M. Satyanarayana et al. / Bioorg. Med. Chem. 16 (2008) 7824–7831
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(60 mL per 4 mmol aminocinnoline). The reaction mixture was
then stirred at reflux under N2 for 5 h. The reaction mixture was
cooled and washed with satd. NaHCO3 solution and brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The product was isolated using flash chromatography eluting with
chloroform:methanol.
2H, J = 6.2), 4.13 (s, 3H), 4.04 (s, 3H), 3.65 (s, 2H), 3.12 (t, 2H,
J = 6.2), 2.94 (m, 1H), 1.00 (d, 6H, J = 6.6); 13C NMR (CDCl3) d
16.8, 47.4, 47.6, 50.0, 53.9, 55.4, 55.6, 98.7, 101.7, 103.2, 105.4,
106.9, 112.6, 118.6, 125.8, 127.2, 127.5, 128.0, 130.0, 133.3,
139.3, 148.2, 149.1, 150.0, 150.3, 153.2, 162.0; HRMS (M++H) Calcd
for C30H30N4O5H: 527.2294, found: 527.2260.
4.2.1. N-(6,7-Methylenedioxycinnnolin-4-yl)-N-[2-
(benzyl(methyl)amino)ethyl]-2-iodo-4,5-dimethoxybenzamide
(5a)
4.4. General procedure for the syntheses of 7a and 7b
To a solution of N-benzylated cinnoline derivative (6a or 6b) in
acetic acid (40 mL) and formic acid (10 mL) was added Pd black
(150 mg) and stirred at room temperature for 45 min. Reaction
mixture was concentrated under reduced pressure, basified with
10% NaOH and extracted with chloroform. The organic layer was
dried over Na2SO4, filtered, and concentrated. Crude was purified
by flash chromatography eluting with chloroform: methanol.
Prepared from 4a (2.5 g, 7.44 mmol) as a brown sticky glue in
85% yield; IR (neat) 1655; 1H NMR (CDCl3) d 9.08 (s, 1H), 7.63
(s, 1H), 7.33 (s, 1H), 7.18 (m, 5H), 6.98 (s, 1H), 6.36 (s, 1H), 6.17
(s, 2H), 4.42 (m, 1H), 3.69 (s, 3H), 3.62 (m, 1H), 3.48 (s, 2H), 3.38
(s, 3H), 2.75 (q, 2H, J = 4.8), 2.13 (s, 3H); 13C NMR (CDCl3) d 41.6,
46.2, 54.4, 54.7, 55.1, 61.6, 95.7, 101.9, 104.5, 109.6, 120.9, 122.0,
126.2, 127.3, 127.5, 128.1, 131.9, 135.1, 137.4, 143.8, 147.2,
149.0, 150.0, 150.7, 151.4, 168.9; HRMS (M++H) Calcd for
C28H27IN4O5H: 627.1104, found: 627.1037.
4.4.1. 2,3-Dimethoxy-8,9-methylenedioxy-11-[(2-methyl-
amino)ethyl]-11H-isoquino[4,3-c]cinnolin-12-one (7a)
Prepared from 6a (200 mg, 0.4 mmol) in 73% yield; mp 245 °C
(decomp.); IR (neat) 3421, 1653; 1H NMR (CDCl3+CD3OD) d 8.55
(s, 1H), 7.77 (s, 1H), 7.74 (s, 1H), 7.69 (s, 1H), 6.21 (s, 2H), 4.56 (t,
2H, J = 6.6), 4.12 (s, 3H), 4.03 (s, 3H), 3.26 (t, 2H, J = 6.6), 2.50 (s,
3H); 13C NMR (CDCl3+ CD3OD) d 35.3, 47.6, 49.8, 55.4, 55.7, 97.8,
101.9, 103.2, 105.3, 106.9, 112.7, 118.5, 128.0, 130.0, 133.4,
137.6, 148.3, 149.4, 150.3, 150.5, 153.5, 162.4; HRMS (M++H) Calcd
for C21H20N4O5H: 409.1512, found: 409.1531.
4.2.2. N-(6,7-Methylenedioxycinnnolin-4-yl)-N-[2-
(benzyl(isopropyl)amino)ethyl]-2-iodo-4,5-dimethoxy-
benzamide (5b)
Prepared from 4b (2.56 g, 7.05 mmol) as a brown sticky glue in
52% yield; IR (neat) 1659; 1H NMR (CDCl3) d 9.08 (s, 1H), 7.83
(s, 1H), 7.48 (s, 1H), 7.47 (s, 1H), 7.29 (s, 1H), 7.19 (m, 5H), 6.39 (s,
2H), 4.45 (m, 1H), 3.89 (s, 3H), 3.69 (s, 2H), 3.52 (s, 3H), 3.41 (m,
1H), 3.18 (m, 3H), 1.24 (d, 3H, J = 7.0), 1.21 (d, 3H, J = 6.8); 13C NMR
(CDCl3) d 17.4, 48.0, 49.1, 51.6, 54.7, 55.0, 55.4, 95.8, 102.1, 104.9,
109.9, 119.5, 121.3, 121.6, 126.1, 127.4, 128.2, 128.7, 132.0, 135.4,
143.8, 147.5, 149.4, 150.2, 151.0, 151.5, 169.0; HRMS (M++H) Calcd
for C30H31IN4O5H: 655.1417, found: 655.1399.
