Unsymmetrically substituted furoxans. Part 19. Methyl and phenylfuroxansulfonic acids and related sulfonamides

Article abstract of DOI:10.1002/jhet.149

(Chemical Equation Presented) Synthesis, structural characterization, and acid dissociation constants (pK_a) of a series of methyl- and phenyl-substituted furoxansulfonic acids and related sulfonamide derivatives, as well as their furazan analog

Full text of DOI:10.1002/jhet.149

866
Unsymmetrically Substituted Furoxans. Part 19. Methyl and
Phenylfuroxansulfonic Acids and Related Sulfonamides
Vol 46
Konstantin Chegaev, Barbara Rolando, Stefano Guglielmo, Roberta Fruttero,
and Alberto Gasco*
`
Dipartimento di Scienza e Tecnologia del Farmaco, Universita degli Studi di Torino,
Via Pietro Giuria 9, 10125 Torino, Italy
*E-mail: alberto.gasco@unito.it
Received December 10, 2008
DOI 10.1002/jhet.149
Published online 2 September 2009 in Wiley InterScience (www.interscience.wiley.com).
Synthesis, structural characterization, and acid dissociation constants (pKa) of a series of methyl- and
phenyl-substituted furoxansulfonic acids and related sulfonamide derivatives, as well as their furazan
analogues are described. The ability of furoxans to dilate rat aorta strips precontracted with phenyleph-
rine is reported as an example of their NO-dependent pharmacological properties.
J. Heterocyclic Chem., 46, 866 (2009).
INTRODUCTION
derivatives to dilate rat aorta strips precontracted with
phenylephrine is also discussed, as an example of their
NO-dependent pharmacological properties.
The interest in furoxan (1,2,5-oxadiazole 2-oxide)
derivatives is continuously expanding as it was shown
that these products are able to release nitric oxide (NO)
in physiological conditions, in the presence of thiol
cofactors [1,2]. Consequently, they display a variety of
pharmacological actions typical of NO [2,3]. A number
of functional groups have been introduced into the sim-
ple furoxan ring, and their chemistry has been recently
reviewed [4]. In previous works, we described the syn-
thesis and chemical properties of many unsymmetrically
substituted furoxans [5]. Currently we are using a num-
ber of them to design new NO-donor hybrid drugs [6,7],
namely polyvalent products obtained by linking an
appropriate drug, or a crucial part of it, with a NO-do-
nor moiety through a suitable spacer. A paramount prob-
lem that must be addressed in this approach is the ‘‘bal-
ance’’ in the final hybrid of the activity deriving from
its ability to release NO and the activity due to the pres-
ence of the native drug. The furoxan system seems to
be a flexible NO-donor moiety for this scope as its NO-
release profile can be easily modulated by changing the
kind of substituent at heteroring. Surprisingly, a search
in literature showed that no furoxan derivatives bearing
either sulfonic or sulfonamide functions have been so
far described. In this article, we report the synthesis,
structural characterization, and ionization constants
(pKa) of a series of methyl- and phenyl-substituted furo-
xansulfonic acids and related sulfonamides, as well as
their furazan analogues (1,2,5-oxadiazoles), devoid of
the capacity to release NO. The ability of the furoxan
RESULTS AND DISCUSSION
Chemistry. The synthesis of sulfonic acids both of
the furoxan and the furazan series, and of the related
sulfonamides is outlined in Scheme 1. The action of
benzyl mercaptane on 4-nitro-substituted furoxans 1a,
2a, and 3-phenylsulfonyl-substituted furoxans 1b, 2b in
acetonitrile solution, in the presence of triethylamine,
afforded the corresponding benzylthiofuroxan deriva-
tives 3a, 4a and 3b, 4b. Corresponding furazan ana-
logues 3c, 4c were obtained by action of refluxing tri-
methyl phosphite on 3a and 4a, respectively. All these
sulphur intermediates were transformed in the related
sulfonyl chlorides 5a-c, 6a-c by action of chlorine in
acetic acid solution in presence of hydrochloric acid. In
this reaction, benzyl chloride formed in equimolar
amount with the expected sulfonyl chlorides. Solid sul-
fonyl chlorides 6a and 6c were purified by crystalliza-
tion. All the attempts to isolate 5a-c and 6b failed due
to their thermal and hydrolytic instability. Consequently,
these compounds were used for further reactions in mix-
ture with benzyl chloride. All sulfonyl chlorides
afforded the final sulfonic acid potassium salts 7a-c, 8a-
c, when treated with 1N KHCO3 in acetone solution.
Sulfonamides derivatives of 3-phenyl and 3-methylfur-
oxan series 9a-16a and related furazans 9c-16c were
obtained by action of the appropriate amines on the
C
V
2009 HeteroCorporation

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Unsymmetrically Substituted Furoxans. Part 19. Methyl and
Phenylfuroxansulfonic Acids and Related Sulfonamides
867
Scheme 1
corresponding sulfonyl chlorides in CH2Cl2, or in water
solution when ammonia or methylamine were used. This
synthetic approach failed in the preparation of the sul-
fonamide isomers of the 4-phenyl and 4-methylfuroxans
series owing to the decomposition of the related sulfonyl
chlorides in the presence of amine reagents. Conse-
quently, we obtained the sulfonamides 9b, 10b, 11b,
13b, 15b, and 16b by thermal isomerization of the cor-
responding 3-phenyl and 3-methyl isomers at 130ꢀC in
1,1,2,2-tetrachloroethane (Cl2CHCHCl2) solution. After
solvent removal the mixtures of isomers were separated
by HPLC. This separation failed in the case of 12a/12b
and 14a/14b mixtures. The equilibrium constants (NMR
or HPLC detection) between the isomer pair of sulfona-
mides, determined at 130ꢀC in Cl2CHCHCl2, are listed
in Table 1. In some cases the equilibrium was
approached from both sides. In all cases the isomers
bearing the sulfonamido groups from the opposite side
NMR spectra, the 3-CH3 resonance signal is upfield
with respect to the one of 4-CH3 [8,9] and that in the
13C NMR spectra the resonances of C(1) and C(4) car-
bons of the 3-Ph group appear upfield with respect to
the corresponding resonances of the 4-Ph group [10].
Finally the chemical shift of C3 and C4 carbon atoms of
the furoxan ring are in keeping with those observed in
aryl- and alkylsulfonyl furoxans [9,11].
