ꢁꢀꢀꢀ
Z. Arghiani et al.: 10H-Benzo[b]pyridazino[3,4-e][1,4]thiazinesꢂ
ꢂ217
J ꢀ=ꢀ 8.0 Hz, 2CH2N-pyr), 4.3 (br s, 2H, NH2, D2O exchangeable), 6.0 (s, (br, 4H, 2CH2N-pyr), 6.8–7.6 (m, 5H, H-5, Ar-H), 9.9 (br s, 2H, NH, D2O
+
1H, H-5), 6.7–7.5 (m, 4H, Ar-H); IR: ν 3403 and 3460 cm-1 (NH2).
exchangeable); IR : 3223 cm-1 (NH); MS: m/z 284 (M ). Anal. Calcd for
C15H16N4S (%): C, 63.35; H, 5.67; N, 19.70; S, 11.28. Found: C, 63.10; H,
2-{[3-Chloro-6-(4-methylpiperidin-1-yl)pyridazin-4-yl] 5.96; N, 19.09; S, 10.99.
thio}aniline (5c)ꢁThis compound was obtained as a yellow powder
in 40% yield; mp 157–159°C; 1H NMR (CDCl3): δ 0.9 (d, J ꢀ=ꢀ 7.5 Hz, 3H, 3-(4-Methylpiperidin-1-yl)-10H-benzo[b]pyridazino[3,4-e][1,4]
CH3-CH), 1.1–1.7 (m, 5H, 2CH2 and CH), 2.8 (m, 4H, 2CH2N), 4.3 (br s, thiazine (6c)ꢁThis compound was obtained as a brown powder in
2H, NH2, D2O exchangeable), 6.0 (s, 1H, H-5), 6.7–7.5 (m, 4H, Ar-H); IR: 39% yield; mp 225°C (dec);1H NMR (DMSO-d6): δ 0.8 (d, J ꢀ=ꢀ 7.5 Hz,
ν 3332 and 3417 cm-1 (NH2).
3H, CH3-CH), 1.1–1.8 (m, 5H, 2CH2 and CH), 2.9 (m, 4H, 2(CH2N), 6.5 (s,
1H, H-5), 6.7–7.3 (m, 4H, Ar-H), 8.6 (br s, 1H, NH, D2O exchangeable);
2-{[3-Chloro-6-(4-methylpiperazin-1-yl)pyridazin-4-yl] IR: ν 3211 cm-1 (NH); MS: m/z 298 (M ). Anal. Calcd for C16H18N4S: C,
thio}aniline (5d)ꢁThis compound was obtained as a yellow powder 64.40; H, 6.08; N, 18.78; S, 10.75. Found: C, 64.78; H, 6.14; N, 18.61;
in 76% yield; mp 165–167°C; 1H NMR (CDCl3): δ 2.3 (s, 3H, N-CH3), 2.4 S, 10.53.
+
(t, 4H, J ꢀ=ꢀ 8.0 Hz, 2CH2N), 3.4 (t, 4H, J ꢀ=ꢀ 8.0 Hz, 2 CH2N-pyr), 4.3 (br s,
2H, NH2, D2O exchangeable), 6.0 (s, 1H, H-5), 6.8–7.5 (m, 4H, Ar-H); IR: 3-(4-Methylpiperazin-1-yl)-10H-benzo[b]pyridazino[3,4-e][1,4]
+
ν 3309 and 3366 cm-1 (NH2); MS m/z: 335, 337 (M ).
thiazine (6d)ꢁThis compound was obtained as a gray powder in
1
60% yield; mp 270°C (dec); H NMR (DMSO-d6): δ 2.7 (s, 3H, N-CH3),
2-{[3-Chloro-6-(4-ethylpiperazin-1-yl)pyridazin-4-yl] 3.2 (br, 4H, 2CH2N), 3.4 (br, 4H, 2CH2N-pyr), 6.8 (s, 1H, H-5), 7.0–7.8 (m,
thio}aniline (5e)ꢁThis compound was obtained as a yellow powder 4H, Ar-H) 9.4 (br s, 1H, NH, D2O exchangeable); IR: ν 3269 cm-1 (NH);
in 76% yield; mp 206–208°C; 1H NMR (CDCl3): δ 1.1 (t, 3H, J ꢀ=ꢀ 8.0 Hz, MS: m/z 299 (M ). Anal. Calcd for C15H17N5S: C, 60.18; H, 5.72; N, 23.39;
+
CH3-(CH2N), 2.5 (m, 6H, 2(CH2N)-CH2), 3.3 (t, 4H, J ꢀ=ꢀ 8.0 Hz, 2CH2N- S, 10.71. Found: C, 60.31; H, 5.62; N, 23.89; S, 10.33.
pyr), 4.3 (br s, 2H, NH2, D2O exchangeable), 6.0 (s, 1H, H-5), 6.7–7.5 (m,
4H, Ar-H); IR: ν 3313 and 3403 cm-1 (NH2).
