I. O. ZhuravelÕ et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5483–5487
5487
2. Bylov, I. E.; Vasylyev, M. V.; Bilokin, Y. V. Eur. J. Med.
Chem. 1999, 34, 997.
3. Hadfield, J. A.; Pavlidis, V. H.; Perry, P. J.; McGown, A.
T. Anti-Cancer Drugs 1999, 10, 591.
4. Cho, S. Y.; Kang, S. Y.; Kim, S. S.; Cheon, H. G.; Choi,
J.-K.; Yum, E. K. Bull. Korean. Chem. Soc. 2001, 22, 1217.
5. Mekheimer, R. A.; Mohamed, N. H.; Sadek, K. U. Bull.
Chem. Soc. Jpn. 1997, 70, 1625.
6. Stoyanov, E. V.; Ivanov, I. C.; Heber, D. Molecules 2000,
5, 19.
7. ZhuravelÕ, I. O.; Kovalenko, S. M.; Ivachtchenko, A. V.;
Chernykh, V. P.; Shinkarenko, P. E. J. Heterocycl. Chem.
2004, 41, 517.
8. Bilokin, Y. V.; Kovalenko, S. N.; Bylov, I. E.; Chernykh,
V. P.; Branytska, O. V.; Kovalenko, S. M. Heterocycl.
Commun. 1998, 4, 257.
9. Kovalenko, S. N.; Bylov, I. E.; Belokon, Ya. V; Chernykh,
V. P. Chem. Heterocycl. Comp. (New York) (Khim.
Geterotsikl. Soed) 2000, 36, 1026.
10. Kovalenko, S. N.; Bylov, I. E.; Belokon; Sytnik, K. M.;
Chernykh, V. P.; Bilokin, Y. V. Molecules 2000, 5,
1146.
11. Melting points were measured with a Buchi B-520 melting
point apparatus and are uncorrected. IR spectra were
recorded on Specord M80 spectrometers in KBr. 1H NMR
spectra were recorded on Varian Gemini-300 spectrome-
ters in DMSO-d6 using TMS as an internal standard.
Chemical shifts were expressed in d (ppm) relative to TMS
as internal standard and coupling constants (J) in hertz.
Elemental analyses were within 0.4% of the theoretical
values. General procedure for the synthesis of 2-imino-5-
hydroxymethyl-8-methyl-2H-pyrano[2,3-c]pyridine-3-(N-
aryl)carboxamides 4a–j. A solution of 10.18 g (50 mmol)
of pyridoxal hydrochloride 1 and 50 mmol of cyanoace-
tamide 2a–j in 100 mL of absolute methanol was heated to
40–45 ꢁC. Distilled piperidine (1.0 mL, 100 mmol) was
slowly added, and the resulting mixture was allowed to
stand at 40–45 ꢁC for 20 min. The formed precipitate was
filtered out, washed by methanol and recrystallized from
ethanol to afford 4a–j as yellow crystalline solid. Repre-
sentative spectral data for compounds 4. 2-Imino-5-
hydroxymethyl-8-methyl-2H-pyrano[3,2-c]pyridin-3-(N-
phenyl)carboxamide 4a. Mp 230–231 ꢁC; IR (m) 3300
(amid N–H), 3202 (imine N–H), 3000 (C–H), 1689 (C@O),
1634 (C@N), 1600 and 1560 (C@C), 1227 (C–O), 1009,
760; 1H NMR (DMSO-d6) d 2.54 (3H, s, Me), 4.71 (2H, d,
J = 8.2 Hz, CH2), 5.41 (1H, t, J = 5.1 Hz, OH), 7.13 (1H,
dt, J = 6.9 Hz, J = 1.6 Hz, ArH), 7.39 (2H, t, J = 7.8 Hz,
ArH), 7.64 (2H, d, J = 9.4 Hz, ArH), 8.23 (1H, s, H-4),
8.61 (1H, s, H-6), 9.41 (1H, s, NH), 12.58 (1H, s, NH);
Anal. Calcd for C17H15N3O3: C, 66.01; H, 4.89; N, 13.53.
Found: C, 66.03; H, 4.89; N, 13.58. 2-Imino-5-hydroxy-
methyl-8-methyl-2H-pyrano[3,2-c]pyridin-3-[N-(2-meth-
ylphenyl)]-carboxamide 4b. Mp 233–235 ꢁC; IR (m) 3302
(amid N–H), 3211 (imine N–H), 3051 (C–H), 1690 (C@O),
1632 (C@N), 1592 and 1562 (C@C),1223 (C–O), 1011,
759; 1H NMR (DMSO-d6) d 2.28 (3H, s, Me), 2.48 (3H, s,
Me), 4.73 (2H, d, J = 5.1 Hz, CH2), 5.37 (1H, t,
J = 6.5 Hz, OH), 7.07 (1H, d, J = 7.5 Hz, ArH), 7.21
(2H, m, ArH), 8.17 (1H, d, J = 8.1 Hz, ArH), 8.24 (1H, s,
H-4), 8.68 (1H, s, H-6), 9.45 (1H, s, NH), 12.38 (1H, s,
NH); Anal. Calcd for C18H17N3O3: C, 66.86; H, 5.30; N,
13.00. Found: C, 66.87; H, 5.29; N, 13.00.
12. Bilokin, Y. V.; Vasylyev, M. V.; Branytska, O. V.;
Kovalenko, S. M.; Chernykh, V. P. Tetrahedron 1999,
55, 13757.