Ionization constants. The pKa values of sulfonamide
derivatives both of the furoxan and of the furazan series
were measured by potentiometric technique using a Sir-
ius GLpKa apparatus. These values are listed in Table 1.
The high acid strength of all the sulfonic acids, which
are in keeping with the electron withdrawing properties
of the furazan and furoxan rings [12], did not allow the
detection of their dissociation constants with this tech-
nique. Some interesting structural considerations can be
derived from the analysis of Table 1. In a pair of iso-
mers the product bearing the sulfonamide function at the
4-position is always just a little less acid than the other
isomer or displays the same acidity. The related fura-
zans are always less acidic than the related furoxans. In
1
of the exocyclic oxygen are favoured. H and 13C NMR
spectra (Experimental) are in keeping with the structural
assignments. In particular, in the case of the furoxan iso-
mers they satisfy the rule that both in 1H and in 13C
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

868
K. Chegaev, B. Rolando, S. Guglielmo, R. Fruttero, and A. Gasco
Vol 46
Table 1
Physicochemical parameters and pharmacological activities of furoxan and furazan sulfonic acids (7, 8) and related sulfonamides (9–16).
Thermal
isomerization
equilibrium
K ([a]/[b])
Vasodilator activity
EC50 ꢁ SE
EC50 ꢁ SE
Comp.
Molecular formula
mp (crystallization solvent)
pKa ꢁ SD
(lM)
(lM) þ 1 lM ODQ
7a
7b
7c
8a
8b
8c
9a
C3H3KN2O5S
C3H3KN2O5S
C3H3KN2O4S
C8H5KN2O5S
>280ꢀC dec. (H2O)
ND
ND
NDd
NDd
NDd
–
277–279ꢀC dec. (H2O)
>270ꢀC dec. without melting (H2O)
214–215ꢀC dec. (H2O)
250–255ꢀC dec. (H2O)
24 ꢁ 6
ND
ND
–
37 ꢁ 4
NDd
NDd
–
C8H5KN2O5S
3
ND
ND
4.3 ꢁ 0.8
C H KN O Sꢂ = H O 255–260ꢀC dec. (H2O)
–
4
2
8
5
2
4
C3H5N3O4S
C3H5N3O4S
C3H5N3O3S
93–93.5ꢀC (ClCH2CH2Cl)
117–118ꢀC (ClCH2CH2Cl)
81–82ꢀC (ClCH2CH2Cl/CCl4)
147–148ꢀC (H2O)
112–114ꢀC (H2O)
149.5–151ꢀC (H2O)
77–78ꢀC (CCl4)
6.85 ꢁ 0.01
6.80 ꢁ 0.01
7.06 ꢁ 0.02
6.88 ꢁ 0.01
6.76 ꢁ 0.01
7.16 ꢁ 0.01
8.03 ꢁ 0.01
8.10 ꢁ 0.01
8.43 ꢁ 0.01
8.12 ꢁ 0.01a
8.58 ꢁ 0.01a
–
2.05b
1.94c
2.11b
NDd
NDd
NDd
–
9b
9c
27 ꢁ 3
–
1.4 ꢁ 0.2
0.61 ꢁ 0.11
–
10a
10b
10c
11a
11b
11c
12a
12c
13a
13b
13c
14a
14c
15a
15b
15c
16a
16b
16c
C H N O Sꢂ = H O
NDd
96 ꢁ 16
–
1
2
2
8
7
3
4
C8H7N3O4S
C8H7N3O3S
C4H7N3O4S
C4H7N3O4S
C4H7N3O3S
C9H9N3O4S
C9H9N3O3S
C7H13N3O4S
C7H13N3O4S
C7H13N3O3S
21 ꢁ 3
2.4 ꢁ 0.3
–
NDd
NDd
–
48–50ꢀC (CCl4)
55–55.5ꢀC (CCl4)
108–109ꢀC (H2O)
94–95ꢀC (H2O)
0.15 ꢁ 0.02
10 ꢁ 1
–
–
54–55ꢀC (hexane)
92–93ꢀC (hexane)
liquid
64–65ꢀC (hexane)
liquid
3.30b
7.3 ꢁ 0.7
0.087 ꢁ 0.011
–
NDd
11 ꢁ 3
–
–
–
C
C
12H15N3O4S
12H15N3O3S
–
–
0.070 ꢁ 0.014
6.5 ꢁ1.1
–
e
–
e
C H BrN O Sꢂ = H O 126–127ꢀC (CCl4)
4.56 ꢁ 0.01a
4.43 ꢁ 0.01a
5.15 ꢁ 0.01a
4.72 ꢁ 0.01a
4.51 ꢁ 0.01a
5.20 ꢁ 0.2a
1.52b
2.15c
1
2
2
9
8
3
4
e
e
e
e
e
e
e
e
e
e
C9H8BrN3O4S
C9H8BrN3O3S
C14H10BrN3O4S
C14H10BrN3O4S
C14H10BrN3O3S
114.5–115.5ꢀC (CCl4)
96.5–97.5ꢀC (CCl4)
149–150ꢀC (CCl4)
158–159ꢀC (CCl4)
131–132ꢀC (CCl4)
a Potentiometric titrations were performed in water containing methanol as a cosolvent in different ratios depending on the solubility of compounds:
pKa values were determined by extrapolation at 0% methanol using the Yasuda-Shedlovsky procedure (experimental).
b NMR determination.
c HPLC determination.
d EC50 could not be calculated as the relaxation at maximum concentration tested (100 lM) did not reach 50%.
e The product completely relaxed the contracted tissue in a concentration independent manner; the tissue did not recover its contractility.
all the series, the presence on sulfonamide function of
the p-bromophenyl group increases the acidity while the
presence of the methyl group decreases it. This is in ac-
cordance with the ability of the former to delocalize the
negative charge of the conjugated anion and with the
opposite effect exerted by the latter.
in the presence of 1 lM 1H-[1,2,4]oxadiazolo[4,3-a]qui-
noxalin-1-one (ODQ), a decrease in the potencies was
observed, in keeping with a NO-induced activation of the
sGC as the mechanism, which underlies this effect. Prod-
ucts bearing a p-bromophenyl moiety behaved differently.
They completely relaxed the contracted tissue in a con-
centration independent manner, both in the presence and
in the absence of ODQ. In addition, the tissue did not
recover its contractility in spite of extensive washing. It is
worthy of note that also the furazan analogues 15c and
16c display similar behavior. This indicates that the vaso-
dilator activity of these specific products is not NO de-
pendent but probably connected with their tissue toxicity.
