Novel Anti-Helicobacter pylori Agents
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19 4297
128.92, 135.33, 136.28, 137.08, 149.69. LC-MS (ESI) for
H+, 100). TOF-MS: exact mass calcd for C21H25N3OS2 (M +
H+), 400.1517; found, 400.1516. Method A (58% MeCN, λ )
287 nm): 99.0% at tR ) 5.0 min. Anal. (C21H25N3OS2) H, N; C:
calcd, 63.12; found, 62.66.
C
26H36N2O5S2 m/z (relative intensity): 543 (M + Na+, 100),
521 (M + H+, 80). Method A (gradient 40-70% MeCN, λ )
287 nm): 98.5% at tR ) 10.3 min. Method B (60% MeCN):
99.0% at tR ) 3.8 min. Anal. (C26H36N2O5S2) C, H, N, S.
2-[((3-iso-Bu tylth io-2-m eth ylp h en yl)m eth yl)th io]-1H-
ben zim id a zole (87). The title compound was prepared from
68 (221 mg, 1.47 mmol) and 33d (307 mg, 1.34 mmol) by the
method described for 75. Preparative LC (65% MeCN) afforded
163 mg (36%) of the desired material. 400 MHz 1H NMR
(CHCl3-d): δ 1.06 (d, 6H), 1.89 (h, 1H), 2.47 (s, 3H), 2.76 (d,
2H), 4.59 (s, 2H), 7.06 (t, 1H), 7.15 (d, 1H), 7.19-7.24 (m, 3H),
7.52 (bs, 2H). LC-MS (ESI) for C19H22N2S2 m/z (relative
intensity): 343 (M + H+, 30). Method A (gradient 58-70%
MeCN, λ ) 288 nm): 99.0% at tR ) 9.2 min. Method B (70%
MeCN): 99.0% at tR ) 6.0 min.
2-[((3-iso-Bu t yloxy-2-m et h ylp h en yl)m et h yl)t h io]b en -
zoth ia zole (81). The title compound was prepared from 69
(0.43 g, 2.58 mmol) and 23a (0.50 g, 2.35 mmol) by the method
described for 75. Purification on silica (CH2Cl2/MeOH; 99/1)
afforded 0.64 g (79%) of the desired material. 600 MHz 1H
NMR (CHCl3-d): δ 1.05 (d, 3H), 1.06 (d, 3H), 2.15 (m, 1H),
2.34 (s, 3H), 3.73 (d, 2H), 4.65 (s, 2H), 6.79 (d, 1H), 7.02 (d,
1H), 7.11 (t, 1H), 7.31 (t, 1H), 7.44 (t, 1H), 7.77 (d, 1H), 7.92
(d, 1H). Method A (70%, λ ) 281 nm): 99.0% at tR ) 10.9 min.
Method C: 98% at tR ) 9.38 min.
2-[((4-iso-Bu tyloxy-3-m eth yl-2-pyr idyl)m eth yl)th io]ben -
zoth ia zole (82). The title compound was prepared from 69
(0.40 g, 2.39 mmol) and 11 (0.57 g, 2.63 mmol) by the method
described for 75. The residue was crystallized from Et2O
affording 0.46 g (56%) of the desired material. 400 MHz 1H
NMR (CHCl3-d): δ 1.06 (d, 6H), 2.15 (m, 1H), 2.35 (s, 3H),
3.78 (d, 2H), 4.80 (s, 2H), 6.65 (d, 1H), 7.28 (t, 1H), 7.42 (t,
1H), 7.78 (d, 1H), 7.95 (d, 1H), 8.30 (d, 1H). Method A (70%
MeCN, λ ) 280 nm): 99.0% at tR ) 7.9 min. Method C: 96%
at tR ) 13.36 min.
2-[((3-iso-Bu tyloxy-2-m eth yl-1-ph en yl)m eth yl)th io]ben -
zoxa zole (83). Compound 70 (195 mg, 1.29 mmol) was added
to a solution of 55% NaH (60 mg, 2.4 mmol) in dry DMF (5
mL) and reacted for 0.5 h at ambient temperature. Compound
23a (250 mg, 1.17 mmol) was added, and the mixture was
stirred at room temperature for 0.5 h and then heated to 70
°C for 18 h. The reaction was quenched with H2O and then
with CH2Cl2. The organic layer was dried and evaporated, and
the resulting oil was chromatographed on silica (CH2Cl2/
MeOH; 9/1) leaving 155 mg (41%) of the desired material. 600
MHz 1H NMR (CHCl3-d): δ 1.10 (d, 6H), 2.16 (m, 1H), 2.39 (s,
3H), 3.76 (d, 2H), 4.66 (s, 2H), 6.83 (d, 1H), 7.07 (d, 1H), 7.15
(t, 1H), 7.28 (t, 1H), 7.32 (t, 1H), 7.47 (d, 1H), 7.68 (d, 1H).
