Synthesis and hypoglycaemic activity of some new flavone derivatives. Part 1: Flavonylsulphonylurea derivatives

Article abstract of DOI:10.1002/(SICI)1521-4184(199912)332:12<435::AID-ARDP435>3.0.CO;2-L

A new series of flavonyl-3'-sulphonylurea derivatives (1-7) was prepared by reaction of several isocyanates with flavone-3'-sulphonamide (III). The prepared compounds were tested for their insulinotropic activities in INS-1 cells. Compounds 1 and 4 were able to increase insulin release in the presence of 8.3 mM glucose at least at the higher concentrations used.

Full text of DOI:10.1002/(SICI)1521-4184(199912)332:12<435::AID-ARDP435>3.0.CO;2-L

Flavonylsulphonylurea Derivatives
435
Synthesis and Hypoglycaemic Activity of Some New
Flavone Derivatives
Part 1: Flavonylsulphonylurea Derivatives
a)
b)
a)
Oya Bozdag , Eugen J. Verspohl , and Rahmiye Ertan *
a) Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, 06100-Tandogan, Ankara, Turkey
b) Department of Pharmacology, Institute of Medicinal Chemistry, Münster University, Hittorfstr. 58–62, 48149 Münster, Germany
Key Words: Flavone; hypoglycaemic activity; flavonylsulphonylurea
Summary
Results and Discussion
Non-substituted flavone (I) was prepared by the Baker-
Venkataraman method. Flavone-3′-sulphonyl chloride (II)
was obtained by I in chlorosulphonic acid. The sulphonyl
A new series of flavonyl-3′-sulphonylurea derivatives (1–7) was
prepared by reaction of several isocyanates with flavone-3′-sul-
phonamide (III). The prepared compounds were tested for their
insulinotropic activities in INS-1 cells. Compounds 1 and 4 were
able to increase insulin release in the presence of 8.3 mM glucose
at least at the higher concentrations used.
chloride group of flavone was converted into sulphonamide
[12]
in NH
. Flavone-3′-sulphonylurea derivatives (1–7) were
3
synthesised by substituted isocyanates and flavone-3′-sul-
phonamide (III) (Scheme 1).
The structure of flavone-3′-sulphonamide (III) was eluci-
1
dated by H NMR, Mass spectral data and IR findings. In
addition the X-ray analysis data of III also prove these
[12]
findings
.
Introduction
All spectral data were in accordance with assumed struc-
tures of 1–7. IR spectra of the compounds showed γ-pyron
Type 2 diabetes is characterised by abnormalities of insulin
–1
1
[1,2]
C=O stretching bonds at 1622–1664 cm . In H NMR spec-
tra, it has seen the characteristic protons belonging the fla-
vone ring at the various δ ppm values. Flavone 5-H proton of
all the compounds except 6 was observed at lower field
between 7.97–8.39 ppm than other flavone ring protons due
to the effect of the CO group of γ-pyron. Synthesised com-
secretion and by insulin resistance of major target tissues
.
The sulphonylurea class of oral antidiabetic agents that are
largely used in the treatment of type 2 diabetes act via a
specific receptor as secretagogues and increase the availabil-
[3, 4]
ity of insulin
. In this study, we report the synthesis and
insulin releasing activities of some sulphonylurea derivatives
+
pounds 1, 2, 4, and 6 have molecular ion (M ) peak, the other
containing flavone ring system that are already known to have
[5–7]
[8–
antidiabetic
and aldose reductase inhibitor activity
not. The characteristic fragmentation ions of flavone and
sulphonylurea moiety of all the compounds are shown (a, b,
11]
.
Scheme 1. General synthesis of 1–7.
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0365-6233/99/1212/0435 $17.50 +.50/0

