Anti-Helicobacter pylori agents. 5. 2-(Substituted guanidino)-4-arylthiazoles and aryloxazole analogues

Article abstract of DOI:10.1021/jm010217j

To extend the SAR study of guanidinothiazoles as a structurally novel class of anti-H. pylori agents, a series of 2-(substituted guanidino)-4-arylthiazoles and some 4-aryloxazole analogues were synthesized and evaluated for antimicrobial activity against

Full text of DOI:10.1021/jm010217j

J . Med. Chem. 2002, 45, 143-150
143
An ti-Helicoba cter pylor i Agen ts. 5. 2-(Su bstitu ted gu a n id in o)-4-a r ylth ia zoles a n d
Ar yloxa zole An a logu es
Yousuke Katsura,*,‡ Shigetaka Nishino,‡ Yoshikazu Inoue,‡ 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 May 18, 2001
To extend the SAR study of guanidinothiazoles as a structurally novel class of anti-H. pylori
agents, a series of 2-(substituted guanidino)-4-arylthiazoles and some 4-aryloxazole analogues
were synthesized and evaluated for antimicrobial activity against H. pylori. Some of them were
also subjected to H2 antagonist and gastric antisecretory assays. Several arylthiazoles were
identified as potent anti-H. pylori agents, and of these, thienylthiazole derivative 44 exhibited
the strongest activity (MIC ) 0.0065 µg/mL) among the compounds obtained in our guanidi-
nothiazole studies. Although 44 was void of H2 antagonist activity, pyridylthiazole derivative
39 had both potent anti-H. pylori and H2 antagonist activities. Thiazolylthiazole derivative
46 also showed potent anti-H. pylori activity, but the H2 antagonist activity was weak. On the
other hand, no attractive activities were found in pyrimidyl, oxazolyl, isoxazolyl, imidazolyl,
and oxadiazolylthiazole derivatives. The anti-H. pylori activity of the aryloxazole analogues
was weaker than those of the corresponding arylthiazole derivatives, though they had potent
H2 antagonist activity.
In tr od u ction
It is well-known that Helicobacter pylori (H. pylori)
is a major causative factor in peptic ulcer diseases.1-18
Several conventional antibiotics and antiprotozoals, e.g.,
amoxicillin, clarithromycin, bismuth salt, and metron-
idazole, have been prescribed for the peptic ulcer
patients infected with H. pylori. However, various
adverse effects, such as nausea, vomiting, and diarrhea,
have been problematic in these drugs. Besides, as these
drugs have susceptibility to a variety of bacteria, the
prescription of them for elimination of H. pylori would
Ch em istr y
disturb the treatment in various systemic infectious
The guanidinothiazoles linked with a six-membered
heteroaromatic ring, pyridine and pyrimidine, were
synthesized by the routes shown in Scheme 1. Cycliza-
tion of bromoacetylpyridine (3)23 with thiourea provided
the 2-aminothiazole derivative 4. Treatment of 4 with
benzoyl isothiocyanate yielded the benzoylthiourea de-
rivative 5, which was hydrolyzed with sodium hydroxide
to give the thiourea derivative 6. After methylation of
6 with methyl iodide, reaction with appropriate amines
afforded the desired 2-(substituted guanidino)-4-py-
ridylthiazoles (28-30, 32-38, 40 and 41) (see Table 1).
Of the pyridine series, n-butylguanidino and 2-(2-
methoxyphenyl)ethylguanidino derivatives (31 and 39)
were prepared by cyclization of 3 with substituted
amidinothioureas.21
diseases because of appearance of resistance strains in
other pathogenic bacteria. Therefore, the development
of novel types of anti-H. pylori agents is an important
medical need.
