Synthesis and structure - Activity relationship of α-sulfonylhydroxamic acids as novel, orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis

Article abstract of DOI:10.1021/jm0205548

The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. These enzymes are strictly regulated by endogenous inhibitors such as tissue inhibitors of

Full text of DOI:10.1021/jm0205548

J . Med. Chem. 2003, 46, 2361-2375
2361
Syn th esis a n d Str u ctu r e-Activity Rela tion sh ip of r-Su lfon ylh yd r oxa m ic Acid s
a s Novel, Or a lly Active Ma tr ix Meta llop r otein a se In h ibitor s for th e Tr ea tm en t
of Osteoa r th r itis
Venkatesan Aranapakam,*,† George T. Grosu,† J amie M. Davis,† Baihua Hu,† J ohn Ellingboe,† J annie L. Baker,†
J erauld S. Skotnicki,† Arie Zask,† J ohn F. DiJ oseph,‡ Amy Sung,‡ Michele A. Sharr,‡ Loran M. Killar,‡
Thomas Walter,‡ Guixian J in,† and Rebecca Cowling†
Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, and Wyeth Research, P.O. Box CN-8000,
Princeton, New J ersey 08543
Received December 5, 2002
The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that
play a key role in both physiological and pathological tissue degradation. These enzymes are
strictly regulated by endogenous inhibitors such as tissue inhibitors of MMPs and R2-
macroglobulins. Overexpression of these enzymes has been implicated in various pathological
disorders such as arthritis, tumor metastasis, cardiovascular diseases, and multiple sclerosis.
Developing effective small-molecule inhibitors to modulate MMP activity is one approach to
treat these degenerative diseases. The present work focuses on the discovery and SAR of novel
N-hydroxy-R-phenylsulfonylacetamide derivatives, which are potent, selective, and orally active
MMP inhibitors.
In tr od u ction
arthritis. Hence, in the present investigation, com-
pounds synthesized for the MMP inhibitor program
were also tested for TACE inhibition. It is the objective
of this article to present the synthesis, SAR, and in vivo
activity of novel and orally active R-phenylsulfonylacetic
acid hydroxamide derivatives 1 (Figure 1) as MMP and
TACE inhibitors. In this connection, it should be men-
tioned that a â-sulfonylhydroxamic acid derivative 2
(Figure 1), synthesized by Roche Bio-Science was ad-
vanced to phase II clinical trials for osteoarthritis. In
addition, several succinic acid and sulfonamide based
broad spectrum MMP inhibitors have been investigated
in the clinic for cancer (Figure 2).
The matrix metalloproteinases (MMPs) are a large
family of calcium-dependent zinc-containing endopep-
tidases involved in the degradation of extracellular
matrix and tissue remodeling. To date, at least 21
mammalian MMPs have been discovered. These include
three collagenases (MMP-1, -8, and -13), two gelatinases
(MMP-2 and -9), three stromelysins (MMP-3, -10, and
-11), five membrane type MMPs (MMP-14 to -17 and
MMP-24), and others such as matrilysin (MMP-7) and
metalloelastase (MMP-12). These enzymes are strictly
controlled by endogenous MMP inhibitors such as R2-
macroglobulins and tissue inhibitors of MMPs (TIMPs).
The overexpression of MMPs results in an imbalance
between the activity of MMPs and TIMPs and the
subsequent degradation of cartilage and loss of joint
movement characteristic of pathological conditions such
as osteoarthritis and rheumatoid arthritis.1-4 Presently
available drugs in the market alleviate the pain or the
inflammation associated with joint synovitis, but they
do little to reduce cartilage destruction. In addition to
arthritis, tumor metastasis, angiogenesis, pulmonary
emphysema, atherosclerosis, and central nervous sys-
tem (CNS) diseases5-11 may also be mediataed by the
aberrant activity of various MMPs. Therefore, in many
of these pathological conditions, selective and orally
active small-molecule MMP inhibitors may prove to be
clinically efficacious. Another closely related zinc-
containing metalloproteinase, tumor necrosis factor-R
(TNF-R) converting enzyme12 (TACE) converts mem-
brane-bound TNF-R to its soluble form, which has been
shown to play a major role in the etiology of rheumatoid
Ch em istr y
The compounds of the present investigation, namely,
substituted R-phenylsulfonylhydroxamide derivatives,
can be conveniently prepared by alkylating the ap-
propriately substituted phenylmercaptan derivatives 3
(Scheme 1) with R-bromoethyl acetate 4 in chloroform
and triethylamine at room temperature or in K2CO3 in
refluxing acetone. The sulfide derivative 5 thus obtained
can be oxidized using Oxone in methanol/water or
mCPBA in CH2Cl2 to give the sulfone derivative 6,
which can be preferentially either monoalkylated using
1 mol of alkyl halide or dialkylated using excess alkyl
halide in boiling acetone/K2CO3 and 18-crown-6. Next,
the bisalkylated compound 8 or the monoalkylated
product 7 can be hydrolyzed to the corresponding
carboxylic acid 9 using 10 N NaOH in THF/MeOH at
room temperature. The saponified product was subse-
quently converted to the hydroxamic acid derivative 1
using oxalyl chloride/hydroxylamine hydrochloride, and
triethylamine. Compounds 56 and 57 were prepared
from 4-hydroxythiophenol 10 as shown in Scheme 2.
* To whom correspondence should be addressed. Phone: (845) 602-
4023. Fax: (845) 602-5561. E-mail: venkata@wyeth.com.
† Wyeth Research, NY.
‡ Wyeth Research, NJ .
10.1021/jm0205548 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/10/2003

2362 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12
Aranapakam et al.
We desired selective compounds that inhibited MMP-
9, MMP-13, or TACE and spared MMP-1 in order to
examine whether the inhibition of MMP-1 is a pos-
sible source of the musculoskeletal side effects that
have been seen in clinical trials of broad spectrum
MMP inhibitors.19 In our discovery pathway, the most
selective and potent inhibitors of MMP-13 were exam-
ined in an in vivo bioactivity model known as the
dialysis implant assay.20 In this model, a solution
containing the target enzyme was put inside dialysis
tubing, which was implanted subcutaneously in the
back of a mouse. Groups of mice were dosed with
drug or vehicle, and after 1 h of exposure, the dialy-
sis bag was retrieved from the mouse. The activity
of the enzyme inside the dialysis bag was measured
by a spectrophotometric assay and compared to the
enzyme activity recovered from dialysis bags from
vehicle-treated mice. Compounds active in this assay
were then put into an in vivo efficacy model known
as the rat sponge-wrapped cartilage model.21 In this
model a sponge containing bovine cartilage and my-
cobacterium is implanted subcutaneously on the
back of the animal (in the present case it is rat). This
leads to granuloma formation, and cytokines induce
MMP production by the chondrocytes in the carti-
lage. Compounds were given orally for 3 weeks, and
at the end, the collagen content of the cartilage was
measured.
F igu r e 1.
F igu r e 2.
4-Hydroxythiophenol 10 was reacted with ethyl 2-bro-
mopropionate 11 in chloroform/triethylamine at room
temperature to give 12 in almost quantitative yield. This
was alkylated on the phenolic oxygen using either
bromoethane or 1-bromobutane to yield 13 or 14,
respectively, which were readily converted to sulfone 15
or 16 using Oxone. Reaction of 4-(2-N,N-diethylamino-
ethoxy)benzyl chloride 17a with 15 or 4-(2-piperidin-1-
ylethoxy)benzyl chloride 17b with 16 in boiling acetone/
K2CO3/18-crown-6 gave 18 and 19, respectively. The
esters 18 and 19 were converted to 56 or 57 via their
respective carboxylic acid derivatives as shown in
Scheme 2.
SAR
The IC50 values of the compounds synthesized are
tabulated in Tables 1-3. An examination of these tables
reveals that monosubstitution R to the hydroxamic acid
functionality decreases MMP inhibitor activity when
compared to the disubstituted compounds. For example,
compound 29 (R3 ) benzyl, R2 ) methyl) is almost 10
times more potent against MMP-9 and MMP-13 than
compound 28 (R3 ) benzyl, R2 ) H). A similar activity
profile is observed with examples 30 and 31. When both
R2 and R3 are substituted with isoprenyl 34, potency
against MMP-9 and MMP-13 and selectivity over MMP-1
increase. This compound also exhibits weak TACE
activity. However, when the isoprenyl moiety is replaced
with an allyl group, as in example 35, the MMP and
TACE potencies decrease. Further deterioration in
activity takes place when the double bond in the allyl
moiety is changed to the n-propyl derivative 37. Com-
parison of examples 38 and 39 reveals that among the
monosubstituted compounds, a branched substituent
such as an isopropyl group R to the hydroxamic acid
moiety decreases MMP-9 and MMP-13 potency. Length-
ening the R-substituent to 12 carbon atoms further
decreases potency (example 41 ). A bispropargyl group
R to the hydroxamic acid 42 slightly increases the
potency of MMP-13 inhibition relative to allyl analogue
35. Even though many of these analogues were very
potent against MMPs, these compounds were inactive
in the dialysis implant assay. It has been shown by
different workers17 that introduction of basic water
solubilizing groups in the molecule increases the in vivo
activity. Hence, we decided to introduce a water solu-
bilizing basic group such as a 3-picolyl group. The in
vivo aspects of these molecules will be discussed at the
latter portion of this article. Example 43, where R2 )
Compound 58 was prepared starting from 4-bro-
mothiophenol 22 (Scheme 3). The intermediate 24 on
reaction with 2-(tributylstannyl)furan/(Ph3P)4Pd yielded
25 in 95% yield. Alkylation of 25 was followed by ester
hydrolysis and transformation into the corresponding
hydroxamic acid 58 by the sequence depicted in
Scheme 3. The other compounds mentioned in this
paper (28-65) were prepared according to Schemes
1-3 starting from the appropriately substituted mer-
captan derivatives. The intermediate 4-(2-N,N-dieth-
ylaminoethoxy)benzyl chloride 17a and other ana-
logues were synthesized by a known literature proce-
dure.13
Biology
All final hydroxamic acid derivatives were eval-
uated in vitro14 for their ability to inhibit MMP-1,
15
MMP-9, MMP-13, and TACE
(Tables 1-3). Inhibi-
tors of MMP-9 are potentially valuable for arresting
tumor metastasis,16 while inhibiting MMP-13 can offer
protection from the cartilage degradation associated
with osteoarthritis.17 Inhibitors of TACE are poten-
tially valuable for the treatment of rheumatoid arthri-
tis, Crohn’s disease, and other inflammatory diseases.18

R-Sulfonylhydroxamic Acids
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12 2363
Sch em e 1. General Method To Synthesize R-Phenylsulfonylacetic Acid Hydroxamides 1
Sch em e 2. Synthesis of Compounds 56 and 57
methyl and R3 ) 3-picolyl, showed good in vitro activity
and moderate selectivity for MMP-13 over MMP-1 (∼10-
fold). Replacement of the methyl group in compound 43
with an isoprenyl group (example 44) increased the
potency of MMP-13 inhibition and also increased selec-
tivity over MMP-1. When the methyl group (R2
methyl) in example 43 is replaced with other long-chain
alkyl substituents (examples 45-48), both the potency
)

2364 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12
Sch em e 3. Synthesis of Compounds 58
Aranapakam et al.
Ta ble 1. In Vitro Data (IC50 Valuesa (nM) and % Inhibition)
compd
R2
R3
MMP-1
MMP-9
MMP-13
TACE
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
benzyl
benzyl
2-CH2-naphthyl
2-CH2-naphthyl
4-CH2-biphenyl
isoprenyl
isoprenyl
allyl
-CH2-CHdCH-Ph
n-propyl
isopropyl
n-butyl
-CH2-cyclohexyl
n-C12H25
propargyl
3-picolyl
3-picolyl
3-picolyl
3-picolyl
H
Me
H
Me
Me
Me
isoprenyl
allyl
Me
n-propyl
H
H
Me
H
propargyl
Me
313 ( 4
100 ( 2
583 ( 14
139 ( 8
158 ( 6
239 ( 9
25 ( 2
211 ( 11
299 ( 13
30%b
107 ( 2
11 ( 1
197 ( 6
8 ( 2
23 ( 3
11 ( 2
0.5 ( 0.2
35 ( 2
16 ( 2
447 ( 16
27%b
128 ( 6
9 ( 2
2930 ( 22
141 ( 10
38 ( 4
9 ( 1
100 ( 2
11 ( 1
14 ( 2
9 ( 2
NT
15%b
160 ( 5
NT
8 ( 2
17%b
14 ( 2
0.4 ( 0.1
39 ( 3
12 ( 2
141 ( 9
188 ( 16
64 ( 4
24 ( 3
319 ( 6
12 ( 2
22 ( 3
3 ( 1
13 ( 1
90 ( 4
127 ( 7
43 ( 2
32 ( 2
8 ( 1
626 ( 21
805 ( 18
7%b
65%b
24%b
647 ( 21
52%b
8%b
54%b
325 ( 26
18%b
180 ( 8
942 ( 9
20%b
300 ( 10
258 ( 9
156 ( 6
1000 ( 15
574 ( 12
1140 ( 15
522 ( 8
672 ( 15
15 ( 2
17%b
isoprenyl
-CH2-CH(CH3)
-(CH2)2-CH(CH3)2
-(CH2)3-CH3
-(CH2)7-CH3
propargyl
203 ( 7
63 ( 4
120 ( 6
88%b
174 ( 3
83 ( 4
9 ( 1
42%b
41%b
3-picolyl
3-picolyl
3-picolyl
764 ( 8
669 ( 18
23%b
CGS-27023A
231 ( 6
a
Inhibitor concentrations were run in triplicate. MMP IC50 values determinations were calculated from a four-parameter logistic fit of
the data within a single experiment. The final values given here are the mean of the triplicate values of the sample. NT ) not tested.b %
inhibition at 10 µM concentration. Dose-response curves were not generated for compounds at <60% incubation at 10 µM concentration.
All the compounds listed here are racemic.
against MMP-13 and the selectivity versus MMP-1
decrease. It is therefore clear that the presence of
smaller substituents, such as a methyl group in the R2
position, favor MMP inhibition.
Next we investigated the effect of different R1 sub-
stituents on these molecules because they presumably
occupy the S1′ pocket of these enzymes. Selectivity for
MMP-13 vs MMP-1 can be tuned by varying the R1

