Synthesis and pharmacological evaluation of K(ATP)-channel openers related to cromakalim: Introduction of arylsulphonylurea moieties

Article abstract of DOI:10.1211/146080899128734587

A series of 4-(arylsulphonylaminocarbonylamino)-3,4-dihydro-2,2-dimethyl-2 H-1-benzopyran derivatives were prepared and evaluated as potential ATP-sensitive potassium-channel activators. Pharmacological studies showed that some compounds expressed vasodilator efficacy on vascular smooth muscle. The compounds had no inhibitory activity on insulin secretion from pancreatic β-cells.

Full text of DOI:10.1211/146080899128734587

Pharm. Pharmacol. Commun. 1999, 5: 189±193
# 1999 Pharm. Pharmacol. Commun.
Synthesis and Pharmacological Evaluation of KATP-channel
Openers Related to Cromakalim: Introduction of
Arylsulphonylurea Moieties
S. KHELILI, Q. -A. NGUYEN*, P. LEBRUN*, J. DELARGE AND B. PIROTTE
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Laboratoire de Chimie Pharmaceutique, Universite de Liege, C.H.U., 1 Avenue de l'Hopital, B-4000 Liege
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and *Laboratoire de Pharmacodynamie et de Therapeutique, Universite Libre de Bruxelles, 808, route de
Lennik, B-1070 Bruxelles, Belgium
Abstract
A series of 4-(arylsulphonylaminocarbonylamino)-3,4-dihydro-2,2-dimethyl-2 H-1-benzo-
pyran derivatives were prepared and evaluated as potential ATP-sensitive potassium-
channel activators.
Pharmacological studies showed that some compounds expressed vasodilator ef®cacy on
vascular smooth muscle. The compounds had no inhibitory activity on insulin secretion
from pancreatic b-cells.
Materials and Methods
ATP-sensitive potassium channels (KATP channels)
attract considerable interest because of their
essential role in diverse fundamental physiological
processes. KATP channels are present in numerous
cell types including endocrine cells (Cook & Hales
1984), smooth muscle cells (Standen et al 1989),
cardiac cells (Noma 1983) and central neurons
(Bernardi et al 1988). Several synthetic agents
belonging to distinct chemical classes of molecules
are activators of KATP channels and present inter-
esting pharmacological and medical applications.
Unfortunately, lack of tissue selectivity which is
responsible for side effects has limited their use.
Thus, the challenge is to ®nd an agent exhibiting
tissue selectivity, with even moderate activity. We
describe here the synthesis and pharmacological
evaluation of some 4-(arylsulphonylaminocarbo-
nylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopy-
ran derivatives (Figure 1), structurally related to
cromakalim and other dihydrobenzopyran potas-
sium-channel openers (Cho et al 1996; Rounyal et
al 1997). The compounds were tested on pancreatic
insulin secreting cells and on vascular smooth
muscle cells.
Chemistry
Melting points were determined on a BuÈchi-Tottoli
capillary apparatus and are uncorrected. IR spectra
were recorded as KBr pellets on a Perkin-Elmer
1000 FT-spectrophotometer. 1H NMR spectra were
recorded on a Bruker AW-80 (80 MHz) using d6-
DMSO as solvent. Chemical shifts (d ppm) refer to
hexamethyldisiloxane which was used as an
internal reference. NH signal appeared as broad
singlets exchangeable with D2O. Key: t ˆ
triplet, s ˆ singlet, d ˆ doublet, q ˆ quartet, m ˆ
multiplet. Elemental analyses (C, H, N or S) were
performed on a Carlo-Erba EA 11008-elemental
analyser.
