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G. Murineddu et al. / Bioorg. Med. Chem. 13 (2005) 3309–3320
IR 1650, 3190; 1H NMR (CDCl3) d 1.89–1.98 (m,
4H), 2.94–3.40 (m, 8H), 6.44 (d, 1H), 6.98 (d, 1H),
7.26–7.28 (m, 1H), 7.48 (s, 2H), 7.57 (br s, 1H, exch.
with D2O), 7.61 (s, 1H); Anal. Calcd for C22H19Cl3N4O:
C, 57.22; H, 4.15; Cl, 23.03; N, 12.13. Found: C, 57.01;
H, 4.29; Cl, 22.89; N, 12.25.
6b (1.64 g, 87.8%) as a white solid. Rf = 0.36 (CHCl3/
MeOH 9.5:0.5); mp 266–267 ꢂC; IR 1685; 1H NMR
(CDCl3) d 2.30 (s, 3H), 2.92–3.19 (m, 4H), 4.22 (br s,
1H, OH exch. with D2O), 6.45 (d, 1H), 6.83 (d, 1H),
7.13 (d, 1H), 7.46 (d, 1H), 7.50 (s, 1H), 7.59 (d, 1H).
Anal. Calcd for C19H14Cl2N2O2: C, 61.14; H, 3.78; Cl,
18.99; N,7.50. Found: C, 61.32; H, 3.59; Cl, 18.82;
N,7.59.
3.1.2.10. 7-Chloro-1-(20,40-dichlorophenyl)-N-[(1-eth-
ylpyrrolidin-2-yl)methyl]-4,5-dihydro-1H-benzo[g]indaz-
ole-3-carboxamide 2j. General procedure I was used to
convert 6a and N-ethyl-2-aminomethylpyrrolidine into
the title product. The mixture was refluxed for 3 h and
purification by crystallization from petroleum ether/
EtOAc afforded 2j (1.23 g, 61.1%) as a white solid.
Rf = 0.56 (CHCl3/CH3OH 9/1); mp 111–112 ꢂC (crystal-
3.1.3.3. 7-Bromo-1-(20,40-dichlorophenyl)-4,5-dihydro-
1H-benzo[g]indazole-3-carboxylic acid 6c. General pro-
cedure II was used to convert 5c into the title product
6c (2.04 g, 93.1%) as a light yellow solid. Rf = 0.54
(CHCl3/MeOH 9:1); mp 248–250 ꢂC; IR 1690, 3350;
1H NMR (CDCl3) d 2.98–3.22 (m, 4H), 3.50 (br s, 1H,
OH exch. with D2O), 6.42 (d, 1H), 7.17 (d, 1H), 7.47–
7.49 (m, 2H), 7.51 (s, 1H), 7.60 (d, 1H). Anal. Calcd
for C18H11BrCl2N2O2: C, 49.35; H, 2.53; Br, 18.24; Cl,
16.18; N, 7.30. Found: C, 49.21; H, 2.59; Br, 18.36; Cl,
16.10; N, 7.19.
1
lized from petroleum ether/EtOAc); IR 1670, 3380; H
NMR (CDCl3) d 1.10 (t, 3H), 1.62–1.98 (m, 4H), 2.10–
2.35 (m, 2H), 2.60–2.70 (m, 1H), 2.82–3.30 (m, 7H),
3.65–3.80 (m, 1H), 6.45 (d, 1H), 6.98 (d, 1H), 7.23–
7.29 (m, 2H, 1H exch. with D2O), 7.47 (m, 2H), 7.62
(s, 1H); Anal. Calcd for C25H25Cl3N4O: C, 59.59; H,
5.00; Cl, 21.11; N, 11.12. Found: C, 59.39; H, 5.11; Cl,
21.02; N, 11.30.
3.1.3.4. 1-(20,40-Dichlorophenyl)-7-iodo-4,5-dihydro-
1H-benzo[g]indazole-3-carboxylic acid 6d. General pro-
cedure II was used to convert 5d into the title product
6d (2.25 g, 93%) as a yellow solid. Rf = 0.69 (CHCl3/
3.1.2.11. 7-Chloro-1-(20,40-dichlorophenyl)-N-(4-meth-
ylpiperazin-1-yl)-4,5-dihydro-1H-benzo[g]indazole-3-car-
boxamide 2k. General procedure I was used to convert
6a and N-amino-N-methyl piperazine into the title prod-
uct. The mixture was refluxed for 3 h and purification by
crystallization from petroleum ether/EtOAc afforded 2k
(0.97 g, 49.2%) as a yellowish solid. Rf = 0.64 (CHCl3/
CH3OH 9/1); mp 205–206 ꢂC (crystallized with petro-
1
MeOH 9:1); mp 264–265 ꢂC; IR 1685, 3400; H NMR
(CDCl3) d 2.97–3.20 (m, 4H), 3.50 (br s, 1H, OH exch.
with D2O), 6.29 (d, 1H), 7.37 (d, 1H), 7.47 (d, 1H),
7.52 (s, 1H), 7.57 (d, 1H), 7.66 (s, 1H). Anal. Calcd
for C18H11Cl2IN2O2: C, 44.56; H, 2.28; Cl, 14.61; I,
26.16; N, 5.77. Found: C, 44.78; H, 2.15; Cl, 14.44; I,
26.00; N, 5.69.
