Inhibitors of Type IV Collagenase
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4 647
Compounds 12a -c,e,g,h ,j,k were prepared from the corre-
sponding 8 or 9 and substituted phenylacetylene using a
procedure similar to that described for the preparation of 12i.
Compounds 13a -c,e,g,i,k and 13h ,j were prepared from
the corresponding 12 using procedures similar to those de-
scribed for the preparation of 11g and 5c, respectively.
Compounds 13d ,f were also prepared from 5p and the corre-
sponding substituted phenylacethylene using a procedure
similar to that described for the preparation of 12i.
was added a solution of 78.4 mg (1.14 mmol) of sodium nitrite
in 1 mL of H2O at 0-5 °C of the internal temperature and
stirred for an additional 15 min. To a solution of 496 mg (1
mmol) of 15b in 5 mL of pyridine was added the above solution
at -15 °C. The mixture was allowed to warm to room
temperature. The mixture was poured into water and ex-
tracted with EtOAc. The organic solution was washed with 2
N HCl, 5% NaHCO3 solution, brine, dried, and evaporated.
The residue was purified by chromatography on silica gel using
1:9 CHCl3-EtOAc to give 374 mg (74%) of 16e as colorless
(2R)-3-Meth y-2-[[5-[(4-m eth ylph en yl)eth yn yl]th ioph en e-
2-su lfon yl]a m in o]bu ta n oic a cid (13i): colorless crystals; mp
crystals: mp 202-203 °C; [R]25 -8.8° (c 0.25, acetone); IR
D
(KBr) 3310, 1705, 1345, 1171 cm-1; 1H NMR (DMSO-d6) δ 0.83
(d, J ) 6.9 Hz, 3H), 0.86 (d, J ) 7.2 Hz, 3H), 1.19 (s, 9H), 2.00
(m, 1H), 2.59 (s, 3H), 3.54 (dd, J ) 6.3, 9.6 Hz, 1H), 7.56 (d, J
) 8.7 Hz, 2H), 8.00 (d, J ) 8.7 Hz, 2H), 8.10 (d, J ) 8.7 Hz,
2H), 8.33 (d, J ) 9.6 Hz, 1H), 8.34 (d, J ) 8.7 Hz, 2H). Anal.
(C23H29N5O4S2‚0.3H2O) C, H, N, S.
157-158 °C; [R]25 -7.6° (c 0.5, DMSO); IR (KBr) 3267, 2208,
D
1712, 1350, 1163 cm-1; 1H NMR (DMSO-d6) δ 0.82 (d, J ) 7.2
Hz, 3H), 0.87 (d, J ) 7.2 Hz, 3H), 2.01 (m, 1H), 2.35 (s, 3H),
3.61 (dd, J ) 5.8, 8.8 Hz, 1H), 7.27 (d, J ) 7.8 Hz, 2H), 7.39
(d, J ) 3.6 Hz, 1H), 7.49 (d, J ) 7.8 Hz, 2H), 7.50 (d, J ) 3.6
Hz, 1H), 8.47 (d, J ) 8.8 Hz, 1H), 12.63 (br s, 1H). Anal.
(C18H19NO4S2‚0.2H2O) C, H, N, S.
Compounds 16c,f were prepared from the corresponding 3
and sulfonyl chloride using a procedure similar to that
described for the preparation of 4a . Compounds 16a ,b,d ,g,h
were prepared from the corresponding 15 and substituted
aniline using a procedure similar to that described for the
preparation of 16e.
Compounds 17a ,b and 17c-h were prepared from the
corresponding 16 using procedures similar to those described
for the preparation of 11g and 5c, respectively.