Vasodilator activity. Furoxan derivatives display va-
sodilator properties. It is commonly accepted that this is
due to their ability to release NO under the action of ves-
sel intracellular thiols. The NO produced activates soluble
guanylate cyclase (sGC) and this induces a series of
events whose final result is dilation of the vessel [13]. All
furoxansulfonamides described in this work were able to
relax rat aorta strips precontracted with phenylephrine in
a concentration dependent manner. The vasodilator poten-
cies EC50, namely the molar concentration able to induce
50% of the relaxing effect to the contracted tissue are
reported in Table 1. When the experiments were repeated
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a Bruker
Avance 300 at 300 and 75 MHz, respectively, using SiMe4 as
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009
Unsymmetrically Substituted Furoxans. Part 19. Methyl and
Phenylfuroxansulfonic Acids and Related Sulfonamides
869
the internal standard. Low resolution mass spectra were
recorded with a Finnigan-Mat TSQ-700. Melting points were
determined with a capillary apparatus (Buchi 540). Flash col-
umn chromatography was performed on silica gel (Merck Kie-
selgel 60, 230–400 mesh ASTM), using the indicated eluents;
PE stands for 40–60 petroleum ether. The progress of the reac-
tions was followed by thin layer chromatography (TLC) on 5
ꢃ 20 cm plates with a layer thickness of 0.2 mm. Anhydrous
magnesium sulfate was used as the drying agent for the or-
ganic phases. Organic solvents were removed under vacuum at
2H, CH2), 7.07–7.25 (m, 5H) 7.39–7.51 (m, 3H), 7.59–7.61
(m, 2H) (2C6H5); 13C NMR (CDCl3): d 34.7, 110.6 (C3 fx),
126.1 (C1 Ph), 127.7, 128.0, 128.7, 128.8, 131.0, 135.5, 157.7
(C4 fx); ms: m/z 284 (M)þ. Anal. Calcd. for C15H12N2O2S: C,
63.36; H, 4.25; N, 9.85. Found: C, 63.15; H, 4.28; N, 9.87.
General procedure for preparation of benzylthiofurazans
(3c and 4c). A solution of appropriate furoxan (45 mmol) in
P(OMe)3 (30 mL, 0.25 mol) was heated at reflux for 12 h. The
reaction was cooled and poured into an ice/4N HCl (80 mL)
mixture. The precipitate formed was filtered, washed with cold
water and crystallized from MeOH to give the title compound
as a white crystalline solid.
ꢀ
R
V
30 C. Preparative HPLC was performed on a LiChrospher
C18 column (250 ꢃ 25 mm, 10 lm) (Merck Darmstadt, Ger-
many) with a Varian ProStar mod-210 with Varian UV detec-
tor mod-325. Elemental analyses (C, H, N) were performed by
REDOX (Monza). Compounds 1a [14], 2a [15], 1b [9], and
2b [16] were synthesized as described elsewhere.
General procedure for preparation of benzylthiofuroxans
(3a,b and 4a,b). To a stirred solution of appropriate furoxan
derivative (24 mmol) in CH3CN (25 mL), cooled at ꢄ15ꢀC,
Et3N (3.4 mL, 24 mmol) was added. To the obtained solution
benzylmercaptane (2.5 mL, 24 mmol) was added in one por-
tion and the reaction was stirred at ꢄ15ꢀC for 30 min. The
cooling bath was removed and the reaction mixture was
allowed to stir at room temperature for an additional 30 min.
Benzylthiofuroxans were isolated as described.
3-Benzylthio-4-methylfurazan (3c). Yield: 77%, mp 28–
1
28.5ꢀC (MeOH); H NMR (CDCl3): d 2.23 (s, 3H, CH3), 4.39
(s, 2H, CH2), 7.25–7.41 (m, 5H, C6H5); 13C NMR (CDCl3): d
8.0, 36.8, 128.0, 128.8, 129.1, 135.7, 149.8, 152.2; ms: m/z
206 (Mþ). Anal. Calcd. for C10H10N2OS: C, 58.23; H, 4.89;
N, 13.58. Found: C, 58.20; H, 5.00; N, 13.60.
3-Benzylthio-4-phenylfurazan (4c). Yield 81%, mp 65.5–
1
66.5ꢀC (MeOH); H NMR (CDCl3): d 4.49 (s, 2H, CH2), 7.25–
7.49 (m, 8H), 7.80–7.82 (m, 2H) (2C6H5); 13C NMR (CDCl3): d
37.3, 125.3, 128.0, 128.0, 128.8, 129.0, 129.2, 130.7, 135.4,
151.1, 152.3; ms: m/z 268 (Mþ). Anal. Calcd. for C15H12N2OS:
C, 67.14; H, 4.51; N, 10.44. Found: C, 67.24; H, 4.49; N, 10.45.
General procedure for preparation of sulfonylchlorides
(5a-c and 6a-c). To the suspension/solution of benzylthioderi-
vatives in acetic acid 4N HCl (0.5 mL) was added and chlorine
was bubbled through reaction mixture for 2 h. After this time
reaction, the mixture was stirred at room temperature for 1 h,
then it was poured into H2O and extracted with PE. The or-
ganic phase was washed with H2O (3ꢃ), brine, dried, and
evaporated. The obtained products were crystallized from hex-
ane (in case of solids 6a and 6c) or used directly for further
reaction in mixture with benzylchloride (1/1 molar ratio).
3-Phenylfuroxan-4-sulfonyl chloride (6a). White solid,
4-Benzylthio-3-methylfuroxan (3a). The reaction mixture
was diluted with CH2Cl2. The organic solvent was washed
with H2O, 1N HCl, NaHCO3 saturated solution, brine, dried,
and evaporated. The obtained oil was solidified by treating
with PE at 0ꢀC. The obtained solid was filtered, washed with
cold PE, and crystallized from hexane to give the title com-
1
pound as a white solid, yield 54%, mp 48–49ꢀC (hexane); H
NMR (CDCl3): d 2.00 (s, 3H, CH3), 4.38 (s, 2H, CH2), 7.31–
7.38 (m, 5H, C6H5); 13C NMR (CDCl3): d 7.5 (3-CH3), 35.2,
112.5 (C3 fx), 128.1, 128.8, 129.1, 135.4, 154.8 (C4 fx); ms:
m/z 222 (Mþ). Anal. Calcd. for C10H10N2O2S: C, 54.04; H,
4.53; N, 12.60. Found: C, 54.35; H, 4.51; N, 12.73.