General procedure for preparing 4-(N-acetyla-
mino)-3,4-dihydro-2,2-dimethyl-2H -1-benzopyrans
(7a±b, 9)
A suspension of 3,4-dihydro-2,2-dimethyl-2 H-1-
benzopyran-4-ols (6a±b, 8) (77Á8 mmol), obtained
as previously described (Buckle et al 1990; Shaw-
cross & Sard 1995), in acetonitrile (200 mL) was
added dropwise to a stirred solution of acetonitrile
(40 mL) in 98% sulphuric acid (10 mL) kept
between 10 and 0ꢀC. The mixture was allowed to
warm to room temperature and stirring was con-
tinued for 1 h. The solution was poured into cold
Correspondence: S. Khelili, Laboratoire de Chimie Pharma-
Â
ceutique, Universite de Liege, C.H.U., 1 Avenue de l'Hopital,
B-4000 Liege, Belgium.
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190
S. KHELILI ET AL
4-(N-Acetylamino)-3,4-Dihydro-2,2-dimethyl-6-
¯uoro-2H-1-benzopyran (7b). White powder (90%
yield); mp 163±165ꢀC; IR (KBr) n: 3282
1
1
(NH) cm ; 1639 (CO) cm . 1H NMR (d6-
DMSO) d: 1Á18 (6H, 2s, 2CH3), 1Á86 (2H, m,
CH2), 1Á93 (3H, s, CH3), 5Á16 (1H, m, CH), 7Á13
(3H, m, CHarom), 8Á27 (1H, d, NH). Calculated for
C13H16FNO2: C, 65Á81; H, 6Á80; N, 5Á90. Found: C,
66Á04; H, 7Á08; N, 6Á02%.
4-(N-Acetylamino)-6-amino-3,4-dihydro-2,2-
dimethyl-2H-1-benzopyran monohydrate (9).
White powder (85% yield); mp 105±107ꢀC; IR
1
1
(KBr) n: 3362, 3274, (NH) cm ; 1629 (CO) cm .
1H NMR (d6-DMSO) d: 1Á11 (6H, 2s, 2CH3), 1Á58
(2H, m, CH2), 2Á00 (3H, s, CH3), 4Á41 (2H, s, NH2),
4Á85 (1H, m, CH), 6Á40 (3H, s, CHarom), 8Á1 (1H, d,
NH). Calculated for C13H18N2O2.H2O: C, 61Á88; H,
7Á99; N, 11Á10. Found: C, 62Á07; H, 8Á2; N, 11Á25%.
6-Amino-3,4-dihydro-2,2-dimethyl-2H-1-benzo-
pyran-4-ol (8). 6-(N-Acetylamino)-3,4-dihydro-
2,2-dimethyl-2H-1-benzopyran-4-ol (6c) (10 g,
42Á32 mmol), obtained as previously described
(Buckle et al 1990; Shawcross & Sard 1995), was
suspended in a solution of 10% sodium hydroxide
(400 mL). The mixture was re¯uxed for 90 min.
After cooling, the precipitate was collected by
®ltration, washed with cold water and dried.
Brown powder (90% yield); mp 151±153ꢀC; IR
1
1
(KBr) n: 3348, 3284, 3200 (NH) cm . H NMR
(d6-DMSO) d: 1Á21 (6H, 2s, 2CH3), 1Á75 (2H, m,
CH2), 4Á48 (3H, m, CH ‡ NH2), 5Á1 (1H, s, OH),
6Á39 (2H, s, CHarom), 6Á67 (1H, s, CHarom). Calcu-
lated for C11H15NO2. C, 68Á37; H, 7Á82; N, 7Á25.
Found: C, 68Á10; H, 8Á01; N, 7Á42%.
Figure 1. Synthesis of 4-(arylsulphonylaminocarbonyla-
mino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran derivatives.
Reagents: i. (CH3CO)2O, H2SO4; ii. AlCl3; iii. CH3COCl,
pyridine; iv. CH3COCl, AlCl3, CS2; v. acetone, pyrrolidine;
vi. NaBH4, CH3OH; vii. CH3CN, H2SO4; viii. HCl 37%; ix.
NaOH 10%; x. CH3CO3H, CH2Cl2; xi. 4-Y-C6H4SO2NCO,
CH2Cl2.