R-Sulfonylhydroxamic Acids
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12 2365
Ta ble 2. In Vitro IC50 Valuesd and Dialysis Implant Model Data
a
b
% inhibition for CGS-27023 at 25 mg/kg, po. % inhibition at 10 µM concentration. Dose-response curves were not generated for
compounds at <60% incubation at 10 µM concentration. c Compounds were dosed at 25 mg/kg, po, and the data were expressed relative
d
to the activity of CGS-27023 (such that CGS-27023 ) 1). Inhibitor concentrations were run in triplicate. MMP IC50 values determinations
were calculated from a four-parameter logistic fit of the data within a single experiment. The final values given here are the mean of the
triplicate values of the sample.
Ta ble 3. In Vitro Activity for Different R1 Substituents (IC50
substituent. Examples 50 and 57 (Table 2) reveal that
Valuesa)
MMP-1
(nM)
MMP-9 MMP-13
TACE
compd
R1
(nM)
(nM)
% inhibitionb
53
56
58
59
-OCH3 318 ( 12 13 ( 3
15 ( 4
16 ( 3
2 ( 1
39
NT
45
-OEt
2-furyl
Br
627 ( 23 11 ( 2
14 ( 2
51 ( 4
4 ( 1
58 ( 2
when the R1 substituent is changed from methoxy to
n-butoxy, MMP-13 potency is retained while MMP-1
activity is significantly lowered (238 vs 760 nM, respec-
tively). This can be attributed to the fact that in MMP-1
the depth of the S1′ pocket is shallow while MMP-13 is
a deep pocket enzyme that can accommodate the longer
butoxy substituent.22 A similar trend is observed for
compounds 53 and 56. However, replacing the ether
functionality with an aryl moiety, such as in the 2-furyl
analogue 58 (Table 3), leads to an increase in potency
but a decrease in selectivity of MMP-13 vs MMP-1.
Comparison of 34 vs 60 (Figure 3 and Table 4) reveals
that the replacement of a methoxy substituent with
methyl decreases inhibitory potency against MMPs and
TACE. Replacement of the aromatic sulfonyl moiety
with aliphatic sulfonyl (61-63) or a heteroaromatic
11 ( 2
NT
a
Inhibitor concentrations were run in triplicate. MMP IC50
values determinations were calculated from a four-parameter
logistic fit of the data within a single experiment. The final values
given here are the mean of the triplicate values of the sample.
b
NT ) not tested. 10 µM concentration. Dose-response curves
were not generated for compounds at <60% incubation at 10 µM
concentration;
group (64 and 65) decreases the potency of both MMP
inhibition and TACE inhibition activity (Figure 3 and
Table 4).
Unfortunately, even though in vitro potency could be
increased by changing the R2 and R3 substituents,
achieving in vivo activity in the dialysis implant model
and the sponge-wrapped cartilage model remained

2366 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12
Aranapakam et al.
F igu r e 3.
Ta ble 4. In Vitro Activity IC50 Valuesa for Compounds in
Figure 3
Ta ble 5. In Vivo Activitya of Selected Compounds in the
Sponge-Wrapped Cartilage Model
MMP-1
(nM)
MMP-9
(nM)
MMP-13
(nM)
TACE
(nM)
compd
% inhibition @ 25 mg/kg, po
compd
50
51
57
69 ( 5 vs 52 ( 4%b (1.3)c
67 ( 4 vs 58 ( 5%b (1.2)c
44 ( 3 vs 58 ( 5%b (0.8)c
34
60
29
61
62
63
64
65
25 ( 2
262 ( 6
100 ( 2
10%b
0.5 ( 1
51 ( 3
11 ( 1
0%b
0.4 ( 1
6 ( 2
11 ( 1
6%b
805 ( 18
36%a
15%a
3%
a
b
Mean % inhibition values of three experiments. CGS-27023.
c Compounds were dosed at 25 mg/kg, po, and the data were
expressed relative to the activity of CGS-27023 (such that CGS-
27023 ) 1).
78%b
71%b
23%b
49%b
79%b
85%b
55%b
37%b
85%b
1%b
10%b
NT
49%b
20%b
51%b
99%b
Ta ble 6. In Vitro Activity IC50 Valuesa (nM) and Dialysis
Implant Data for the Dextro and Levo Isomers of Compound 50
a
Inhibitor concentrations were run in triplicate. MMP IC50
values determinations were calculated from a four-parameter
logistic fit of the data within a single experiment. The final values
given here are the mean of the triplicate values of the sample.
compd 50
isomer
MMP-1
MMP-9 MMP-13
% inhibitionc
b
dextro
levo
154 ( 3
2530 ( 18 112 ( 6
5 ( 1
4 ( 1
86 ( 5
69 ( 4 vs 68b ( 3 (1)d
NT ) not tested. % inhibition at 10 µM concentration.
15 ( 3 vs 60b ( 4 (0.25)d
a
Inhibitor concentrations were run in triplicate. MMP IC50
values determinations were calculated from a four-parameter
logistic fit of the data within a single experiment. The final
values given here are the mean of the triplicate values of the
challenging. The picolyl compounds (examples 43-49)
(Table 1) did not show any significant activity in the
dialysis implant model. To increase the basic nature of
the nitrogen, examples 50-57 were prepared. Their in
vitro and in vivo data are tabulated in Table 2. All these
compounds (examples 50-57) showed weak activity
against TACE and good potency against MMP-13 and
MMP-9. In addition, all of the compounds, listed in
Table 2, were active in the dilaysis implant model. The
in vivo bioactivity of these compounds were measured
relative to CGS 27023 (Figure 2). Thus, compound 50
showed 78% enzyme inhibition in the dialysis implant
model, given orally at a dose of 25 mg/kg. In the same
experiment, CGS 27023 was used as a standard and
showed an enzyme inhibition of 77% at 25 mg/kg, po.
On the basis of the selectivity and potency, three
compounds, examples 50, 51, and 57 (Table 2), were
chosen for the sponge-wrapped cartilage model. In the
same experiments, CGS 27023 was used as a compara-
tor. Compounds were dosed orally at 25 mg/kg, qd, for
3 weeks, and the percentage inhibition of bovine carti-
lage degradation was measured. The results are shown
in Table 5, and all three compounds exhibited slightly
better activity than CGS 27023.
sample. % inhibition of CGIS-27023 c Dialysis implant data.
Compounds were dosed at 25 mg/kg, po, and the data were
expressed relative to the activity of CGS-27023 (such that CGS-
27023 ) 1).
b
d
On the basis of the above-mentioned facts, examples
50 and 57 turned out to be the best candidates.
However, compound 57 in the sponge-wrapped cartilage
assay proved to be less active than 50. Compound 50
protected bovine cartilage by 68.8% (25 mg/kg, po, qd).
Its oral bioavailability in rats was found to be 81% with
a t1/2 of 1.5 h. This compound was always tested as a
racemic mixture, and attempts to prepare it in chiral
form turned out to be unsuccessful. However, the two
enantiomers were separated on a small scale by pre-
parative chiral HPLC. The dextro isomer (stereochem-
istry not determined) was found to be 20-fold more
potent against MMP-13 (Table 6) than the levo isomer.
This potency also translated into increased in vivo
activity, when tested in the dialysis implant model, in
which the levo isomer was found to be 4.6-fold less active
than its corresponding dextro isomer.

R-Sulfonylhydroxamic Acids
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12 2367
layer was concentrated. The residue obtained was extracted
with chloroform, washed well with water, dried over anhydrous
MgSO4, filtered, and concentrated. The product obtained was
purified by silica gel column chromatography, eluting with 30%
ethyl acetate/hexane. The product 2-(4-methoxybenzenesulfo-
nyl)-3-phenylpropionic acid ethyl ester was isolated as a low
melting solid. Yield: 3.0 g, 86%. MS, m/z: 349 (M + H)+.
To a stirred solution of 2-(4-methoxybenzenesulfonyl)-3-
phenylpropionic acid ethyl ester (348 mg, 1 mmol) in methanol
(25 mL), 10 N NaOH (10 mL) was added. The reaction mixture
was stirred at room temperature for 48 h. At the end, the
reaction mixture was concentrated and carefully neutralized
with dilute HCl. The residue obtained was extracted with
chloroform, washed well with water, dried, and concentrated.
The product obtained was purified by silica gel column
chromatography, eluting with ethyl acetate/methanol (95:5)
to afford 2-(4-methoxybenzenesulfonyl)-3-phenylpropionic acid
as a colorless oil. Yield: 250 mg, 89%. MS, m/z: 321 (M +
H)+.
Con clu sion
To summarize the SAR of molecules of general
structure 1, selectivity for MMP-13 vs MMP-1 can be
achieved by varying the R1 substituent. When R1 is
equal to long-chain alkoxy groups, the selectivity for
MMP-13 over MMP-1 improves. Aromatic sulfonyl
compounds are more potent than aliphatic or heteroaro-
matic sulfonyl derivatives. Compounds disubstituted at
R2 and R3 are more potent MMP inhibitors than simple
monosubstituted compounds (R3 ) H). To achieve in
vivo activity, an aliphatic basic amine is essential. On
the basis of the in vivo efficacy, compound 50 turned
out to be the candidate of choice for further development
even though it has moderate selectivity of MMP-13 over
MMP-1.
Exp er im en ta l Section
To a stirred solution of 2-(4-methoxybenzenesulfonyl)-3-
phenylpropionic acid (200 mg, 0.625 mmol) and DMF (2 drops)
in CH2Cl2 (100 mL) at 0 °C, oxalyl chloride (1.0 g, 8 mmol)
was added in a dropwise manner. After the addition, the
reaction mixture was stirred at room temperature for 1 h.
Simultaneously, in a separate flask a mixture of hydroxy-
lamine hydrochloride (2.0 g, 29 mmol) and triethylamine (5
mL, excess) was stirred in THF/water (5:1, 30 mL) at 0 °C for
1 h. At the end of 1 h, the oxalyl chloride reaction mixture
was concentrated and the pale-yellow residue was dissolved
in 10 mL of CH2Cl2. The mixture was added slowly to the
hydroxylamine at 0 °C. The reaction mixture was stirred at
room temperature for 24 h and concentrated. The residue
obtained was extracted with chloroform and washed well with
water. The product obtained was purified by silica gel column
chromatography and eluted with ethyl acetate. The N-hydroxy-
2-(4-methoxybenzenesulfonyl)-3-phenylpropionamide was iso-
lated as a brown solid. Yield: 71%. Mp 180 °C. MS, m/z: 336
Gen er a l Meth od s. Melting points were determined in open
capillary tubes on a Meltemp melting point apparatus and are
uncorrected. 1H NMR spectra were determined with a Bruker
DPX-300 spectrometer at 300 MHz. Chemical shifts δ are
reported in parts per million relative to residual chloroform
(7.26 ppm), TMS (0 ppm), or dimethyl sulfoxide (2.49 ppm) as
an internal reference with coupling constants (J ) reported in
hertz (Hz). The peak shapes are denoted as follows: s, singlet;
d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.
Electrospray (ES) mass spectra were recorded in positive or
negative mode on a Micromass Platform spectrometer. Elec-
tron impact and high-resolution mass spectra were obtaned
on a Finnigen MAT-90 spectrometer. Combustion analyses
were obtained using a Perkin-Elmer series II 2400 CHNS/O
analyzer. Chromatographic purifications were performed by
flash chromatography using Baker 40 µm silica gel. Thin-layer
chromatography (TLC) was performed on Analtech silica gel
GHLF 250 M prescored plates. The terms “concentrated” and
“evaporated” refer to removal of solvents using a rotary
evaporator at water aspirator pressure with a bath tempera-
ture equal to or less than 60 °C. Unless otherwise noted,
reagents were obtained from commercial sources and were
used without further purification.
N-H yd r oxy-2-(4-m et h oxyb en zen esu lfon yl)-3-p h en yl-
p r op ion a m id e (28). To a stirred solution of 4-methoxyben-
zenethiol (2.8 g, 20 mmol) and anhydrous K2CO3 (10 g, excess)
in dry acetone (100 mL), R-bromoethyl acetate (3.3 g, 20 mmol)
was added in a round-bottom flask. The reaction mixture was
heated at reflux for 8 h with good stirring. At the end, the
reaction mixture was cooled, the potassium salts were filtered
off, and the reaction mixture was concentrated. The residue
was extracted with chloroform and washed with 0.5 N NaOH
solution. The organic layer was further washed well with
water, dried over MgSO4, filtered, and concentrated. (4-
Methoxyphenylsulfanyl)acetic acid ethyl ester was isolated as
pale-yellow oil. Yield: 4.4 g, 100%. MS, m/z: 227 (M + H)+.
To a stirred solution of 60% 3-chloroperoxybenzoic acid (14.0
g, 40 mmol) in methylene chloride (100 mL) at 0 °C, (4-
methoxyphenylsulfanyl)acetic acid ethyl ester (4.4 g, 20 mmol)
in CH2Cl2 (15 mL) was added slowly. The reaction mixture
turned cloudy and was stirred at room temperature for 6 h.
The reaction mixture was then diluted with hexanes (300
mL) and stirred for 15 min. The solids were filtered off, and
Na2SO3 solution was added to the organic layer, which was
stirred for at least 3 h before the mixture was extracted with
CHCl3 and washed with H2O. The organic layer was dried over
MgSO4, filtered, and concentrated, and the colorless (4-
methoxyphenylsulfonyl)acetic acid ethyl ester was isolated as
an oil. Yield: 100%. MS, m/z: 259.1 (M + H)+.
1
(M + H)+. H NMR (300 MHz, CDCl3): δ 3.2 (m, 1H), 3.8 (s,
3H), 4.0-4.2 (m, 2H), 7.0-8.0 (m, 9H). Anal. (C16H17NO5S) C,
H, N.
N-Hyd r oxy-2-(4-m eth oxyben zen esu lfon yl)-2-m eth yl-3-
p h en ylp r op ion a m id e (29). To a stirred solution of 2-(4-
methoxybenzenesulfonyl)-3-phenylpropionic acid ethyl ester
(1.0 g, 3 mmol) (from example 28), methyl iodide (1 mL,
excess), and 18-crown-6 (500 mg) in acetone (250 mL), K2CO3
(10 g, excess) was added. The reaction mixture was refluxed
for 24 h. At the end, the reaction mixture was filtered and the
acetone layer was concentrated. The residue obtained was
extracted with chloroform, washed well with water, dried over
anhydrous MgSO4, filtered, and concentrated. The product
obtained was purified by silica gel column chromatography by
eluting it with 30% ethyl acetate/hexanes to afford 2-(4-
methoxybenzenesulfonyl)-2-methyl-3-phenylpropionic acid eth-
yl ester as a colorless oil. Yield: 1.0 g, 98%. MS, m/z: 349 (M
+ H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-2-methyl-3-
phenylpropionic acid ethyl ester (900 mg, 2.7 mmol), 850 mg
(quantitative) of 2-(4-methoxybenzenesulfonyl)-2-methyl-3-
phenylpropionic acid was isolated by following the procedure
as outlined in example 28. A colorless oil was obtained. MS,
m/z: 335 (M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-2-methyl-3-
phenylpropionic acid (900 mg, 2.7 mmol) and following the
procedure as outlined in example 28, 450 mg of N-hydroxy-
2-(4-methoxybenzenesulfonyl)-2-methyl-3-phenylpropion-
amide was isolated as a brown solid. Yield: 48%. Mp 58 °C.
MS, m/z: 350 (M + H)+. 1H NMR (300 MHz, CDCl3): δ 1.4 (s,
3H), 3.1 (d, J ) 9 Hz, 1H), 3.6 (d, J ) 9 Hz, 1H), 3.9 (s, 3H),
6.8-7.8 (m, 9H). Anal. (C17H19NO5S) C, H, N.
To a stirred solution of the (4-methoxybenzenesulfonyl)acetic
acid ethyl ester (2.5 g, 10 mmol), benzyl bromide (1.8 g,10
mmol) and 18-crown-6 (500 mg) in acetone (250 mL) was added
K2CO3 (10 g, excess). The mixture was refluxed for 24 h. At
the end, the reaction mixture was filtered and the acetone
N-Hyd r oxy-2-(4-m eth oxyben zen esu lfon yl)-3-n a p h th a -
len -2-ylp r op ion a m id e (30). Following the procedure as
outlined in example 28, 2-(4-methoxybenzensulfonyl)-3-naph-
thalen-2-ylpropionic acid ethyl ester was prepared, starting
from 2-(4-methoxybenzenesulfonyl)acetic acid ethyl ester (5.0