3-Benzylthio-4-methylfuroxan (3b). The reaction mixture
was diluted with CH2Cl2. The organic solvent was washed
with H2O, 1N HCl, NaHCO3 saturated solution, brine, dried,
and evaporated. The obtained oil was purified by flash chroma-
tography (eluent 8/2 PE/CH2Cl2) to give the title compound as
a colorless oil, yield 79%; 1H NMR (CDCl3): d 1.90 (s, 3H,
CH3), 4.08 (s, 2H, CH2), 7.14–7.18 (m, 2H) 7.24–7.31 (m, 3H)
(C6H5); 13C NMR (CDCl3): d 10.9 (4-CH3), 34.9, 111.2 (C3
fx), 128.0, 128.7, 128.9, 135.4, 157.1 (C4 fx); ms: m/z 222
(M)þ. Anal. Calcd. for C10H10N2O2S: C, 54.04; H, 4.53; N,
12.60. Found: C, 54.26; H, 4.46; N, 12.42.
1
yield 80%, mp 94–96ꢀC (hexane); H NMR (CDCl3): d 7.56–
7.61 (m, 3H), 7.75–7.79 (m, 2H) (C6H5); 13C NMR (CDCl3)
d: 110.8 (C3 fx), 119.3 (C1 Ph), 129.1, 129.4, 132.1 (C4 Ph),
158.2 (C4 fx); ms: m/z 260/262 (Mþ). Anal. Calcd. for
C8H5ClN2O4S: C, 36.86; H, 1.93; N, 10.75. Found: C, 37.05;
H, 1.99; N, 10.75.
3-Phenylfurazan-4-sulfonyl chloride (6c). White solid,
1
yield 58%, mp 52–53ꢀC (hexane); H NMR (CDCl3): d 7.54–
7.67 (m, 3H), 7.76–7.82 (m, 2H) (C6H5); 13C NMR (CDCl3)
d: 122.0, 129.3, 129.4, 132.2, 151.5, 156.9; ms: m/z 244/246
(Mþ). Anal. Calcd. for C8H5ClN2O3S: C, 39.27; H, 2.06; N,
11.45. Found: C, 39.34; H, 2.21; N, 11.30.
General procedure for preparation of sulfonic acid po-
tassium salts (7a-c and 8a-c). To a solution of the appropriate
sulfonylchloride (2.5 mmol) in acetone (20 mL) 1N KHCO3
(7.5 mL, 7.5 mmol) was added at 0ꢀC. The reaction was
allowed to reach room temperature and stirred for 2 h. The or-
ganic solvent was evaporated, the residue was dissolved in
H2O and the resulting solution was washed with CH2Cl2 (2ꢃ),
filtered, and evaporated. The obtained solid was crystallized
from water to give the title compound as a white solid.
Potassium 3-methylfuroxan-4-sulfonate (7a). White solid,
yield 38% (for two synthetic steps), mp > 280ꢀC dec. (H2O);
1H NMR (D2O): d 2.31 (s, 3H, CH3); 13C NMR (D2O): d 7.7
(3-CH3), 114.9 (C3 fx), 160.5 (C4 fx). Anal. Calcd. for
C3H3KN2O5S: C, 16.51; H, 1.39; N, 12.83. Found: C, 16.46;
H, 1.41; N, 12.76.
4-Benzylthio-3-phenylfuroxan (4a). The product precipi-
tated from the reaction mixture. It was filtered, washed with
cold CH3CN, and crystallized from EtOH to give the title
compound as a white solid, yield 57%, mp 111–113ꢀC
1
(EtOH); H NMR (CDCl3): d 4.45 (s, 2H, CH2), 7.31–7.49 (m,
8H), 7.83–7.87 (m, 2H) (2C6H5); 13C NMR (CDCl3): d 35.5,
114.1 (C3 fx), 122.4 (C1 Ph), 127.3, 128.1, 128.8, 129.0,
129.3, 130.7 (C4 Ph), 135.0, 154.1 (C4 fx); ms: m/z 284 (M)þ.
Anal. Calcd. for C15H12N2O2S: C, 63.36; H, 4.25; N, 9.85.
Found: C, 63.58; H, 4.23; N, 9.84.
3-Benzylthio-4-phenylfuroxan (4b). The organic solvent
was removed and the obtained oil was purified by flash chro-
matography (eluent 7/3 PE/CH2Cl2) to give the title compound
1
as a colorless oil, yield 85%; H NMR (DMSO-d6): d 4.16 (s,
Journal of Heterocyclic Chemistry
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K. Chegaev, B. Rolando, S. Guglielmo, R. Fruttero, and A. Gasco
Vol 46
C3H5N3O3S: C, 22.08; H, 3.09; N, 25.75. Found: C, 22.10; H,
3.08; N, 25.50.
Potassium 4-methylfuroxan-3-sulfonate (7b). White solid,
yield 15% (for two synthetic steps), mp 277–280ꢀC dec.
(H2O); 1H NMR (D2O): d 2.47 (s, 3H, CH3); 13C NMR
(D2O): d 12.1 (4-CH3), 120.2 (C3 fx), 154.4 (C4 fx). Anal.
Calcd. for C3H3KN2O5S: C, 16.51; H, 1.39; N, 12.83. Found:
C, 16.45; H, 1.50; N, 12.65.
3-Phenylfuroxan-4-sulfonamide (10a). Product precipitated
from acidified reaction mixture. It was filtered, washed with
cold H2O, and crystallized from H2O to give the title com-
1
pound as a white solid, yield 75%, mp 147–148ꢀC (H2O); H
NMR (DMSO-d6): d 7.57–7.64 (m, 3H), 7.85–7.90 (m, 2H)
(C6H5), 8.81 (s, 2H, NH2); 13C NMR (DMSO-d6): d 112.7 (C3
fx), 121.0 (C1 Ph), 128.7, 128.8, 131.0 (C4 Ph), 159.7 (C4 fx);
Potassium 3-methylfurazan-4-sulfonate (7c). White solid,
yield 34% (for two synthetic steps), mp > 270ꢀC dec. without
melting (H2O); 1H NMR (D2O): d 2.06 (s, 3H, CH3); 13C
þ
1
ms: m/z 242 [(MþH) ]. Anal. Calcd. for C H N O S = H O:
NMR (D2O):
d
8.4, 150.8, 157.5. Anal. Calcd. for
2
2
8
7
3
4
C, 38.40; H, 3.22; N, 16.79. Found: C, 38.45; H, 3.34; N,
16.42.
