Benzodioxins as Lipid Peroxidation Inhibitors
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23 3911
(1H, d, H3, J ) 3.05 Hz, J b ) 11.3 Hz), 4.30-4.12 (2H, m,
CHAr, H3), 3.80-3.50 (4H, m, Hpiperaz), 2.53-2.29 (4H, m,
Hpiperaz). MS: m/z 467 (M + 1). Anal. (C26H24N2O4F2) C, H, N.
7-Hyd r oxy-2-{[4-(2,3,4-tr im eth oxyben zyl)p ip er a zin -1-
yl]oxo}-2,3-d ih yd r o-1,4-ben zod ioxin (22). With a similar
amine b in 78% yield. Mp: 219-220 °C. IR (KBr): 3574-
3302-2715 (NH), 1718 (CdO), 1642 (CdO). 1H NMR (CDCl3):
δ 7.36 (4H, dd, Harom, J ) 8.70 Hz, J ) 5.3 Hz), 6.98 (4H, t,
H
arom, J ) 8.7 Hz), 6.86 (1H, d, H5, J ) 2.4 Hz), 6.76 (1H, dd,
H7, J ) 8.7 Hz, J ) 2.4 Hz), 6.56 (1H, s, H3), 6.55 (1H, d, H8,
J ) 8.7 Hz), 6.29 (1H, s, NH), 4.26 (1H, s, CHAr), 3.57-3.53
(4H, m, Hpiperaz), 2.42-2.38 (4H, m, Hpiperaz), 1.50 (9H, s,
(CH3)3C). MS: m/z 564 (M + 1). Anal. for (C31H31N3O5F2) C,
H, N.
procedure, 22 was prepared from acid 12 and amine c in 75%
1
yield. Mp: 92-93 °C. H NMR (CDCl3): δ 6.97 (1H, d, Harom
,
J ) 8.5 Hz), 6.74 (1H, d, Harom, J ) 8.5 Hz), 6.64 (1H, d, H5, J
) 8,1 Hz), 6.44 (1H, d, H8, J ) 2.5 Hz), 6.33 (1H, dd, J ) 2.5
Hz, J ) 8,2 Hz), 4.82 (1H, dd, H2, J ) 2.1 Hz, J ) 8.3 Hz),
4.40 (1H, dd, H3, J ) 2.1 Hz, J ) 11.4 Hz), 4.21 (1H, dd, H3,
J ) 8.3 Hz, J ) 11.4 Hz), 3.69-3.89 (9H, 3s, 3 × CH3O), 3.78-
3.52 (4H, m, Hpiperaz), 3.54 (s, 2H, NCH2Ar), 2.52-2.49 (4H,
m, Hpiperaz). MS: m/z 445 (M + 1). Anal. (C23H28N2O7) C, H, N.
6-H yd r oxy-N-p h en yl-1,4-b en zod ioxin -2-ca r b oxa m id e
(23). With a similar procedure, 23 was prepared from acid 13
and amine a in 72% yield. Mp: 209-210 °C. IR (KBr): 3610-
3000 (OH), 3380 (NH), 1675 (CdO). 1H NMR (DMSO): δ 9.50
6-Am in o-2-{{4-[bis(4-flu or op h en yl)m eth yl]p ip er a zin -
1-yl}oxo}-1,4-ben zod ioxin (30). Compound 30 was prepared
by acidic hydrolysis of 1 mmol of amide 29 in the presence of
2.5 mL of HCl (3 N). After 6 h at room temperature, the
aqueous phase was basified with NaHCO3. The product was
extracted with ethyl acetate. The organic layers were dried
over magnesium sulfate and evaporated in vacuo. Compound
30 was obtained in 95% yield. IR (KBr): 3600-3420-3310-
3100 (NH2), 1635 (CdO). 1H NMR (CDCl3 + D2O): δ 7.33 (4H,
dd, Harom, J ) 8.8 Hz, J ) 5.1 Hz), 6.97 (4H, t, Harom, J ) 8.8
Hz), 6.54 (1H, s, H3), 6.43 (1H, d, H8, J ) 8.4 Hz), 6.12 (1H,
dd, H7, J ) 2.9 Hz, J ) 8.4 Hz), 6.05 (1H, d, H5, J ) 2.9 Hz),
3.67-3.58 (4H, m, Hpiperaz), 2.46-2.38 (4H, m, Hpiperaz). MS: m/z
464 (M + 1), 481 (M + 18). Anal. (C26H23N3O3F2) C, H, N.