1
leum ether/EtOAc); IR 1670, 3200; H NMR (CDCl3)
d 2.32 (s, 3H), 2.63–2.70 (m, 4H), 2.90–3.22 (m, 8H),
6.44 (d, 1H), 6.97 (d, 1H), 7.29 (s, 1H), 7.48 (s, 2H),
7.59 (br s, 1H, exch. with D2O), 7.62 (s, 1H); Anal.
Calcd for C23H22Cl3N5O: C, 56.28; H, 4.52; Cl, 21.67;
N, 14.27. Found: C, 56.15; H, 4.39; Cl, 21.85; N, 14.33.
3.1.3.5. 1-(20,40-Dichlorophenyl)-4,5-dihydro-1H-benzo-
[g]indazole-3-carboxylic acid 6e. General procedure II
was used to convert 5e into the title product 6e (1.32 g,
75%) as a yellowish solid. Rf = 0.73 (CHCl3/MeOH
1
8:2); mp 267 ꢂC; IR 1685, 3400; H NMR (CDCl3) d
2.90–3.20 (m, 4H), 4.39 (br s, 1H, OH exch. with D2O),
6.56 (d, 1H), 7.01 (t, 1H), 7.19 (t, 1H), 7.28 (d, 1H),
7.48 (d, 1H), 7.53 (s, 1H), 7.58 (d, 1H). Anal. Calcd for
C18H12Cl2N2O2: C, 60.18; H, 3.36; Cl, 19.74; N,7.79.
Found: C, 60.33; H, 3.42; Cl, 19.62; N, 7.68.
3.1.3. General procedure II: synthesis of carboxylic acids.
To a mixture of ester 5 (1.0 equiv, 5 mmol) in methanol
(25 mL) was added a solution of potassium hydroxide
(2.0 equiv) in methanol (18 mL). The resulting mixture
was heated under reflux overnight. The mixture was al-
lowed to cool to room temperature and then poured into
water and acidified with 1 N hydrochloric acid. The pre-
cipitate was filtered, washed with water and air-dried to
yield the analytically pure acid.
3.1.3.6. 7-Chloro-1-(40-chlorophenyl)-4,5-dihydro-1H-
benzo[g]indazole-3-carboxylic acid 6f. General procedure
II was used to convert 5f into the title product 6f (1.76 g,
98%) as a white solid. Rf = 0.78 (CHCl3/MeOH 8.5:1.5);
1
mp 251 ꢂC; IR 1590, 1710, 3440; H NMR (CDCl3) d
3.1.3.1. 7-Chloro-1-(20,40-dichlorophenyl)-4,5-dihydro-
1H-benzo[g]indazole-3-carboxylic acid 6a. General pro-
cedure II was used to convert 5a into the title product
6a (1.87 g, 95.2%) as a bright pink solid. Rf = 0.54
(CHCl3/MeOH 9:1); mp 247–249 ꢂC; IR 1690, 1710,
2.90–3.10 (m, 4H), 6.71 (d, 1H), 7.01 (d, 1H), 7.30 (br
s, 1H, OH exch. with D2O), 7.34 (s, 1H), 7.47–7.52
(m, 4H). Anal. Calcd for C18H12Cl2N2O2: C, 60.18; H,
3.36; Cl, 19.74; N, 7.79. Found: C, 60.33; H, 3.25; Cl,
19.89; N, 7.68.
1
3440; H NMR (CDCl3) d 2.94–3.28 (m, 4H), 3.50 (br
s, 1H, OH exch. with D2O), 6.49 (d, 1H), 6.99 (d, 1H),
7.47 (d, 1H), 7.49 (s, 1H), 7.53 (s, 1H), 7.58 (d, 1H). Anal.
Calcd for C18H11Cl3N2O2: C, 54.92; H, 2.81; Cl, 27.01;
N,7.11. Found: C, 54.88; H, 2.93; Cl, 27.31; N,7.01.
3.1.3.7. 7-Chloro-1-phenyl-4,5-dihydro-1H-benzo[g]-
indazole-3-carboxylic acid 6g. General procedure II
was used to convert 5g into the title product 6g
(1.59 g, 98%) as a yellowish solid. Rf = 0.76 (CHCl3/
MeOH 8.5:1.5); mp 258 ꢂC; IR 1690; 1H NMR
(CDCl3/DMSO) d 2.91–3.12 (m, 4H), 6.67 (d, 1H),
6.96 (d, 1H), 7.29 (br s, 1H, OH exch. with D2O), 7.31
(s, 1H), 7.47–7.52 (m, 5H). Anal. Calcd for
3.1.3.2. 1-(20,40-Dichlorophenyl)-7-methyl-4,5-dihydro-
1H-benzo[g]indazole-3-carboxylic acid 6b. General pro-
cedure II was used to convert 5b into the title product