As a result of efforts to find a novel class of anti-H.
pylori agents, we recently reported that some 2-(sub-
stituted guanidino)-4-furylthiazoles (1) showed potent
antimicrobial activities for H. pylori.19-21 In the follow-
ing study, we also found that 4-phenyl analogues (2)
maintained potent activities.22 The success of bioisos-
teric replacement of the furan ring with a phenyl ring
encouraged us to extend the investigation into a wide
range of biaryl structural derivatives. In this paper we
describe the synthesis and structure-activity relation-
ships (SARs) of various arylthiazoles and some aryl-
oxazole analogues.
Bromination of 4-acetyl-2-methylpyrimidine (7)24 with
N-bromosuccinimide followed by treatment with potas-
sium phthalimide gave 4-acetyl-2-phthalimidometh-
ylpyrimidine (8). Reaction of 8 with bromine and
subsequent cyclization with n-butylamidinothiourea
provided pyrimidylthiazole derivative 9, which was
successively treated with hydrazine hydrate and acetic
* Address for correspondence: Research Planning, Research Divi-
sion, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa-
ku, Osaka 532-8514, J apan. Phone: +81-6-6390-1335. Fax: +81-6-
6304-5385. E-mail: yousuke_katsura@po.fujisawa.co.jp.
‡ Medicinal Chemistry Research Laboratories.
† Medicinal Biology Research Laboratories.
10.1021/jm010217j CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/16/2001

144 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1
Katsura et al.
Sch em e 1a
a
Reagents: (a) H2NCSNH2; (b) PhCONCS; (c) NaOH/aq MeOH; (d) (1) MeI, (2) RNH2; (e) (1) N-bromosuccinimide, (2) potassium
phthalimide; (f) Br2; (g) RHNC(dNH)NHCSNH2; (h) (1) H2NNH2‚H2O, (2) Ac2O.
anhydride to afford the desired pyrimidylthiazole de-
rivative 42.
In the preceding furyl and phenylthiazole series, the
n-butyl and 2-(2-methoxyphenyl)ethyl groups were
found as the favorable substituents on the guanidino
moiety. Therefore, to evaluate the new biaryl templates,
we have synthesized and compared the activity of the
derivatives with those substituents. In the guanidi-
nothiazole series, pyridyl (31 and 39), thienyl (43 and
44), and thiazolyl (45 and 46) derivatives showed potent
anti-H. pylori activities. Of these, compound 44 dem-
onstrated the strongest activity among the compounds
obtained through all our guanidinothiazole studies
including our earlier works,19-22 and the potency (MIC
) 0.0065 µg/mL) was 3-10 times higher than those of
the referenced antibiotics, amoxicillin (MIC ) 0.021 µg/
mL) and clarithromycin (MIC ) 0.057 µg/mL). On the
other hand, pyrimidyl (42), isoxazolyl (48), imidazolyl
(49), and oxadiazolyl (50) derivatives did not have
attractive activities. Though the activity of oxazolyl
derivative 47 was significant, the potency was 200 times
less than that of the most potent compound 44. The
result of the SAR assessment for the substituents on
guanidino moiety in the pyridylthiazole series was the
same as the previous observations in the furyl- and
phenylthiazole series, i.e., (a) the introduction of bulky
substituents tended to increase the activity, (b) the
incorporation of a heteroatom (33-35), a basic function
(36), or an ionizable hydrogen (37) were disadvanta-
geous.
The synthetic routes of the guanidinothiazole deriva-
tives linked with a variety of five-membered heteroaro-
matic rings are shown in Scheme 2. The thienylthiazole
derivatives 43 and 44 were obtained by cyclization of
chloroacetyl derivative 1025 with substituted amidi-
nothiourea. Treatment of acetylthiazole (11)26 with
bromine followed by cyclization with substituted ami-
dinothiourea gave the thiazolylthiazole derivatives 45
and 46. The oxazolylthiazole derivative 47 was prepared
from 2-acetyl-5-methyloxazole (12)27 by a method simi-
lar to that of the pyrimidyl derivative 42. Condensation
of propanone 1-oxime (15) with N-acetylpropargylamine
provided the key intermediate 16 for the preparation
of the isoxazolylthiazole derivative. The key intermedi-
ate 20 for the synthesis of the imidazolylthiazole deriva-
tive was obtained by the reaction protocols described
by Reiter.28 These intermediates 16 and 20 were con-
verted to the final compounds 48 and 49 by treatment
with bromine followed by cyclization with substituted
amidinothioureas. Condensation of ethyl bromopyruvate
(21) with n-butylamidinothiourea gave thiazole deriva-
tive 22, which was cyclized with aminoacetaldoxime to
afford the desired oxadiazolylthiazole derivative 50.
