Nicorandil analogues containing NO-donor furoxans and related furazans

Article abstract of DOI:10.1016/S0968-0896(00)00098-5

The synthesis and in vitro vasodilating properties of hybrid compounds in which furoxan (1,2,5-oxadiazole 2-oxide) moieties, endowed with different NO-donor properties, were substituted for the nitroxy function of Nicorandil are reported. The corresponding cyanoguanidine analogues are also considered. This approach has led to a series of vasorelaxing compounds devoid of affinity for K(ATP) channels, whose activity is prevalently due to their ability to activate sGC, at the concentrations of the experiments. Related furazan (1,2,5-oxadiazole) derivatives, unable to release nitric oxide were also prepared and studied for control. The amide analogues of Nicorandil display feeble vasorelaxing action not involving the activation of K⁺ channels, while in the guanidine analogues, this mechanism seems to underlie this action. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(00)00098-5

Bioorganic & Medicinal Chemistry 8 (2000) 1727±1732
Nicorandil Analogues Containing NO-Donor Furoxans and
Related Furazans
Donatella Boschi,a Clara Cena,b Antonella Di Stilo,b Roberta Frutterob
and Alberto Gascob,*
aDipartimento di Scienze Chimiche, Alimentari, Farmaceutiche, Farmacologiche, V.le Ferrucci 33, I-28100, Novara, Italy
bDipartimento di Scienza e Tecnologia del Farmaco, Via P. Giuria 9, I-10125, Turin, Italy
Received 8 December 1999; accepted 15 March 2000
AbstractÐThe synthesis and in vitro vasodilating properties of hybrid compounds in which furoxan (1,2,5-oxadiazole 2-oxide)
moieties, endowed with di€erent NO-donor properties, were substituted for the nitroxy function of Nicorandil are reported. The
corresponding cyanoguanidine analogues are also considered. This approach has led to a series of vasorelaxing compounds devoid
of anity for KATP channels, whose activity is prevalently due to their ability to activate sGC, at the concentrations of the experi-
ments. Related furazan (1,2,5-oxadiazole) derivatives, unable to release nitric oxide were also prepared and studied for control. The
amide analogues of Nicorandil display feeble vasorelaxing action not involving the activation of K+ channels, while in the guani-
dine analogues, this mechanism seems to underlie this action. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Recently, attention has been devoted to furoxan deri-
vatives as NO-donors.7,8 These compounds are able,
normally under the action of thiol cofactors, to produce
NO through a complex mechanism, not yet completely
understood. Di€erent redox forms of nitric oxide could
be involved in the process. The possibility of modulat-
ing the NO release by changing the substitution pattern
at the ring,9 renders these structures ¯exible tools in
designing compounds with a dual activity, one of which
is dependent on their NO donor capacity.10 In this
paper we describe the synthesis and in vitro vasodilating
properties of hybrid compounds in which furoxan moi-
eties, endowed with di€erent NO-donor properties, were
substituted for the nitroxy function of Nicorandil (deri-
vatives 7 and 9) and of their cyanoguanidine analogues
(derivatives 18 and 20). Related furazan derivatives 8,
10, 19, 21, unable to release nitric oxide, were also pre-
pared and studied for control.
Potassium channel activators (KCAs) represent an
important class of compounds with a great therapeutic
potential in the management of disorders caused by
smooth muscle contraction.1,2 Several chemically
diverse types of compounds, endowed with K+channel
opening properties, have been identi®ed. Among these,
pyridine derivatives, such as Nicorandil (1, Fig. 1 ), have
been the object of several structural modi®cations.3,4
This compound displays strong vasodilating activity
through hyperpolarisation of the cell membrane in vas-
cular smooth muscle due to its ability to open princi-
pally ATP-dependent K+ channels (KATP).1 This action
is antagonised by Glibenclamide, an inhibitor of this
type of channel,1,5 and it is associated to the pyridyl
moiety.3 The vasodilating properties of Nicorandil are
also partly due to soluble guanylate cyclase (sGC) acti-
vation generated by the NO-donor nitroxy side chain.1,3
This latter group is important not only for the activa-
tion of sGC, but also for its degree of potency as KCA.6
The dual action of this compound can produce a more
bene®cial coronary vasodilation than a pure K+ chan-
nel activator.
Results
Chemistry
Synthesis. Synthesis of the models 7 and 8 was realised
according to the pathway reported in Scheme 1a.