(2R)-2-[[4-[(Ben zen esu lfon ylh yd r a zon o)m et h yl]b en -
zen esu lfon yl]a m in o]-3-m eth ylbu ta n oic Acid ter t-Bu tyl
Ester (15b). Ozone gas was bubbled through a solution of
5.09 g (15 mmol) of 14b in 300 mL of CH2Cl2 at -78 °C until
the solution had turned pale blue. To the mixture was added
22.0 mL (300 mmol) of methyl sulfide, and the resulting
mixture was allowed to warm to room temperature. The
mixture was concentrated in vacuo to give 6.03 g of crude
aldehyde, which was used for the next reaction without further
purification. To a solution of the above product in 60 mL of
EtOH and 15 mL of THF was added 2.72 g (15.8 mmol) of
benzenesulfonyl hydrazide at room temperature. After being
stirred for 2 h, the mixture was concentrated in vacuo. The
residue was purified by chromatography on silica gel using
1:4 CHCl3-EtOAc to give 4.44 g (60% for two steps) of 15b as
(2R)-3-Meth yl-2-[[4-[2-[4-(m eth ylm er ca p to)p h en yl]-2H-
tetr azol-5-yl]ben zen esu lfon yl]am in o]bu tan oic acid (17e):
colorless crystals; 98% yield; mp 194-195 °C; [R]23.5 -10.1 (c
D
1
0.5, DMSO); IR (KBr) 3432, 1720, 1343, 1166 cm-1; H NMR
(DMSO-d6) δ 0.81 (d, J ) 6.6 Hz, 3H), 0.85 (d, J ) 6.9 Hz,
3H), 1.98 (m, 1H), 2.59 (s, 3H), 3.59 (m, 1H), 7.56 (d, J ) 9.0
Hz, 2H), 8.00 (d, J ) 8.7 Hz, 2H), 8.11 (d, J ) 9.0 Hz, 2H),
8.24 (br s, 1H), 8.33 (d, J ) 8.7 Hz, 2H). Anal. (C19H21N5O4S2)
C, H, N, S.
colorless crystals: mp 163-164 °C; [R]23.5 -11.6° (c 0.5,
D
DMSO); IR (KBr) 3430, 3274, 1711, 1364, 1343, 1172 cm-1
;
1H NMR (CDCl3) δ 0.84 (d, J ) 6.9 Hz, 3H), 0.99 (d, J ) 6.6
Hz, 3H), 1.19 (s, 9H), 2.00 (m, 1H), 3.63 (dd, J ) 4.5, 9.9 Hz,
1H), 5.16 (d, J ) 9.9 Hz, 1H), 7.50-7.68 (m, 5H), 7.73 (s, 1H),
7.78-7.84 (m, 2H), 7.96-8.02 (m, 2H), 8.16 (br s, 1H). Anal.
(C22H29N3O6S2) C, H, N, S.
Componuds 19a -c were prepared from the corresponding
18 using a similar to that procedure for the preparation of 5a .
(2R)-3-Met h yl-2-[[4-[(4-n it r ob en zoyl)a m in o]b en zen e-
su lfon yl]a m in o]bu ta n oic Acid ter t-Bu tyl Ester (20d ). To
a solution of 500 mg (1.52 mmol) of 19b in 10 mL of CH2Cl2
were added 423 mg (2.28 mmol) of 4-nitrobenzoyl chloride and
0.33 mL (3.04 mmol) of N-methylmorpholine at 0 °C. The
mixture was allowed to warm to room temperature and stirred
for 24 h. The mixture was poured into water and extracted
with EtOAc. The organic solution was washed with 1 N HCl,
5% NaHCO3 solution, and brine, dried, and evaporated. The
residue was purified by chromatography on silica gel using
30:1 CHCl3-MeOH to give 680 mg (94%) of 20d as pale yellow
crystals: mp 172-173 °C; [R]22D +5.8° (c 1.0, DMSO); IR (KBr)
3365, 1717, 1528, 1369, 1160, 1138 cm-1; 1H NMR (DMSO-d6)
δ 0.82 (d, J ) 6.2 Hz, 3H), 0.85 (d, J ) 6.2 Hz, 3H), 1.23 (s,
9H), 1.93 (m, 1H), 3.45 (m, 1H), 7.77 (d, J ) 8.6 Hz, 2H), 7.96
(d, J ) 8.6 Hz, 2H), 8.01 (br s, 1H), 8.20 (d, J ) 8.6 Hz, 2H),
8.39 (d, J ) 8.6 Hz, 2H), 10.87 (s, 1H). Anal. (C22H27N3O7S)
C, H, N, S.
Compound 15c was prepared from 14c using a procedure
similar to that described for the preparation of 15b.