2368 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12
Aranapakam et al.
g, 20 mmol) and 2-bromomethylnaphthalene (4.4 g, 20 mmol).
following the procedure as outlined in example 28. Mp 161
°C. MS, m/z: 411 (M + H)+.
Yield: 7.2 g, 91%. Colorless oil. MS, m/z: 399 (M + H)+.
Starting from 3-(biphenyl-4-yl)-2-(4-methoxybenzenesulfo-
nyl)-2-methylpropionic acid (2.0 g, 4.8 mmol) and following the
procedure as outlined in example 28, 1.2 g of 3-(biphenyl-4-
yl)-N-hydroxy-2-(4-methoxybenzenesulfonyl)-2-methylpropi-
onamide was isolated as a colorless solid. Yield: 58%. Mp
Starting from 2-(4-methoxybenzenesulfonyl)-3-naphthalen-
2-ylpropionoic acid ethyl ester (3.7 g, 9 mmol), 3.3 g (96%) of
2-(4-methoxybenzenesulfonyl)-3-naphthalen-2-ylpropionoic acid
was isolated as a colorless oil by following the procedure as
outlined in example 28. MS, m/z: 369.1 (M - H)-.
1
177 °C. MS, m/z: 426 (M + H)+. H NMR (300 MHz, CDCl3):
Starting from 2-(4-methoxybenzenesulfonyl)-3-naphthalen-
2-ylpropionic acid (2.2 g, 5.9 mmol) and following the procedure
as outlined in example 28, 820 mg of N-hydroxy-2-(4-meth-
oxybenzenesulfonyl)-3-naphthalen-2-ylpropionamide was iso-
lated as a light-brown solid. Yield: 36%. Mp 161-163 °C. MS,
δ 1.4 (s, 3H), 3.2 (d, J ) 9 Hz, 1H), 3.7 (d, J ) 9 Hz, 1H), 3.9
(s, 3H), 7.0-7.8 (m, 13H), 9.7 (bs, 1H). Anal. (C23H23NO5S) C,
H, N.
2-(4-Meth oxyben zen esu lfon yl)-2,5-d im eth ylh ex-4-en o-
ic Acid Hyd r oxya m id e (33). Following the procedure as
outlined in example 31, 2-(4-methoxybenzenesulfonyl)-2,5-
dimethylhex-4-enoic acid ethyl ester was prepared, starting
from 2-(4-methoxybenzenesulfonyl)propionic acid ethyl ester
(1 g, 3.6 mmol) and isoprenyl bromide (1.0 g, 6 mmol). Yield:
1.0 g, 81%. Colorless oil. MS, m/z: 341 (M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-2,5-dimethyl-
hex-4-enoic acid ethyl ester (900 mg, 2.6 mmol), 800 mg (96%)
of 2-(4-methoxybenzenesulfonyl)-2,5-dimethylhex-4-enoic acid
was isolated as a semisolid by following the procedure as
outlined in example 28. MS, m/z: 313 (M + H)+.
1
m/z: 385.9 (M + H)+. H NMR (300 MHz, CDCl3): δ 3.32 (d,
J ) 7.0 Hz, 1H), 3.69 (d, J ) 7.0 Hz, 1H), 3.82 (s, 3H), 5.02 (s,
1H), 6.92-7.89 (m, 11H). Anal. (C20H19NO5S) C, H, N.
N-Hyd r oxy-2-(4-m eth oxyben zen esu lfon yl)-2-m eth yl-3-
n a p h th a len -2-ylp r op ion a m id e (31). To stirred solution of
4-methoxybenzenethiol (2.8 g, 20 mmol) and anhydrous
K2CO3 (10 g, excess) in dry acetone (100 mL), ethyl 2-bro-
mopropionate (3.6 g, 20 mmol) was added in a round-bottom
flask, and the reaction mixture was heated at reflux for 8 h
with good stirring. At the end, the reaction mixture was
allowed to cool, the potassium salts were filtered off, and the
reaction mixture was concentrated. The residue was extracted
with chloroform and washed with water and 0.5 N NaOH
solution. The organic layer was further washed well with
water, dried over MgSO4, filtered, and concentrated to afford
2-(4-methoxyphenylsulfanyl)propionic acid ethyl ester as a
light-yellow oil. Yield: 4.5 g, 94%. MS, m/z: 241 (M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-2,5-dimethyl-
hex-4-enoic acid (1.0 g, 3.2 mmol) and following the procedure
as outlined in example 28, 700 mg of 2-(4-methoxybenzene-
sulfonyl)-2,5 dimethylhex-4-enoic acid hydroxyamide was iso-
lated as a low-melting solid. Yield: 67%. MS, m/z: 328 (M +
1
H)+. H NMR (300 MHz, CDCl3): δ 1.3 (s, 3H), 1.5 (d, J ) 6.2
Hz, 6H), 2.5-3.0 (m, 2H), 3.9 (s, 3H), 7.0 (d, J ) 11 Hz, 2H),
7.8 (d, J ) 11 Hz, 2H). Anal. (C15H21NO5S) C, H, N.
2-(4-Meth oxyben zen esu lfon yl)-5-m eth yl-2-(3-m eth ylbu t-
2-en yl)h ex-4-en oic Acid Hyd r oxya m id e (34). Following the
procedure as outlined in example 28, 2-(4-methoxybenzene-
sulfonyl)-5-methyl-2-(3-methylbut-2-enyl)hex-4-enoic acid ethyl
ester was prepared, starting from 2-(4-methoxybenzenesulfo-
nyl)acetic acid ethyl ester (5.0 g, 20 mmol) and isoprenyl
bromide (6.0 g, 40 mmol). Yield: 7.0 g, 88%. Colorless oil. MS,
m/z: 395 (M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-5-methyl-2-(3-
methylbut-2-enyl)hex-4-enoic acid ethyl ester (3.5 g, 9 mmol),
3.3 g (97%) of 2-(4-methoxybenzenesulfonyl)-5-methyl-2-(3-
methylbut-2-enyl)hex-4-enoic acid was isolated as a colorless
oil by following the procedure as outlined in example 28. MS,
m/z: 365 (M - H)-.
To a stirred solution of 2-(4-methoxyphenylsulfanyl)propi-
onic acid ethyl ester (2.41 g. 10 mmol) in methanol/THF (1:1,
100 mL) an aqueous solution of Oxone (10 g, excess, in 100
mL of water) was added at room temperature. The reaction
mixture was stirred for 4 h and filtered. The filtrate was
concentrated and extracted with ethyl acetae. The organic
layer was ashed with water and dried over anhydrous MgSO4.
It was filtered and concentrated. The product was found to be
98% pure (by HPLC) and was taken to next step with out any
purification. It was obtained as an oil. Yield: 2.5 g, 95%. MS,
m/z: 273 (M + H)+.
Following the procedure as outlined in example 28, 2-(4-
methoxybenzenesulfonyl)-2-methyl-3-naphthalen-2-ylpropion-
ic acid ethyl ester was prepared, starting from 2-(4-methoxy-
benzenesulfonyl)propionic acid ethyl ester (5.4 g, 20 mmol) and
2-bromomethylnaphthalene (4.4 g, 20 mmol). Yield: 8.0 g, 97%.
Colorless crystals. Mp 182-184 °C. MS, m/z: 413 (M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-2-methyl-3-
naphthalen-2-ylpropionic acid ethyl ester (4.6 g, 11 mmol), 4.2
g (98%) of 2-(4-methoxybenzenesulfonyl)-2-methyl-3-naphtha-
len-2-ylpropionic acid was isolated as colorless crystals by
following the procedure as outlined in example 28. Mp 144-
146 °C. MS, m/z: 384.9 (M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-2-methyl-3-
naphthalen-2-ylpropionic acid (2.4 g, 6.2 mmol) and following
the procedure as outlined in example 28, 1.6 g of N-hydroxy-
2-(4-methoxybenzenesulfonyl)-2-methyl-3-naphthalen-2-ylpro-
pionamide was isolated as a light, colorless solid. Yield: 64%.
Mp 185-187 °C. MS, m/z: 400.2 (M + H)+. 1H NMR (300 MHz,
CDCl3): δ 1.56 (s, 3H), 3.28 (d, J ) 8.0 Hz, 1H), 3.81 (d, J )
8 Hz, 1H), 3.93 (s, 3H), 4.88 (bs, 1H), 7.02-7.92 (m, 11H). Anal.
(C21H21NO5S) C, H, N.
Starting from 2-(4-methoxybenzenesulfonyl)-5-methyl-2-(3-
methylbut-2-enyl)hex-4-enoic acid (2.6 g, 7.0 mmol) and fol-
lowing the procedure as outlined in example 28, 1.36 g of 2-(4-
methoxybenzenesulfonyl)-5-methyl-2-(3-methylbut-2-enyl)hex-
4-enoic acid hydroxyamide was isolated as a colorless solid.
1
Yield: 67%. Mp 93-96 °C. MS, m/z: 383 (M + H)+. H NMR
(300 MHz, CDCl3): δ 1.68 (s, 6H), 1.73 (s, 6H), 2.72 (m, 4H),
3.82 (s, 3H), 5.12 (m, 2H), 6.92 (d, J ) 8 Hz, 2H), 7.33 (bs,
1H), 7.72 (d, J ) 8 Hz, 2H), 9.71 (bs, 1H). Anal. (C19H27NO5S)
C, H, N.
2-Allyl-2-(4-m eth oxyben zen esu lfon yl)pen t-4-en oic Acid
Hyd r oxya m id e (35). Following the procedure as outlined in
example 28, 2-allyl-2-(4-methoxybenzenesulfonyl)pent-4-enoic
acid ethyl ester was prepared, starting from 2-(4-methoxyben-
zenesulfonyl)acetic acid ethyl ester (3.0 g, 11.6 mmol) and allyl
bromide (4 mL, excess). Yield: 3.6 g, 92%. Yellow oil. MS,
m/z: 338 (M + H)+.
3-(Biph en yl-4-yl)-N-h ydr oxy-2-(4-m eth oxyben zen esu lfo-
n yl)-2-m eth ylp r op ion a m id e (32). Following the procedure
as outlined in example 31, 3-(biphenyl-4-yl)-2-(4-methoxyben-
zenesulfonyl)-2-methylpropionic acid ethyl ester was prepared,
starting from 2-(4-methoxybenzenesulfonyl)propionic acid eth-
yl ester (2.7 g,10 mmol) and 4-(chloromethyl)biphenyl (2.5 g,
12 mmol). Yield: 4.0 g, 91%. Colorless oil. MS, m/z: 438 (M +
H)+.
Starting from 3-(biphenyl-4-yl)-2-(4-methoxybenzenesulfo-
nyl)-2-methylpropionic acid ethyl ester (3 g, 6.8 mmol), 2.5 g
(89%) of 3-(biphenyl-4-yl)-2-(4-methoxybenzenesulfonyl)-2-
methylpropionic acid was isolated as a colorless solid by
2-Allyl-2-(4-methoxybenzenesulfonyl)pent-4-enoic acid was
prepared starting from 2-allyl-2-(4-methoxybenzenesulfo-
nyl)pent-4-enoic acid ethyl ester (2.2 g, 6.5 mmol) dissolved
in methanol (50 mL) and 10 N NaOH (30 mL). The re-
sulting reaction mixture was worked up as outlined in ex-
ample 28. Yield: 1.76 g, 87%. Yellowish oil. MS, m/z: 311 (M
+ H)+.
Starting from 2-allyl-2-(4-methoxybenzenesulfonyl)pent-4-
enoic acid (1.5 g, 4.8 mmol) and following the procedure as
outlined in example 28, 1.5 g of 2-allyl-2-(4-methoxybenzene-
sulfonyl)pent-4-enoic acid hydroxyamide was isolated as a
colorless solid. Mp 114-116 °C. Yield: 99%. MS, m/z: 326 (M