Nucleophilic substitution of the nitro group in deriva-
tives 3 and 4 by the N-(2-hydroxyethyl)nicotinamide
(2), was run in THF at room temperature, under basic
*Corresponding author. Tel.: +39-11-670-7670; fax: +39-11-670-
7687; e-mail: gasco@pharm.unito.it
0968-0896/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(00)00098-5

1728
D. Boschi et al. / Bioorg. Med. Chem. 8 (2000) 1727±1732
serves as a basis for inferring its previous presence. In
the presence of thiols, besides this oxidation, a variety of
interrelated reactions with distinct reaction rates can
occur.7 In order to evaluate thiol-induced NO genera-
tion by furoxan models, the appropriate compound was
incubated in pH 7.4 bu€ered water at 37 ꢀC for 1 h, in
the presence of a large excess of cysteine (1:50). Nitrites
were determined by Griess reaction.9 The results
expressed as percentage NO2 (mol/mol) are entered in
Table 2.
Figure 1.
conditions. Benzenesulfonyl analogues 9 and 10 were
prepared in a similar manner by nucleophilic substitu-
tion of one of the two benzenesulfonyl groups present in
5 and 6. It is known that 5, dissolved in THF, reacts
with ethanol under basic conditions giving 3-benzene-
sulfonyl-4-ethoxyfuroxan (5a).11 For this reason we
assigned a 3-benzenesulfonylfuroxan-4-yl structure to 9.
This assignment was con®rmed by the analysis of 13C
NMR spectra (Table 1). In particular, the signals at
110.7 and at 159.0 ppm are indicative for C(3) and C(4)
carbons respectively of a 4-alkoxy-3-benzenesulphonyl
substituted furoxan ring.12 Cyanoguanidine analogues
18±21 were synthesised according to the sequential
pathway reported in Scheme 1b. O,O-Diphenyl-N-cya-
nocarbonimidate (11) was used as starting material.
This compound shows a very high reactivity towards
nucleophiles.13 Displacement of the ®rst phenoxy group
occurs under mild conditions, even with poor nucleo-
philes. Thus, intermediate 13 was obtained simply on
stirring 11 in iso-propanol (i-PrOH) at room tempera-
ture with 3-aminopyridine (12). Longer reaction times
were necessary for the displacement of the second
phenoxy group by amines 14±17 in order to obtain the
®nal derivatives 18±21. 13C and 1H NMR data for these
compounds are in keeping with the proposed structures
(Table 1 and experimental session).
Pharmacology
The vasodilating activity of all the ®nal furoxan and
furazan derivatives was examined by measuring their
inhibitory e€ects on the 25 mM KCl-induced contrac-
tions of endothelium denuded rat thoracic aorta strips.
Nicorandil and LY211808, an analogue of Pinacidil,3
were considered as reference compounds. All the deri-
vatives triggered a concentration-dependent response.
EC50 values were calculated from the cumulative con-
centration-response curves. In order to prove the invol-
vement of nitric oxide in the relaxation process, the
experiments were repeated in the presence of methylene
blue (MB), an inhibitor of sGC. Similarly, in order to
evaluate the involvement of K+ channel opening in the
process, the experiments were also run in the presence
either of Glibenclamide or of a co-administration of
MB-Glibenclamide. The results, expressed as mean
EC50 (mM) Æ S.E. are reported in Table 2.
Discussion
Analysis of the data collected in Table 2 shows that the
strict analogues of Nicorandil, compounds 7 and 9, dis-
play good vasodilating activity. EC50 of benzenesulfonyl
derivative 9 is about one hundred times less than EC50
of the reference 1, while the potency of the phenyl
analogue 7 is about the same. When vasodilating
Nitrite detection. Nitrites are the major oxidation pro-
ducts of NO in an aqueous system and their detection
Scheme 1.

D. Boschi et al. / Bioorg. Med. Chem. 8 (2000) 1727±1732
1729
Table 1. 13C NMR chemical shifts (ppm) of the ®nal compounds (DMSO-d6, TMS int.)