Scheme 3 shows the synthetic route to prepare the
guanidinoxazoles. Potassium acetate was reacted with
haloketones to give the acetoxymethylcarbonyl deriva-
tives 25. Cyclization of 25 with the appropriate cyan-
oguanidine (27), which were derived from sodium
dicyanamide (26), afforded the final compounds 51-54.
Concerning the H2 antagonist and gastric antisecre-
tory activities, pyridyl derivatives (31, 32, 39, and 40)
showed potent activities over or comparable to those of
the referenced H2 antagonists. On the other hand, the
thienyl derivatives 43 and 44 did not have H2 antago-
nist activity. The thiazole derivatives 45 and 46 and the
oxazole derivative 47 showed only weak to moderate
activities except for the H2 antagonist activity of 45.
Resu lts a n d Discu ssion
The compounds obtained were evaluated for antimi-
crobial activity against H. pylori. Several derivatives,
mainly having minimum inhibitory concentration (MIC)
less than 1 µg/mL, were also tested for H2 antagonist
and gastric antisecretory activities since the prototype
compound in this series was obtained from a study of
H2 antagonists.26 The results are summarized in Table
2.
Next, we evaluated the guanidinoxazole derivatives
to consider the possibility of bioisosteric conversion for
the guanidinothiazole moiety. Compounds 51-54 had
moderate to high H2 antagonist and gastric antisecre-
tory activities. However, these compounds were one or

Anti-Helicobacter pylori Agents
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1 145
Ta ble 1. Physical Properties for 2-(Substituted guanidino)-4-arylthiazoles and Aryloxazoles
a
b
A ) EtOH, D ) N,N-dimethylformamide, E ) Et2O, EA ) ethyl acetate, I ) diisopropyl ether, M ) MeOH, W ) H2O. Analyses for
C, H, and N are within (0.4% of the theoretical values.
two orders of magnitude less potent in anti-H. pylori
activity than the corresponding guanidinothiazole ana-
logues.19,21,22
for the other organisms at the test dose of 100 µg/mL
(see Experimental Section).
The specific target of the compounds in this series is
unclear. However, regarding the mode of anti-H. pylori
action, it was shown that the representative compounds
had bactericidal action by measurement of viability in
a growth curve test (data to be published elsewhere).
Regarding the antimicrobial selectivity toward H.
pylori, the clinically available drugs for the eradication
therapy, bismuth salicylate, metronidazole, and amox-
icillin, showed susceptibility for a variety of microorgan-
isms, which have been reported in our previous publi-
cations,20-22 but the representative compounds in this
investigation (39, 44, and 46) did not have susceptibility
Con clu sion
To assess the possibility of bioisosteric conversion for
the 2-guanidino-4-furylthiazole template, we have pre-

146 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1
Katsura et al.
Sch em e 2a
a
Reagents: (a) Br2; (b) RHNC(dNH)NHCSNH2; (c) (1) N-bromosuccinimide, (2) potassium phthalimide; (d) (1) H2NNH2‚H2O, (2) Ac2O;
(e) (1) Cl2, (2) HCtCCH2NHAc; (f) AcNHCH2COOH; (g) H2/Pd-C; (h) NaOH; (i) AcNHCH2C(dNOH)NH2.
