Anti-Helicobacter pylori agents. 3. 2-[(Arylalkyl)guanidino]-4- furylthiazoles

Article abstract of DOI:10.1021/jm9900671

A series of 2-[(arylalkyl)guanidino]-4-[(5-acetamidomethyl)furan-2- yl]thiazoles and some 4-acetamidomethyl positional isomers were synthesized and evaluated for antimicrobial activity against Helicobacter pylori. Among the compounds that had potent antim

Full text of DOI:10.1021/jm9900671

2920
J . Med. Chem. 1999, 42, 2920-2926
An ti-Helicoba cter pylor i Agen ts. 3. 2-[(Ar yla lk yl)gu a n id in o]-4-fu r ylth ia zoles
Yousuke Katsura,* Shigetaka Nishino, Mitsuko Ohno, Kazuo Sakane, Yoshimi Matsumoto,† Chizu Morinaga,†
Hirohumi Ishikawa,† and Hisashi Takasugi
Medicinal Chemistry Research Laboratories and Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical
Company, Ltd., 2-1-6, Kashima, Yodogawa-ku, Osaka 532-8514, J apan
Received February 8, 1999
A series of 2-[(arylalkyl)guanidino]-4-[(5-acetamidomethyl)furan-2-yl]thiazoles and some 4-acet-
amidomethyl positional isomers were synthesized and evaluated for antimicrobial activity
against Helicobacter pylori. Among the compounds that had potent antimicrobial activity (MIC
< 0.1 µg/mL), compounds 31 and 36 additionally possessed H2 antagonist and gastric
antisecretory activities. Though compound 51, an analogue incorporating a methyl group onto
the furan nucleus of 36, and compound 54, a positional isomer of 51, also showed potent anti-
H. pylori activity, the H2 antagonism profile was eliminated from these compounds. Thus,
two types of potent anti-H. pylori agents could be derived from the same scaffold.
In tr od u ction
In the course of research on a novel class of H2
antagonists, we have prepared several series of com-
pounds with new structural features. Among them,
compound 1, a structurally rigid analogue of traditional
H2 antagonists, demonstrated a significant antimicro-
bial activity against H. pylori (MIC ) 27 µg/mL), which
was roughly comparable to that of bismuth subcitrate
(MIC ) 18 µg/mL).15 With this finding as the starting
point of the research program exploring anti-H. pylori
agents, we have carried out several kinds of modifica-
tions of 1 to obtain more potent anti-H. pylori agents.
Peptic ulcers are caused by an imbalance between
gastrointestinal defensive factors (forces of mucosal
resistance) and aggresive factors (gastric acid and
pepsin secretion), a concept known as Shay’s balance
theory. In light of this theory, many antiulcer drugs
which have gastroprotective effects and/or gastric anti-
secretory effects have been developed over the last three
decades. Among them, strong antisecretory agents, such
as histamine H2-receptor antagonists (H2 antagonists)
and proton-potassium ATPase inhibitors, dramatically
increased the healing ratio for peptic ulcers to 90-95%.
On the other hand, the high ratio of recurrence of the
ulcers following the cessation of treatment with such
antisecretory agents has been problematic. Therefore
recurrence has gained recognition as a part of the
natural history of peptic ulcers.
The discovery of a new spiral organism in stomach
named Helicobacter pylori (H. pylori)1 dramatically
changed the concept of pathology in peptic ulcers. After
numerous studies on the pathogenic role, it is now
widely accepted that H. pylori is a major causative factor
in peptic ulcer diseases, and eradication of this bacteria
results in a dramatic decrease in the recurrence rate in
peptic ulcer patients.2-14 A variety of drugs with sus-
ceptibility for H. pylori, such as antibiotics (â-lactams,
macrolides, and quinolones), bactericidal agents (bis-
muth salts), and an antiprotozoal agent (metronidazole),
have been clinically useful. However, several adverse
effects (e.g., nausea, vomiting, and diarrhea) have been
problematic in these drugs.9-14 Besides, as these drugs
possess a wide bactericidal spectrum, the prescription
of them for elimination of H. pylori would disturb the
treatment in various systematic infectious diseases
because of acquired resistance to the other bacteria.
Therefore the development of novel types of anti-H.
pylori agents is needed.