Compound
n
R
X
C2(Pyr) C6(Pyr) C3(Pyr) C4(Pyr) C5(Pyr) CˆO
c
d
C1(Ph) C2(Ph)/ C3(Ph) C4(Ph) CˆN CꢁN
a
b
7
8
9
10
18
19
20
21
1
0
1
0
1
0
1
0
Ph
Ph
PhSO2
PhSO2
Ph
CˆO
CˆO
152.1
152.0
152.1
152.1
148.4
148.4
148.5
148.5
129.8
129.8
129.8
129.7
134.3
134.4
134.4
134.3
135.0
135.0
135.1
135.1
131.5a
131.8a
131.5
131.6
123.6 165.4 162.3 107.6 122.1
123.6 165.4 163.4 145.3 124.5
123.6 165.4 159.0 110.7 137.3
123.6 165.3 161.1 148.9 137.0
123.8 123.8 162.2 107.7 122.0
123.8 123.8 163.4 145.3b 124.4
123.8 123.8 159.0 110.7 137.2
123.9 123.9 161.1 148.9 137.0
128.9/126.3
129.2/127.4
129.9/128.4
130.1/128.8
129.1/126.3
129.4/127.4
130.1/128.5
130.3/128.8
130.7
131.1
136.1
136.1
38.2 69.3
38.3 71.3
38.0 69.6
38.1 72.1
CˆO
CˆO
-NHCˆN-CꢁN
-NHCˆN-CꢁN
146.0/145.4
130.7a 158.5 116.9 40.4 69.1
131.4a 158.5 116.9 40.5 71.2
136.2 158.4 116.9 40.5 69.4
136.3 158.4 116.9 40.5 71.9
Ph
PhSO2 -NHCˆN-CꢁN
145.9/145.3b
146.0/145.4
146.0/145.4
PhSO2 -NHCˆN-CꢁN
aInterchangeable.
bOverlapped.
Table 2. Pharmacological activity of compounds under evaluation
Compound
Structure
R
EC50 (mM)
NO2 % (+L-cys)
+ MB
+ GLIB
+ MB+ GLIB
1
7
A
A
2.9Æ0.4
3.1Æ0.5
24Æ2
6.3Æ1.2
107Æ23
1.0Æ0.1
1.3Æ0.1
20Æ3
3.8Æ0.6
22Æ1
8
A
28Æ4
26Æ2
26Æ3
Ð
Ð
9
A
A
0.024Æ0.005
26Æ6
0.38Æ0.05
25Æ4
0.023Æ0.003
22Æ4
0.40Æ0.04
39Æ4
10
Ð
Ð
LY211808
B
B
7.6Æ1.1
1.5Æ0.2
7.8Æ1.0
415Æ32
1.6Æ0.6
438Æ23
7.8Æ0.7
Ð
18
6.9Æ 0.4
1.4Æ 0.2
19
B
86Æ8
82Æ14
166Æ30
Ð
Ð
20
21
B
B
0.021Æ0.003
29Æ4
0.44Æ0.03
28Æ4
0.023Æ0.003
47Æ5
0.47Æ0.09
26Æ1
Ð
Ð

1730
D. Boschi et al. / Bioorg. Med. Chem. 8 (2000) 1727±1732
experiments were performed in the presence of Glib-
enclamide, no rightward shift of the dose±response
curve was observed for either compound and conse-
quently no changes in their EC50 values. On the other
hand, both the models displayed a marked increase in
EC50 values when the experiments were done in the
presence of MB. Co-administration of MB-Glib-
enclamide resulted in no further modi®cation of the
potencies. This means that in these hybrids nitric oxide
has a predominant role in the vasodilating action. Their
order of potency is in keeping with their ability to pro-
duce nitrite ions. Interestingly the most potent com-
pound 9 displays a potency similar to that of the related
simple furoxan 5a (EC50= 0.0070Æ0.0004 mM), under
the same experimental conditions. Furazan analogues 8
and 10 show similar potency, about ten times lower
than that of Nicorandil. No shift to the right of con-
centration±response curves was observed either in the
presence of MB or of Glibenclamide. This strongly
suggests that neither NO, as anticipated, nor the acti-
vation of K+ channels underlies this feeble action.
