2
784
I. C. César et al. / Bioorg. Med. Chem. 22 (2014) 2783–2790
N
2.3.1. N-(2-Hydroxyethyl)nicotinamide (1A)
Yield 64%): mp 88.0 °C. IR (ATR): 3321, 3173, 2876, 1659, 1550,
N
N
N
H
N
H
N
H
N
(
ONO
2
ONO2
ONO2
1
1
3
1
422, 1296, 1057, 1028, 702. H NMR (200 MHz, DMSO-d
.39 (m, 2H), 3.57 (t, 2H, J = 5.8 Hz), 4.83 (br s, 1H), 7.42–7.50 (m,
H), 8.19 (d, 1H, J = 8.0 Hz), 8.66–8.68 (m, 2H), 9.02 (s, 1H). 13
): 42.3, 59.8, 123.4, 130.1, 135.0, 148.5,
51.7, 165.1. Anal. Calcd for C . Calcd (%): C, 57.82; H,
6
): 3.34–
O
O
O
O
O
(
1)
(2)
(3)
C
N
NMR (50 MHz, DMSO-d
6
1
6
N
H
N
H
N
H
N
8 10 2 2
H N O
OH
OH
OH
.07; N, 16.86. Found (%): C, 56.94; H, 6.03; N, 16.88.
O
(
1A)
(2A)
(3A)
2
.3.2. N-(2-Hydroxyethyl)picolinamide (2A)
Figure 1. Chemical structures of nicorandil (1), ortho-nicorandil (2) and para-nicorandil
(Yield 92%): mp 36.0 °C. IR (ATR): 3364, 3297, 2932, 2876, 1645,
1569, 1436, 1365, 1298, 1060, 1044, 821, 752. H NMR (200 MHz,
1
(
(
3) and their respective main metabolites N-(2-hydroxyethyl)nicotinamide (NHN)
1A), N-(2-hydroxyethyl)picolinamide (NHP) (2A) and N-(2-hydroxyethyl)isonico-
3
CDCl ): 3.60–3.68 (m, 2H), 3.84 (t, 2H, J = 5.0 Hz), 4.85 (br s, 1H),
tinamide (NHI) (3A).
7
.32–7.41 (m, 1H), 7.78 (td, 1H, J = 7.6, 1.6 Hz), 8.10 (d, 1H,
13
J = 7.8 Hz), 8.47 (d, 1H, J = 4.3 Hz), 8.64 (br s,1H).
C NMR
(
1
1
50 MHz, CDCl
3
): 41.6, 60.8, 121.6, 125.7, 136.9, 147.6, 149.0,
To further explore the structure-activity relationships, we deter-
mined some pharmacokinetic parameters of the three isomers, as
well as the plasma concentrations of the corresponding main deni-
trated metabolites (Fig. 1) and also the plasma concentrations of
nicotinamide and nitrite after the administration of each isomer
in mice.
64.6. Anal. Calcd for C . Calcd (%): C, 57.82; H, 6.07; N,
6.86. Found (%): C, 57.78; H, 6.12; N, 16.85.
8 10 2 2
H N O
2
.3.3. N-(2-Hydroxyethyl)isonicotinamide (3A)
(
Yield 88%): mp 135.5 °C. IR (ATR): 3317, 3173, 3058, 2931,
1
1
660, 1548, 1410, 1314, 1237, 1065, 1041, 1003, 816, 751.
): 3.32–3.40 (m, 2H), 3.47–3.59 (m, 2H),
4.81 (t, 1H, J = 5.4 Hz), 7.76 (d, 2H, J = 4.8 Hz), 8.69-8.75 (m, 3H).
H
NMR (200 MHz, DMSO-d
6
2
2
. Material and methods
1
3
C NMR (50 MHz, DMSO-d
6
): 42.3, 59.5, 121.3, 141.5, 150.1,
.1. Chemical and reagents
164.8. Anal. Calcd for C H N O . Calcd (%): C, 57.82; H, 6.07; N,
8
10
2 2
1
6.86. Found (%): C, 58.72; H, 6.04; N, 16.97.
All chemicals were obtained from commercial suppliers and
The nitrated compounds were obtained by mixing fuming nitric
used without further purification. Melting points were determined
acid (10 mmol) and the hydroxylated precursors (1 mmol) at
À5.0 °C and stirring for 2 h. The reaction mixture was poured into
a mixture of water and ice. The pH was adjusted to 6.0 by adding
1
in a Gehaka PF 1500 apparatus and are uncorrected. H nuclear
magnetic resonance (NMR) spectra and 13C NMR spectra were re-
corded on a Bruker Avance DPX/200. Chemical shift values (d) were
given in parts per million (ppm). Infrared (IR) spectra were re-
corded on a Spectro One Perkin Elmer. The elemental analyses
were performed with a Perkin-Elmer apparatus.