Sch em e 3a
a
Reagents: (a) Br2; (b) MeCOOK; (c) RNH2; (d) 27.
pared a series of 2-guanidino-4-arylthiazole and some
4-aryloxazole derivatives and tested for antimicrobial
activity against H. pylori. Among the derivatives ob-
tained, the 4-thienylthiazole derivative with a 2-(2-
methoxyphenyl)ethyl substituent on the guanidino moi-
ety (44) was identified as the most potent compound in
all the series of our guanidinothiazole studies. Although
compound 44 was void of H2 antagonist activity, the
4-pyridylthiazole analogue 39 possessed both potent
antimicrobial and H2 antagonist activities. The 4-thia-
zolylthiazole analogue 46 also showed potent antimi-
crobial activity, but the H2 antagonist activity was
weak. The other 4-arylthiazole analogues 47-49 did not
have any attractive activities. In the previous studies,
we demonstrated that the guanidino and acetamidom-
ethyl groups were the necessary functions to exhibit
potent anti-H. pylori or H2 antagonist activities and the
substituent on the guanidino moiety modulated the
potency of those activities. On the other hand, from the
results of this study, it can be concluded that the aryl
junction between the guanidinothiazole and acetami-
domethyl moieties is not a simple spacer but plays a
role in regulating the pharmacological character (anti-
microbial and/or H2 antagonist) in this series of com-
pounds.
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 using a Hitachi 260-10 spectrometer.
Proton nuclear magnetic resonance (1H NMR) spectra were
recorded in dimethyl sulfoxide-d6 (DMSO) with tetramethyl-
silane as an internal standard on a Bruker AC-200P spec-
trometer. 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 Mg2SO4 and
concentrated to dryness on a rotary evaporator under reduced
pressure.
4-[6-(Ace t a m id om e t h yl)p yr id in -2-yl]-2-a m in ot h ia -
zole (4). A solution of 2-acetamidomethyl-6-bromoacethylpy-
ridine (3)23 (5.0 g, 18 mmol) and thiourea (1.4 g, 18 mmol) in
EtOH (50 mL) was refluxed for 2 h with stirring. After removal
of the solvent, the residue was dissolved in water. The solution

Anti-Helicobacter pylori Agents
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1 147
Ta ble 2. Pharmacological Activities of 2-(Substituted guanidino)-4-arylthiazoles and Aryloxazoles
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. n.e.: less than 10%. e At 1 × 10-4 g/mL.
d

148 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1
Katsura et al.
was made basic to pH 10 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 4 (3.7 g, 80%): mp 179-180
concentrated to give a residue, which was chromatographed
on silica gel eluting with CHCl3/MeOH (50/1) to afford 2-[2-
(n-butyl)guanidino]-4-[(2-phthalimidomethyl)pyrimidin-4-yl]-
thiazole (9). 1H NMR: δ 0.90 (3H, t, J ) 7 Hz), 1.29-1.48 (4H,
m), 3.13-3.23 (2H, m), 5.01 (2H, s), 7.36 (3H, brs), 7.47 (1H,
s), 7.76 (1H, d, J ) 5 Hz), 7.88-8.00 (5H, m), 8.73 (1H, d, J )
5 Hz).
1
°C. IR (Nujol): 3325, 3250, 3120, 1650 cm-1. H NMR: δ 1.93
(3H, s), 4.36 (2H, d, J ) 6 Hz), 7.11 (2H, s), 7.13 (1H, d, J )
7 Hz), 7.26 (1H, s), 7.68 (1H, d, J ) 7 Hz), 7.76 (1H, t, J ) 7
Hz), 8.45 (1H, t, J ) 6 Hz). MS: m/z 249 (M+ + 1).