Other mechanisms must be involved. Phosphodiesterase
inhibition could be one of them. In fact it is known that
some nicotinamide derivatives display this kind of
activity.14 Furoxan cyanoguanidine hybrids 18 and 20
trigger vasodilating responses very close to the ones of
the amide analogues 7 and 9. At the concentrations of
the experiments, their activity is prevalently NO-like, as
the decrease in the potency in the presence of MB and
the constancy of the potency in the presence of Glib-
enclamide demonstrate. Derivative 20 displays a higher
activity than 18, in keeping with its higher capacity to
produce nitrite ions. Its potency is similar to that of the
related simple furoxan 5a, as for 9. The furazan analo-
gues of this series (derivatives 19 and 21) behave as fee-
ble vasodilating products, similarly to the related amide
derivatives, but their activity is in part due to the acti-
vation of K+ channels. In fact the response is partially
inhibited in the presence of Glibenclamide. The poten-
cies of the two models are ten and four times less than
that of LY211808, respectively. The lower anity of
the two compounds for KATP channels with respect
to the reference compound is probably due to the lack
of the lateral short branched alkyl moiety. In fact it is
known that in LY211808 and related compounds
this substructure confers optimal activity and tissue
selectivity.3
Experimental
Chemistry
Melting points were measured on a Buchi 530 capillary
apparatus and are uncorrected. Melting points with
decomposition were determined after introducing the
sample into the bath at a temperature 10 ꢀC lower than
the melting point; a heating rate of 3 ꢀC min 1 was used.
The compounds were routinely checked by infrared
spectrometry (Shimadzu FT-IR 8101M). 1H and 13C
NMR spectra were recorded in DMSO-d6 at 200 and 50
MHz, respectively, with a Bruker AC-200 spectrometer.
The 13C-chemical shifts of the ®nal compounds are
reported in Table 1. The assignments of these spectra
were con®rmed by DEPT pulse sequence. Column
chromatography was performed on silica gel (Merck
Kieselgel 60, 230±400 mesh ASTM) with the indicated
solvent system. Anhydrous magnesium sulphate was
used as the drying agent of the organic extracts. Solvent
removal was achieved under reduced pressure at room
temperature. Elemental analyses of the new compounds
were performed by REDOX (Cologno M.) and the
results are within 0.4% of theoretical values. Com-
pounds 2,15 3,16 4,17 5,11 6,18 11,13 14,18 15,18 16,9 1718
were synthesised according to literature methods.
General procedure for the preparation of compounds 7±10.
0.48 g of 50% w/w water NaOH solution (6.0 mmol)
were added portionwise to a stirred solution of 2 (0.50 g,
3.0 mmol) and of the appropriate oxadiazoles 3±6 (3.0
mmol) in THF (20 mL), while the temperature was
maintained at 25 ꢀC. The reaction mixture was stirred at
25 ꢀC for 2±5 h. Solvent removal gave a residue which
was treated with water and ®ltered (for 7, 8 and 10) or
extracted with ethyl acetate (for 9) to obtain the expec-
ted product.
N-(2-(3-Phenylfuroxan-4-yloxy)ethyl)nicotinamide (7).
Reaction time 3 h; yield 52%; mp 166±167 ꢀC dec.
(EtOH). H NMR (DMSO-d6) d 9.02 (d, 2H, 2-pyr and
NH), 8.71 (dd, H, 6-pyr), 8.19 (m, H, 4-pyr), 8.07 (m,
2H, Ph), 7.53 (m, 4H, 5-pyr and Ph), 4.65 (t, 2H,
CH2O), 3.85 (q, 2H, NCH2). Anal. for C16H14N4O4: C,
58.89; H, 4.32; N, 17.17. Found: C, 59.14; H, 4.33; N,
17.15.
1
N-(2-(4-Phenylfurazan-3-yloxy)ethyl)nicotinamide (8).
Reaction time 4 h; yield 87%; mp 149±150 ꢀC (MeOH).
1H NMR (DMSO-d6) d 9.01 (m, 2H, 2-pyr and NH),
8.71 (m, H, 6-pyr), 8.18 (m, H, 4-pyr), 7.97 (m, 2H, Ph),
7.55 (m, 4H, 5-pyr and Ph), 4.63 (t, 2H, CH2O), 3.84±
3.87 (q, 2H, NCH2). Anal. for C16H14N4O3: C, 61.93;
H, 4.55; N, 18.05. Found: C, 62.05; H, 4.53; N: 17.95.
Conclusions
The attempt to use two NO-donor furoxan sub-
structures, endowed with di€erent NO-donor proper-
ties, to prepare hybrid drugs related to Nicorandil, has
led to a class of vasorelaxing compounds devoid of a-
nity for KATP channels, whose activity is prevalently
due to their ability to activate sGC. Related furazan
structures, unable to release NO, behave in di€erent
manners. Strict analogues of Nicorandil display vaso-
relaxing action not involving the activation of K+
channels, while in guanidine analogues this mechanism
seems to underlie the action.