C3H3KN2O4S: C, 17.82; H, 1.50; N, 13.85. Found: C, 17.71;
H, 1.52; N, 13.66.
3-Phenylfurazan-4-sulfonamide (10c). The product precipi-
tated from acidified reaction mixture. It was filtered, washed
with cool water, and crystallized from H2O to give the title
compound as a white solid, yield 72%, mp 149.5–151ꢀC
Potassium 3-phenylfuroxan-4-sulfonate (8a). White solid,
yield 45%, mp 214–215ꢀC (H2O); 1H NMR (D2O): d 7.58–
7.60 (m, 3H), 7.86–7.90 (m, 2H) (C6H5); 13C NMR (D2O): d
116.0 (C3 fx), 121.7 (C1 Ph), 129.4, 129.6, 132.0 (C4 Ph),
159.7 (C4 fx). Anal. Calcd. for C8H5KN2O5S: C, 34.28; H,
1.80; N, 9.99. Found: C, 34.05; H, 1.79; N, 9.83.
1
(H2O); H NMR (DMSO-d6): d 7.57–7.68 (m, 3H), 7.89–7.97
(m, 2H) (C6H5), 8.92 (s, 2H, NH2); 13C NMR (DMSO-d6): d
123.3, 129.1 (two signals overlapped), 131.5, 151.9, 157.3;
ms: m/z 225 [(MþH)þ]. Anal. Calcd. for C8H7N3O3S: C,
42.66; H, 3.13; N, 18.65. Found: C, 42.62; H, 3.19; N, 18.54.
Potassium 4-phenylfuroxan-3-sulfonate (8b). White solid,
1
yield 35% (for two synthetic steps), mp 250–255ꢀC (H2O); H
NMR (D2O): d 7.55–7.65 (m, 3H), 7.76–7.79 (m, 2H) (C6H5);
13C NMR (D2O): d 119.4 (C3 fx), 126.1 (C1 Ph), 129.3,
129.7, 132.1 (C4 Ph), 156.4 (C4 fx). Anal. Calcd. for
C8H5KN2O5S: C, 34.28; H, 1.80; N, 9.99. Found: C, 34.28; H,
1.93; N, 9.97.
Potassium 3-phenylfurazan-4-sulfonate (8c). White solid,
yield 75%, mp 255–260ꢀC (H2O); 1H NMR (D2O): d 7.55–
7.64 (m, 3H), 7.92–7.95 (m, 2H) (C6H5); 13C NMR (D2O): d
124.4, 129.6, 129.7, 132.0, 153.1, 156.6. Anal. Calcd. for
N-Methyl-3-methylfuroxan-4-sulfonamide
(11a). The
acidified reaction mixture was extracted with CH2Cl2. The or-
ganic solvent was washed with H2O, brine, dried, and evapo-
rated. The obtained solid was crystallized from CCl4 to give the
title compound as a white solid, yield 61% (for two synthetic
1
steps), mp 77–79ꢀC (CCl4); H NMR (CDCl3): d 2.13 (s, 3H,
CH3), 3.01 (d, 3H, CH3), 5.19 (broad s., 1H, NH); 13C NMR
(CDCl3): d 8.0 (3-CH3), 30.2, 110.3 (C3 fx), 157.9 (C4 fx); ms:
m/z 193 (Mþ). Anal. Calcd. for C4H7N3O4S: C, 24.87; H, 3.65;
N, 21.75. Found: C, 24.79; H, 3.77; N, 21.41.
3
C H KN O S = H O: C, 34.58; H, 2.35; N, 10.08. Found: C,
4
2
8
5
2
4
34.50; H, 2.17; N, 10.07.
N-Methyl-3-methylfurazan-4-sulfonamide
(11c). The
General procedure for preparation of sulfonylamides
(9a, 9c, 10a, and 10c) and N-methyl sulfonylamides (11a,
11c, 12a, and 12c). An appropriate sulfonylchloride derivative
was added to the vigorously stirred concentrated solution of
amine in H2O at ꢄ10ꢀC. The ice-salt bath was removed and
the reaction was stirred for 2 h at room temperature. Then
reaction mixture was cooled again, the pH was adjusted to one
with concentrated HCl and the product was purified as
described.
3-Methylfuroxan-4-sulfonamide (9a). The acidified mix-
ture was extracted with EtOAc. The organic phase was washed
with H2O, brine, dried, and evaporated. The resulting oil was
purified by flash chromatography (eluent 8/2 PE/EtOAc) to
give the colorless oil, which solidified at ꢄ78ꢀC. The title
compound was crystallized from 1,2-dichloroethane. White
solid, yield 50% (for two synthetic steps), mp 93–93.5ꢀC (1,2-
dichloroethane); 1H NMR (DMSO-d6): d 2.27 (s, 3H, CH3),
8.67 (s, 2H, NH2); 13C NMR (DMSO-d6): d 7.7 (3-CH3),
110.9 (C3 fx), 160.2 (C4 fx); ms: m/z 179 (Mþ). Anal. Calcd.
for C3H5N3O4S: C, 20.11; H, 2.81; N, 23.45. Found: C, 20.07;
H, 2.86; N, 23.34.
3-Methylfurazan-4-sulfonamide (9c). The acidified mixture
was extracted with EtOAc. The organic phase was washed
with H2O, brine, dried, and evaporated. The resulting oil was
purified by flash chromatography (eluent 8/2 PE/EtOAc) to
give the colorless oil, which solidified at ꢄ78ꢀC. The title
compound was crystallized from 1,2-dichloroethane/CCl4 mix-
ture. White solid, yield 34% (for two synthetic steps), mp 81–
82ꢀC (1,2-dichloroethane/CCl4); 1H NMR (DMSO-d6): d 2.54
(s, 3H, CH3), 8.66 (s, 2H, NH2); 13C NMR (DMSO-d6): d 8.1,
149.6, 157.8; ms: m/z 164 [(MþH)þ]. Anal. Calcd. for
acidified reaction mixture was extracted with EtOAc. The or-
ganic solvent was washed with H2O, brine, dried, and evapo-
rated. The obtained oil was purified by flash chromatography
(eluent 9/1 PE/EtOAc) to give the colorless oil, which solidi-
fied by treating with PE at ꢄ78ꢀC. The obtained solid was
crystallized from CCl4 to give the title compound as a white
solid, yield 32% (for two reaction steps), mp 55–55.5ꢀC
(CCl4); 1H NMR (DMSO-d6): d 2.53 (s, 3H, CH3), 2.69 (s,
3H, CH3), 8.79 (br.s., 1H, NH); 13C NMR (DMSO-d6): d 8.2,
28.6, 149.9, 155.2; ms: m/z 178 [(MþH)þ]. Anal. Calcd. for
C4H7N3O3S: C, 27.12; H, 3.98; N, 23.72. Found: C, 27.11; H,
4.01; N, 23.60.
