Preparation of 3-(4-chlorophenyl)-2-(2-aminothiazol-4-yl)-5-methoxybenzo[b] furan derivatives and their leukotriene B4 inhibitory activity

Article abstract of DOI:10.1039/b711391a

A series of 3-(4-chlorophenyl)-2-(2-aminothiazol-4-yl)benzo[b]furan derivatives 6-10 were prepared and their leukotriene B₄ inhibitory activity was evaluated. We found that several compounds showed strong inhibition of calcium mobilization in C

Full text of DOI:10.1039/b711391a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Preparation of 3-(4-chlorophenyl)-2-(2-aminothiazol-4-yl)-5-
methoxybenzo[b]furan derivatives and their leukotriene B4 inhibitory activity†
Yoko Sakata,a Mari Kuramoto,a Kumiko Ando,a Mami Yamaguchi,a Ikuo Kawasaki,a Jun-ichi Kunitomo,a
Takehiko Yokomizob and Yoshitaka Ohishi*a
Received 25th July 2007, Accepted 21st August 2007
First published as an Advance Article on the web 31st August 2007
DOI: 10.1039/b711391a
A series of 3-(4-chlorophenyl)-2-(2-aminothiazol-4-yl)benzo-
[b]furan derivatives 6–10 were prepared and their leukotriene
B4 inhibitory activity was evaluated. We found that sev-
eral compounds showed strong inhibition of calcium
mobilization in CHO cells overexpressing human BLT1
and BLT2 receptors. Among them, 3-(4-chlorophenyl)-2-
[5-formyl-2-[(dimethylamino)methyleneamino]thiazol-4-yl]-
5-methoxybenzo[b]furan 9b showed the most potent and
selective inhibition for the human BLT2 receptor, and its IC50
value was smaller than that of the selected positive control
compound, ZK-158252.
Introduction
Leukotriene B4 (LTB4), a dihydroxy fatty acid produced mainly
by macrophages and neutrophils, has been shown to be a potent
mediator of the inflammatory process, playing important physi-
ological roles in leukocyte trafficking to the site of infection and
clearance of invading microorganisms.1 However, elevated levels
of LTB4 have been observed in patients with various inflammatory
diseases.2
Much work has been done to develop LTB4 receptor antagonists
for clinical use as an anti-inflammatory drug.3 The structures
of representative compounds are shown in Fig. 1.4 However,
no antagonist has yet been developed for clinical applications.
Recently, a second LTB4 receptor (BLT2) was found and its molec-
ular cloning established.5 The results encouraged new studies
to find novel BLT1 and/or BLT2 inhibitors, which may lead to
the development of new clinical drugs for immunosuppression
of allograft rejection in organ transplantation,6 arteriosclerosis,7
psoriasis,8 cancer,9 and rheumatoid arthritis.10
Fig. 1 Structures of representive LTB4 receptor antagonists.
may affect the inhibitory potency and the selectivity for BLT1
and/or BLT2.
In the present study, the (E)-2-alkylcarbamoyl-1-methylvinyl
group, the conjugated chain functional group, was modified to
an aromatic five-membered heterocyclic ring with the (dimethy-
lamino)methyleneamino group. The thiazole ring may be advan-
tageous to various types of receptors,13 including leukotriene D4.14
2-(2-Aminothiazol-4-yl)benzo[b]furan was prepared as the key
intermediate and several derivatives were prepared to investigate
their activity for the LTB4 receptor.15
In a previous paper, we reported the preparation of 2- and
4-[(2-alkylcarbamoyl)-1-methylvinyl]benzo[b]furan derivatives 1
and 2, and their selective LTB4 receptor (BLT1, BLT2) in-
hibitory activities.11 We also demonstrated that several furo[2,3,4-
jk][2]benzazepin-4(3H)-one derivatives 3 showed moderate human
BLT2 receptor inhibitory activity (Fig. 2).12 From these studies, we
suggested that the torsion angle between the benzo[b]furan ring
plane and the (2-alkylcarbamoyl)-1-methylvinyl functional group
Fig. 2 Structures of reported LTB4 receptor inhibitory benzo[b]furan
derivatives.
aSchool of Pharmaceutical Sciences, Mukogawa Women’s University,
11-68, Koshien Kyuban-cho, Nishinomiya, 663–8179, Japan. E-mail:
yohishi@mukogawa-u.ac.jp; Fax: +798 45 9953; Tel: +798 45 9953
bDepartment of Medical Biochemistry, Graduate School of Medical Sciences,
Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan
Here we describe the preparation of 2-(2-aminothiazol-4-
yl)benzo[b]furan derivatives and the evaluation of their inhibitory
potency and selectivity for BLT1 and/or BLT2.
