New α-substituted succinate-based hydroxamic acids as TNFα convertase inhibitors

Article abstract of DOI:10.1021/jm990377j

Tumor necrosis factor α convertase (TACE), the enzyme responsible for the processing of proTNFα to TNFα, has been reported to be a metalloproteinase closely related to matrix metalloproteinases (MMPs). Current inhibitors of TACE such as succinate-based hy

Full text of DOI:10.1021/jm990377j

4890
J . Med. Chem. 1999, 42, 4890-4908
New r-Su bstitu ted Su ccin a te-Ba sed Hyd r oxa m ic Acid s a s TNF r Con ver ta se
In h ibitor s
Bernard Barlaam,*,† T. Geoffrey Bird,† Christine Lambert-van der Brempt,† Douglas Campbell,‡
Steve J . Foster,‡ and Rose Maciewicz‡
AstraZeneca, Zeneca Pharma, Centre de Recherches, Z.I. La Pompelle, BP1050, 51689 Reims Cedex 2, France, and
AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, England
Received J uly 20, 1999
Tumor necrosis factor R convertase (TACE), the enzyme responsible for the processing of pro-
TNFR to TNFR, has been reported to be a metalloproteinase closely related to matrix
metalloproteinases (MMPs). Current inhibitors of TACE such as succinate-based hydroxamic
acids exemplified by Marimastat (TACE IC50: 3.8 nM; blood IC50: 7 µM) and BB1101 (TACE
IC50: 0.2 nM; blood IC50: 2.3 µM) suffer from modest potency in blood and poor in vivo
properties. The introduction of new bulky R-substituents into these succinate-based hydroxamic
acids was studied. Substituents such as thioethers, sulfonamides, and ethers showed improved
potency against TACE when compared with Marimastat. Although this improvement did not
translate into better blood potency for thioether or ether substituents, the sulfonamide series
exhibited improved potency both against TACE and in blood when compared with Marimastat.
Optimization of this sulfonamide series has culminated in the identification of heterocyclic
bicyclic sulfonamides such as 3t (TACE IC50: 0.57 nM; blood IC50: 0.28 µM).
In tr od u ction
converting enzyme (TACE), probably the major enzyme
responsible for this conversion, belongs to a family
closely related to the MMPs11 and that a subset of MMP
inhibitors blocks TNF production in vitro and in vivo.12
Matrix metalloproteases (MMPs) are a family of
tightly regulated zinc-containing proteinases involved
in tissue remodeling. They are capable of degrading all
major extracellular matrix components under both
physiological and pathological conditions.1 While their
role in normal and pathological turnover of these tissues
still remains unclear, elevated levels of these enzymes
have been implicated in various diseases such as
cancer,2 arthritis,3 and periodontal and ocular disease.
Therefore, there have been considerable efforts in the
design and synthesis of MMP inhibitors: several of
them have advanced into human clinical trials for the
treatment of cancer, arthritis, and corneal ulceration.
This field has been extensively reviewed.4
Tumor necrosis factor R5 (TNFR), a cytokine produced
mainly by activated macrophages/monocytes, is a major
mediator of inflammatory and immune responses and
a strong inducer of other proinflammatory cytokines
such as IL-1â, IL-6, and IL-8. Elevated TNFR levels
occur in diseases6 such as rheumatoid arthritis (RA),
septic shock, inflammatory bowel disease (IBD), graft
vs host disease (GvHD), cachexia, and adult respiratory
distress syndrom (ARDS). Agents which inhibit TNFR
production7 could be effective in the treatment of such
diseases, as illustrated by advanced clinical trials
underway with TNF soluble receptors (Enbrel)8 or TNF
antibodies such as cA2.9
TNFR is produced as a proform, 26 kDa membrane-
bound pro-TNF, the activity of which is still unclear.10
Processing of this 26 kDa precursor into the 17 kDa
mature form is performed by specific proteolytic cleav-
age between Ala-76 and Val-77 of pro-TNF. The poten-
tial utility of MMP inhibitors as therapeutic agents has
further expanded with the recent recognition that TNFR
F igu r e 1. MMP inhibitors.
The most widely pursued approach toward MMP
inhibition has been the design of molecules that bind
to the catalytic site of the enzymes. Peptidomimetics or
pseudopeptidic structures that incorporate a zinc ligand
and a P1′ side chain are the most common class of MMP
inhibitors, although sulfonamide- and biphenyl ketone-
based inhibitors have been reported.4 The vast majority
of MMP inhibitors incorporate an hydroxamic acid
group as the zinc binding ligand whereas other ligands
such carboxylic acids, thiols, phosphinates, and phos-
phonates have been studied less thoroughly and appear
† AstraZeneca, Zeneca Pharma.
‡ AstraZeneca Pharmaceuticals.
10.1021/jm990377j CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/18/1999

MMP/ TNFR Convertase Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4891
to be less potent.4 This approach has culminated in the
design of Marimastat, which is a potent MMP inhibitor
and which also inhibits TNF release from cells.4d
However, the MMP inhibitors disclosed to date, such
as Marimastat, GW9471,12b BB1101,13 1,14 or AG 334015
(Figure 1) have shown only moderate inhibition of TNF
production in our tests (IC50: 2-15 µM in human whole
blood assay, Table 1). Moreover, several reports14,16 have
highlighted their poor in vivo properties, i.e., poor
pharmacokinetics, possibly due to metabolism of the
hydroxamic acid group,17 and poor bioavailability.
1).19 The dianion of 7 was reacted with disulfides to give
thioethers 8 and 9 as a mixture of two diastereoiso-
mers,20 which were separated at this stage. The anti-
isomer 8 was coupled with L-tert-leucine methylamide
under classical HOBT/EDCI conditions. Deprotection of
the tert-butyl ester 10 with TFA and subsequent con-
version of acid 11 to the hydroxamic acid by coupling of
hydroxylamine or protected hydroxylamines such as
Me3SiONH2, tBuMe2SiONH2, and O-(2,4-dimethoxy-
benzyl)hydroxylamine21 with EDCI afforded the desired
inhibitors 2,22 after removal of the protecting group
when necessary.
a
Ta ble 1. Activity of Disclosed MMPIs in Our Tests (IC50
)
Sch em e 1a
MMP-1 (nm) MMP-8 (nm)
published
published
compd
TACE (nM)
1.8
resultsb
resultsb
blood (µM)
GW 9471
5.3
Marimastat 3.8 ( 1.7 (7) 2.1
5
2
3
7 ( 3 (77)
BB1101 0.2
10
10c
8.2
4
2.3
Ro31-9790 20 ( 3 (3)
3.5
>50
16.6 ( 6.1 (2)
8.8
AG3340
5.5 ( 0.1 (2) 16
1 ( 0.05 (2)
0.2
1
20
a
IC50s are single determinations except where indicated oth-
erwise. Where more than one value has been determined, IC50s
b
are shown ( SD (number of determinations). Data from ref 4d.
c Data from ref 4b.
In an attempt to find more potent TNFR convertase
inhibitors, with modified physicochemical properties and
potentially better pharmacokinetic profile, we have
investigated the wide derivatization of the position R
to the hydroxamic acid. The modifications could indeed
help us to identify new interactions with the enzyme,
thus increasing in vitro potency of these succinate-based
hydroxamic acids. Moreover, the introduction of bulky
substituents has been investigated as a means of
preventing metabolism, and possibly improving absorp-
tion, which could result in overall improved pharmaco-
kinetics. This hypothesis was supported by in-house
molecular dynamics simulations performed on various
bulky R-substituted succinates. This study showed that
such a substitution could significantly reduce the con-
formational flexibility of compounds and favor confor-
mations where the R-substituent is placed in the vicinity
of the hydroxamate group,18 providing potential protec-
tion against metabolic enzymes.
a
(a) 2 LDA, THF, R1SSR1, -78 °C; (b) L-tert-leucine methyl-
amide, EDCI, HOBT, DMF; (c) TFA/CH2Cl2 (1:1); (d) 11, NH2OH‚
HCl, lutidine, EDCI, DMF; (e) 11, NH2OTMS, lutidine, EDCI,
DMF; (f) 11, NH2ODMB, EDCI, DMF; 5% TFA, CH2Cl2; (g)
(COCl)2, cat. DMF.
In a few cases when 8 and 9 were not easily separable,
the same sequence was carried out on the diastereo-
meric mixture, and the two diastereoisomers 2 and 12
were separated at the final stage. Proof of the stereo-
chemistry23 of the R-thioether substituent in 2a (R1 )
Ph) was established by preparing the anhydrides 13a
and 14a from 8a and 9a , respectively, with oxalyl
chloride.
The route to sulfonamides 3 and amides 4 started
from intermediate 1524 (Scheme 2): sulfonamide/amide
coupling, followed by conversion of the tert-butyl ester
into the hydroxamic acid according to the same methods
used for the thioether series, gave the expected sulfon-
amides 3 and amides 4. Sulfonamides 3 and amides 4
could equally be obtained from 23 by sulfonamide/amide
coupling followed by acidic deprotection of the 2,4-
dimethoxybenzyl group (optionally on solid phase24).
We disclose here several series with new R-substitu-
ents (Figure 2) and discuss the SAR of these inhibitors
for TACE and TNF production in human blood.
Sch em e 2a
F igu r e 2.
Ch em istr y
a
(a) R1dRSO2: RSO2Cl, py, cat. DMAP, CH2Cl2; (b) R1dRCO:
The inhibitors of the present study were prepared
using the following sequences. Synthesis of the thio-
ether-based inhibitors 2 started from succinate 7 (Scheme
RCO2H, EDCI, DMAP; (c) TFA/CH2Cl2 (1:1); (d) EDCI, TMSONH2,
DMF; (e) EDCI, NH2ODMB; 5% TFA, CH2Cl2; (f) 16, R2-halide,
K2CO3, DMF.

4892 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Barlaam et al.
Sch em e 5a
N-Alkylated sulfonamides 22 were obtained by alky-
lation of the corresponding sulfonamides 16 with the
corresponding halide and subsequent conversion of the
tert-butyl ester into the hydroxamic acid by methods
already described.
Amines 5a and 5b were obtained from 15 and 23,
respectively, by alkylation of the amino group with
2-iodoethyl ether and 1,4-diiodobutane and subsequent
transformation of the tert-butyl ester or the protected
hydroxamate into the hydroxamic acid by methods
already described. Reductive amination of aldehydes
with 2324 followed by 2,4-dimethoxybenzyl deprotection
(optionally on solid phase24) in 5% TFA/CH2Cl2 afforded
the corresponding amines 5c-g (Scheme 3).
a
(a) TFA/CH2Cl2 (1:1); (b) H2NODMB (for 30) or TMBN-
HODMB (for 31), EDCI, DMF; (c) R1-halide, NaI, NaH, 15-crown-
5, THF; (d) 10% TFA, CH2Cl2.
Sch em e 3a
Hydroxamates 6l-m were made from succinates
3226 and 3326 (readily accessible by Evans’ oxazolidi-
none chemistry) according to the same methodology
(Scheme 6).
Sch em e 6
a
(a) RCHO, NaBH3CN, 1% AcOH, MeOH; (b) 5% TFA, CH2Cl2.
The synthesis of the ether-based inhibitors 6a -k also
began from succinate 7 (Scheme 4). Reaction of the
dianion of 7 with carbon tetrachloride as a source of
chlorine afforded the syn chloro derivative 24, which
reacted with L-tert-leucine methylamide to give 26 via
the intermediate lactone 25. This lactone can be isolated
by treatment of 24 with ether/aqueous sodium bicarbon-
ate. Alkylation of 26 and subsequent conversion of the
tert-butyl esters into the hydroxamic acids afforded the
expected ethers 6a -f.
Discu ssion
The inhibitory potency of the aforementioned inhibi-
tors was determined against a partially purified TACE
preparation using a fluorogenic substrate. TNF inhibi-
tion in cells was determined in LPS-stimulated human
whole blood. The results are summarized in Tables 1
and 2. Selected inhibitors were also tested against
MMP-1 and MMP-8 for selectivity evaluation (Table 3).
As previously noted with MMPs, succinate-based
hydroxamic acids lead to potent TACE inhibitors. The
hydroxamate zinc ligand is essential for TACE inhibi-
tion: its replacement by other zinc binding ligands such
as a carboxylic acid, for example, leads to inactive
compounds (Figure 3) as illustrated by 11a (TACE IC50
> 100 nM) and 17a (TACE IC50 > 10 µM).
Sch em e 4a
a
(a) 2 LDA, THF, CCl4, -78 °C; (b) L-tert-leucine methylamide,
MeCN; (c) R1-halide, NaH, NaI, THF; (d) TFA/CH2Cl2 (1:1); (e)
NH2OTMS, lutidine, EDCI, DMF.
Access to ethers 6g-k is depicted in Scheme 5.
Deprotection of 26 with TFA/CH2Cl2 (1:1) afforded the
known acid 29,25 which was either converted to the
O-protected hydroxamate 30 or the N,O-diprotected
hydroxamate 31 by coupling with O-(2,4-dimethoxyben-
zyl)hydroxylamine21 (DMBONH2) or O-(2,4-dimethoxy-
benzyl)-N-(2,4,6-trimethoxybenzyl)hydroxylamine21
(DMBONHTMB), respectively. Alkylation of 30 or 31
with various halides, followed by deprotection of the
hydroxamate with 10% TFA/CH2Cl2, gave the expected
ethers 6. This is exemplified in the experimental data
for 6g and 6j from 30 and 6h , 6i, and 6k from 31.
F igu r e 3.
R-Substitution of succinate-based hydroxamic acids
improves both activity against the TACE isolated en-
zyme and inhibition of TNF production in human
whole blood as demonstrated by Marimastat, GW9471,
BB1101, 2a , 3a , and 6a compared with Ro31-9790.
Moreover, the correct stereochemistry of this R-substit-
uent is critical for TACE inhibition as illustrated by 2a
vs 12a (TACE IC50: 1 nM vs 188 nM); this observation
is in accordance with the published SAR27,28 for MMPs.

MMP/ TNFR Convertase Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4893
a
Ta ble 2. Inhibition of TACE and TNF Production in Blood by R-Substituted Hydroxamates (IC50
)
compd
R
TACE (nM)
1 (2)
188 ( 71 (2)
1.2 ( 0.4 (2)
1.4 ( 0.4 (2)
blood (µM)
compd
R
TACE (nM)
blood (µM)
2a
(S)-PhS
(R)-PhS
3v
3w
22a
22b
22c
22d
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
(E)-PhCHdCHSO2NH
MeSO2NH
0.54 ( 0.35 (2) 0.77 ( 0.25 (2)
12a
2b
2c
2.2 1.6 ( 0.05 (2)
3,4-(MeO)2C6H3S
1-(Me)-2-(oxo)-1,2,3,4-
tetrahydroquinoline-6-S
4-(CN)C6H4S
4-(MeO2S)C6H4S
3,5-Cl2C6H3S
PhSO2(Me)N
0.61 ( 0.26 (2) 3 ( 0.05 (2)
6.6
quinoline-8-SO2(Me)N
4.4
10
85 ( 33 (2)
2 ( 0.9 (3)
9.5
22
4.5
quinoline-8-SO2(n-Pr)N
quinoline-8-SO2(PhCH2)N
quinoline-8-CONH
quinoline-6-CONH
pyridine-3-CONH
PhCONH
naphthalene-2-CONH
AcNH
O(CH2CH2)2N
2d
2e
2f
2g
2h
2i
0.63 ( 0.15 (2) 3.3 ( 1.4 (2)
1.25 ( 0.55 (2) 2.1
0.42 ( 0.18 (2) 4.9 ( 1.3 (2)
1.1
0.8
1.6
1.6
1.5 ( 0.5 (2)
1.5 ( 0.1 (2)
1.3 ( 0.5 (2)
1
17 ( 7 (2)
9.7
13
9 ( 2 (2)
1.5
8 ( 3 (2)
2-Cl-4-FC6H3S
11
(8-quinoline)CH2S
3-(NC(Me)2C)C6H4S
MeS
6.2 ( 2.8 (3)
2.8 ( 1 (2)
2.3 ( 0.9 (3)
5.6 ( 1.7 (6)
1.3 ( 0.6 (6)
1.2
9
3.3
13
>20
2j
2k
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
EtS
PhSO2NH
3.4 ( 1.5 (2)
2.8
0.23 ( 0.14 (3) 3.4 ( 0.5 (2)
2.8
3 ( 0.8 (5)
6.1
(CH2)4N
4-(AcNH)C6H4SO2NH
3,5-Cl2C6H3SO2NH-
2-(CN)C6H4SO2NH
2-Cl-4-FC6H3SO2NH
2,4,6-(iPr)3C6H2SO2NH
3-Me(imidazole)-5-SO2NH
thiophene-2-SO2NH
pyridine-3-SO2NH
4-(HO2C)C6H4SO2NH
4-BrC6H4SO2NH
naphthalene-2-SO2NH
naphthalene-1-SO2NH
quinoline-8-SO2NH
isoquinoline-5-SO2NH
4-(oxo)-3,4 dihydroquin-
azoline-8-SO2NH
quinoline-8-CH2NH
PhCH2NH
naphthalene-2-CH2NH
quinoline-2-CH2NH
MeS(CH2)3NH
1-Me-2-oxo-1,2-dihydro-
quinoline-6-CH2O
1-Me-2-oxo-1,2-dihydro-
quinoline-3-CH2O
quinoline-8-CH2O
MeO
2-Me-4-oxo-3,4-dihydro-
quinazoline-6-CH2O
2-Me-4-oxo-3,4-dihydro-7-Br- 0.33 ( 0.05 (2) 4.3 ( 1.3 (2)
quinazoline-6-CH2O
naphthalene-1-CH2O
coumarine-6-CH2O
quinoxaline-5-CH2O
naphthalene-2-CH2O
2-(Me)benzothiazole-5-CH2O 0.21
0.8
11.3
6.1
6.7
5.7
4.6
0.57
5f
5g
6a
1
1.3
1 ( 0.7 (3)
1.44 ( 0.45 (3)
2.8
3.8
4.4
4.4
2.1
3.2
1.4
6b
0.44 ( 0.02 (2) 2.35 ( 0.15 (2)
6c
6d
6e
0.4 ( 0.06 (2)
1.5
0.43
8.2 ( 1.2 (2)
5 ( 1 (2)
2.4 ( 1.1 (4)
0.66 ( 0.1 (2)
1.2 ( 0.4 (2)
4.2 ( 0.5 (2)
3.1
1.2 ( 0.5 (4)
3.1 ( 0.9 (2)
8.1 ( 3.4 (3)
1.1 ( 0.1 (2)
4.9 ( 3.3 (2)
6f
3.4 ( 0.15 (2)
6g
6h
6i
6j
6k
6l
0.33 ( 0.11 (2) 7.6 ( 1.2 (2)
0.79 ( 0.21 (2) 3.6
1.1
3q
1-(Me)-2-(oxo)-1,2,3,4-tetra- 2.9
hydroquinoline-6-SO2NH
2-oxindole-5-SO2NH
quinoline-6-SO2NH
4-(oxo)-3,4 dihydroquin-
azoline-6-SO2NH
3 ( 1.7 (2)
7.6
7.3
3.5
6.5 ( 3 (2)
3r
3s
3t
2.8
1.6
1.5 ( 0.5 (2)
0.44 ( 0.08 (3)
0.6 ( 0.24 (2)
0.57 ( 0.17 (3) 0.28 ( 0.07 (5)
6m
12 ( 0.5 (2)
3u
4-(pyridine)CH2CH2SO2NH 1.3 ( 0.8 (4)
0.7 ( 0.3 (3)
a
IC50s are single determinations except where indicated otherwise. Where more than one value has been determined, IC50s are shown
( SD (number of determinations).
Ta ble 3. Inhibition of MMPs by Selected R-Substituted
TACE inhibitors (6k : 0.21 nM; 6g: 0.33 nM). Neverthe-
less, potent TACE inhibitors were also found in the
thioether (2f: 0.42 nM; 2h : 0.8 nM), sulfonamide (3v:
0.54 nM), and amine (5c: 0.23 nM) series. Only car-
boxamides (4a : 2 nM) are significantly less active than
the previous series.
Inhibition of TNF production in whole blood is in the
2-10 µM range in the thioether and oxygen series: thus
we observe a 2000-20000 drop between the enzyme and
blood potencies. This is similar to that found for Mari-
mastat, BB1101, and GW9471 in terms of intrinsic
activity and ratio between enzyme potency and whole
blood activity. More generally, in all series, the lipophi-
licity of compounds (i.e., 2f vs 2j; 6g vs 6a ) broadly
correlates with the loss in potency from enzyme to cell.
Although factors such as serum protein binding30 or
penetration into cells may be implicated, another ex-
planation for this general drop of potency could be an
entropic effect due to the localization of both the enzyme
and the pro-TNF substrate on the membrane.
a
Hydroxamates (IC50
)
MMP-1 MMP-8
MMP-1
(nM)
MMP-8
(nM)
compd
(nM)
(nM)
3.7
compd
2h
3n
3o
3s
3t
22a
22b
2.8
1.1
2.6
1.2
1.3
1.5
2.4
4a
5a
5c
6a
6l
2.2 ( 0.6 (2)
2.2
1.7
0.2
0.88
730 ( 253 (2)
330 ( 5 (2)
6m
a
IC50s are single determinations except where indicated oth-
erwise. Where more than one value has been determined, IC50s
are shown ( SD (number of determinations).
A wide range of R-substituents in these series is
allowed; whether bulky or small, electron donating or
withdrawing, many substituents give subnanomolar
TACE inhibition (0.2-5 nM range). However, highly
polar substituents appear less suitable for TACE activ-
ity (e.g., imidazole 3g: TACE IC50: 9 nM), probably due
to the high hydrophobicity of the enzyme S region29
occupied by the R-substituent.
Globally, in the sulfonamide series, as illustrated by
3a (TACE IC50: 1.5 nM; blood IC50: 1.3 µM), this ratio
is smaller (ca. 300-3000-fold), although highly lipophilic
compounds such as 3c also show a much higher ratio.
This result prompted us to explore more widely substi-
Some compounds in these series show improvement
against the enzyme compared with Marimastat. In
particular, the oxygen series gives exquisitely potent

4894 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Barlaam et al.
tution in the sulfonamide series: N-methyl substitution
on the sulfonamide is allowed but does not significantly
increase the potency against TACE (22a : 0.61 nM/3a :
1.5 nM or 22b: 4.4 nM/3n : 4.2 nM) whereas larger
N-substituents show loss of activity (propyl (22c): 10
nM; benzyl (22d ): 85 nM). Ortho-substitution on the
phenyl decreases the activity (3d : 17 nM; 3e: 9.7 nM;
3f: 13 nM vs 3a : 1.5 nM) while this is allowed in the
oxygen (6f: 0.33 nM) and thioether series (2g: 1.1 nM).
Wide modifications of the phenyl substituent led to
â-substituted bicyclic rings (3l: TACE IC50: 0.66 nM,
blood IC50: 1.2 µM), whereas R-substituted bicyclic rings
(such as 3m : TACE IC50: 1.2 nM, blood IC50: 3.1 µM)
are slightly less potent either against TACE or in blood.
Our next goal was to reduce the lipophilicity of these
compounds: introduction of heterocycles such as 3s gave
similar TACE potency, but increased blood activity
(TACE IC50: 1.6 nM, blood IC50: 0.44 µM). Finally,
based on a homology model of TACE,31 we exploited
potential new hydrogen bonding interactions between
quinazolinones and the enzyme backbone in its S
region: 3t (TACE IC50: 0.57 nM, blood IC50: 0.28 µM)
gave a significant increase (about 10-fold) in potency in
blood compared with Marimastat and BB1101. Similar
substitution in the carboxamide or amine series did not
show the improvement seen with the sulfonamides.
These compounds are also MMP-1 and MMP-8 inhibi-
tors as illustrated by 3t (MMP-1 IC50: 1.3 nM; MMP-8
IC50: 3.7 nM). The necessity for selectivity for TACE
against other MMPs remains to be seen, although it is
known from early clinical trials that broad MMP inhibi-
tors such as Marimastat or AG3340 show side effects
such as tendonitis and musculoskeletal pain.32 The
precise cause of joint pain with these compounds is still
unknown; different explanations have emerged such as
the implication of MMP-1.
Other groups have previously shown that MMP-1
cannot accommodate large groups in its S1′ pocket.26
Variation of the isobutyl P1′ substitution has led to more
selective compounds as exemplified by 6l (TACE: 0.8
nM, MMP-1: 730 nM, blood: 6.5 µM) or 6m (TACE: 12
nM, MMP-1: 330 nM) bearing benzyloxybutyl and
benzyloxypropyl P1′ chains, respectively.
The pharmacokinetics of these compounds have been
evaluated in rat and marmoset: for example, after p.o.
administration at 25 mg/kg to the marmoset, 3t and 5a
gave lower blood levels than Marimastat (respectively,
310 ng/mL and 520 ng/mL vs 870 ng/mL for Marimastat
after 0.5 h; 36 ng/mL and 36 ng/mL vs 190 ng/mL after
8 h). These blood levels are much lower than the
concentrations required for inhibition of TNF production
in whole blood and probably remain inadequate for TNF
inhibition in vivo, although BB1101 despite its poor in
vivo properties has been shown to inhibit TNF produc-
tion in vivo.13 The influence of these bulky R-substitu-
ents on in vitro metabolism of the hydroxamate group
needs to be further investigated. The fate of these
compounds in vivo will help in the search of new potent
TACE inhibitors with adequate in vivo properties.
compared with Marimastat. Whereas thioether- and
oxygen-based inhibitors also showed increased TACE
potency, this improvement did not translate into better
blood potency. This approach has culminated in the
identification of heterocyclic bicyclic sulfonamides such
as 3t (TACE: 0.57 nM; blood: 0.28 µM) with improved
potencies in blood compared with BB1101. Despite this,
the in vivo properties of these products are still inad-
equate. It is expected that the availability of these
highly potent TACE inhibitors will aid in the elucidation
of the role of TACE in disease states.
Exp er im en ta l Section
TACE Assa y. Partially purified TACE enzyme was ob-
tained from the membranes of THP-1.33 This enzyme prepara-
tion cleaves 21 kDa soluble pro-TNFR at the correct cleavage
site (Ala-Val), and enzyme activity is inhibited by matrix
metalloprotease inhibitors.34 4′,5′-Dimethoxyfluoresceinyl‚Ser‚
Pro‚Leu‚Ala‚Gln‚Ala‚Val‚Arg‚Ser‚Ser‚Ser‚Arg‚Cys(4-(3-succin-
imid-1-yl)fluorescein)-NH2 was used as the substrate to mea-
sure TACE activity.
Test compounds were solubilized in DMSO prior to serial
dilutions in assay buffer (50 mM Tris-HCl, pH 7.4, containing
0.1% (w/v) Triton X-100 and 2 mM CaCl2). Fifty microliters of
each concentration was added to appropriate wells of a 96-
well plate (Labsystems, catalog no. 9502817). Assay buffer (50
µL) was added to control wells. TACE enzyme (25 µL, 0.264
units/mL in assay buffer) was added (25 µL assay buffer was
added to “substrate alone” control wells). Plates were incubated
for 15 min at 26 °C, prior to addition of 25 µL of substrate (40
µM stock solution in assay buffer). Plates were read at time 0
to obtain background values (Fluoroskan II fluorometer) and
after incubation at 26 °C for 18 h. IC50 values were calculated
using a Microcal Origin package.
MMP Assa ys. The purified enzymes (purchased from Pr
G. Murphy University of East Anglia, Norwich) can be used
to monitor inhibitors of activity as follows: purified pro-MMPs
were activated using 1 mM aminophenylmercuric acid (APMA),
20 h at 21 °C; they (11.25 ng per assay) were incubated for
4-5 h at 35 °C in assay buffer (0.1 M Tris-HCl, pH 7.5,
containing 0.1 M NaCl, 20 mM CaCl2, 0.02 mM ZnCl2, and
0.05% (w/v) Brij 35) using (7-methoxycoumarin-4-yl)acetyl‚Pro‚
Leu‚Gly‚Leu‚N-3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl‚
Ala‚Arg‚NH2 as the substrate in the presence or absence of
inhibitors. Activity was determined by measuring the fluores-
cence at 328 and 393 nm. IC50s were calculated on a Microcal
Origin package. This protocol35 was adjusted for each MMP
using substrates and buffers conditions optimal for the par-
ticular MMP.
Hu m a n Wh ole Blood Assa y. Human whole blood assay
was performed using a modification of the procedure36 reported
by Desch: Compounds were solubilized in DMSO at 50 mM,
diluted 1:100 dilution in RPMI 1640 medium (GibcoBRL
31870-025), prior to serial dilutions in RPMI 1640 medium
containing 1% DMSO (DMSO final concentration in all wells
was 0.1%). Heparinized (10 units/mL) human blood (160 µL)
obtained from healthy volunteers was incubated with 20 µL
of test compound (triplicate cultures) for 30 min at 37 °C in a
humidified (5% CO2/95% air) incubator, prior to addition of
20 µL of LPS (E. coli 0111:B4, Sigma L-4130, final concentra-
tion 10 µg/mL). The 96-well round-bottom plates (Costar 4799)
were then incubated for 6 h at 37 °C (humidified incubator),
centrifuged (2000 rpm for 10 min; 4 °C), plasma harvested
(50-100 µL), and stored in 96-well plates at -70 °C. TNFR
content in plasma samples was determined by ELISA (R&D
MAB610 & BAF210 anti-human TNFR antibodies).
P h a r m a cok in etics. Groups of marmosets (n ) 3) were
dosed orally with the test compound, and serial blood samples
were removed. TACE inhibition activity was extracted and
assayed against TACE; alternatively, the test compound was
quantified by HPLC/MS. Concentration was calculated against
a standard curve.
Con clu sion
Detailed variation of the R-substitution on succinate-
based hydroxamic acids has led to improved potency in
the sulfonamide series both against TACE and in blood