N-Methyl-3-phenylfuroxan-4-sulfonamide
(12a). The
acidified reaction mixture was kept at 4ꢀC overnight. The next
day a precipitate formed, was filtered, washed with cold H2O,
and crystallized from H2O to give the title compound as a
white solid, yield 77%, mp 108–109ꢀC (H2O); 1H NMR
(CDCl3): d 3.02 (d, 3H, CH3), 5.04–5.13 (m, 1H, NH), 7.54–
7.56 (m, 3H), 7.93–7.96 (m, 2H) (C6H5); 13C NMR (CDCl3):
d 30.7, 112.5 (C3 fx), 120.6 (C1 Ph), 128.5, 129.1, 131.5 (C4
Ph), 157.4 (C4 fx); ms: m/z 255 (Mþ). Anal. Calcd. for
C9H9N3O4S: C, 42.35; H, 3.55; N, 16.46. Found: C, 42.31; H,
3.57; N, 16.43.
N-Methyl-3-phenylfurazan-4-sulfonamide (12c). The prod-
uct precipitated from acidified reaction mixture was filtered,
washed with cold H2O, and crystallized from H2O to give the
title compound as a white solid, yield 84%, mp 94–95ꢀC
(H2O); 1H NMR (DMSO-d6): d 2.79 (s, 3H, CH3), 7.59–7.68
(m, 3H), 7.91–7.94 (m, 2H) (C6H5), 9.11 (s, 2H, NH2); 13C
NMR (DMSO-d6): d 29.1, 123.2, 129.0, 129.1, 131.5, 152.2,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009
Unsymmetrically Substituted Furoxans. Part 19. Methyl and
Phenylfuroxansulfonic Acids and Related Sulfonamides
871
155.0; ms: m/z 239 (Mþ). Anal. Calcd. for C9H9N3O3S: C,
45.18; H, 3.79; N, 17.56. Found: C, 45.27; H, 3.66; N, 17.52.
General procedure for preparation N,N-diethylsulfona-
mides (13a, 13c 14a, and 14c). To the solution of correspond-
ing sulfonylchloride (1.9 mmol) in CH2Cl2 (15 mL) a solution
of Et2NH (0.50 mL, 4.8 mmol) in CH2Cl2 (10 mL) was added
dropwise at 0ꢀC. The ice bath was removed and the reaction
was stirred at room temperature for 1 h. The obtained solution
was washed with 1N HCl, H2O, NaHCO3 saturated solution,
brine, dried, and evaporated. The obtained oil was purified by
flash chromatography with the indicated eluents.
110.3 (C3 fx), 121.4, 125.7, 132.9, 132.9, 157.4 (C4 fx); ms:
þ
1
m/z 333/335 (M ). Anal. Calcd. for C H BrN O S = H O: C,
2
2
9
8
3
4
31.50; H, 2.64; N, 12.25. Found: C, 31.25; H, 2.34; N, 11.86.
N-(4-Bromophenyl)-3-methylfurazan-4-sulfonamide (15c). Yield
42% (for two reaction steps), mp 96.5–97.5ꢀC (CCl4); 1H
NMR (DMSO-d6): d 2.48 (s, 3H, CH3), 7.14–7.19 (m, 2H),
7.55–7.60 (m, 2H), (C6H4), 11.69 (broad s., 1H, NH); 13C
NMR (DMSO-d6): d 8.1, 118.1, 123.5, 132.3, 134.9, 150.0,
155.1; ms: m/z 317/319 (Mþ). Anal. Calcd. for C9H8BrN3O3S:
C, 33.98; H, 2.53; N, 13.20. Found: C, 33.93; H, 2.44; N,
13.14.
N,N-Diethyl-3-methylfuroxan-4-sulfonamide
(13a). The
N-(4-Bromophenyl)-3-phenylfuroxan-4-sulfonamide(16a). Yield
1
76%, mp 149–150ꢀC (CCl4); H NMR (CDCl3): d 7.03 (s, 1H,
obtained oil was purified by flash chromatography (eluent 7/3
PE/CH2Cl2) to give a solid, which was crystallized from hex-
ane to give the title compound as a white solid, yield 36% (for
NH), 7.11 (d, 2H), 7.43 (d, 2H) (C6H4), 7.53–7.54 (m, 3H),
7.79–7.82 (m, 2H) (C6H5); 13C NMR (CDCl3): d 112.3 (C3
fx), 120.1, 121.0 (C1 Ph), 125.3, 128.6, 129.2, 131.5 (C4 Ph),
132.7, 133.1, 156.8 (C4 fx); ms: m/z 395/397 (Mþ). Anal.
Calcd. for C14H10BrN3O4S: C, 42.44; H, 2.54; N, 10.61.
Found: C, 42.15; H, 2.55; N, 10.45.
1
two reaction steps), mp 54–55ꢀC (hexane); H NMR (CDCl3):
d 1.30 (t, 6H, 2CH3), 2.35 (s, 3H, CH3), 3.49 (q, 4H, 2CH2);
13C NMR (CDCl3): d 8.1 (3-CH3), 14.4, 43.4, 110.4 (C3 fx),
158.7 (C4 fx); ms: m/z 235 (Mþ). Anal. Calcd. for
C7H13N3O4S: C, 35.74; H, 5.57; N, 17.86. Found: C, 35.97; H,
5.59; N, 17.69.
N-(4-Bromophenyl)-3-phenylfurazan-4-sulfonamide (16c). Yield
1
79%, mp 131–132ꢀC (CCl4); H NMR (DMSO-d6): d 7.19 (d,
N,N-Diethyl-3-methylfurazan-4-sulfonamide
(13c). The
2H), 7.48 7.71 (m, 5H), 7.78–7.87 (m, 2H) (C6H5 þ C6H4),
11.94 (broad s. 1H, NH); 13C NMR (DMSO-d6): d 118.0,
122.8, 123.5, 129.0, 129.2, 131.5, 132.2, 135.2, 152.3, 154.9;
ms: m/z 379/381 (Mþ). Anal. Calcd. for C14H10BrN3O3S: C,
44.23; H, 2.65; N, 11.05. Found: C, 44.10; H, 2.64; N, 11.03.