(2R)-2-[[4-[(Ben zen esu lfon ylh yd r a zon o)m et h yl]b en -
zen esu lfon yl]a m in o]-3-(1H -in d ol-3-yl)p r op ion ic Acid
Meth yl Ester (15a ). To a solution of 9.0 g (23.4 mmol) of
14a in 100 mL of THF and 10 mL of H2O were added 2.92 g
(25.8 mmol) of trimethylamine N-oxide and 7.45 mL of 4%
osmium tetroxide solution in H2O at 0 °C. The mixture was
allowed to warm to room temperature and stirred for 4 h. The
mixture was poured into 100 mL of 1 M Na2S2O3 solution and
extracted with EtOAc. The organic solution was washed with
1 N HCl, 5% NaHCO3 solution, and brine, dried, and evapo-
rated. The residual crude diol was used in the next reaction
without further purification. To a solution of the above product
in 150 mL of THF was added a solution of 6.01 g (28.1 mmol)
of sodium periodate in 20 mL of H2O at 0 °C. After being
stirred for 1 h, the mixture was poured into water and
extracted with EtOAc. The organic solution was washed with
1 N HCl, 5% NaHCO3 solution, and brine, dried, and evapo-
rated. Without further purification, the residual crude alde-
hyde was introduced to 15a using a procedure similar to that
described for the preparation of 15b: colorless crystals; 46%
Compounds 4n , 20a -c, and 20e-h were prepared from the
corresponding 19 and substituted benzoyl chloride using a
procedure similar to that for the preparation of 20d .
Compounds 5n , 21a -b, and 21c-h were prepared from 4n
or the corresponding 20 using procedures similar to those for
the preparation of 11g and 5c, respectively.
(2R)-3-Met h yl-2-[[4-[(4-n it r ob en zoyl)a m in o]b en zen e-
su lfon yl]a m in o]bu ta n oic a cid (21d ): pale yellow crystals;
yield for three steps; mp 218-219 °C; [R]25 +18.3° (c 1.0,
D
DMSO); IR (KBr) 3465, 3292, 1726, 1355, 1166 cm-1; 1H NMR
(DMSO-d6) δ 2.84 (dd, J ) 7.8, 14.1 Hz, 1H), 3.04 (dd, J ) 6.6,
14.1 Hz, 1H), 3.94 (m, 1H), 6.80-6.95 (m, 2H), 7.06 (d, J )
2.4 Hz, 1H), 7.13-7.24 (m, 2H), 7.48-7.70 (m, 7H), 7.88-7.94
(m, 3H), 8.51 (d, J ) 8.4 Hz, 1H), 10.76 (s, 1H), 11.79 (br s,
1H); HR-FABMS m/z 540.1143 M+ (calcd for C25H24N4O6S2 m/z
540.1138).
99% yield; mp 240-242 °C; [R]22 -7.0° (c 1.0, DMSO);
D
IR (KBr) 3402, 1726, 1688, 1591, 1347, 1166 cm-1
;
1H
NMR (DMSO-d6) δ 0.80 (d, J ) 6.9 Hz, 3H), 0.84 (d, J ) 6.6
Hz, 3H), 1.95 (m, 1H), 3.52 (dd, J ) 5.7, 9.6 Hz, 1H), 7.78 (d,
J ) 8.7 Hz, 2H), 7.95 (d, J ) 8.7 Hz, 2H), 7.95 (d, J ) 9.6 Hz,
1H), 8.20 (d, J ) 8.4 Hz, 2H), 8.39 (d, J ) 8.4 Hz, 2H), 10.87
(s, 1H), 12.51 (br s, 1H). Anal. (C18H19N3O7S‚0.4H2O) C, H,
N, S.
4-(2-P h en yl-2H-tetr a zol-5-yl)ben zen esu lfon yl Ch lor id e
(22a ). To a solution of 38.65 g (0.128 mol) of 5-(4-bromophen-
yl)-2-phenyl-1,2,3,4-tetrazole in 450 mL of THF was added 88
(2R)-3-Meth yl-2-[[4-[2-[4-(m eth ylm er ca p to)p h en yl]-2H-
tetr a zol-5-yl]ben zen esu lfon yl]a m in o]bu ta n oic Acid ter t-
Bu tyl Ester (16e). To a solution of 0.14 mL (1.22 mmol) of
4-(methylmercapto)aniline in 5 mL of EtOH and 5 mL of H2O