A solution of 9 (250 mg, 0.57 mmol) and hydrazine hydrate
(70 mg, 1.4 mmol) in EtOH (10 mL) was refluxed for 1 h. After
cooling to room temperature, Ac2O (1 mL) was added dropwise
to the mixture, and the resulting mixture was stirred for 2 h
at room temperature. The solution was concentrated, and the
residue was added to AcOEt-saturated aqueous NaHCO3. The
organic layer was separated, dried, and concentrated to give
a residue, which was chromatographed on silica gel eluting
with CHCl3/MeOH (95/5) and recrystallized from MeOH to
4-[6-(Aceta m id om eth yl)p yr id in -2-yl]-2-(3-ben zoylth io-
u r eid o)th ia zole (5). A suspension of 4 (3.6 g, 15 mmol) and
benzoyl isothiocyanate (2.6 g, 16 mmol) in Me2CO (70 mL) was
refluxed for 3 h. The resulting precipitate was collected by
filtration to afford 5 (3.8 g, 63%): mp 226-227 °C. IR (Nujol):
1
3300, 1670, 1640 cm-1. H NMR: δ 1.95 (3H, s), 4.42 (2H, d,
J ) 6 Hz), 7.19-7.33 (1H, m), 7.49-7.80 (3H, m), 8.02-8.06
(5H, m), 8.50 (1H, t, J ) 6 Hz), 12.16 (1H, s), 14.29 (1H, s).
MS: m/z 412 (M+ + 1).
afford 42 (140 mg, 74%). IR (Nujol): 3350, 3150, 1655 cm-1
.
1H NMR: δ 0.92 (3H, t, J ) 7 Hz), 1.30-1.50 (4H, m), 1.93
(3H, s), 3.15-3.21 (2H, m), 4.45 (2H, d, J ) 6 Hz), 7.38 (2H,
brs), 7.72 (1H, d, J ) 5 Hz), 7.75 (1H, s), 8.36 (1H, t, J ) 6
Hz), 8.76 (1H, d, J ) 5 Hz).
4-[6-(Acet a m id om et h yl)p yr id in -2-yl]-2-(t h iou r eid o)-
th ia zole (6). A solution of NaOH (0.36 g, 90 mmol) in water
(4 mL) was added to a suspension of 5 (3.7 g, 90 mmol) in
MeOH (40 mL), and the mixture was stirred at 60 °C for 2 h.
After removal of the solvent, the residue was added to water-
AcOEt. The organic layer was separated, washed with water,
dried, and concentrated to give a residue, which was recrystal-
lized from AcOEt-IPE to afford 6 (2.4 g, 87%): mp 212-213
5-Aceta m id om eth yl-3-a cetylisoxa zole (16). Cl2 gas was
bubbled into a solution of propanone 1-oxime (15) (9.5 g, 110
mmol) in CHCl3 (300 mL) at -10 °C for 3 h. After removal of
the solvent, the residue was washed with Et2O-hexane to give
a semisolid material (11.1 g). The material was added por-
tionwise to a mixture of N-acetylpropargylamine (8.8 g, 90
mmol) and K2CO3 (12.6 g, 90 mmol) in CHCl3 (150 mL) at 0
°C with stirring. The mixture was stirred at room temperature
for 5 h and poured into water. The organic layer was separated,
washed with water, dried, and concentrated to give a residue,
which was chromatographed on silica gel eluting with AcOEt/
CHCl3 (9/1) to afford 16 (7.5 g, 37%) as a semisolid material.
1
°C. IR (Nujol): 3300, 3175, 1640 cm-1. H NMR: δ 1.94 (3H,
s), 4.41 (2H, s), 7.21-7.30 (1H, m), 7.75-7.92 (3H, m). MS:
m/z 308 (M+ + 1).
4-[6-(Acet a m id om et h yl)p yr id in -2-yl]-2-[2-(2-p h en yl-
eth yl)gu a n id in o]th ia zole (38). A suspension of 6 (1.35 g, 5
mmol) and MeI (0.73 g, 5 mmol) in MeOH (15 mL) was
refluxed for 3 h with stirring. After removal of the solvent,
â-phenethylamine (4.8 g, 40 mmol) and EtOH (40 mL) were
added to the residue, and the resulting mixture was refluxed
for 48 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.
The extract was dried and concentrated to give a residue,
which was recrystallized from EtOH-IPE to afford 38 (0.72
IR (Nujol): 1700, 1660 cm-1 1H NMR: δ 1.88 (3H, s), 2.57
.