MMP/ TNFR Convertase Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4895
Ch em istr y. All experiments were carried out under an inert
atmosphere unless otherwise stated. Flash chromatography
was carried out on Merck Kieselgel 60 (Art. 9385). TLCs were
performed on precoated silica gel plates (Merck Art. 5715).
Melting points were determined on a Kofler Block or with a
Bu¨chi melting point apparatus and are uncorrected. Proton
and 13C NMR spectra were recorded on a J EOL J MM-EX400
spectrometer at 400 and 100 MHz, respectively, with TMS as
an internal standard. Chemical shifts are expressed in units
of δ (ppm), and peak multiplicities are expressed as follows:
s, singlet; d, doublet; dd, doublet of doublet; t, triplet; s br,
broad singlet; m, multiplet. Mass spectra were obtained on a
Finnigan SSQ7000 mass spectrometer by electronic impact
(EI) or electrospray (ESI) ionization techniques. Elemental
analyses were performed on a Carlo Erba EA1108 instrument.
Unless otherwise stated, HPLC retention times were measured
on a 125/4.6 mm Kromasil C18, 5 µm HPLC column; eluant:
methanol and water/1% AcOH, linear gradient from 30:70 to
90:10 for 10 min then 100:0 for 5 min, flow rate 1.5 mL/min;
UV detection 254 nm and light scattering.
1H, J ) 8.4 Hz), 7.32 (s br, 1H), 6.91 (d, 1H, J ) 8.4 Hz), 3.52
(d, 1H, J ) 10.3 Hz), 3.34 (s, 3H), 2.88 (t, 2H, J ) 7.3 Hz),
2.76 (m, 1H), 2.65 (t, 2H, J ) 7.3 Hz), 1.89 (m, 1H), 1.8-1.6
(m, 2H), 1.39 (s, 9H), 0.95 (d, 6H, J ) 6.6 Hz); MS (ESI) 444
(MNa+).
3S-(4-Cyan oph en ylth io)-2S-isobu tylbu tan -1,4-dioic Acid
4-ter t-Bu tyl Ester (8d ). From di-(4-cyanophenyl) disulfide38
were similarly obtained 8d (1.2 g, 50%) and 9d (300 mg, 13%).
8d : 1H NMR (CDCl3) 7.56 (m, 4H), 3.82 (d, 1H, J ) 9.9 Hz),
2.99 (m, 1H), 1.8-1.55 (m, 2H), 1.41 (s, 9H), 1.28 (m, 1H), 0.92
(m, 6H). 9d : 1H NMR (CDCl3) 7.57 (m, 4H), 3.82 (d, 1H, J )
10.2 Hz), 2.89 (m, 1H), 1.8-1.5 (m, 3H), 1.37 (s, 9H), 0.92 (d,
6H, J ) 5.9 Hz).
2S-Isobu tyl-3S-(4-(m eth ylsu lfon yl)p h en ylth io)bu ta n -
1,4-d ioic Acid 4-ter t-Bu tyl Ester (8e). From di-(4-(methyl-
sulfonyl)phenyl) disulfide39 (dissolved in DMF instead of THF)
was similarly obtained a 1:1 mixture of 8e and 9e (800 mg,
34%): 1H NMR (CDCl3) 7.86 (m, 2H), 7.63 (m, 2H), 3.85 (d,
1H, J ) 10.2 Hz), 3.05 (s, 3H), 3.01 and 2.89 (m, 1H), 1.8-1.3
(m, 3H), 1.42 and 1.38 (s, 9H), 0.94 (m, 6H).
3S-(3,5-Dich lor op h en ylt h io)-2S-isob u t ylb u t a n -1,4-d i-
oic Acid 4-ter t-Bu tyl Ester (8f). From di-(3,5-dichlorophenyl)
disulfide were similarly obtained 8f (1.0 g, 36%) and 9f (300
mg, 11%). 8f: 1H NMR (CDCl3) 7.38 (d, 2H, J ) 1.8 Hz), 7.26
(1H), 3.70 (d, 1H, J ) 10.3 Hz), 2.97 (m, 1H), 1.8-1.5 (m, 2H),
1.43 (s, 9H), 1.25 (m, 1H), 0.94 (d, 3H, J ) 6.6 Hz), 0.92 (d,
3H, J ) 6.6 Hz). 9f: 1H NMR (CDCl3) 7.39 (d, 2H, J ) 1.8
Hz), 7.28 (t, 1H, J ) 1.8 Hz), 3.69 (d, 1H, J ) 10.2 Hz), 2.83
(m, 1H), 1.8-1.5 (m, 3H), 1.40 (s, 9H), 0.94 (m, 6H).
3S-(2-Ch lor o-4-flu or op h en ylt h io)-2S-isob u t ylb u t a n -
1,4-d ioic Acid 4-ter t-Bu tyl Ester (8g). From di-(2-chloro-4-
fluorophenyl) disulfide were similarly obtained 8g (2.5 g, 54%)
and 9g. 8g: 1H NMR (CDCl3) 7.61 (dd, 1H, J ) 8.8 Hz, J ′ )
5.8 Hz), 7.17 (dd, 1H, J ) 8.8 Hz, J ′ ) 2.5 Hz), 6.96 (m, 1H),
3.76 (d, 1H, J ) 9.9 Hz), 2.98 (m, 1H), 1.75 (m, 1H), 1.62 (m,
1H), 1.39 (s, 9H), 1.30 (m, 1H), 0.93 (d, 3H, J ) 6.6 Hz),
0.91 (d, 3H, J ) 6.6 Hz); MS (ESI) 415 (M{37Cl}Na+), 413
(M{35Cl}Na+). 9g: 1H NMR (CDCl3) 7.61 (dd, 1H, J ) 8.8
Hz, J ′ ) 5.8 Hz), 7.20 (dd, 1H, J ) 8.8 Hz, J ′ ) 2.5 Hz), 6.96
(m, 1H), 3.76 (d, 1H, J ) 9.2 Hz), 2.88 (m, 1H), 1.9-1.6 (m,
3H), 1.32 (s, 9H), 0.96 (d, 3H, J ) 6.6 Hz), 0.94 (d, 3H, J ) 6.6
Hz).
2S-Isobu tyl-3S-(qu in olin -8-ylm eth ylth io)bu ta n -1,4-d i-
oic Acid 4-ter t-Bu t yl E st er (8h ). From di-(quinolin-8-yl-
methyl) disulfide40 was obtained a 1:1 mixture of 8h and 9h
(487 mg from 1.74 mmol of 7) contaminated with ca. 20% of 7:
1H NMR (CDCl3) 8.96 (m, 1H), 8.15 (m, 1H), 7.75 (m, 2H), 7.48
(m, 1H), 7.40 (m, 1H), 4.70-4.50 (m, 2H), 3.40 and 3.37 (d,
1H, J ) 10.3 Hz), 3.02 and 2.79 (m, 1H), 1.8-1.2 (m, 3H), 1.49
and 1.46 (s, 9H), 0.95-0.7 (m, 6H); MS (ESI) 404 (MH+).
3S-[3-(1-Cya n o-1-m et h ylet h yl)p h en ylt h io]-2S-isob u -
tylbu ta n -1,4-d ioic Acid 4-ter t-Bu tyl Ester (8i). From di-
[3-(1-cyano-1-methylethyl)phenyl] disulfide were similarly
obtained 8i (565 mg, 36%) and 9i (not isolated). 8i: 1H NMR
(CDCl3) 7.61 (s br, 1H), 7.45 (m, 2H), 7.34 (m, 1H), 3.67 (d,
3H, J ) 10.2 Hz), 2.97 (m, 1H), 1.8-1.55 (m, 2H), 1.72 (s, 6H),
1.40 (s, 9H), 1.25 (m, 1H), 0.91 (d, 3H, J ) 6.6 Hz), 0.90 (d,
3H, J ) 6.6 Hz); MS (ESI) 428 (MNa+).
Di-[3-(1-cyano-1-methylethyl)phenyl] disulfide was prepared
as follows: alkylation of (3-bromophenyl)acetonitrile with
excess sodium hydride/methyl iodide in THF gave 2-(3-
bromophenyl)-2-methylpropionitrile (100%): 1H NMR (CDCl3)
7.60 (s br, 1H), 7.45 (m, 2H), 7.25 (m, 1H), 1.72 (s, 6H). This
compound gave 2-(3-(tert-butylthio)phenyl)-2-methylpropioni-
trile (37%) by reaction with tBuSH (1.3 equiv) and tBuOK (1.35
equiv) in DMSO at 80 °C in the presence of Pd(PPh3)4 (0.05
equiv): 1H NMR (CDCl3) 7.62 (s br, 1H), 7.49 (m, 2H), 7.36
(m, 1H), 1.74 (s, 6H), 1.29 (s, 9H). This was converted to 2-(3-
mercaptophenyl)-2-methylpropionitrile (82%) by reaction with
TFA (1.7 equiv) and CF3SO3H (1 equiv) in thioanisole at room
temperature: 1H NMR (CDCl3) 7.6-7.2 (m, 4H), 3.53 (s, 1H),
1.71 (s, 6H). Oxidation of this thiol in DMSO gave the desired
disulfide (73%): 1H NMR (CDCl3) 7.60 (s br, 2H), 7.45 (m, 2H),
7.33 (m, 4H), 1.69 (m, 12H).
2S-Isobu tyl-3S-p h en ylth iobu ta n -1,4-d ioic Acid 4-ter t-
Bu t yl E st er (8a ) a n d 2S-isob u t yl-3R-p h en ylt h iobu t a n -
1,4-d ioic Acid 4-ter t-Bu tyl Ester (9a ). To a stirred solution
of LDA [32.8 mmol; prepared by addition of 1.6 M nBuLi (20.5
mL, 32.8 mmol) in hexane to a solution of diisopropylamine
(4.4 mL, 33.75 mmol) in THF (20 mL) at -78 °C] cooled at
-78 °C was added 7 (3.45 g, 15 mmol) in THF (15 mL)
dropwise. The mixture was stirred for 90 min at -78 °C, and
a solution of diphenyl disulfide (4.2 g, 19 mmol) in THF (15
mL) was added. The mixture was stirred for 30 min at -78
°C, warmed to room temperature and stirred for 2 h at room
temperature. The solution was cooled to -78 °C and quenched
by addition of methanol (6 mL). The solution was warmed to
room temperature, and the solvents were evaporated in vacuo.
Ice was added to the residue, and the mixture was acidified
with 2 N HCl to pH 4. The solution was extracted with Et2O
(3 × 100 mL). The combined organic extracts were dried over
MgSO4 and filtered, and the solvents were removed. The
residue was purified by flash chromatography on silica using
petroleum ether-EtOAc (gradient from 8/2 to 0/10) as eluant
to give a 1:1 mixture of 8a and 9a (4.77 g). Preparative normal
phase HPLC purification using EtOAc-cyclohexane (5:95) as
eluant gave first 8a (2.3 g, 45%): 1H NMR (CDCl3) 7.50 (m,
2H), 7.28 (m, 3H), 3.68 (d, 1H, J ) 10.3 Hz), 2.98 (m, 1H),
1.72 (m, 1H), 1.63 (m, 1H), 1.39 (s, 9H), 1.26 (m, 1H), 0.85 (d,
3H, J ) 7 Hz), 0.83 (d, 3H, J ) 7.3 Hz). Further elution gave
9a (2.2 g, 43%): 1H NMR (CDCl3) 7.49 (m, 2H), 7.30 (m, 3H),
3.62 (d, 1H, J ) 10.3 Hz), 2.81 (m, 1H), 1.86 (m, 1H), 1.6-
1.75 (m, 2H), 1.35 (s, 9H), 0.93 (d, 6H, J ) 6.2 Hz).
3S-(3,4-Dim et h oxyp h en ylt h io)-2S-isob u t ylb u t a n -1,4-
d ioic Acid 4-ter t-Bu t yl E st er (8b ). From di-(3,4-dimeth-
oxyphenyl)disulfide were similarly obtained 8b (1.05 g, 60%)
and 9b (550 mg, 31%). 8b: 1H NMR (CDCl3) 7.1 (m, 2H), 6.78
(d, 1H, J ) 8.1 Hz), 3.87 (s, 3H), 3.86 (s, 3H), 3.54 (d, 1H, J )
10.3 Hz), 2.96 (m, 1H), 1.75-1.55 (m, 2H), 1.42 (s, 9H), 1.26
(m, 1H), 0.91 (d, 3H, J ) 6.6 Hz), 0.90 (d, 3H, J ) 6.6 Hz).
9b: 1H NMR (CDCl3) 7.09 (dd, 1H, J ) 8.1 Hz, J ′ ) 2.2 Hz),
7.02 (d, 1H, J ) 2.2 Hz), 6.80 (d, 1H, J ) 8.1 Hz), 3.88 (s,
3H), 3.87 (s, 3H), 3.50 (d, 1H, J ) 10.3 Hz), 2.78 (m, 1H), 1.86
(m, 1H), 1.75-1.55 (m, 2H), 1.38 (s, 9H), 0.94 (d, 6H, J )
6.6 Hz).
2S-Isobu tyl-3S-(1-m eth yl-2-oxo-1,2,3,4-tetr a h yd r oqu in -
olin -6-ylth io)bu ta n -1,4-d ioic Acid 4-ter t-Bu tyl Ester (8c).
From di-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) dis-
ulfide37 were similarly obtained 8c (950 mg, 40%) and 9c (603
mg, 25%) after purification on C18 preparative HPLC eluting
with 0.2% aqueous ammonium carbonate-acetonitrile (gradi-
ent from 100:0 to 72.5:27.5). 8c: 1H NMR (CDCl3) 7.41 (d br,
1H, J ) 8.4 Hz), 7.33 (s br, 1H), 6.90 (d, 1H, J ) 8.4 Hz), 3.56
(d, 1H, J ) 10.6 Hz), 3.33 (s, 3H), 2.95 (m, 1H), 2.88 (t, 2H, J
) 7.3 Hz), 2.65 (t, 2H, J ) 7.3 Hz), 1.8-1.5 (m, 2H), 1.43 (s,
9H), 1.26 (s, 1H), 0.92 (d, 3H, J ) 6.6 Hz), 0.91 (d, 3H, J ) 6.6
Hz); MS (ESI) 444 (MNa+). 9c: 1H NMR (CDCl3) 7.39 (d br,

4896 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Barlaam et al.
2S-Isobu tyl-3S-m eth ylth iobu ta n -1,4-d ioic Acid 4-ter t-
Bu tyl Ester (8j). From dimethyl disulfide was similarly
obtained a 1:3 mixture of 8j and 9j (1.06 g, 89%): 1H NMR
(CDCl3) 3.20 (d, J ) 10.6 Hz, 9j) and 3.17 (d, J ) 11.3 Hz, 8j)
(1H), 2.97 (m, 8j) and 2.77 (m, 9j) (1H), 2.18 (s, 8j) and 2.13
(s, 9j) (3H), 1.8-1.3 (m, 3H), 1.49 (s, 8j) and 1.46 (s, 9j) (9H),
0.94 (m, 6H).
3S-Eth ylth io-2S-isobu tylbu ta n -1,4-d ioic Acid 4-ter t-
Bu tyl Ester (8k ). From diethyl disulfide was similarly
obtained a 3:2 mixture of 8k and 9k (380 mg, 61%): 1H NMR
(CDCl3) 3.26 (d, J ) 10.3 Hz, 9k ) and 3.23 (d, J ) 11 Hz, 8k )
(1H), 2.95 (m, 8k ) and 2.77 (m, 9k ) (1H), 2.70-2.60 (m, 2H),
1.8-1.3 (m, 3H), 1.49 (s, 8k ) and 1.46 (s, 9k ) (9H), 1.29-1.22
(m, 3H), 0.96-0.90 (m, 6H).
N 2-[4-ter t-Bu t yloxy-3S-(3,5-d ich lor op h en ylt h io)-2S-
isob u t ylsu ccin yl]-L-ter t-leu cin e-N1-m et h yla m id e (10f).
Similarly 10f was obtained (1.0 g, 77%) as a white foam: 1H
NMR (CDCl3) 7.34 (d, 2H, J ) 1.8 Hz), 7.22 (t, 1H, J ) 1.8
Hz), 6.44 (d, 1H, J ) 9.2 Hz), 5.77 (m, 1H), 4.22 (d, 1H, J )
9.2 Hz), 3.75 (d, 1H, J ) 11 Hz), 2.81 (d, 3H, J ) 5.1 Hz), 2.68
(m, 1H), 1.74 (m, 1H), 1.47 (m, 1H), 1.41 (s, 9H), 1.17 (m, 1H),
1.04 (s, 9H), 0.91 (d, 3H, J ) 6.2 Hz), 0.85 (d, 3H, J ) 6.2 Hz);
MS (ESI) 559 (M{37Cl,37Cl}Na+), 557 (M{35Cl,37Cl}Na+), 555
(M{35Cl,35Cl}Na+). Anal. (C25H38Cl2N2O4S) C H N S.
N2-[4-ter t-Bu tyloxy-3S-(2-ch lor o-4-flu or op h en ylth io)-
2S-isobu tylsu ccin yl]-L-ter t-leu cin e-N1-m eth ylam ide (10g).
Similarly 10g was obtained (2.38 g, 72%) as a white foam: 1H
NMR (CDCl3) 7.59 (dd, 1H, J ) 8.8 Hz, J ′ ) 5.8 Hz), 7.14 (dd,
1H, J ) 8.8 Hz, J ′ ) 2.6 Hz), 6.94 (m, 1H), 6.49 (d br, 1H, J )
9.2 Hz), 6.04 (m., 1H), 4.28 (d, 1H, J ) 9.2 Hz), 3.81 (d, 1H, J
) 10.6 Hz), 2.81 (d, 3H, J ) 4.8 Hz), 2.71 (m, 1H), 1.76 (m,
1H), 1.46 (m, 1H), 1.35 (s, 9H), 1.19 (m, 1H), 1.05 (s, 9H), 0.90
(d, 3H, J ) 6.6 Hz), 0.85 (d, 3H, J ) 6.6 Hz); MS (ESI) 541
(M{37Cl}Na+), 539 (M{35Cl}Na+).
N2-[4-ter t-Bu tyloxy-2S-isobu tyl-3S-(qu in olin -8-ylm eth -
ylth io)su ccin yl]-L-ter t-leu cin e-N1-m eth ylam ide (10h ). Simi-
larly, from a mixture of 8h and 9h (450 mg, 1.12 mmol,
contaminated with 7) was obtained 10h and its epimer (451
mg, 1:1): 1H NMR (CDCl3) 8.95 (m, 1H), 8.13 (m, 1H), 7.72
(m, 2H), 7.48 (m, 1H), 7.41 (m, 1H), 6.65 and 6.45 (m, 1H),
6.0-5.9 (m, 1H), 4.65 and 4.62 (AB system, 1H, J ) 13.2 Hz),
4.46 and 4.43 (AB system, 1H, J ) 9.9 Hz), 4.19 and 4.12 (d,
1H, J ) 9.2 Hz), 3.44 (d, J ) 9.9 Hz) and 3.40 (d, J ) 10.7 Hz)
(1H), 2.75 (m, 4H), 1.46 and 1.42 (s, 9H), 1.6-1.2 (m, 3H), 1.0-
0.7 (m, 15H).
N 2-[4-t er t -Bu t yloxy-3S -[3-(1-cya n o-1-m e t h yle t h yl)-
p h en ylth io]-2S-isobu tylsu ccin yl]-L-ter t-leu cin e-N1-m eth -
yla m id e (10i). Similarly, 10i was obtained (495 mg, 67%) as
a white foam: 1H NMR (CDCl3) 7.54 (s br, 1H), 7.40 (m, 2H),
7.31 (m, 1H), 6.46 (d br, 1H, J ) 9.2 Hz), 5.79 (m, 1H), 4.24
(d, 1H, J ) 9.2 Hz), 3.72 (d, 1H, J ) 11 Hz), 2.81 (d, 3H, J )
4.8 Hz), 2.68 (m, 1H), 1.75 (m, 1H), 1.71 (s, 6H), 1.46 (m, 1H),
1.36 (s, 9H), 1.15 (m, 1H), 1.05 (s, 9H), 0.90 (d, 3H, J ) 6.6
Hz), 0.85 (d, 3H, J ) 6.6 Hz); MS (ESI) 554 (MNa+).
N2-[4-ter t-Bu tyloxy-2S-isobu tyl-3S-m eth ylth iosu ccin yl]-
L-ter t-leu cin e-N1-m eth yla m id e (10j). Similarly, from a 1:3
mixture of 8j and 9j was obtained 10j and its epimer (913 mg,
79%, 1:3). 10j: 1H NMR (CDCl3) 6.38 (m, 1H), 5.90 (m, 1H),
4.22 (d, 1H, J ) 9.2 Hz), 3.22 (d, 1H, J ) 11 Hz), 2.80 (d, 3H,
J ) 4.6 Hz), 2.62 (m, 1H), 2.17 (s, 3H), 1.49 (s, 9H), 1.8-1.3
(m, 3H), 1.04 (s, 9H), 0.89 (d, 3H, J ) 6.6 Hz), 0.84 (d, 3H, J
) 6.6 Hz). Epimer: 1H NMR (CDCl3) 6.54 (m, 1H), 5.90 (m,
1H), 4.16 (d, 1H, J ) 9.2 Hz), 3.28 (d, 1H, J ) 10.2 Hz), 2.79
(d, 3H, J ) 4.6 Hz), 2.62 (m, 1H), 2.11 (s, 3H), 1.45 (s, 9H),
1.8-1.3 (m, 3H), 0.99 (s, 9H), 0.92 (d, 3H, J ) 6.6 Hz), 0.89 (d,
3H, J ) 6.6 Hz); MS (ESI) 425 (MNa+).
N2-[4-ter t-Bu tyloxy-3S-eth ylth io-2S-isobu tylsu ccin yl]-
L-ter t-leu cin e-N1-m eth yla m id e (10k ). Similarly, from a 3:2
mixture of 8k and 9k was obtained 10k and its epimer (200
mg, 56%, 3:2): 1H NMR (CDCl3) 6.65 and 6.35 (m, 1H), 5.80
(m, 1H), 4.20 and 4.13 (d, 1H, J ) 9.2 Hz), 3.32 and 3.26 (d,
1H, J ) 9.9 Hz), 2.80 and 2.79 (d, 3H, J ) 4.8 Hz), 2.62 (m,
3H), 1.8-1.2 (m, 3H), 1.49 and 1.46 (s, 9H), 1.27 and 1.22 (t,
3H, J ) 7.3 Hz), 1.04 and 1.00 (s, 9H), 0.92 and 0.84 (d, 3H, J
) 6.6 Hz), 0.89 (d, 3H, J ) 6.6 Hz); MS (ESI) 439 (MNa+).
N2-[4-H yd r oxy-2S-isob u t yl-3S-p h en ylt h iosu ccin yl]-L-
ter t-leu cin e-N1-m eth yla m id e (11a ). TFA (8.3 mL) was
added to a solution of 10a (3.0 g, 6.05 mmol) in dry CH2Cl2
(19 mL). The solution was stirred at 0 °C for 18 h. The solvents
were evaporated in vacuo. The residue was taken up in
toluene, and the solvent was removed in vacuo (3×) to give
white crystals which were washed with pentane and dried in
vacuo. 11a : (2.56 g, 97%) mp ) 226-228 °C; 1H NMR (DMSO-
d6) 8.13 (d br, 1H, J ) 9.2 Hz), 7.86 (q, 1H, J ) 4.4 Hz), 7.43-
7.24 (m, 5H), 4.26 (d, 1H, J ) 9.2 Hz), 3.62 (d, 1H, J ) 11 Hz),
3.03 (m, 1H), 2.57 (d, 3H, J ) 4.4 Hz), 1.56 (m, 1H), 1.40 (m,
1H), 1.06 (m, 1H), 0.96 (s, 9H), 0.87 (d, 1H, J ) 6.6 Hz), 0.79
N2-[4-ter t-Bu tyloxy-2S-isobu tyl-3S-ph en ylth iosu ccin yl]-
L-ter t-leu cin e-N1-m eth yla m id e (10a ). To a solution of 8a
(2.75 g, 8.1 mmol) in DMF (16 mL) at 0 °C were added
successively HOBT (1.32 g, 9.8 mmol) and N-ethyl-N′-(3-
dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (1.87
g, 9.8 mmol). After 15 min, L-tert-leucine methylamide (1.41
g, 9.8 mmol) and DMAP (195 mg, 1.6 mmol) were added. The
mixture was stirred at room temperature for 3 h. The mix-
ture was poured into cold water and extracted with Et2O (2 ×
100 mL). The combined organic layers were washed with
saturated NaHCO3 and brine and dried over MgSO4. The
solvents were evaporated in vacuo, and the residue was
purified by flash chromatography on silica using EtOAc-
petroleum ether (3:7) as eluant to give 10a (3.0 g, 79%) as a
white solid: 1H NMR (CDCl3) 7.47 (m, 2H), 7.27 (m, 3H), 6.45
(d, 1H, J ) 9.2 Hz), 5.95 (m, 1H), 4.27 (d, 1H, J ) 9.2 Hz),
3.71 (d, 1H, J ) 11 Hz), 2.80 (d, 3H, J ) 4.8 Hz), 2.67 (m, 1H),
1.74 (m, 1H), 1.45 (m, 1H), 1.34 (s, 9H), 1.17 (m, 1H), 1.06 (s,
9H), 0.90 (d, 3H, J ) 6.2 Hz), 0.84 (d, 3H, J ) 6.6 Hz); MS
(ESI) 487 (MNa+).
N2-[4-ter t-Bu tyloxy-3S-(3,4-d im eth oxyp h en ylth io)-2S-
isobu tylsu ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (10b).
Similarly 10b was obtained (1.1 g, 84%) as a white foam: 1H
NMR (CDCl3) 7.05 (m, 2H), 6.77 (d, 1H, J ) 8.8 Hz), 6.44 (d
br, 1H, J ) 9.2 Hz), 5.76 (m, 1H), 4.25 (d, 1H, J ) 9.2 Hz),
3.88 (s, 3H), 3.87 (s, 3H), 3.61 (d, 1H, J ) 10.6 Hz), 2.81 (d,
3H, J ) 4.4 Hz), 2.66 (m, 1H), 1.73 (m, 1H), 1.45 (m, 1H), 1.39
(s, 9H), 1.12 (m, 1H), 1.06 (s, 9H), 0.89 (d, 3H, J ) 6.6 Hz),
0.84 (d, 3H, J ) 6.6 Hz); MS (ESI) 547 (MNa+).
N2-[4-ter t -Bu t yloxy-2S-isob u t yl-3S-(1-m e t h yl-2-oxo-
1,2,3,4-tetr a h yd r oqu in olin -6-ylth io)su ccin yl]-L-ter t-leu -
cin e-N1-m eth yla m id e (10c). Similarly was obtained 10c (250
mg, 50%) as a white foam after C18 preparative HPLC eluting
with 0.2% aqueous ammonium carbonate-acetonitrile (gradi-
ent from 90:10 to 50:50): 1H NMR (CDCl3) 7.37 (dd, 1H, J )
8.4 Hz, J ′ ) 2.2 Hz), 7.30 (d, 1H, J ) 2.2 Hz), 6.88 (d, 1H, J )
8.4 Hz), 6.44 (d br, 1H J ) 9.2 Hz), 5.77 (m, 1H), 4.25 (d, 1H,
J ) 9.2 Hz), 3.62 (d, 1H, J ) 10.6 Hz), 3.33 (s, 3H), 2.87 (m,
2H), 2.82 (d, 3H, J ) 4.8 Hz), 2.65 (m, 3H), 1.75 (m, 1H), 1.43
(m, 1H), 1.39 (s, 9H), 1.14 (m, 1H), 1.07 (s, 9H), 0.90 (d, 3H, J
) 6.2 Hz), 0.84 (d, 3H, J ) 6.2 Hz); MS (ESI) 570 (MNa+).
Anal. (C29H45N3O5S) C H calcd 8.28 found 8.85, N S.
N2-[4-ter t-Bu tyloxy-3S-(4-cya n op h en ylth io)-2S-isobu -
tylsu ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (10d ). Simi-
larly 10d was obtained (1.09 g, 74%) as a white foam: 1H NMR
(CDCl3) 7.52 (s, 4H), 6.44 (d br, 1H, J ) 9.2 Hz), 5.68 (m, 1H),
4.18 (d, 1H, J ) 9.2 Hz), 3.84 (d, 1H, J ) 10.8 Hz), 2.81 (d,
3H, J ) 4.6 Hz), 2.71 (m, 1H), 1.76 (m, 1H), 1.45 (m, 1H), 1.39
(s, 9H), 1.18 (m, 1H), 1.00 (s, 9H), 0.91 (d, 3H, J ) 6.6 Hz),
0.86 (d, 3H, J ) 6.6 Hz); MS (ESI) 512 (MNa+).
N2-[4-ter t-Bu tyloxy-2S-isobu tyl-3S-(4-(m eth ylsu lfon yl)-
ph en ylth io)su ccin yl]-L-ter t-leu cin e-N1-m eth ylam ide (10e).
Similarly, from a 1:1 mixture of 8e and 9e (800 mg) was
obtained a mixture of 10e and its epimer (800 mg, 78%) as a
white foam: 1H NMR (CDCl3) 7.83 (m, 2H), 7.62 (m, 2H), 6.47
(m, 1H), 5.70 (m, 1H), 4.20 and 4.14 (d, 1H, J ) 9.2 Hz), 3.94
(d, J ) 9.9 Hz) and 3.87 (d, J ) 11.2 Hz) (1H), 3.05 and 3.03
(s, 3H), 2.81 (m, 3H), 2.72 (m, 1H), 1.8-1.1 (m, 3H), 1.41 and
1.34 (s, 9H), 1.01 and 0.99 (s, 9H), 0.92-0.85 (m, 6H); MS (ESI)
565 (MNa+).