In our previous papers,16,17 we described some struc-
ture-activity relationships (SARs) in a series of com-
pounds incorporating alkyl substituents into the guani-
dino moiety of 1. Among the compounds obtained, a
cyclohexylethyl derivative (2) showed strong anti-H.
pylori activity (MIC ) 0.069 µg/mL) and compound 3,
an unsaturated analogue of 2, also maintained strong
activity (MIC ) 0.052 µg/mL). In pursuing further
extensive SAR study in this series, these findings
* Address for correspondence: Research Planning, Research Divi-
sion, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa-
ku, Osaka 532-8514, J apan.
† Medicinal Biology Research Laboratories.
10.1021/jm9900671 CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/13/1999

Anti-Helicobacter pylori Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2921
Sch em e 1a
a
Reagents: (a) H2NCSNH2/EtOH; (b) PhCONCS/Me2CO; (c) NaOH/aq MeOH; (d) (i) MeI/MeOH, (ii) R-NH2/EtOH; (e) 10 or 12/EtOH;
(f) MeI/MeOH; (g) 2-ClPhCH2NH2/EtOH; (h) 2-MeOPh(CH2)2NH2/EtOH-AcOH.
Sch em e 2a
followed by successive reduction and acetylation yielded
the 2- or 3-acetamidomethyl derivatives 19a and 19b.
Friedel-Crafts acylation of 19a and 19b gave the
chloroacetyl derivatives 20a and 20b, which were
condensed with 12 to afford the required compounds 51
and 54. Introduction of phenyl group on the furan ring
was achieved by Suzuki coupling reaction on 3-furyl-
borate, which was obtained from 3-bromofuran, with
phenyl triflate. 3-Phenylfuran (22) was treated with
chlorosulfonyl isocyanate to give the nitrile derivative
23. Reduction of 23 followed by acetylation and then
Friedel-Crafts acylation gave the chloroacetyl deriva-
tive 25, which was condensed with 12 to afford the
desired compound 52.
a
Reagents: (a) H2/Pd-C/MeOH; (b) Ac2O-Et3N/CH2Cl2-DMF.
encouraged us to prepare a new series of compounds
with an aromatic group in place of the alicyclic part. In
this paper we describe the synthesis and the pharma-
cological evaluations of a series of 2-[(arylalkyl)guani-
dino]-4-furylthiazoles.
Resu lts a n d Discu ssion
The compounds obtained were evaluated for antimi-
crobial activity against H. pylori. Several derivatives
with minimum inhibitory concentration (MIC) under 1
µg/mL were also tested for H2 antagonist and gastric
antisecretory activities with a few exceptions. The
results are summarized in Table 2.
Ch em istr y
Most of the targeted compounds were synthesized by
treatment of the thiourea derivative 7 with methyl
iodide followed by reaction with the appropriate amines
as previously described.16 2-[(Chlorobenzyl)guanidino]-
and 2-[(methoxyphenethyl)guanidino]thiazoles (34 and
36) were obtained by cyclization of the chloroacetyl
derivative 4 with the substituted guanidines 10 and 12
which were prepared from dithiobeulet (8) or amidi-
nothiourea (11) as the starting material, respectively
(Scheme 1). Reduction of the nitro group on 39 gave the
2-[(aminophenethyl)guanidino] derivative 40, which was
treated with acetic anhydride to afford the 2-(acetami-
dophenethyl) derivative 41 (Scheme 2).
The synthetic pathways for the acetamidomethyl
positional isomer of 36 and the derivatives incorporating
a methyl or phenyl on the furan ring are shown in
Schemes 3-5. Mitsunobu reaction of 3-(hydroxymethyl)-
furan (13) with potassium phthalimide followed by
treatment successively with hydrazine, acetic anhy-
dride, and chloroacetyl chloride gave 2-(chloroacetyl)-
4-acetamidofuran (16), which was cyclized with 12 to
afford the desired compound 53. Amidation of the
methyl 2- or 3-methylfurancarboxylate (17a and 17b)
The anti-H. pylori activities of the benzyl (27) and
phenethyl (35) derivatives were more potent than that
of the phenylpropyl analogue 44. Introduction of a
2-methoxy group (28 and 36) to the benzyl and phen-
ethyl substituents increased the activity. The phenyl
analogue 26 was less potent than 28 and 36. Thus,
regarding the length (n) of the alkyl chain connecting
the phenyl and guanidino parts, n ) 1 and 2 are
preferable to n ) 0 and 3. In the methoxy positional
isomers, the order of potency was as follows: 2-methoxy
(28 and 36) > 3-methoxy (29 and 37) > 4-methoxy (30
and 38). Conversion of the 2-MeO on 28 and 36 to EtO
(31), Me (33), Cl (34), or NO2 (39) did not produce a
marked change in activity. On the other hand, conver-
sion to substituents with an ionizable hydrogen, OH
(32), NH2 (40), and AcNH (41), displayed a considerable
decrease in activity. Incorporation of a heteroatom into
the connecting alkyl chain (42 and 43) also resulted in
great loss of activity. In the heteroaryl series, the order

2922 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15
Katsura et al.