436
Bozdag, Verspohl, and Ertan
Table 1. Spectral data of 1–7.
—————————————————————————————————————————————————————————————–
No
1H NMR ( ppm)
MS (70 eV)
m/z
IR (cm–1
(γ-pyron CO)
)
—————————————————————————————————————————————————————————————–
1
0.95 (t, 3H, CH3), 3.00–3.05 (m, 2H, CH2), 6.30 (broad s,1H, CONH),
6.94 (s, 1H, 3-H), 7.45 (ddd, 1H, J6,5=J6,7=7.34 Hz, 6-H), 7.66–7.77
(m, 3H, 5′, 7, 8-H), 8.01 (s, 1H, 2′-H), 8.08 (dd, 2H, 4′, 6′-H), 8.25
(d, 1H, J5,6=7.42 Hz, 5-H), 8.51 (s, 1H, SO2NH)
372(M+),327,301,221,
194,121,120,105,101,
92,71,64,63, 56 (100%)
1655
2
3.66 (t, 2H, NHCH2), 4.99–5.09 (dd, 2H, CH=CH2), 5.69–5.79
(m, 1H, CH2-CH=CH2), 6.55 (t, 1H, CONH), 6.99 (s, 1H, 3-H),
7.49 (ddd, 1H, J6,5=J6,7=7.31 Hz, 6-H), 7.70–7.83 (m, 3H, 5′, 7, 8-H),
8.05 (s, 1H, 2′-H), 8.1–8.14 (dd, 2H, 4′, 6′-H), 8.29 (d, 1H, J5,6=7.88 Hz,
5-H), 8.56 (s, 1H, SO2NH)
386(M+),328,327,301,
221,194,121,120,105,
101,92,84,64(100%),
63, 57
1645
3
4
5
6
1.02 (d, 6H, CH3), 3.65–3.75 (m, 1H, CH), 6.00 (broad s, 1H, CONH),
6.86 (s, 1H, 3-H), 7.41 (ddd, 1H, J6,5=J6,7=7.55 Hz, 6-H), 7.60–7.78
(m, 3H, 5′, 7, 8-H), 7.80 (s, 1H, 2′-H), 8.08 (dd, 2H, 4′, 6′-H), 8.14
(d, 1H, J5,6=7.73 Hz, 5-H), 8.49 (s, 1H, SO2NH)
327,301,221,194,121,120,
105,101, 92(100%),85,
64, 63
1653
1664
1648
1622
0.74 (t, 3H, CH3), 1.04–1.31 (m, 4H, (CH2)2CH3), 2.93 (m, 2H, NHCH2),
6.69 (t, 1H, CONH), 7.11 (s, 1H, 3-H), 7.52 (ddd, 1H, J6,5=J6,7=6.79 Hz,
6-H), 7.76–7.85 (m, 3H, 5′, 7, 8-H), 7.90 (s, 1H, 2′-H), 8,0–8.10 (dd, 2H,
4′,6′-H) 8.39 (d, 1H, J5,6=7.86 Hz, 5-H), 8.52 (s, 1H, SO2NH)
400(M+),328,327,301,
221,194,121, 120 (100%),
!05, 101, 99, 92, 73, 64,
63, 57
1.06–1.71 (m, 11H, cyclohexyl protons), 6.20 (d, 1H, CONH), 6.93
(s, 1H, 3-H), 7.45 (ddd, 1H, J6,5=J6,7=7.52 Hz, 6-H), 7.65–7.76
(m, 3H, 5′, 7, 8-H), 7.96 (s, 1H, 2′-H), 8.09 (dd, 2H, 4′, 6′-H),
8.23 (d, 1H, J5,6=8.01 Hz, 5-H), 8.50 (s, 1H, SO2NH)
328,327,301,285,221,
194,125,121,120,105,
101, 99, 92(100%),64,
63, 57
6.72 (ddd, 1H, Jc,b=7.34 Hz, c), 6.86 (s, 1H, 3-H), 7.04 (ddd, 2H,
Jb,a=7.54 Hz, bb′), 7.40 (ddd, 1H, J6,5=J6,7=7.66, 6H), 7.45 (dd, 2H, aa′),
7.53 (ddd, 1H, J7,8=J7,6=7.81 Hz, 7-H), 7.61 (d, 1H, J8,7=8.38 Hz, 8-H),
7.72 (ddd, 1H, J5′,4′=J5′,6′=7.04 Hz, 5′-H), 7.91 (s, 1H, 2′-H), 7.94
(s, 1H, CONH), 7.97 (d, 1H, J5,6=7.97 Hz, 5-H), 8.06–8.09 (m, 2H,
4′, 6′-H), 8.49 (s, 1H, SO2NH)
420(M+),328,327,301,
285,221,194,121,120,
119,105,101,93,92,64,
63 (100%)
7
2.15 (s, 3H, CH3), 6.85 (d, 2H, Jba=8.30 Hz, bb′), 6.89 (s, 1H, 3-H),
7.29 (d, 2H, Jab=8.34 Hz, aa′), 7.43 (ddd, 1H, J6,7=J6,5=7.35 Hz, 6-H),
7.55 (ddd, 1H, J7,6=J7,8=7.81 Hz, 7-H), 7.65 (d, 1H, J8,7=8.33 Hz, 8-H),
7.75 (ddd, 1H, J5′,4′=j5′,6′=7.11 Hz, 5′-H), 7.99 (s, 1H, 2′-H), 8.01
(d, 1H, 5-H), 8.08 (d, 2H, 4′, 6′-H), 8.48 (s, 1H, SO2NH)
328, 327, 301, 285, 221,
194, 133 (100%), 121,
120, 107, 105, 101, 92,
64, 63
!624
—————————————————————————————————————————————————————————————–
Scheme 2. Mass fragmentations
of 1–7.
Arch. Pharm. Pharm. Med. Chem. 332, 435–438 (1999)