13. General procedure for the synthesis of 2-(N-aryl)-imino-
5-hydroxymethyl-8-methyl-pyrano[3,2-c]pyridine-3-(N-ar-
yl)carboxamides 5{1–35}. To a solution of aromatic
amine (1 mmol) in glacial acetic acid (5 mL) was added a
solution of imine 4a–j (1 mmol) in acetic acid, and the
mixture was refluxed for 20–30 min. Then the reaction
mixture was cooled, and the precipitated product was
filtered and recrystallizated from EtOH, DMF, or
EtOH–DMF. Structures and yields of 5{1-35} are shown
in Table 1. Representative spectral data for the active
compounds 5: 2-[N-(3,4-Dimethylphenyl)]-imino-5-hy-
droxymethyl-8-methyl-2H-pyrano[3,2-c]pyridin-3-[N-(3-
1
methylphenyl)]-carboxamide (5{14}). Mp 268–269 ꢁC; H
NMR (d) 2.27 (s, 9H, Me), 2.40 (s, 3H, Me), 4.71 (d, 2H,
J = 4 Hz, CH2), 5.42 (t, 1H, J = 3.6 Hz, OH), 6.94 (d,
1H, J = 7.8 Hz, ArH), 7.18–7.29 (m, 4, ArH), 7.48 (m,
2H, ArH), 8.28 (s, 1H, H-6), 8.60 (s, 1H, H-4), 12.23 (s,
1H, NH). Anal. Calcd for C26H25N3O3: C, 73.05; H,
5.89; N, 9.83. Found: C, 73.05; H, 5.90; N, 9.80. 2-N-[4-
(6-Methyl-1,3-benzothiazol-2-yl)phenyl]-imino-5hydroxy-
methyl-8-methyl-2H-pyrano[3,2-c]pyridin-3-[N-(2-ethyl-
1
phenyl)] carboxamide (5{29}). Mp 273–274 ꢁC; H NMR
(d) 1.11 (t, 3H, J = 9.0 Hz, Et), 2.47 (s, 6H, Me), 2.70 (q,
2H, J = 10.3 Hz, Et), 4.75 (d, 2H, J = 5.2 Hz, CH2), 5.49
(t, 1H, J = 3.9 Hz, OH), 7.10 (m, 1H, ArH), 7.21–7.35
(m, 3H, ArH), 7.52 (d, 2H, J = 9.4 Hz, ArH), 7.90 (d,
2H, J = 8.5 Hz, ArH), 8.13 (d, 2H, J = 9.4 Hz, ArH),
8.23 (d, 1, J = 8.6 Hz, ArH), 8.31 (s, 1H, H-6), 8.81 (s,
1H, H-4), 11.92 (s, 1H, NH). Anal. Calcd for
C33H28N4O3S: C, 70.69; H, 5.03; N, 9.99; S, 5.72.
Found: C, 70.70; H, 5.05; N, 10.00; S, 5.70. 2-[N-(3,4-
Dichlorophenyl)]-imino-5-hydroxymethyl-8-methyl-2H-
pyrano[3,2-c]pyridin-3-[N-(4-methoxyphenyl)]-carboxamide
1
(5{31}). Mp 228 ꢁC; H NMR (d) 2.32 (s, 3H, Me), 3.70
(s, 3H, OCH3), 4.71 (d, 2H, J = 6.2 Hz, CH2), 5.42 (t,
1H, J = 4.7 Hz, OH), 6.92 (d, 2H, J = 9.5 Hz, ArH), 7.36
(dd, J = 9.3 Hz, J = 0.9 Hz, 1H, ArH), 7.60 (d,
J = 9.5 Hz, 2, ArH), 7.61 (d, J = 3.6 Hz, 1H, ArH),
7.75 (d, J = 0.9 Hz, 1H, ArH), 8.30 (s, 1H, H-6), 8.68 (s,
1H, H-4), 11.61 (s, 1H, NH). Anal. Calcd for
C24H19Cl2N3O4: C, 59.52; H, 3.95; N, 8.68. Found: C,
59.50; H, 3.96; N, 8.68.
14. Dhar, M. L.; Dhar, M. M.; Dhawan, B. N.; Mehrotra, B.
N.; Ray, C. Indian J. Exp. Biol. 1968, 6, 232.
15. Experimental determination of antimicrobial activity. The
bacterial strains were grown in HottingerÕs broth (0.1%
amine nitrogen and 0.5% NaCl, pH 7.0–7.2), and the
fungal strain was grown in SabouraudÕs dextrose broth.
The tests were performed in assay tubes (12 · 75 mm) in
triplicate. Ten tubes were filled with the seeded broth
(2 mL). The test compound (2 mL of 1 mg/mL solution in
DMF) was added to the first tube and 2 mL of this
solution was transferred to the second tube and so on so
forth. Then bacterial and fungal strains were inoculated in
the tubes (bacteria 2 · 105 cfu/mL, fungi 5 · 105 cfu/mL).
The tubes were incubated at 37 ꢁC for bacteria (for 18–
24 h) and 30 ꢁC for fungi (for 48 h). The MICs (in lg/mL)
were recorded by visual observation.
16. Davis, R.; Markham, A.; Balfour, J. A. Drugs 1996, 51,
1019.