(3H, s), 4.44 (2H, d, J ) 6 Hz), 6.62 (1H, s), 8.56 (1H, t, J ) 6
Hz). MS: m/z 183 (M+ + 1).
2-[2-(n -Bu tyl)gu an idin o]-4-eth oxycar bon ylth iazole (22).
Ethyl bromopyruvate (21) (7.15 g, 33 mmol) was added
dropwise to a mixture of n-butylamidinothiourea (5.22 g, 30
mmol) and NaHCO3 (10.1 g, 120 mmol) in dimethoxyethane
(75 mL) at room temperature. After being refluxed for 20 min,
the mixture was poured into water and extracted with AcOEt.
The extract was washed with water, dried, and concentrated
to give a residue, which was chromatographed on silica gel
eluting with CHCl3/MeOH (20/1) and recrystallized from
AcOEt-IPE to afford 22 (5.7 g, 70%): mp 102-104 °C. IR
1
g, 36%). IR (Nujol): 3320, 1645, 1615 cm-1. H NMR: δ 1.93
(3H, s), 2.84 (2H, t, J ) 7 Hz), 3.51-3.38 (2H, m), 4.36 (2H, d,
J ) 6 Hz), 7.50-7.14 (9H, m), 7.70-7.55 (1H, br s), 7.78 (1H,
t, J ) 7.5 Hz), 8.45 (1H, t, J ) 6 Hz).
4-Acetyl-2-(p h th a lim id om eth yl)p yr im id in e (8). A mix-
ture of 4-acetyl-2-methylpyrimidine (7)24 (2.0 g, 14.6 mmol),
N-bromosuccinimide (2.9 g, 16.2 mmol), and benzoylperoxide
(0.2 g, 0.83 mmol) in CCl4 (60 mL) was refluxed for 3 h with
stirring. After cooling, 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 CHCl3/hexane (1/1) to afford 4-acetyl-2-bromo-
methylpyrimidine (0.96 g, 31%) as an oil. 1H NMR: δ 2.65 (3H,
s), 4.80 (2H, s), 7.80 (1H, d, J ) 8 Hz), 9.11 (1H, d, J ) 8 Hz).
MS: m/z 215, 217 (M+ + 1).
1
(Nujol): 3400, 1695 cm-1. H NMR: δ 0.90 (3H, t, J ) 7 Hz),
1.28 (2H, t, J ) 7 Hz), 1.24-1.58 (4H, m), 3.15 (2H, q, J ) 6.5
Hz), 4.23 (2H, q, J ) 7 Hz), 7.42 (2H, br s), 7.60 (1H, s). MS:
m/z 271 (M+ + 1).
4-(3-Aceta m id om eth yl-1,2,4-oxa d ia zol-5-yl)-2-[2-(n -bu -
tyl)gu a n id in o]th ia zole (50). NaH (60% dispersion in min-
eral oil) (320 mg, 8 mmol) was added portionwise to a solution
of 2-acetamido-1-aminoacetaldoxime (520 mg, 4 mmol) in THF
(5 mL) at room temperature, and the mixture was stirred for
30 min. A solution of 22 (540 mg, 2 mmol) in THF (5 mL) was
added to the mixture, and the resulting mixture was refluxed
for 1 h. After cooling, the reaction mixture was poured into
cold water, adjusted to pH 8 with AcOH, and extracted with
AcOEt. The extract was dried and concentrated to give a
residue, which was chromatographed on silica gel eluting with
CHCl3/MeOH (50/1) and recrystallized from AcOEt-MeOH to
A mixture of 4-acetyl-2-bromomethylpyrimidine (0.84 g, 4
mmol) and potassium phthalimide (0.72 g, 4 mmol) in N,N-
dimethylformamide (DMF) (10 mL) was stirred for 1 h at room
temperature. After removal of the solvent, the residue was
added to water-AcOEt and the organic layer was separated.
