Preparation of 3-acetoacetylaminobenzo[b]furan derivatives with cysteinyl leukotriene receptor 2 antagonistic activity.

Article abstract of DOI:10.1039/b307468d

Novel 3-acetoacetylaminobenzo[b]furan derivatives with a modified triene system at the 3-position were prepared through acylation of the 3-aminobenzo[b]furans with 5-methylisoxazole-4-carboxylic acid chloride followed by basic cleavage of the isoxazole ring and several of these compounds showed moderate cysteinyl leukotriene receptor 2 antagonistic activity.

Full text of DOI:10.1039/b307468d

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Preparation of 3-acetoacetylaminobenzo[b]furan derivatives with
cysteinyl leukotriene receptor 2 antagonistic activity
Eriko Tsuji,a Kumiko Ando,a Jun-ichi Kunitomo,a Masayuki Yamashita,b Shunsaku Ohta,b
Shigekatsu Kohnob and Yoshitaka Ohishi*a
a School of Pharmaceutical Sciences, Mukogawa-Women’s University,
11-68 Koshien Kyuban-cho, Nishinomiya 663-8179, Japan.
E-mail: yohishi@mwu.mukogawa-u.ac.jp; Fax: ϩ798 41 2792; Tel: ϩ798 45 9953
b Kyoto Pharmaceutical University, Misasagi, Yamashinaku, Kyoto 607-8412, Japan
Received 1st July 2003, Accepted 5th August 2003
First published as an Advance Article on the web 15th August 2003
Novel 3-acetoacetylaminobenzo[b]furan derivatives with
a modified triene system at the 3-position were prepared
through acylation of the 3-aminobenzo[b]furans with
5-methylisoxazole-4-carboxylic acid chloride followed by
basic cleavage of the isoxazole ring and several of
these compounds showed moderate cysteinyl leukotriene
receptor 2 antagonistic activity.
3-aminobenzo[b]furans (7 and 9) were acylated with 5-methyl-
isoxazole-4-carboxylic acid chloride to give the corresponding
amides (10), isoxazole rings of which were easily cleaved by
treatment with Et3N to afford the corresponding enol isomers
(11) of the 3-acetoacetylaminobenzo[b]furan derivatives
(Scheme 1).
On the other hand, the primary amino group of 3-amino-
benzo[b]furans showed an enamine property, for example,
treatment of 3,5-diamino-2-ethylbenzo[b]furan5 with hydro-
chloric acid afforded 5-amino-2-ethyl-3(2H )-benzo[b]furanone
as a hydrolysis product. The enamine property of 11 may assist
in keeping the conjugation and planarity of the C2 substituent
through the C3 side-chain of 11 as shown in Fig. 1. The stereo-
structure of 11g was determined by X-ray analysis as shown in
Fig. 2,6 which clearly shows the conjugation and planarity of
the C2 substituent through the C3 side-chain as we expected.
The cysteinyl leukotrienes (cysLTs) are potent biological
mediators in the pathophysiology of inflammatory disorders, in
particular asthma. Studies of cysLTs receptors indicated the
existence of at least two types of cysLTs receptors, designated
cysLT1 and cysLT2. The cysLT1 receptor was cloned, and the
cysLT2 receptor has been cloned and characterized recently.1
BAY u9773 (1)1b and DUO-LT (2)2 were reported to be dual
cysLT1 and cysLT2 antagonists. Discovery of the stable dual
antagonist and/or selective cysLT2 antagonist may lead to
possible therapeutic opportunities.
Fig. 1
In this communication, we report the synthesis of 3-aceto-
acetylaminobenzo[b]furans (3) and their antagonistic activities
to cysLT1 and cysLT2. π-Conjugation and planarity of the
bold-line portion of 3 may be kept as shown in Fig. 1. It was
also considered that the modified triene system (the bold-line
portion) of 3 might be exactly simulated in the C7–C12 portion
of cysLTs (4) (Fig. 1).3
3-Amino-5-bromobenzo[b]furan derivatives (7a–d) were pre-
pared starting with 4-bromo-2-cyanophenol (5) via the inter-
molecular cyclization of 4-bromo-2-cyanophenylmethylether
derivatives (6).4 The bromides (6b and 7d) were subjected to the
Heck reaction with N,N-diethylcrotonamide in the presence of
Pd(OAc)2 and tri-o-tolylphosphine to afford successfully the
corresponding Heck products 8b and 9d. Treatment of 8b with
NaH afforded 9b. Heck reaction of 6a under similar con-
ditions afforded 9a accompanied by cyclization. The obtained
Fig. 2 X-Ray structure of 11g.