4.4.2. 2,3-Dimethoxy-8,9-methylenedioxy-11-[(2-isopropy
lamino)ethyl]-11H-isoquino[4,3-c]cinnolin-12-one (7b)
Prepared from 6b (150 mg, 0.285 mmol) in 82% yield; mp
267 °C (dec); IR (neat) 3444, 1652; 1H NMR (CDCl3) d 8.57 (s,
1H), 7.90 (s, 1H), 7.78 (s, 1H), 7. 73 (s, 1H), 6.21 (s, 2H), 4.52
(t, 2H, J = 6.6), 4.14 (s, 3H), 4.05 (s, 3H), 3.34 (t, 2H, J = 6.6),
2.97 (m, 1H), 1.12 (d, 6H, J = 6.2); 13C NMR (CDCl3) d 22.7, 45.0,
47.9, 48.1, 55.4, 55.7, 98.4, 101.8, 103.3, 105.5, 106.8, 112.6,
118.5, 128.1, 130.0, 133.2, 148.3, 149.2, 150.2, 150.4, 153.3,
162.1; HRMS (M++H) Calcd for C23H24N4O5H: 437.1825, found:
437.1830.
4.3. General procedure for the preparation of 11-substituted
11H-isoquino[4,3-c]cinnolin-12-ones via cyclization of
o-iodobenzamides (6a and 6b)
A mixture of the 4-amino-6,7-methylenedioxycinnoline-o-iod-
obenzamide derivative (1.0 equiv), Pd(OAc)2 (0.2 equiv), P(o-tolyl)3
(0.4 equiv), and Ag2CO3 (2.0 equiv) was heated to reflux in DMF
(30 mL per equiv) under nitrogen atmosphere with stirring for
30 min. The reaction mixture was allowed to cool to room temper-
ature, diluted with CHCl3, and filtered through Celite. The sicciate
was extensively washed with 10% CH3OH in CHCl3. The filtrate
was concentrated under reduced pressure, and the residue chro-
matographed on silica gel using chloroform: methanol.
4.5. 2,3-Dimethoxy-8,9-methylenedioxy-11H-isoquino[4,3-
c]cinnolin-12-one-11-[2-N,N,N,-trimethyethanaminium]iodide
(8)
To a solution of ARC-31 (100 mg, 0.237 mmol) in a mixture of
DCM and methanol (20 mL, 4:1) was added methyl iodide
(0.145 mL, 2.3 mmol) drop wise at room temperature and stirred
overnight. Reaction mixture was concentrated under reduced pres-
sure and dried under high vacuum to give 8 in quantitative yield;
mp 255 °C (dec); IR (neat) 1461; 1H NMR (DMSO-d6) d 8.38 (s,
1H), 7.82 (s, 1H), 7.69 (s, 1H), 7. 67 (s, 1H), 6.40 (s, 2H), 4.96 (t,
2H, J = 6.2), 4.04 (s, 3H), 3.95 (s, 3H), 3.79 (t, 2H, J = 6.2), 3.19 (s,
9H); 13C NMR (DMSO-d6) d 54.7, 55.6, 55.8, 61.0, 98.1, 103.2,
105.0, 107.5, 112.6, 118.4, 127.9, 129.6, 133.6, 148.6, 150.4,
150.8, 151.1, 153.9, 161.7; HRMS (M++H) Calcd for C23H24IN4O5H:
437.1825, found: 437.1805.
4.3.1. 2,3-Dimethoxy-8,9-methylenedioxy-11-[(2-
benzyl(methyl)amino)ethyl]-11H-isoquino[4,3-c]cinnolin-12-
one (6a)
Prepared from 5a (1.5 g, 2.4 mmol) in 29% yield; mp 245–
247 °C; IR (neat) 1657; 1H NMR (CDCl3) d 8.56 (s, 1H), 8.02 (s,
1H), 7.77 (s, 1H), 7.72 (s, 1H), 7.23 (m, 5H), 6.24 (s, 2H), 4.61 (t,
2H, J = 6.6), 4.13 (s, 3H), 4.04 (s, 3H), 3.57 (s, 2H), 3.07 (t, 2H,
J = 6.6), 2.30 (s, 3H); 13C NMR (CDCl3) d 41.6, 46.6, 54.7, 55.4,
55.7, 62.3, 98.6, 101.7, 103.2, 105.4, 106.8, 112.6, 118.5, 126.2,
127.3, 128.0, 128.1, 129.9, 133.2, 137.6, 148.3, 149.1, 150.2,
150.4, 153.3, 161.9; HRMS (M++H) Calcd for C28H26N4O5H:
499.1981, found: 499.1950.
4.6. 2,3-Dimethoxy-8,9-methylenedioxy-11-[2-(1,3-dihydroxy-
2-(hydroxymethyl)propan-2-ylamino)ethyl]-1H-isoquino[4,3-
c]cinnolin-12-one (9)
4.3.2. 2,3-Dimethoxy-8,9-methylenedioxy-11-[(2-
benzyl(isopropyl)amino)ethyl]-11H-isoquino[4,3-c]cinnolin-
12-one (6b)
Prepared from 5b (2.4 g, 3.67 mmol) in 9% yield; mp 235–
237 °C; IR (neat) 1653; 1H NMR (CDCl3) d 8.57 (s, 1H), 7.96 (s,
1H), 7.77 (s, 1H), 7. 72 (s, 1H), 7.15 (m, 5H), 6.24 (s, 2H), 4.48 (t,
To a solution of 8 (113 mg, 0.2 mmol) in anhydrous DMSO
(6 mL) in a sealed tube was added tris(hydroxymethyl)amino-
methane (242 mg, 2.0 mmol) and stirred at 150 °C for 4 h. DMSO
was removed by Kugelrohr distillation, and the crude was purified
by flash chromatography eluting with chloroform:methanol to give
compounds 9 and 10.