Flavonylsulphonylurea Derivatives
437
+.
+.
+.
Table 2. Effects of various compounds on glucose-mediated insulin release
from INS-1 cells. INS-1 cells in multi-wells were washed three times and
incubated in KRBH-buffer for 90 min at 8.3 mM glucose. The results are
expressed as percent insulin release at 8.3 mM glucose alone. Values ob-
tained in the presence of 3.0 mM glucose (substimulatory concentration) and
glibenclamide (1 µg/ml) in the presence of 8.3 mM glucose serve as controls.
Each value represents the mean ± S.E.M., number of independent experi-
ments in parentheses.
A , B , B ). Some spectral data of the compounds are
1
summarised shown in Table 1.
Compounds 1–7 were evaluated for their in vitro insulin
releasing activity by using INS-1 cells (Table 2). Inhibitory
effects were observed using some compounds, especially
using the lower concentrations of compounds 4 and 6. There
was a tendency for inhibition of insulin release with respect
to compound 2 and 7. Compound 5 exhibits no effect.
What we need are new insulin stimulatory compounds;
compounds 1 and 4 were able to increase insulin release at
least at the higher concentrations used.
Insulin release at 8.3 mM glucose was normalised to 100%.
Control experiments were performed with either low glucose
(3.0 mM) or glibenclamide (1 µg/ml) at 8.3 mM glucose, one
of the leading sulphonylureas in treatment of diabetes. Sub-
stimulatory glucose (3.0 mM) has a low effect (63.0% of that
at 8.3 mM glucose). 1 µg/ml glibenclamide at 8.3 mM glu-
cose increased insulin release from 100 to 210.4%. This is to
compare the effects of various compounds with that of an
established control compound.
——————————————————————————————
Compound
Insulin release (%)
——————————————————————————————
Glucose [3.0 mM]
Glucose [8.3 mM]
plus 1 [1 µg/ml]
plus 1 [10 µg/ml]
plus 2 [1 µg/ml]
plus 2 [10 µg/ml]
plus 3 [1 µg/ml]
plus 3 [10 µg/ml]
plus 4 [1 µg/ml]
plus 4 [10 µg/ml]
plus 5 [1 µg/ml]
plus 5 [10 µg/ml]
plus 6 [1 µg/ml]
plus 6 [10 µg/ml]
plus 7 [1 µg/ml]
plus 7 [10 µg/ml]
plus Glibenclamide
[1 µg/ml]
62.96 ± 5.68 (9)
100 (9)
101.6 ± 1.58 (3)
160.2 ± 13.3 (3)
85.63 ± 15.42 (3)
118.6 ± 11.09 (3)
138.7 ± 11.96 (3)
85.63 ± 15.42 (3)
82.84 ± 7.10 (3)
152.6 ± 14.1 (3)
87.26 ± 5.23 (3)
92.60 ± 11.76 (3)
53.35 ± 6.18 (3)
107.5 ± 11.2 (3)
86.29 ± 13.3 (3)
124.3 ± 10.4 (3)
210.4 ± 15.6 (11)
Acknowledgements
This work was supported by Research Organization of Ankara University,
Turkey (No.97030002) and TÜBITAK (No.SBAG-AYD-158). The excel-
lent technical assistance of I. Kaiserling-Buddemeier and B. Tollkühn is
acknowledged. We thank Hoechst AG (Germany) for supplying (mono
125I-Tyr A14)-porcine insulin.
——————————————————————————————
Table 3. Reaction conditions of 1–7.
—————————————————————————————————————————————————————————————–
No
Formula
React.
time
React.
temp. °C
Purification procedure
Yield
%
Mp (°C)
—————————————————————————————————————————————————————————————–
1
2
3
4
5
6
7
C18H16N2O5S, 0.8H2O
1-(3′-Flavone)sulphonyl-3-ethylurea
10
10
12
12
3
40
60
60
60
60
60
60
Crystallisation from ethanol
Crystallisation from ethanol
32.37
48.74
62.71
67.73
28.26
35.83
55.48
206–208
178–180
173–174
184–186
228–229
269–270
294–296
C19H16N2O5S
1-(3′-Flavone)sulphonyl-3-allylurea
C19H18N2O5S,1.1(CH3)2CHOH
1-(3′-Flavone)sulphonyl-3-isopropylurea
CHCl3:isopropanol (1:0.1)
(Flash chrom.)
C20H20N2O5S, 0.2H2O
1-(3′-Flavone)sulphonyl-3-n-buthylurea
Crystallisation from ethanol
Crystallisation from ethanol
CHCl3 (Flash chrom.)
C22H22N2O5S, 0.35H2O
1-(3′-Flavone)sulphonyl-3-cyclohexylurea
C22H16N2O5S,0.3CHCl3,O.1H2O
1-(3′-Flavone)sulphonyl-3-phenylurea
12
4
C23H18N2O5S,0.3(CH3)2CHOH,1H2O
1-(3′-Flavone)sulphonyl-3-p-tolylurea
CHCl3:isopropanol (1:0.1)
(Flash chrom.)
—————————————————————————————————————————————————————————————–
Arch. Pharm. Pharm. Med. Chem. 332, 435–438 (1999)

438
Bozdag, Verspohl, and Ertan
Insulin Release
Experimental
Chemistry
To measure insulin secretion, half-confluent cells in micro-wells were
incubated for 90 min at 37 °C in the aforementioned KRBH buffer. Insulin
released into the medium was assayed with a radioimmunoassay using rat
insulin (Novo Nordisk, Bagsvaerd, Denmark) as a standard, (mono 125I-Tyr
A14)-porcine insulin as the labelled compound (Hoechst, Germany) and
anti-insulin antibodies from Linco (St. Louis, U.S.A.). Each compound had
been checked for non-interference with the insulin radioimmunoassay. The
data were corrected for the effects of solubilizing compounds (ethanol,
DMSO).
Melting points were determined with a Büchi SMP-20 melting point
apparatus and are uncorrected. All the instrumental analysis were performed
by Instrumental Analysis Lab. of Scientific and Technical Research Council
of Turkey (TUBITAK, Ankara, Turkey), with a Jasco FT/IR 420 spectrome-
ter (IR spectra were recorded as potassium bromide discs), a Bruker AC 400
NMR spectrometer (the 1H NMR spectra were measured in DMSO-d6 and
CDCl3, all chemical shifts were reported as δ (ppm) values) and VG Platform
II Mass spectrometer. Elementary analysis were performed on a Leco CHNS
932 analyser and satisfactory results ± 0.4% of calculated values (C, H, N,
S) were obtained. For the chromatographic analysis Merck Silica Gel 60
(230–400 mesh ASTM) was used. The chemical reagents used in synthesis
were purchased from E. Merck (Darmstadt, FRG) and Aldrich (Milwaukee,
USA). Flavone-3′-sulphonamide (III) [12] was synthesised in our laboratory.
References
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Received: August 2,1999 [FP417]
Arch. Pharm. Pharm. Med. Chem. 332, 435–438 (1999)