(m, 1H), 3.60-3.75 (m, 2H), 3.9-4.1 (m, 2.5H), 4.5-4.6 (m,
0.5H), 7.2-7.3 (m, 4H), 7.48 (d, J ) 8.7 Hz, 2H), 7.81 (s, 0.5H),
7.85-7.95 (m, 2H), 8.13 (s, 0.5H), 9.63 (br s, 0.5H), 10.0 (br s,
0.5H). MS (ESI) m/z: 506 (M + 1), 523 (M + NH4). Anal.
(C21H22F3NO8S) C, H, N.
1
20a ; mp 123-125 °C. H NMR (DMSO-d6): δ 3.03-3.15 (m,
4H), 3.37-3.41 (m, 1H), 3.43-3.82 (m, 7H), 4.51 (m, 0.5H),
5.04 (m, 0.5H), 7.21-7.30 (m, 4H), 7.48 (d, J ) 9.0 Hz, 2H),
7.86 (s, 0.5H), 7.90 (dd, J ) 9.0, 3.0 Hz, 2H), 8.12 (s, 0.5H),
9.82 (s, br, 0.5H), 10.12 (s, br, 0.5H). MS (ESI) m/z: 569 (M +
H), 586 (M + NH4), 591 (M + Na). Anal. (C21H23F3N2O9S2) C,
H, N.
Biologica l Meth od s. In Vitr o En zym e Assa y. The IC50
values were determined using fluorimetric assays for MMP
enzyme inhibition as detailed by Marcotte and Davidsen in
ref 27. The IC50 values for all compounds except as noted are
from a single determination done in triplicate (variability <
2-fold).
Other metalloproteinase IC50s were determined as detailed
by Marcotte et al. in ref 28.
Cellu la r Assa y. TNFR release assays were performed as
detailed by Glaser et al. in ref 29.
In Vivo Tu m or Mod el. The murine tumor growth model
was conducted as detailed by Chirivi et al. in ref 30 and Albert
and Davidsen in ref 31.
Refer en ces
(1R)-N-[1-((4S)-2,2-Dim eth yl[1,3]d ioxola n -4-yl)-2-(4-(4-
t r iflu or om et h oxyp h en oxy)p h en ylsu lfon yl)et h yl]-N-h y-
d r oxyfor m a m id e (19x). Compound 19x was prepared as
described for 6. The minor product (4S)-4-((1R)-1-(hydroxyami-
no)-2-(4-(4-trifluoromethoxyphenoxy)phenylsulfonyl)ethyl)-2,2-
dimethyl[1,3]dioxolane (18x) from the conjugate addition of
hydroxylamine was carried on to the title compound; mp 149-
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1
150 °C. H NMR (DMSO-d6): δ 1.04 (s, 1.5H), 1.13 (s, 1.5H),
1.20 (s, 1.5H), 1.23 (s, 1.5H), 3.57-4.11 (m, 5.5H), 4.39 (t, J )
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