General procedure for thermal isomerization of furoxan-
sulfonamides (9b, 10b, 13b, 15b, 16b). A solution of the
appropriate 3-methyl or 3-phenyl sulfonamide derivative in
Cl2CHCHCl2 was heated at 130ꢀC for 24 h. The solvent was
evaporated and the obtained mixture of isomers was separated
by HPLC with the eluent indicated. Analytically pure samples
of 4-methyl and 4-phenyl substituted furoxansulfonamides
were obtained by crystallization.
4-Methylfuroxan-3-sulfonamide (9b). HPLC (70/30 CH3CN/
H2O þ 0.1% CF3COOH; 20 mL/min), second eluted. The
obtained solid was crystallized from 1,2-dichloroethane to give
the title compound as a white crystalline solid, mp 117–118ꢀC
(1,2-dichloroethane); 1H NMR (DMSO-d6): d 2.45 (s, 3H,
CH3), 8.29 (s, 2H, NH2); 13C NMR (DMSO-d6): d 12.5 (4-
CH3), 119.1 (C3 fx), 153.2 (C4 fx); ms: m/z 179 (Mþ). Anal.
Calcd. for C3H5N3O4S: C, 20.11; H, 2.81; N, 23.45. Found: C,
20.19; H, 2.70; N, 23.41.
obtained oil was purified by flash chromatography (eluent 8/2
PE/CH2Cl2) to give the title compound as colorless oil, yield
1
35% (for two reaction steps); H NMR (CDCl3): d 1.16 (t, 6H,
2CH3), 2.54 (s, 3H, CH3), 3.39 (q, 4H, 2CH2); 13C NMR
(CDCl3): d 8.4, 14.2, 42.8, 150.6, 156.5; ms: m/z 219 (Mþ).
Anal. Calcd. for C7H13N3O3S: C, 38.35; H, 5.98; N, 19.16.
Found: C, 38.40; H, 5.99; N, 19.06.
N,N-Diethyl-3-phenylfuroxan-4-sulfonamide
(14a). The
obtained oil was purified by flash chromatography (eluent 7/3
PE/CH2Cl2) to give a pale yellow oil, which became solid on
standing. The title product was obtained by crystallization
from hexane, yield 57%, mp 64–65ꢀC (hexane); 1H NMR
(CDCl3): d 1.28 (t, 6H, 2CH3), 3.48 (q, 4H, 2CH2), 7.50–7.54
(m, 3H), 7.94–7.97 (m, 2H) (C6H5); 13C NMR (CDCl3): d
14.7, 44.0, 112.7 (C3 fx), 120.9 (C1 Ph), 128.6, 129.0, 131.3
(C4 Ph), 157.9 (C4 fx);. ms: m/z 298 [(MþH)þ]. Anal. Calcd.
for C12H15N3O4S: C, 48.47; H, 5.08; N, 14.13. Found: C,
48.30; H, 5.00; N, 13.92.
N,N-Diethyl-3-phenylfurazan-4-sulfonamide
(14c). The
obtained oil was purified by flash chromatography (eluent 9/1
PE/CH2Cl2) to give the pale yellow oil, which was further
purified with HPLC (75/25 CH3CN/H2O) to give the title com-
4-Phenylfuroxan-3-sulfonamide (10b). HPLC (40/60 CH3CN/
H2O þ 0.1% CF3COOH; 20 mL/min), second eluted. The
obtained solid was crystallized from H2O to give the title com-
pound as a white crystalline solid, mp 112–114ꢀC (H2O); 1H
NMR (CDCl3): d 5.56 (s, 1H, NH), 7.50–7.61 (m, 3H), 7.73–
7.75 (m, 2H) (C6H5); 13C NMR (DMSO-d6): d 118.4 (C3 fx),
125.3 (C1 Ph), 128.4, 129.3, 131.1 (C4 Ph), 154.8 (C4 fx);
ms: m/z 241 (Mþ). Anal. Calcd. for C8H7N3O4S: C, 39.83; H,
2.92; N, 17.42. Found: C, 39.90; H, 2.94; N, 17.41.
1
pound as a colorless oil, yield 84%; H NMR (CDCl3): d 1.29
(t, 6H, 2CH3), 3.49 (q, 4H, 2CH2), 7.49–7.59 (m, 3H), 7.98–
8.00 (m, 2H) (C6H5); 13C NMR (CDCl3): d 14.3, 43.3, 123.1,
129.0, 129.1, 131.5, 152.3, 154;. ms: m/z 281 (Mþ). Anal.
Calcd. for C12H15N3O3S: C, 51.23; H, 5.37; N, 14.93. Found:
C, 50.91; H, 5.42; N, 15.10.
General procedure for preparation N-(4-bromophenyl)-
sulfonamides (15a, 15c 16a, and 16c). To a solution of the
appropriate sulfonylchloride (1.2 mmol) in CH2Cl2 (15 mL) p-
bromoaniline (0.50 g, 2.9 mmol) was added and the reaction
was stirred at room temperature for 4 days. The obtained solu-
tion was diluted with CH2Cl2 washed with 1N HCl, H2O,
brine, dried, and evaporated. The obtained solids were crystal-
lized from CCl4 to give the title compounds as white solids.
N-(4-Bromophenyl)-3-methylfuroxan-4-sulfonamide(15a). Yield
N-Methyl-4-methylfuroxan-3-sulfonamide
(11b). HPLC
(25/75 CH3CN/H2O þ 0.1% CF3COOH), second eluted. The
obtained solid was crystallized from CCl4 to give the title com-
pound as a white solid, mp 48–50ꢀC (CCl4); 1H NMR (CDCl3):
d 2.55 (s, 3H, CH3), 2.83 (d, 3H, CH3), 5.47 (broad s., 1H, NH);
13C NMR (CDCl3): d 12.2 (4-CH3), 29.5, 117.2 (C3 fx), 152.9
(C4 fx); ms: m/z 193 (Mþ). Anal. Calcd. for C4H7N3O4S: C,
24.87; H, 3.65; N, 21.75. Found: C, 24.83; H, 3.67; N, 21.51.
