RCHH HARM
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Arch. Pharm. Chem. Life Sci. 2017, 350, e1700240
Phthalazine Derivatives as VEGFR-2 Inhibitors
Archiv der Pharmazie
6-(2-(2,4-Dichlorobenzylidene)hydrazinyl)-[1,2,4]-
triazolo[3,4-a]phthalazine (6d)
(300 MHz, DMSO-d6): 3.83 (s, 3H, OCH3), 7.04–7.06 (m, 2H,
H-3, and H-5 of phenyl), 7.71–7.74 (m, 2H, H-2, and H-6 of
phenyl), 7.93 (m, H, H-8 of phthalazine), 8.02 (m, H, H-9 of
phthalazine), 8.45–8.51 (m, 3H, H-7, and H-10 of phthalazine
and N¼CH), 9.30 (s, 1H, CH of triazole ring), 11.12 (s, 1H, NH)
(D2O exchangeable); Anal. calcd. for C17H14N6O (m.w. 318): C,
64.14; H, 4.43; N, 26.40. Found: C, 64.29; H, 4.51; N, 26.59.
Yield, 87%; m.p. 265–7°C; IRnmax (cmꢁ1): 3157 (NH), 3091 (C–H
aromatic), 2919 (C–H aliphatic), 1565 (C¼N); 13C NMR
(400 MHz, DMSO-d6): d ¼ 161.09 (C, C-6), 149.21 (CH,
NHN¼CH), 146.35 (C, C-10b), 141.66 (CH, C-3), 140.03 (C, C-
10), 133.74 (CH, C-9), 130.96 (CH, C-8), 128.92 (2C, 2CCl), 127.53
(CH, C-30), 124.88 (CH, C-10), 123.77 (C, C-10a), 123.31 (CH, C-
7), 118.24 (C, 6a), 114.82 (2CH, C-50, and C-60); MS (m/z): 361
(Mþþ4, 0.83%), 360 (Mþþ2, 1.67%), 359 (Mþþ2, 4.49%), 357
(Mþ, 7.98%), 185 (100%, base peak), 129 (41.81%); Anal.
calcd. for C16H10Cl2N6 (m.w. 357): C, 53.80; H, 2.82; N, 23.53.
Found: C, 53.96; H, 2.84; N, 23.72.
2-([1,2,4]Triazolo[3,4-a]phthalazin-6-yl)-N-
substitutedhydrazine-1-carboxamide (7a,b)
A mixture of the hydrazine (5) (0.4 g, 0.002 mol) and the
appropriate isocyanate namely cyclohexyl and/or phenyl
isocyanate (0.002 mol), was refluxed in ethanol (25 mL) for
4 h. The reaction mixture was cooled and the formed solid was
filtered and re-crystallized from ethanol to obtain compounds
7a,b, respectively.
6-(2-(2,6-Dichlorobenzylidene)hydrazinyl)-[1,2,4]-
triazolo[3,4-a]phthalazine (6e)
Yield, 88%; m.p. 266–8°C; IRnmax (cmꢁ1): 3192 (NH), 3092 (C–H
aromatic), 2902 (C–H aliphatic), 1565 (C¼N); 1H NMR
(300 MHz, DMSO-d6): 7.42–7.60 (m, 3H, H-3, H-4, and H-5 of
phenyl), 7.91–7.96 (m, H, H-8 of phthalazine), 8.01–8.06 (m, H,
H-9 of phthalazine), 8.50–8.56 (m, 2H, H-7, and H-10 of
phthalazine), 8.65 (s, 1H, N¼CH), 9.28 (s, 1H, CH of triazole
ring), 11.57 (s, 1H, NH) (D2O exchangeable); Anal. calcd. for
2-([1,2,4]Triazolo[3,4-a]phthalazin-6-yl)-N-
cyclohexylhydrazine-1-carboxamide (7a)
Yield, 83%; m.p. 274–6°C; IRnmax (cmꢁ1): 3289 (3NH over-
lapped), 3055 (C–H aromatic), 2927 (C–H aliphatic), 1627
(C¼O), 1579 (C¼N); 1H NMR (300 MHz, DMSO-d6): 1.18–1.23
(m, 4H, C-3, and C-5 cyclohexyl), 1.62 (m, 2H, C-4 cyclohexyl),
1.73–1.76 (m, 4H, C-2, and C-6 cyclohexyl), 3.40 (m, 1H,
cyclohexyl), 5.91 (s, 1H, NH-cyclohexyl) (D2O exchangeable),
7.79 (s, 1H, NH) (D2O exchangeable), 7.85–7.87 (m, H, H-8 of
phthalazine), 7.94–7.97 (m, H, H-9 of phthalazine), 8.33–8.36
(d, H, H-7 of phthalazine, J ¼ 8.1 Hz), 8.43–8.45 (d, H, H-10 of
phthalazine, J ¼ 7.8 Hz), 9.18 (s, 1H, CH of triazole ring), 9.42
(s, 1H, NHCO) (D2O exchangeable); Anal. calcd. for
C
16H10Cl2N6 (m.w. 357): C, 53.80; H, 2.82; N, 23.53. Found: C,
54.04; H, 2.80; N, 23.67.
6-(2-(4-Hydroxybenzylidene)hydrazinyl)-[1,2,4]-
triazolo[3,4-a]phthalazine (6f)
Yield, 78%; m.p. 270–2°C; IRnmax (cmꢁ1): 3223 (NH), 3084 (C-H
aromatic), 2945 (C–H aliphatic), 1594 (C¼N); 1H NMR
(300 MHz, DMSO-d6): 6.86–6.88 (m, 2H, H-3, and H-5 of
phenyl), 7.60–7.62 (m, 2H, H-2, and H-6 of phenyl), 7.89–7.92
(m, H, H-8 of phthalazine), 7.96–7.98 (m, H, H-9 of
phthalazine), 8.39 (s, 1H, N¼CH), 8.46–8.48 (m, 2H, H-7, and
H-10 of phthalazine), 9.27 (s, 1H, CH of triazole ring), 9.90 (s,
1H, OH) (D2O exchangeable), 11.02 (s, 1H, NH)
(D2O exchangeable); Anal. calcd. for C16H12N6O (m.w. 304):
C, 63.15; H, 3.97; N, 27.62. Found: C, 63.53; H, 3.95; N, 27.80.
C
16H19N7O (m.w. 325): C, 59.06; H, 5.89; N, 30.13. Found: C,
59.18; H, 5.94; N, 30.37.
2-([1,2,4]Triazolo[3,4-a]phthalazin-6-yl)-N-
phenylhydrazine-1-carboxamide (7b)
Yield, 83%; m.p. 282–4°C; IRnmax (cmꢁ1): 3226 (3NH over-
lapped), 3061 (C–H aromatic), 2930 (C–H aliphatic), 1635
(C¼O), 1573 (C¼N); 1H NMR (300 MHz, DMSO-d6): 7.21–7.26
(m, 1H, H-4 phenyl), 7.30–7.35 (m, 2H, H-3 and H-5 phenyl),
7.41–7.44 (m, 2H, H-2 and H-6 phenyl), 7.82–7.87 (m, H, H-8 of
phthalazine), 7.88–7.97 (m, H, H-9 of phthalazine), 8.24–8.26
(d, H, H-7 of phthalazine, J ¼ 8.7 Hz), 8.40–8.42 (d, H, H-10 of
phthalazine, J ¼ 8.4 Hz), 8.44 (s, 1H, NH) (D2O exchangeable),
9.08 (s, 1H, CH of triazole ring), 9.66 (s, 1H, NHCO)
6-(2-(2-Methoxybenzylidene)hydrazinyl)-[1,2,4]-
triazolo[3,4-a]phthalazine (6g)
Yield, 76%; m.p. 271–3°C; IRnmax (cmꢁ1): 3226 (NH), 3085 (C–H
aromatic), 2955 (C–H aliphatic), 1594 (C¼N); 1H NMR
(300 MHz, DMSO-d6): 3.90 (s, 3H, OCH3), 7.03–7.08 (m, H, H-
3 of phenyl), 7.11–7.14 (m, H, H-5 of phenyl), 7.39–7.44 (m, H,
H-4 of phenyl), 7.89–8.03 (m, 3H, H-6 of phenyl, H-8 and H-9 of
phthalazine), 8.48–8.53 (m, 2H, H-7, and H-10 of phthalazine),
8.85 (s, 1H, N¼CH), 9.30 (s, 1H, CH of triazole ring), 11.26 (s, 1H,
NH) (D2O exchangeable); Anal. calcd. for C17H14N6O (m.w.
318): C, 64.14; H, 4.43; N, 26.40. Found: C, 64.35; H, 4.49; N,
26.56.
(D2O
exchangeable),
10.21
(s,
1H,
NH-phenyl)
(D2O exchangeable). MS (m/z): 320 (Mþþ1, 5.39%), 319
(Mþ, 9.96%), 119 (100%, base peak); Anal. calcd. for
C
16H13N7O (m.w. 319): C, 60.18; H, 4.10; N, 30.70. Found: C,
60.43; H, 4.17; N, 30.85.
2-([1,2,4]Triazolo[3,4-a]phthalazin-6-yl)-N-
substitutedhydrazine-1-carbothioamide (8a-c)
6-(2-(4-Methoxybenzylidene)hydrazinyl)-[1,2,4]-
triazolo[3,4-a]phthalazine (6h)
A mixture of the hydrazine (5) (0.4 g, 0.002 mol) and the
appropriate isothiocyanate, namely ethyl, propyl, and/or
phenyl isothiocyanate (0.002 mol), was refluxed in ethanol
(25 mL) for 6 h. the reaction mixture was cooled and the
Yield, 77%; m.p. 273–5°C; IRnmax (cmꢁ1): 3226 (NH), 3084 (C–H
aromatic), 2935 (C–H aliphatic), 1594 (C¼N); 1H NMR
ß 2017 Deutsche Pharmazeutische Gesellschaft
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