The prepared enol isomers (11) were evaluated for their
cysLT1 and cysLT2 antagonistic activity (Table 1).7 The
novel 3-acetoacetylaminobenzo[b]furan derivatives (11b,d,g)
showed valuable antagonistic activities, especially 11d which
demonstrated specific activity for cysLT2. In contrast, 128 was
inactive on the Ca assay which reveals a significant role for
the benzo[b]furan ring in the appearance of antagonistic
activity. Among these compounds, we selected 11d, which
showed valuable activities as a lead compound for structure-
optimization. Investigations along this line are underway in our
laboratory.
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 1 3 9 – 3 1 4 1
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Table 1 Antagonistic activities
Ca Assay
Inhibition (%)
(10 µM)
Binding assay
Inhibition (%)
(10 µM)
IC50/µM
cysLT1
IC50/µM
cysLT2
Compound
cysLT1
cysLT2
cysLT2
cysLT2
11b
49.8
52.1
51.0
61.4
67.1
57.6
>10
>10
9.7
0.44
>10
>10
4.8
9.5
85
>10
3.7
11d
11g
BAY u9773
12
7.7
0.301a
0.597 0.2971b
16.1
2.3
>10
Scheme 1 Reagents: (a) ClCH2COCH3 or BrCH2CO2C2H5 or ClCH2CN or ClCOCH2C6H4(4-CN)/K2CO3; (b) (C2H5)3N or NaH; (c) Pd(OAc)2/
[(2-CH3)C6H4]3P/(C2H5)3N/(E)-CH3CH᎐CHCON(C2H5)2/THF; (d) NaH; (e) ClC(O)–C᎐N–O–C(CH3)᎐᎐CH; (f ) (C2H5)3N.
᎐
᎐
room temperature, a resulting precipitate was collected by fil-
Experimental
5-Bromo-2-(4-cyanobenzoyl)-3-(5-methylisoxazol-4-carbonyl)-
aminobenzo[b]furan (10d)
tration. The precipitate was recrystallized from MeOH to give
1
10d (850 mg, 34%) as yellow needles. Mp 236 ЊC. H-NMR
(CDCl3): δ 2.90 (3H, s, CH3), 7.42 (1H, d, J = 9.1 Hz, 7-H), 7.70
(1H, dd, J = 9.1, 1.9 Hz, 6-H), 7.86–7.88 (2H, m, 3Ј-, 5Ј-H),
8.32–8.35 (2H, m, 2Ј-, 6Ј-H), 8.71 (1H, s, isoxazole-H), 8.91
(1H, d, J = 1.9 Hz, 4-H), 11.30 (1H, bs, NH). MS: m/z 449 (Mϩ,
56.56), 341 (100.00). HRMS: C21H12BrN3O4, m/z 449.0001
(calc. 449.0012).
To a solution of 7d (0.2 g, 0.57 mmol) in anhydrous THF
(6 mL) was added dropwise 5-methylisoxazole-4-carboxylic
acid chloride (0.14 g, 1.1 mmol) in anhydrous THF (3 mL)
under a N2 atmosphere with vigorous stirring at 26 ЊC. The
solution was stirred at 65 ЊC for 7 h. The mixture was cooled to
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 1 3 9 – 3 1 4 1
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J. J. Foley, D. B. Schmidt, R. S. Muccitelli, O. Jenkins, P. R. Murdock,
5-Bromo-2-(4-cyanobenzoyl)-3-[Z-(2-cyano-3-hydroxybut-2-
enoyl)amino]benzo[b]furan (11d)
N. C. Herrity, W. Halsey, G. Sathe, A. I. Muir, P. Nuthulaganti,
G. M. Dytko, P. T. Buckley, S. Wilson, D. J. Bergsma and D. W. P.
Hay, Mol. Pharmacol., 1999, 56, 657–663.
2 American Thoracic Society – 98th International Conference (May
2002, Atlanta) [D38] [Poster F4], Characterization of DUO-LT: A
novel Dual Cysteinyl Receptor Antagonist .
A solution of 10d (0.8 g, 1.8 mmol) and Et3N (2.4 mL) in
anhydrous THF (30 mL) was heated at 68 ЊC for 6 h, and the
solvent was evaporated off. The residue was poured into ice–
water, and made acid with 5% HCl solution and extracted with
CHCl3. The extract was washed with brine and dried. Evapor-
ation of the extract gave a residue which was recrystallized from
CH3CN to give 11d (0.66 g, 82%) as colorless needles. Mp 269
3 I. Fleming, Frontier Orbitals and Organic Chemical Reactions, Wiley,
NY, 1976, pp. 58.