MMP/ TNFR Convertase Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4897
(d, 1H, J ) 6.6 Hz); MS (ESI) 409 (MH+). Anal. (C21H32N2O4S‚
0.38H2O) C H N S.
Acids 11b-k were obtained from 10b-k using the method
described above for 11a .
1H, J ) 11 Hz), 2.85 (m, 4H), 2.22 (s, 3H), 1.7-1.4 (m, 3H),
1.03 (s, 9H), 0.84 (d, 3H, J ) 6.6 Hz), 0.82 (d, 3H, J ) 6.6 Hz).
Epimer 1H NMR (CDCl3) 7.7 (m, 1H), 6.60 (m, 1H), 4.41 (d,
1H, J ) 9.9 Hz), 3.44 (d, 1H, J ) 7.3 Hz), 2.90 (m, 1H), 2.85
(d, 3H, J ) 5.1 Hz), 2.24 (s, 3H), 1.7-1.4 (m, 3H), 1.01 (s, 9H),
0.89 (d, 3H, J ) 6.2 Hz), 0.87 (d, 3H, J ) 6.2 Hz); MS (ESI)
369 (MNa+), 347 (MH+).
N2-[3S-Eth ylth io-4-h ydr oxy-2S-isobu tylsu ccin yl]-L-ter t-
leu cin e-N1-m eth yla m id e (11k ). From a mixture of 10k and
its epimer was similarly obtained a 3:2 mixture of 11k and
its epimer (199 mg, 100%) as a white solid: 1H NMR (CDCl3)
7.4 (m, 1H), 6.3 and 5.9 (m, 1H), 4.40 and 4.26 (d, 1H, J ) 9.5
Hz), 3.55 (d, J ) 6.6 Hz) and 3.45 (d, J ) 10.3 Hz) (1H), 2.86
and 2.83 (d, 3H, J ) 4.7 Hz), 2.80-2.71 (m, 3H), 1.8-1.3 (m,
3H), 1.22 (m, 3H), 1.03 (s, 9H), 0.98-0.82 (m, 6H); MS (ESI)
383 (MNa+), 361 (MH+).
N2-[4-(N-H yd r oxya m in o)-2S-isob u t yl-3S-p h en ylt h io-
su ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (2a ). To acid 11a
(2.15 g, 5.1 mmol) in DMF (15 mL) was added HOBT (770 mg,
5.7 mmol), followed by EDCI (1.09 g, 5.7 mmol). The mixture
was stirred at room temperature for 1 h. NH2OH‚HCl (529
mg, 7.6 mmol) was added immediately followed by 2,6-lutidine
(830 µL, 7.6 mmol) and DMAP (62 mg, 0.51 mmol). The
resulting solution was stirred at room temperature for 3 h.
The resulting mixture was purified by C18 preparative HPLC
using as eluant methanol and water/1% AcOH (gradient from
20:80 to 60:40) to give 2a (520 mg, 24%): mp ) 198-200 °C;
1H NMR (DMSO-d6) 10.75 (m, 1H), 9.0 (s br, 1H), 8.00 (d, 1H,
J ) 9.5 Hz), 7.79 (q, 1H, J ) 4.8 Hz), 7.4-7.15 (m, 5H), 4.22
(d, 1H, J ) 9.5 Hz), 3.56 (d, 1H, J ) 11.3 Hz), 3.00 (m, 1H),
2.55 (d, 3H, J ) 4.8 Hz), 1.5-1.3 (m, 2H), 1.0-0.9 (m, 1H),
0.93 (s, 9H), 0.84 (d, 3H, J ) 6.6 Hz), 0.76 (d, 3H, J ) 6.6 Hz);
MS (ESI) 446 (MNa+). Anal. (C21H33N3O4S) C H N.
N2-[3S-(3,4-Dim eth oxyph en ylth io)-4-(N-h ydr oxyam in o)-
2S-isobu tylsu ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (2b).
Similarly, 2b was obtained (170 mg, 37%) as a white solid:
mp ) 218-220 °C; 1H NMR (DMSO-d6) 10.53 (s br, 1H), 8.98
(s br, 1H), 7.99 (d, 1H, J ) 9.5 Hz), 7.81 (q, 1H, J ) 4.4 Hz),
6.99 (s, 1H), 6.88 (m, 2H), 4.29 (d, 1H, J ) 9.5 Hz), 3.76 (s,
3H), 3.75 (s, 3H), 3.37 (d, 1H, J ) 11.4 Hz), 2.98 (m, 1H), 2.58
(d, 3H, J ) 4.4 Hz), 1.40 (m, 2H), 1.0 (m, 1H), 0.98 (s, 9H),
0.85 (d, 3H, J ) 6.2 Hz), 0.77 (d, 3H, J ) 6.2 Hz); MS (ESI)
506 (MNa+). Anal. (C23H37N3O6S) C H calcd 7.66 found 8.13,
N S.
N2-[3S-(3,4-Dim eth oxyph en ylth io)-4-h ydr oxy-2S-isobu -
t ylsu ccin yl]-L-ter t-leu cin e-N1-m et h yla m id e (11b ): (795
mg, 100%) white solid; 1H NMR (DMSO-d6) 8.10 (m, 1H), 7.88
(m, 1H), 7.03-6.89 (m, 3H), 4.30 (d, 1H, J ) 9.5 Hz), 3.76 (s,
3H), 3.75 (s, 3H), 3.49 (d, 1H, J ) 11 Hz), 2.99 (m, 1H), 2.58
(d, 3H, J ) 4.4 Hz), 1.53 (m, 1H), 1.40 (m, 1H), 1.05 (m, 1H),
0.98 (s, 9H), 0.87 (d, 3H, J ) 6.2 Hz), 0.78 (d, 3H, J ) 6.2 Hz);
MS (ESI) 491 (MNa+), 469 (MH+).
N2-[4-Hyd r oxy-2S-isobu tyl-3S-(1-m eth yl-2-oxo-1,2,3,4-
tetr a h yd r oqu in olin -6-ylth io)su ccin yl]-L-ter t-leu cin e-N1-
m et h yla m id e (11c): (370 mg, 100%) white solid; 1H NMR
(CDCl3) 7.7 (s br, 1H), 7.40 (dd, 1H, J ) 8.4 Hz, J ′ ) 2.2 Hz),
7.29 (d, 1H, J ) 2.2 Hz), 6.38 (d, 1H, J ) 8.4 Hz), 4.37 (d, 1H,
J ) 9.6 Hz), 3.81 (d, 1H, J ) 9.2 Hz), 3.36 (s, 3H), 2.93 (m,
1H), 2.86 (m, 2H), 2.82 (d, 3H, J ) 4.7 Hz), 2.63 (m, 2H), 1.70
(m, 1H), 1.46 (m, 1H), 1.34 (m, 1H), 1.03 (s, 9H), 0.88 (d, 3H,
J ) 6.3 Hz), 0.84 (d, 3H, J ) 6.6 Hz).
N2-[3S-(4-Cya n op h en ylth io)-4-h yd r oxy-2S-isobu tylsu c-
cin yl]-L-ter t-leu cin e-N1-m eth yla m id e (11d ): (737 mg, 77%)
white solid: 1H NMR (CDCl3 + DMSO-d6) 7.53 (s, 4H), 7.1-
7.0 (m, 2H), 4.29 (d, 1H, J ) 6.9 Hz), 3.91 (d, 1H, J ) 10.6
Hz), 2.90 (m, 1H), 2.74 (d, 3H, J ) 4.4 Hz), 1.75 (m, 1H), 1.45
(m, 1H), 1.24 (m, 1H), 0.99 (s, 9H), 0.91 (d, 3H, J ) 6.6 Hz),
0.86 (d, 3H, J ) 6.6 Hz); MS (ESI) 456 (MNa+), 434 (MH+).
N 2-[4-H yd r oxy-2S -isob u t yl-3S -(4-(m e t h ylsu lfon yl)-
ph en ylth io)su ccin yl]-L-ter t-leu cin e-N1-m eth ylam ide (11e).
From a mixture of 10e and its epimer was similarly obtained
a mixture of 11e and its epimer (500 mg, 73%) as a white solid.
1H NMR (DMSO-d6) 8.20 (m, 1H), 7.90 (m, 1H), 7.86 (m, 2H),
7.68 and 7.60 (d, 2H, J ) 8.8 Hz), 4.22 and 4.19 (d, 1H, J )
9.2 Hz), 3.97 (d, J ) 10 Hz) and 3.85 (d, J ) 11 Hz) (1H), 3.23
and 3.22 (s, 3H), 3.13 and 3.02 (m, 1H), 2.57 (m, 3H), 1.65-
1.35 (m, 2H), 1.12 (m, 1H), 0.93 and 0.90 (s, 9H), 0.90-0.78
(m, 6H); MS (ESI) 509 (MNa+).
N2-[3S-(3,5-Dich lor op h en ylt h io)-4-h yd r oxy-2S-isob u -
tylsu ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (11f): (775 mg,
87%) white solid; 1H NMR (DMSO-d6) 8.21 (d br, 1H, J ) 9.6
Hz), 7.90 (q, 1H, J ) 4.4 Hz), 7.52 (s, 1H), 7.45 (s, 2H), 4.26
(d, 1H, J ) 9.6 Hz), 3.72 (d, 1H, J ) 10.6 Hz), 3.09 (m, 1H),
2.56 (d, 3H, J ) 4.4 Hz), 1.57 (m, 1H), 1.40 (m, 1H), 1.1 (m,
1H), 0.93 (s, 9H), 0.87 (d, 3H, J ) 6.2 Hz), 0.80 (d, 3H, J ) 6.6
Hz).
N2-[4-(N-H yd r oxya m in o)-2S-isob u t yl-3S-(1-m et h yl-2-
oxo-1,2,3,4-tetr a h yd r oqu in olin -6-ylth io)su ccin yl]-L-ter t-
leu cin e-N1-m eth yla m id e (2c). Similarly, 2c was obtained
(75 mg, 20%) as a white solid: mp ) 235 °C (decomposition);
1H NMR (DMSO-d6) 10.8-10.5 (m, 1H), 9.1-8.9 (m, 1H), 8.00
(d, 1H, J ) 9.2 Hz), 7.85-7.8 (m, 1H), 7.26 (d, 1H, J ) 8.5
Hz), 7.2 (s, 1H), 7.02 (d, 1H, J ) 8.5 Hz), 4.26 (d, 1H, J ) 9.2
Hz), 3.46 (d, 1H, J ) 11.3 Hz), 3.24 (s, 3H), 3.00 (m, 1H), 2.83
(m, 2H), 2.6-2.5 (m, 2H), 2.57 (d, 3H, J ) 4.8 Hz), 1.5-1.3
(m, 2H), 1.05-0.95 (m, 1H), 0.97 (s, 9H), 0.85 (d, 3H, J ) 6.6
Hz), 0.76 (d, 3H, J ) 6.6 Hz); MS (ESI) 529 (MNa+). Anal.
(C25H38N4O5S‚1H2O) C H N S.
N2-[3S-(2-Ch lor o-4-flu or op h en ylt h io)-4-h yd r oxy-2S-
isobu tylsu ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (11g):
(2.0 g, 97%) white solid; 1H NMR (DMSO-d6) 8.15 (m, 1H), 7.85
(m, 1H), 7.60 (dd, 1H, J ) 8.8 Hz, J ′ ) 5.8 Hz), 7.49 (dd, 1H,
J ) 8.8 Hz, J ′ ) 2.6 Hz), 7.27 (m, 1H), 4.20 (d, 1H, J ) 9.2
Hz), 3.71 (d, 1H, J ) 10.6 Hz), 3.07 (m, 1H), 2.55 (d, 3H, J )
4.4 Hz), 1.57 (m, 1H), 1.39 (m, 1H), 1.09 (m, 1H), 0.93 (s, 9H),
0.86 (d, 3H, J ) 6.6 Hz), 0.78 (d, 3H, J ) 6.6 Hz); MS (ESI)
485 (M{37Cl}Na+), 483 (M{35Cl}Na+).
N2-[4-H yd r oxy-2S-isob u t yl-3S-(q u in olin -8-ylm et h yl-
th io)su ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (11h ). From
a mixture of 10h and its epimer was similarly obtained a
mixture of 11h and its epimer as the trifluoroacetate salt. MS
(EI): 474 (MH+); C18 HPLC (50% MeOH, 1% AcOH-water)
tR 5.4 and 9 min.
N2-[3S-(4-Cya n op h en ylt h io)-4-(N-h yd r oxya m in o)-2S-
isob u t ylsu ccin yl]-L-ter t-leu cin e-N1-m et h yla m id e (2d ).
From 11d were similarly obtained 2d (68 mg, 22%, eluting
1
first) as a white solid: mp ) 238-241 °C; H NMR (DMSO-
d6) 10.90-10.75 (m, 1H), 9.15-9.05 (m, 1H), 8.09 (d, 1H, J )
9.2 Hz), 7.83-7.75 (m, 1H), 7.73 (d, 2H, J ) 8.8 Hz), 7.51 (d,
2H, J ) 8.8 Hz), 4.17 (d, 1H, J ) 9.2 Hz), 3.80 (d, 1H, J ) 11
Hz), 3.15-3.06 (m, 1H), 2.55 (d, 3H, J ) 4.8 Hz), 1.53-1.3 (m,
2H), 1.08-0.97 (m, 1H), 0.88 (s, 9H), 0.86 (d, 3H, J ) 6.6 Hz),
0.78 (d, 3H, J ) 6.6 Hz); MS (ESI) 471 (MNa+). Anal.
(C22H32N4O4S‚1.7H2O) C H N S. Compound 12d (20 mg)
was also obtained as a white solid formed by epimerization
during the reaction: 1H NMR (DMSO-d6) 10.85 (s, 1H), 8.94
(s, 1H), 7.85-7.75 (m, 2H), 7.80 (d, 2H, J ) 8.4 Hz), 7.60 (d,
2H, J ) 8.4 Hz), 4.15 (d, 1H, J ) 9.5 Hz), 3.88 (d, 1H, J ) 9.5
Hz), 3.04-2.97 (m, 1H), 2.56 (d, 3H, J ) 4.4 Hz), 1.6-1.38
(m, 3H), 0.88 (s, 9H), 0.80 (d, 3H, J ) 6 Hz), 0.76 (d, 3H, J )
6 Hz).
N2-[3S-[3-(1-Cya n o-1-m et h ylet h yl)p h en ylt h io]-4-h y-
d r oxy-2S -isob u t ylsu ccin yl]-L-t er t -le u cin e -N 1-m e t h yl-
1
a m id e (11i): (440 mg, 99%) white solid; H NMR (DMSO-d6)
8.14 (d br, 1H, J ) 9.6 Hz), 7.88 (m, 1H), 7.52 (s, 1H), 7.40 (m,
3H), 4.27 (d, 1H, J ) 9.6 Hz), 3.66 (d, 1H, J ) 11.4 Hz), 3.07
(m, 1H), 2.57 (d, 3H, J ) 4.4 Hz), 1.68 (s, 6H), 1.56 (m, 1H),
1.41 (m, 1H), 1.07 (m, 1H), 0.96 (s, 9H), 0.88 (d, 3H, J ) 6.6
Hz), 0.79 (d, 3H, J ) 6.6 Hz); MS (ESI) 498 (MNa+).
N2-[4-Hyd r oxy-2S-isob u t yl-3S-m et h ylt h iosu ccin yl]-L-
ter t-leu cin e-N1-m eth yla m id e (11j). From a mixture of 10j
and its epimer was similarly obtained a 1:3 mixture of 11j and
its epimer (1.7 g, 99%) as a white solid. 11j: 1H NMR (CDCl3)
7.85 (m, 1H), 6.80 (m, 1H), 4.53 (d, 1H, J ) 9.9 Hz), 3.36 (d,

4898 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Barlaam et al.
N2-[4-(N-Hyd r oxya m in o)-2S-isobu tyl-3S-(4-(m eth ylsu l-
fon yl)p h e n ylt h io)su ccin yl]-L-t er t -le u cin e -N 1-m e t h yl-
a m id e (2e). Similarly, except that TMSONH2 was used
instead of NH2OH‚HCl, from the 1:1 mixture of 11e and its
epimer was obtained 2e (105 mg, 22%, eluting first) as a white
solid after purification of the crude mixture by C18 preparative
HPLC using as eluant methanol and water/1% AcOH (gradient
from 0:100 to 45:55): mp ) 222-224 °C; 1H NMR (DMSO-d6)
10.85 (s br, 1H), 9.15 (s, 1H), 8.1 (d, 1H, J ) 9.2 Hz), 7.83 (m,
3H), 7.61 (d, 2H, J ) 8.8 Hz), 4.23 (d, 1H, J ) 9.2 Hz), 3.86 (d,
1H, J ) 11.3 Hz), 3.26 (s, 3H), 3.15 (m, 1H), 2.60 (d, 3H, J )
4.8 Hz), 1.55 (m, 1H), 1.44 (m, 1H), 1.08 (m, 1H), 0.94 (s, 9H),
0.91 (d, 3H, J ) 6.2 Hz), 0.83 (d, 3H, J ) 6.6 Hz); MS (ESI)
524 (MNa+). Anal. (C22H35N3O6S2‚0.5H2O) C, H calcd 7.11
found 7.65, N calcd 8.23 found 8.83. Further elution gave 12e
(77 mg, 16%) as a white solid: 1H NMR (DMSO-d6) 10.9 (s br,
1H), 8.97 (s, 1H), 7.89 (m, 4H), 7.71 (d, 2H, J ) 8.4 Hz), 4.21
(d, 1H, J ) 9.2 Hz), 3.41 (d, 1H, J ) 9.2 Hz), 3.27 (s, 3H), 3.03
(m, 1H), 2.62 (d, 3H, J ) 4.4 Hz), 1.48 (m, 3H), 0.93 (s, 9H),
0.85 (d, 3H, J ) 6.6 Hz), 0.82 (d, 3H, J ) 6.6 Hz); MS (ESI)
524 (MNa+).
N2-[3S-(3,5-Dich lor op h en ylth io)-4-(N-h yd r oxya m in o)-
2S-isobu tylsu ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (2f).
Similarly was obtained 2f (80 mg, 11%) as a white solid: mp
) 199-202 °C; 1H NMR (DMSO-d6) 10.6 (m, 1H), 9.1 (s br,
1H), 8.13 (d, 1H, J ) 9.5 Hz), 7.85 (q, 1H, J ) 4.4 Hz), 7.46 (t,
1H, J ) 1.8 Hz), 7.42 (d, 2H, J ) 1.8 Hz), 4.24 (d, 1H, J ) 9.5
Hz), 3.68 (d, 1H, J ) 11 Hz), 3.10 (m, 1H), 2.56 (d, 3H, J ) 4.4
Hz), 1.37 (m, 2H), 1.01 (m, 1H), 0.91 (s, 9H), 0.86 (d, 3H, J )
6.2 Hz), 0.78 (d, 3H, J ) 6.2 Hz); MS (ESI) 518 (M{37Cl,37Cl}-
Na+), 516 (M{35Cl,37Cl}Na+), 514 (M{35Cl,35Cl}Na+). Anal.
(C21H31Cl2N3O4S‚0.7H2O) C H N.
(C25H36N4O4S‚1.25H2O‚0.05AcOH‚0.45CF3CO2H) C calcd 55.22
found 54.80, H N S. Compound 12h was not isolated.
N2-[3S-(3-(1-Cya n o-1-m et h ylet h yl)p h en ylt h io)-4-(N-
h yd r oxya m in o)-2S-isob u t ylsu ccin yl]-L-ter t-leu cin e-N1-
m eth yla m id e (2i). Similarly to 2g, from 11i was obtained 2i
(170 mg, 40%) as a white solid after treatment of the crude
reaction mixture with HCl (2 N, 3 mL) and purification by C18
preparative HPLC using as eluant methanol and water/1%
1
AcOH (gradient from 20:80 to 65:35): mp ) 202-206 °C; H
NMR (DMSO-d6) 10.72 (s, 1H), 9.05 (s, 1H), 8.04 (d, 1H, J )
9.2 Hz), 7.81 (m, 1H), 7.44-7.35 (m, 4H), 4.25 (d, 1H, J ) 9.2
Hz), 3.62 (d, 1H, J ) 11.4 Hz), 3.04 (m, 1H), 2.57 (d, 3H, J )
4.4 Hz), 1.69 (s, 6H), 1.47 (m, 1H), 1.37 (m, 1H), 1.01 (m, 1H),
0.94 (s, 9H), 0.86 (d, 3H, J ) 6.6 Hz), 0.78 (d, 3H, J ) 6.6 Hz);
MS (ESI) 513 (MNa+). Anal. (C25H38N4O4S‚1.3H2O) C H calcd
7.96 found 8.45, N S. Compound 12i was not isolated.
N2-[4-(N-H yd r oxya m in o)-2S-isob u t yl-3S-m et h ylt h io-
su ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (2j). Similarly to
2g, from 11j and its epimer was obtained, after treatment of
the crude reaction mixture with HCl (2 N, 3 mL) and
purification by C18 preparative HPLC using as eluant metha-
nol and water/1% AcOH (gradient from 40:60 to 60:40), 2j (150
mg, 9%) as a white solid: mp ) 214-218 °C; 1H NMR (DMSO-
d6) 10.58 (s, 1H), 9.0 (m, 1H), 7.95 (d, 1H, J ) 9.2 Hz), 7.81 (q,
1H, J ) 4.4 Hz), 4.23 (d, 1H, J ) 9.2 Hz), 3.01 (m, 2H), 2.54
(d, 3H, J ) 4.4 Hz), 2.11 (s, 3H), 1.45-1.25 (m, 2H), 1.0-0.85
(m, 1H), 0.96 (s, 9H), 0.84 (d, 3H, J ) 6.2 Hz), 0.75 (d, 3H, J
) 6.2 Hz); MS (ESI) 384 (MNa+). Anal. (C16H31N3O4S‚1.5H2O‚
0.1AcOH) C H N S. Further elution afforded 12j (560 mg,
1
32%): mp ) 125-128 °C; H NMR (DMSO-d6) 10.7 (m, 1H),
8.8 (s, 1H), 7.8 (q, 1H, J ) 4.4 Hz), 7.57 (d, 1H, J ) 9.5 Hz),
4.14 (d, 1H, J ) 9.5 Hz), 3.08 (d, 1H, J ) 10 Hz), 2.89-2.84
(m, 1H), 2.54 (d, 3H, J ) 4.4 Hz), 2.11 (s, 3H), 1.57-1.43 (m,
2H), 1.0-0.8 (m, 1H), 0.91 (s, 9H), 0.89 (d, 3H, J ) 6.2 Hz),
0.84 (d, 3H, J ) 6.2 Hz); MS (ESI) 384 (MNa+).
N2-[3S-(2-Ch lor o-4-flu or op h en ylt h io)-4-(N-h yd r oxy-
a m in o)-2S -isob u t ylsu ccin yl]-L -t er t -le u cin e -N 1-m e t h -
yla m id e (2g). Similarly, except that tBuMe2SiONH2 (1.1
equiv) was used instead of NH2OH‚HCl, there was obtained
2g (451 mg, 45%) as a white solid after purification of the crude
mixture by C18 preparative HPLC using as eluant methanol
and water/1% AcOH (gradient from 20:80 to 65:35): mp )
N2-[3S-Eth ylth io-4-(N-h yd r oxya m in o)-2S-isobu tylsu c-
cin yl]-L-ter t-leu cin e-N1-m eth yla m id e (2k ). Similarly to 2h ,
from 11k and its epimer was obtained, after purification by
C18 preparative HPLC using as eluant methanol and water/
1% AcOH (45:55), 2k (190 mg, 37%) as a white solid: mp )
1
231-233 °C; H NMR (DMSO-d6) 10.72 (s, 1H), 9.03 (s, 1H),
1
190-196 °C; H NMR (DMSO-d6) 10.6 (s br, 1H), 8.95 (s br,
8.07 (d, 1H, J ) 9.5 Hz), 7.80 (m, 1H), 7.60 (dd, 1H, J ) 8.8
Hz, J ′ ) 5.8 Hz), 7.46 (dd, 1H, J ) 8.8 Hz, J ′ ) 2.9 Hz), 7.23
(td, 1H, J t ) 8.8 Hz, J d ) 2.9 Hz), 4.20 (d, 1H, J ) 9.5 Hz),
3.69 (d, 1H, J ) 11 Hz), 3.05 (m, 1H), 2.56 (d, 3H, J ) 4.8 Hz),
1.49 (m, 1H), 1.37 (m, 1H), 1.03 (m, 1H), 0.92 (s, 9H), 0.86 (d,
3H, J ) 6.6 Hz), 0.78 (d, 3H, J ) 6.6 Hz); MS (ESI) 500 (M{37-
Cl}Na+), 498 (M{35Cl}Na+). Anal. (C21H31ClFN3O4S‚0.2H2O)
C H N calcd 8.76 found 8.25, S. Compound 12g was not
isolated.
1H), 7.89 (d, 1H, J ) 9.2 Hz), 7.78 (q, 1H, J ) 4.4 Hz), 4.23 (d,
1H, J ) 9.2 Hz), 3.06 (d, 1H, J ) 11.3 Hz), 2.96 (m, 1H), 2.64
(m, 2H), 2.56 (d, 3H, J ) 4.4 Hz), 1.5-1.3 (m, 2H), 1.08 (t, 3H,
J ) 7.3 Hz), 1.0-0.9 (m, 1H), 0.96 (s, 9H), 0.84 (d, 3H, J ) 6.2
Hz), 0.76 (d, 3H, J ) 6.2 Hz); MS (ESI) 376 (MH+). Anal.
(C17H33N3O4S) C H N. Further elution afforded a mixture of
2k and 12k (130 mg).
N2-[4-(N-H yd r oxya m in o)-2S-isob u t yl-3R-p h en ylt h io-
su ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (12a ). Similarly
to 10a , N2-[4-tert-butyloxy-2S-isobutyl-3R-phenylthiosuccinyl]-
L-tert-leucine-N1-methylamide (540 mg, 78%) was obtained
from 9a as a white foam: 1H NMR (CDCl3) 7.49 (m, 2H), 7.30
(m, 3H), 6.56 (d, 1H, J ) 9.2 Hz), 5.88 (q, 1H, J ) 5.1 Hz),
4.14 (d, 1H, J ) 9.2 Hz), 3.73 (d, 1H, J ) 9.9 Hz), 2.78 (d, 3H,
J ) 5.1 Hz), 2.64 (m, 1H), 1.79 (m, 1H), 1.64 (m, 1H), 1.51 (m,
1H), 1.33 (s, 9H), 0.99 (s, 9H), 0.88 (d, 3H, J ) 6.6 Hz), 0.87
(d, 3H, J ) 6.6 Hz). Similarly to 11a , this compound was
converted to N2-[4-hydroxy-2S-isobutyl-3R-phenylthiosucci-
nyl]-L-tert-leucine-N1-methylamide (460 mg, 100%) as a white
solid: 1H NMR (CDCl3) 7.7 (m, 1H), 7.50 (m, 2H), 7.32 (m,
3H), 6.28 (s br, 1H), 4.38 (d, 1H, J ) 9.5 Hz), 3.84 (d, 1H, J )
6.6 Hz), 2.97 (m, 1H), 2.86 (d, 3H, J ) 5.1 Hz), 1.80-1.55 (m,
3H), 1.06 (s, 9H), 0.87 (d, 3H, J ) 6.2 Hz), 0.84 (d, 3H, J ) 6.2
Hz); MS (ESI) 409 (MH+). Similarly to 2a (except that lutidine
was replaced by N-methylmorpholine), this acid (170 mg, 0.41
mmol) was converted to 2a (55 mg, 32%, eluting first) and 12a
(49 mg, 29%) after purification by C18 preparative HPLC using
as eluant methanol and water/1% AcOH (gradient from 20:80
to 60:40). 12a : mp ) 194-198 °C; 1H NMR (DMSO-d6) 10.75
(m, 1H), 8.86 (s, 1H), 7.78 (q, 1H, J ) 4.8 Hz), 7.69 (d, 1H, J
) 9.5 Hz), 7.5-7.2 (m, 5H), 4.12 (d, 1H, J ) 9.5 Hz), 3.62 (d,
1H, J ) 9.5 Hz), 2.88 (m, 1H), 2.55 (d, 3H, J ) 4.8 Hz), 1.6-
1.3 (m, 3H), 0.87 (s, 9H), 0.79 (d, 3H, J ) 6.6 Hz), 0.75 (d, 3H,
N2-[4-(N-Hyd r oxya m in o)-2S-isobu tyl-3S-(qu in olin -8-yl-
m eth ylth io)su ccin yl]-L-ter t-leu cin e-N1-m eth ylam ide (2h ).
To a solution of 11h and its epimer (460 mg, 1:1, 0.97 mmol)
in DMF (5 mL) cooled at 0 °C were added HOBT (270 mg, 2
mmol), N-methylmorpholine (400 µL), O-(2,4-dimethoxyben-
zyl)hydroxylamine21 (366 mg, 2 mmol), and EDCI (382 mg, 2
mmol). The mixture was stirred at room temperature for 18
h. The mixture was partitioned between water and EtOAc. The
organic layer was washed with saturated NaHCO3 and brine,
dried over MgSO4, and filtered. The solvents were evaporated
in vacuo to give the O-protected hydroxamate. To this crude
material in CH2Cl2 (10 mL) was added TFA (0.7 mL). The
mixture was stirred at room temperature for 15 min. The
solvents were evaporated in vacuo. Methanol was added (20
mL); the solids were filtered. The filtrate was concentrated
and purified by C18 preparative HPLC using as eluant
methanol and water/1% AcOH (gradient from 0:100 to 50:50)
to give 2h (76 mg, 36% based on 11h , eluting first): mp )
1
205-215 °C; H NMR (DMSO-d6) 10.75 (s, 1H), 9.04 (s, 1H),
8.93 (m, 1H), 8.36 (m, 1H), 7.89 (m, 2H), 7.80 (m, 2H), 7.55
(m, 2H), 4.54 (d, 1H, J ) 12.5 Hz), 4.43 (d, 1H, J ) 12.5 Hz),
4.20 (d, 1H, J ) 9.2 Hz), 3.28 (d, 1H, J ) 11 Hz), 3.08 (m, 1H),
2.56 (d, 3H, J ) 4.4 Hz), 1.5-1.3 (m, 2H), 1.04 (m, 1H), 0.86
(m, 12H), 0.78 (d, 3H, J ) 6.6 Hz); MS (EI) 488 (M+•). Anal.