Method A (70% MeCN, λ ) 280 nm): 98.0% at tR ) 10.2 min.
Method D: 98% at tR ) 5.04 min.
2-[((4-iso-Bu tyloxy-3-m eth yl-2-pyr idyl)m eth yl)th io]ben -
zoxa zole (84). The title compound was prepared from 70 (294
mg, 1.95 mmol) and 11 (375 mg, 1.95 mmol) by the method
described for 75 with the exception that EtOH was used as
solvent instead of MeOH. Purification on silica (PhCH3/EtOAc;
6/1) afforded 319 mg (64%) of the desired material. 500 MHz
1H NMR (CHCl3-d): δ 1.06 (d, 6H), 2.18 (m, 1H), 2.35 (s, 3H),
3.80 (d, 2H), 4.80 (s, 2H), 6.73 (d, 1H), 7.25 (t, 1H), 7.28 (t,
1H), 7.45 (d, 1H),7.65 (d, 1H), 8.34 (d, 1H). 126 MHz 13C NMR
(CHCl3-d): δ 10.75, 19.14, 28.15, 37.12, 74.43, 105.81, 109.88,
118.36, 120.83, 123.79, 124.18, 141.97, 148.00, 151.85, 153.46,
163.44, 165.23. FAB-MS (3-nitrobenzyl alcohol) for C18H20N2O2S
m/z (relative intensity): 329 (M + H+, 100). Method A (70%
MeCN, λ ) 244 nm): 99.0% at tR) 5.7 min. Method D: 98%
at tR ) 4.36 min.
2-[((2-Meth yl-3-((2-m or ph olin o)eth oxy)ph en yl)m eth yl)-
th io]-1H-ben zim id a zole (85). The title compound was pre-
pared from 68 (0.25 g, 1.65 mmol) and 23d (0.40 g, 1.50 mmol)
by the method described for 75. Crystallization from EtOAc
afforded 0.30 g (52%) of the desired material. 500 MHz 1H
NMR (CHCl3-d): δ 2.30 (s, 3H), 2.65 (m, 4H), 2.87 (m, 2H),
3.75 (m, 4H), 4.13 (m, 2H), 4.60 (s, 2H), 6.80 (d, 1H), 6.97 (d,
1H), 7.09 (t, 1H), 7.19-7.30 (m, 2H), 7.33 (d, 1H), 7.74 (d, 1H).
Method A (gradient 40-70% MeCN, λ ) 286 nm): 98.0% at tR
) 10.6 min. Method D: 98% at tR ) 2.87 min.
2-[[[2-Met h yl-3-[2-(2-m et h yl-5-n it r oim id a zol-1-yl)et h -
ylth io]p h en yl]m eth yl]th io]-1H-ben zim id a zole (88). A so-
lution of 33e (586 mg, 1.8 mmol) in 10 mL of MeCN was
reacted with 68 (300 mg, 2 mmol) and K2CO3 (1 g, 7.2 mmol)
in an inert atmosphere for 2 h at reflux. The organic layer
was evaporated, and the residue was treated with 50 mL of
water. The solid material was collected and recrystallized from
25 mL of MeCN affording 440 mg (55%) of crystalline title
compound. 300 MHz 1H NMR (CH3OH-d4): δ 2.26 (s, 3H), 2.43
(s, 3H), 3.29 (t, 2H), 4.40 (t, 2H), 4.49 (s, 2H), 4.89 (broad, >3H
exchangeable hydrogens), 7.02 (t, 1H), 7.09-7.19 (m, 3H), 7.29
(d, 1H), 7.36-7.49 (m, 2H) 7.79 (s, 1H). 75.5 MHz 13C NMR
(CH3OH-d4): δ 13.94, 16.52, 33.54, 36.99, 46.63, 123.52,
127.61, 129.83, 130.18, 132.69, 136.05, 137.17, 138.37, 139.89,
150.83, 152.24. Anal. (C21H21N5O2S2‚3/2H2O) C, H, N, S.
2-[[[2-Meth yl-3-[2-(1,2,4-tr ia zol-1-yl)eth ylth io]p h en yl]-
m eth yl]th io]-1H-ben zim id a zole (89). A solution of 33f (107
mg, 0.4 mmol) in 10 mL of MeCN was reacted with 68 (150
mg, 1 mmol) and K2CO3 (1 g, 7.25 mmol) in an inert
atmosphere for 1 h at reflux. The solvent was evaporated, and
the residue was partitioned between EtOAc and water. The
organic layer was collected, dried, and evaporated. Purification
on silica (EtOAc/iso-PrOH; 95/5) afforded 100 mg (65%) of the
1
title compound. 300 MHz H NMR (CHCl3-d): δ 2.37 (s, 3H),
3.28 (t, 2H), 4.30 (t, 2H), 4.43 (s, 2H), 6.86-7.00 (m, 2H), 7.10-
7.22 (m, 3H), 7.32-7.72 (broad, 2H), 7.87 (s, 1H), 7.91 (s, 1H).
75.5 MHz13C NMR (CHCl3-d): δ 16.25, 33.05, 36,70, 49.24,
122.23, 126.25, 128.73, 129.41, 133.92, 136.12, 137.38, 143.23,
149.06, 151.74. Anal. (C19H19N5S2) C, H, N, S.
5-E t h oxyca r b on yl-2-[((2-m et h yl-3-(2-(2-(2-(2-(2-m et h -
oxye t h oxy)e t h oxy)e t h oxy)e t h oxy)e t h ylt h io)p h e n yl)-
m eth yl)th io]]-1H-ben zim id a zole (90). The title compound
was prepared from 71 (225 mg, 1.00 mmol), prepared by the
standard procedure described in ref 48, and 33b (375 mg, 0.92
mmol) by the method described for 75. Preparative LC (50%
1
MeCN) afforded 128 mg (22%). 500 MHz H NMR (CHCl3-d):
δ 1.41 (t, 3H), 2.45 (s, 3H), 3.02 (t, 2H), 3.32 (s, 3H), 3.49-
3.58 (m, 7H), 3.58-3.63 (m, 11H), 4.39 (q, 2H), 4.61 (s, 2H),
7.03 (t, 1H), 7.19 (d, 1H), 7.26 (d, 1H), 7.50 (d, 1H), 7.93 (t,
1H), 8.20 (s, 1H), 10.79 (d, 1H). 126 MHz 13C NMR (CHCl3-d):
δ 14.36, 16.28, 33.00, 35.79, 58.89, 60.86, 69.66, 70.21, 70.39,
70.45, 70.49, 71.79, 109.00, 112.21, 117.37, 120.00, 123.55,
124.00, 124.32, 126.20, 128.32, 129.04, 136.34, 137.11, 138.99,
216.60. LC-MS (ESI) for C29H40N2O7S2 m/z (relative inten-
sity): 615 (M + Na+, 10), 593 (M + H+, 100). Method A
(gradient 40-70% MeCN, λ ) 226 nm): 99.0% at tR ) 13.2
min. Method B (60% MeCN): 99.0% at tR ) 4.5 min.
2-[((2-Met h yl-3-(2-(2-(2-(2-(2-m et h oxyet h oxy)et h oxy)-
eth oxy)eth oxy)eth ylth io)p h en yl)m eth yl)th io]-5-(p r op yl-
1-on e)-1H-ben zim id a zole (91). The title compound was
prepared from 72 (146 mg, 0.71 mmol), prepared by the
standard procedure described in ref 48, and 33b (260 mg, 0.64
mmol) by the method described for 75. Preparative LC (50%
MeCN) afforded 200 mg (49%) of the desired material. 500
2-[((2-Met h yl-3-((2-m or p h olin o)et h ylt h io)p h en yl)m e-
th yl)th io]-1H-ben zim id a zole (86). The title compound was
prepared from 68 (56 mg, 0.37 mmol) and 33c (100 mg, 0.34
mmol) by the method described for 75. Purification on silica
(EtOAc) afforded 54 mg (40%) of the desired material. 400 MHz
1H NMR (CHCl3-d): δ 2.50 (s, 7H), 2.68 (m, 2H), 3.03 (m, 2H),
3.72 (m, 4H), 4.61 (s, 2H), 7.08 (t, 1H), 7.18 (d, 1H), 7.20-7.28
(m, 2H), 7.35 (d, 1H), 7.75 (d, 1H). FAB-MS (3-nitrobenzyl
alcohol) for C21H25N3OS2 m/z (relative intensity): 400 (M +
1
MHz H NMR (CHCl3-d): δ 1.25 (t, 3H), 2.44 (s, 3H), 3.01 (t,
1H), 3.06 (q, 1H), 3.32 (s, 3H), 3.49-3.58 (m, 4H), 3.58-3.62
(m, 17H), 4.61 (s, 2H), 7.03 (t, 1H), 7.19 (d, 1H), 7.25 (d, 1H),
7.53 (d, 1H), 7.88 (d of d, 1H), 8.19 (s, 1H). 126 MHz 13C NMR
(CHCl3-d): δ 8.57, 16.23, 31.75, 32.91, 35.74, 58.86, 69.62,