R-Sulfonylhydroxamic Acids
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12 2369
1
+ H)+. H NMR (300 MHz, CDCl3): δ 1.62 (s, 1H), 2.70-2.80
Starting from 2-(4-methoxyphenylsulfanyl)hexanoic acid
ethyl ester (2.8 g 10 mmol) and following the procedure as
outlined in example 28, 3 g of 2-(4-methoxybenzenesulfonyl)-
hexanoic acid ethyl ester was isolated as a colorless solid.
Yield: 95%. Mp 62 °C. MS, m/z: 314 (M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)hexanoic acid
ethyl ester (2 g, 6.3 mmol), 1.5 g (83%) of 2-(4-methoxybenze-
nesulfonyl)hexanoic acid was isolated as a colorless solid by
following the procedure as outlined in example 28. Mp 116
°C. MS, m/z: 287 (M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)hexanoic acid
(1.0 g, 3.1 mmol) and following the procedure as outlined in
example 28, 700 mg of 2-(4-methoxybenzenesulfonyl)hexanoic
acid hydroxyamide was isolated as a colorless solid. Yield:
60%. Mp 130 °C. MS, m/z: 302 (M + H)+. 1H NMR (300 MHz,
CDCl3): δ 0.786 (t, J ) 7.2 Hz, 3H), 1.1-1.3 (m, 4H), 1.6-1.8
(m, 2H), 3.7 (m, 1H), 3.9 (s, 3H),7.2 (d, J ) 11 Hz, 2H), 7.8 (d,
J ) 11 Hz, 2H), 9.3 (s, 1H), 10.9 (s, 1H). Anal. (C13H19NO5S)
C, H, N.
3-Cycloh exyl-N-h ydr oxy-2-(4-m eth oxyben zen esu lfon yl)-
2-m eth ylp r op ion a m id e (40). Following the procedure as
outlined in example 31, 3-cyclohexyl-2-(4-methoxybenzene-
sulfonyl)-2-methylpropionic acid ethyl ester was prepared,
starting from 2-(4-methoxybenzenesulfonyl)propionic acid eth-
yl ester (2.7 g, 10 mmol) and bromomethylcyclohexane (1.8 g,
10 mmol). Yield: 3.5 g, 95%. Yellow oil. MS, m/z: 369 (M +
H)+.
(m,4H), 3.9 (s, 3H), 5.16-5.27 (m, 4H), 5.81-5.94 (m, 2H), 7.12
(d, J ) 8 Hz, 2H). Anal. (C15H19NO5S) C, H, N.
2-(4-Meth oxyben zen esu lfon yl)-2-m eth yl-5-p h en ylp en t-
4-en oic Acid Hyd r oxya m id e (36). Following the procedure
as outlined in example 28, 2-(4-methoxybenzenesulfonyl)-2-
methyl-5-phenylpent-4-enoic acid ethyl ester was prepared,
starting from 2-(4-methoxybenzenesulfonyl)propionic acid
ethyl ester (3.0 g, 11 mmol) and cinnamyl bromide (2.1 g,
11 mmol). Yield: 3.51 g, 82%. Colorless oil. MS, m/z: 389 (M
+ H)+.
2-(4-Methoxybenzenesulfonyl)-2-methyl-5-phenylpent-4-eno-
ic acid was prepared starting from 2-(4-methoxybenzenesulfo-
nyl)-2-methyl-5-phenylpent-4-enoic acid ethyl ester (3.0 g, 11
mmol) dissolved in methanol (50 mL) and 10 N NaOH (30 mL).
The resulting reaction mixture was worked up as outlined in
example 28. Yield: 1.9 g, 68%. Yellowish oil. MS, m/z: 361
(M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-2-methyl-5-
phenylpent-4-enoic acid (440 mg, 1.2 mmol) and following the
procedure as outlined in example 28, 420 mg of 2-(4-methoxy-
benzenesulfonyl)-2-methyl-5-phenylpent-4-enoic acid hydroxy-
amide was isolated as a colorless solid. Mp 162-164 °C.
Yield: 92%. MS, m/z: 376 (M + H)+. 1H NMR (300 MHz,
CDCl3): δ 1.41 (s, 3H), 3.0-3.16 (m, 1H), 3.30 (d, J ) 11 Hz,
2H), 3.92 (s, 3H), 5.9-6.1 (m, 1H), 6.53 (d, J ) 11 Hz, 1H),
7.1-7.72 (m, 9H), 9.12 (bs,1H). Anal. (C19H21NO5S) C, H, N.
2-(4-Meth oxyben zen esu lfon yl)-2-pr opylpen tan oic Acid
Hyd r oxya m id e (37). 2-Allyl-2-(4-methoxybenzenesulfonyl)-
pent-4-enoic acid hydroxyamide (326 mg, 1.0 mmol) (example
35) was dissolved in methanol (50 mL) and hydrogenated over
10% Pd/C (100 mg) at room temperature under 49 psi for 4 h.
At the end, the reaction mixture was filtered and methanol
was removed. The resulting solid was crystallized from
methanol. Yield: 250 mg, 75%. MS, m/z: 330 (M + H)+. 1H
NMR (300 MHz, CDCl3): δ 0.92 (t, J ) 4.0 Hz, 6H), 1.27-
1.59 (m, 4H), 1.78-2.02 (m, 4H), 3.86 (s, 3H), 6.04 (bs, 1H),
Starting from 3-cyclohexyl-2-(4-methoxybenzenesulfonyl)-
2-methylpropionic acid ethyl ester (3 g, 8.1 mmol), 2.5 g (90%)
of 3-cyclohexyl-2-(4-methoxybenzenesulfonyl)-2-methylpropi-
onic acid was isolated as colorless solid by following the
procedure as outlined in example 28. Mp 116 °C. MS, m/z: 341
(M + H)+.
Starting from 3-cyclohexyl-2-(4-methoxybenzenesulfonyl)-
2-methylpropionic acid (2.0 g, 5.8 mmol) and following the
procedure as outlined in example 28, 1.1 g of 3-cyclohexyl-N-
hydroxy-2-(4-methoxybenzenesulfonyl)-2-methylpropion-
amide was isolated as colorless solid. Yield: 55%. Mp 58 °C.
6.97 (d, J ) 9 Hz, 2H), 7.76 (d,J ) 9 Hz, 2H). Anal. (C15H23
NO5S) C, H, N.
-
1
MS, m/z: 356 (M + H)+. H NMR (300 MHz, CDCl3) δ 1.4 (s,
N-H yd r oxy-2-(4-m et h oxyb en zen esu lfon yl)-3-m et h yl-
bu tyr a m id e (38). 2-(4-Methoxyphenylsulfanyl)-3-methylbu-
tyric acid ethyl ester was prepared according to the general
method as outlined in example 28. Starting from ethyl 2-bro-
mo-3-methylbutanoate (20.9 g, 100 mmol) and 4-methoxyben-
zenethiol (14.0 g, 100 mmol), 30 g of 2-(4-methoxyphenylsul-
fanyl)-3-methylbutyric acid ethyl ester was isolated. Yield:
99%. Light yellow oil. MS, m/z: 269 (M + H)+.
Starting from 2-(4-methoxyphenylsulfanyl)-3-methylbutyric
acid ethyl ester (2.68 g 10 mmol) and following the procedure
as outlined in example 28 for oxidation, 3 g of 2-(4-methoxy-
benzenesulfonyl)-3-methylbutyric acid ethyl ester was iso-
lated as a colorless solid. Yield: 99%. Mp 53 °C. MS, m/z: 273
(M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-3-methylbu-
tyric acid ethyl ester (3 g, 10 mmol), 2.7 g (96%) of 2-(4-
methoxybenzenesulfonyl)-3-methylbutyric acid was isolated as
a colorless solid by following the procedure as outlined in
example 28. Mp 96 °C. MS, m/z: 273 (M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-3-methylbu-
tyric acid (2.0 g, 7.34 mmol) and following the procedure as
outlined in example 28, 590 mg of N-hydroxy-2-(4-methoxy-
benzenesulfonyl)-3-methylbutyramide was isolated as a color-
less solid. Mp 220 °C. Yield: 28%. MS, m/z: 288 (M + H)+. 1H
NMR (300 MHz, DMSO-d6): δ 0.88 (d, J ) 6.7 Hz, 3H), 1.07
(d, J ) 6.7 Hz, 3H), 2.09-2.20 (bs, 1H), 3.53 (d, J ) 9, 1H),
7.12-7.17 (m, 2H), 7.74-7.79 (m, 2H). Anal. (C12H17NO5S) C,
H, N.
3H), 2.3-1.0 (m, 13 H), 3.9 (s, 3H), 7.0 (d, 8.8 Hz, 2H), 7.69
(d, 9.0 Hz, 2H). Anal. (C17H25NO5S) C, H, N.
2-(4-Meth oxyben zen esu lfon yl)tetr a d eca n oic Hyd r oxy-
a m id e (41). 2-(4-Methoxyphenylsulfanyl)tetradecanoic acid
ethyl ester was prepared according to the general method as
outlined in example 28. Starting from the corresponding ethyl
2-bromomyristate (5.0 g, 14.9 mmol) and 4-methoxythiophenol
(1.9 g, 13.4 mmol), 5.0 g of the product was isolated. Yield:
98%. Light-yellow oil. MS, m/z: 393 (M + H)+.
Starting from 2-(4-methoxyphenylsulfanyl)tetradecanoic acid
ethyl ester (3.9 g 10 mmol) and following the procedure as
outlined in example 31, 3.2 g of 2-(4-methoxybenzenesulfonyl)-
tetradecanoic acid ethyl ester was isolated as a colorless solid.
Yield: 76%. Oil. MS, m/z: 425 (M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)tetradecanoic
acid ethyl ester (2.5 g, 5.9 mmol), 2.0 g (85%) of 2-(4-meth-
oxybenzenesulfonyl)tetradecanoic acid was isolated as a color-
less solid by following the procedure as outlined in example
28. Mp 82 °C. MS, m/z: 397 (M + H)+.
Starting from 2-(4-methoxybenzene sulfonyl)tetradecanoic
acid (1.14 g, 2.9 mmol) and following the procedure as outlined
in example 28, 670 mg of 2-(4-methoxybenzenesulfonyl)-
tetradecanoic hydroxyamide was isolated as an off-white solid.
Yield: 57%. Mp 114 °C. MS, m/z: 414 (M + H)+. 1H NMR (300
MHz, DMSO-d6): δ 0.85 (t, J ) 7 Hz, 3H), 1.16-1.27 (m, 20
H), 1.66 (m, 2H), 3.62-3.70 (m, 1H), 3.87 (s, 3H), 7.12 (d, J )
15 Hz, 2H), 7.73 (d, J ) 15 Hz, 2H). Anal. (C21H35NO5S) C, H,
N.
2-(4-Meth oxyben zen esu lfon yl)h exan oic Acid Hydr oxy-
a m id e (39). 2-(4-Methoxyphenylsulfanyl)hexanoic acid ethyl
ester was prepared according to the general method as outlined
in example 28. Starting from ethyl 2-bromohexanoate (7 g, 32
mmol) and 4-methoxybenzenethiol (4.2 g, 30 mmol), 8.3 g of
the product was isolated. Yield: 98%. Light-yellow oil. MS,
m/z: 283 (M + H)+.
2-(4-Met h oxyb en zen esu lfon yl)-2-p r op -2-yn ylp en t -4-
yn oic Acid Hyd r oxya m id e (42). 2-(4-Methoxybenzenesulfo-
nyl)-2-prop-2-ynylpent-4-ynoic acid tert-butyl ester was pre-
pared according to the procedure as outlined in example 28.
Starting from 2-(4-methoxybenzenesulfonyl)acetic acid tert-
butyl ester (2.0 g, 7.0 mmol) and propargyl bromide (1.77 g,