MMP/ TNFR Convertase Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4899
J ) 6.6 Hz); MS (ESI) 446 (MNa+). Anal. (C21H33N3O4S) C H
calcd 7.85 found 8.33, N S.
3H), 1.37 (s, 9H), 0.98 (s, 9H), 0.89 (d, 3H, J ) 6.2 Hz), 0.88
(d, 3H, J ) 6.2 Hz); MS (ESI) 516 (MH+).
An h yd r id e 13a . To a solution of 8a (130 mg, 0.38 mmol)
in CH2Cl2 was added oxalyl chloride (76 µL, 0.88 mmol) and
DMF (1 drop). The mixture was stirred at room temperature
for 2 h. Evaporation of the solvents afforded 13a (quantitative
yield): 1H NMR (CDCl3) 7.55 (m, 2H), 7.39 (m, 3H), 4.20 (d,
1H, J ) 8.4 Hz), 3.37 (ddd, 1H, J ) J ′ ) 8.4 Hz, J ′′ ) 5.5 Hz),
1.9 (m, 3H), 1.04 (d, 3H, J ) 5.9 Hz), 1.00 (d, 3H, J ) 5.9 Hz);
13C NMR (CDCl3) 168.6, 134.6, 130.2, 129.9, 50.1, 43.3, 34.1,
26.0, 22.6, 21.7; MS (EI) 264 (M+•).
N2-[4-ter t-Bu tyloxy-2R-isobu tyl-3S-(th iop h en e-2-su lfo-
n yla m in o)su ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (16h ).
Similarly from thiophene-2-sulfonyl chloride was obtained 16h
(567 mg, 82%) as a white foam: 1H NMR (CDCl3) 7.58 (d, 1H,
J ) 3.7 Hz), 7.54 (d, 1H, J ) 5.1 Hz), 7.05 (dd, 1H, J ) 5.1 Hz,
J ′ ) 3.7 Hz), 6.48 (m, 1H), 6.26 (m, 1H), 5.68 (m, 1H), 4.07 (d,
1H, J ) 9.2 Hz), 4.04 (m, 1H), 2.86 (m, 1H), 2.83 (d, 3H, J )
4.8 Hz), 1.7-1.0 (m, 3H), 1.29 (s, 9H), 0.96 (s, 9H), 0.91 (d,
6H, J ) 6.2 Hz); MS (ESI) 540 (MNa+).
An h yd r id e 14a . Similarly, from 9a (300 mg, 0.89 mmol)
was obtained 14a (quantitative yield): 1H NMR (CDCl3) 7.55
(m, 2H), 7.40 (m, 3H), 3.80 (d, 1H, J ) 5.5 Hz), 2.96 (ddd, 1H,
J ) 8.8 Hz, J ′ ) 6.2 Hz, J ′′ ) 5.5 Hz), 1.9-1.75 (m, 2H), 1.60
(m, 1H), 0.98 (d, 3H, J ) 6.2 Hz), 0.97 (d, 3H, J ) 6.2 Hz); MS
(EI) 264 (M+•).
N2-[4-ter t-b u t yloxy-2R-isob u t yl-3S-(3-p yr id in esu lfo-
n yla m in o)su ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (16i).
Similarly from 3-pyridinesulfonyl chloride (360 mg) was
obtained 16i (500 mg, 73%) as a white foam: 1H NMR (CDCl3)
9.06 (s br, 1H), 8.75 (m, 1H), 8.16 (m, 1H), 7.40 (m, 1H), 6.73
(d br, 1H, J ) 9.9 Hz), 6.27 (d br, 1H, J ) 9.2 Hz), 5.63 (m,
1H), 4.05 (d, 1H, J ) 9.2 Hz), 4.04 (m, 1H), 2.87 (m, 1H), 2.83
(d, 3H, J ) 4.8 Hz), 1.7-1.3 (m, 3H), 1.24 (s, 9H), 0.95 (s, 9H),
0.92 (d, 6H, J ) 6.6 Hz); MS (ESI) 535 (MNa+), 513 (MH+).
N2-[4-ter t-Bu tyloxy-2R-isobu tyl-3S-(n a p h th a len e-2-su l-
fon ylam in o)su ccin yl]-L-ter t-leu cin e-N1-m eth ylam ide (16l).
Similarly from naphthalene-2-sulfonyl chloride was obtained
16l (690 mg, 77%) as a white foam: 1H NMR (DMSO-d6) 8.39
(s, 1H), 8.18-8.00 (m, 3H), 7.92 (m, 1H), 7.80-7.60 (m, 5H),
4.15 (d, 1H, J ) 9.4 Hz), 3.75 (m, 1H), 2.83 (m, 1H), 2.57 (d,
3H, J ) 4.4 Hz), 1.45-1.20 (m, 2H), 1.02 (s, 9H), 0.95 (m, 1H),
0.89 (s, 9H), 0.74 (d, 3H, J ) 6.6 Hz), 0.71 (d, 3H, J ) 6.6 Hz);
MS (ESI) 584 (MNa+).
N 2-[4-t er t -Bu t yloxy-2R -isob u t yl-3S -(n a p h t h a le n e -1-
s u lfo n y la m in o )s u c c in y l]-L -t er t -le u c in e -N 1 -m e t h y l-
a m id e(16m ). Similarly from naphthalene-1-sulfonyl chloride
(403 mg) was obtained 16m (620 mg, 69%) as a white foam:
1H NMR (DMSO-d6) 8.55 (d, 1H, J ) 8.4 Hz), 8.24 (d, 1H, J )
8.4 Hz), 8.10 (m, 2H), 7.97 (m, 2H), 7.80-7.60 (m, 4H), 4.20
(d, 1H, J ) 9.2 Hz), 3.67 (t, 1H, J ) 8.8 Hz), 2.80 (m, 1H),
2.58 (d, 3H, J ) 4.8 Hz), 1.30 (m, 1H), 1.10 (m, 1H), 0.94 (s,
9H), 0.90 (s, 9H), 0.74 (m, 1H), 0.67 (d, 3H, J ) 6.6 Hz), 0.59
(d, 3H, J ) 6.6 Hz); MS (ESI) 584 (MNa+).
N2-[3S-Ben zen esu lfon ylam in o-4-ter t-bu tyloxy-2R-isobu -
tylsu ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (16a ). To a
solution of 15 (740 mg, 1.98 mmol) in CH2Cl2 (10 mL) at 0 °C
was added successively pyridine (500 µL, 6.18 mmol), ben-
zenesulfonyl chloride (310 µL, 2.43 mmol), and DMAP (a few
crystals). The mixture was stirred at room temperature for
18 h. The reaction mixture was poured into 2 N HCl (50 mL)
and extracted with EtOAc (2 × 60 mL). The combined organic
layers were washed with brine and dried over MgSO4. The
solvents were evaporated in vacuo, and the residue was
purified by flash chromatography on silica using EtOAc-
petroleum ether (1:1) as eluant to give 16a (849 mg, 84%) as
a white foam: 1H NMR (CDCl3) 7.86 (d, 2H, J ) 7 Hz), 7.55-
7.45 (m, 3H), 6.37 (d br, 1H, J ) 9.9 Hz), 6.26 (d br, 1H, J )
9.1 Hz), 5.75 (s br, 1H), 4.08 (d, 1H, J ) 9.1 Hz), 3.98 (dd, 1H,
J ) 9.9 Hz, J ) 3.3 Hz), 2.82 (d, 3H, J ) 4.7 Hz), 1.65-1.40
(m, 3H), 1.23 (s, 9H), 0.96 (s, 9H), 0.89 (d, 3H, J ) 6.6 Hz),
0.88 (d, 3H, J ) 6.6 Hz).
N2-[3S-(4-Aceta m id oben zen esu lfon yla m in o)-4-ter t-bu -
t yloxy-2R-isob u t ylsu ccin yl]-L-ter t-le u cin e -N1-m e t h yl-
a m id e (16b). Similarly from 4-acetamidobenzenesulfonyl
chloride was obtained 16b (790 mg, 87%) as a white foam: 1H
NMR (DMSO-d6) 7.91 (m, 1H), 7.75-7.65 (m, 5H), 7.50 (d br,
1H, J ) 9.2 Hz), 4.15 (d, 1H, J ) 9.2 Hz), 3.66 (m, 1H), 2.81
(m, 1H), 2.56 (d, 3H, J ) 4.4 Hz), 2.10 (s, 3H), 1.5-1.2 (m,
2H), 1.22 (s, 9H), 0.98 (m, 1H), 0.90 (s, 9H), 0.77 (m, 6H); MS
(ESI) 591 (MNa+).
N2-[4-ter t-Bu t yloxy-3S-(3,5-d ich lor ob en zen e-1-su lfo-
n yla m in o)-2R-isobu tylsu ccin yl]-L-ter t-leu cin e-N1-m eth -
yla m id e (16c). Similarly from 3,5-dichlorobenzenesulfo-
nyl chloride was obtained 16c (629 mg, 81%) as a white
foam: 1H NMR (CDCl3) 7.74 (d, 2H, J ) 1.8 Hz), 7.50 (t, 1H,
J ) 1.8 Hz), 6.74 (m, 1H), 6.26 (m, 1H), 5.62 (m, 1H), 4.05 (d,
1H, J ) 9.2 Hz), 4.00 (m, 1H), 2.89 (m, 1H), 2.84 (d, 3H, J )
4.8 Hz), 1.7-1.4 (m, 3H), 1.28 (s, 9H), 0.96 (s, 9H), 0.92 (d,
6H, J ) 6.2 Hz); MS (ESI) 604 (M{37Cl,35Cl}Na+), 602 (M-
{35Cl,35Cl}Na+).
N 2-[4-t er t -Bu t yloxy-3S -(2-cya n ob e n ze n e -1-su lfon yl-
a m in o)-2R -isob u t ylsu ccin yl]-L -t er t -le u cin e -N 1-m e t h -
yla m id e (16d ). Similarly from 2-cyanobenzenesulfonyl chlo-
ride was obtained 16d (507 mg, 71%) as a white foam: 1H
NMR (CDCl3) 8.01 (d, 1H, J ) 7.7 Hz), 7.75 (d, 1H, J ) 7.7
Hz), 7.65-7.52 (m, 2H), 6.92 (m, 1H), 6.21 (d br, 1H, J ) 9.2
Hz), 5.59 (m, 1H), 4.11-4.02 (m, 2H), 2.86 (m, 1H), 2.76 (d,
3H, J ) 5.2 Hz), 1.7-1.1 (m, 3H), 1.19 (s, 9H), 0.88 (s, 9H),
0.83 (d, 3H, J ) 6.6 Hz), 0.81 (d, 3H, J ) 6.6 Hz); MS (ESI)
559 (MNa+).
N2-[4-ter t-Bu tyloxy-2R-isobu tyl-3S-(1-m eth ylim idazole-
4-su lfon yla m in o)su ccin yl]-L -t er t -le u cin e -N 1-m e t h yl-
a m id e (16g). Similarly, except that the crude reaction mixture
after evaporation of the solvents was directly purified by flash
chromatography on silica using CH2Cl2-methanol (95:5) as
eluant, from 1-methyl-imidazole-4-sulfonyl chloride was ob-
tained 16g (953 mg, 98%) as a white foam: 1H NMR (CDCl3)
7.45 (s, 1H), 7.42 (s, 1H), 6.50 (d br, 1H, J ) 9.5 Hz), 6.12 (m,
1H), 5.83 (m, 1H), 4.26 (m, 1H), 4.11 (d, 1H, J ) 9.2 Hz), 3.72
(s, 3H), 2.85 (m, 1H), 2.81 (d, 3H, J ) 4.8 Hz), 1.7-1.0 (m,
N2-[4-ter t-bu tyloxy-2R-isobu tyl-3S-(qu in olin e-8-su lfo-
n yla m in o)su ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (16n ).
Similarly from 8-quinolinesulfonyl chloride was obtained 16n
(375 mg, 50%) as a white foam: 1H NMR (CDCl3) 9.09 (m,
1H), 8.36 (d br, 1H, J ) 7.3 Hz), 8.23 (d br, 1H, J ) 8.4 Hz),
8.01 (d br, 1H, J ) 8.4 Hz), 7.61 (dd, 1H, J ) 8.4 Hz, J ′ ) 7.3
Hz), 7.53 (dd, 1H, J ) 8.4 Hz, J ′ ) 4 Hz), 7.32 (d br, 1H, J )
9.2 Hz), 6.29 (d br, 1H, J ) 9.2 Hz), 5.85 (m, 1H), 4.34 (dd,
1H, J ) 9.2 Hz, J ′ ) 4.7 Hz), 4.14 (d, 1H, J ) 9.2 Hz), 2.83 (m,
1H), 2.82 (d, 3H, J ) 4.4 Hz), 1.7-1.3 (m, 3H), 0.98 (s, 9H),
0.93 (s, 9H), 0.85 (d, 3H, J ) 6.6 Hz), 0.81 (d, 3H, J ) 6.6 Hz);
MS (ESI) 563 (MH+).
N2-[4-ter t-Bu tyloxy-2R-isobu tyl-3S-(isoqu in olin e-5-su l-
fon ylam in o)su ccin yl]-L-ter t-leu cin e-N1-m eth ylam ide (16o).
Similarly from isoquinoline-5-sulfonyl chloride was obtained
16o (580 mg, 77%) as a white foam: 1H NMR (CDCl3) 9.32
(s, 1H), 8.72 (d, 1H, J ) 6.2 Hz), 8.53 (d, 1H, J ) 6.2 Hz), 8.41
(d, 1H, J ) 8 Hz), 8.17 (d, 1H, J ) 8 Hz), 7.66 (t, 1H, J ) 8
Hz), 6.98 (d br, 1H, J ) 9.5 Hz), 6.25 (d br, 1H, J ) 9.2 Hz),
5.58 (m, 1H), 4.05 (d, 1H, J ) 9.2 Hz), 3.94 (dd, 1H, J ) 9.5
Hz, J ′ ) 3.3 Hz), 2.83 (d, 3H, J ) 4.8 Hz), 2.79 (m, 1H), 1.5-
1.2 (m, 2H), 1.06 (s, 9H), 1.00 (m, 1H), 0.96 (s, 9H), 0.79 (d,
3H, J ) 6.2 Hz), 0.72 (d, 3H, J ) 6.2 Hz); MS (ESI) 585
(MNa+).
N2-[4-ter t-Bu tyloxy-2R-isobu tyl-3S-(4-oxo-3,4-d ih yd r o-
qu in a zolin e-8-su lfon yla m in o)su ccin yl]-L-ter t-leu cin e-N1-
m eth yla m id e (16p ) a n d N2-[4-ter t-bu tyloxy-2R-isobu tyl-
3S-(4-oxo-3,4-d ih yd r oqu in a zolin e-6-su lfon yla m in o)su c-
cin yl]-L-ter t-leu cin e-N1-m eth yla m id e (16t). Similarly, from
a mixture of 4-oxo-3,4-dihydroquinazoline-6-sulfonyl chloride
and 4-oxo-3,4-dihydroquinazoline-8-sulfonyl chloride [1.5 g, 1:1,
prepared by heating of 3,4-dihydroquinazolin-4-one with excess
of chlorosulfonic acid at 140 °C: 1H NMR (DMSO-d6) 9.03 and
8.92 (s, 1H), 8.34 (d, 0.5H, J ) 1.8 Hz), 8.25 (m, 1H), 8.11 (dd,
0.5H, J ) 8.4 Hz, J ′ ) 1.8 Hz), 7.75 (m, 1H); MS (EI): 244

