Quinazolinone Inhibitors of PARP
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5253
ArH), 8.20 (d, 2H, J ) 8.5 Hz, 3′/5′-ArH); HRMS (EI) m/z
279.1000[M+calcd for C16H13N3O2 279.1008]. Anal. (C16H13N3O2)
C, H, N.
8-Meth yl-2-(4′-n itr op h en yl)qu in a zolin -4(3H)-on e (18).
Compound 18 was prepared according to method II from
2-amino-3-methylbenzamide (0.5 g, 3.3 mmol) and 4-nitroben-
zoyl chloride (0.93 g, 5.0 mmol), employing aqueous NaOH (2.5
M, 15 mL) at 100 °C for 2 h in the cyclization step: IR 3088,
2-[N-(4′-Azid oben zoyl)a m in o]-3-m eth ylben za m id e (13).
Compound 13 was synthesized from 2-amino-3-methylbenz-
amide (2.5 g, 16.7 mmol) and 4-azidobenzoyl chloride (3.6 g,
22.9 mmol): IR 3379, 3301, 3189, 2128, 2088, 1653 cm-1; 1H
NMR δ 2.31 (s, 3H, CH3), 7.34-7.49 (m, 3H, 7-ArH + 3′/5′-
ArH), 7.49-7.54 (m, 3H, 5/6-ArH + NH), 7.82 (br s, 1H, NH),
8.11 (d, 2H, 2′/6′-ArH), 10.31 (br s, 1H, NH); HRMS (EI) m/z
1
1683, 1522, 1350 cm-1; H NMR δ 2.77 (s, 3H, CH3), 7.58 (t,
1H, 6-ArH), 7.86 (d, 1H, 7-ArH), 8.14 (d, 1H, 5-ArH), 8.51 (d,
2H, J ) 9.2 Hz, 2′/6′-ArH), 8.59 (d, 2H, J ) 9.2 Hz, 3′/5′-ArH),
12.90 (br s, 1H, NH); HRMS (EI) m/z 281.0790 [M+ calcd for
C15H11N3O3 281.0800]. Anal. (C15H11N3O3) C, H, N.
295.1066 [M+ calcd for C15H13N5O2 295.1069]. Anal. (C15H13
N5O2) C, H, N.
-
8-Meth oxy-2-(4′-n itr oph en yl)qu in azolin -4(3H)-on e (19).
Compound 19 was prepared according to method III by
treatment of 3-methoxy-2-[N-(4′-nitrobenzoyl)amino]benz-
amide (11) (0.5 g, 1.6 mmol) with aqueous NaOH (2.5 M, 15
8-Su bstitu ted-qu in azolin -4(3H)-on es: Meth od II. Gen -
er a l P r oced u r e. The appropriate 3-substituted-2-nitrobenz-
amide was dissolved in dry THF (10-20 mL), and dry pyridine
(1.3 mol equiv) was added. To the resulting solution stirred
under N2 at room temperature was added the requisite acid
chloride in dry THF (5 mL) dropwise over 15 min. The
reaction mixture was stirred at room temperature until TLC
analysis indicated the absence of starting materials. Removal
of solvent afforded a residue which was suspended in aqueous
NaOH (0.5 M unless indicated otherwise) and stirred, with
warming if necessary, until complete dissolution was observed.
The solution was neutralized with concentrated aqueous HCl,
and the solid which deposited was collected by filtration and
washed with water. The product was purified by chromatog-
raphy on silica and/or recrystallization from a suitable solvent.
1
mL) at 100 °C for 2 h: IR 3037, 1686, 1522, 1348 cm-1; H
NMR δ 4.06 (s, 3H, OCH3), 7.54 (d, 1H, 7-ArH), 7.62 (t, 1H,
6-ArH) 7.84 (d, 1H, Ar-5H), 8.50 (s, 4H, 2′/3′/5′,6-ArH), 12.95
(br s, 1H, NH); HRMS (EI) m/z 297.0766 [M+ calcd for
C15H11N3O4 297.0750]. Anal. (C15H11N3O4‚0.3H2O) C, H, N.
8-Me t h yl-2-[4′-(t r iflu or om e t h yl)p h e n yl]q u in a zolin -
4(3H)-on e (20). Compound 20 was prepared by method II
from 2-amino-8-methylbenzamide (0.2 g, 1.3 mmol) and 4-(tri-
fluoromethyl)benzoyl chloride (0.22 mL, 1.5 mmol): IR 3175,
1
1666, 1336, 1320 cm-1; H NMR δ 2.75 (s, 3H, CH3), 7.56 (t,
1H, 6-ArH), 7.83 (d, 1H, 7-ArH), 8.08 (m, 3H, 5-ArH, and 2′/
6′-ArH), 8.51 (d, 2H, 3′/5′-ArH), 12.85 (br s, 1H, NH); MS (EI)
m/z 304 (M+). Anal. (C16H11N2OF3) C, H, N.
