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D.V. Kravchenko et al. / European Journal of Medicinal Chemistry 40 (2005) 1377–1383
of chloride (1) (15 g, 0.05 mmol) in 1,4-dioxane (150 ml) at
5 °C. The reaction mixture was stirred at 5 °C for 1 h, then
ice-cold water (200 ml) was slowly added. The formed pre-
cipitate was filtered off, washed with ice-cold water and dried
5.1.3. Selected data
5.1.3.1. Methyl (2S)-4-methyl-2-[4-methyl-8-(morpholin-4-
ylsulfonyl)-1,3-dioxo-1,3-dihydro-2H-pyrrolo[3,4-c]quinolin-
2-yl]pentanoate 7{22}. This compound was obtained in 56%
yield. 1H NMR: d = 0.88–0.93 (m, 6H), 1.55–1.66 (m, 1H),
1.86-1.95 (m, 1H), 2.12-2.21 (m, 1H), 3.00 (s, 3H), 3.02 (m,
4H), 3.65 (m, 3H), 3.67 (s, 3H), 8.20 (dd, Jo = 9.2 Hz,
Jm = 1.8 Hz, 1H), 8.36 (d, Jo = 9.2 Hz, 1H), 9.01 (d,
Jm = 1.8 Hz, 1H); 13C NMR: d = 167.9, 167.5, 167.2, 158.4,
152.2, 137.9, 137.4, 125.7, 123.2, 119.7, 66.1, 54.7, 54.1, 47.2,
44.3, 34.9, 24.0, 22.5, 22.1 ppm; LC MS m/z 524 (M + 1).LC
MS m/z 490 (M + 1).
1
by lyophilization to give 16.1 g (92%) of (2). H NMR:
d = 11.88 (s, 1H, exch. with D2O), 7.92 (d, Jm = 1.8 Hz, 1H),
7.80 (dd, Jo = 8.4 Hz, Jm = 1.8 Hz), 7.23 (d, Jo = 8.4 Hz,
1H), 3.64 (m, 4H), 2.89 (m, 4H); 13C NMR: d = 169.02,
143.58, 132.70, 129.60, 129.47, 123.90, 112.24, 73.82, 65.23,
45.82; LCMS m/z 352 (M + 1); HRMS: m/z [M + H+] calcd
for C12H12Cl2N2O4S: 351.2097; found: 351.2099.
5.1.1.2. 5-(Morpholin-4-ylsulfonyl)-1H-indole-2,3-dione
(3). Morpholide (2) (15.8 g, 0.045 mol) was added to a solu-
tion of AcOH (150 ml) in water (150 ml). The mixture was
stirred under reflux overnight, concentrated in vacuo to one
third of original volume, then ice-cold water (200 ml) was
slowly added. The formed precipitate was filtered off, washed
with water and dried to give 11.9 g (89%) of (3). 1H NMR:
d = 11.49 (s, 1H, exch D2O), 7.91 (dd, J = 8.2 Hz, J = 2.1 HZ,
1H), 7.69 (d, J = 2.1 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 3.63
(m, 4H), 2.88 (m, 4H); 13C NMR: d = 159.45, 153.92, 137.10,
128.26, 123.46, 118.25, 112.79, 65.21, 45.85; HRMS: m/z
[M + H+] calcd for C12H12N2O5S: 297.0540; found: 297.0552.
5.1.3.2. Methyl (2S)-2-[4-methyl-8-(morpholin-4-ylsulfonyl)-
1,3-dioxo-1,3-dihydro-2H-pyrrolo[3,4-c]quinolin-2-yl]-3-
phenylpropanoate 7{24}. This compound was obtained in
1
76% yield. H NMR: d = 2.93 (s, 3H), 3.01 (m, 4H), 3.50–
3.80 (m, 6H), 5.29–5.33 (m, 1H), 7.05–7.35 (m,5H), 8.19 (dd,
Jo = 9.2 Hz, Jm = 1.8 Hz, 1H), 8.34 (d, Jo = 9.2 Hz, 1H), 8.93
(d, Jm = 2.0 Hz, 1H); 13C NMR: d = 169.7, 167.5, 167.4,
158.7, 152.4, 137.7, 137.1, 136.1, 131.6, 130.6, 129.8, 129.3,
127.6, 125.9, 123.5, 120.0, 66.3, 54.1, 53.8, 46.7, 34.9,
22.9 ppm; LC MS m/z 524 (M + 1).