3-(4-Ethylpiperazin-1-yl)-10H-benzo[b]pyridazino[3,4-e][1,4]
thiazine (6e)ꢁThis compound was obtained as a yellow powder in
2-{[3-Chloro-6-(4-phenylpiperazin-1-yl)pyridazin-4-yl] 70% yield; mp 282°C (dec); 1H NMR (DMSO-d6): δ 1.0 (t, J ꢀ=ꢀ 8.0 Hz, 3H,
thio}aniline (5f)ꢁThis compound was obtained as a yellow powder CH3-CH2N), 3.2 [br, 6H, 2(CH2N)-CH2], 3.6 (m, 4H, 2CH2N-pyr), 6.7–7.4
in 75% yield; mp 176–178°C; 1H NMR (CDCl3): δ 3.3 (t, J ꢀ=ꢀ 8.0 Hz, 4H, (m, 5H, H-5, Ar-H), 9.9 (br s, 1H, NH, D2O exchangeable); IR: ν 3225 cm-
+
2CH2N-ph), 3.6 (t, J ꢀ=ꢀ 8.0 Hz, 4H, 2CH2N-pyr), 4.3 (br s, 2H, NH2, D2O 1 (NH); MS: m/z 313 (M ). Anal. Calcd for C16H19N5S: C, 61.31; H, 6.11; N,
exchangeable), 6.0 (s, 1H, H-5), 6.7–7.5 (m, 9H, Ar-H); IR: ν 3338 and 22.34; S, 10.23. Found: C, 61.14; H, 6.32; N, 22.63; S, 9.98.
3444 cm-1 (NH2).
3-(4-Phenylpiperazin-1-yl)-10H-benzo[b]pyridazino[3,4-e][1,4]
2-{[3-Chloro-6-(4-morpholinopyridazin-4-yl]thio}aniline thiazine (6f)ꢁThis compound was obtained as a brown powder in
(5g)ꢁThis compound was obtained as a yellow powder in 72% yield; 65% yield; mp 200°C (dec); 1H NMR (DMSO-d6): δ 3.3 (br, 8H, 2CH2N-
mp 198–200°C; 1H NMR (CDCl3): δ 3.4 (t, J ꢀ=ꢀ 8.0 Hz, 4H, 2CH2-N(, 3.7 (t, ph, 2CH2N), 6.4 (s, 1H, H-5), 6.5–7.2 (br, 9H, Ar-H) 9.6 (br s, 1H, NH, D2O
+
J ꢀ=ꢀ 8.0 Hz, 4H, 2CH2-O(, 4.3 (br s, 2H, NH2, D2O exchangeable), 6.0 (s, exchangeable); IR: ν 3223 cm-1 (NH); MS: m/z 357 (M ). Anal. Calcd for
1H, H-5), 6.7–7.5 (m, 4H, Ar-H); IR: ν 3346 and 3439 cm-1 (NH2). Anal. C20H19N5S: C, 66.46; H, 5.30; N, 19.37; S, 8.87. Found: C, 66.21; H, 5.32;
Calcd for C14H15ClN4OS: C, 52.09; H, 4.68; N, 17.36; S, 9.93. Found: C, N, 19.43; S, 8.86.
52.10; H, 4.56; N, 17.09; S, 9.65.
4-(10H-Benzo[b]pyridazino[3,4-e][1,4]thiazine-3-yl)morpho-
line (6g)ꢁThis compound was obtained as a dark yellow powder
1
General procedure for the conversion of (5a–g) to 10H-
benzo[b]pyridazino[3,4-e][1,4]thiazines (6a–g)
in 67% yield; mp 269°C (dec); H NMR (DMSO-d6): δ 3.2–3.7 [br,
8H, CH2-(O,N)], 6.7–7.4 (m, 5H, H-5, Ar-H), 10.0 (br s, 1H, NH, D2O
+
exchangeable); IR: ν 3259 cm-1 (NH); MS: m/z 286 (M ). Anal. Calcd
for C14H14N4OS: C, 58.72; H, 4.93; N, 19.57; S, 11.20. Found: C, 58.73; H,
4.86; N, 19.51; S, 11.25.
A mixture of compound 5a–g (10 mmol) and NaNH2 (30 mmol, 1.2 g)
in DMF (20 mL) was heated at 80°C for 12 h. The solvent was removed
under reduced pressure and a solution of acetic acid (0.7 g) in water
(20 mL) was added to the residue. The solid material of 6a–g was
filtered off, washed with water, and crystallized from ethanol.
Acknowledgments: We are grateful to Ferdowsi University
of Mashhad for financial support of this work.
3-(Pyrrolidin-1-yl)-10H-benzo[b]pyridazino[3,4-e][1,4]thiazine
(6a)ꢁThis compound was obtained as a dark green powder in 50%
1
yield; mp 310°C (dec); H NMR (DMSO-d6): δ 1.95 [br, 4H, 2((CH2)-
References
CH2N)], 3.4 (br, 4H, 2CH2N), 6.5 (s, 1H, H-5), 6.8–7.5 (m, 4H, Ar-H), 9.8
(br s, 1H, NH, D2O exchangeable); IR: ν 3215 cm-1 (NH); MS: m/z 270
+
(M ). Anal. Calcd for C14H14N4S: C, 62.20; H, 5.22; N, 20.72; S, 11.86.
[1] Bakavoli, M.; Nikpour, M.; Rahimizadeh, M.; Saberi, M. R.;
Sadeghian, H. Design and synthesis of pyrimido[4,5-b][1,4]
benzothiazine derivatives, as potent 15-lipoxygenase inhibitors.
Bioorg. Med. Chem. 2007, 15, 2120–2126.
[2] Bakavoli, M.; Sadeghian, H.; Tabatabaei, Z.; Rezaei, E.;
Rahimizadeh, M.; Nikpour, M. SAR comparative studies on
Found: C, 62.55; H, 5.89; N, 20.59; S, 11.80.
3-(Piperidin-1-yl)-10H-benzo[b]pyridazino[3,4-e][1,4]thiazine
(6b)ꢁThis compound was obtained as a dark green powder in 45%
yield; mp 280°C (dec); 1H NMR (DMSO-d6): δ 1.4–1.7 (m, 6H, 3CH2), 3.3
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