4900 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Barlaam et al.
1
(M{35Cl}+•)], there was obtained 16p (332 mg, 29%) as a foam
and 16t (428 mg, 37%) after purification on HPLC using EtOAc
as eluant. 16p : 1H NMR (CDCl3) 8.49 (dd, 1H, J ) 8.1 Hz, J ′
) 1.5 Hz), 8.46 (d, 1H, J ) 3.3 Hz), 8.36 (dd, 1H, J ) 8.1 Hz,
J ′ ) 1.5 Hz), 7.53 (t, 1H, J ) 8.1 Hz), 7.15 (m, 1H), 7.07 (d,
1H, J ) 9.9 Hz), 6.77 (d br, 1H, J ) 9.5 Hz), 4.55 (d, 1H, J )
9.9 Hz), 4.24 (dd, 1H, J ) 9.9 Hz, J ′ ) 3.7 Hz), 3.00 (m, 1H),
2.84 (d, 3H, J ) 4.8 Hz), 1.8 (m, 2H), 1.45 (m, 1H), 1.10 (s,
9H), 0.94-0.90 (m, 15H); MS (ESI) 602 (MNa+). 16t: 1H NMR
(CDCl3) 8.84 (d, 1H, J ) 1.8 Hz), 8.21 (dd, 1H, J ) 8.8 Hz, J ′
) 1.8 Hz), 8.11 (d, 1H, J ) 1.8 Hz), 7.83 (d, 1H, J ) 8.8 Hz),
6.86 (m, 2H), 6.05 (m, 1H), 4.20 (d, 1H, J ) 9.2 Hz), 4.06 (dd,
1H, J ) 10.3 Hz, J ′ ) 4.4 Hz), 2.95 (m, 1H), 2.84 (d, 3H, J )
4.8 Hz), 1.7-1.4 (m, 3H), 1.21 (s, 9H), 0.98 (s, 9H), 0.87 (d,
3H, J ) 6.2 Hz), 0.85 (d, 3H, J ) 6.2 Hz); MS (ESI) 602
(MNa+).
N2-[4-ter t-Bu t yloxy-2R-isob u t yl-3S-(1-m et h yl-2-oxo-
1,2,3,4-tetr a h yd r oqu in olin e-6-su lfon yla m in o)su ccin yl]-
L-ter t-leu cin e-N1-m eth ylam ide (16q). Similarly from 1-meth-
yl-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonyl chloride39 was
obtained 16q (679 mg, 85%) as a white foam: 1H NMR (CDCl3)
7.76 (dd, 1H, J ) 8.8 Hz, J ′ ) 2.2 Hz), 7.66 (d, 1H, J ) 2.2
Hz), 7.02 (d, 1H, J ) 8.8 Hz), 6.37 (d br, 1H, J ) 9.9 Hz), 6.26
(d, 1H, J ) 9.2 Hz), 5.66 (m, 1H), 4.06 (d, 1H, J ) 9.2 Hz),
3.97 (dd, 1H, J ) 9.9 Hz, J ′ ) 3.6 Hz), 3.36 (s, 3H), 2.95 (m,
2H), 2.83 (d, 3H, J ) 4.8 Hz), 2.66 (m, 2H), 1.7-1.1 (m, 3H),
1.25 (s, 9H), 0.96 (s, 9H), 0.90 (d, 6H, J ) 6.6 Hz); MS (ESI)
617 (MNa+).
mg, 98%): mp ) 120-130 °C; H NMR (DMSO-d6) 7.88 (m,
1H), 7.75 (m, 2H), 7.65-7.5 (m, 5H), 4.12 (d, 1H, J ) 9.2 Hz),
3.74 (dd, 1H, J ) 9.5 Hz, J ) 7.7 Hz), 2.83 (m, 1H), 2.56 (d,
3H, J ) 4.4 Hz), 1.5-1.2 (m, 2H), 0.97 (m, 1H), 0.88 (m, 1H),
0.76 (d, 3H, J ) 6.2 Hz), 0.74 (d, 3H, J ) 6.2 Hz); MS (ESI)
478 (MNa+), 456 (MH+). Anal. (C21H33N3O6S‚0.3H2O) C calcd
54.72 found 55.17, H calcd 7.35 found 7.87, N S calcd 6.96
found 6.50.
The following compounds were obtained similarly.
17b: (656 mg, 97%) white solid; H NMR (DMSO-d6) 7.89
1
(m, 1H), 7.72 (d, 2H, J ) 8.8 Hz), 7.66 (d, 2H, J ) 8.8 Hz),
7.60 (d br, 1H, J ) 9.2 Hz), 7.38 (d br, 1H, J ) 9.2 Hz), 4.12
(d, 1H, J ) 9.2 Hz), 3.70 (t, 1H, J ) 8.1 Hz), 2.81 (m, 1H),
2.57 (d, 3H, J ) 4.4 Hz), 2.10 (s, 3H), 1.45-1.20 (m, 2H), 0.95
(m, 1H), 0.89 (s, 9H), 0.76 (d, 3H, J ) 6.6 Hz), 0.74 (d, 3H, J
) 6.6 Hz); MS (ESI) 535 (MNa+), 513 (MH+).
17c: (480 mg, 92%) white solid; 1H NMR (CDCl3) 7.74 (s br,
2H), 7.53 (s br, 1H), 7.25 (m, 1H), 6.60 (m, 1H), 5.90 (m, 1H),
4.19 (d, 1H, J ) 9.5 Hz), 3.99 (m, 1H), 3.13 (m, 1H), 2.82 (d,
3H, J ) 4.8 Hz), 1.6-1.2 (m, 3H), 0.96 (s, 9H), 0.90 (d, 6H, J
) 6.2 Hz); MS (ESI) 548 (M{37Cl,35Cl}Na+), 546 (M{35Cl,35Cl}-
Na+).
1
17d : (400 mg, 93%) white solid; H NMR (CDCl3) 8.07 (d,
1H, J ) 7.7 Hz), 7.86 (d, 1H, J ) 7.7 Hz), 7.75-7.63 (m, 2H),
7.21 (m, 1H), 6.89 (m, 1H), 6.04 (m, 1H), 4.21 (d, 2H, J ) 9.5
Hz), 3.14 (m, 1H), 2.80 (d, 3H, J ) 4.8 Hz), 1.55-1.2 (m, 3H),
0.92 (s, 9H), 0.87 (d, 3H, J ) 5.8 Hz), 0.83 (d, 3H, J ) 5.8 Hz);
MS (ESI) 503 (MNa+), 481 (MH+).
N2-[4-ter t-Bu t yloxy-2R-isob u t yl-3S-(oxin d ole-5-su lfo-
n yla m in o)su ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (16r ).
Similarly from oxindole-5-sulfonyl chloride (prepared by reac-
tion of oxindole with chlorosulfonic acid) was obtained 16r (660
mg, 87%) as a white foam: 1H NMR (CDCl3 + DMSO-d6) 10.23
(s, 1H), 7.70 (d, 1H, J ) 8.1 Hz), 7.65 (s, 1H), 6.90 (m, 2H),
6.73 (m, 2H), 4.15 (d, 1H, J ) 9.2 Hz), 3.85 (dd, 1H, J ) 9.9
Hz, J ′ ) 5.1 Hz), 3.49 (s, 2H), 2.81 (m, 1H), 2.76 (d, 3H, J )
4.8 Hz), 1.6-1.2 (m, 3H), 1.28 (s, 9H), 0.96 (s, 9H), 0.86 (d,
3H, J ) 6.2 Hz), 0.85 (d, 3H, J ) 6.2 Hz); MS (ESI) 589
(MNa+).
N2-[4-ter t-Bu tyloxy-2R-isobu tyl-3S-(qu in olin e-6-su lfo-
n yla m in o)su ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (16s).
Similarly from quinoline-6-sulfonyl chloride41 was obtained 16s
(510 mg, 67%) as a white foam: 1H NMR (CDCl3) 9.03 (dd,
1H, J ) 4.4 Hz, J ′ ) 1.8 Hz), 8.41 (d, 1H, J ) 1.8 Hz), 8.26
(dd, 1H, J ) 8.4 Hz, J ′ ) 1.8 Hz), 8.20 (d, 1H, J ) 8.4 Hz),
8.10 (dd, 1H, J ) 8.4 Hz, J ′ ) 1.8 Hz), 7.52 (dd, 1H, J ) 8.4
Hz, J ′ ) 4.4 Hz), 6.62 (d br, 1H, J ) 9.2 Hz), 6.27 (d br, 1H, J
) 9.2 Hz), 5.63 (m, 1H), 4.06 (m, 2H), 2.85 (m, 1H), 2.83 (d,
3H, J ) 4.8 Hz), 1.7-1.4 (m, 3H), 1.10 (s, 9H), 0.95 (s, 9H),
0.88 (d, 3H, J ) 6.2 Hz), 0.85 (d, 3H, J ) 6.2 Hz); MS (ESI)
563 (MH+).
17g: trifluoroacetate salt (819 mg, 82%) white solid; 1H NMR
(DMSO-d6) 7.90 (m, 1H), 7.77 (m, 2H), 7.68 (s, 1H), 7.16 (d,
1H, J ) 9.5 Hz), 4.14 (d, 1H, J ) 9.2 Hz), 3.77 (m, 1H), 3.69
(s, 3H), 2.88 (m, 1H), 2.56 (d, 3H, J ) 4.4 Hz), 1.31 (m, 2H),
1.01 (m, 1H), 0.89 (s, 9H), 0.78 (d, 3H, J ) 6.2 Hz), 0.74 (d,
3H, J ) 6.2 Hz); MS (ESI) 460 (MH+).
1
17h : (518 mg, 96%) white solid; H NMR (CDCl3) 7.60 (m,
2H), 7.09-7.00 (m, 2H), 6.22 (m, 1H), 5.68 (m, 1H), 4.17 (d,
1H, J ) 9.5 Hz), 3.96 (m, 1H), 3.11 (m, 1H), 2.85 (d, 3H, J )
4.8 Hz), 1.5-1.2 (m, 3H), 1.02 (s, 9H), 0.92 (d, 3H, J ) 6.6
Hz), 0.90 (d, 3H, J ) 6.6 Hz); MS (ESI) 484 (MNa+), 462 (MH+).
1
17i: (340 mg, 81%) white solid; H NMR (DMSO-d6 + CF3-
CO2D) 9.07 (s br, 1H), 8.90 (d, 1H, J ) 4.8 Hz), 8.40 (d, 1H, J
) 8.1 Hz), 7.79 (dd, 1H, J ) 8.1 Hz, J ′ ) 4.8 Hz), 4.11 (s, 1H),
3.91 (d, 1H, J ) 7.3 Hz), 2.90 (m, 1H), 2.56 (s, 3H), 1.43 (m,
2H), 1.09 (m, 1H), 0.87 (s, 9H), 0.79 (d, 3H, J ) 6.2 Hz), 0.78
(d, 3H, J ) 6.2 Hz); MS (ESI) 479 (MNa+), 457 (MH+).
17l: (540 mg, 93%) white solid; 1H NMR (DMSO-d6) 8.36 (s,
1H), 8.12-8.00 (m, 3H), 7.85 (m, 1H), 7.75-7.55 (m, 5H), 4.08
(d, 1H, J ) 9.5 Hz), 3.76 (dd, 1H, J ) 10.5 Hz, J ′ ) 8 Hz), 2.80
(m, 1H), 2.53 (d, 3H, J ) 4.4 Hz), 1.4-1.2 (m, 2H), 0.94 (m,
1H), 0.83 (s, 9H), 0.68 (d, 3H, J ) 6.2 Hz), 0.64 (d, 3H, J ) 6.2
Hz); MS (ESI) 528 (MNa+), 506 (MH+). Anal. (C25H35N3O6S)
C H N.
N 2-[4-t er t -B u t y lo x y -2R -iso b u t y l-3S -m e t h a n e su lfo -
n yla m in osu ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (16w ).
Similarly from methanesulfonyl chloride was obtained 16w
(372 mg, 62%) as a white foam: 1H NMR (CDCl3) 6.31 (d br,
1H, J ) 9.2 Hz), 6.23 (d br, 1H, J ) 9.5 Hz), 5.63 (m, 1H),
4.07 (m, 2H), 3.01 (s, 3H), 2.95 (m, 1H), 2.83 (d, 3H, J ) 4.8
Hz), 1.8-1.4 (m, 3H), 1.47 (s, 9H), 0.97 (s, 9H), 0.96 (d, 3H, J
) 6.2 Hz), 0.93 (d, 3H, J ) 6.2 Hz); MS (ESI) 472 (MNa+).
1
17m : (518 mg, 96%) white solid; H NMR (DMSO-d6) 8.56
(d, 1H, J ) 8.4 Hz), 8.24 (d, 1H, J ) 8.4 Hz), 8.11 (m, 2H),
7.92 (m, 1H), 7.80-7.60 (m, 5H), 4.14 (d, 1H, J ) 9.2 Hz), 3.68
(dd, 1H, J ) 9.2 Hz, J ′ ) 6.6 Hz), 2.85 (m, 1H), 1.15 (m, 1H),
0.97 (m, 1H), 0.89 (s, 9H), 0.71 (m, 1H), 0.59 (d, 3H, J ) 6.6
Hz), 0.45 (d, 3H, J ) 6.6 Hz); MS (ESI) 528 (MNa+), 506 (MH+).
1
17n : (315 mg, 100%) white solid; H NMR (DMSO-d6) 9.03
N 2-[4-t er t -Bu t yloxy-2R -isob u t yl-3S -(4-p yr id in e e t h -
a n esu lfon yla m in o)su ccin yl]-L-ter t-leu cin e-N1-m et h yl-
a m id e (16u ). To 15 (1 g, 2.69 mmol) in CH2Cl2 were added
NEt3 (3 mL) and 4-pyridineethanesulfonyl chloride hydrochlo-
ride42 (1.8 g, 7.4 mmol) in small portions over 2 h. The residue
was partitioned between EtOAc and water. The organic layer
was dried on MgSO4 to give 16u (1.38 g, 95%) after evaporation
of the solvents: 1H NMR (CDCl3) 8.54 (m, 2H), 7.18 (m, 2H),
6.45 (m, 1H), 6.33 (m, 1H), 5.75 (m, 1H), 4.10 (m, 2H), 3.31
(m, 3H), 3.12 (m, 1H), 2.95 (m, 1H), 2.83 (d, 3H, J ) 4.8 Hz),
1.75-0.9 (m, 3H), 1.45 (s, 9H), 0.98 (s, 9H), 0.97 (d, 3H, J )
6.6 Hz), 0.94 (d, 3H, J ) 6.6 Hz); MS (ESI) 541 (MH+).
(m, 1H), 8.53 (d, 1H, J ) 8.4 Hz), 8.25 (d, 1H, J ) 8.4 Hz),
8.20 (d, 1H, J ) 7 Hz), 7.92 (m, 2H), 7.72-7.62 (m, 3H), 4.13
(d, 1H, J ) 9.2 Hz), 3.96 (dd, 1H, J ) 8.8 Hz, J ′ ) 5.1 Hz),
3.01 (m, 1H), 2.54 (d, 3H, J ) 4.4 Hz), 1.3-1.1 (m, 2H), 0.82
(s, 9H), 0.80 (m, 1H), 0.64 (d, 3H, J ) 6.6 Hz), 0.49 (d, 3H, J
) 6.6 Hz); MS (ESI) 507 (MH+).
1
17o: (450 mg, 91%) white solid; H NMR (DMSO-d6) 9.47
(s, 1H), 8.72 (d, 1H, J ) 6.2 Hz), 8.43 (d, 1H, J ) 8 Hz), 8.31
(m, 2H), 7.92 (m, 2H), 7.79 (t, 1H, J ) 8 Hz), 7.69 (d br, 1H, J
) 9.2 Hz), 4.12 (d, 1H, J ) 9.2 Hz), 3.69 (m, 1H), 2.80 (m, 1H),
2.56 (d, 3H, J ) 4.4 Hz), 1.25 (m, 1H), 1.10 (m, 1H), 0.86 (s,
9H), 0.75 (m, 1H), 0.63 (d, 3H, J ) 6.6 Hz), 0.53 (d, 3H, J )
6.6 Hz); MS (ESI) 507 (MH+).
17p : (260 mg, 97%) solid; 1H NMR (DMSO-d6) 8.32 (dd, 1H,
J ) 8.1 Hz, J ′ ) 1.5 Hz), 8.22 (d, 1H, J ) 3.3 Hz), 8.17 (dd,
N2-[3S-Ben zen esu lfon yla m in o-4-h yd r oxy-2R-isobu tyl-
su ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (17a ). Using the
procedure described for 11a , from 16a was obtained 17a (676

MMP/ TNFR Convertase Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4901
1H, J ) 8.1 Hz, J ′ ) 1.5 Hz), 7.91 (m, 2H), 7.60 (t, 1H, J ) 8.1
Hz), 7.42 (d, 1H, J ) 9.5 Hz), 4.13 (d, 1H, J ) 9.5 Hz), 3.90
(m, 1H), 3.01 (m, 1H), 2.55 (d, 3H, J ) 4.8 Hz), 1.30 (m, 2H),
0.87 (m, 1H), 0.84 (s, 9H), 0.72 (d, 3H, J ) 5.9 Hz), 0.65 (d,
3H, J ) 5.9 Hz); MS (ESI) 524 (MH+).
(m, 1H), 0.91 (s, 9H), 0.90 (m, 1H), 0.78 (d, 6H, J ) 6.6 Hz);
MS (ESI) 522 (MNa+), 500 (MH+). Anal. (C22H37N5O6S‚1H2O)
C H N.
N2-[3S-(4-Acet a m id ob en zen esu lfon yla m in o)-4-(N-h y-
d r oxya m in o)-2R -isob u t ylsu ccin yl]-L -t er t -le u cin e -N 1-
m eth yla m id e (3b). To 17b (512 mg, 1 mmol) in DMF (8 mL)
were added EDCI (230 mg, 1.2 mmol), 2,6-lutidine (128 µL,
1.1 mmol), and tBuMe2SiONH2 (191 mg, 1.3 mmol). The
mixture was stirred at room temperature for 2 h. Addition of
1 N HCl (1 mL) to the crude mixture at the end of the reaction
and purification on C18 preparative HPLC using as eluant
methanol and water/1% AcOH (gradient from 0:100 to 40:60)
afforded 3b (335 mg, 63%) as a white solid: mp ) 272-274
1
17q: (520 mg, 88%) white solid; H NMR (DMSO-d6) 7.89
(m, 1H), 7.61 (m, 3H), 7.42 (d, 1H, J ) 9.9 Hz), 7.22 (d, 1H, J
) 8.4 Hz), 4.12 (d, 1H, J ) 9.5 Hz), 3.71 (dd, 1H, J ) 9.9 Hz,
J ′ ) 8.1 Hz), 3.29 (s, 3H), 2.94 (m, 2H), 2.83 (m, 1H), 2.59 (m,
2H), 2.57 (d, 3H, J ) 4.8 Hz), 1.50-1.25 (m, 2H), 0.99 (m, 1H),
0.89 (s, 9H), 0.76 (d, 3H, J ) 6.9 Hz), 0.75 (d, 3H, J ) 6.9 Hz);
MS (ESI) 561 (MNa+), 539 (MH+).
17r : (496 mg, 87%) solid; 1H NMR (DMSO-d6) 10.7 (s, 1H),
7.86 (m, 1H), 7.60-7.50 (m, 3H), 7.31 (d, 1H, J ) 9.9 Hz), 6.89
(d, 1H, J ) 8 Hz), 4.09 (d, 1H, J ) 9.5 Hz), 3.64 (m, 1H), 3.53
(s, 2H), 2.79 (m, 1H), 2.55 (d, 3H, J ) 4.4 Hz), 1.42-1.25 (m,
2H), 0.96 (m, 1H), 0.87 (s, 9H), 0.74 (d, 3H, J ) 6.9 Hz), 0.72
(d, 3H, J ) 6.9 Hz); MS (ESI) 533 (MNa+).
17s: (530 mg, 100%) white solid; 1H NMR (DMSO-d6 + CF3-
CO2D) 9.31 (d br, 1H, J ) 4.8 Hz), 9.07 (d, 1H, J ) 8.1 Hz),
8.71 (s br, 1H), 8.31 (d, 1H, J ) 8.1 Hz), 8.25 (d, 1H, J ) 8.1
Hz), 8.01 (dd, 1H, J ) 8.1 Hz, J ′ ) 4.8 Hz), 7.65 (d, 1H, J )
9.2 Hz, NH not exchanged), 4.12 (d, 1H, J ) 9.2 Hz), 3.86 (d,
1H, J ) 7.5 Hz), 2.88 (m, 1H), 2.56 (s, 3H), 1.5-1.3 (m, 1H),
1.01 (m, 1H), 0.86 (s, 9H), 0.74 (d, 3H, J ) 6.6 Hz), 0.71 (d,
3H, J ) 6.6 Hz); MS (ESI) 507 (MH+).
17t: (360 mg, 100%) solid; 1H NMR (DMSO-d6) 8.42 (d, 1H,
J ) 2.2 Hz), 8.24 (s, 1H), 8.07 (dd, 1H, J ) 8.5 Hz, J ′ ) 2.2
Hz), 7.9-7.75 (m, 3H), 7.56 (d br, 1H, J ) 9.2 Hz), 4.11 (d,
1H, J ) 9.2 Hz), 3.75 (t, 1H, J ) 8.8 Hz), 2.79 (m, 1H), 2.55
(d, 3H, J ) 4.4 Hz), 1.42 (m, 1H), 1.31 (m, 1H), 0.96 (m, 1H),
0.86 (s, 9H), 0.74 (d, 3H, J ) 6.6 Hz), 0.72 (d, 3H, J ) 6.6 Hz);
MS (ESI) 524 (MH+).
1
°C; H NMR (DMSO-d6) 10.73 (s, 1H), 10.31 (s, 1H), 8.83 (s,
1H), 7.90 (m, 1H), 7.73 (d, 2H, J ) 8.8 Hz), 7.67 (d, 2H, J )
8.8 Hz), 7.47 (m, 1H), 7.28 (d, 1H, J ) 9.5 Hz), 4.16 (d, 1H, J
) 9.2 Hz), 3.67 (m, 1H), 2.72 (m, 1H), 2.61 (d, 3H, J ) 4.4 Hz),
2.15 (s, 3H), 1.49 (m, 1H), 1.32 (m, 1H), 0.96 (m, 1H), 0.95 (s,
9H), 0.80 (d, 3H, J ) 6.2 Hz), 0.79 (d, 3H, J ) 6.2 Hz); MS
(ESI) 550 (MNa+). Anal. (C23H37N5O7S‚0.3H2O) C H N S.
Hydroxamic acids 3c, 3g-i, 3l-t, and 3w were obtained
using the protocole described above for 3b.
N2-[3S-(3,5-Dich lor ob en zen e-1-su lfon yla m in o)-4-(N-
h yd r oxya m in o)-2R-isob u t ylsu ccin yl]-L-ter t-leu cin e-N1-
m eth yla m id e (3c): (310 mg, 68%) white solid; mp ) 239-
1
242 °C; H NMR (DMSO-d6) 10.79 (s, 1H), 8.86 (s, 1H), 8.12
(d, 1H, J ) 9.5 Hz), 7.88 (m, 2H), 7.67 (s, 2H), 7.17 (d, 1H, J
) 9.5 Hz), 4.12 (d, 1H, J ) 9.5 Hz), 3.65 (t, 1H, J ) 9.5 Hz),
2.67 (m, 1H), 2.56 (d, 3H, J ) 4.4 Hz), 1.43 (m, 1H), 1.29 (m,
1H), 0.95 (m, 1H), 0.89 (s, 9H), 0.76 (d, 3H, J ) 6.6 Hz), 0.75
(d, 3H, J ) 6.6 Hz); MS (ESI) 563 (M{35Cl,37Cl}Na+), 561 (M-
{35Cl,35Cl}Na+). Anal. (C21H32Cl2N4O6S) C H N S.
N 2-[4-(N -H yd r oxya m in o)-2R -isob u t yl-3S -(1-m e t h yl
im id a zole-4-su lfon yla m in o)su ccin yl]-L-ter t-leu cin e-N1-
m eth yla m id e (3g): (265 mg, 46%) white solid. Obtained after
addition of water (2 mL) and acetic acid (1 mL) to the crude
mixture at the end of the reaction and purification on C18
preparative HPLC using as eluant methanol and water/1%
17u : trifluoroacetate salt (194 mg, 91%) solid; 1H NMR
(DMSO-d6) 8.73 (m, 2H), 7.90 (m, 1H), 7.73 (m, 3H), 7.28 (d
br, 1H, J ) 9.5 Hz), 4.16 (d, 1H, J ) 9.5 Hz), 3.90 (m, 1H),
3.50-3.13 (m, 4H), 2.98 (m, 1H), 2.58 (d, 3H, J ) 4 Hz), 1.50
(m, 2H), 1.26 (m, 1H), 0.91 (s, 9H), 0.86 (d, 3H, J ) 5.8 Hz),
0.84 (d, 3H, J ) 5.8 Hz); MS (ESI) 485 (MH+). Anal.
(C22H36N4O6S‚0.22AcOH‚2H2O) C H calcd 7.72 found 7.29, N
S. (An analytical sample of 17u was obtained by purification
on C18 HPLC eluting with MeOH/1% AcOH-water.)
1
AcOH (gradient from 0:100 to 40:60): mp ) 222-224 °C; H
NMR (DMSO-d6) 10.59 (s, 1H), 8.74 (s, 1H), 7.84 (m, 1H), 7.70
(s, 1H), 7.51 (s, 1H), 7.41 (d, 1H, J ) 9.2 Hz), 7.17 (d, 1H, J )
9.1 Hz), 4.14 (d, 1H, J ) 9.1 Hz), 3.67 (s, 3H), 3.62 (t, 1H, J )
8.8 Hz), 2.75 (m, 1H), 2.56 (d, 3H, J ) 4.4 Hz), 1.41 (m, 1H),
1.29 (m, 1H), 0.92 (s, 9H), 0.90 (m, 1H), 0.76 (d, 3H, J ) 6.2
Hz), 0.75 (d, 3H, J ) 6.2 Hz); MS (ESI) 497 (MNa+). Anal.
(C19H34N6O6S) C H calcd 7.22 found 7.65, N S.
1
17w : (292 mg, 98%) white solid; H NMR (DMSO-d6) 7.91
(m, 1H), 7.70 (d, 1H, J ) 9.5 Hz), 7.04 (d, 1H, J ) 9.5 Hz),
4.16 (d, 1H, J ) 9.2 Hz), 3.84 (dd, 1H, J ) 9.1 Hz, J ′ ) 7.3
Hz), 2.92 (m, 1H), 2.88 (s, 3H), 2.57 (d, 3H, J ) 4.4 Hz), 1.5-
1.1 (m, 3H), 0.91 (s, 9H), 0.85 (d, 3H, J ) 6.2 Hz), 0.83 (d, 3H,
J ) 6.2 Hz).
N2-[4-(N-Hyd r oxya m in o)-2R-isobu tyl-3S-(th iop h en e-2-
s u lfo n y la m in o )s u c c in y l]-L -t er t -le u c in e -N 1 -m e t h y l-
a m id e (3h ): (245 mg, 60%) white solid; mp ) 195-197 °C; 1H
NMR (DMSO-d6) 10.75 (s, 1H), 8.84 (s, 1H), 7.86 (m, 2H), 7.79
(m, 1H), 7.47 (d, 1H, J ) 4.0 Hz), 7.23 (m, 1H), 7.10 (t, 1H, J
) 4.0 Hz), 4.12 (d, 1H, J ) 9.1 Hz), 3.69 (d br, 1H, J ) 9.9
Hz), 2.71 (m, 1H), 2.56 (d, 3H, J ) 4.4 Hz), 1.46 (m, 1H), 1.29
(m, 1H), 0.93 (m, 1H), 0.91 (s, 9H), 0.76 (d, 3H, J ) 6.2 Hz),
0.75 (d, 3H, J ) 6.2 Hz); MS (ESI) 499 (MNa+). Anal.
(C19H32N4O6S2) C H N S.
N2-[4-(N-H yd r oxya m in o)-2R-isob u t yl-3S-(3-p yr id in e-
s u lfo n y la m in o )s u c c in y l]-L -t er t -le u c in e -N 1 -m e t h y l-
a m id e (3i): (315 mg, 94%) white solid; mp ) 228-231 °C; 1H
NMR (DMSO-d6) 10.75 (m, 1H), 8.86 (s, 1H), 8.81 (m, 1H), 8.76
(d, 1H, J ) 4.8 Hz), 8.04 (d, 1H, J ) 8 Hz), 7.96 (m, 1H), 7.87
(m, 1H), 7.56 (dd, 1H, J ) 8 Hz, J ′ ) 4.8 Hz), 7.20 (m, 1H),
4.10 (d, 1H, J ) 9.5 Hz), 3.69 (d br, 1H, J ) 9.9 Hz), 2.68 (m,
1H), 2.56 (d, 3H, J ) 4.8 Hz), 1.44 (m, 1H), 1.29 (m, 1H), 0.90
(m, 1H), 0.88 (s, 9H), 0.76 (d, 3H, J ) 6.6 Hz), 0.75 (d, 3H, J
) 6.6 Hz); MS (ESI) 494 (MNa+). Anal. (C20H33N5O6S‚0.5AcOH‚
0.7H2O) C H N S.
N2-[3S-Ben zen esu lfon yla m in o-4-(N-h yd r oxya m in o)-
2R-isobu tylsu ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (3a ).
To 17a (600 mg, 1.32 mmol) in DMF (10 mL) were added
sucessively HOBT (231 mg, 1.7 mmol), EDCI (324 mg, 1.7
mmol), and 2,6-lutidine (181 µL, 1.6 mmol). The mixture was
stirred at room temperature for 1 h. A solution of NH2OH‚
HCl (270 mg, 3.9 mmol) and 2,6-lutidine (453 µL, 3.9 mmol)
in DMF (1 mL) was added. The resulting solution was stirred
at room temperature for 18 h. The resulting mixture was
purified by C18 preparative HPLC using as eluant methanol
and water/1% AcOH (gradient from 0:100 to 45:55) to give 3a
(228 mg, 37%): mp ) 220-222 °C; 1H NMR (DMSO-d6) 10.74
(s, 1H), 8.82 (s, 1H), 7.89 (m, 1H), 7.75 (d, 2H, J ) 7.7 Hz),
7.67-7.52 (m, 4H), 7.27 (m, 1H), 4.12 (d, 1H, J ) 9.2 Hz), 3.70
(t br, 1H, J ) 9.2 Hz), 2.73 (m, 1H), 2.59 (d, 3H, J ) 4.4 Hz),
1.47 (m, 1H), 1.31 (m, 1H), 0.92 (m, 1H), 0.91 (s, 9H), 0.79 (d,
3H, J ) 5.9 Hz), 0.77 (d, 3H, J ) 5.9 Hz); MS (ESI) 493
(MNa+). Anal. (C21H34N4O6S) C H calcd 7.28 found 7.80, N S.
N 2 -[3S -(4-P y r id in e t h a n e s u lfo n y la m in o )-4-(N -h y -
d r oxya m in o)-2R -isob u t ylsu ccin yl]-L -t er t -le u cin e -N 1-
m eth yla m id e (3u ). Similarly to 3a , from 17t was obtained
3t (55 mg, 14%) as a white solid: mp ) 194-195 °C; 1H NMR
(DMSO-d6 + CD3CO2D) 8.48 (m, 2H), 7.34 (m, 2H), 4.15 (m,
1H), 3.64 (d, 1H, J ) 10.3 Hz), 3.21 (m, 1H), 3.03 (m, 2H),
2.91 (m, 1H), 2.75 (m, 1H), 2.56 (s, 3H), 1.54 (m, 1H), 1.34
N2-[4-(N-Hyd r oxya m in o)-2R-isobu tyl-3S-(n a p h th a len e-
2-su lfon yla m in o)su ccin yl]-L -t er t -le u cin e -N 1-m e t h yl-
a m id e (3l): (362 mg, 73%) white solid; mp ) 214-216 °C; 1H
NMR (DMSO-d6) 10.79 (s, 1H), 8.79 (s, 1H), 8.39 (s, 1H), 8.14-
8.06 (m, 3H), 7.89 (m, 1H), 7.78-7.68 (m, 4H), 7.27 (m, 1H),
4.13 (d, 1H, J ) 9.2 Hz), 3.76 (m, 1H), 2.75 (m, 1H), 2.60 (d,
3H, J ) 4.4 Hz), 1.46 (m, 1H), 1.30 (m, 1H), 0.92 (m, 1H), 0.90