† Electronic supplementary information (ESI) available: Physical and
experimental detail for 9a, 10a and 10b. See DOI: 10.1039/b711391a
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dimethylformimidamide 9b in 60% yield as the sole product.
Although the N,N-dimethylformimidamide group derived from 2-
amino-4-phenylthiazole has been reported to be relatively sensitive
to hydrolysis conditions,20 the 3-(4-chlorophenyl)-2-[5-formyl-2-
[(dimethylamino)methyleneamino]thiazol-4-yl]-5-methoxybenzo-
[b]furan 9b that we prepared was stable enough to allow evaluation
of its biological activities.
The imine derivatives 10a and 10b were obtained by condensa-
tion of the aldehyde 9b with 2-aminoethanol or glycine ethyl ester
in 72% and 17% yields, respectively.
Chemistry
In the literature, only a few examples of the preparation of 2-(2-
aminothiazol-4-yl)benzo[b]furan derivatives have been reported.16
We planned the preparation of a series of 2-(2-aminothiazol-
4-yl)benzo[b]furan derivatives by applying Hantzsch thiazole
synthesis as a key step to construct the thiazole moiety at the 2-
position of the benzo[b]furan ring by using 2-(chloroacetyl)benzo-
[b]furan 5 and thiourea (Scheme 1).17
Chloromethyl ketone 5 was prepared by the reaction of
chloroacetyl chloride with 3-(4-chlorophenyl)-5-methoxybenzo-
[b]furan 4, which was easily obtained from 1-(4-chlorophenyl)-
2-(4-methoxyphenoxy)ethanone by dehydration with polyphos-
phoric acid.18 Thiazole ring formation by treatment of the
chloromethylketone 5 with thiourea proceeded smoothly in re-
fluxing EtOH to give 2-(2-aminothiazol-4-yl)-3-(4-chlorophenyl)-
5-methoxybenzo[b]furan 6 in 56% yield as a crystalline com-
pound. Acylation of the aminothiazole 6 with acetyl chloride
or 5-methylisoxazole-4-carbonyl chloride gave the corresponding
carboxamides 7a and 7b in 77% and 31% yields, respectively.
Treatment of the 5-methylisoxazol-4-yl derivative 7b with Et3N
in refluxing THF afforded the characteristic (Z)-2-cyano-3-
hydroxybut-2-enoyl compound 8 in 50% yield by opening of the
isoxazole ring followed by enolization of the a-cyano-b-ketoamide.
The structure of 8 was supported by the observation of enol OH
proton at 14.49 ppm in the 1H-NMR spectrum.19
Biological study
The prepared 2-(2-aminothiazol-4-yl)-3-(4-chlorophenyl)-5-
methoxybenzo[b]furan derivatives 6, 7a, 7b, 8, 9a, 9b, 10a and 10b
were evaluated for their LTB4 inhibitory activity by inhibition of
calcium mobilization in both CHO cells overexpressing human
BLT1 (CHO-hBLT1) and human BLT2 (CHO-hBLT1)21 together
with 1 and 2.11 First, all thiazolyl derivatives were evaluated at
a concentration of 10 lM, with the results shown in Table 1.
Six 2-(2-aminothiazol-4-yl)benzo[b]furans 7a, 8, 9a, 9b, 10a and
10b prepared in this study showed more than 70% inhibition of
calcium mobilization in CHO-hBLT2 cells. In contrast, the 5-
methylisoxazole-4-yl carboxamide 7b was inactive to both hBLT1
and hBLT2. All of the active 2-(2-aminothiazol-4-yl)benzo[b]furan
compounds 6, 7a, 8, 9a, 9b, 10a and 10b were more potent for
CHO-hBLT2 than CHO-hBLT1.
In order to formylate the 5-position of the thiazole ring,
aminothiazole 6 was treated with 2 equiv. of POCl3 in DMF at −10
◦
to −5 C. The reaction proceeded smoothly and selectively only
The 2-cyano-3-hydroxy-2-butenamide 8 and N,N-dimethyl-Nꢀ-
(2-thiazolyl)formamidines 9b, 10a and 10b were selected based on
the results of screening at a concentration of 10 lM, and were
evaluated at five concentrations (1, 10, 100 nM, 1 and 10 lM)
in comparison with ZK-158252.4a All of the evaluated compounds
at the primary amino group of the 2-position on the thiazole ring
to give the N,N-dimethylformimidamide product 9a in 74% yield.