8-Su bstitu ted-qu in azolin -4(3H)-on es: Meth od III. Gen -
er a l P r oced u r e. The appropriate 3-substituted-2-(N-acyl-
amino)benzamide was suspended in aqueous NaOH, and the
solution was stirred, with warming if necessary, until complete
dissolution was observed. After neutralization with concen-
trated aqueous HCl, the resulting precipitate was collected by
filtration, washed with water, and dried.
8-Met h oxy-2-[4′-(t r iflu or om et h yl)p h en yl]q u in a zolin -
4(3H)-on e (21). Compound 21 was synthesized according to
method II from 2-amino-3-methoxybenzamide (0.2 g, 1.2 mmol)
and 4-(trifluoromethyl)benzoyl chloride (0.2 mL, 1.3 mmol): IR
3116, 1660 cm-1 1H NMR δ 4.06 (s, 3H, OCH3), 7.50-7.64
;
(m, 2H, 6/7-ArH), 7.83 (d, 1H, Ar-5H), 8.04 (d, 2H, J ) 8.4 Hz,
2′/6′-ArH), 8.47 (d, 2H, J ) 8.4 Hz, 3′/5′-ArH), 12.91 (br s, 1H,
NH); MS (EI) m/z 320 (M+). Anal. (C16H11N2O2F3) C, H, N.
2,8-Dim eth ylqu in a zolin -4(3H)-on e (14). Compound 14
was prepared according to method II from 2-amino-3-methyl-
benzamide (0.5 g, 3.3 mmol) and acetyl chloride (0.36 mL, 5.0
mmol): IR 3171, 1683 cm-1; 1H NMR δ 2.44 (s, 3H, CH3), 2.57
(s, 3H, CH3), 7.40 (t, 1H, 6-ArH), 7.68-7.72 (m, 1H, 7-ArH),
7.94 (dd, 1H, Ar-5H), 12.25 (br s, 1H, NH); HRMS (EI) m/z
8-Meth yl-2-(4′-cya n op h en yl)qu in a zolin -4(3H)-on e (22).
Compound 22 was prepared according to method II from
2-amino-3-methylbenzamide (0.39 g, 2.6 mmol) and 4-cy-
anobenzoyl chloride (0.48 g, 2.9 mmol): IR 3170, 2228, 1683
1
cm-1; H NMR δ 2.73 (s, 3H, CH3), 7.55 (t, 1H, J ) 7.6 Hz,
174.0790 [M+ calcd for C10H10N2O 174.0793]. Anal. (C10
10N2O) C, H, N.
8-Meth oxy-2-m eth ylqu in a zolin -4(3H)-on e (15). Com-
-
6-ArH), 7.83 (d, 1H J ) 7.6 Hz, 7-ArH), 8.13-8.17 (m, 3H,
5-ArH and J ) 8.7 Hz, 2′/6′-ArH), 8.49 (d, 2H, J ) 8.7 Hz,
3′/5′-ArH), 12.90 (br s, 1H, NH); HRMS (EI) m/z 261.0912 [M+
calcd for C16H11N3O 261.0912]. Anal. (C16H11N3O) C, H, N.
H
pound 15 was prepared according to method II from 2-amino-
3-methoxybenzamide (1.5 g, 9.0 mmol) and acetyl chloride (1.4
8-Meth oxy-2-(4′-cyan oph en yl)qu in azolin -4(3H)-on e (23).
Compound 23 was prepared according to method II from
2-amino-3-methoxybenzamide (0.5 g, 3.0 mmol) and 4-cy-
anobenzoyl chloride (0.55 g, 3.3 mmol): IR 3413, 2841, 2230,
1
mL, 19.9 mmol): IR 3171, 3034, 1676 cm-1; H NMR δ 2.43
(s, 3H, CH3), 3.97 (s, 3H, OCH3), 7.39 (dd, 1H, J ) 1.9, 7.9 Hz,
7-ArH), 7.46 (t, 1H, J ) 7.8 Hz, 6-ArH), 7.71 (dd, 1H, J ) 1.9,
7.8 Hz, 5-ArH); HRMS (EI) m/z 190.0740 [M+ calcd for
1
1681 cm-1; H NMR δ 4.05 (s, 3H, OCH3), 7.48-7.53 (m, 1H,
C
10H10N2O2 190.0742]. Anal. (C10H10N2O‚0.1H2O) C, H, N.