4902 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Barlaam et al.
(s, 9H), 0.77 (d, 3H, J ) 7 Hz), 0.75 (d, 3H, J ) 7 Hz); MS
(ESI) 543 (MNa+). Anal. (C25H36N4O6S) C H calcd 6.97 found
7.44, N S.
(m, 1H), 0.85 (s, 9H), 0.74 (d, 3H, J ) 7 Hz), 0.72 (d, 3H, J )
7 Hz); MS (ESI) 522 (MH+). Anal. (C24H35N5O6S‚0.3H2O) C H
N S.
N2-[4-(N-Hyd r oxya m in o)-2R-isobu tyl-3S-(4-oxo-3,4-d i-
h yd r oqu in a zolin e-6-su lfon yla m in o)su ccin yl]-L-ter t-leu -
cin e-N1-m eth yla m id e (3t): (195 mg, 56%) solid; mp ) 248-
N2-[4-(N-Hydr oxya m in o)-2R-isobu tyl-3S-(n a p h th a len e-
1-su lfon yla m in o)su ccin yl]-L -t er t -le u cin e -N 1-m e t h yl-
a m id e (3m ): (342 mg, 62%) white solid; mp ) 162-170 °C;
1H NMR (DMSO-d6) 10.79 (s, 1H), 8.67-8.57 (m, 2H), 8.25-
8.05 (m, 3H), 7.92 (s br, 1H), 7.80-7.55 (m, 4H), 7.45 (m, 1H),
4.16 (d, 1H, J ) 9.2 Hz), 3.72 (d br, 1H, J ) 8.8 Hz), 2.75 (m,
1H), 2.60 (d, 3H, J ) 4.4 Hz), 1.35 (m, 1H), 1.20 (m, 1H), 0.92
(s, 9H), 0.91 (m, 1H), 0.70 (d, 3H, J ) 6.2 Hz), 0.65 (d, 3H, J
) 5.9 Hz); MS (ESI) 543 (MNa+). Anal. (C25H36N4O6S) C H N
calcd 10.76 found 10.27, S.
N2-[4-(N-Hyd r oxya m in o)-2R-isobu tyl-3S-(qu in olin e-8-
s u lfo n y la m in o )s u c c in y l]-L -t er t -le u c in e -N 1 -m e t h y l-
a m id e (3n ): (190 mg, 59%) white solid; mp ) 178-181 °C; 1H
NMR (DMSO-d6) 10.47 (m, 1H), 9.06 (m, 1H), 8.53-8.44 (m,
2H), 8.25-8.19 (m, 2H), 7.83-7.68 (m, 4H), 7.39 (m, 1H), 4.15
(d, 1H, J ) 9.2 Hz), 3.84 (m, 1H), 2.83 (m, 1H), 2.56 (d, 3H, J
) 4.8 Hz), 1.3-1.0 (m, 2H), 0.86 (s, 9H), 0.82 (m, 1H), 0.65 (d,
3H, J ) 6.6 Hz), 0.62 (d, 3H, J ) 6.6 Hz); MS (ESI) 544
(MNa+), 522 (MH+). Anal. (C24H35N5O6S‚0.25H2O) C H N.
1
250 °C; H NMR (DMSO-d6) 10.74 (s, 1H), 8.70 (m, 1H), 8.44
(s, 1H), 8.24 (s, 1H), 8.02 (dd, 1H, J ) 8.5 Hz, J ′ ) 2.2 Hz),
7.85 (m, 2H), 7.75 (d, 1H, J ) 8.5 Hz), 7.21 (d, 1H, J ) 9.5
Hz), 4.11 (d, 1H, J ) 9.2 Hz), 3.67 (m, 1H), 2.67 (m, 1H), 2.56
(d, 1H, J ) 4.4 Hz), 1.43 (m, 1H), 1.27 (m, 1H), 0.90 (m, 1H),
0.88 (s, 9H), 0.73 (m, 6H); MS (ESI) 539 (MH+). Anal.
(C23H34N6O7S‚0.5H2O) C H N S calcd 5.85 found 5.29.
N2-[4-(N-Hydr oxyam in o)-2R-isobu tyl-3S-m eth an esu lfo-
n yla m in osu ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (3w ):
1
(230 mg, 83%) solid; mp ) 169-171 °C; H NMR (DMSO-d6)
10.9 (m, 1H), 9.09 (m, 1H), 7.88 (m, 1H), 7.30 (d, 1H, J ) 9.2
Hz), 7.15 (m, 1H), 4.16 (d, 1H, J ) 9.2 Hz), 3.61 (d, 1H, J )
9.9 Hz), 2.77 (s, 3H), 2.73 (m, 1H), 2.57 (d, 3H, J ) 4.4 Hz),
1.50 (m, 1H), 1.33 (m, 1H), 0.93 (s, 9H), 0.90 (m, 1H), 0.79 (d,
6H, J ) 6.6 Hz); MS (ESI) 431 (MNa+). Anal. (C16H32N4O6S)
C H N calcd 13.71 found 13.30, S calcd 7.85 found 7.40.
N 2-[3S -(2-Cya n ob e n ze n e -1-su lfon yla m in o)-4-(N -h y-
d r oxya m in o)-2R -isob u t ylsu ccin yl]-L -t er t -le u cin e -N 1-
m eth yla m id e (3d ). Acid 17d (380 mg, 0.79 mmol), tBuMe2-
SiONH2 (175 mg, 1.19 mmol), and 2-ethoxy-1-ethoxycarbonyl-
1,2-dihydroquinoline (254 mg, 1.03 mmol) in CHCl3 (5 mL)
were stirred for 18 h. Evaporation of the solvents, partitioning
between Et2O and water, and filtration of the resulting solid
afforded 3d (202 mg, 52%) as a white solid: mp ) 200-205
°C; 1H NMR (DMSO-d6) 10.57 (s, 1H), 8.67 (s, 1H), 8.04-7.76
(m, 6H), 7.56 (d, 1H, J ) 9.2 Hz), 4.18 (d, 1H, J ) 9.2 Hz),
3.67 (t, 1H, J ) 9.6 Hz), 2.84 (m, 1H), 2.58 (d, 3H, J ) 4.4
Hz), 1.46 (m, 1H), 1.30 (m, 1H), 0.93 (s, 9H), 0.91 (m, 1H),
0.77 (d, 3H, J ) 6 Hz), 0.75 (d, 3H, J ) 6 Hz); MS (ESI) 518
(MNa+). Anal. (C22H33N5O6S) C H N.
N2-[4-(N-Hyd r oxya m in o)-2R-isobu tyl-3S-(E-â-styr en e-
s u lfo n y la m in o )s u c c in y l]-L -t er t -le u c in e -N 1 -m e t h y l-
a m id e (3v). To amine 23 (450 mg, 0.93 mmol) in CH2Cl2 (15
mL) were added pyridine (2 mL) and E-â-styrenesulfonyl
chloride (285 mg, 1.4 mmol). The mixture was stirred at room
temperature for 18 h. The mixture was diluted with EtOAc,
washed with water and brine, and dried over MgSO4. After
evaporation of the solvents, trituration of the residue with
Et2O afforded the protected hydroxamate (421 mg, 70%) as a
yellowish solid: MS (ESI) 647 (MH+). This compound in 5%
TFA/CH2Cl2 (15 mL) was stirred for 15 min. After evaporation
of the solvent, the residue was triturated with methanol (15
mL) and filtered. Purification of the filtrates on a C18 silica
cartridge (methanol/water 1:1) afforded 3v (217 mg, 74%) as
a solid: mp ) 242-243 °C (decomposition); 1H NMR (DMSO-
d6) 10.82 (s, 1H), 9.01 (s br, 1H), 7.88 (m, 1H), 7.60 (m, 2H),
7.50-7.30 (m, 6H), 6.83 (d, 1H, J ) 15.3 Hz), 4.18 (d, 1H, J )
9.6 Hz), 3.61 (t, 1H, J ) 9.6 Hz), 2.76 (m, 1H), 2.57 (d, 3H, J
) 4.4 Hz), 1.50 (m, 1H), 1.32 (m, 1H), 0.93 (m, 1H), 0.92 (s,
9H), 0.79 (m, 6H); MS (ESI) 497 (MH+). Anal. (C23H36N4O6S‚
0.8H2O) C H N.
N2-[4-(N-Hyd r oxya m in o)-2R-isobu tyl-3S-(isoqu in olin e-
5-su lfon yla m in o)su ccin yl]-L -t er t -le u cin e -N 1-m e t h yl-
a m id e (3o): (204 mg, 46%) white solid; mp ) 208-210 °C; 1H
NMR (DMSO-d6) 10.60 (s, 1H), 9.45 (s, 1H), 8.71 (d, 1H, J )
6.3 Hz), 8.57 (s, 1H), 8.39 (d, 1H, J ) 7.7 Hz), 8.33 (d, 1H, J
) 6.3 Hz), 8.27 (d, 1H, J ) 7.7 Hz), 7.99 (d, 1H, J ) 8.8 Hz),
7.90 (m, 1H), 7.76 (t, 1H, J ) 7.7 Hz), 7.35 (d, 1H, J ) 9.1
Hz), 4.14 (d, 1H, J ) 9.1 Hz), 3.69 (m, 1H), 2.70 (m, 1H), 2.56
(d, 3H, J ) 4.4 Hz), 1.41 (m, 1H), 1.23 (m, 1H), 0.90 (m, 1H),
0.89 (s, 9H), 0.71 (d, 3H, J ) 6.6 Hz), 0.67 (d, 3H, J ) 6.6 Hz);
MS (ESI) 522 (MH+). Anal. (C24H35N5O6S‚0.3H2O) C H N S.
N2-[4-(N-Hyd r oxya m in o)-2R-isobu tyl-3S-(4-oxo-3,4-d i-
h yd r oqu in a zolin e-8-su lfon yla m in o)su ccin yl]-L-ter t-leu -
cin e-N1-m eth yla m id e (3p ): (158 mg, 64%) solid; mp ) 212-
1
214 °C; H NMR (DMSO-d6) 10.44 (s, 1H), 8.48 (s, 1H), 8.31
(d, 1H, J ) 7.9 Hz), 8.24 (s, 1H), 8.16 (d, 1H, J ) 7.9 Hz), 7.84
(m, 1H), 7.76 (d, 1H, J ) 9.5 Hz), 7.59 (t, 1H, J ) 7.9 Hz),
7.14 (d, 1H, J ) 9.9 Hz), 4.17 (d, 1H, J ) 9.2 Hz), 3.76 (m,
1H), 2.56 (d, 3H, J ) 4.4 Hz), 1.35 (m, 1H), 1.25 (m, 1H), 0.90
(m, 1H), 0.89 (s, 9H), 0.71 (m, 6H); MS (ESI) 539 (MH+). Anal.
(C23H34N6O7S‚0.3H2O) C H N calcd 15.45 found 15.02.
N2-[4-(N-H yd r oxya m in o)-2R-isob u t yl-3S-(1-m et h yl-2-
oxo-1,2,3,4-tetr a h yd r oqu in olin e-6-su lfon yla m in o)su cci-
n yl]-L-ter t-leu cin e-N1-m eth yla m id e (3q): (322 mg, 63%)
1
white solid; mp ) 260-262 °C; H NMR (DMSO-d6) 10.72 (s,
1H), 8.76 (s, 1H), 7.85 (m, 1H), 7.57 (m, 2H), 7.42 (m, 1H),
7.25 (d, 1H, J ) 8.8 Hz), 7.17 (d, 1H, J ) 8.4 Hz), 4.12 (d, 1H,
J ) 9.1 Hz), 3.63 (m, 1H), 3.29 (s, 3H), 2.92 (m, 2H), 2.69 (m,
1H), 2.59 (m, 2H), 2.56 (d, 3H, J ) 4.4 Hz), 1.44 (m, 1H), 1.28
(m, 1H), 0.91 (s, 9H), 0.90 (m, 1H), 0.76 (d, 3H, J ) 6.6 Hz),
0.74 (d, 3H, J ) 6.6 Hz); MS (ESI) 576 (MNa+). Anal.
(C25H39N5O7S‚0.3H2O) C H N S.
N2-[4-(N-H yd r oxya m in o)-2R-isob u t yl-3S-(oxin d ole-5-
s u lfo n y la m in o )s u c c in y l]-L -t er t -le u c in e -N 1 -m e t h y l-
a m id e (3r ): (228 mg, 47%) white solid; mp ) 232-234 °C; 1H
NMR (DMSO-d6) 10.75 (s, 1H), 10.69 (s, 1H), 8.76 (s, 1H), 7.85
(m, 1H), 7.55 (d, 1H, J ) 8 Hz), 7.52 (s, 1H), 7.32 (m, 1H),
7.25 (m, 1H), 6.86 (d, 1H, J ) 8 Hz), 4.11 (d, 1H, J ) 9.1 Hz),
3.59 (m, 1H), 3.53 (s, 2H), 2.68 (m, 1H), 2.56 (d, 3H, J ) 4.8
Hz), 1.41 (m, 1H), 1.27 (m, 1H), 0.90 (s, 9H), 0.85 (m, 1H),
0.74 (d, 3H, J ) 6.6 Hz), 0.73 (d, 3H, J ) 6.6 Hz); MS (ESI)
548 (MNa+). Anal. (C23H35N5O7S‚0.6H2O) C H N S.
N2-[4-(N-Hyd r oxya m in o)-2R-isobu tyl-3S-(qu in olin e-6-
s u lfo n y la m in o )s u c c in y l]-L -t er t -le u c in e -N 1 -m e t h y l-
a m id e (3s): (204 mg, 40%) white solid; mp ) 248-250 °C; 1H
NMR (DMSO-d6) 10.76 (s, 1H), 9.05 (m, 1H), 8.74 (s, 1H), 8.54
(d, 1H, J ) 9.1 Hz), 8.43 (s, 1H), 8.12 (d, 1H, J ) 9.1 Hz), 7.97
(d, 1H, J ) 9.1 Hz), 7.83 (m, 2H), 7.68 (m, 1H), 7.22 (d, 1H, J
) 9.1 Hz), 4.11 (d, 1H, J ) 9.1 Hz), 3.73 (m, 1H), 2.70 (m, 1H),
2.56 (d, 3H, J ) 4.4 Hz), 1.45 (m, 1H), 1.27 (m, 1H), 0.89
Sulfonamides 3e-f and 3j-k were obtained by solid phase
synthesis.24
N2-[3S-(2-Ch lor o-4-flu or oben zen e-1-su lfon yla m in o)-4-
(N-h yd r oxya m in o)-2R-isob u t ylsu ccin yl]-L-ter t-leu cin e-
N1-m eth yla m id e (3e): 15 mg; MS (ESI) 525 (M{37Cl}H+), 523
(M{35Cl}H+); HPLC tR 8.0 min.
N2-[4-(N-H yd r oxya m in o)-2R-isob u t yl-3S-(2,4,6-t r iiso-
p r op ylben zen e-1-su lfon yla m in o)su ccin yl]-L-ter t-leu cin e-
N1-m eth yla m id e (3f): 22.3 mg; MS (ESI) 597 (MH+); HPLC
tR 12.6 min.
N2-[3S-(4-Ca r b oxyben zen e-1-su lfon yla m in o)-4-(N-h y-
d r oxya m in o)-2R -isob u t ylsu ccin yl]-L -t er t -le u cin e -N 1-
m eth yla m id e (3j): 13.5 mg; MS (ESI) 515 (MH+); HPLC tR
6.6 min.
N 2-[3S -(4-Br om ob e n ze n e -1-su lfon yla m in o)-4-(N -h y-
d r oxya m in o)-2R -isob u t ylsu ccin yl]-L -t er t -le u cin e -N 1-

MMP/ TNFR Convertase Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4903
m eth yla m id e (3k ): 11.8 mg; MS (ESI) 551 (M{81Br}H+), 549
(M{79Br}H+); HPLC tR 8.8 min.
7.55 (m, 1H), 5.13 (d, 1H, J ) 7.7 Hz), 4.11 (d, 1H, J ) 9.2
Hz), 3.4-3.3 (m, 2H), 3.10 (m, 1H), 2.56 (d, 3H, J ) 4.4 Hz),
1.7-1.4 (m, 4H), 1.17 (m, 1H), 0.87 (s, 9H), 0.86 (d, 3H, J )
6.6 Hz), 0.79 (d, 3H, J ) 6.6 Hz), 0.68 (t, 3H, J ) 7.3 Hz); MS
(ESI) 549 (MH+).
N2-[3S-(N-Ben zen esu lfon yl-N-m eth yla m in o)-4-ter t-bu -
t yloxy-2R-isob u t ylsu ccin yl]-L-ter t-le u cin e -N1-m e t h yl-
a m id e (20a ). To 16a (511 mg, 1 mmol) in acetone (10 mL)
were added K2CO3 (207 mg, 1.5 mmol) and MeI (1 mL, 15
mmol). The mixture was stirred at room temperature for 18
h, diluted with EtOAc, and washed with water and brine. The
organic layers were dried over MgSO4, and the solvents were
removed in vacuo to give 20a (460 mg, 88%) as a yellowish
solid: 1H NMR (CDCl3) 7.83 (d, 2H, J ) 7.4 Hz), 7.6-7.45 (m,
3H), 6.25 (d br, 1H, J ) 8.8 Hz), 6.00 (m, 1H), 4.62 (d, 1H, J
) 9.6 Hz), 4.17 (d, 1H, J ) 8.8 Hz), 2.93 (s, 3H), 2.91 (m, 1H),
2.80 (d, 3H, J ) 4.8 Hz), 1.75-1.5 (m, 2H), 1.23 (s, 9H), 1.1
(m, 1H), 1.01 (s, 9H), 0.90 (d, 3H, J ) 6.6 Hz), 0.88 (d, 3H, J
) 6.6 Hz); MS (ESI) 548 (MNa+).
1
21d : (286 mg, 98%) white solid; H NMR (DMSO-d6) 8.94
(m, 1H), 8.44 (d, 1H, J ) 8.2 Hz), 8.07 (d, 1H, J ) 8.2 Hz),
7.93 (m, 1H), 7.76 (d br, 1H, J ) 9.2 Hz), 7.64 (m, 2H), 7.32 (t,
1H, J ) 8.2 Hz), 7.06-6.80 (m, 5H), 5.43 (d, 1H, J ) 7.4 Hz),
5.00 (d, 1H, J ) 15.4 Hz), 4.59 (d, 1H, J ) 15.4 Hz), 4.16 (d,
1H, J ) 9.2 Hz), 3.17 (m, 1H), 2.57 (d, 3H, J ) 4.4 Hz), 1.64
(m, 1H), 1.37 (m, 1H), 1.16 (m, 1H), 0.97 (s, 9H), 0.77 (d, 3H,
J ) 6.6 Hz), 0.73 (d, 3H, J ) 6.6 Hz); MS (ESI) 597 (MH+).
N2-[3S-(N-Ben zen esu lfon yl-N-m et h yla m in o)-4-(N-h y-
d r oxya m in o)-2R -isob u t ylsu ccin yl]-L -t er t -le u cin e -N 1-
m eth yla m id e (22a ). According to the procedure described for
3d , from 21a was obtained 22a (202 mg; 58%) as a white
N2-[4-ter t-Bu tyloxy-2R-isobu tyl-3S-(N-m eth yl-N-(qu in -
olin e-8-su lfon yl)a m in o)su ccin yl]-L-ter t-leu cin e-N1-m eth -
yla m id e (20b). Similarly from 16n was obtained 20b (429 mg,
93%) as a yellowish solid: 1H NMR (CDCl3) 9.03 (m, 1H), 8.51
(d br, 1H, J ) 7.3 Hz), 8.22 (d br, 1H, J ) 8.4 Hz), 8.03 (d br,
1H, J ) 8.4 Hz), 7.63 (dd, 1H, J ) 8.4 Hz, J ′ ) 7.3 Hz), 7.50
(dd, 1H, J ) 8.4 Hz, J ′ ) 4 Hz), 6.39 (d br, 1H, J ) 8.4 Hz),
6.19 (m, 1H), 4.86 (d, 1H, J ) 9.5 Hz), 4.16 (d, 1H, J ) 8.4
Hz), 3.32 (s, 3H), 3.07 (m, 1H), 2.83 (d, 3H, J ) 4.8 Hz), 1.75-
1.5 (m, 2H), 1.2 (m, 1H), 1.07 (s, 9H), 0.90 (d, 3H, J ) 6.6 Hz),
0.88 (d, 3H, J ) 6.6 Hz), 0.81 (s, 9H); MS (ESI) 599 (MNa+).
N2-[4-ter t-Bu tyloxy-2R-isobu tyl-3S-(N-p r op yl-N-(qu in -
olin e-8-su lfon yl)a m in o)su ccin yl]-L-ter t-leu cin e-N1-m eth -
yla m id e (20c). Similarly, except that the reaction mixture
was heated at 40 °C for 72 h, KI (1 equiv) was added, and
acetone was replaced by DMF, from 16n and propyl bromide
was obtained 20c (200 mg, 42%): 1H NMR (CDCl3) 9.02 (m,
1H), 8.52 (d br, 1H, J ) 7.3 Hz), 8.22 (d br, 1H, J ) 8.4 Hz),
8.03 (d br, 1H, J ) 8.4 Hz), 7.64 (dd, 1H, J ) 8.4 Hz, J ′ ) 7.3
Hz), 7.50 (dd, 1H, J ) 8.4 Hz, J ′ ) 4 Hz), 6.65 (m, 1H), 6.27
(m, 1H), 4.92 (d br, 1H, J ) 9.5 Hz), 4.17 (d, 1H, J ) 9.2 Hz),
3.93 (m, 1H), 3.52 (m, 1H), 3.13 (m, 1H), 2.82 (d, 3H, J ) 4.8
Hz), 1.8-0.8 (m, 14H), 1.08 (s, 9H), 0.89 (s, 9H); MS (ESI) 605
(MH+).
N2-[3S-(N-Ben zyl-N-(q u in olin e-8-su lfon yl)a m in o)-4-
t er t -b u t yloxy-2R -isob u t ylsu ccin yl]-L-t er t -le u cin e -N 1-
m eth yla m id e (20d ). Similarly, except that KI (1 equiv) was
added and the reaction was refluxed for 2 h, from 16n and
benzyl bromide was obtained 20d (353 mg, 62%): 1H NMR
(CDCl3) 9.01 (m, 1H), 8.20 (d br, 1H, J ) 8 Hz), 8.13 (d, 1H, J
) 8 Hz), 7.94 (d, 1H, J ) 8 Hz), 7.50 (dd, 1H, J ) 8 Hz, J ′ )
4.6 Hz), 7.42 (t, 1H, J ) 8 Hz), 7.30-7.05 (m, 5H), 6.50 (m,
1H), 6.05 (m, 1H), 5.42 (d, 1H, J ) 15.8 Hz), 5.22 (d, 1H, J )
7.4 Hz), 4.73 (d, 1H, J ) 15.8 Hz), 4.11 (d, 1H, J ) 9.2 Hz),
2.98 (m, 1H), 2.78 (d, 3H, J ) 4.7 Hz), 1.65 (m, 1H), 1.43 (m,
1H), 1.15 (m, 1H), 1.07 (s, 18H), 0.80 (d, 3H, J ) 6.6 Hz), 0.76
(d, 3H, J ) 6.6 Hz); MS (ESI) 653 (MH+).
1
solid: mp ) 209-211 °C; H NMR (DMSO-d6) 10.88 (s, 1H),
8.84 (s, 1H), 7.94 (d, 1H, J ) 9.2 Hz), 7.85 (m, 1H), 7.75 (d,
2H, J ) 8 Hz), 7.64 (m, 1H), 7.55 (m, 2H), 4.35 (d, 1H, J ) 11
Hz), 4.14 (d, 1H, J ) 9.2 Hz), 3.16 (m, 1H), 2.91 (s, 3H), 2.57
(d, 3H, J ) 4.4 Hz), 1.47 (m, 1H), 1.38 (m, 1H), 0.85 (m, 13H),
0.79 (d, 3H, J ) 6.6 Hz); MS (ESI) 507 (MNa+). Anal.
(C22H36N4O6S‚1H2O) C H N.
According to the protocol described for 3b, 21b-d were
converted to hydroxamic acids 22b-d .
N2-[4-(N-Hyd r oxya m in o)-2R-isobu tyl-3S-(N-m eth yl-N-
(qu in olin e-8-su lfon yl)a m in o)su ccin yl]-L-ter t-leu cin e-N1-
m eth yla m id e (22b): (250 mg, 61%) mp ) 166-168 °C; 1H
NMR (DMSO-d6) 10.54 (s, 1H), 9.03 (m, 1H), 8.48 (m, 1H),
8.29 (d, 1H, J ) 7.3 Hz), 8.22 (d, 1H, J ) 8.4 Hz), 7.92 (d, 1H,
J ) 9.2 Hz), 7.82 (m, 1H), 7.66 (m, 3H), 4.40 (d, 1H, J ) 10.7
Hz), 4.14 (d, 1H, J ) 9.1 Hz), 3.32 (s, 3H), 3.18 (m, 1H),
2.56 (d, 3H, J ) 4 Hz), 1.45 (m, 1H), 1.36 (m, 1H), 0.90 (m,
1H), 0.88 (s, 9H), 0.84 (d, 3H, J ) 6.6 Hz), 0.77 (d, 3H, J ) 6.6
Hz); MS (ESI) 558 (MNa+). Anal. (C25H37N5O6S‚0.2H2O) C H
N S.
N2-[4-(N-Hyd r oxya m in o)-2R-isobu tyl-3S-(N-p r op yl-N-
(qu in olin e-8-su lfon yl)a m in o)su ccin yl]-L-ter t-leu cin e-N1-
m eth yla m id e (22c): (42 mg, 41%) white solid; mp ) 148-
1
150 °C; H NMR (DMSO-d6) 10.6 (s, 1H), 9.01 (m, 1H), 8.72
(m, 1H), 8.48 (m, 1H), 8.31 (d, 1H, J ) 8.1 Hz), 8.23 (d, 1H, J
) 8.1 Hz), 7.67 (m, 4H), 4.53 (d, 1H, J ) 10.2 Hz), 3.99 (d, 1H,
J ) 8.8 Hz), 3.72 (m, 1H), 3.59 (m, 1H), 3.15 (m, 1H), 2.56 (d,
3H, J ) 4.8 Hz), 1.65-1.3 (m, 4H), 0.87-0.70 (m, 19H); MS
(ESI) 564 (MH+). Anal. (C27H41N5O6S‚0.55H2O) C H N S.
N2-[3S-(N-Ben zyl-N-(qu in olin e-8-su lfon yl)a m in o)-4-(N-
h yd r oxya m in o)-2R-isob u t ylsu ccin yl]-L-ter t-leu cin e-N1-
m eth yla m id e (22d ): (76 mg, 28%) white solid; mp ) 149-
1
154 °C; H NMR (DMSO-d6) 11.03 (s, 1H), 9.04 (m, 1H), 8.39
(m, 1H), 7.97 (d, 1H, J ) 8.4 Hz), 7.84 (m, 1H), 7.65-7.5 (m,
4H), 7.20 (m, 1H), 6.9-6.6 (m, 5H), 5.28 (d, 1H, J ) 14.3 Hz),
4.96 (d, 1H, J ) 9.5 Hz), 4.65 (d, 1H, J ) 14.3 Hz), 4.13 (d,
1H, J ) 8.5 Hz), 3.26 (m, 1H), 2.57 (d, 3H, J ) 4 Hz), 1.62 (m,
1H), 1.41 (m, 1H), 1.05 (s, 9H), 1.0 (m, 1H), 0.86 (d, 3H, J )
6.6 Hz), 0.82 (d, 3H, J ) 6.6 Hz); MS (ESI) 634 (MNa+). Anal.
(C31H41N5O6S‚1.3H2O) C H N.
N2-[3S-(N-Ben zen esu lfon yl-N-m eth ylam in o)-4-h ydr oxy-
2R-isobu tylsu ccin yl]-L-ter t-leu cin e-N1-m eth ylam ide (21a).
According to the method described for 17a , from 20a was
obtained 21a (676 mg, 98%): 1H NMR (DMSO-d6) 7.99 (d, 1H,
J ) 9.2 Hz), 7.89 (m, 1H), 7.71 (d, 2H, J ) 8.1 Hz), 7.65-7.50
(m, 3H), 4.46 (d, 1H, J ) 11 Hz), 4.15 (d, 1H, J ) 9.2 Hz), 3.08
(m, 1H), 2.88 (s, 3H), 2.56 (d, 3H, J ) 4.4 Hz), 1.50 (m, 1H),
1.35 (m, 1H), 0.85 (s, 9H), 0.84 (m, 4H), 0.77 (d, 3H, J ) 6.6
Hz); MS (ESI) 492 (MNa+), 470 (MH+).
N2-[4-(N-Hyd r oxya m in o)-2R-isobu tyl-3S-(8-qu in olin e-
ca r b oxa m id o)su ccin yl]-L-ter t-leu cin e-N1-m et h yla m id e
(4a ). A solution of 15 (428 mg, 1.16 mmol), 8-quinoline
carboxylic acid (261 mg, 1.5 mmol), HOBT (216 mg, 1.6 mmol),
N-methyl morpholine (300 µL, 2.7 mmol), and EDCI (305 mg,
1.6 mmol) in DMF (8 mL) was stirred for 18 h. The mixture
was diluted with EtOAc, washed with 5% NaHCO3 and brine,
and dried over MgSO4. Chromatography on silica gel (eluant:
EtOAc/petroleum ether 7:3) gave 18a (562 mg, 92%) as a white
foam: 1H NMR (CDCl3) 9.00 (m, 1H), 8.82 (d br, 1H, J ) 8
Hz), 8.26 (d br, 1H, J ) 8 Hz), 7.97 (d br, 1H, J ) 8 Hz), 7.67
(t, 1H, J ) 8 Hz), 7.47 (dd, 1H, J ) 8 Hz, J ′ ) 4 Hz), 6.57 (m,
1H), 5.93 (m, 1H), 5.10 (dd, 1H, J ) 8.1 Hz, J ′ ) 4.4 Hz), 4.22
(d, 1H, J ) 9.2 Hz), 3.07 (m, 1H), 2.73 (d, 3H, J ) 4.8 Hz),
1.8-1.4 (m, 3H), 1.48 (s, 9H), 0.96 (s, 9H), 0.88 (d, 3H, J ) 6.2
Hz), 0.87 (d, 3H, J ) 6.2 Hz); MS (ESI) 527 (MH+). 18a was
converted to acid 19a (487 mg, 97%) using the same method
Similarly, the following compounds were obtained.
1
21b: (427 mg, 99%) white solid; H NMR (DMSO-d6) 8.98
(m, 1H), 8.50 (d br, 1H, J ) 8.4 Hz), 8.32 (d br, 1H, J ) 8.4
Hz), 8.26 (d br, 1H, J ) 8.4 Hz), 7.90 (m, 1H), 7.81 (d br, 1H,
J ) 9.2 Hz), 7.74-7.65 (m, 2H), 4.78 (d, 1H, J ) 9.9 Hz), 4.18
(d, 1H, J ) 9.2 Hz), 3.14 (s, 3H), 3.10 (m, 1H), 2.57 (d, 3H, J
) 4.4 Hz), 1.57 (m, 1H), 1.38 (m, 1H), 1.02 (m, 1H), 0.91 (s,
9H), 0.85 (d, 3H, J ) 6.2 Hz), 0.79 (d, 3H, J ) 6.2 Hz); MS
(ESI) 521 (MH+).
1
21c: (121 mg, 79%) white solid; H NMR (DMSO-d6) 8.94
(m, 1H), 8.49 (d br, 1H, J ) 8.4 Hz), 8.34 (d br, 1H, J ) 8.4
Hz), 8.24 (d br, 1H, J ) 8.4 Hz), 7.90 (m, 1H), 7.70 (m, 2H),