7-Hyd r oxy-2-{[4-(2,3,4-tr im eth oxyben zyl)p ip er a zin -1-
yl]oxo}-1,4-ben zod ioxin (31). With a similar procedure, 31
was prepared from acid 14 and amine c in 73% yield. Mp: 87-
88 °C. IR (KBr): 3610-3300 (OH), 1600 (CdO), 1590 (CdC).
(1H, s, OH), 7.68 (d, 2H, Harom, J ) 7.9 Hz), 7.32 (t, 2H, Harom
,
J ) 7.9 Hz), 7.09 (t, 1H, Harom, J ) 7.9 Hz), 7.07 (1H, s, H3),
6.78 (1H, d, H8, J ) 8.7 Hz), 6.37 (1H, dd, H7, J ) 8.7 Hz, J )
3.1 Hz), 6.27 (1H, d, H5, J ) 3.1 Hz), 4.64 (1H, s, NH). MS:
m/z 270 (M + 1). Anal. (C15H11NO4) C, H, N.
7-H yd r oxy-N-p h en yl-1,4-b en zod ioxin -2-ca r b oxa m id e
(24). With a similar procedure, 24 was prepared from acid 14
and amine a in 63% yield. Mp: 205-206 °C. IR (KBr): 3500-
1
2980 (OH), 3310 (NH), 1640 (CdO), 1220. H NMR (CDCl3):
1H NMR (CDCl3): δ 6.97 (1H, d, J ) 8.3 Hz), 6.63 (1H, d, Harom
,
δ 7.83 (1H, s, NH), 7.59 (2H, d, Harom, J ) 7.9 Hz), 7.36 (2H,
t, Harom, J ) 7.9 Hz), 7.16 (1H, t, Harom, J ) 7.9 Hz), 7.08 (1H,
s, H3) 6.64 (1H, d, H5, J ) 8.3 Hz), 6.38 (1H, d, H8, J ) 2.8
Hz), 6.36 (1H, dd, H6, J ) 2.8 Hz, J ) 2.3 Hz), 4.95 (1H, s,
OH). MS: m/z 270 (M + 1). Anal. (C15H11N O4) C, H, N.
6-Hydr oxy-2-{{4-[bis(4-flu or oph en yl)m eth yl]piper azin -
1-yl}oxo}-1,4-ben zod ioxin (25). With a similar procedure,
25 was prepared from acid 13 and amine b in 85% yield. Mp:
162-163 °C. IR (KBr): 3610-2980 (OH), 1665 (CdO). 1H NMR
(CDCl3): δ 7.34 (4H, dd, Harom, J ) 8.7 Hz, J ) 5.5 Hz), 6.98
(4H, t, Harom, J ) 8.7 Hz), 6.57 (1H, s, H3), 6.48 (1H, d, H8, J
) 8.7 Hz), 6.29 (1H, dd, H7, J ) 8.7 Hz, J ) 3.1 Hz), 6.23 (1H,
d, H5, J ) 3.1 Hz), 5.60 (1H, s, OH), 4.25 (1H, s, NCHAr), 3.65-
3.40 (4H, m, Hpiperaz), 2.39-2.29 (4H, m, Hpiperaz). MS: m/z 465
(M + 1). Anal. (C26H22N2O4F2) C, H, N.