5.1.3.3. 2-(2,6-Dicyclopropylphenyl)-4-methyl-8-(morpholin-
4-ylsulfonyl)-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione
7{36}. This compound was obtained in 84% yield. 1H NMR:
d = 1.06–1.2 (m, 12H,), 2.83–2.86 (m, 2H, CH), 3.02–3.15
(m, 4H, CH2), 3.00 (s, 3H, CH3), 3.63 (s, 3H, CH3), 3.62–
3.69 (m, 3H, CH2), 7.34 (d, J = 7.6 Hz, 2H), 7.49 (t, 1H,ArH),
8.21 (dd, Jo = 9.2 Hz, Jm = 2.0 Hz, 1H, ArH), 8.37 (d,
5.1.1.3. 2-Methyl-6-(morpholin-4-ylsulfonyl)-3,4-quinolinedi-
carboxylic acid (4). KOH (20 g) was added to a suspension
of (3) (13.33 g, 45 mmol) in water (100 ml) in nitrogen atmo-
sphere. Ethyl acetoacetate (16 ml, 126 mmol) was added and
the reaction mixture was stirred for 12 h. The mixture was
cooled to 0 °C, then conc. HCl (40 ml) was slowly added.
The formed precipitate was filtered off, washed with water
and dried in vacuo at 70 °C to give 32.6 g (68%) of (4). LCMS
(ELSD and UV254 nm detectors), m/z 381 (M + 1).
Jo = 9.2 Hz, 1H, ArH), 9.02 (d, Jm = 2.0 Hz, 1H, ArH); 13
C
NMR: d = 168.6, 164.1, 152.0, 146.1, 137.2, 136.4, 135.7,
133.8, 131.4, 130.1, 128.7, 127.1, 126.7, 123.1, 120.7, 109.6,
68.3, 54.9, 47.3, 23.4, 16.4, 5.9 ppm; LC MS m/z 522 (M +
1).
5.1.1.4. 4-Methyl-8-(morpholin-4-ylsulfonyl)-furo[3,4-
c]quinoline-1,3-dione (5). A mixture of (4) (1.3 g, 3.43 mmol)
and acetic anhydride (15 ml, 158.68 mmol) was heated to
reflux until all of the initial (4) was dissolved. The obtained
solution was cooled to 0 °C and kept at this temperature for
4 h. The formed precipitate was filtered off, washed with ether
and hexane, and dried in vacuo at 60 °C to give 1.1 g (88%)
of (5). LCMS (ELSD and UV254 nm detectors), m/z 361 (M•+
– 1).
5.1.3.4. Methyl 3-[4-methyl-8-(morpholin-4-ylsulfonyl)-1,3-
dioxo-1,3-dihydro-2H-pyrrolo[3,4-c]quinolin-2-yl]-1H-
pyrazole-4-carboxylate 7{43}. This compound was obtained
in 51% yield. 1H NMR: d = 2.98-3.00 (m, 4H, CH2), 3.00 (s,
3H, CH3), 3.60 (s, 3H, CH3), 3.62 (m, 3H, CH2), 8.21 (dd,
Jo = 9.2 Hz, Jm = 2.0 Hz, 1H, ArH), 8.38 (d, Jo = 9.2 Hz, 1H,
ArH), 8.57 (s, 1H,ArH), 9.01 (d, Jm = 2.0 Hz, 1H,ArH), 13.93
(br. s., 1H); 13C NMR: d = 167.1, 162.7, 159.2, 152.5, 140.8,
137.8, 136.2, 135.5, 131.8, 130.8, 126.1, 124.4, 120.4, 109.7,
66.3, 52.4, 46.8, 23.2 ppm; LC MS m/z 486 (M + 1).
5.1.2. General procedure for preparation of 2-substituted
4-methyl-8-(morpholin-4-ylsulfonyl)-1,3-dihydro-
pyrrolo[3,4-c]quinoline-1,3-diones 7{1–63}
Amine (6{1–63}) (60 mmol) was added to a solution of
(5) (21.7 g, 60 mmol) in pyridine (50 ml) at r.t. and the result-
ing mixture was stirred for 30 min. Acetic anhydride (50 ml)
was added and the mixture was heated to reflux for 3 h. The
reaction mixture was evaporated to dryness in vacuo, the resi-
due was washed with isopropanol and dried to give the cor-
responding imide (7{1–63}) in 45–97% yield.
5.1.3.5. 2-(3,5-Dimethyl-1H-pyrazol-4-yl)-4-methyl-8-
(morpholin-4-ylsulfonyl)-1H-pyrrolo[3,4-c]quinoline-
1,3(2H)-dione 7{49}. This compound was obtained in 89%
1
yield. H NMR: d = 2.05 (s, 6H, 2CH3), 2.98–3.01 (m, 4H,
CH2), 2.99 (s, 3H, CH3), 3.62 (m, 2H, CH2), 8.17 (dd,
Jo = 9.2 Hz, Jm = 2.0 Hz, 1H, ArH), 8.35 (d, Jo = 9.2 Hz, 1H,
ArH), 9.04 (d, Jm = 2.0 Hz, 1H, ArH), 12.58 (br. s., 1H); LC