4904 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Barlaam et al.
described for 17a . 19a : 1H NMR (CDCl3) 9.10 (m, 1H), 8.68
(d, 1H, J ) 7.3 Hz), 8.40 (d, 1H, J ) 8.7 Hz), 8.07 (d, 1H, J )
8 Hz), 7.74 (dd, 1H, J ) 8 Hz, J ′ ) 7.3 Hz), 7.61 (dd, 1H, J )
8.7 Hz, J ′ ) 4.4 Hz), 7.30 (m, 1H), 5.97 (m, 1H), 5.00 (m, 1H),
4.28 (d, 1H, J ) 9.5 Hz), 3.35 (m, 1H), 2.84 (d, 3H, J ) 4.8
Hz), 1.75-1.45 (m, 3H), 1.01 (s, 9H), 0.86 (d, 3H, J ) 5.8 Hz),
0.85 (d, 3H, J ) 5.8 Hz); MS (ESI) 471 (MH+). Anal.
(C25H34N4O5‚0.3H2O‚0.9CF3CO2H) C H N. Using the procedure
described for 2h , from 19a was obtained 4a (173 mg, 75%) as
a white solid: mp ) 147-155 °C; 1H NMR (DMSO-d6) 9.14
(m, 1H), 8.56 (m, 2H), 8.20 (d, 1H, J ) 7 Hz), 7.91 (d, 1H, J )
9.5 Hz), 7.80-7.65 (m, 3H), 4.65 (t, 1H, J ) 9.2 Hz), 4.08 (d,
1H, J ) 9.5 Hz), 3.19 (m, 1H), 1.57 (m, 1H), 1.41 (m, 1H), 1.11
(m, 1H), 0.90 (d, 3H, J ) 6.6 Hz), 0.83 (d, 3H, J ) 6.6 Hz),
0.46 (s, 9H); MS (EI) 485 (M+•). Anal. (C25H35N5O5‚1H2O‚1CF3-
CO2H) C H N.
8-carboxaldehyde (100 mg, 0.64 mmol) in methanol (10 mL)
was added NaBH3CN (14 mg, 0.22 mmol) and AcOH (2 drops).
The mixture was stirred for 30 min, diluted with EtOAc,
washed with 5% NaHCO3 and brine, and dried over MgSO4.
Evaporation of the solvent gave the corresponding amine (330
mg, 100%): 1H NMR (DMSO-d6) 11.21 (s br, 1H), 8.88 (m, 1H),
8.34 (d br, 1H, J ) 8 Hz), 7.80 (m, 3H), 7.66 (d br, 1H, J ) 9.5
Hz), 7.51 (m, 2H), 7.24 (d, 1H, J ) 8 Hz), 6.56 (s br, 1H), 6.40
(d br, 1H, J ) 8 Hz), 4.75 (s, 2H), 4.34 (m, 1H), 4.19 (d, 1H, J
) 9.5 Hz), 4.04 (m, 1H), 3.78 (s, 3H), 3.73 (s, 3H), 3.08 (m,
1H), 2.76 (m, 1H), 2.55 (d, 3H, J ) 4.8 Hz), 1.49 (m, 1H), 1.35
(m, 1H), 0.9-0.8 (m, 4H), 0.81 (s, 9H), 0.77 (d, 3H, J ) 6.9
Hz). This amine was deprotected using the method described
for 3v to give 5c (118 mg, 48%) after purification on C18
preparative HPLC (eluant MeOH/0.2% aqueous ammonium
1
carbonate from 0:100 to 60:40): mp ) 176-178 °C; H NMR
Amides 4b-f were obtained by solid phase synthesis.24
4b: 27 mg; MS (ESI) 486 (MH+); HPLC tR 6.7 min.
(DMSO-d6) 10.75 (s, 1H), 8.99 (s, 1H), 8.89 (m, 1H), 8.36 (d
br, 1H, J ) 8.4 Hz), 7.82 (m, 3H), 7.67 (d br, 1H, J ) 9.6 Hz),
7.60-7.5 (m, 2H), 4.36 (m, 1H), 4.21 (d, 1H, J ) 9.6 Hz), 3.99
(m, 1H), 3.13 (m, 1H), 2.80 (m, 1H), 2.56 (d, 3H, J ) 4.4 Hz),
1.50 (m, 1H), 1.34 (m, 1H), 0.95 (m, 1H), 0.83 (m, 15H); MS
(ESI) 472 (MH+). Anal. (C25H37N5O4 0.7H2O) C H N.
4c: 21 mg; MS (ESI) 436 (MH+); HPLC tR 5.8 min.
4d : 14.7 mg; MS (ESI) 435 (MH+); HPLC tR 7.7 min.
4e: 22.6 mg; MS (ESI) 485 (MH+); HPLC tR 9.5 min.
4f: 18.2 mg; MS (ESI) 373 (MH+); HPLC tR 5.1 min.
Compounds 5d -g were made on solid phase.24
N2-[4-(N-Hyd r oxya m in o)-2R-isobu tyl-3S-m or p h olin o-
su ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (5a ). A solution
of 15 (500 mg, 1.35 mmol), 2-iodoethyl ether (1.76 g, 5.4 mmol),
and iPr2EtN (700 µL, 4.1 mmol) in DMF (5 mL) was stirred at
room temperature in the dark for 8 days. The mixture was
diluted with EtOAc, washed with water, and dried over
MgSO4. Purification on silica gel (EtOAc/CH2Cl2 3:1) afforded
the corresponding morpholine contaminated with traces of
2-iodoethyl ether (500 mg, 84%): 1H NMR (CDCl3) 6.63 (d br,
1H, J ) 9.2 Hz), 5.80 (m, 1H), 4.23 (d, 1H, J ) 9.2 Hz), 3.64
(m, 4H), 3.25 (d, 1H, J ) 11.7 Hz), 2.81 (d, 3H, J ) 4.8 Hz),
2.78-2.70 (m, 3H), 2.55-2.50 (m, 2H), 1.7-1.4 (m, 2H), 1.50
(s, 9H), 1.06 (m, 1H), 1.03 (s, 9H), 0.89 (d, 3H, J ) 6.2 Hz),
0.85 (d, 3H, J ) 6.2 Hz). According to the procedure described
for 16a , this compound was converted to the carboxylic acid:
1H NMR (DMSO-d6 + CF3CO2D) 8.29 (d br, 1H, J ) 9.2 Hz,
NH not exchanged), 4.20 (d, 1H, J ) 9.2 Hz), 3.99 (m, 1H),
3.84 (m, 4H), 3.25 (m, 5H), 2.56 (s, 3H), 1.65 (m, 1H), 1.39 (m,
1H), 1.15 (m, 1H), 0.93 (s, 9H), 0.84 (d, 3H, J ) 6.4 Hz), 0.80
(d, 3H, J ) 6.4 Hz); MS (ESI) 386 (MH+). Anal. (C19H35N3O5
0.8H2O) C H N. According to the method described for 3a , this
acid was converted to hydroxamic acid 5a (120 mg, 22%): mp
) 195-200 °C; 1H NMR (DMSO-d6) 10.52 (s, 1H), 8.85 (s, 1H),
7.88 (q, 1H, J ) 4.4 Hz), 7.83 (d, 1H, J ) 9.2 Hz), 4.26 (d, 1H,
J ) 9.2 Hz), 3.48 (m, 4H), 3.0 (m, 2H), 2.8-2.77 (m, 2H), 2.56
(d, 3H, J ) 4.4 Hz), 2.37-2.34 (m, 2H), 1.40-1.25 (m, 2H),
0.96 (s, 9H), 0.89 (m, 1H), 0.82 (d, 3H, J ) 6.2 Hz), 0.75 (d,
3H, J ) 6.2 Hz); MS (ESI) 401 (MH+). Anal. (C19H36N4O5‚
0.8H2O‚0.11AcOH) C H N.
5d : 10 mg, 48%; MS (ESI) 421 (MH+); HPLC tR 6.4 min.
5e: 23 mg, 98%; MS (ESI) 471 (MH+); HPLC tR 9.2 min.
5f: 25 mg, 106%; MS (ESI) 472 (MH+); HPLC tR 5.8 min.
5g: 22.4 mg, 107%; MS (ESI) 419 (MH+); HPLC tR 4.0 min.
3R-Ch lor o-2S-isobu tylbu ta n -1,4-d ioic Acid 4-ter t-Bu tyl
Ester (24). To a stirred solution of LDA [45.5 mmol; prepared
by addition of 2.5 M n-butyllithium (18.2 mL, 45.5 mmol) in
hexane to a solution of diisopropylamine (6.3 mL, 48.3 mmol)
in dry THF (20 mL) at -78 °C] cooled to -78 °C was added
dropwise a solution of 7 (5.0 g, 21.7 mmol) in dry THF (15
mL). The mixture was stirred for 45 min at -78 °C, and a
solution of carbon tetrachloride (2.3 mL, 23.9 mmol) in dry
THF (3 mL) was added slowly, dropwise over ca. 8 min
avoiding that the internal temperature rises above -65 °C.
The mixture was allowed to stir at -78 °C for 30 min, warmed
to room temperature, and stirred for 1 h at room temperature.
The solution was cooled to -78 °C and quenched by addition
of HCl (2 N, 3.3 mL). The solution was warmed to room
temperature and extracted with diethyl ether. The combined
organic extracts were dried over MgSO4 and filtered, and the
solvents were removed to give directly one crude single isomer.
The residue was purified by flash chromatography on silica
using acetonitrile as eluant to give 24 (5.6 g, 98%) as a pale
brown oil: 1H NMR (CDCl3) 4.41 (d, 1H, J ) 8.1 Hz), 3.1-
3.05 (m, 1H), 1.8-1.65 (m, 2H), 1.55 (m, 1H), 1.48 (s, 9H), 0.95
(d, 3H, J ) 4.8 Hz), 0.94 (d, 3H, J ) 4.8 Hz); MS (EI) 266
(M{37Cl}H+), 264 (M{35Cl}H+).
N2-[3S-Hyd r oxy-2R-isobu tyl-4-ter t-bu tyloxysu ccin yl]-
L-ter t-leu cin e-N1-m eth yla m id e (26). To a stirred solution
of 24 (4.0 g, 15 mmol) in acetonitrile (100 mL) was added L-tert-
leucine N-methylamide (2.8 g, 19.4 mmol). The mixture was
stirred at room temperature for 24 h. A further quantity of
acetonitrile (25 mL) was added, and the mixture was stirred
for 12 h. The solvents were evaporated in vacuo, and the
residue was partitioned between water and EtOAc. The
combined organic extracts were dried over MgSO4 and filtered,
and the solvents were removed. The residue was purified by
flash chromatography on silica using MeCN/CH2Cl2 (gradient
from 20:80 to 25:75) as eluant to give 26 (2.48 g, 45%) as a
beige solid: 1H NMR (CDCl3) 6.68 (d, 1H, J ) 9.1 Hz), 5.88
(m, 1H), 4.13 (d, 1H, J ) 8.8 Hz), 4.1 (m, 1H), 3.73 (d, 1H, J
) 5.9 Hz), 2.79 (d, 3H, J ) 5.1 Hz), 2.75 (m, 1H), 1.75-1.55
(m, 3H), 1.47 (s, 9H), 0.99 (s, 9H), 0.96 (d, 3H, J ) 6.2 Hz),
0.92 (d, 3H, J ) 6.2 Hz); MS (EI) 373 (MH+).
N2-[4-(N-Hyd r oxya m in o)-2R-isob u t yl-3S-p yr r olid in o-
su ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (5b). A solution
of 23 (400 mg, 0.83 mmol), 1,4-diiodobutane (438 µL, 3.3
mmol), and iPr2EtN (434 µL, 2.49 mmol) in DMF (10 mL) was
stirred at room temperature in the dark for 3 days. Aqueous
workup and purification on silica gel (eluant: EtOAc) afforded
the protected hydroxamate (170 mg, 38%): 1H NMR (DMSO-
d6) 10.95 (s, 1H), 7.80 (m, 2H), 7.20 (d, 1H, J ) 8.4 Hz), 6.56
(s br, 1H), 6.51 (d br, 1H, J ) 8.4 Hz), 4.72 (s, 2H), 4.23 (d,
1H, J ) 9.5 Hz), 3.77 (s, 3H), 3.76 (s, 3H), 3.16 (d, 1H, J ) 11
Hz), 2.93 (m, 1H), 2.69 (m, 2H), 2.55 (d, 3H, J ) 4.4 Hz), 2.53
(m, 2H), 1.6-1.2 (m, 7H), 0.88 (s, 9H), 0.83 (d, 3H, J ) 6.2
Hz), 0.75 (d, 3H, J ) 6.2 Hz); MS (ESI) 535 (MH+), which was
deprotected using the method described for 3v to give 5b (100
1
mg, 87%) as a solid: mp ) 138-144 °C; H NMR (DMSO-d6
+ CF3CO2D) 4.17 (s, 1H), 3.92 (d, 1H, J ) 7.8 Hz), 3.45-3.15
(m, 5H), 2.59 (s, 3H), 1.96 (m, 4H), 1.6-1.4 (m, 2H), 1.2 (m,
1H), 0.97 (s, 9H), 0.94 (d, 3H, J ) 6.2 Hz), 0.91 (d, 3H, J ) 6.2
Hz); MS (ESI) 385 (MH+). Anal. (C19H36N4O4‚1H2O‚1CF3-
COOH) C H N.
3R-Isobu tyl-4-oxo-2S-oxeta n eca r boxylic Acid ter t-Bu -
tyl Ester (25). To a stirred solution of 24 (2.3 g, 8.7 mmol) in
Et2O (50 mL) was added an aqueous solution (5%) of NaHCO3
(45 mL), and the biphasic mixture was vigorously stirred at
room temperature for 48 h. The layers were separated, the
organic phase was washed with water, dried over MgSO4, and
filtered, and the solvents were removed to give directly 25
N2-[4-(N-Hyd r oxya m in o)-2R-isobu tyl-3S-(8-qu in olin e-
m et h yla m in o)su ccin yl]-L-ter t-leu cin e-N1-m et h yla m id e
(5c). To a solution of 23 (250 mg, 0.52 mmol) and quinoline

MMP/ TNFR Convertase Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4905
(1.3 g, 68%) as a brown gum: 1H NMR (CDCl3) 4.47 (d, 1H, J
) 4.03 Hz), 3.7 (m, 1H), 1.85-1.7 (m, 3H), 1.52 (s, 9H), 0.98
(d, 3H, J ) 6.2 Hz), 0.94 (d, 3H, J ) 6.2 Hz); MS (EI) 229
(MH+).
(s, 3H), 2.83 (m, 1H), 2.77 (d, 3H, J ) 4.76 Hz), 1.73 (m, 1H),
1.62 (m, 1H), 1.47 (s, 9H), 1.46 (m, 1H), 0.98 (s, 9H), 0.94 (d,
3H, J ) 6.6 Hz), 0.91 (d, 3H, J ) 6.6 Hz); MS (ESI) 566
(MNa+), 544 (MH+). 28b: 1H NMR (DMSO-d6) 7.3-7.92 (m,
7H), 4.37 (dd, 2H), 4.23 (d, 1H, J ) 9.16 Hz), 4.03 (d, 1H, J )
8.8 Hz), 3.64 (s, 3H), 2.95 (m, 1H), 2.54 (d, 3H, J ) 4.4 Hz),
1.52 (m, 1H), 1.4 (m, 1H), 1.05 (m, 1H), 0.86 (d, 3H, J ) 6.6
Hz), 0.85 (s, 9H), 0.81 (d, 3H, J ) 6.6 Hz); MS (ESI) 525
(MNa+), 503 (MH+). 6b: mp ) 158-161 °C; 1H NMR (DMSO-
d6) 10.96 (s br, 1H), 9.12 (s br, 1H), 7.89 (m, 2H), 7.81 (m, 1H),
7.65-7.55 (m, 3H), 7.33 (m, 1H), 4.38 (d, 1H, J ) 15.0 Hz),
4.23 (d, 1H, J ) 9.1 Hz), 4.22 (d, 1H, J ) 15.0 Hz), 3.87 (d,
1H, J ) 9.5 Hz), 3.65 (s, 3H), 3.04 (m, 1H), 2.56 (d, 3H, J )
4.4 Hz), 1.48-1.38 (m, 2H), 0.95 (m, 1H), 0.86 (d, 3H, J ) 6.6
Hz), 0.85 (s, 9H), 0.80 (d, 3H, J ) 6.6 Hz); MS (ESI) 525
(MNa+), 503 (MH+). Anal. (C26H38N4O6‚0.3H2O) C H N.
Alter n a tive P r ep a r a tion of 26 fr om 25. To a stirred
solution of 25 (1.2 g, 5.3 mmol) in acetonitrile (15 mL) was
added L-tert-leucine N-methylamide (0.98 g, 6.8 mmol). The
mixture was stirred at room temperature for 36 h. The solvents
were evaporated in vacuo, and the residue was partitioned
between water and Et2O. The combined organic extracts were
dried over MgSO4 and filtered, and the solvents were removed.
The residue was purified by flash chromatography on silica
using MeCN/CH2Cl2 (gradient from 10:90 to 30:70) as eluant
to give 26 (1.27 g, 66%) as a beige solid.
P r ep a r a tion of 6a -f fr om 26: N2-[4-(N-Hyd r oxya m in o)-
2R-isobu tyl-3S-(1-m eth yl-2-oxo-1,2-d ih yd r oqu in olin -6-yl-
)m eth oxysu ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (6a ). A
solution of 26 (400 mg, 1.07 mmol) was prepared in THF (10
mL). Sodium hydride (50 mg, 60% in oil, 1.2 mmol) was added
followed 3 min later by a solution of 6-bromomethyl-1-methyl-
2-oxo-1,2-dihydroquinoline43 (325 mg, 1.3 mmol) in THF (10
mL) and sodium iodide (161 mg, 1.07 mmol). The resulting
mixture was stirred at room temperature overnight. The
mixture was treated with a saturated solution of NH4Cl and
extracted with EtOAc. The combined organic extracts were
dried over MgSO4 and filtered, and the solvents were removed.
The residue was purified by flash chromatography on silica
using MeCN/CH2Cl2 (gradient from 3/7 to 3/2) as eluant to give
27a (469 mg, 81%) as a foam: 1H NMR (CDCl3) 7.67 (d, 1H, J
) 9.52 Hz), 7.57 (m, 2H), 7.35 (d, 1H, J ) 8.8 Hz), 6.83 (d, 1H,
J ) 8.8 Hz), 6.73 (d, 1H, J ) 9.52 Hz), 6.22 (m, 1H), 4.76 (d,
1H, J ) 10.62 Hz), 4.49 (d, 1H, J ) 11 Hz), 4.07 (d, 1H, J )
9.16 Hz), 3.97 (d, 1H, J ) 5.49 Hz), 3.72 (s, 3H), 2.79 (d, 3H,
J ) 4.77 Hz), 2.76 (m, 1H), 1.67 (m, 1H), 1.52 (m, 1H), 1.48 (s,
9H), 1.33 (m, 1H), 0.92 (d, 3H, J ) 6.6 Hz), 0.89 (d, 3H, J )
6.6 Hz), 0.85 (s, 9H); MS (ESI) 566 (MNa+), 544 (MH+).
Trifluoroacetic acid (1.38 mL) was added dropwise to a solution
of 27a (489 mg, 0.9 mmol) in dry dichloromethane (2 mL). The
solution was stirred at room temperature overnight. The
solvents were evaporated in vacuo. The residue was taken up
in toluene, and the solvent was removed in vacuo (three times).
The residue was taken up in Et2O, triturated, and filtered to
give 28a (440 mg, 100%): 1H NMR (DMSO-d6 + CD3CO2D)
7.48-7.84 (m, 5H), 6.63 (d, 1H, J ) 9.52 Hz), 4.51 (dd, 2H),
4.2 (m, 1H), 3.95 (d, 1H, J ) 8.8 Hz), 3.62 (s, 3H), 2.9 (m, 1H),
2.53 (d, 3H, J ) 5 Hz), 1.5 (m, 1H), 1.4 (m, 1H), 1.05 (m, 1H),
0.84 (d, 3H, J ) 6.6 Hz), 0.83 (s, 9H), 0.79 (d, 3H, J ) 6.6 Hz);
MS (ESI) 510 (MNa+), 488 (MH+). A solution of 28a (435 mg,
0.89 mmol) was prepared in DMF (8 mL). HOBT (180 mg, 1.35
mmol) was added, followed by EDCI (256 mg, 1.35 mmol), 2,6-
lutidine (207 µL, 1.78 mmol), and O-(tert-butyldimethylsilyl)-
hydroxylamine (180 mg, 1.16 mmol). The resulting solution
was stirred at room temperature overnight. The crude reaction
mixture was treated with HCl (2 N, 1.5 mL) and purified by
C18 preparative HPLC using as eluant a mixture of acetoni-
trile and water/1% AcOH (gradient from 1/9 to 35/65). Elution
yielded 6a (200 mg, 45% yield) as a white solid: mp ) 160-
N2-[4-(N-H yd r oxya m in o)-2R-isob u t yl-3S-(q u in olin -8-
yl)m eth oxysu ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (6c).
From 26 and 8-iodomethylquinoline (prepared by treatment
of commercially available 8-bromomethylquinoline with so-
dium iodide in acetone) was similarly obtained 27c (540 mg,
79%) as a gum, 28c (432 mg, 94.5%) as a white solid, and 6c
(280 mg, 65%) as a white solid. 27c: 1H NMR (CDCl3) 8.91
(m, 1H), 8.18 (m, 1H), 7.4-7.9 (m, 4H), 7.06 (m, 1H), 6.6 (m,
1H), 5.34 (m, 2H), 4.15 (d, 1H, J ) 4.03 Hz), 4.05 (d, 1H, J )
9.16 Hz), 2.8 (m, 1H), 2.75 (d, 3H, J ) 4.76 Hz), 1.62 (m, 1H),
1.52 (m, 1H), 1.48 (s, 9H), 1.45 (m, 1H), 0.86 (s, 9H), 0.85 (m,
6H); MS (ESI) 536 (MNa+), 514 (MH+). 28c: 1H NMR (DMSO-
d6) 8.91 (m, 1H), 8.45 (m, 1H), 7.52-7.95 (m, 6H), 5.1 (dd, 2H),
4.25 (s br, 1H), 4.17 (d, 1H, J ) 9.16 Hz), 4.11 (d, 1H, J ) 8.79
Hz), 3.0 (s, 1H), 2.52 (d, 3H, J ) 4.4 Hz), 1.55 (m, 1H), 1.4 (m,
1H), 1.1 (m, 1H), 0.85 (d, 3H, J ) 6.6 Hz), 0.8 (d, 3H, J ) 6.6
Hz), 0.79 (s, 9H); MS (ESI) 480 (MNa+), 458 (MH+). 6c: mp )
118-121 °C; 1H NMR (DMSO-d6) 11.2 (s br, 1H), 9.1 (s br,
1H), 8.89 (m, 1H), 8.4 (m, 1H), 7.91-7.76 (m, 4H), 7.60-7.53
(m, 2H), 5.14 (d, 1H, J ) 13.9 Hz), 4.93 (d, 1H, J ) 13.9 Hz),
4.17 (d, 1H, J ) 9.2 Hz), 3.97 (d, 1H, J ) 9.2 Hz), 3.04 (m,
1H), 2.55 (d, 3H, J ) 4.8 Hz), 1.37-1.52 (m, 2H), 1.0 (m, 1H),
0.87 (d, 3H, J ) 6.2 Hz), 0.81 (d, 3H, J ) 6.2 Hz), 0.80 (s, 9H);
MS (ESI) 495 (MNa+), 473 (MH+). Anal. (C25H36N4O5‚0.8H2O)
C H N.
N2-[4-(N-Hyd r oxya m in o)-2R-isobu tyl-3S-m eth oxysu c-
cin yl]-L-ter t-leu cin e-N1-m eth yla m id e (6d ). From 26 and
methyl iodide was similarly obtained 27d (180 mg, 93%) as a
brown foam, 28d (110 mg, 73%) as a white solid, and 6d (280
mg, 65%) as a white solid. 27d : 1H NMR (CDCl3) 6.83 (m, 1H),
6.4 (m, 1H), 4.11 (d, 1H, J ) 8.79 Hz), 3.71 (d, 1H, J ) 5.5
Hz), 3.43 (s, 3H), 2.78 (d, 3H, J ) 4.76 Hz), 2.68 (m, 1H), 1.68
(m, 1H), 1.55 (m, 1H), 1.48 (s, 9H), 1.31 (m, 1H), 1.02 (s, 9H),
0.92 (d, 3H, J ) 6.6 Hz), 0.89 (d, 3H, J ) 6.6 Hz); MS (ESI)
409 (MNa+). 28d : 1H NMR (DMSO-d6) 7.8 (m, 1H), 7.5 (m,
1H), 4.21 (d, 1H, J ) 9.52 Hz), 3.62 (d, 1H, J ) 8.8 Hz), 3.17
(s, 3H), 2.8 (m, 1H), 2.56 (d, 3H, J ) 4.4 Hz), 1.46 (m, 1H),
1.35 (m, 1H), 0.97 (m, 1H), 0.89 (s, 9H), 0.82 (d, 3H, J ) 6.6
Hz), 0.78 (d, 3H, J ) 6.6 Hz); MS (ESI) 353 (MNa+). 6d : mp
) 127-130 °C; 1H NMR (DMSO-d6) 10.76 (s br, 1H), 9.01 (m,
1H), 7.78 (m, 1H), 7.71 (d, 1H, J ) 9.5 Hz), 4.23 (d, 1H, J )
9.5 Hz), 3.48 (d, 1H, J ) 9.9 Hz), 3.11 (s, 3H), 2.84 (m, 1H),
2.57 (d, 3H, J ) 4.7 Hz), 1.41-1.31 (m, 2H), 0.92 (m, 1H), 0.92
(s, 9H), 0.83 (d, 3H, J ) 6.6 Hz), 0.78 (d, 3H, J ) 6.6 Hz); MS
(ESI) 345 (M+•). Anal. (C16H31N3O5‚0.3H2O) C H N.
1
169 °C; H NMR (DMSO-d6) 10.87 (s, 1H), 9.11 (s, 1H), 7.82
(d, 1H, J ) 9.5 Hz), 7.8-7.7 (m, 2H), 7.59 (s, 1H), 7.48 (m,
2H), 6.64 (d, 1H, J ) 9.1 Hz), 4.51 (d, 1H, J ) 11.7 Hz), 4.32
(d, 1H, J ) 11.7 Hz), 4.20 (d, 1H, J ) 9.1 Hz), 3.80 (d, 1H, J
) 9.5 Hz), 3.62 (s, 3H), 2.95 (m, 1H), 2.56 (d, 3H, J ) 4.4 Hz),
1.49-1.32 (m, 2H), 0.91 (m, 1H), 0.85 (d, 3H, J ) 6.2 Hz), 0.81
(s, 9H), 0.79 (d, 3H, J ) 6.2 Hz); MS (ESI) 541 (MK+), 525
(MNa+). Anal. (C26H38N4O6‚0.5H2O) C H N.
N2-[4-(N-H yd r oxya m in o)-2R-isob u t yl-3S-(1-m et h yl-2-
oxo-1,2-d ih yd r oq u in olin -3-yl)m et h oxysu ccin yl]-L-ter t-
leu cin e-N1-m eth yla m id e (6b). From 26 and 3-bromomethyl-
1-methyl-2-oxo-1,2-dihydroquinoline44 was similarly obtained
27b (383 mg, 88%) as a gum, 28b (294 mg, 74%) as a solid,
and 6b (150 mg, 50%) as a white solid. 27b: 1H NMR (CDCl3)
7.92 (s, 1H), 7.24-7.65 (m, 4H), 6.96 (d, 1H, J ) 8.79 Hz),
6.38 (m, 1H), 4.71 (d, 1H, J ) 13.56 Hz), 4.61 (d, 1H, J ) 13.92
Hz), 4.16 (d, 1H, J ) 9.16 Hz), 4.10 (d, 1H, J ) 5.13 Hz), 3.74
N2-[4-(N-H yd r oxya m in o)-2R-isob u t yl-3S-(2-m et h yl-4-
oxo-3,4-d ih yd r oqu in a zolin -6-yl)m eth oxysu ccin yl]-L-ter t-
leu cin e-N1-m eth yla m id e (6e). From 26 and 6-bromomethyl-
2-methyl-4-oxo-3,4-dihydroquinazoline,45 except that 15-crown-5
(1 drop) was also added, was similarly obtained 27e (530 mg,
57%) as a foam, 28e (480 mg, 100%), and 6e (152 mg, 32%) as
a white solid. 27e: 1H NMR (CDCl3) 8.18 (s, 1H), 7.73 (d, 1H,
J ) 8.43 Hz), 7.63 (d, 1H, J ) 8.43 Hz), 6.84 (m, 1H), 6.81 (m,
1H), 4.81 (d, 1H, J ) 11.36 Hz), 4.46 (d, 1H, J ) 11.35 Hz),
4.28 (d, 1H, J ) 9.15 Hz), 3.88 (d, 1H, J ) 6.96 Hz), 2.79 (d,
3H, J ) 4.77 Hz), 2.75 (m, 1H), 2.33 (s, 3H), 1.6 (m, 1H), 1.52
(s, 9H), 1.5 (m, 1H), 1.25 (m, 1H), 0.96 (s, 9H), 0.89 (d, 3H, J
) 6.6 Hz), 0.86 (d, 3H, J ) 6.6 Hz); MS (EI): 545 (MH+). 28e:

4906 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Barlaam et al.
1H NMR (DMSO-d6) 8.01 (d, 1H, J ) 1.84 Hz), 7.77-7.7 (m,
3H), 7.53 (d, 1H, J ) 8.42 Hz), 4.53 (dd, 2H), 4.17 (d, 1H, J )
9.16 Hz), 3.94 (d, 1H, J ) 9.16 Hz), 2.95 (m, 1H), 2.53 (d, 3H,
J ) 4.39 Hz), 2.4 (s, 3H), 1.5 (m, 1H), 1.4 (m, 1H), 1.02 (m,
1H), 0.83 (d, 3H, J ) 6.6 Hz), 0.79 (d, 3H, J ) 6.6 Hz), 0.78 (s,
9H); MS (ESI) 511 (MNa+), 489 (MH+). 6e: mp ) 180-187
CH2Cl2 (10 mL) was added dropwise at 3-4 °C. The solution
was stirred at room temperature for 35 min. The solvents were
evaporated in vacuo. The residue was taken up in toluene, and
the solvent was removed in vacuo (three times). The residue
was passed through a short column of C18 using MeOH as
eluant, the MeOH evaporated, and the residue was triturated
with Et2O and filtered to give 6g (191 mg, 68%) as a white
1
°C; H NMR (DMSO-d6) 12.16 (br, 1H), 10.91 (s br, 1H), 9.12
1
solid: mp ) 128-132 °C; H NMR (DMSO-d6) 10.96 (s, 1H),
(s br, 1H), 7.96 (d, 1H, J ) 1.47 Hz), 7.74-7.68 (m, 2H), 7.63
(dd, 1H, J ) 8.4 Hz, J ′ ) 1.8 Hz), 7.49 (d, 1H, J ) 8.4 Hz), 4.5
(d, 1H, J ) 11.7 Hz), 4.34 (d, 1H, J ) 11.7 Hz), 4.16 (d, 1H, J
) 9.1 Hz), 3.81 (d, 1H, J ) 9.5 Hz), 2.97 (m, 1H), 2.56 (d, 3H,
J ) 4.4 Hz), 2.35 (s, 3H), 1.45-1.3 (m, 2H), 0.89 (m, 1H), 0.84
(d, 3H, J ) 6.6 Hz), 0.78 (d, 3H, J ) 6.6 Hz), 0.76 (s, 9H); MS
(ESI) 526 (MNa+).
9.16 (s, 1H), 8.0-7.4 (m, 9H), 4.88 (d, 1H), 4.62 (d, 1H), 4.06
(d, 1H, J ) 9.2 Hz), 3.91 (d, 1H, J ) 9.5 Hz), 2.95 (m, 1H), 2.5
(d, 3H, J ) 4.4 Hz), 1.34-1.47 (m, 2H), 0.9 (m, 1H), 0.82 (d,
3H, J ) 6.6 Hz), 0.77 (d, 3H, J ) 6.6 Hz), 0.6 (s, 9H); MS (ESI)
494 (MNa+), 472 (MH+).
N2-[4-(N-Hyd r oxya m in o)-2R-isobu tyl-3S-(n a p h th a len -
2-yl)m eth oxysu ccin yl]-L-ter t-leu cin e-N1-m eth ylam ide (6j).
From 30 and 2-(bromomethyl)naphthalene was similarly
obtained 6j (94 mg, 86%) as a white solid: mp ) 148-152 °C;
1H NMR (DMSO-d6) 10.88 (s, 1H), 9.1 (s, 1H), 7.9-7.4 (m, 9H),
4.59 (d, 1H), 4.41 (d, 1H), 4.19 (d, 1H, J ) 9.5 Hz), 3.85 (d,
1H, J ) 9.5 Hz), 2.98 (m, 1H), 2.54 (d, 3H, J ) 4.8 Hz), 1.45-
1.34 (m, 2H), 0.9 (m, 1H), 0.84 (d, 3H, J ) 6.6 Hz), 0.8 (s, 9H),
0.78 (d, 3H, J ) 6.6 Hz); MS (ESI) 494 (MNa+), 472 (MH+).
N2-[4-(N-2,4-Dim eth oxyben zyloxy-N-2,4,6-tr im eth oxy-
b en zyla m in o)-3S-h yd r oxy-2R-isob u t ylsu ccin yl]-L-ter t-
leu cin e-N1-m eth yla m id e (31). HOBT (5.1 g, 37.9 mmol) was
added to a solution of 29 (8.0 g, 25.3 mmol) in DMF (150 mL),
followed by EDCI (7.2 g, 37.9 mmol), 2,6-lutidine (588 µL, 5
mmol), and O-2,4-dimethoxybenzyl-N-2,4,6-trimethoxybenzyl
hydroxylamine21 (10.1 g, 27.8 mmol). The resulting solution
was stirred at room temperature overnight. The crude reaction
mixture was concentrated and partitioned between water and
EtOAc. The combined organic extracts were washed with HCl
(1 N) and brine, dried over MgSO4, and filtered, and the
solvents were removed. The residue was purified by flash
chromatography on silica using acetonitrile-dichloromethane
(2/3) as eluant to give 31 (8.8 g, 53% yield) as a white solid:
1H NMR (CDCl3) 7.0-6.85 (m, 3H), 6.4 (m, 2H), 6.14 (s, 2H),
5.14 (d, 1H, J ) 14.2 Hz), 4.89 (d, 1H, J ) 13.9 Hz), 4.81 (m,
2H), 4.52 (m, 1H), 4.12 (d, 1H, J ) 8.4 Hz), 3.83 (s, 3H), 3.79
(s, 6H), 3.76 (s, 6H), 3.37 (d, 1H, J ) 4.0 Hz), 2.79 (d, 3H, J )
4.8 Hz), 2.69 (m, 1H), 1.64-1.37 (m, 3H), 1.04 (s, 9H), 0.81 (d,
3H, J ) 6.2 Hz), 0.7 (d, 3H, J ) 6.2 Hz).
P r ep a r a tion of 6h , 6i, a n d 6k fr om 31. N2-[4-(N-Hy-
dr oxyam in o)-2R-isobu tyl-3S-(cou m ar in -6-yl)m eth oxysu c-
cin yl]-L-ter t-leu cin e-N1-m eth yla m id e (6h ). Sodium hydride
(18 mg, 60% in oil, 0.43 mmol) was added to a solution of 31
(250 mg, 0.37 mmol) in THF (8 mL), followed 5 min later by
2-(bromomethyl)coumarin (99 mg, 0.41 mmol) and 15-crown-5
(1 drop). The resulting mixture was stirred at room temper-
ature for 3 h. The mixture was treated with a saturated
solution of NH4Cl and extracted with EtOAc. The combined
organic extracts were washed with water, brine, dried over
MgSO4, and filtered, and the solvents were removed. The
residue was purified by flash chromatography on silica using
MeCN/CH2Cl2 (gradient from 20:80 to 60:40) as eluant to give
a foam (248 mg, 84%): MS (ESI) 842 (MNa+), 820 (MH+). This
intermediate was immediately dissolved in the minimum CH2-
Cl2, and a 10% solution of TFA in CH2Cl2 (12 mL) was added
dropwise at 3-4 °C. The solution was stirred at room tem-
perature for 2 h, toluene was added, and the solvent was
removed in vacuo (three times). The residue was passed
through a short column of C18 using MeOH/water (70:30) as
eluant, the solvent evaporated, and the residue was triturated
with Et2O and filtered to give 6h (103 mg, 73%): 1H NMR
(DMSO-d6) 10.86 (s, 1H), 9.1 (s, 1H), 7.98 (d, 1H, J ) 9.5 Hz),
7.76-7.7 (m, 2H), 7.57 (s, 1H), 7.48 (d, 1H, J ) 8.4 Hz), 7.4 (d,
1H, J ) 8.4 Hz), 6.51 (d, 1H, J ) 9.5 Hz), 4.47 (d, 1H), 4.29 (d,
1H), 4.17 (d, 1H, J ) 9.5 Hz), 3.79 (d, 1H, J ) 9.9 Hz), 2.94
(m, 1H), 2.54 (d, 3H, J ) 4.4 Hz), 1.43-1.35 (m, 2H), 0.9 (m,
1H), 0.83 (d, 3H, J ) 6.6 Hz), 0.78 (s, 9H), 0.77 (d, 3H, J ) 6.6
Hz); MS (ESI) 512 (MNa+), 490 (MH+).
N2-[4-(N-H yd r oxya m in o)-2R-isob u t yl-3S-(7-b r om o-2-
m eth yl-4-oxo-3,4-d ih yd r oqu in a zolin -6-yl)m eth oxysu cci-
n yl]-L-ter t-leu cin e-N1-m eth ylam ide (6f). From 26 and 7-bro-
mo-6-bromomethyl-2-methyl-4-oxo-3,4-dihydroquinazoline46 was
similarly obtained 27f (500 mg, 64%) as a foam, 28f (387 mg,
85%) as a white solid, and 6f (140 mg, 40%) as a white powder.
27f: 1H NMR (CDCl3) 8.24 (s, 1H), 7.89 (s, 1H), 6.89 (m, 1H),
6.84 (m, 1H), 4.86 (d, 1H, J ) 11.73 Hz), 4.64 (d, 1H, J ) 11.72
Hz), 4.26 (d, 1H, J ) 8.79 Hz), 3.94 (d, 1H, J ) 6.59 Hz), 2.8
(m, 1H), 2.78 (d, 3H, J ) 4.76 Hz), 2.38 (s, 3H), 1.63 (m, 1H),
1.52 (s, 9H), 1.48 (m, 1H), 1.33 (m, 1H), 0.94 (s, 9H), 0.88 (d,
3H, J ) 6.6 Hz), 0.86 (d, 3H, J ) 6.6 Hz); MS (ESI) 647 (M-
{81Br}Na+), 645 (M{79Br}Na+). 28f: 1H NMR (DMSO-d6) 8.17
(s, 1H), 7.81 (m, 1H), 7.79 (s, 1H), 7.74 (m, 1H), 4.62 (d, 1H, J
) 12.82 Hz), 4.52 (d, 1H, J ) 12.82 Hz), 4.14 (d, 1H, J ) 9.16
Hz), 4.03 (d, 1H, J ) 8.79 Hz), 2.99 (m, 1H), 2.53 (d, 3H, J )
4.4 Hz), 1.5 (m, 1H), 1.4 (m, 1H), 1.05 (m, 1H), 0.84 (d, 3H, J
) 6.6 Hz), 0.79 (d, 3H, J ) 6.6 Hz), 0.76 (s, 9H); MS (ESI) 567
(M{79Br}H+), 569 (M{81Br}H+). 6f: mp ) 184-188 °C; 1H NMR
(DMSO-d6) 12.3 (s br, 1H), 11.0 (s br, 1H), 9.15 (s br, 1H), 8.17
(s, 1H), 7.83 (d, 1H, J ) 9.15 Hz), 7.78 (s, 1H), 7.7 (m, 1H),
4.53 (d, 1H, J ) 13.2 Hz), 4.44 (d, 1H, J ) 12.8 Hz), 4.14 (d,
1H, J ) 9.5 Hz), 3.9 (d, 1H, J ) 9.9 Hz), 3.12 (m, 1H), 2.55 (d,
3H, J ) 4.4 Hz), 2.35 (s, 3H), 1.45-1.32 (m, 2H), 0.9 (m, 1H),
0.86 (d, 3H, J ) 6.6 Hz), 0.8 (d, 3H, J ) 6.6 Hz), 0.72 (s, 9H);
MS (ESI) 584 (M{81Br}H+), 582 (M{79Br}H+). Anal. (C25H36
BrN5O6‚0.55H2O) C H N.
-
N2-[4-(N-2,4-Dim eth oxyben zyloxya m in o)-3S-h yd r oxy-
2R-isobu tylsu ccin yl]-L-ter t-leu cin e-N1-m eth yla m id e (30).
HOBT (512 mg, 3.8 mmol) was added to a solution of 2925 (800
mg, 2.5 mmol) in DMF (20 mL), followed by EDCI (725 mg,
3.8 mmol), 2,6-lutidine (55 µL, 0.5 mmol), and O-(2,4-
dimethoxybenzyl)hydroxylamine21 (420 mg, 2.78 mmol). The
resulting solution was stirred at room temperature overnight.
The crude reaction mixture was diluted with EtOAc, and
washed with water, 2% NaHCO3, and brine. Purification on
silica gel (eluant MeCN/CH2Cl2 from 40:60 to 55:45) afforded
30 (710 mg, 60%): 1H NMR (CDCl3) 9.4 (s, 1H), 7.17 (m, 1H),
6.68 (m, 1H), 6.48-6.45 (m, 2H), 5.69 (m, 1H), 5.01 (m, 1H),
4.92 (m, 2H), 4.1 (m, 2H), 3.85 (s, 3H), 3.81 (s, 3H), 3.06 (m,
1H), 2.81 (d, 3H, J ) 4.8 Hz), 1.8-1.5 (m, 3H), 0.98 (s, 9H),
0.94 (d, 3H, J ) 6.2 Hz), 0.90 (d, 3H, J ) 6.2 Hz); MS (ESI)
504 (MNa+), 482 (MH+).
P r epar ation of 6g an d 6j fr om 30. N2-[4-(N-Hydr oxyam i-
n o)-2R-isobu tyl-3S-(n a p h th a len -1-yl)m eth oxysu ccin yl]-
L-ter t-leu cin e-N1-m eth yla m id e (6g). Sodium hydride (63
mg, 60% in oil, 1.6 mmol) was added to a solution of 30 (350
mg, 0.72 mmol) in THF (20 mL), followed 5 min later by
1-(bromomethyl)naphthalene (176 mg, 0.8 mmol), 15-crown-5
(1 drop), and sodium iodide (108 mg, 0.72 mmol). The resulting
mixture was stirred at room temperature for 2 h. The mixture
was treated with a saturated solution of NH4Cl, the pH
reduced to 3-4 with 2 N HCl, and the aqueous phase extracted
with EtOAc. The combined organic extracts were washed with
water and brine, dried over MgSO4, and filtered, and the
solvents were removed. The residue was purified by flash
chromatography on silica using MeCN/CH2Cl2 (gradient from
20:80 to 60:40) as eluant to give a foam (373 mg, 83%): MS
(ESI) 644 (MNa+), 622 (MH+). This intermediate was im-
mediately dissolved in CH2Cl2, and a 10% solution of TFA in
N2-[4-(N-Hyd r oxya m in o)-2R-isobu tyl-3S-(qu in oxa lin -
5-yl)m eth oxysu ccin yl]-L-ter t-leu cin e-N1-m eth ylam ide (6i).
From 31 and 5-bromomethylquinoxaline47 was similarly ob-

MMP/ TNFR Convertase Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4907
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tained 6i (82 mg, 43%) as a white solid: mp ) 170-174 °C;
1H NMR (DMSO-d6) 10.98 (s, 1H), 9.12 (s, 1H), 8.97 (d, 1H, J
) 1.8 Hz), 8.92 (d, 1H, J ) 1.8 Hz), 8.01 (d, 1H, J ) 8.4 Hz),
7.9 (d, 1H, J ) 7.3 Hz), 7.81-7.75 (m, 3H), 5.1 (d, 1H), 4.96
(d, 1H), 4.14 (d, 1H, J ) 9.5 Hz), 3.94 (d, 1H, J ) 9.9 Hz), 3.03
(m, 1H), 2.53 (d, 3H, J ) 4.4 Hz), 1.5-1.35 (m, 2H), 0.93 (m,
1H), 0.85 (d, 3H, J ) 6.2 Hz), 0.79 (d, 3H, J ) 6.2 Hz), 0.75 (s,
9H); MS (ESI) 496 (MNa+), 474 (MH+). Anal. (C24H35N5O5‚
0.6H2O) C H N.
N2-[4-(N-Hyd r oxya m in o)-2R-isobu tyl-3S-(2-m eth ylben -
zoth ia zol-5-yl)m eth oxysu ccin yl]-L-ter t-leu cin e-N1-m eth -
yla m id e (6k ). From 31 and 5-bromomethyl-2-methylbenzothi-
azole48 was similarly obtained 6k (110 mg, 40%) as a white
1
solid: mp ) 133-136 °C; H NMR (DMSO-d6) 10.86 (s, 1H),
9.1 (s, 1H), 7.93 (d, 1H, J ) 8.1 Hz), 7.65-7.8 (m, 3H), 7.27 (d,
1H, J ) 8.4 Hz), 4.55 (d, 1H), 4.37 (d, 1H), 4.18 (d, 1H, J ) 9.2
Hz), 3.8 (d, 1H, J ) 9.5 Hz), 2.95 (m, 1H), 2.79 (s, 3H), 2.54 (d,
3H, J ) 4.4 Hz), 1.5-1.35 (m, 2H), 0.88 (m, 1H), 0.83 (d, 3H,
J ) 6.6 Hz), 0.8 (s, 9H), 0.77 (d, 3H, J ) 6.6 Hz); MS (ESI)
515 (MNa+), 493 (MH+). Anal. (C24H36N4O5S‚1.2H2O) C H N
S.
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N2-[4-(N-Hyd r oxya m in o)-2R-(4-ben zyloxy)bu tyl-3S-(1-
m eth yl-2-oxo-1,2-dih ydr oqu in olin -6-yl)m eth oxysu ccin yl]-
L-ter t-leu cin e-N1-m eth yla m id e (6l). In a manner analogous
to that described for examples 6a -f, from 32 and 6-bromo-
methyl-1-methyl-2-oxo-1,2-dihydroquinoline43 was obtained 6l
1
(145 mg, 47%) as a white solid: mp ) 188-190 °C; H NMR
(CDCl3) 9.6 (s br, 2H), 7.69 (d, 1H, J ) 1.5 Hz), 7.65 (d, 1H, J
) 9.5 Hz), 7.61 (dd, 1H, J ) 8.4 Hz, J ′ ) 1.8 Hz), 7.55 (d, 1H,
J ) 8.8 Hz), 7.38-7.25 (m, 6H), 7.0-6.95 (m, 1H), 6.72 (d, 1H,
J ) 9.5 Hz), 4.96 (d, 1H, J ) 11.0 Hz), 4.5 (d, 1H, J ) 11.0
Hz), 4.45 (d, 2H, J ) 1.5 Hz), 4.1 (d, 1H, J ) 3.3 Hz), 3.94 (d,
1H, J ) 9.2 Hz), 3.7 (s, 3H), 3.41 (t, 2H, J ) 6.23 Hz), 3.05-
3.1 (m, 1H), 2.89 (d, 3H, J ) 4.39 Hz), 1.8-1.5 (m, 4H), 1.45-
1.39 (m, 2H), 0.86 (s, 9H); MS (ESI) 631 (MNa+), 609 (MH+).
Anal. (C33H44N4O7‚1.1H2O) C H N.
N2-[4-(N-H yd r oxya m in o)-2R-(3-b en zyloxy)p r op yl-3S-
(2-m eth yl-4-oxo-3,4-d ih yd r oqu in a zolin -6-yl)m eth oxysu c-
cin yl]-L-ter t-leu cin e-N1-m eth yla m id e (6m ). From 33 and
6-bromomethyl-2-methyl-4-oxo-3,4-dihydroquinazoline45 was
similarly obtained 6m (430 mg, 41%) as a white solid: mp )
189-194 °C; 1H NMR (DMSO-d6) 14.2 (s, 1H), 10.9 (s, 1H),
9.1 (s, 1H), 7.93 (s, 1H), 7.79 (m, 2H), 7.61 (d, 1H, J ) 8.1 Hz),
7.47 (d, 1H, J ) 8.4 Hz), 7.36-7.25 (m, 5H), 4.5 (d, 1H), 4.40
(s, 2H), 4.34 (d, 1H), 4.17 (d, 1H, J ) 9.2 Hz), 3.86 (d, 1H, J )
9.9 Hz), 3.32 (m, 2H), 2.93 (m, 1H), 2.53 (d, 3H, J ) 4.4 Hz),
2.33 (s, 3H), 1.5-1.2 (m, 4H), 0.77 (s, 9H); MS (ESI) 618
(MNa+), 596 (MH+). Anal. (C31H41N5O7‚1.2H2O) C H N.
Ack n ow led gm en t. We warmly thank Dr. Graham
Crawley, Dr. Philip Edwards, and Dr. Edward R. H.
Walker for fruitful discussions; Annie Hamon, Patrice
Koza, Marie-J eanne Pasquet, and J acques Pelleter for
the synthesis of these inhibitors; Heather Wightman
and Carole Biddulph for determination of biological
activity; and J ude Leigh, Catherine Kerr, and Sue
Hincliffe for technical support during the purification
of TACE.
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with DMBONH2 or TMSONH2 led a mixture of 2 and 12 due to
epimerization of the arylthio substituent.
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to SPh.
1MNC). Subsequently, it became evident that TACE was a new
member of the mammalian Adamalysin family (or ADAMs),
which presents a good level of sequence homology with the snake
venom metalloproteinase family (SVMPs). We built a homology
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two closely related SVMPs, Adamalysin and Atrolysin-c (PDB
entry codes 1IAG and 1HTC). Whereas many inclusions left our
model imprecise, the high level of sequence similarity within
the active site itself enabled us to use this model for the design
of small, nonselective, inhibitory molecules. The recent publica-
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structural similarity between the MMPs, the SVMPs, and
ADAMs in the vicinity of the zinc binding site.
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