7-Hydr oxy-2-{{4-[bis(4-flu or oph en yl)m eth yl]piper azin -
1-yl}oxo}-1,4-ben zod ioxin (26). With a similar procedure,
26 was prepared from acid 14 and amine b in 85% yield. Mp:
220-221 °C. IR (KBr): 3300 (OH), 1650 (CdO). 1H NMR
(CDCl3): δ 7.36 (4H, dd, 2 × Harom, Harom, J ) 8.7 Hz, J ) 5.6
Hz), 7.00 (4H, t, Harom, J ) 8.7 Hz, J ) 8.7 Hz), 6.58-6.52
(2H, m, H3, H5), 6.29 (1H, dd, H6, J ) 8.1 Hz, J ) 2.5 Hz),
6.23 (1H, d, H8, J ) 2.5 Hz), 5.40 (1H, br s, OH), 4.27 (1H, s,
CHAr), 3.69-3.63 (4H, m, Hpiperaz), 2.45-2.39 (4H, m, Hpiperaz).
MS: m/z 465 (M + 1). Anal. (C26H22N2O4F2) C, H, N.
J ) 8.3 Hz), 6.54 (1H, s, H3), 6.53 (1H, d, H5, J ) 8.3 Hz), 6.31
(1H, dd, H6, J ) 2.1 Hz, J ) 8.3 Hz), 6.25 (1H, d, H8, J ) 2.1
Hz), 3.87-3.89 (9H, 3s, 3 · CH3O), 3.61 (4H, m, Hpiperaz), 3.51
(s, 2H, NCH2Ar), 2.53 (4H, m, Hpiperaz). MS: m/z 443 (M + 1).
Anal. (C23H26N2O7) C, H, N.
N-Bu t yl-6-h yd r oxy-N-p h en yl-1,4-b en zod ioxin -2-ca r -
boxa m id e (32). With a similar procedure, 32 was prepared
from acid 13 and amine d in 80% yield. Mp: 123-124 °C. IR
1
(KBr): 3610-2980 (OH, NH), 1660 (CdO). H NMR (CDCl3):
δ 7.40-7.18 (5H, m, 5Harom), 6.62 (1H, s, H3), 6.14 (1H, d, H5,
J ) 2.9 Hz), 6.1 (1H, dd, H7, J ) 8.3 Hz, J ) 2.9 Hz), 5.71
(1H, d, H8, J ) 8.3 Hz), 5.14 (1H, s, OH), 3.90-3.70 (2H, m,
NCH2), 1.56-1.47 (2H, m, CH2), 1.50-1.20 (2H, m, CH2), 0.61
(3H, t, CH3, J ) 7.3 Hz). MS: m/z 326 (M + 1). Anal. (C19H19
NO4) C, H, N.
-
N-Bu t yl-7-h yd r oxy-N-p h en yl-1,4-b en zod ioxin -2-ca r -
boxa m id e (33). With a similar procedure, 33 was prepared
from acid 14 and amine d in 83% yield. Mp: 155-156 °C. IR
1
(KBr): 3610-2980 (OH, NH), 1660 (CdO). H NMR (CDCl3):
δ 7.43-7.17 (m, 5Harom), 6.60 (1H, d, H8, J ) 2.9 Hz), 6.44 (1H,
d, H5, J ) 8.7 Hz), 6.42 (1H, s, H3), 6.2 (1H, dd, H6, J ) 2.9
Hz, J ) 8.7 Hz), 5.56 (1H, s, OH), 3.76 (2H, t, NCH2, J ) 7.8
Hz), 1.70-1.48 (2H, m, CH2), 1.43-1.26 (2H, m, CH2), 0.89
(3H, t, CH3, J ) 7.31 Hz). MS: m/z 326 (M + 1). Anal. for
(C19H19NO4) C, H, N.