N-(2-(3-Benzensulfonylfuroxan-4-yloxy)ethyl)nicotinamide
(9). Reaction time 5 h; yield 81%; mp 171±172 ꢀC dec.
(MeOH). H NMR (DMSO-d6) d 9.04 (m, H, 2-pyr),
8.91 (t, H, NH), 8.76 (m, H, 6-pyr), 8.23 (m, H, 4-pyr),
8.03±7.60 (m, 5H, Ph), 7.55 (m, H, 5-pyr), 4.60 (t, 2H,
CH2O), 3.77 (q, 2H, NCH2). Anal. for C16H14N4O6S:
C, 49.23; H, 3.61; N, 14.35. Found: C, 49.69; H, 3.56; N,
14.21.
1

D. Boschi et al. / Bioorg. Med. Chem. 8 (2000) 1727±1732
1731
N-(2-(4-Benzensulfonylfurazan-3-yloxy)ethyl)nicotinamide
(10). Reaction time 2 h; yield 60%; mp 162±163 ꢀC
(EtOH). 1H NMR (DMSO-d6) d 9.01 (m, H, 2-pyr),
8.87 (t, H, NH), 8.76 (m, H, 6-pyr), 8.19 (m, H, 4-pyr),
8.11±7.53 (m, 6H, Ph and 5-pyr), 4.57 (t, 2H, CH2O),
3.75 (q, 2H, NCH2). Anal. for C16H14N4O5S: C, 51.33;
H, 3.77; N, 14.97. Found: C, 51.30; H, 3.72; N, 14.86.
N7O5S: C, 47.55; H, 3.52; N, 22.83. Found: C, 47.34; H,
3.51; N, 22.70.
1-(2-(4-Benzensulfonylfurazan-3-yloxy)ethyl)-2-cyano-3-
(3-pyridinyl)guanidine (21). Isopropanol; reaction time:
6 days; yield 44%; mp 141±144 ꢀC dec. (CHCl3). 1H
NMR (DMSO-d6) d 9.34 (s, H, pyr-NH), 8.49 (d, H, 2-
pyr), 8.39 (m, H, 6-pyr), 8.14±7.68 (m, 6H, Ph and 4-
pyr), 7.58 (t, H, NHCH2), 7.44±7.36 (m, H, 5-pyr), 4.53
(t, 2H, CH2O), 3.70 (q, 2H, NCH2). Anal. for C17H15
N7O4S0.25H2O: C, 48.86; H, 3.74; N, 23.46. Found: C,
48.87; H, 3.71; N, 23.41.
3-Cyano-1-(3-pyridinyl)-2-phenylisourea (13). The pro-
duct was prepared according to a similar scheme
described in literature:19 3-aminopyridine (1.88 g; 20.0
mmol) was added to a mixture of 11 (4.76 g; 20.0 mmol)
in isopropanol (25 mL) and the mixture was stirred at
room temperature for 24 h. Then the mixture was
cooled in an ice bath, ®ltered, and the residue washed
with cooled isopropanol and dried. Yield 74%; mp 147±
148 ꢀC dec. (i-PrOH). 1H NMR (DMSO-d6) d 11.02 (br,
H, NH), 8.71 (s, H, 2-pyr), 8.46 (d, H, 6-pyr), 7.95 (m,
H, 4-pyr), 7.51±7.29 (m, 6H, Ph and 5-pyr); 13C NMR
(DMSO-d6) d 160.5, 151.4, 146.8, 145.0, 133.2, 131.6,
129.9, 126.6, 123.6, 121.3, 113.3. Anal. for C13H10N4O:
C, 65.54; H, 4.23; N, 23.52. Found: C, 65.48; H, 4.26; N,
23.51.
Pharmacology
Vasoactivity determination. Thoracic aortas were iso-
lated from male Wistar rats weighing 180±200 g, which
had been anaesthetised with CO2 and killed by decap-
itation. All animals were dealt with in a humane way in
accordance with recognised guidelines on experimenta-
tion. As few rats as possible were used and generally
three strips per animal were obtained. The purposes and
the protocols of our studies have been approved by the
Ministero della Sanita, Rome, Italy. The vessels were
helically cut and the endothelium removed. The tissues
were mounted under 0.7 g tension in organ baths con-
taining 30 mL of Krebs-bicarbonate solution (NaCl 112
mM, KCl 5.0 mM, CaCl2 2.5 mM, MgSO4 1.2 mM,
KH2PO4 1.0 mM, NaHCO3 12 mM, glucose 11 mM)
maintained at 37 ꢀC and gassed with 95% O2±5% CO2
(pH 7.4). Responses were recorded on a 7070 Gemini
Recorder through an Isotonic Transducer (Ugo Basile,
Varese, Italy). The aortic strips were allowed to equili-
brate for 1 h and then were depolarized by addition of a
solution of KCl to a ®nal K+ concentration 25 mM.