Sch em e 3a
a
Reagents: (a) potassium phthalimide/EtOOCNdNCOOEt/PPh3/THF; (b) (1) H2HNH2/EtOH, (2) Ac2O; (c) ClCH2COCl/AlCl3/CH2Cl2;
(d) 12/EtOH.
Sch em e 4a
a
Reagents: (a) HCONH2/NaOMe; (b) (1) LiAlH4/THF, (2) Ac2O; (c) ClCH2COCl/AlCl3/CH2Cl2; (d) 12/EtOH.
Sch em e 5a
Concerning the gastric antisecretory and H2 antago-
nist activities, three compounds (31, 36, and 37) showed
comparable potency to the referenced H2 antagonist,
cimetidine. However, no clear correlations between
these pharmacological activities and the structural
features could be observed.
Finally, we have assessed the selectivity of two
representative compounds from this study toward H.
pylori (Table 3). The therapeutically useful drugs for the
treatment of H. pylori eradication, bismuth salicylate,
metronidazole, and amoxicillin, showed susceptibility for
a variety of organisms. On the other hand, the antimi-
crobial activities of the representative compounds (31
and 54) were specific for H. pylori.
a
Reagents: (a) (1) B(i-C3H7O)3/n-BuLi/THF, (2) PhOTf/Pd-
(PPh3)4/Et3N/DMF; (b) ClSO2NCO/CH2Cl2-DMF; (c) (1) LiAlH4/
Et2O, (2) Ac2O; (d) ClCH2COCl/AlCl3/CH2Cl2; (e) 12/EtOH.
In conclusion, a series of 2-[(arylalkyl)guanidino]-4-
furylthiazoles were prepared and evaluated as new
structural anti-H. pylori agents. The anti-H. pylori
activity strictly depends on the nature of the arylalkyl
moiety. Especially, the existence of an ionizable hydro-
gen on the arylalkyl moiety caused a remarkable
decrease in the anti-H. pylori activity. Therefore, it is
conceivable that a lipophilic nature is required for the
guanidino substituent region. Among the compounds
tested, several compounds demonstrated potent anti-
H. pylori activity with an MIC under 0.1 µg/mL. From
the viewpoint of the pharmacological profile, these
compounds could be categorized into two types: com-
pounds with H2 antagonist activity (31 and 36) and
compounds without H2 antagonist activity (51 and 54).
The interesting conversion of the pharmacological pro-
file was possible with only minor alteration of the
substitution on the same scaffold.
of potency roughly seems to follow the lipophilic nature
of aromatics; i.e., thiophene (47) > furan (46) > pyridine
(48). Similarly to the phenylalkyl series, the imidazolyl
derivative 50 which has an ionizable hydrogen dramati-
cally decreased the activity. From these SARs in anti-
H. pylori activity, it can be concluded that (a) a one- or
two-methylene length between the aryl and guanidino
moieties is preferable as the connecting group, (b) the
incorporation of a heteroatom to the connecting group
is disadvantageous, and (c) an ionizable hydrogen is not
tolerated in the arylalkyl substituent region.
To extend the SAR study within this series, we have
also investigated the effects of an additional substitution
on the furan ring and the acetamidomethyl positional
isomers. Introduction of a methyl (51) to the adjacent
position of the acetamidomethyl group on 36 maintained
the activity; however, replacement of the methyl with
phenyl (52) led to a dramatic decrease in activity.
Compound 54, the acetamidomethyl positional isomer
of 51, maintained high activity. On the other hand,
compound 53, the positional isomer of 36, did not show
any significant activity contrary to our expectation.