N,N-Diethyl-4-methylfuroxan-3-sulfonamide (13b). HPLC
(40/60 CH3CN/H2O; 20mL/min), second eluted. The obtained
1
50% (for two reaction steps), mp 126–127ꢀC (CCl4); H NMR
(CDCl3): d 2.20 (s, 3H, CH3), 7.17–7.22 (m, 3H), 7.48–7.53
(m, 2H), (C6H4 þ NH); 13C NMR (CDCl3): d 8.0 (3-CH3),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

872
K. Chegaev, B. Rolando, S. Guglielmo, R. Fruttero, and A. Gasco
Vol 46
solid was crystallized from hexane to give the title compound
as a white solid, mp 92–93ꢀC (hexane); 1H NMR (CDCl3): d
1.22 (t, 6H, 2CH3), 2.53 (s, 3H, CH3), 3.45 (q, 4H, 2CH2); 13C
NMR (CDCl3): d 12.5 (4-CH3), 14.4, 43.5, 118.5 (C3 fx),
152.7 (C4 fx); ms: m/z 235 (Mþ). Anal. Calcd. for
C7H13N3O4S: C, 35.74; H, 5.57; N, 17.86. Found: C, 35.69; H,
5.56; N, 17.72.
have been approved by the Ministero della Salute, Rome, Italy.
Experiments were performed according to procedures
described earlier [18]. Results are expressed as EC50 ꢁ SE
(lM). Responses were recorded by an isometric transducer
connected to the MacLab System PowerLab (ADInstruments,
Bella Vista, Australia). Addition of the drug vehicle (DMSO)
had no appreciable effect on contraction level.
N-(4-Bromophenyl)-4-methylfuroxan-3-sulfonamide (15b). HPLC
(70/30 CH3CN/H2O þ 0.1% CF3COOH; 20 mL/min), second
eluted. The obtained solid was crystallized from CCl4 to give
the title compound as a white solid, mp 114.5–115.5ꢀC (CCl4);
1H NMR (CDCl3): d 2.38 (s, 3H, CH3), 7.11 (d, 2H), 7.43–
7.50 (m, 3H) (C6H4 þ NH); 13C NMR (CDCl3): d 12.1 (4-
CH3), 117.2 (C3 fx), 125.2, 132.4, 133.1, 152.8 (C4 fx); ms:
m/z 333/335 (Mþ). Anal. Calcd. for C9H8BrN3O4S: C, 32.35;
H, 2.41; N, 12.58. Found: C, 32.42; H, 2.42; N, 12.57.
N-(4-Bromophenyl)-4-phenylfuroxan-3-sulfonamide (16b). HPLC
(60/40 CH3CN/H2O þ 0.1% CF3COOH; 20 mL/min) second
eluted. The obtained solid was crystallized from CCl4 to give
REFERENCES AND NOTES
[1] Feelisch, M.; Shoenafinger, K.; Noack, E. Biochem Pharma-
col 1992, 44, 1149.
¨
[2] Gasco, A.; Shonafinger, K. In Nitric Oxide Donors; Wang,
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[3] Cerecetto, H.; Porcal, W. Mini Rev Med Chem 2005, 5, 57.
[4] Sheremetev, A. B.; Makhova, N. N. Adv Heterocycl Chem
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1
the title compound as a white solid, mp 158–159ꢀC (CCl4); H
[5] Boschi, D.; Sorba, G.; Bertinaria, M.; Fruttero, R.; Calvino,
R.; Gasco, A. J Chem Soc Perkin Trans 1 2001, 15, 1751, and referen-
ces therein.
NMR (CDCl3): d 7.02–7.07 (m, 2H), 7.41–7.60 (m, 7H)
(C6H5, C6H4), 7.26 (s, 1H, NH); 13C NMR (CDCl3): d 117.2,
121.3 (C3 fx), 124.4 (C1 Ph), 124.9, 128.7, 129.2, 131.8 (C4
Ph), 132.5, 133.0, 155.3 (C4 fx); ms: m/z 396/398 [(MþH)þ].
Anal. Calcd. for C14H10BrN3O4S: C, 42.44; H, 2.54; N, 10.61.
Found: C, 42.31; H, 2.62; N, 10.54.
[6] Gasco, A.; Fruttero, R.; Rolando, B. Mini Rev Med Chem
2005, 5, 217.
[7] Cena, C.; Chegaev, K.; Balbo, S.; Lazzarato, L.; Rolando,
B.; Giorgis, M.; Marini, E.; Fruttero, R.; Gasco, A. Bioorg Med Chem
2008, 16, 5199 and references therein.
Ionization constants measurements. The ionization con-
stants were determined by a potentiometric method using GLpKa
apparatus (Sirius Analytical Instruments, Forest Row, East Sussex,
UK). The titrations were carried out under nitrogen atmosphere, at
constant ionic strength (I ¼ 0.15M KCl) and temperature (t ¼ 25.0
ꢁ 0.5ꢀC). Ionization constants of 9a-c, 10a-c, and 11a-c, were
determined by at least three aqueous titration: solutions of the com-
pounds (20 mL, about 1 mM) were initially acidified to pH 1.8
with 0.5N HCl and the solutions were then titrated with standar-
dized 0.5N KOH to pH 10.0. Because of the low aqueous solubil-
ity, compounds of 12a, 12c, 15a-c, and 16a-c required titrations in
methanol–water mixtures according to the following procedure. At
least five different hydro-organic solutions of the compounds (20
mL, about 1 mM in 15–65 Wt % methanol) were titrated with the
same protocol aforementioned. The apparent ionization constants
in water–methanol mixtures (psKas) were obtained and aqueous
pKa values were determined by extrapolation at 0% methanol
using the Yasuda-Shedlovsky procedure [17].
[8] Gasco, A.; Boulton, A. J. Adv Heterocycl Chem 1981, 29,
251.
[9] Calvino, R.; Fruttero, R.; Ghigo, D.; Bosia, A.; Pescarmona,
G.P.; Gasco, A. J Med Chem 1992, 35, 3297.
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[11] Fruttero, R.; Sorba, G.; Ermondi, G.; Lolli, M.; Gasco, A.
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[12] Fruttero, R.; Boschi, D.; Fornatto, E.; Serafino, A.; Gasco,
A.; Exner, O. J Chem Res 1998, 495.
[13] Kerwin, J. F., Jr.; Lancaster, J. R., Jr.; Feldman, P. L.
J Med Chem 1995, 38, 4343.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet