Synthesis of 6,7-Methylenedioxyphthalazin-1(2H)-ones
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 15 2857
(C-4), 149.59 (C-3′), 151.44 (C-7), 151.53 (C-6), 157.96 (C-1);
MS (ESI+) 282 (M++1, 100), 240 (92). Anal. (C15H11N3O3) C,
H, N.
(s, 2H, OCH2O), 6.78 (d, 2H, J ) 7.5, H-3′,5′), 7.16 (s, 1H, H-5),
7.42 (d, 2H, J ) 7.5, H-2′,6′), 7.85 (s, 1H, H-8), 9.62 (bs, 1H,
NH); 13C NMR 13.77 (CH3), 20.26, 31.85, 41.21 (CH2), 103.39
(OCH2O), 103.64 (C-5), 104.20 (C-8), 117.23 (C-3′,5′), 123.82
(C-1′), 124.63 (C-8a), 126.20 (C-4a), 129.64 (C-2′,6′), 146.35 (C-
4), 148.81 (C-4′), 151.36 (C-7), 152.04 (C-6), 158.88 (C-1)
166.33 (CdO); MS (ESI+) 381 (M++1, 93), 282 (100). Anal.
(C20H20N4O4) C, H, N.
4-(4-Am in op h e n yl)-6,7-m e t h yle n e d ioxyp h t h a la zin -
1(2H)-on e (16): mp >300 °C (241 mg, 89%); 1H NMR
(CDCl3): 3.88 (bs, 2H, NH2) 6.16 (s, 2H, OCH2O), 6.81 (d, 2H,
J ) 8.2, H-3′,5′), 7.15 (s, 1H, H-5), 7.35 (d, 2H, J ) 8.2, H-2′,6′),
7.83 (s, 1H, H-8), 9.82 (bs, 1H, NH); 13C NMR 102.82 (OCH2O),
103.59 (C-5), 104.38 (C-8), 113.42 (C-3′,5′), 122.31 (C-1′), 124.61
(C-8a), 126.40 (C-4a), 130.00 (C-2′,6′), 146.31 (C-4), 149.39 (C-
4′), 150.51 (C-7), 151.88 (C-6), 158.69 (C-1); MS (ESI+) 282
(M++1, 100). Anal. (C15H11N3O3) C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of 2-(Cyclo)-
a lk ylca r ba m oyl-4-(3- or 4-a m in op h en yl)-6,7-m eth ylen e-
d ioxyp h th a la zin -1(2H)-on es 17-23. To a solution of 13 or
14 (0.3 g, 0.96 mmol) in CH2Cl2 (60 mL) were added trieth-
ylamine (1.2 mL, 8.6 mmol) and the suitable isocyanate (4.8
mmol). The reaction mixture was stirred at room temperature
for 36 h, then was neutralized with 0.1 N HCl and washed
with water. The organic phase was concentrated in vacuo, and
the resulting residue was purified by column chromatography
with CHCl3/EtOAc (70:30) as eluant. The subsequent hydro-
genation was carried out according to the procedure reported
for compounds 15-16. All compounds were recrystallized from
EtOAc.
4-(4-Am in op h en yl)-6,7-m et h ylen ed ioxy-2-p en t ylca r -
ba m oylp h th a la zin -1(2H)-on e (22): mp 137-139 °C (255 mg,
1
67%); H NMR 0.93 (t, 3H, J ) 7.0, CH3), 1.31-1.43 (m, 4H,
CH2CH2), 1.67 (m, 2H, CH2), 3.48 (m, 2H, CH2), 3.90 (bs, 2H,
NH2), 6.18 (s, 2H, OCH2O), 6.78 (d, 2H, J ) 8.5, H-3′,5′), 7.16
(s, 1H, H-5), 7.41 (d, 2H, J ) 8.5, H-2′,6′), 7.85 (s, 1H, H-8),
9.63 (bs, 1H, NH); 13C NMR 13.97 (CH3), 22.34, 29.00, 29.08,
41.07 (CH2), 102.75 (OCH2O), 105.46 (C-5), 105.75 (C-8), 114.73
(C-3′,5′), 121.47 (C-1′), 124.66 (C-8a), 126.76 (C-4a), 130.72 (C-
2′,6′), 147.71 (C-4′), 148.09 (C-4), 151.26 (C-7), 152.51 (C-6),
157.09 (C-1), 161.26 (CdO); MS (ESI+) 395 (M++1, 100), 282
(48). Anal. (C21H22N4O4) C, H, N.
4-(4′-Am in op h en yl)-2-cycloh exylca r ba m oyl-6,7-m eth -
ylen ed ioxyp h th a la zin -1(2H)-on e (23): mp 141-144 °C (231
mg, 59%); 1H NMR 0.87-1.44 (m, 10H, CH2), 3.65 (m, 1H, CH),
3.91 (bs, 2H, NH2), 6.18 (s, 2H, OCH2O), 6.78 (d, 2H, J ) 7.9,
H-3′,5′), 7.15 (s, 1H, H-5), 7.41 (d, 2H, J ) 7.9, H-2′,6′), 7.85
(s, 1H, H-8), 9.67 (bs, 1H, NH); 13C NMR 24.90, 25.57, 33.90
(CH2-cyclohexyl), 49.17 (CH-cyclohexyl), 102.18 (OCH2O),
104.88 (C-5), 105.77 (C-8), 114.38 (C-3′,5′), 122.10 (C-1′), 124.36
(C-8a), 126.18 (C-4a), 130.42 (C-2′,6′), 147.32 (C-4′), 148.31 (C-
4), 151.15 (C-7), 152.67 (C-6), 157.34 (C-1), 161.30 (CdO). Anal.
(C22H22N4O4) C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of 4-Ar yl-6,7-
m eth ylen ed ioxyp h th a la zin e-1(2H)-th ion es 24, 25. A solu-
tion of 12 or 16 (1 mmol) and Lawesson’s reagent (0.22 g, 0.55
mmol) in dry toluene (50 mL) was heated to reflux for 2 h.
The solution was then cooled at room temperature and filtered.
The toluene was removed in vacuo and the residue was
crystallized from EtOH.
6,7-Me t h y le n e d i o x y -1-p h e n y lp h t h a la z i n e -1(2H )-
th ion e (24): mp >300 °C (270 mg, 85%); 1H NMR 6.20 (s, 2H,
OCH2O), 7.10 (s, 1H, H-5), 7.55 (m, 5H, ArH), 8.40 (s, 1H, H-8),
11.56 (bs, 1H, NH); 13C NMR 102.68 (OCH2O), 104.13 (C-5),
104.63 (C-8), 124.88 (C-8a), 126.37 (C-4a), 128.83 (C-3′,5′),
129.24 (C-2′,6′), 129.71 (C-4′), 134.33 (C-1′), 146.46 (C-4),
151.65 (C-7), 152.02 (C-6), 197.28 (C-1); MS (ESI+) 283 (M++1,
0), 251 (100). Anal. (C15H10N2O2S) C, H, N.
4-(4-Am in op h en yl)-6,7-m et h ylen ed ioxyp h t h a la zin e-
1(2H)-th ion e (25): mp >300 °C (260 mg, 82%); 1H NMR 3.88
(bs, 2H, NH2), 6.18 (s, 2H, OCH2O), 6.81 (d, 2H, J ) 8.2,
H-3′,5′), 7.14 (s, 1H, H-5), 7.35 (d, 2H, J ) 8.2, H-2′,6′), 8.40
(s, 1H, H-8), 11.56 (bs, 1H, NH); 13C NMR 101.57 (OCH2O),
103.05 (C-5), 104.08 (C-8), 113.12 (C-3′,5′), 122.58 (C-1′), 124.31
(C-8a), 126.12 (C-4a), 129.84 (C-2′,6′), 146.12 (C-4), 148.16 (C-
4′), 150.92 (C-7), 152.15 (C-6), 199.13 (C-1); MS (ESI+) 298
(M++1, 0), 266 (100). Anal. (C15H11N3O2S) C, H, N.
4-(4-Am in op h en yl)-2-m eth ylca r ba m oyl-6,7-m eth ylen e-
d ioxyp h th a la zin -1(2H)-on e (17): mp >300 °C (239 mg,
1
87%); H NMR 3.06 (d, 3H, J ) 4.8, CH3), 3.96 (bs, 2H, NH2)
6.18 (s, 2H, OCH2O), 6.78 (d, 2H, J ) 8.5, H-3′,5′), 7.15 (s, 1H,
H-5), 7.40 (d, 2H, J ) 8.5, H-2′,6′), 7.85 (s, 1H, H-8), 9.52 (bs,
1H, NH); 13C NMR 26.76 (CH3), 102.93 (OCH2O), 104.32 (C-
5), 104.93 (C-8), 114.24 (C-3′,5′), 122.57 (C-1′), 125.12 (C-8a),
126.88 (C-4a), 131.85 (C-2′,6′), 147.15 (C-4), 149.35 (C-4′),
151.15 (C-7), 152.35 (C-6), 158.12 (C-1) 163.45 (CdO); MS
(ESI+) 339 (M++1, 68), 282 (100). Anal. (C17H14N4O4) C, H,
N.
4-(4-Am in op h en yl)-2-et h ylca r b a m oyl-6,7-m et h ylen e-
d ioxyp h th a la zin -1(2H)-on e (18): mp >300 °C (272 mg,
1
80%); H NMR 1.30 (t, 3H, J ) 7.2, CH3), 3.52 (m, 2H, CH2),
3.90 (bs, 2H, NH2) 6.18 (s, 2H, OCH2O), 6.78 (d, 2H, J ) 8.3,
H-3′,5′), 7.15 (s, 1H, H-5), 7.41 (d, 2H, J ) 8.3, H-2′,6′), 7.85
(s, 1H, H-8), 9.60 (bs, 1H, NH); 13C NMR 14.34 (CH3), 35.37
(CH2), 103.25 (OCH2O), 104.29 (C-5), 104.76 (C-8), 113.37 (C-
3′,5′), 121.36 (C-1′), 124.56 (C-8a), 126.10 (C-4a), 130.19 (C-
2′,6′), 146.52 (C-4), 149.86 (C-4′), 151.13 (C-7), 152.57 (C-6),
157.24 (C-1), 165.50 (CdO); MS (ESI+) 353 (M++1, 100), 282
(84). Anal. (C18H16N4O4) C, H, N.
4-(4-Am in op h en yl)-6,7-m et h ylen ed ioxy-2-p r op ylca r -
ba m oylp h th a la zin -1(2H)-on e (19): mp >300 °C (268 mg,
1
76%); H NMR 1.02 (t, 3H, J ) 7.4, CH3), 1.70 (m, 2H, CH2),
3.46 (m, 2H, CH2), 3.91 (bs, 2H, NH2) 6.18 (s, 2H, OCH2O),
6.78 (d, 2H, J ) 8.4, H-3′,5′), 7.15 (s, 1H, H-5), 7.41 (d, 2H, J
) 8.4, H-2′,6′), 7.85 (s, 1H, H-8), 9.62 (bs, 1H, NH); 13C NMR
11.46 (CH3), 22.55, 42.40 (CH2), 102.78 (OCH2O), 104.18 (C-
5), 105.30 (C-8), 118.31 (C-3′,5′), 124.23 (C-1′), 124.37 (C-8a),
126.05 (C-4a), 129.88 (C-2′,6′), 146.43 (C-4), 149.81 (C-4′),
151.25 (C-7), 152.34 (C-6), 158.17 (C-1) 166.12 (CdO); MS
(ESI+) 367 (M++1, 100), 282 (73). Anal. (C19H18N4O4) C, H,
N.
Lip op h ilicity Mea su r em en ts. The relative lipophilicity
(Rm) of the compounds was measured by reversed-phase high-
performance thin-layer chromatography (RP-HPTLC) accord-
ing to the method previously described.19 Briefly, Whatman
KC 18F plates were used as the nonpolar stationary phase.
The plates were dried at 105 °C for 1 h before use. The polar
mobile phase was a 2:1 (v/v) mixture of acetone and water.
Each compound was dissolved in CHCl3 (2 mg/mL), and 1 µL
of solution was applied onto the plate. The experiments were
repeated five times with different disposition of the compounds
on the plate. The Rf values were expressed as the mean values
of the five determinations. The Rm values were calculated from
4-(3-Am in op h en yl)-2-b u t ylca r b a m oyl-6,7-m et h ylen e-
d ioxyp h th a la zin -1(2H)-on e (20): mp 138-141 °C (250 mg,
1
68%); H NMR 0.97 (t, 3H, J ) 7.3, CH3), 1.46 (m, 2H, CH2),
1.67 (m, 2H, CH2), 3.49 (m, 2H, CH2), 3.88 (bs, 2H, NH2) 6.18
(s, 2H, OCH2O), 6.80-7.00 (m, 4H, ArH), 7.13 (s, 1H, H-5),
7.84 (s, 1H, H-8), 9.65 (bs, 1H, NH); 13C NMR 13.76 (CH3),
20.12, 31.36, 40.98 (CH2), 102.82 (OCH2O), 104.92 (C-5), 105.69
(C-8), 115.98 (C-2′), 116.06 (C-4′), 119.61 (C-6′), 129.31 (C-5′),
124.57 (C-8a), 126.50 (C-4a), 135.85 (C-1′), 146.70 (C-4), 149.22
(C-3′), 151.42 (C-7), 151.97 (C-6), 158.26 (C-1), 165.33 (CdO);
MS (ESI+) 381 (100), 282 (84). Anal. (C20H20N4O4) C, H, N.
4-(4-Am in op h en yl)-2-b u t ylca r b a m oyl-6,7-m et h ylen e-
d ioxyp h th a la zin -1(2H)-on e (21): mp >300 °C (261 mg,
the experimental Rf values according to the formula Rm
)
log[(1/Rf) - 1]. Higher Rm values indicate higher lipophilicity.
The log P values reported in Table 1 were calculated by using
the PALLAS 2.0 program (Compudrug Chemistry Ltd.). Cal-
culated log P and experimental Rm values are linearly cor-
related with an r2 value of 0.86 at 95% confidence limits.
Testin g of An ticon vu lsa n t Activity a ga in st Au d io-
1
71%); H NMR 0.97 (t, 3H, J ) 7.3, CH3), 1.46 (m, 2H, CH2),
1.67 (m, 2H, CH2), 3.49 (m, 2H, CH2), 3.88 (bs, 2H, NH2) 6.18