Exp er im en ta l Section
Melting points were determined on a Thomas-Hoover capil-
lary melting point apparatus and are uncorrected. Infrared
(IR) spectra were taken in Nujol using a Hitachi 260-10
spectrometer. Proton nuclear magnetic resonance (1H NMR)

Anti-Helicobacter pylori Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2923
Ta ble 1. Physical Properties for 2-[(Arylalkyl)guanidino]-4-furylthiazoles
compd
R
n
X
Y
mp (°C)
recryst solventa
yield (%)
formulab
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
2-MeOPh
Ph
0
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Ph
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
H
132-133
189-191
159-160
178-179
154-156
151-153
213-214
143-145
164-165
100-102
188-190
125-128
147-148
133-134
161-162
224-225
113-115
170-171
117-118
182-183
134-135
163-164
67-68
E/M
E/M
E/M
EA/M
I/M
E/M
E/M
E/M
E/EA
EA
EA/M
E/M
E/M
I/M
E/EA
EA/M
M
E/EA
E/EA
T/M
T/M
T/M
T/M
M
T/M
A/EA
E/M
I/M
48
56
60
54
71
79
47
71
52
79
85
77
34
74
86
57
51
68
38
53
33
54
68
80
23
91
26
54
77
C18H19N5O3S
C18H19N5O2S
C19H21N5O3S
C19H21N5O3S‚C2H2O4
C19H21N5O3S‚1/2H2O
C20H23N5O3S
C18H19N5O3S
C19H21N5O2S
C17H16ClN5O2S
C19H21N5O2S
C20H23N5O3S‚C2H2O4
C20H23N5O3S
C20H23N5O3S
C29H20N6O4S
C19H22N6O2S
C21H24N6O3S‚1/2H2O
C19H22N6O2S
C20H23N5O4S
C20H23N5O2S
C16H17N5O3S
C17H19N5O3S
C17H19N5O2S2
C18H20N6O2S‚H2O
C18H20N6O2S
C16H19N7O2S‚1/2H2O
C21H25N5O3S‚HCl
C26H27N5O3S
C20H23N5O3S‚1/4H2O
C21H25N5O3S‚HCl
2-MeOPh
3-MeOPh
4-MeOPh
2-EtOPh
2-HOPh
2-MePh
2-Cl Ph
Ph
2-MeOPh
3-MeOPh
4-MeOPh
2-NO2Ph
2-NH2Ph
2-AcNHPh
PhNH
2-MeOPhO
Ph
furan-2-yl
furan-2-yl
thiophen-2-yl
pyridin-2-yl
pyridin-4-yl
imidazol-4-yl
2-MeOPh
2-MeOPh
2-MeOPh
2-MeOPh
237-239
189-191
187-188
161-163
180-186
185-186
CH2NHAc
CH2NHAc
Me
I/M
a
b
A ) EtOH, E ) Et2O, EA ) ethyl acetate, I ) (i-Pr)2O, M ) MeOH, T ) toluene. Analyses for C, H, and N are within (0.4% of the
theoretical values.
spectra were recorded in dimethyl sulfoxide-d6 (DMSO) with
tetramethylsilane as an internal standard on a Bruker AC-
200P spectrometer. Mass spectral measurements (MS) were
made on a J EOL J MS D-300 mass spectrometer. Analytical
results are within (0.4% of the theoretical values unless
otherwise indicated. All extracted solutions were dried over
magnesium sulfate and concentrated to dryness on a rotary
evaporator under reduced pressure.
12 (13.2 g, 30%): mp 102-103 °C. IR: 3460, 3325, 1645, 1620
cm-1. 1H NMR: δ 2.75 (2H, t, J ) 7.5 Hz), 3.25-3.35 (2H, m),
3.79 (3H, s), 6.88 (1H, t, J ) 7.4 Hz), 6.96 (1H, d, J ) 7.4 Hz),
7.00 (4H, br s), 7.19 (1H, d, J ) 7.4 Hz), 7.21 (1H, t, J ) 7.4
Hz), 7.90 (1H, br s). MS: m/z 253 (M+ + 1). Anal. (C11H16N4-
OS) C, H, N.
3-(P h th a lim id om eth yl)fu r a n (14). Diethyl azodicarboxy-
late (17.7 mL, 0.11 mol) was added dropwise to a solution of
3-(hydroxymethyl)furan (13) (10 g, 0.10 mol), phthalimide (15
g, 0.10 mol), and triphenylphosphine (29.4 g, 0.10 mol) in
tetrahydrofuran (THF) (100 mL) at 0 °C, and the mixture was
stirred at room temperature for 3 h. After removal of the
solvent, the residue was added to water and extracted with
AcOEt. The extract was dried and concentrated to give a
residue, which was added to AcOEt/hexane, and the resulting
insoluble material was removed by filtration. The filtered
solution was concentrated to give a residue, which was
chromatographed on silica gel eluting with AcOEt/hexane (1/
4) to afford 14 (19.8 g, 85%). An analytical sample was obtained
by recrystallization from aqueous DMF: mp 165-167 °C. IR:
[(2-Ch lor oben zyl)a m id in o]th iou r ea (10). A mixture of
dithiobeulet (8) (3.7 g, 25 mmol) and MeI (1.6 mL, 25 mmol)
in MeOH (50 mL) was refluxed for 3 h with stirring. After
removal of the solvent, 2-chlorobenzylamine (14.1 g, 100 mmol)
and EtOH (50 mL) were added to the residue, and the resulting
mixture was refluxed for 3 h. The solution was concentrated
to dryness. The residue was added to AcOEt-water, and the
resulting mixture was acidified to pH 3 with 6 N HCl. The
aqueous layer was separated, saturated with NaCl, and then
extracted with AcOEt. The extract was made basic to pH 9
with 20% aqueous K2CO3. The resulting obtained organic layer
was dried and concentrated to give a residue, which was
recrystallized from AcOEt/Et2O to afford 10 (4.9 g, 79%): mp
1
1770, 1710 cm-1. H NMR: δ 4.62 (2H, s), 6.43-6.44 (1H, m),
176-178 °C. IR: 3300, 3150, 1700, 1640 cm-1
.
1H NMR: δ
7.59-7.61 (1H, m), 7.69 (1H, s), 7.82-7.92 (4H, m). MS: m/z
4.68 (2H, d, J ) 4.5 Hz), 7.30-7.60 (4H, m), 8.8 (1H, br s),
9.20-9.50 (3H, m), 10.00 (1H, br s), 11.80 (1H, br s). MS: m/z
243 and 245 (M+ + 1). Anal. (C9H11N4ClS) C, H, N.
228 (M+ + 1).
3-(Aceta m id om eth yl)fu r a n (15). A solution of 14 (39 g,
0.17 mol) and hydrazine hydrate (10 mL, 0.20 mol) in EtOH
(500 mL) was refluxed for 2 h with stirring. After cooling, the
resulting insoluble material was removed by filtration. The
filtered solution was concentrated, and the residue was added
to AcOEt (100 mL). Ac2O (35 mL, 0.37 mol) was added
dropwise to the mixture at 0 °C, and the resulting mixture
was stirred at room temperature for 3 h. After removal of the
insoluble material by filtration, the filtered solution was
concentratred to give a residue, which was chromatographed
on silica gel eluting with CHCl3/MeOH (95/5) to afford 15 (4.6
g, 25%) as an oil. IR (film): 3275, 1630 cm-1. 1H NMR: δ 1.83
[2-(2-Meth oxyp h en yl)eth yla m id in o]th iou r ea (12). A
mixture of amidinothiourea (11) (20.6 g, 0.17 mol), 2-(2-
methoxyphenyl)ethylamine (52.7 g, 0.34 mol), and AcOH (30
mL) in EtOH (100 mL) was refluxed for 22 h with stirring.
The solution was poured into EtOH (80 mL)/water (720 mL),
and the resulting precipitate was collected by filtration. A
suspension of the material in water was adjusted to pH 8.5
with 20% aqueous K2CO3 and extracted with AcOEt. The
extract was dried and concentrated to give a residue, which
was recrystallized from AcOEt/diisopropyl ether (IPE) to afford

2924 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15
Katsura et al.
Ta ble 2. Pharmacological Activities of 2-[(Arylalkyl)guanidino]-4-furylthiazoles
inhibition (%)
MIC (µg/mL)a
gastric secretion
H2 antagonismc
compd
R
n
X
Y
mean
range
(rat,b 1 mg/kg iv) (1 × 10-6 g/mL)
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
2-MeOPh
Ph
0
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
3
1
2
2
2
2
2
2
2
2
2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Ph
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
CH2NHAc
H
0.24
0.085
0.035
0.074
0.28
0.026
5.8
0.091
0.11
0.13
0.052
0.36
0.90
0.14
1.01
4.1
0.1-0.39
0.025-0.2
0.0125-0.1
0.025-0.2
0.1-0.78
0.0125-0.05
1.56-12.5
0.025-0.2
0.025-0.2
0.05-0.2
0.025-0.1
0.1-0.78
0.39-1.56
0.025-0.39
0.39-0.13
0.78-12.5
0.78-3.13
0.78-6.25
0.1-0.39
0.2-0.78
0.1-0.39
0.025-0.2
0.2-1.56
0.39-6.25
12.5-50
0.0125-0.1
3.13-12.5
0.78-6.25
0.025-0.1
0.025-0.1
1.56-25
8
40
37
35
26
28
2-MeOPh
3-MeOPh
4-MeOPh
2-EtOPh
2-HOPh
2-MePh
2-Cl Ph
Ph
2-MeOPh
3-MeOPh
4-MeOPh
2-NO2Ph
2-NH2Ph
2-AcNHPh
PhNH
62
42
41
11
24
54
65
5
88
50
71
67
70
27
66
39
1.79
2.5
2-MeOPhO
Ph
0.27
0.48
0.24
0.112
0.73
1.92
0
0
0
40
46
63
83
0
furan-2-yl
furan-2-yl
thiophene-2-yl
pyridin-2-yl
pyridin-4-yl
imidazol-4-yl
2-MeOPh
2-MeOPh
2-MeOPh
2-MeOPh
21
31
0.030
9.47
2.21
0.046
0.057
5.4
0d
0d
CH2NHAc
CH2NHAc Me
clarithromycin
metronidazole
bismuth subcitrate
cimetidine
18
1130
12.5-25
800-1600
53
43
a
Minimum inhibitory concentration (MIC) was determined as the lowest drug concentration that inhibited macroscopic colonial growth.
b
Mean MIC and range of MICs were obtained from the results of 10 different strains. Inhibition of histamine-stimulated gastric acid
secretion in lumen-perfused stomach of anesthetized rats (n ) 2). c Inhibition of histamine-stimulated chronotropic response in isolated
guinea pig right atrium. No significant inhibition (<10%) was observed at the concentration of 1 × 10-4 g/mL.
d
Ta ble 3. Antimicrobial Activity of 31, 54, and the Reference Compounds against Various Organisms
MIC (range)
organisms (n)
H. pylori (10)
31
54
bismuth salicylate
8.7
metonidazole
amoxicillin
0.026
(0.0125-0.05)
0.046
(0.025-0.1)
23
5.4
(0.56-25)
30
0.021
(0.0063-0.1)
2.2
C. jejuni (8)
23
7.4
(12.5-50)
(12.5-50)
(6.25-12.5)
(0.78-100)
(0.39-6.25)
0.28
(0.1-0.78)
0.027
(0.025-0.05)
2.1
(0.2-12.5)
7.7
C. difficile (4)
>100
>100
50
0.2
(0.1-0.39)
1.75
(0.78-3.13)
0.59
C. perfrigens (6)
B. fragilis (10)
>100
>100
>100
>100
>100
>100
>100
>100
>100
50
(0.39-0.78)
>100
N. gonorrhoeas (10)
N. meningitidis (10)
4.7
(3.13-6.25)
12.5
(3.13-100)
(0.39-100)
0.056
(0.05-0.1)
>100
(3H, s), 4.07 (2H, d, J ) 8.5 Hz), 6.40 (1H, d, J ) 1.5 Hz), 7.54
(1H, d, J ) 1.5 Hz), 7.57-7.59 (1H, m), 8.16 (1H, br s). MS:
m/z 140 (M+ + 1).
3-Meth yl-2-fu r a n ca r boxa m id e (18a ). A solution of meth-
yl 3-methylfuran-2-carboxylate (14) (50 g, 0.36 mol) and
NaOMe (75 g, 1.4 mol) in HCONH2 was stirred at 100 °C for
30 min. The reaction mixture was poured into ice-water (400
mL) and extracted with AcOEt. The extract was dried and
concentratred to give a residue, which was chromatographed
on silica gel eluting with CHCl3 to afford 18a (27.9 g, 63%):
mp 89-90 °C. IR: 3315, 3200, 1650 cm-1 1H NMR: δ 2.27
.
(3H, s), 6.48 (1H, d, J ) 1.6 Hz), 7.27 (1H, br s), 7.51 (1H, br
s), 7.64 (1H, d, J ) 1.6 Hz). MS: m/z 126 (M+ + 1).
2-(Aceta m id om eth yl)-3-m eth ylfu r a n (19a ). A solution of
18a (27.8 g, 0.22 mol) in THF (250 mL) was added dropwise
to a suspension of LiAlH4 (12.6 g, 0.33 mol) in THF (250 mL)

Anti-Helicobacter pylori Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2925
1
at 5-10 °C with stirring under a N2 atmosphere. The mixture
was stirred for 5 h at 50-60 °C. After cooling, 50% aqueous
THF (60 mL) was added dropwise to the mixture at 5-10 °C.
The resulting precipitate was removed by filtration, and the
filtered solution was dried and concentrated to give an oil. Ac2O
(19 mL, 0.2 mol) was added dropwise to a solution of the oil in
AcOEt (100 mL), and the mixture was stirred for 1 h at room
temperature. After removal of the solvent, the residue was
distilled under reduced pressure to give 19a (22.3 g, 87%): bp1.5
) 120-124 °C. IR: 3250, 1650 cm-1. 1H NMR: δ 1.80 (3H, s),
1.96 (3H, s), 4.18 (2H, d, J ) 8.5 Hz), 6.26 (1H, d, J ) 2.6 Hz),
57%): mp 224-225 °C. IR: 3300, 3250, 1625 cm-1. H NMR:
δ 1.85 (3H, s), 2.06 (3H, s), 2.73-2.89 (2H, m), 3.35-3.42 (2H,
m), 4.26 (2H, d, J ) 5.5 Hz), 6.29 (1H, d, J ) 3 Hz), 6.55 (1H,
d, J ) 3 Hz), 6.79 (1H, s), 7.14-7.40 (7H, m), 8.35 (1H, t, J )
5.5 Hz), 9.37 (1H, s).
An tim icr obia l Activity. In vitro antimicrobial activity
against H. pylori was determined by the agar dilution method.
Test strain was precultured in Brucella agar containing 3%
horse serum and 2% starch at 37 °C for 3 days and suspended
in buffered saline to give the turbidity equivalent to McFarland
No. 1. 102-Fold dilution of the bacterial suspensions were
inoculated with a multipoint replicator onto a Brucella agar
plus 7% lysed horse blood plate containing serial 2-fold
dilutions of each drug at 37 °C for 3 days. Incubation was
carried out in an atmosphere of 10% CO2. MIC was read after
incubation as the lowest drug concentration that inhibited
macroscopic colonial growth. Mean MIC was determined from
the MICs in 10 strains: H. pylori 8001, 8003, 8004, 8007, 8008,
8009, 8011, 9005, FP1530, and FP1532.
Hista m in e H2-Recep tor An ta gon ist Activity. The atrial
strip isolated from guinea pig was suspended under an initial
tension of 0.3-0.6 g in an organ bath containing Thyrode
solution at 30 °C and aerated by 95% O2-5% CO2 gas. The
beating rate and amplitude of contraction of the atrium were
recorded by means of a transducer and a polygraph. Histamine
hydrochloride (1 × 10-6 g/mL) was added to the beating fluid,
and the increase in beating rate after dosing was measured.
Addition of test compounds (1 × 10-6 g/mL) was done 30 min
after washing out the histamine hydrochloride. The percent
inhibitory effect of the test compound was calculated by
comparing histamine-induced increases in beating rate before
and 30 min after dosing with the test compounds.
Ga st r ic An t isecr et or y Act ivit y in Lu m en -P er fu sed
Ra ts. Male Sprague-Dawley rats weighing about 250 g were
used. Rats were deprived of food for 24 h. The animals were
anesthetized with 1.25 g/kg urethane intraperitoneally. The
abdomen was opened, and the gastric lumen was perfused with
saline throughout the experiment. The perfusate was titrated
by an autotitrator with 25 mM NaOH as a titrant. Gastric
secretion was stimulated by intravenous infusion with hista-
mine (3 mg/kg/h). After reaching a plateau, the test compound
(1 mg/kg) was given intravenously. The effect of the drug was
expressed as maximal inhibition by acid output.
7.46 (1H, d, J ) 2.6 Hz), 8.21 (1H, br s). MS: m/z 154 (M+
+
1).
2-(Aceta m id om eth yl)-5-(ch lor oa cetyl)-3-m eth ylfu r a n
(20a ). Chloroacetyl chloride (17.2 mL, 0.22 mol) was added
dropwise to a solution of AlCl3 (38 g, 0.28 mol) in CH2Cl2 (150
mL) at room temperature, and the mixture was stirred for 1
h. A solution of 19a (22.3 g, 0.14 mol) in CH2Cl2 (30 mL) was
added dropwise to the mixture at 0 °C, and the resulting
mixture was stirred for 2 h. The reaction mixture was poured
into ice-water, and the organic layer was separated. The
solution was washed with water, dried, and concentrated to
give a residue, which was washed with Et2O to afford 20a (24.8
g, 75%): mp 105-108 °C. IR: 3340, 1675, 1640 cm-1 1H
.
NMR: δ 1.82 (3H, s), 2.04 (3H, s), 4.27 (2H, d, J ) 8.5 Hz),
4.80 (1H, s), 7.45 (1H, s), 8.44 (1H, br s). MS: m/z 230 and
232 (M+ + 1).
4-[2-(Acet a m id om et h yl)-3-m et h ylfu r a n -5-yl]-2-[[2-(2-
m et h oxyp h en yl)et h yl]gu a n id in o]t h ia zole H yd r och lo-
r id e (51). A mixture of 20a (0.69 g, 3 mmol) and 12 (0.76 g, 3
mmol) in EtOH (10 mL) was stirred at room temperature for
5 h. After removal of the solvent, the residue was recrystallized
from EtOH/AcOEt to give 51 (1.3 g, 91%): mp 187-188 °C.
IR: 3425, 3230, 1685, 1630 cm-1 1H NMR: δ 1.82 (3H, s),
.
2.02 (3H, s), 2.91 (2H, t, J ) 6.6 Hz), 3.63-3.66 (2H, m), 3.76
(3H, s), 4.24 (2H, d, J ) 5.4 Hz), 7.27 (1H, br s), 6.87 (1H, t, J
) 7.5 Hz), 6.96 (1H, t, J ) 7.5 Hz), 7.18-7.29 (3H, m), 8.34
(1H, t, J ) 5.2 Hz), 8.58 (2H, br s), 9.14 (1H, br s).
4-[5-(Aceta m id om eth yl)fu r a n -2-yl]-2-[[(2-n itr op h en yl)-
eth yl]gu a n id in o]th ia zole (39). A suspension of 4-[5-(acet-
amidomethyl)furan-2-yl]-2-thioureidothiazole (7)16 (3.6 g, 12
mmol) and MeI (0.77 mL, 12 mmol) in MeOH (70 mL) was
refluxed for 4 h with stirring. After removal of the solvent,
2-(2-nitrophenyl)ethylamine (7 g, 42 mmol) and EtOH (60 mL)
were added to the residue, and the resulting mixture was
refluxed for 72 h. The solution was concentrated to dryness,
and the residue was dissolved in water. The solution was made
basic to pH 10 with 20% aqueous K2CO3 and extracted with
AcOEt/THF. The extract was dried and concentrated to give
a residue, which was recrystallized from MeOH/IPE to afford
39 (3.8 g, 74%): mp 133-134 °C. IR: 3400, 3330, 1660, 1520
Ack n ow led gm en t. We are grateful to Drs. Hi-
rokazu Tanaka and Glen W. Spears for their valuable
suggestions. Thanks are also due to the staff members
of our analytical division for elemental analyses and
measurement of spectral data.
1
cm-1. H NMR: δ 1.85 (3H, s), 3.07 (2H, t, J ) 7 Hz), 3.44-
Refer en ces
3.54 (2H, m), 4.26 (2H, d, J ) 5.5 Hz), 6.29 (1H, d, J ) 3 Hz),
6.55 (1H, d, J ) 3 Hz), 6.80 (1H, s), 7.44-7.56 (5H, m), 7.63-
7.71 (1H, m), 7.96 (1H, d, J ) 8 Hz), 8.34 (1H, t, J ) 5.5 Hz).
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1984, 1311-1315.
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4-[5-(Acetam idom eth yl)fu r an -2-yl]-2-[[(2-am in oph en yl)-
eth yl]gu a n id in o]th ia zole (40). A solution of 39 (3.3 g, 7.7
mmol) in MeOH (50 mL) was hydrogenated over 10% Pd-C
(0.5 g) under atomospheric pressure of H2 at room tempera-
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mp 161-162 °C. IR: 3400, 3350, 3275, 3250, 1650 cm-1 1H
.
NMR: δ 1.86 (3H, s), 2.63-2.71 (2H, m), 3.20-3.40 (2H, m),
4.27 (2H, d, J ) 5.5 Hz), 5.18 (2H, br s), 6.30 (1H, d, J ) 3
Hz), 6.48 (1H, t, J ) 7 Hz), 6.59 (1H, d, J ) 3 Hz), 6.60-6.71
(1H, m), 6.83 (1H, s), 6.88-6.96 (2H, m), 7.53 (3H, br s), 8.38
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