CaCO . The obtained solid was vacuum filtered and recrystallized
3
2
3,24
in ethanol, which furnished a white solid in all cases.
2.3.4. N-(2-Nytroxyethyl)nicotinamide (nicorandil; 1)
Yield 40%): mp 91.0 °C. IR (ATR): 3241, 3073, 1717, 1627, 1590,
(
1
2
.2. Syntheses of nicorandil and its isomers
1554, 1372, 1361, 1319, 1286, 1012, 1000, 860, 824, 705. H NMR
200 MHz, DMSO-d ): 3.65 (q, 2H, J = 5.1 Hz), 4.67 (t, 2H,
J = 5.1 Hz), 7.46–7.55 (m, 1H), 8.18 (d, 1H, J = 7.8 Hz), 8.71 (d, 1H,
(
6
Nicorandil (1) and its positional isomers (2 and 3) were synthe-
1
3
sized, as shown in Scheme 1. In summary, the corresponding esters
were treated with ethanolamine under reflux, which furnished the
hydroxylated precursors 1A to 3A. Compounds 1A–3A were trea-
ted with fuming nitric acid at À5 °C, which lead to the nitrates 1
J = 4.4 Hz), 8.94–9.02 (m, 2H). C NMR (50 MHz, DMSO-d ): 36.8,
6
72.1, 123.5, 129.5, 135.0, 148.3, 152.0, 165.2. Anal. Calcd for
C H N O . Calcd (%): C, 45.50; H, 4.30; N, 19.90. Found (%): C,
8
9
3 4
45.62; H, 4.31; N, 20.03.
1
to 3. All synthesized compounds were characterized by H and
1
3
C NMR, infrared, melting point and elemental analysis; the data
2.3.5. N-(2-Nytroxyethyl)picolinamide (ortho-nicorandil; 2)
are in accordance with previous reports.2
3,24
(Yield 63%): mp 62.5 °C. IR (ATR): 3391, 2956, 1664, 1630, 1520,
1
1
275, 1012, 858, 752. H NMR (200 MHz, DMSO-d
6
): 3.64–3.74 (m,
2
.3. Chemistry and biological assays
2H), 4.69 (t, 2H, J = 5.1 Hz), 7.55–7.61 (m, 1H), 7.94–8.07 (m, 2H),
1
3
8
.62 (d, 1H, J = 4.4 Hz), 9.08–9.10 (m, 1H). C NMR (50 MHz,
For the synthesis of the hydroxylated precursors, ethanolamine
DMSO-d ): 36.4, 72.2, 121.9, 126.6, 137.7, 148.3, 149.5, 164.3. Anal.
6
(
1.5 mmol) was added slowly to the esters (1 mmol) at 55 °C and
Calcd for C H N O . Calcd (%): C, 45.50; H, 4.30; N, 19.90. Found
8
9
3 4
stirred for 3 h. The reaction mixture was stirred at room tempera-
ture for 15 h. The residue was purified by silica gel column chro-
matography (eluent/ethyl acetate/hexane 8:2) or recrystallized
from ethyl acetate. The progress of the reaction was monitored
by TLC.
(%): C, 45.45; H, 4.21; N, 19.86.
2.3.6. N-(2-Nytroxyethyl)isonicotinamide (para-nicorandil; 3)
(Yield 55%): mp 112 °C. IR (ATR): 3265, 1647, 1618, 1545, 1322,
1
1280, 1018, 877, 754. H NMR (200 MHz, DMSO-d ): 3.65 (q, 2H,
6
OH
N
O
O
H N
N
O
HNO3, -5 oC, 2h
N
2
O
Reflux, 3h
HN
HN
OH
ONO2
ortho -substituted (2A) (92%)
meta-substituted (1A) (64%)
para-substituted (3A) (88%)
ortho -Nicorandil (2) (63%)
Nicorandil (1) (40%)
para -Nicorandil (3) (55%)
Scheme 1. Synthesis of nicorandil (1) and its isomers 2 and 3.