4-(N-Acetylamino)-3,4-dihydro-2,2-dimethyl-6-
nitro-2H-1-benzopyran (10). A solution of 4-(N-
acetylamino)-6-amino-3,4-dihydro-2,2-dimethyl-
2H-1-benzopyran (9) (1 g, 4Á27 mmol) in dichloro-
methane (20 mL) was added dropwise to a stirred
cooled solution ( 10 to 0ꢀC) of peroxyacetic acid
(5 mL; 32% weight in acetic acid) in dichloro-
methane (5 mL). Stirring was continued for 3 h
and the temperature raised to room temperature.
After dilution with dichloromethane (20 mL), the
solution was washed with water, 5% sodium bicar-
bonate solution and ®nally brine. The organic layer
was dried with magnesium sulphate and dichloro-
methane was removed under reduced pressure. The
product was puri®ed by ¯ash chromatography
using ethyl acetate as mobile phase and silica gel
(60 F254) as solid phase. White crystals (80%
yield); mp 153±155ꢀC; IR (KBr) n: 3242
water and the white precipitate collected by
®ltration, washed with water and dried. Compound
9, a sulphate salt, was precipitated in its nonionic
form by making the solution alkaline using sodium
hydroxide. It was then collected by ®ltration,
washed with water and dried.
4-(N-Acetylamino)-6-bromo-3,4-dihydro-2,2-
dimethyl-2H-1-benzopyran (7a). White powder
(95% yield); mp 165±167ꢀC; IR (KBr) n: 3287
1
1 1
(NH) cm ; 1647 (CO) cm . H NMR (d6-DMSO)
d: 1Á18 (6H, 2s, 2CH3), 1Á85 (2H, m, CH2), 2Á00
(3H, s, CH3), 5Á19 (1H, m, CH), 6Á7 (1H, m,
CHarom), 7Á2 (2H, m, CHarom), 8Á33 (1H, d, NH).
Calculated for C13H16BrNO2: C, 52Á36; H, 5Á41; N,
4Á70. Found: C, 52Á48; H, 5Á59; N, 4Á85%.
1
1
(NH) cm ; 1631 (CO) cm ; 1Á38 (6H, 2s,

NEW ATP-SENSITIVE POTASSIUM-CHANNEL OPENERS
191
2CH3), 2Á35 (2H, m, CH2), 5Á11 (1H, m, CH), 6Á95
4-(Benzenesulphonylaminocarbonylamino)-6-
(1H, m, CHarom), 8Á03 (2H, m, NH ‡ CHarom), 8Á38
(1H, d, CHarom). Calculated for C13H16N2O4: C,
59Á08; H, 6Á10; N, 10Á60. Found: C, 59Á19; H, 6Á28;
N, 10Á73%.
bromo-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran
(12a). White powder (85% yield); mp 209±211ꢀC;
IR (KBr) n: 3341, 3170 (NH), 1666 (CO), 1291,
1
1
1168 cm (SO2); H NMR (d6-DMSO) d: 1Á22
(6H, 2s, 2CH3), 1Á9 (2H, m, CH2), 4Á7 (1H, m, CH),
7Á3 (8H, m, CHarom), 10Á7 (1H, s, NH). Calculated
for C18H19BrN2O4S: C, 49Á21; H, 4Á36; N, 6Á38; S,
7Á30. Found: C, 48Á80; H, 4Á55; N, 6Á45; S, 7Á69%.
General procedure for preparing 4-amino-3,4-
dihydro-2,2-dimethyl-2H -1-benzopyrans (11a±c)
A suspension of 4-(N-acetylamino)-3,4-dihydro-
2,2-dimethyl-2H-1-benzopyrans
(7a±b,
10)
6-Bromo-3,4-dihydro-2,2-dimethyl-4-(4-methylben-
zenesulphonylaminocarbonylamino)-2H-1-benzo-
pyran (12b). White powder (90% yield); mp 225±
227ꢀC; IR (KBr) n: 3261, 3164 (NH), 1693 (CO),
1261, 1166 cm (SO2); H NMR (d6-DMSO) d:
1Á10 (6H, 2s, 2CH3), 1Á9 (2H, m, CH2), 2Á35 (3H, s,
CH3), 4Á73 (1H, m, CH), 7Á3 (7H, m, CHarom),
10Á65 (1H, s, NH). Calculated for C19H21BrN2O4S:
C, 50Á34; H, 4Á67; N, 6Á18; S, 7Á07. Found: C,
50Á37; H, 4Á75; N, 6Á45; S, 7Á16%.
(75Á7 mmol) in 37% hydrochloric acid (250 mL)
was re¯uxed for 10 h. Hydrochloric acid was
removed under vacuum and the residue was dis-
solved in water (200 mL). The solution was cooled
and 10% aqueous sodium hydroxide was added
until alkaline. The amine, which precipitated from
the solution, was collected by ®ltration, washed
with water and dried under vacuum.
1
1
4-Amino-6-bromo-3,4-dihydro-2,2-dimethyl-2H-1-
benzopyran (11a). White powder (90% yield); mp
1
64±66ꢀC; H NMR (d6-DMSO) d: 1Á3 (6H, 2s,
6-Bromo-4-(4-chlorobenzenesulphonylaminocarbo-
nylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzo-
pyran (12c). White powder (95% yield); mp 228±
230ꢀC; IR (KBr) n: 3341, 3160 (NH), 1669 (CO),
2CH3), 1Á89 (2H, m, CH2), 3Á2 (2H, s, NH2), 3Á94
(1H, m, CH), 6Á7 (1H, d, CHarom), 7Á25 (1H, d,
CHarom) 7Á83 (1H, s, CHarom). Calculated for
C11H14BrNO: C, 51Á58; H, 5Á51; N, 5Á47. Found:
C, 51Á47; H, 5Á68; N, 5Á51%.
1
1
1262, 1169 cm (SO2); H NMR (d6-DMSO) d:
1Á11 (6H, 2s, 2CH3), 1Á85 (2H, m, CH2), 4Á9 (1H,
m, CH), 7Á31 (7H, m, CHarom), 10Á9 (1H, s, NH).
Calculated for C18H18BrClN2O4S: C, 45Á63; H,
3Á83; N, 5Á91; S, 6Á77. Found: C, 45Á99; H, 4Á01;
N, 6Á05; S, 6Á70%.
4-Amino-3,4-dihydro-2,2-dimethyl-6-¯uoro-2H-1-
benzopyran (11b). White powder (90% yield); mp
1
59±61ꢀC; H NMR (d6-DMSO) d: 1Á26 (6H, 2s,
2CH3), 1Á83 (2H, m, CH2), 2Á85 (2H, s, NH2), 3Á85
(1H, m, CH), 6Á81 (2H, m, CHarom), 7Á42 (1H, dd,
CHarom). Calculated for C11H14FNO: C, 67Á67; H,
7Á23; N, 7Á17. Found: C, 67Á53; H, 7Á02; N, 7Á10%.
4-(Benzenesulphonylaminocarbonylamino)-3,4-
dihydro-2,2-dimethyl-6-¯uoro-2H-1-benzopyran
(12d). White powder (90% yield); mp 206±208ꢀC;
IR (KBr) n: 3334, 3171 (NH), 1675 (CO), 1255,
1
1
1171 cm (SO2); H NMR (d6-DMSO) d: 1Á22
(6H, 2s, 2CH3), 1Á83 (2H, m, CH2), 4Á7 (1H, m,
CH), 7Á34 (8H, m, CHarom), 10Á77 (1H, s, NH).
Calculated for C18H19FN2O4S: C, 57Á13; H, 5Á06;
N, 7Á40; S, 8Á47. Found: C, 57Á01; H, 5Á22; N, 7Á49;
S, 7Á93%
4-Amino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1-
benzopyran (11c). White powder (90% yield); mp
1
84±86ꢀC; H NMR (d6-DMSO) d: 1Á37 (6H, 2s,
2CH3), 2Á18 (2H, m, CH2), 2Á85 (2H, s, NH2), 4Á74
(1H, m, CH), 7Á06 (1H, m, CHarom), 8Á11 (1H, m,
CHarom), 8Á79 (1H, m, CHarom). Calculated for
C11H14N2O3: C, 59Á45; H, 6Á35; N, 12Á60. Found:
C, 59Á58; H, 6Á63; N, 12Á53%.
3,4-Dihydro-2,2-dimethyl-6-¯uoro-4-(4-methylben-
zenesulphonylaminocarbonylamino)-2H-1-benzo-
pyran (12e). White powder (85% yield); mp 192±
194ꢀC; IR (KBr) n: 3333, 3272 (NH), 1700 (CO),
1248, 1190 cm 1 (SO2);1H NMR (d6-DMSO) d: 1Á18
(6H, 2s, 2CH3), 1Á85 (2H, m, CH2), 2Á4 (3H, s, CH3),
4Á72 (1H, m, CH), 7Á21 (7H, m, CHarom). Calculated
forC18H19FN2O4S:C,57Á13;H,5Á06;N,7Á40;S,8Á48.
Found: C, 57Á01; H, 5Á22; N, 7Á49; S, 8Á48%
General procedure for preparing 4-(arylsulphonyl-
aminocarbonylamino)-3,4-dihydro-2,2-dimethyl-
2H-1-benzopyrans (12a±i)
To the solution of 4-amino-3,4-dihydro-2,2-dime-
thyl-2H-1-benzopyrans (11a±c) (1Á35 mmol) in
anhydrous dichloromethane, the appropriate aryl-
sulphonyl isocyanate (1Á2 eq.) was added. After
20 min, the precipitate formed was collected by ®l-
tration, washed with petroleum ether 40/65 to elim-
inate excess arylsulphonyl isocyanate, and dried.
4-(4-Chlorobenzenesulphonylaminocarbonyl-
amino)-3,4-dihydro-2,2-dimethyl-6-¯uoro-2H-1-
benzopyran (12f). White powder (90% yield); mp

192
S. KHELILI ET AL
190±192ꢀC; IR (KBr) n: 3335, 3240 (NH), 1660
(CO), 1250, 1168 cm
4-(4-Chlorobenzenesulphonylaminocarbonyl-
1
(SO2); 1H NMR (d6-
amino)-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1-ben-
zopyran (12i). White powder (90% yield); mp
213±215ꢀC; IR (KBr) n: 3343, (NH), 1664 (CO),
DMSO) d: 1Á33 (6H, 2s, 2CH3), 1Á88 (2H, m,
CH2), 4Á78 (1H, m, CH), 7Á33 (7H, m, CHarom).
Calculated for C18H18ClFN2O4S: C, 52Á36; H, 4Á39;
N, 6Á78; S, 7Á77. Found: C, 52Á04; H, 4Á53; N, 6Á99;
S, 7Á99%.
1
1
1277, 1166 cm (SO2); H NMR (d6-DMSO) d:
1Á41 (6H, 2s, 2CH3), 1Á95 (2H, m, CH2), 4Á91 (1H,
m, CH), 7Á64 (7H, m, CHarom). Calculated for
C18H18ClN3O6S: C, 49Á15; H, 4Á12; N, 9Á55; S,
7Á29. Found: C, 49Á44; H, 4Á43; N, 9Á68; S, 7Á70%.
4-(4-Benzenesulphonylaminocarbonylamino)-3,4-
dihydro-2,2-dimethyl-6-nitro-2H-1-benzopyran
(12g). White powder (95% yield); mp 221±223ꢀC;
IR (KBr) n: 3340, (NH), 1669 (CO), 1275,
1167 cm
1
(SO2); 1H NMR (d6-DMSO) d: 1Á3
(6H, 2s, 2CH3), 1Á97 (2H, m, CH2), 4Á84 (1H, m,
CH), 7Á03 (1H, m, CHarom), 7Á76 (7H, m, CHarom).
Calculated for C18H19N3O6S: C, 53Á32; H, 4Á72; N,
10Á36; S, 7Á91. Found: C, 53Á38; H, 4Á97; N, 10Á48;
S, 7Á98%.
Results and Discussion
The esters 2a±b were synthesized from p-sub-
stituted phenols according to a classic esteri®cation
reaction catalysed by concentrated sulphuric acid.
The acetophenones 4a±b were synthesized by Fries
rearrangement of phenolic acetates 2a±b according
to Fries reaction (Shawcross & Sard 1995). How-
ever, acetophenone 4c was prepared from the
methyl ether of 4-(N-acetylamino)phenol 3 by
Friedel±Crafts reaction and cleavage of the methyl
ether in-situ by the excess of aluminium chloride
(Chang et al 1961). Compound 3 was prepared
from p-anisidine by simple acylation with acetyl
chloride. Treatment of acetophenones 4a±c with
acetone in the presence of pyrrolidine led to the
3,4-Dihydro-2,2-dimethyl-4-(4-methylbenzenesulph-
onylaminocarbonylamino)-6-nitro-2H-1-benzo-
pyran (12h). White powder (95% yield); mp 229±
231ꢀC; IR (KBr) n: 3337, (NH), 1666 (CO), 1278,
1166 cm (SO2); H NMR (d6-DMSO) d: 1Á32
(6H, 2s, 2CH3), 1Á89 (2H, m, CH2), 4Á87 (1H, m,
CH), 7Á48 (7H, m, CHarom). Calculated for
C19H21N3O6S: C 54Á41; H, 5Á05; N, 10Á02; S,
7Á64. Found: C, 54Á69; H, 5Á45; N, 10Á18; S, 7Á70%.
1
1
Table 1. Effects of the new dihydrobenzopyrans on insulin secretion from rat pancreatic islets and on the contractile activity of
K
‡
depolarized rat aorta rings.
Compound (50 mM)
X
Y
Residual insulin secretion (%)
n
Myorelaxant activity
(ED50 (mM))
n
12a
12b
12c
12d
12e
12f
12g
12h
12i
Br
Br
Br
F
F
F
NO2
NO2
NO2
H
CH3
Cl
H
CH3
Cl
H
CH3
Cl
99Á9Æ 6Á8
85Á1Æ 5Á3
80Á0Æ 5Á7
99Á0Æ 4Á8
91Á6Æ 7Á4
100Á2Æ 5Á0
106Á6Æ 5Á8
99Á6Æ 4Á3
107Á2Æ 5Á0
16
14
15
16
14
15
16
15
16
125Á0Æ 18Á0
65Á4Æ 14Á7
34Á8Æ 3Á7
4
6
5
4
4
4
5
4
4
>300
211Á0Æ 33Á0
111Á0Æ 21Á0
163Á0Æ 39Á0
66Á2Æ 15Á6
91Á5Æ 15Á5
Rat pancreatic islets were incubated in the presence of 16Á7 mM glucose. ED50 is the drug concentration causing 50% relaxation
of the 30 mM KCl-induced contraction of rat aorta rings. Results on pancreatic b-cells and on rat aorta are expressed as
meansÆ s.e.m.; n refers to the number of samples.

NEW ATP-SENSITIVE POTASSIUM-CHANNEL OPENERS
193
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Table 1 shows the pharmacological results
obtained with the newly synthesized dihy-
drobenzopyrans on the pancreatic and vascular
tissues. Results on pancreatic b-cells were expres-
sed as the percentage residual insulin secretion
from rat pancreatic islets incubated in the presence
of 16Á7 mM glucose (de Tullio et al 1996). All drugs
were tested at 50 mM. The myorelaxant activity of
the drugs was expressed as ED50, the drug con-
centration giving 50% relaxation of the 30 mM
KCl-induced contraction of rat aorta rings (de
Tullio et al 1996).
None of the compounds inhibited insulin secre-
tion. It was concluded that the drugs did not exert
signi®cant KATP-channel opening activity on pan-
creatic b-cells. The compounds did however exhi-
bit myorelaxant properties. The rank order of
preference for the X-substituent appeared to be
Br > NO2 > F, while that for the Y-substituent was
Cl > CH3 > H. Further pharmacological investiga-
tions are required to identify the active compounds
as new potassium-channel activators targeting
vascular smooth muscle cells.
‡
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