2-{{4-[Bis(4-flu or op h en yl)m eth yl]p ip er a zin -1-yl}oxo}-
1,4-ben zod ioxin (27). With a similar procedure, 27 was
prepared from acid 17 and amine b in 90% yield. Mp: 156-
158 °C. IR (KBr): 1670 (CdO). 1H NMR (DMSO): δ 7.43
(4H, dd, 2 × Harom, Harom, J ) 8.8 Hz, J ) 5.2 Hz), 7.12 (4H, t,
N-Bu t yl-6-h yd r oxy-7-ter t-b u t yl-N-p h en yl-1,4-b en zo-
d ioxin -2-ca r boxa m id e (34). With a similar procedure, 34
was prepared from acid 15 and amine d in 77% yield. Mp:
225-226 °C. IR (KBr): 3610-3010 (OH), 1640 (CdO). 1H NMR
(CDCl3): δ 7.39-7.190 (5H, m, Harom aniline), 6.63 (1H, s, H3),
6.04 (1H, s, H8), 5.73 (1H, s, H5), 5.04 (1H, s, OH), 3.75 (t, 2H,
NCH2, J ) 7.6 Hz), 1.60-1.25 (4H, m, CH2), 1.22 (9H, s,
(CH3)3C), 0.87 (3H, t, CH3, J ) 7.1 Hz). MS: m/z 382 (M + 1).
Anal. (C23H27NO4) C, H, N.
6-Hyd r oxy-2-{{4-[bis(4-flu or op h en yl)m eth ylen e]p ip e-
r id in -1-yl}oxo}-1,4-ben zod ioxin (35). With a similar pro-
cedure, 35 was prepared from acid 13 and amine e in 80%
yield. Mp: 165-166 °C. IR (KBr): 3610-3010 (OH), 1645 (Cd
O). 1H NMR (CDCl3): δ 7.11-6.95 (m, 8H, Harom), 6.57 (1H, s,
H3), 6.54 (1H, d, H8, J ) 8.6 Hz), 6.31 (1H, dd, H7, J ) 2.6 Hz,
J ) 8.6 Hz), 6.25 (1H, d, H5, J ) 2.6 Hz), 5.13 (1H, s, OH),
3.69-3.59 (4H, m, Hpiperid), 2.48-2.38 (4H, m, Hpiperid). MS: m/z
462 (M + 1). Anal. (C27H21NO4F2) C, H, N.
H
arom, J ) 8.8 Hz), 6.92-6.78 (4H, m, Harom), 6.74 (1H, s, H3),
4.43 (1H, s, NCHAr), 3.70-3.40 (4H, m, Hpiperaz), 2.30-2.15
(4H, m, Hpiperaz). MS: m/z 449 (M + 1). Anal. (C26H22N2O3F2)
C, H, N.
6-Hyd r oxy-7-ter t-bu tyl-2-{{4-[bis(4-flu or op h en yl)m eth -
yl]p ip er a zin -1-yl}oxo}-1,4-ben zod ioxin (28). With a simi-
lar procedure, 28 was prepared from acid 15 and amine b in
84% yield. Mp: 242-244 °C. IR (KBr): 3600-3000 (OH), 1640
(CdO). 1H NMR (DMSO): δ 9.36 (1H, s, OH), 7.43 (4H, dd,
H
arom, J ) 8.3 Hz, J ) 5.8 Hz), 6.98 (4H, t, Harom, J ) 8.3 Hz),
6.64 (1H, s, H3), 6.52 (1H, s, H8 or H5), 6.24 (1H, s, H5 or H8),
4.44 (1H, s, NCHAr), 3.60-3.46 (4H, m, Hpiperaz), 2.50-2.10
(4H, m, Hpiperaz), 1.25 (9H, s, (CH3)3C). MS: m/z 521 (M + 1).
Anal. for (C30H30N2O4F2) C, H, N.
6-[N-(ter t-Bu toxyca r bon yl)a m in o]-2-{{4-[bis(4-flu or o-
p h en yl)m eth yl]p ip er a zin -1-yl}oxo}-1,4-ben zod ioxin (29).
With a similar procedure, 29 was prepared from acid 16 and
Typ ica l P r oced u r e for th e Syn th esis of Am in om eth yl
Der iva tives 36 a n d 37 (Sch em e 4). To a stirred suspension
of 1.5 mmol (0.05 g) of lithium aluminum hydride in 30 mL