2370 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12
Aranapakam et al.
15 mmol), 1.9 g of the product was isolated. Yield: 75%. White
solid. Mp 113-115 °C. MS, m/z: 362.1 (M + H)+.
worked up as outlined in example 28. Yield: 3.2 g, 87%. Ivory
solid. Mp 117-119 °C. MS, m/z: 390 (M + H)+.
2-(4-Methoxybenzenesulfonyl)-2-prop-2-ynylpent-4-ynoic acid
was prepared according to the procedure as outlined in
example 28. To a stirred solution of 2-(4-methoxybenzene-
sulfonyl)-2-prop-2-ynylpent-4-ynoic acid tert-butyl ester (1.70
g, 4.7 mmol) in CH2Cl2 (100 mL) trifluoroacetic acid (20 mL)
was added at room temperature. The reaction mixture was
stirred at room temperature for 24 h. At the end, the reaction
mixture was concentrated and extracted with chloroform,
washed well with water, and dried over anhydrous MgSO4.
The organic layer was concentrated, and the separated white
solid was crystallized from aqueous methanol. An amount of
1.30 g of 2-(4-methoxybenzenesulfonyl)-2-prop-2-ynylpent-4-
ynoic acid was isolated as a white solid. Yield: 90%. Mp 156
°C. MS, m/z: 305.1 (M - H)-.
Starting from 2-(4-methoxybenzenesulfonyl)-5-methyl-2-py-
ridin-3-ylmethylhex-4-enoic acid (2.1 g, 5.4 mmol) and follow-
ing the procedure as outlined in example 28, 1.82 g of 2-(4-
methoxybenzenesulfonyl)-5-methyl-2-pyridin-3-ylmethylhex-
4-enoic acid hydroxyamide was isolated as a colorless solid.
1
Yield: 82%. Mp 89-92 °C. MS, m/z: 405 (M + H)+. H NMR
(300 MHz, CDCl3): δ 1.63 (s, 3H), 1.76 (s, 3H), 2.62-2.78 (m,
2H), 3.3 (d, J ) 4.0 Hz, 1H), 3.63 (d, J ) 4.0 Hz, 1H), 3.82 (s,
3H), 5.26 (m, 1H), 7.12-7.88 (m, 6H), 8.27-8.33 (m, 2H). Anal.
(C20H24N2O5S) C, H, N.
2-(4-Met h oxyb en zen esu lfon yl)-4-m et h yl-2-p yr id in -3-
ylm eth ylp en ta n oic Acid Hyd r oxya m id e (45). Following
the procedure as outlined in example 28, 2-(4-methoxyben-
zenesulfonyl)-4-methylpentanoic acid ethyl ester was prepared,
starting from 2-(4-methoxybenzenesulfonyl)acetic acid ethyl
ester (5.0 g, 20 mmol) and 1-bromo-2-methylpropane (2.6 g,
20 mmol). Yield: 6.0 g, 95%. Colorless oil. MS, m/z: 315 (M +
H)+.
Following the procedure as outlined in example 43, 2-(4-
methoxybenzenesulfonyl)-4-methyl-2-pyridin-3-ylmethylpen-
anoic acid ethyl ester was prepared, starting from 2-[(4-
methoxybenzenesulfonyl)-4-methyl pentanoic acid ethyl ester
(3.1 g, 10 mmol) and 3-picolyl chloride hydrochloride (1.8 g,
11 mmol). Yield: 3.0 g, 75%. Colorless oil. MS, m/z: 406 (M +
H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-4-methyl-2-py-
ridin-3-ylmethylpentanoic acid ethyl ester (1.2 g, 2.9 mmol),
1.0 g (91%) of 2-(4-methoxybenzenesulfonyl)-4-methyl-2-pyri-
din-3-ylmethylpentanoic acid was isolated as colorless crystals
by following the procedure as outlined in example 28. Mp 188-
186 °C. MS, m/z: 378 (M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-4-methyl-2-py-
ridin-3-ylmethylpentanoic acid (800 mg, 2.1 mmol) and fol-
lowing the procedure as outlined in example 28, 180 mg of
2-(4-methoxybenzenesulfonyl)-4-methyl-2-pyridin-3-ylmethyl-
pentanoic acid hydroxyamide was isolated as a colorless solid.
Yield: 21%. Mp 78 °C. MS, m/z: 393.4 (M + H)+. 1H NMR
(300 MHz, CDCl3): δ 0.65 (d, 6.3 Hz, 3H), 0.89 (d, J ) 6.2 Hz,
3H), 1.7 (m, 1H), 2.06 (m, 2H), 3.85 (s, 3H), 6.8-8.5 (m, 10H).
Anal. (C19H24N2O5S) C, H, N.
2-(4-Met h oxyb en zen esu lfon yl)-5-m et h yl-2-p yr id in -3-
ylm eth ylh exa n oic Acid Hyd r oxya m id e (46). Following the
procedure as outlined in example 28, 2-(4-methoxybenzene-
sulfonyl)-5-hexanoic acid ethyl ester was prepared, starting
from 2-(4-methoxybenzenesulfonyl)acetic acid ethyl ester (10.0
g, 39 mmol) and 1-bromo-3-methylbutane (6.0 g, 40 mmol).
Yield: 8.5 g, 62%. Colorless oil. MS, m/z: 329 (M + H)+.
Following the procedure as outlined in example 43, 2-(4-
methoxybenzenesulfonyl)-5-methyl-2-pyridin-3-ylmethylhex-
anoic acid ethyl ester was prepared, starting from 2-(4-
methoxybenzenesulfonyl)-5-methylhexanoic acid ethyl ester
(6.0 g, 18 mmol) and picolyl chloride hydrochloride (4.1 g, 25
mmol). Yield: 4.5 g, 60%. Brown oil. MS, m/z: 420 (M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-5-methyl-2-py-
ridin-3-ylmethylhexanoic acid ethyl ester (3.0 g, 7.1 mmol), 2.6
g (92%) of 2-(4-methoxybenzenesulfonyl)-5-methyl-2-pyridin-
3-ylmethylhexanoic acid was isolated as a colorless solid by
following the procedure as outlined in example 28. Mp 173
°C. MS, m/z: 392 (M + H)+.
2-(4-Methoxybenzenesulfonyl)-2-prop-2-ynylpent-4-ynoic acid
hydroxyamide was prepared according to the method as
outlined in example 28. Starting from (4-methoxybenzene-
sulfonyl)-2-prop-2-ynylpent-4-ynoic acid (0.25 g, 0.81 mmol)
and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.22 g of
the product was isolated. Yield: 85%. White solid. Mp 156 °C.
1
MS, m/z: 321.9 (M + H)+. H NMR (300 MHz, DMSO-d6): δ
2.00-2.13 (m, 2H), 3.00-3.30 (m, 4H), 3.90(s, 3H), 7.01 (d, J
) 9.0 Hz, 2H), 7.82 (d, J ) 9.0 Hz, 2H), 8.76 (brs, 1H), 10.65
(brs, 1H). Anal. (C15H15NO5S) C, H, N.
N-Hyd r oxy-2-(4-m eth oxyben zen esu lfon yl)-2-m eth yl-3-
p yr id in -3-ylp r op ion a m id e (43). To a stirred solution of 2-(4-
methoxybenzenesulfonyl)propionic acid ethyl ester (2.7 g, 10
mmol), 3-picolyl chloride hydrochloride (3.2 g, 20 mmol), and
triethylbenzylammonium chloride (1 g) in methylene chloride
(400 mL), 10 N NaOH (30 mL) was added. The reaction was
continued at room temp for 48 h. At the end, the organic layer
was separated and washed well with water. The organic layer
was dried, filtered, and concentrated. The crude product
obtained was purified by silica gel column chromatography.
The column was eluted with 50% ethyl acetate/hexane.
2-(4-Methoxybenzensulfonyl)-2-methyl-3-pyridin-3-ylpropi-
onic acid ethyl ester was isolated as a brown oil. Yield: 3.0 g,
82%. MS, m/z: 364 (M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-2-methyl-3-py-
ridin-3-ylpropionic acid ethyl ester (2.5 g, 6.8 mmol), 1.8 g
(79%) of 2-(4-methoxybenzenesulfonyl)-2-methyl-3-pyridin-3-
ylpropionic acid was isolated as a colorless solid by following
the procedure as outlined in example 28. Mp 58 °C. MS, m/z:
336 (M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-2-methyl-3-py-
ridin-3-ylpropionic acid (410 mg, 1 mmol) and following the
procedure as outlined in example 28, 225 mg of N-hydroxy-
2-(4-methoxybenzenesulfonyl)-2-methyl-3-pyridin-3-ylpropi-
onamide was isolated as a colorless solid. Yield: 52%. Mp 98
°C. MS, m/z: 351 (M + H)+. 1H NMR (300 MHz, CDCl3): δ
1.4 (s, 3H), 3.1 (d, J ) 9.0, 1H), 3.65 (d, J ) 9.1, 1H), 3.9 (s,
3H), 7-8.5 (m, 8H). Anal. (C16H18N2O5S) C, H, N.
2-(4-Met h oxyb en zen esu lfon yl)-5-m et h yl-2-p yr id in -3-
ylm eth ylh ex-4-en oic Acid Hyd r oxya m id e (44). Following
the procedure as outlined in example 28, 2-(4-methoxyben-
zenesulfonyl)-5-methylhex-4-enoic acid ethyl ester was pre-
pared, starting from 2-(4-methoxybenzenesulfonyl)acetic acid
ethyl ester (6.0 g, 23 mmol) and isoprenyl bromide (3.0 g,
20 mmol). Yield: 6.52 g, 86%. Colorless oil. MS, m/z: 327 (M
+ H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-5-methyl-2-py-
ridin-3-ylmethylhexanoic acid (1.0 g, 2.5 mmol) and following
the procedure as outlined in example 28, 800 mg of 2-(4-
methoxybenzenesulfonyl)-5-methyl-2-pyridin-3-ylmethylhex-
anoic acid hydroxyamide was isolated as a colorless solid. The
hydrochloride was prepared by passing hydrogen chloride gas
through a methanol solution of the hydroxyamide. Yield: 72%.
Following the procedure as outlined in example 43, 2-(4-
methoxybenzenesulfonyl)-5-methyl-2-pyridin-3-ylmethylhex-
4-enoic acid ethyl ester was prepared, starting from 2-(4-
methoxybenzenesulfonyl)-5-methylhex-4-enoic acid ethyl ester
(6.0 g, 23 mmol) and 3-picolyl chloride hydrochloride (2.1 g,
13 mmol). Yield: 4.14 g, 81%. Brown oil. MS, m/z: 418 (M +
H)+.
1
Mp 62 °C (HCl salt). MS, m/z: 408 (M + H)+. H NMR (300
MHz, CDCl3): δ 0.76 (m, 6H), 1.2-2.0 (m, 5H), 3.5 (brq, 2H),
7.1-8.8 (m, 8H), 11.1 (brs,1H). Anal. (C20H26N2O5S) C, H, N.
2-(4-Met h oxyb en zen esu lfon yl)-2-p yr id in -3-ylm et h yl-
h exa n oic Acid Hyd r oxya m id e (47). (4-Methoxyphenylsul-
fanyl)acetic acid tert-butyl ester was prepared according to the
2-(4-Methoxybenzenesulfonyl)-5-methyl-2-pyridin-3-ylmeth-
ylhex-4-enoic acid was prepared starting from 2-(4-methoxy-
benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethylhex-4-enoic acid
ethyl ester (4.0 g, 9.5 mmol) dissolved in methanol (50 mL)
and 10 N NaOH (30 mL). The resulting reaction mixture was

R-Sulfonylhydroxamic Acids
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12 2371
general method as outlined in example 28. Starting from the
corresponding 1-bromo tert-butylacetate (5.3 g, 27 mmol) and
4-methoxybenzenethiol (3.7 g, 27 mmol), 6.4 g of the product
was isolated. Yield: 98%. Light-yellow oil. MS, m/z: 255 (M
+ H)+.
2-(4-Methoxybenzenesulfonyl)acetic acid tert-butyl ester was
prepared according to the general method as outlined in
example 31. Starting from 2-(4-methoxybenzenesulfanyl)acetic
acid tert-butyl ester (5.0 g, 20 mmol) and 3-chloroperoxybenzoic
acid 57% (12.0 g, 40 mmol), 5.3 g of the product was isolated.
Yield: 92%. Waxy solid. MS, m/z: 287.1 (M + H)+.
1H), 3.5 (d, J ) 14 Hz, 1H), 3.9 (s, 3H), 6.8-8.6 (m, 8H). Anal.
(C23H32N2O5S) C, H, N.
2-(4-Met h oxyb en zen esu lfon yl)-2-p yr id in -3-ylm et h yl-
p en t-4-yn oic Acid Hyd r oxya m id e (49). 2-(4-Methoxyben-
zenesulfonyl)-2-pyridin-3-ylmethylpent-4-ynoic acid tert-butyl
ester was prepared according to the procedure as outlined in
example 28. Starting from 2-(4-methoxybenzenesulfonyl)-
pyridin-3-ylpropionic acid tert-butyl ester (3.77 g, 10 mmol)
and propargyl bromide (1.74 g, 13 mmol), 2.50 g of the product
was isolated. Yield: 60%. Yellowish solid. Mp 132-133 °C. MS,
m/z: 416.0 (M + H)+.
2-(4-Methoxybenzenesulfonyl)-2-pyridin-3-ylmethylpent-4-
ynoic acid was prepared according to the procedure as outlined
in example 47. Starting from 2-(4-methoxybenzenesulfonyl)-
2-pyridin-3-ylmethylpent-4-ynoic acid tert-butyl ester (2. 0 g,
4.8 mmol), 1.2 g of the product was isolated. Yield: 69%. White
solid. Mp 119-121 °C. MS, m/z: 358.1 (M - H)-.
2-(4-Methoxybenzenesulfonyl)-2-pyridin-3-ylmethylpent-4-
ynoic acid hydroxyamide was prepared according to the
method as outlined in example 28. Starting from 2-(4-meth-
oxybenzenesulfonyl)-2-pyridin-3-ylmethylpent-4-ynoic acid (0.29
g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10
mmol), 0.065 g of the product was isolated. Yield: 25%. Off-
white solid. Mp 70 °C. MS, m/z: 375.0 (M + H)+. 1H NMR
(300 MHz, DMSO-d6): δ 1.19 (brs, 1H), 2.90-3.00 (m, 2H),
3.55 (d, J ) 13.8 Hz, 1H), 3.67 (d, J ) 13.8 Hz, 1H), 3.89 (s,
3H), 7.18 (d, J ) 9.0 Hz, 2H), 7.75 (d, J ) 9.0 Hz, 2H), 7.80-
7.89 (m, 1H), 8.35-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.1 (brs,
1H). Anal. (C18H18N2O5S) C, H, N.
N-H yd r oxy-2-(4-m et h oxyb en zen esu lfon yl)-2-m et h yl-
3-[4-(2-p ip er id in -1-yleth oxy)p h en yl]p r op ion a m id e (50).
Following the procedure as outlined in example 31, 2-(4-meth-
oxybenzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-ylethoxy)phen-
yl]propionic acid ethyl ester was prepared, starting from 2-(4-
methoxybenzenesulfonyl)propionic acid ethyl ester (2.7 g, 10
mmol) and the 4-(2-piperidin-1-ylethoxy)benzyl chloride (2.9
g, 10 mmol). Yield: 4.8 g, 98%. Brown oil. MS, m/z: 490 (M +
H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-2-methyl-3-[4-
(2-piperidin-1-ylethoxy)phenyl]propionic acid ethyl ester (4.0
g, 7.9 mmol), 3.5 g (yield: 94%) of 2-(4-methoxybenzenesulfo-
nyl)-2-methyl-3-[4-(2-piperidin-1-ylethoxy)phenyl]propionic acid
was isolated as colorless crystals by following the procedure
as outlined in example 28. Mp 106 °C. MS, m/z: 462.5 (M +
H)+.
2-(4-Methoxybenzenesulfonyl)pyridin-3-ylpropionic acid tert-
butyl ester was prepared according to the procedure as
outlined in example 43. Starting from 2-(4-methoxybenzene-
sulfonyl)acetic acid tert-butyl ester (20.0 g, 70.0 mmol) and
3-picolyl chloride (7.28 g, 44.4 mmol), 10.5 g of the product
was isolated by silica gel chromatography (50% ethyl acetate/
hexane). Yield: 63%. White solid. Mp 93-94 °C. MS, m/z:
378.0 (M + H)+.
2-(4-Methoxybenzenesulfonyl)-2-pyridin-3-ylmethylhexa-
noic acid tert-butyl ester was prepared according to the
procedure as outlined in example 28. Starting from 2-(4-
methoxybenzenesulfonyl)pyridin-3-ylpropionic acid tert-butyl
ester (2.0 g, 5.3 mmol) and n-butyl bromide (0.73 g, 5.3 mmol),
1.20 g of the product was isolated. Yield: 52%. Yellowish gum.
MS, m/z: 434.3 (M + H)+.
A mixture of the 2-(4-methoxybenzenesulfonyl)-2-pyridin-
3-ylmethylhexanoic acid tert-butyl ester (1.1 g, 2.5 mmol) in
methylene chloride/TFA (1:1) was stirred at room temperature
for about 2 h. The solvents were then evaporated, and the 2-(4-
methoxybenzenesulfonyl)-2-pyridin-3-ylmethylhexanoic acid
was purified by silica gel chromatography (30% methanol/
methylene chloride). Yield: 0.90 g, 94%. White solid. Mp 70°
C. MS, m/z: 376.1 (M - H)-.
2-(4-Methoxybenzenesulfonyl)-2-pyridin-3-ylmethylhexa-
noic acid hydroxyamide was prepared according to the method
as outlined in example 28. Starting from 2-(4-methoxyben-
zenesulfonyl)-2-pyridin-3-ylmethylhexanoic acid (0.31 g, 0.81
mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol),
0.13 g of the product was isolated. Yield: 37%. pale-yellowish
solid. Mp 65 °C. MS, m/z: 392.9 (M + H)+. 1H NMR (300 MHz,
DMSO-d6): δ 0.80 (t, J ) 7.2 Hz, 3H), 1.10-1.25 (m, 2H),
1.25-1.50 (m, 2H), 1.70-2.00 (m, 2H), 3.53 (d, J ) 14.4 Hz,
1H), 3.62 (d, J ) 14.4 Hz, 1H), 3.88 (s, 3H), 7.15 (d, J ) 8.9
Hz, 2H), 7.71 (d, J ) 8.9 Hz, 2H), 7.90-8.00 (m, 1H), 8.40-
8.45 (m, 1H), 8.70-8.85 (m, 2H), 11.0 (brs, 1H). Anal.
(C19H24N2O5S) C, H, N.
Starting from 2-(4-methoxybenzenesulfonyl)-2-methyl-3-[4-
(2-piperidin-1-ylethoxy)phenyl]propionic acid (2.0 g, 4.2 mmol)
and following the procedure as outlined in example 28, 1 g of
N-hydroxy-2-(4-methoxybenzenesulfonyl)-2-methyl-3-[4-(2-pi-
peridin-1-ylethoxy)phenyl]propionamide was isolated as a
colorless solid. Yield: 1 g, 48%. Mp 98 °C. MS, m/z: 477 (M +
H)+. 1H NMR (300 MHz, CDCl3): δ 1.2 (s, 3H), 3.5-1.5 (m, 16
H), 3.9 (s, 3H), 4.4 (m, 1H), 6.5-7.8 (m, 8H), 10.8 (bs, 1H).
Anal. (C24H32N2O6S) C, H, N.
2-(4-Met h oxyb en zen esu lfon yl)-2-p yr id in -3-ylm et h yl-
d eca n oic Acid Hyd r oxya m id e (48). Starting from 2-(4-
methoxybenzenesulfonyl)acetic acid ethyl ester (7.5 g, 29
mmol) and 1-bromooctane (6.7 g, 35 mmol), 8 g of the mono-
octylated compound 2-(4-methoxybenzenesulfonyl)decanoic acid
ethyl ester was isolated by following the procedure outlined
in example 28. Yield: 8.0 g, 74%. MS, m/z: 370 (M + H)+.
2-[4-(2-Azep a n -1-ylet h oxy)b en zyl]-2-(4-m et h oxyb en -
zen esu lfon yl)p r op ion ic a cid Hyd r oxya m id e (51). Follow-
ing the procedure as outlined in example 31, 2-[4-(2-azepan-
1-ylethoxy)benzyl]-2-(4-methoxybenzenesulfonyl)propionic acid
ethyl ester was prepared, starting from 2-(4-methoxybenzene-
sulfonyl)propionic acid ethyl ester (2.7 g, 10 mmol) and the
1-[2-(4-chloromethylphenoxy)ethyl]azepane (3.03 g, 10 mmol).
Yield: 4.5 g, 90%. Brown oil. MS, m/z: 504 (M + H)+.
Starting from 2-[4-(2-azepan-1-ylethoxy)benzyl]-2-(4-meth-
oxybenzenesulfonyl)propionic acid ethyl ester (4.0 g, 7.9 mmol),
3.5 g (yield: 94%) of 2-[4-(2-azepan-1-ylethoxy)-benzyl]-2-(4-
methoxybenzenesulfonyl)propionic acid was isolated as a
semisolid by following the procedure as outlined in example
28. MS, m/z: 476 (M + H)+.
Starting from 2-[4-(2-azepan-1-ylethoxy)benzyl]-2-(4-meth-
oxybenzenesulfonyl)propionic acid (2.0 g, 4.2 mmol) and fol-
lowing the procedure as outlined in example 28, 1 g of
2-[4-(2-azepan-1-ylethoxy)benzyl]-2-(4-methoxybenzenesul-
fonyl)propionic acid hydroxyamide was isolated as a colorless
solid. Yield: 1.8 g, 87%. Mp 68°C. MS, m/z: 491 (M + H)+. 1H
Following the procedure as outlined in example 43, 2-(4-
methoxybenzenesulfonyl)-2-pyridin-3-ylmethyldecanoic acid
ethyl ester was prepared, starting from 2-(4-methoxybenzene-
sulfonyl)decanoic acid ethyl ester (8.0 g, 21.6 mmol) and
3-picolyl chloride hydrochloride (4.1 g, 25 mmol). Yield: 6.5 g,
68%. Brown oil. MS, m/z: 462 (M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-2-pyridin-3-
ylmethyldecanoic acid ethyl ester (5.0 g, 11 mmol), 4.5 g
(91%) of 2-(4-methoxybenzenesulfonyl)-2-pyridin-3-ylmethyl-
decanoic acid was isolated as a colorless solid by following the
procedure as outlined in example 28. Mp 159 °C. MS, m/z: 434
(M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-2-pyridin-3-
ylmethyldecanoic acid (2.5 g, 5.7 mmol) and following the
procedure as outlined in example 28, 1.4 g of 2-(4-methoxy-
benzenesulfonyl)-2-pyridin-3-ylmethyldecanoic acid hydroxy-
amide was isolated as a colorless solid. Yield: 50%. Mp 62 °C.
1
MS, m/z: 448 (M + H)+. H NMR (300 MHz, CDCl3): δ 0.86
(t, J ) 6.9 Hz, 3H), 1.25-2.17 (m, 14 H), 3.3 (d, J ) 14 Hz,

2372 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12
Aranapakam et al.
NMR (300 MHz, CDCl3): δ 1.23 (s, 3H), 3.5-1.7 (m, 18 H),
3.8 (s, 3H), 4.2 (m, 1H), 6.4-7.89 (m, 8H), 10.9 (brs, 1H). Anal.
(C25H34N2O6S) C, H, N.
pionic acid (3.0 g, 5.1 mmol) and following the procedure as
outlined in example 28, 1.8 g of 3-(4-{3-[4-(3-chlorophenyl)-
piperazin-1-yl]propoxy}phenyl)-N-hydroxy-2-(4-methoxyben-
zenesulfonyl)-2-methylpropionamide was isolated as pale-
yellow solid. Yield: 1.8 g, 55%. Mp 122°C (HCl salt). MS, m/z:
640 (M + H)+. 1H NMR (300 MHz, CDCl3): δ 1.2 (s, 3H), 3.4-
1.5 (m, 14 H), 3.9 (s, 3H), 4.5 (m, 2H), 6.5-8.2 (m, 12H), 10.3
(brs, 1H). Anal. (C30H36ClN3O6S) C, H, N.
2-(4-Met h oxyb en zen esu lfon yl)-2-m et h yl-3-[4-(2-m or -
p h olin -4-yleth oxy)p h en yl]p r op ion ic Hyd r oxya m id e Hy-
d r och lor id e (55). Following the procedure as outlined in
example 31, 2-(4-methoxybenzenesulfonyl)-2-methyl-3-[4-(2-
morpholin-1-ylethoxy)phenyl]propionic acid ethyl ester was
prepared, starting from 2-(4-methoxybenzenesulfonyl)propionic
acid ethyl ester (4.0 g, 15 mmol) and 4-(morpholin-1-ylethoxy)-
benzyl chloride hydrochloride (2.9 g, 10 mmol). Yield: 4.8 g,
98%. Brown oil. MS, m/z: 492 (M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-2-methyl-3-[4-
(2-morpholin-1-ylethoxy)phenyl]propionic acid ethyl ester (4.0
g, 8.1 mmol), 3.2 g (yield: 84%) of 2-(4-methoxybenzenesulfo-
nyl)-2-methyl-3-[4-(2-morpholin-1-ylethoxy)phenyl]propionic acid
was isolated as colorless crystals by following the procedure
as outlined in example 28. Mp 171 °C. MS, m/z: 464 (M +
H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-2-methyl-3-[4-
(2-morpholin-1-ylethoxy)phenyl]propionic acid (4.0 g, 8.6 mmol)
and following the procedure as outlined in example 28, 2.5 g
of 2-(4-methoxybenzenesulfonyl)-2-methyl-3-[4-(2-morpholin-
1-ylethoxy)phenyl]propionic hydroxyamide was isolated as
colorless solid. The hydrochloride salt was prepared by reacting
the free base with methanolic hydrogen chloride at 0 °C.
Yield: 2.5 g, 60%. Mp 98°C. MS, m/z: 479 (M + H)+. 1H NMR
(300 MHz, CDCl3): 1.36 (s, 3H), 3.8-12.6 (m, 16 H), 3.9 (s,
3H), 4.1-4.3 (m, 1H), 6.6 (d, J ) 8 Hz, 2H), 6.96 (d, J ) 9 Hz,
2H), 7.1 (d, J ) 8 Hz, 2H), 7.84 (d, J ) 9 Hz, 2H), 10.8 (brs,
1H). Anal. (C23H30N2O7S) C, H, N.
N-H yd r oxy-2-(4-et h oxyb en zen esu lfon yl)-2-m et h yl-3-
[4-(2-N,N-dieth ylam in oeth oxy)ph en yl]pr opion am ide (56).
To a stirred solution of 4-hydroxythiophenol (12.6 g, 100 mmol)
and triethylamine (15.0 g, 150 mmol) in chloroform (400 mL)
2-bromo ethylpropionate (18. 2 g, 100 mmol) was added
dropwise. The reaction mixture was refluxed for 1 h and cooled
to room temperature. The reaction mixture was washed with
water, dried, and concentrated. 2-(4-Hydroxyphenylsulfanyl)-
propionic acid ethyl ester was isolated as a colorless oil.
Yield: 22.0 g, 99%, MS, m/z: 227 (M + H)+.
To stirred solution of 2-(4-hydroxyphenylsulfanyl)propionic
acid ethyl ester (11.3 g, 50 mmol) and K2CO3 (50 g, excess) in
acetone (300 mL) ethyl iodide (20 mL, excess) was added. The
mixture was refluxed for 8 h. At the end, reaction mixture was
filtered and concentrated. The residue obtained was extracted
with chloroform and washed well with water. It was dried and
concentrated. The product 2-(4-ethoxyphenylsulfanyl)propionic
acid ethyl ester was isolated as a colorless oil. Yield: 12.0 g,
98%. MS, m/z: 255 (M + H).
N-H yd r oxy-2-(4-m et h oxyb en zen esu lfon yl)-2-m et h yl-
3-[4-(2-N ,N -d i i s o p r o p y la m i n o e t h o x y )p h e n y l]p r o -
p ion a m id e (52). Following the procedure as outlined in
example 31, 2-(4-methoxybenzenesulfonyl)-2-methyl-3-[4-(2-
N,N-diisopropylaminoethoxy)phenyl]propionic acid ethyl ester
was prepared, starting from 2-(4-methoxybenzenesulfonyl)-
propionic acid ethyl ester (5.4 g, 20 mmol) and the 4-(2-N,N-
diisopropylaminoethoxy)benzyl chloride (6.1 g, 20 mmol).
Yield: 8.9 g, 88%. Yellow oil. MS, m/z: 506.5 (M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-2-methyl-3-[4-
(2-N,N-diisopropylaminoethoxy)phenyl]propionic acid ethyl
ester (4.0 g, 7.9 mmol), 3.5 g (yield: 92%) of 2-(4-methoxyben-
zenesulfonyl)-2-methyl-3-[4-(2-N,N-diisopropylaminoethoxy)-
phenyl]propionic acid was isolated as colorless crystals by
following the procedure as outlined in example 28. Mp 68 °C.
MS, m/z: 478.6 (M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-2-methyl-3-[4-
(2-N,N-diisopropylaminoethoxy)phenyl]propionic acid (2.0 g,
4.1 mmol) and following the procedure as outlined in ex-
ample 28, 1 g of 2-(4-methoxybenzenesulfonyl)-2-methyl-3-[4-
(2-N,N-diisopropylaminoethoxy)phenyl]propionamide was iso-
lated as a colorless solid. Yield: 1 g, 49%. Mp 98 °C (HCl salt).
MS, m/z: 493 (M + H)+. 1H NMR (300 MHz, CDCl3): δ 1.2 (s,
3H), 1.3 (d,6H), 1.4 (d,6H), 3.5-1.5 (m, 6 H), 3.9 (s, 3H), 4.4
(s, 2H), 6.5-7.8 (m, 8H), 10.8 (brs, 1H). Anal. (C25H36N2O6S)
C, H, N.
N-Hyd r oxy-2-(4-m eth oxyben zen esu lfon yl)-2-m eth yl-3-
[4-(2-N,N-dieth ylam in oeth oxy)ph en yl]pr opion am ide (53).
Following the procedure as outlined in example 31, 2-(4-
methoxybenzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-
ethoxy)phenyl]propionic acid ethyl ester was prepared, starting
from 2-(4-methoxybenzenesulfonyl)propionic acid ethyl ester
(5.4 g, 20 mmol) and the 4-(2-N,N-diethylaminoethoxy)benzyl
chloride (5.5 g, 20 mmol). Yield: 8.5 g, 89%. Brown oil. MS,
m/z: 478.6 (M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-2-methyl-3-[4-
(2-N,N-diethylaminoethoxy)phenyl]propionic acid ethyl ester
(3.5 g, 7.7 mmol), 3.0 g (yield: 85%) of 2-(4-methoxybenzene-
sulfonyl)-2-methyl-3-[4-(2-N,N-diethylaminoethoxy)phenyl]-
propionic acid was isolated as colorless crystals by following
the procedure as outlined in example 28. Mp 96-98 °C. MS,
m/z: 450.5 (M + H)+.
Starting from 2-(4-methoxybenzenesulfonyl)-2-methyl-3-[4-
(2-N,N-diethylaminoethoxy)phenyl]propionic acid (2.0 g, 4.4
mmol) and following the procedure as outlined in example
28, 1 g of 2-(4-methoxybenzenesulfonyl)-2-methyl-3-[4-(2-
N,N-diethylaminoethoxy)phenyl]propionamide was isolated
as a colorless solid. Yield: 1 g, 48%. Mp 56-59°C (HCl Salt).
1
MS, m/z: 465.5 (M + H)+. H NMR (300 MHz, CDCl3): δ 1.1
(t, 6H), 1.3 (s, 3H), 3.2-3.9 (m, 8 H), 3.9 (s, 3H), 4.3 (s, 2H),
6.5-7.8 (m, 8H), 10.8 (bs, 1H). Anal. (C23H32N2O6S‚HCl) C,
H, N.
2-(4-Ethoxyphenylsulfanyl)propionic acid ethyl ester was
converted to 2-(4-ethoxyphenylsulfonyl)propionic acid ethyl
ester by following the procedure as described in example 31.
Following the procedure as outlined in example 31, 2-(4-
ethoxybenzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylami-
noethoxy)phenyl]propionic acid ethyl ester was prepared,
starting from 2-(4-ethoxybenzenesulfonyl)propionic acid ethyl
ester (3.5 g, 12.2 mmol) and the 4-(2-N,N-diethylaminoethoxy)-
benzyl chloride (3.5 g, 12.2 mmol). Yield: 4.8 g, 80%. Brown
oil. MS, m/z: 492.6 (M + H)+.
Starting from 2-(4-ethoxybenzenesulfonyl)-2-methyl-3-[4-(2-
N,N-diethylaminoethoxy)phenyl]propionic acid ethyl ester (4.0
g, 8.1 mmol), 3.2 g (yield: 80%) of 2-(4-ethoxybenzenesulfonyl)-
2-methyl-3-[4-(2-N,N-diethylaminoethoxy)phenyl]propionic acid
was isolated as a colorless semisolid by following the procedure
as outlined in example 28. MS, m/z: 464.5 (M + H)+.
Starting from 2-(4-ethoxybenzenesulfonyl)-2-methyl-3-[4-(2-
N,N-diethylaminoethoxy)phenyl]propionic acid (2.0 g, 4.3 mmol)
and following the procedure as outlined in example 28, 1.2 g
3-(4-{3-[4-(3-Ch lor op h en yl)p ip er a zin -1-yl]p r op oxy}-
p h e n yl)-N -h yd r oxy-2-(4-m e t h oxyb e n ze n e su lfon yl)-2-
m et h ylp r op ion a m id e (54). Following the procedure as
outlined in example 31, 3-(4-{3-[4-(3-chlorophenyl)piperazin-
1-yl]propoxy}phenyl)-2-(4-methoxybenzenesulfonyl)-2-methyl-
propionic acid ethyl ester was prepared, starting from 2-(4-
methoxybenzenesulfonyl)propionic acid ethyl ester (2.72 g, 10
mmol) and the 1-[2-(4-chloromethylphenoxy)ethyl]-4-(3-chlo-
rophenyl)piperazine (4.2 g, 11 mmol). Yield: 5.5 g, 89%. Brown
oil. MS, m/z: 616 (M + H)+.
Starting from 3-(4-{3-[4-(3-chlorophenyl)piperazin-1-yl]-
propoxy}phenyl)-2-(4-methoxybenzenesulfonyl)-2-methylpro-
pionic acid ethyl ester (4.0 g, 6.5 mmol), 3.0 g (yield: 78%) of
3-(4-{3-[4-(3-chlorophenyl)piperazin-1-yl]-propoxy}phenyl)-2-
(4-methoxybenzenesulfonyl)-2-methylpropionic acid was iso-
lated as colorless crystals by following the procedure as
outlined in example 28. Mp 196 °C. MS, m/z: 588.1 (M + H)+.
Starting from 3-(4-{3-[4-(3-chlorophenyl)piperazin-1-yl]-
propoxy}phenyl)-2-(4-methoxybenzenesulfonyl)-2-methylpro-

R-Sulfonylhydroxamic Acids
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12 2373
of 2-(4-ethoxybenzenesulfonyl)-2-methyl-3-[4-(2-N,N-dieth-
ylaminoethoxy)phenyl]propionamide was isolated as a colorless
low-melting solid. Yield: 1.2 g, 57% (HCl salt). MS, m/z: 478.5
(M + H)+. 1H NMR (300 MHz, CDCl3): δ 0.9 (t, 3H), 1.1 (t,
6H), 1.3 (s,3H), 3.2-3.9 (m, 8 H), 3.9 (s, 3H), 4.3 (s, 2H), 6.5-
7.8 (m, 8H), 10.8 (brs, 1H). Anal. (C24H34N2O6S‚HCl) C, H, N.
N-H yd r oxy-2-(4-n -b u t oxyb en zen esu lfon yl)-2-m et h yl-
3-[4-(2-p ip er id in -1-yleth oxy)p h en yl]p r op ion a m id e (57).
Following the procedure as outlined in example 31, 2-(4-n-
butoxybenzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-ylethoxy)-
phenyl]propionic acid ethyl ester was prepared, starting from
2-(4-n-butoxybenzenesulfonyl)propionic acid ethyl ester (3.1 g,
10 mmol) (prepared from 2-(4-hydroxyphenylsulfanyl)propionic
acid ethyl ester and n-butylbromide following the procedure
outlined in example 56) and the 4-(2-piperidin-1-ylethoxy)-
benzyl chloride (3.0 g, 10.1 mmol). Yield: 4.5 g, 84%. Brown
6H), 1.4 (s, 2H), 2.8 (q,4H), 3.0 (t, 2 H), 4.1 (t, 2H), 6.5-8.0
(m, 7H). Anal. (C26H32N2O6S‚HCl) C, H, N.
5-Meth yl-2-(3-m eth ylbu t-2-en yl)-2-(tolu en e-4-su lfon yl)-
h ex-4-en oic Acid Hyd r oxya m id e (60). 5-Methyl-2-(3-meth-
ylbut-2-enyl)-2-(toluene-4-sulfonylhex-4-enoic acid ethyl ester
was prepared according to the general method as outlined in
example 28, starting from ethyl R-(p-tolylsulfonyl)acetate (2.9
g, 10.9 mmol) and 4-bromo-2-methylbutene (3.42 g, 23 mmol).
Yield: 4.6 g. Tan oil. MS, m/z: 379.2 (M + H)+.
5-Methyl-2-(3-methylbut-2-enyl)-2-(toluene-4-sulfonyl)hex-
4-enoic acid was prepared according to the general method as
outlined in example 28, starting from 5-methyl-2-(3-methylbut-
2-enyl)-2-(toluene-4-sulfonylhex-4-enoic acid ethyl ester (4.5 g,
11 mmol), ethanol (15 mL), and 10 N sodium hydroxide.
Starting from 5-methyl-2-(3-methylbut-2-enyl)-2-(toluene-
4-sulfonyl)hex-4-enoic acid (4.1 g, 11 mmol) and following the
procedure as outlined in example 28, 1.07 g of 5-methyl-2-(3-
methylbut-2-enyl)-2-(toluene-4-sulfonyl)hex-4-enoic acid hy-
droxyamide was isolated as a colorless solid. Yield: 30%.
Mp 108-110 °C. MS, m/z: 366.2 (M + H)+. 1H NMR (300
MHz, DMSO-d6): δ 1.49 (s, 6H), 1.62 (s, 6H), 2.41 (s, 3H),
2.53-2.63 (m, 4H), 5.00-5.05 (t, 2H), 7.40-7.43 (d, 2H),
7.59-7.62 (d, 2H), 9.04 (s, 1H), 10.80 (s, 1H). Anal.
(C19H27NO4S) C, H, N.
N-H yd r oxy-2-(4-m et h oxyp h en ylm et h a n esu lfon yl)-2-
m eth yl-3-p h en ylp r op ion ic Acid Hyd r oxa m id e (61). A
mixture of 4-methoxybenzylmercaptan (7.0 g, 45 mmol), ethyl
2-bromopropionate (8.2 g, 46 mmol), and powdered oven-dried
potassium carbonate (10 g, 72 mmol) in 150 mL of acetone
was heated at reflux for 18 h. The mixture was cooled and
filtered, and the filtrate was concentrated. The residue was
taken up in 150 mL of methylene chloride, washed with water
(150 mL), dried over anhydrous sodium sulfate, and evapo-
rated to yield 12 g (99%) of a colorless liquid. MS, m/z: 255.1
(M + H)+. This product is used without further purification.
To an ice-cold (5 °C) solution of 2-(4-methoxyphenylmethane-
sulfanyl)propionic acid ethyl ester (5.7 g, 21 mmol) in 100 mL
of CH2Cl2 was added portionwise m-chloroperbenzoic acid (7.2
g, 40 mmol), and the mixture was stirred for 1 h. The reaction
mixture was diluted with hexanes (500 mL) and stirred at 25
°C for 30 min at room temperature. The mixture was filtered,
and the organic layer was treated with saturated aqueous
sodium bisulfite (200 mL). The hexanes solution containing
the product was washed with water, dried (Na2SO4), and
concentrated. Yield: 5.5 g, 91%. Colorless oil. MS, m/z: 287.1
(M + H)+.
Following the procedure as outlined in example 28, 2-(4-
methoxyphenylmethanesulfonyl)-2-methyl-3-phenylpropion-
ic acid ethyl ester was prepared, starting from 2-(4-methoxy-
phenylmethanesulfonyl)propionic acid ethyl ester (2 g, 7 mmol)
and benzyl bromide (1.3 g, 7.7 mmol). Yield: 3.0 g, 100%. Low-
melting solid. MS, m/z: 377 (M + H)+.
2-(4-Methoxyphenylmethanesulfonyl)-2-methyl-3-phenyl-
propionic acid was prepared starting from 2-(4-methoxyphen-
ylmethanesulfonyl)-2-methyl-3-phenylpropionic acid ethyl es-
ter (3.5 g, 9.0 mmol) dissolved in methanol (50 mL) and 10 N
NaOH (30 mL). The resulting reaction mixture was worked
up as outlined in example 28. Yield: 930 mg, 31%. Colorless
solid. Mp 106-108 °C. MS, m/z: 347 (M - H)+.
Starting from 2-(4-methoxyphenylmethanesulfonyl)-2-meth-
yl-3-phenylpropionic acid (2.7 g, 7.0 mmol) and following the
procedure as outlined in example 28, 266 mg of N-hydroxy-
2-(4-methoxyphenylmethanesulfonyl)-2-methyl-3-phenylpropi-
onic acid hydroxamide was isolated as light colorless solid.
Yield: 10%. Mp 58-59 °C. MS, m/z: 364.2 (M + H)+. 1H NMR
(300 MHz, DMSO-d6): δ 1.28 (s, 3H), 2.84-2.88 (d, 1H), 3.75
(s, 3H), 3.81-3.86 (d, 1H), 4.59-4.63 (d, 1H), 4.69-4.74 (d,
1H), 6.94-6.98 (d, 2H), 7.19 (m, 2H), 7.29-7.33 (d, 4H), 9.24
(s, 1H), 10.88 (s, 1H). Anal. (C18H21NO5S) C, H, N.
N-H yd r oxy-2-m et h yl-2-(oct a n e-1-su lfon yl)-3-p h en yl-
p r op ion a m id e (62). 2-(Octane-1-sulfonyl)propionic acid ethyl
ester was prepared according to the general method as outlined
in example 31, starting from 2-(octane-1-sulfonyl)propionic
acid ethyl ester (6.39 g, 26 mmol) and sodium peroxymono-
oil. MS, m/z: 532.7 (M + H)+
.
Starting from 2-(4-n-butoxybenzenesulfonyl)-2-methyl-3-[4-
(2-piperidin-1-ylethoxy)phenyl]propionic acid ethyl ester (5.0
g, 9.4 mmol), 4.2 g (yield: 88%) of 2-(4-n-butoxybenzenesulfo-
nyl)-2-methyl-3-[4-(2-piperidin-1-ylethoxy)phenyl]propionic acid
was isolated as a colorless solid by following the procedure as
outlined in example 28. MS, m/z: 504.6 (M + H)+
Starting from 2-(4-n-butoxybenzenesulfonyl)-2-methyl-3-[4-
(2-piperidin-1-ylethoxy)phenyl]propionic acid (3.0 g, 5.9 mmol)
and following the procedure as outlined in example 28, 1.3 g
of 2-(4-n-butoxybenzenesulfonyl)-2-methyl-3-[4-(2-piperidine-
1-ylethoxy)phenyl]propionamide was isolated as a colorless
solid. Mp 65° C. Yield: 1.3 g, 42% (HCl salt). MS, m/z: 478.5
(M + H)+. 1H NMR (300 MHz, CDCl3): δ 0.9 (t, 3H), 1.2 (s,
3H), 1.3-1.9 (m,10H), 2.8-4.5 (m, 12 H), 6.8-7.8 (m, 8H), 10.8
(bs, 1H). Anal. (C27H38N2O6S‚HCl) C, H, N.
3-[4-(2-Diet h yla m in oet h oxy)p h en yl]-2-(4-fu r a n -2-yl-
ben zen esu lfon yl)-N-h ydr oxy-2-m eth ylpr opion am ide (58).
To a stirred solution of 4-bromothiophenol (19.0 g, 100 mmol)
and triethylamine (15.0 g, 150 mmol) in chloroform (400 mL)
2-bromo ethylpropionate (18. 2 g, 100 mmol) was added
dropwise. The reaction mixture was refluxed for 1 h and cooled
to room temperature. The reaction mixture was washed with
water, dried, and concentrated. 2-(4-Bromophenylsulfanyl)-
propionic acid ethyl ester was isolated as colorless oil. Yield:
28.0 g, 99%, MS, m/z: 290 (M + H).
2-(4-Bromophenylsulfanyl)propionic acid ethyl ester was
converted to 2-(4-bromophenylsulfonyl)propionic acid ethyl
ester by following the procedure as described in example 31.
A mixture of 2-(4-bromophenylsulfonyl)propionic acid ethyl
ester (6.4 g, 20 mmol), 2-(tributylstannyl)furan (7.5 g, 21 mmol)
and (Ph3P)4Pd (500 mg) was refluxed in degassed tolune (250
mL) for 8 h. At the end, the reaction mixture was filtered
through Celite and concentrated. The product was purified by
silica gel column chromatography by eluting it with 50% ethyl
acetate/hexane. Colorless oil. Yield: 5.9 g, 95%, MS, m/z: 309
(M + H)+.
Following the procedure as outlined in example 31, 2-(4-
(2-furanylbenzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylami-
noethoxy)phenyl]propionic acid ethyl ester was prepared,
starting from (3.08 g, 10.0 mmol) of 2-(4-(2-furanylbenzene-
sulfonyl)propionic acid ethyl ester and the 4-(2-N,N-dieth-
ylaminoethoxy)benzyl chloride (3.5 g, 12.2 mmol). Yield: 5.0
g, 97%. Brown oil. MS, m/z: 514.6 (M + H)+.
Starting from 2-(4-(2-furanylbenzenesulfonyl)-2-methyl-3-
[4-(2-N,N-diethylaminoethoxy)phenyl]propionic acid ethyl es-
ter (5.1 g, 10.0 mmol), 3.8 g (yield: 78%) of 2-(4-(2-furanyl-
benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylaminoethoxy)-
phenyl]propionic acid was isolated as a colorless solid by
following the procedure as outlined in example 28. Mp 58 °C.
MS, m/z: 486.5 (M + H)+.
Starting from 2-(4-(2-furanylbenzenesulfonyl)-2-methyl-3-
[4-(2-N,N-diethylaminoethoxy)phenyl]propionic acid (5.0 g,
10.3 mmol) and following the procedure as outlined in example
28, 1.2 g of 2-(4-ethoxybenzenesulfonyl)-2-methyl-3-[4-(2-N,N-
diethylaminoethoxy)phenyl]propionamide was isolated as col-
orless low-melting solid. Yield: 3.2 g, 62% (HCl salt). MS,
m/z: 502 (M + H)+. 1H NMR (300 MHz, CDCl3): δ 1.23 (t,

2374 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12
Aranapakam et al.
persulfate (64 g, 104 mmol). Yield: 6.2 g, 86%. Colorless liquid.
ethyl]piperidine (5.3 g, 19.5 mmol). Yield: 96%. Semisolid. MS,
MS, m/z: 279 (M + H)+.
m/z: 466 (M + H)+.
2-Methyl-2-(octane-1-sulfonyl)-3-phenylpropionic acid ethyl
ester was prepared according to the general method as outline
in example 28, starting from 2-(octane-1-sulfonyl)propionic
acid ethyl ester (2.78 g, 10 mmol) and benzyl bromide (1.72 g,
10 mmol) to give 2.5 g (40% yield) of the product as a colorless
oil. MS, m/z: 369 (M + H)+.
2-Methyl-2-(octane-1-sulfonyl)-3-phenylpropionic acid was
prepared according to the general method as outline in
example 28, starting from 2-methyl-2-(octane-1-sulfonyl)-3-
phenylpropionic acid ethyl ester (3.68 g, 10 mmol), ethanol (15
mL), and 10 N sodium hydroxide (15 mL). Yield: 2.8 g, 82%.
Colorless oil. MS, m/z: 357 (M + NH3)+.
Starting from 2-methyl-2-(octane-1-sulfonyl)-3-phenylpro-
pionic acid (2.5 g, 7.0 mmol) and following the procedure as
outlined in example 28, 641 mg of N-hydroxy-2-methyl-2-
(octane-1-sulfonyl)-3-phenylpropionamide was isolated as an
amber-colored oil. Yield: 25%. MS, m/z: 356.0 (M + H)+. Anal.
(C18H29NO4S) C, H, N.
2-(Octan e-1-su lfon yl)-3-[4-(2-piper idin yleth oxy)ph en yl]-
p r op ion ic Acid Hyd r oxa m id e (63). 2-(Octane-1-sulfonyl)-
3-[4-(2-piperidin-ylethoxy)phenyl]propionic acid ethyl ester
was prepared according to the general method as outlined in
example 31, starting from 2-(octane-1-sulfonyl)propionic acid
ethyl ester (5.0 g, 18 mmol) and 1-[2-(4-chloromethylphenoxy)-
ethyl]piperidine (5.6 g, 19.7 mmol). Yield: 8.9 g, 96%. Amber
oil. MS, m/z: 495 (M + H)+.
2-Methyl-3-[4-(2-piperidin-1-ylethoxy)phenyl-2-(thiophene-
2-sulfonyl)propionic acid was prepared acording to the general
method as outlined in example 28, starting from 2-methyl-3-
[4-(2-piperidin-1-ylethoxy)phenyl-2-sulfonyl)propionic acid eth-
yl ester (9.8 g, 20 mmol) dissolved in ethanol (20 mL) and 10
N sodium hydroxide (20 mL). The resulting mixture was
worked up as outline in example 1. Yield: 4.5 g, 49%. White
solid. Mp 170-172 °C. MS, m/z: 436.3 (M - H)-.
Starting from 2-methyl-3-[4-(2-piperidin-1-ylethoxy)phenyl-
2-(thiophene-2-sulfonyl)propionic acid (3.6 g, 8.0 mmol) and
following the procedure as outlined in example 28, 345 mg of
2-methyl-3-[4-(2-piperidin-1-ylethoxy)phenyl-2-(thiophene-2-
sulfonyl)propionic acid hydroxyamide was isolated as light
colorless solid. Yield: 10%. Mp 115-118 °C. MS, m/z: 451.2
(M + H)+. 1H NMR (300 MHz, DMSO-d6): δ 1.29 (s, 3H), 1.66-
1.78 (m, 6H), 2.85 (d, 1H), 2.96-3.99 (m, 4H), 3.39-3.47 (m,
2H), 3.55 (d, 1H), 4.32 (m, 2H), 6.73 (d 1H), 6.91 (d, 2H), 7.01-
7.20 (m, 3H), 7.31-7.33 (m, 1H), 7.69-7.72 (m, 1H), 7.83-
7.84 (m, 1H), 8.07-8.08 (dd, 1H), 8.17 (dd, 1H), 9.0 (s, 1H),
10.0 (s, 1H), 10.78 (s, 1H). Anal. (C21H28N2O5S2) C, H, N.
Ack n ow led gm en t. The authors thank Dr. Tarek
Mansour, Dr. Semiramis Ayral-kaloustian, and Dr.
J eremy Levin of Wyeth Research, for critical reading
of this manuscript, and the members of the Wyeth
Discovery Analytical Chemistry group for analytical and
spectral determinations.
2-(Octane-1-sulfonyl)-3-[4-(2-piperidinylethoxy)phenyl]pro-
pionic acid was prepared according to the general method as
outlined in example 28, starting from 2-(octane-1-sulfonyl)-3-
[4-(2-piperidinylethoxy)phenyl]propionic acid ethyl ester (8.9
g, 18 mmol), ethanol (25 mL), and 10 N sodium hydroxide (25
mL). Yield: 6.0 g, 72%.
Refer en ces
(1) J ohnson, L. L.; Dyer, R.; Hupe, D. J . Matrix Metalloproteinases.
Curr. Opin. Chem. Biol. 1998, 2, 466.
Starting from 2-(octane-1-sulfonyl)-3-[4-(2-piperidinyleth-
oxy)phenyl]propionic acid (3.6 g, 7.7 mmol) and following the
procedure as outlined in example 28, 3.3 g of 2-(octane-1-
sulfonyl)-3-[4-(2-piperidinylethoxy)phenyl]propionic acid hy-
droxyamide was isolated as a tan solid. Yield: 89%. Mp
69-70 °C. MS, m/z: 483.2 (M + H)+. 1H NMR (300 MHz,
DMSO-d6): δ 0.687 (t, 3H), 1.27-1.69 (m, 15H), 2.73 (d, 1H),
3.51 (s, 3H), 3.67 (d, 1H), 6.88 (d, 2H), 7.10 (d, 2H), 9.16 (s,
1H), 10.70 (s, 1H). Anal. (C25H42N2O5S) C, H, N.
2-Met h yl-3-p h en yl-2-(t h iop h en e-2-su lfon yl)p r op ion -
ic Acid Hyd r oxa m id e (64). 2-Methyl-3-phenyl-2-(thiophene-
2-sulfonyl)propionic acid ethyl ester was prepared according
to the general method as outlined in example 29, starting from
2-(thiophen-2-sulfonyl)propionic acid ethyl ester (3.0 g, 12
mmol) and benzyl bromide (2.48 g, 15 mmol). Yield: 5.2 g. Tan
oil. MS, m/z: 339.1 (M + H)+.
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2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)propionic acid was
prepared according to the general method as outlined in
example 28, starting from 2-methyl-3-phenyl-2-(thiophen-2-
sulfonyl)propionic acid ethyl ester (5.0 g, 15 mmol), ethanol
(30 mL), and 10 N sodium hydroxide (10 mL). Yield: 5.6 g,
MS, m/z: 310.0 (M + H)+.
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Starting from 2-methyl-3-phenyl-2-(thiophene-2-sulfonyl)-
propionic acid (5.0 g, 16 mmol) and following the procedure
as outlined in example 28, 1.8 g of 2-methyl-3-phenyl-2-
(thiophene-2-sulfonyl)propionic acid hydroxyamide was iso-
lated as a colorless solid. Yield: 40%. Mp 116-117 °C. MS,
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here are the mean of the triplicate values of the sample.
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1
m/z: 325.9 (M + H)+. H NMR (300 MHz, DMSO-d6): δ 1.29
(s, 3H), 3.33 (d, 1H), 3.69 (d 1H), 7.18-7.30 (m, 5H), 7.74 (m,
1H), 8.22 (m, 1H), 9.13 (s, 1H), 10.80 (s, 1H). Anal. (C14H15
NO4S2) C, H, N.
-
2-Met h yl-3-[4-(2-p ip er id in -1-ylet h oxy)p h en yl-2-(t h io-
p h en e-2-su lfon yl)p r op ion ic Acid H yd r oxa m id e (65).
2-Methyl-3-[4-(2-piperidin-1-ylethoxy)phenyl-2-(thiophene-2-
sulfonyl)propionic acid ethyl ester was prepared acording to
the general method as outlined in example 31, starting from
2-(thiophene-2-sulfonyl)propionic acid ethyl ester (prepared
from 2-mercaptothiophene and 2-bromopropionic acid ethyl
ester) (4.4 g, 17.7 mmol) and 1-[2-(4-chloromethylphenoxy)-
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R-Sulfonylhydroxamic Acids
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collagenase-3 (MMP-13) complexed with
a hydroxamic acid
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J M0205548