7-ArH), 7.59 (t, 1H, 6-ArH), 7.79-7.83 (m, 1H, 5-ArH), 8.14
(d, 2H, J ) 8.5 Hz, 2′/6′-ArH,), 8.43 (d, 2H, J ) 8.5 Hz, 3′/5′-
ArH), 12.95 (br s, 1H, NH); HRMS (EI) m/z 277.0853 [M+ calcd
for C16H11N3O2 277.0851]. Anal. (C16H11N3O2‚0.75H2O) C, H,
N.
Compound 15 was also prepared by method III from 2-(N-
acetylamino)-3-methoxybenzamide (7) (0.07 g, 0.34 mmol) and
aqueous NaOH solution (0.5 M, 2 mL) at room temperature.
8-Met h yl-2-p h en ylq u in a zolin -4(3H )-on e (16). Com-
pound 16 was prepared according to method III from 3-methyl-
2-(N-benzoylamino)benzamide (8) (1.0 g, 0.4 mmol) and aque-
ous NaOH solution (0.5 M, 25 mL) at room temperature: IR
8-Met h yl-2-(4′-m et h oxyp h en yl)q u in a zolin -4(3H )-on e
(24). Compound 24 was prepared as described in method II
from 2-amino-3-methylbenzamide (0.2 g, 1.3 mmol) and ben-
zoyl chloride (0.22 mL, 1.5 mmol), with the addition of
4-(dimethylamino)pyridine (8 mg, 5 mmol): IR 3177, 1674
3165, 1675 cm-1 1H NMR δ 2.72 (s, 3H, CH3), 7.49 (t, 1H,
;
6-ArH), 7.66 (m, 3H, 3′/4′/5′-PhH), 7.79 (d, 1H, 7-ArH), 8.09
(d, 1H, 5-ArH), 8.30-8.35 (m, 2H, 2′/6′-PhH), 12.65 (br s, 1H,
NH); HRMS (EI) m/z 236.0943 [M+ calcd for C15H12N3O
236.0950]. Anal. (C15H12N2O‚0.1H2O) C, H, N.
1
cm-1; H NMR δ 2.71 (s, 3H, CH3), 3.95 (s, 3H, OCH3), 7.20
(d, 2H, J ) 8.9 Hz, 3′/5′-ArH), 7.46 (t, 1H, 6-ArH), 7.78 (d, 1H,
7-ArH), 8.07 (d, 1H, 5-ArH), 8.29 (d, 2H, 2′/6′-ArH), 12.63 (br
s, 1H, NH); HRMS (EI) m/z 266.1046 [M+ calcd for C16H14N2O2
266.1055]. Anal. (C16H14N2O2) C, H, N.
8-Meth oxy-2-p h en ylqu in a zolin -4(3H)-on e (17). Com-
pound 17 was prepared according to method II from 2-amino-
3-methoxybenzamide (1.0 g, 6 mmol) and benzoyl chloride (0.8
mL, 6.6 mmol): IR 3191, 3162, 1662 cm-1; 1H NMR δ 4.06 (s,
3H, OCH3), 7.47-7.61 (m, 2H, 6/7-ArH), 7.63-7.69 (m, 3H,
3′/4′/5′-PhH), 7.83 (dd, 1H, Ar-5H), 8.27-8.32 (m, 2H, 2′/6′-
PhH), 12.70 (br s, 1H, NH); HRMS (EI) m/z 252.0895 [M+ calcd
for C15H12N2O2 252.0899]. Anal. (C15H12N2O2) C, H, N.
8-Me t h oxy-2-(4′-m e t h oxyp h e n yl)q u in a zolin -4(3H )-
on e (25). Compound 25 was prepared according to method
II from 2-amino-3-methoxybenzamide (0.25 g, 0.8 mmol) and
4-methoxybenzoyl chloride (0.5 mL, 3.3 mmol) with the addi-
tion of 4-(dimethylamino)pyridine (18 mg, 0.2 mmol): IR 3174,
1667 cm-1; 1H NMR δ 3.94 (s, 3H, OCH3), 4.04 (s, 3H, OCH3),
7.19 (d, 2H, J ) 9.0 Hz, 3′/5′-ArH), 7.42-7.55 (m, 2H, 6/7-
ArH), 7.76-7.81 (m, 1H, 5-ArH), 8.29 (d, 2H, J ) 9.0 Hz,
2′/6′-ArH); HRMS (EI) m/z 282.1008 [M+ calcd for C16H13N2O3
Compound 17 was also prepared according to method III
from 3-methoxy-2-(N-benzoylamino)benzamide (9) (0.2 g, 0.74
mmol) and aqueous NaOH (0.5 M, 2 mL) at room temperature.