The solution was dried and concentrated to give a residue,
which was chromatographed on silica gel eluting with CHCl3
to afford 8 (0.26 g, 47%): mp 195-198 °C. IR (Nujol): 1770,
afford 50 (160 mg, 22%). IR (Nujol): 3350, 3200, 1650 cm-1
.
1
1700 cm-1. H NMR: δ 2.47 (3H, s), 5.13 (2H, s), 7.77 (1H, d,
1H NMR: δ 0.91 (3H, t, J ) 7 Hz), 1.18-1.56 (4H, m), 1.88
(3H, s), 3.14-3.23 (2H, m), 4.41 (2H, d, J ) 6 Hz), 7.56 (3H,
brs), 8.58 (1H, t, J ) 6 Hz). MS: m/z 338 (M+ + 1).
J ) 7.5 Hz), 7.89-8.00 (4H, m), 9.01 (1H, d, J ) 7.5 Hz). MS:
m/z 282 (M+ + 1).
4-(2-Acet a m id om et h ylp yr im id in -4-yl)-2-[2-(n -b u t yl)-
gu a n id in o]th ia zole (42). A mixture of 8 (0.49 g, 1.7 mmol),
phenyltrimethylammonium tribromide (0.85 g, 2.3 mmol) in
tetrahydrofuran (THF) (10 mL) was stirred for 1 h at room
temperature. After removal of the solvent, the residue and
n-butylamidinothiourea (0.3 g, 1.7 mmol) were dissolved in
MeCN (10 mL), and the solution was refluxed for 1 h. After
concentration, the residue was added to AcOEt-saturated
aqueous NaHCO3. The organic layer was separated, dried, and
1-Cya n o-2-[2-(2-m eth oxyp h en yl)eth yl]gu a n id in e (27a ).
A mixture of 2-(2-methoxyphenyl)ethylamine (29.8 g, 0.20 mol),
sodium dicyanamide (19.3 g, 0.22 mol), and concentrated HCl
(16.5 mL) was heated at 100 °C for 8 h. After cooling, the
reaction mixture was added to saturated aqueous NaCl (100
mL) and extracted with AcOEt. The extract was dried and
concentrated to afford 27a (39.5 g, 92%): mp 104-105 °C. IR
1
(Nujol): 3420, 3300, 3170, 2150, 1660 cm-1. H NMR: δ 2.71

Anti-Helicobacter pylori Agents
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1 149
(2H, t, J ) 7.5 Hz), 3.20-3.30 (2H, m), 3.78 (3H, s), 6.65 (2H,
brs), 6.68 (1H, dt, J ) 1 and 7 Hz), 6.96 (1H, d, J ) 7 Hz),
7.12-7.25 (2H, m). MS: m/z 219 (M+ + 1).
Ack n ow led gm en t. We are grateful to Dr. Hirokazu
Tanaka and Dr. 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.
3-(Acetam idom eth yl)-r-acetoxyacetoph en on e (25b). Br2
(4.4 g, 28 mmol) was added dropwise to a solution of 3-acet-
amidomethylacetophenone (5.0 g, 26 mmol) in dioxane (50 mL)
at room temperature. After being stirred for 5 h, the solution
was concentrated and the residue was dissolved in acetone (50
mL). Sodium acetate (4.3 g, 52 mmol) was added to the
solution, and the mixture was refluxed for 23 h. After removal
of the solvent, the residue was added to water (100 mL). The
mixture was made basic to pH 9.5 with 20% aqueous K2CO3
and extracted with AcOEt. The extract was dried and concen-
trated to give a residue, which was chromatographed on silica
gel eluting with CHCl3/MeOH (20/1) and recrystallized from
AcOEt-IPE to afford 25b (3.1 g, 48%): mp 72-73 °C. IR
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(Nujol): 3300, 1740, 1700, 1650 cm-1 1H NMR: δ 1.88 (3H,
.
s), 2.15 (3H, s), 4.32 (2H, d, J ) 6 Hz), 5.45 (2H, s), 7.47-7.59
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.
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