Synthesis and insulin-sensitizing activity of a novel kind of benzopyran derivative

Article abstract of DOI:10.1016/S0960-894X(03)00734-0

A series of benzopyran derivatives was synthesized and their insulin-sensitizing activities were evaluated in 3T3-L1 cells. Compounds 6 and 11 exhibited more potent insulin-sensitizing activity than rosiglitazone.

Full text of DOI:10.1016/S0960-894X(03)00734-0

Bioorganic & Medicinal Chemistry Letters 13 (2003) 3437–3440
Synthesis and Insulin-Sensitizing Activity of a Novel Kind of
Benzopyran Derivative
Lei Tang, Juanhong Yu, Ying Leng, Ying Feng, Yushe Yang* and Ruyun Ji
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences,
Chinese Academy of Sciences, Shanghai 200031, China
Received 10 June 2003; revised 14 July 2003; accepted 15July 2003
Abstract—A series of benzopyran derivatives was synthesized and their insulin-sensitizing activities were evaluated in 3T3-L1 cells.
Compounds 6 and 11 exhibited more potent insulin-sensitizing activity than rosiglitazone.
# 2003 Elsevier Ltd. All rights reserved.
Non-insulin-dependent diabetes mellitus (NIDDM) is a
metabolic disorder characterized by hyperglycemia as
well as insulin resistance and/or impaired insulin secre-
tion. Hyperglycemia often leads to several compli-
cations such as neuropathy, retinopathy, nephropathy
and premature atherosclerosis.1 Therefore, it is impor-
tant to maintain an appropriate blood glucose level,
especially during the early stage of the disease. The
therapy for NIDDM is often by a combination of diet,
exercise, or with pharmacological agents.2 Since the
pioneer thiazolidinedione compound, ciglitazone, was
reported improving blood glucose level by increasing
insulin sensitivity,3 several new thiazolidine-2,4-diones
such as troglitazone,4 piglitazone,5 rosiglitazone6 were
launched into market since 1997 (Chart 1). However,
possibly due to their common thiazolidine-2,4-dione
group, thiazolidinedione compounds are associated with
a poor safety profile.7 The first-marketed troglitazone
was even called back from the market for its severe
hepatic toxicity in 1999. The research of non-thiazolidi-
nedione insulin sensitizer has attracted much more
attention in recent years.
in ob/ob mice8 and increasing insulin-sensitizing activity
in 3T3-L1 cells respectively.9 Meanwhile, we found that
compound 2 possesses weak insulin sensitizing activity
in our previous research (not published). Both two
compounds contain a alkoxyphenyl structure, which
intrigued us to design a series of benzopyran agents on
the base of them (Chart 2). Coumarin-3-carboxylic
methyl acid ester was selected as the core structure in
our original design. Some of the known heterocycle
structures in thiazolidinedione insulin sensitizer were
attached to this core structure with the link of the
alkyloxy group.
Condensation of 7-hydroxy-coumarin-3-carboxylic acid
methyl acid ester 3 with the desired heterocyclic alcohol
We were interested in developing a series of non-thia-
zolidinedione insulin sensitizer, which might surmount
the hepatic toxicity problems associated with the known
thiazolidinediones. Of all non-thiazolidinedione insulin
sensitizers, 1,3-dicarbonyl compounds 1 and JTP-20993
(Chart 1) were reported decreasing blood glucose level
*Corresponding author. Tel.: +86-21-5080-6600-3405; e-mail:
ysyang@mail.schnc.ac.cn
Chart 1.
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00734-0

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L. Tang et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3437–3440
via Mitsunobu reaction yielded compounds 4–6. Saponi-
fication of 4–6 with NaOH afforded compounds 7–9,
respectively. Catalytic hydrogenation of compounds 4
and 6 gave compounds 10 and 11 (Scheme 1). Com-
pound 13 was prepared from compound 12 via Mitsu-
nobu reaction. Hydrogenation of compound 13, and
then removal of tert-butyl group with trifluoroacetic
acid gave compound 14 (Scheme 2). The procedure for
the synthesis of compound 16 was outlined in Scheme 3.
Condensation of compound 3 with 2-(N-tert-butoxy-
carbonyl-N-methlyamino)ethanol afforded compound
15. Catalytic hydrogenation of compound 15 followed
by removal of the Boc group and addition to 2-chloro-
benzoxazole gave compound 16. Compounds 17 and 18
were prepared from 6-hydroxy-coumarin-3-carboxylic
acid methyl ester via the procedure similar to that in
Scheme 1.
All compounds were screened for insulin-sensitizing
activity by measuring the triglyceride accumulation
Chart 2.
Scheme 1. Reagents: (a) R-OH, Ph3P, DEAD, THF; (b) 10% NaOH aqueous; (c) H2-Pd/C, MeOH/dioxane (3:1).
Scheme 2. Reagents: (a) 2-(5-methyl-2-phenyl-oxazol-4-yl)ethanol, Ph3P, DEAD, THF, 36%; (b) H2-Pd/C, MeOH/dioxane (1:1); (c) trifluoroacetic
acid, CH2Cl2, 70% for two steps.
Scheme 3. Reagents: (a) Ph3P, DEAD, 2-(N-Boc-N-methlyamino)ethanol, THF, 73%; (b) H2-Pd/C, dioxane; (c) trifluoroacetic acid, CH2Cl2;
(d) 2-chlorobenzoxazole, triethylamine, 50% for three steps.