During this ®rst contraction the absence of intact endo-
thelium was veri®ed by adding 1 mM acetylcholine,
which failed to induce relaxation. The preparations were
then extensively washed with Krebs-bicarbonate bu€er
and after equilibration for 2.5 h, a second contraction
was evoked by K+-depolarization (25 mM). When the
response reached its plateau, cumulative concentrations
of the vasodilating agent were added. The e€ect of MB
10 mM, Glibenclamide 10 mM and of MB-Glibenclamide
co-administration on relaxation were evaluated in a
separate series of experiments by adding the inhibitors 5
min before K+-depolarization.
General procedure for the preparation of compounds 18±
21. Compound 13 (0.95 g, 4.0 mmol) was added to a
solution of the appropriate amine 14±17 (4.0 mmol) in
isopropanol (50 mL) or THF (30 mL). The mixture was
stirred at room temperature over the reported time. The
formed precipitated was obtained by ®ltration for the
compounds 18, 19 and 21. In the case of 20 no pre-
cipitation occurred and so the reaction mixture was
evaporated and the residue was puri®ed by ¯ash chro-
matography.
2-Cyano-1-(2-(3-phenylfuroxan-4-yloxy)ethyl)-3-(3-pyrid-
inyl)guanidine (18). Isopropanol; reaction time: 10 h;
yield 54%; mp 186±187 ꢀC dec. (EtOH). 1H NMR
(DMSO-d6) d 9.36 (s, H, NH-pyr), 8.48 (d, H, 2-pyr),
8.37 (m, H, 6-pyr), 8.12±8.07 (m, 2H, Ph), 7.69±7.56 (m,
5H, Ph and 4-pyr and NHCH2), 7.34 (m, 1H, 5-pyr),
4.60 (t, 2H, CH2O), 3.79 (q, 2H, NCH2). Anal. for
C17H15N7O3: C, 55.89; H, 4.14; N, 26.84. Found: C,
55.67; H, 4.10; N, 26.66.
2-Cyano-1-(2-(4-phenylfurazan-3-yloxy)ethyl)-3-(3-pyrid-
inyl)guanidine (19). THF; reaction time: 24 h; yield
65%; mp 200±201 ꢀC (EtOH). H NMR (DMSO-d6) d
1
9.34 (s, H, pyr-NH), 8.46 (d, H, 2-pyr), 8.36 (m, H, 6-
pyr), 8.06±7.97 (m, 2 H, Ph), 7.67±7.51 (m, 5H, Ph and
4-pyr and NHCH2), 7.30 (m, 1H, 5-pyr), 4.58 (t, 2H,
CH2O), 3.76 (q, 2H, NCH2). Anal. C17H15N7O2: C,
58.45; H, 4.33; N, 28.07. Found: C, 58.37; H, 4.27; N,
28.10.
Acknowledgements
We acknowledge the support received from MURST.
We are grateful to M. H. Niedenthal (Eli Lilly and
Company) and to L. Boitel (Rhone Poulenc Rorer SpA)
for kindly providing us with LY211808 and Nicorandil
respectively.
1-(2-(3-Benzensulfonylfuroxan-4-yloxy)ethyl)-2-cyano-3-
(3-pyridinyl)guanidine (20). Reagent ratio 1:1.2; THF;
reaction time: 96 h; eluent: CH2Cl2:CH3OH 9.5:0.5;
yield 52%; mp 145±147 ꢀC dec. (EtOAc). 1H NMR
(DMSO-d6) d 9.35 (s, H, pyr-NH), 8.52 (d, H, 2-pyr),
8.39 (m, H, 6-pyr), 8.06±7.71 (m, 6H, Ph and 4-pyr),
7.60 (t, H, NHCH2), 7.41 (m, H, 5-pyr), 4.59 (t,
2H,CH2O), 3.72 (q, 2H, NCH2). Anal. for C17H15
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