4 K. Gewald and H. J. Kaensch, J. Prakt. Chem., 1973, 315, 779–785;
V. P. Baidya, S. B. Mahajam and Y. S. Agasimundin, Indian J. Chem.,
Sect. B: Org. Chem. Incl. Med. Chem., 1981, 20, 391–393; W. K. R. W.
Mederski, M. Osswald, D. Dorsch, M. Christadler, C.-J. Schmitges
and C. Wilm, Bioorg. Med. Chem. Lett., 1999, 9, 619–622; S. Rádl,
P. Hezký, J. Urbánková, P. Váchal and I. Krejcf, Collect. Czech.
Chem. Commun., 2000, 65, 280–297; S. Rádl, P. Hezký, P. Konvicka
and I. Krejcf, Collect. Czech. Chem. Commun., 2000, 65, 1093–1108;
S. S. Sangapure and S. Y. Agasimundin, Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem., 1976, 14, 6886–6891.
1
ЊC. H-NMR (DMSO-d6): δ 2.19 (3H, s, CH3), 7.61 (1H, d,
J = 8.7 Hz, 7-H), 7.71 (1H, dd, J = 8.7, 2.0 Hz, 6-H), 8.05 (2H,
m, 2Ј-, 6Ј-H or 3Ј-, 5Ј-H), 8.16 (2H, m, 2Ј-, 6Ј-H or 3Ј-, 5Ј-H),
8.66 (1H, d, J = 2.1 Hz, 4-H), 12.53 (1H, bs, NH). MS: m/z
449 (Mϩ, 55.84), 340 (100.00). HRMS: C21H12BrN3O4, m/z
449.0011 (calc. 449.0012).
5 3,5-Diamino-2-ethylbenzo[b]furan was obtained by catalytic hydro-
genation of 2-ethyl-3,5-dinitrobenzo[b]furan over Pd/C in EtOH.
6 Formula C29H26N4O5, formula weight = 522.56, monoclinic, space
group P21/c (no. 14), a = 17.709(3), b = 7.553(2), c = 19.656(2) Å,
Acknowledgements
We thank staff of the instrumental analysis centre of
Mukogawa Women’s University for 1H NMR and MS.
β = 100.926(8)Њ, V = 2581.5(7) Å3, T = 296 K, Z = 4, Dc = 1.344 g cmϪ3
,
F000 = 1096.00, µ(Cu-Kα) = 7.65 cmϪ1. 5184 reflections measured,
4619 (2θ < 135.15), Rint = 0.016, R1 = 0.058 (Rw = 0.170). CCDC
reference number 214287. See http://www.rsc.org/suppdata/ob/b3/
b307468d/ for crystallographic data in CIF or other electronic format.
7 The assays were achieved according to the procedure reported by
Nothacker et al. (ref. 1a).
8 E. Kuo, P. Hambleton, D. Kay, P. Evans, S. Matharu, E. Little,
C. McDowall, B. Jones, C. Hedgecock, C. Yea, A. Chan, P. Hairsine,
I. Ager, W. Tully, R. Williamson and R. Westwood, J. Med. Chem.,
1996, 39, 4608–4621; S. Greene, K. Watanabe, J. Braatz-Trulson and
L. Lou, Biochem. Pharmacol., 1995, 50, 861–867.
Notes and references
1 (a) H.-P. Nothacker, Z. Wang, Y. Zhu, R. K. Reinscheid, S. H. S. Lin
and O. Civelli, Mol. Pharmacol., 2000, 58, 1601–1608; (b) C. E. Heise,
B. F. O’Dowd, D. J. Figueroa, N. Sawyer, T. Nguyen, D.-S. Im,
R. Stocco, J. N. Bellefeuille, M. Abramovitz, R. Cheng, D. V.
Williams Jr., Z. Zeng, Q. Liu, L. Ma, M. K. Clements, N. Coulombe,
Y. Liu, C. P. Austin, S. R. George, G. P. O’Neill, K. M. Metters,
K. R. Lynch and J. F. Evans, J. Biol. Chem., 2000, 275, 30531–30536;
(c) H. M. Sarau, R. S. Ames, J. Chambers, C. Ellis, N. Elshourbagy,
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