L. Tang et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3437–3440
3439
resulting from insulin-regulated differentiation of 3T3-
L1 cells.9 The marketed insulin-sensitizing drug rosigli-
tazone was selected as positive control. All compounds’
activities in Table 1 are given as a percentage of rosigli-
tazone response for insulin-sensitizing activity at 1 mM
concentration, and the EC30 values (effective concen-
tration for 30% enhancement of insulin-induced trigly-
ceride accumulation in 3T3-L1 cells) of some
compounds are also given.
As indicated in Table 1, compounds 610 and 1111
exhibited more potent insulin-sensitizing activity than
Table 1. Screening data of insulin-sensitizing activity for benzopyran derivatives
Compd
R
X
Double bond a
Insulin-sensitizing activity
Triglyceride accumulation at 1 mMb
EC30c (M)
4
CH3
CH3
CH3
H
Yes
Yes
Yes
Yes
Yes
Yes
No
46
108
129
15
5
3.44Â10À7
8.00Â10À9
6
7
8
H
25
9
H
103
27
3.00Â10À7
10
CH3
CH3
Bu-t
H
11
No
132
89
1.56Â10À8
3.82Â10À7
1.10Â10À7
13
Yes
No
14
98
15
CH3
CH3
Yes
No
115
108
33
16
2.19Â10À7
17
18
28
Rosiglitazone
100
2.03Â10À8
aYes: 3,4-double bond; No: 3,4-single bond.
b% activity of rosiglitazone at 1 mM. Values are means of three experiments.
cEffective concentration (M) for 30% enhancement of insulin-induced triglyceride accumulation in 3T3-L1 cells.

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L. Tang et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3437–3440
rosiglitazone according to their EC30 values. By com-
paring compound 4 with 10, and 6 with 11, the single-
bond and double-bond derivatives did not show much
difference on activity. The activities of those compounds
with a free carboxy group were lower than their corre-
sponding methyl ester derivatives. Replacement of
methyl group in compound 6 with tert-butyl group
(compound 13) resulted in a dramaticly reduced activ-
ity. The example of compounds 17 and 18 suggested
that position of substituent have important effect on
activity. Both these synthesized compounds and JTP-
20993 contain a 1,3-dicarbonyl group, which suggests
this kind of structure is important in the search of non-
thiazolidinedione insulin-sensitizing agents.
4. Yoshioka, T.; Fujita, T.; Kanai, T.; Aizawa, Y.; Kur-
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32, 421.
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Thurlby, P. L. J. Med. Chem. 1994, 37, 3977.
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8. (a) Smithkline Beecham PLC. World Patent 9413650, 1994.
(b) Buckle, D.R; Cantello, B. C. C.; Cawthorne, M. A.; Coyle,
P. J.; Dean, D. K.; Faller, A.; Haigh, D.; Hindley, R. M.;
Jefcott, L. J.; Lister, C. A.; Pinto, I. L.; Rami, H. K.; Smith,
D. G.; Smith, S. A. Bioorg. Med. Chem. Lett. 1996, 6, 2127.
9. Shinkai, H.; Onogi, S.; Tanaka, M.; Shibata, T.; Iwao, M.;
Wakitani, K.; Uchida, I. J. Med. Chem. 1998, 41, 1927.
10. Data of 6: colorless crystals, mp 139–140, 1H NMR
(CDCl3, 400 MHz) d 2.36 (s, 3H), 3.02 (t, J=6.6 Hz, 2H), 3.91
(s, 3H), 4.34 (t, J=6.5Hz, 2H), 6.80 (d, J=2.2 Hz, 1H), 6.85
(dd, J=8.7 Hz, 2.3 Hz, 1H), 7.35–7.42 (m, 3H), 7.46 (d, J=8.8
Hz, 1H), 7.90–7.98 (m, 2H), 8.50 (s, 1H). EI-MS (m/z): 405
(16, M+), 186 (100).
In summary, we have discovered a novel class of ben-
zopyran derivatives which possessing potent insulin-
sensitizing activity. This could be used as a lead struc-
ture in the search of non-thiazolidinedione insulin-sen-
sitizing agents.
11. Data of 11: colorless crystals, mp 128–131, 1H NMR
(CDCl3, 400 MHz) d 2.37 (s, 3H), 2.97 (t, J=6.5Hz, 2H), 3.08
(dd, J=15.9 Hz, 6.1 Hz, 1H), 3.34 (dd, J=15.7 Hz, 8.6 Hz,
1H), 3.65-3.78 (m, 4H), 4.22 (t, J=6.4 Hz, 2H), 6.60 (d, J=2.2
Hz, 1H), 6.64 (dd, J=8.5Hz, 2.3 Hz, 1H), 7.06 (d, J=8.4 Hz,
1H), 7.30–7.48 (m, 3H), 7.92–8.05(m, 2H). EI-MS ( m/z): 407
(20, M+), 186 (100).
References and Notes
1. Porte, D., Jr.; Schwartz, M. W. Science 1996, 272, 699.
2. Taylor, S. I.; Accili, D.; Imai, Y. Diabetes 1994, 43, 735.
3. Sohda, T.; Mizuno, K.; Imamiya, E.; Sugiyama, Y.; Fujita,
T.; Kawamatsu, Y. Chem. Pharm. Bull. 1982, 30, 3580.