However, the same reaction using a large excess (8 equiv.) of POCl3
at room temperature provided the Nꢀ-(5-formylthiazol-2-yl)-N,N-
Scheme 1 Preparation of a series of 2-(2-aminothiazol-4-yl)benzo[b]furan derivatives. Reagents and conditions: (a) ClCH2COCl, AlCl3, CHCl3, reflux,
79%. (b) H2NC(S)NH2, EtOH, reflux, 56%. (c) CH3COCl, THF, reflux, 77% (7a). (d) 5-methylisoxazole-4-carbonyl chloride, THF, reflux, 31% (7b).
(e) Et3N, THF, reflux, 50% (from 7b). (f) 2 equiv. POCl3, DMF, −10 to −5 ◦C, 74% (9a). (g) 8 equiv. POCl3, DMF, rt, 60% (9b). (h) NH2CH2CH2OH,
˚
EtOH, reflux, 72% (10a). (i) NH2CH2CO2Et·HCl, EtOH, 3 A molecular sieves, reflux, 17% (10b).
3084 | Org. Biomol. Chem., 2007, 5, 3083–3086
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Table 1 Evaluation of prepared compounds for LTB4 receptor (BLT1,
exhibited dose-dependent inhibition of hBLT1 and hBLT2 (Fig. 3),
and IC50 values are summarized in Table 1.
BLT2) inhibitory activitiesa
Three of the compounds tested, 9b, 10a and 10b, showed potent
inhibitory activity to the LTB4 receptor, and inhibited BLT2 16.0–
19.5 times more potently than BLT1. In contrast, ZK-158252
showed nearly equal inhibition of BLT1 and BLT2. Compounds
9b, 10a and 10b inhibited BLT2 3.4–6.0 times more strongly than
ZK-158252. In comparison with 1, found in our current study to
be a BLT2-selective compound, the test compounds 9b, 10a and
10b were more potent and selective inhibitors of BLT2. These three
compounds showed lower inhibitory activity than ZK-158252 to
BLT1.
In summary, among the 2-(2-aminothiazol-4-yl)benzo[b]furans
6–10, the 2-[2-[(dimethylamino)methyleneamino]-5-substituted-
thiazol-4-yl]benzo[b]furans 9b, 10a and 10b show highly potent
and significantly selective inhibitory activity to BLT2. These results
indicate that substituents at both the 2- and 5-positions on the
thiazolyl group (at the 2-position of the benzo[b]furan skeleton)
have a significant effect on the selective and potent BLT2 inhibitory
activity of these compounds.
% Inhibition (10 lM)
IC50/lM
Compound CHO-hBLT1 CHO-hBLT2 CHO-hBLT1 CHO-hBLT2
6
4.8
11.2
N.I.b
13.6
11.6
24.4
51.3
49.4
69.9
92.6
—
70.6
68.7
—
—
—
—
—
—
—
3.29
—
0.19
0.20
0.35
0.48
0.68
1.18
7a
7b
N.I.b
8
82.1
72.0
97.9
>100
88.3
>100
92.8
9a
—
9b
3.55
3.19
6.81
2.88
0.42
1.70
10a
10b
1
2c
ZK158252
—
a Effect of calcium mobilization by LTB4 (300 nM) in CHO-hBLT1 and
CHO-hBLT2 cells, unless otherwise noted. b Not inhibited. c Stimulated by
LTB4 at 100 nM.
Conclusion
Several 2-(2-aminothiazol-4-yl)benzo[b]furan derivatives 6–10
were prepared in order to find more potent and selective
BLT2 inhibitors on the basis of 2- and 4-[(2-alkylcarbamoyl)-
1-methylvinyl]benzo[b]furan derivatives 1 and 2. The potent
and selective inhibitors 9b, 10a, 10b were found. A common
structural feature of these compounds is the 2-[(dimethylamino)-
methyleneamino]thiazole group with substituents at the 5-
position. Their inhibitory potencies towards BLT2 were 6.2–
3.4 times higher than ZK-158252. Further experiments to confirm
these preliminary results are in progress, with the ultimate aim of
developing them as agents for clinical purposes.
Acknowledgements
This research was financially supported in part by a grant from the
Ministry of Education, Culture, Sports, Science and Technology
of Japan for a ‘University-Industry Joint Research’ Project (2004–
2008). The authors thank the staff of the Instrument Analysis
1
Center of Mukogawa Women’s University for the H NMR and
MS measurements and elemental analyses.
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