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6.1.4. 6-Amino-7-[4-(11-ethyl-6-oxo-5,11-dihydro-6H-
dipyrido[3,2-b:20,30-e][1,4]diazepin-9-yl)piperazin-1-yl]-1-
methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (1)
143.7, 152.0, 152.7, 167.4. C17H20N6O: C 62.95, H 6.21, N 25.91,
found C 62.95, H 6.18, N 25.78.
To
a
mixture of
7
(0.05 g, 0.2 mmol) and DIPEA (0.07 g,
6.1.7. 7-[4-(11-Ethyl-6-oxo-5,11-dihydro-6H-dipyrido[3,2-
b:20,30-e][1,4]diazepin-8-yl)piperazin-1-yl]-1-methyl-6-nitro-4-
oxo-1,4-dihydroquinoline-3-carboxylic acid (13)
0.6 mmol) in DMSO (10 mL) maintained at 80 °C, 6-amino-1-
methyl-4-oxo-7-piperazin-1-yl-1,4-dihydroquinoline-3-carboxylic
acid 817 (0.18 g, 0.6 mmol) was added. After 7 h the reaction mix-
ture was cooled, poured into ice/water and extracted with EtOAc.
The organic layers were evaporated to dryness, to give a residue
which was purified by flash chromatography eluting with CHCl3/
MeOH (99:1), to give 1 (0.035 g, 32%): mp 245–246 °C; 1H NMR
(DMSO d6) d 1.2 (t, J = 7.0 Hz, 3H, CH2CH3), 3.05–3.15 and 3.85–
3.95 (m, each 4H, piperazine CH2), 4.00 (s, 3H, CH3), 4.05–4.10 (q,
J = 7.0 Hz, 2H, CH2CH3), 5.60 (br s, 2H, NH2), 7.10 (d, J = 8.0 Hz,
1H, H-70), 7.20 (s, 1H, H-8), 7.30 (dd, J = 4.0 and 8.0 Hz, 1H, H-30),
7.50 (s, 1H, H-5), 7.80 (d, J = 8.0 Hz, 1H, H-80), 8.10 (dd, J = 1.2
and 8.2 Hz, 1H, H-40), 8.40 (dd, J = 1.3 and 4.8 Hz, 1H, H-20), 8.70
(s, 1H, H-2), 16.00 (br s, 1H, COOH); 13C NMR (DMSO d6) d 15.2,
38.4, 42.0, 44.9, 49.8, 105.7, 106.2, 106.8, 107.9, 113.1, 118.7,
122.6, 127.4, 133.4, 135.1, 142.4, 142.5, 144.1, 145.6, 146.5,
147.7, 147.9, 151.3, 159.1, 167.4, 176.6; Anal. calcd for
To a mixture of 7-chloro-1-methyl-6-nitro-4-oxo-1,4-dihydro-
quinoline-3-carboxylic acid 1230 (0.05 g, 0.17 mmol) and Et3N
(0.08 g, 0.85 mmol) in DMF (5 mL), compound 11 (0.17 g,
0.53 mmol) was added, and the mixture was maintained at
100 °C for 5 h. After cooling the reaction mixture was evaporated
to dryness, giving a residue which was treated with water giving
a solid that was filtered and crystallized from a mixture of EtOH/
DMF, to give 8 (0.07 g, 78%): mp 308–309 °C; 1H NMR (DMSO d6)
d 1.10 (t, J = 7.0 Hz, 3H, CH2CH3), 3.15–3.45 (m, 8H, piperazine
CH2), 4.00 (q, J = 7.0 Hz, 2H, CH2CH3), 4.10 (s, 3H, CH3), 7.10 (dd,
J = 5.0 and 8.0 Hz, 1H, H-30), 7.25 (s, 1H, H-8), 7.45 (dd, J = 2.0
and 8.0 Hz, 1H, H-40), 7.60 (d, J = 3.0 Hz, 1H, H-70), 8.10 (dd,
J = 2.0 and 5.0 Hz, 1H, H-20), 8.25 (d, J = 3.0 Hz, 1H, H-90), 8.65 (s,
1H, H-5), 9.00 (s, 1H, H-2), 10.45 (s, 1H, CONH), 14.70 (s, 1H,
COOH). C28H26N8O6: C 58.94, H 4.59, N 19.64, found C 58.79, H
4.40, N 19.60.
C
28H28N8O4: C 62.21, H 5.22, N 20.73, found C 62.38, H 5.45, N
20.57.
6.1.8. 6-Amino-7-[4-(11-ethyl-6-oxo-5,11-dihydro-6H-
6.1.5. 8-Amino-11-ethyl-5,11-dihydro-6H-dipyrido[3,2-b:20,30-
e][1,4]diazepin-6-one (10)
dipyrido[3,2-b:20,30-e][1,4]diazepin-8-yl)piperazin-1-yl]-1-
methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (2)
A solution of 13 (0.06 g, 0.1 mmol) in DMF (10 ml) was hydro-
genated over a catalytic amount of Raney nickel at room temper-
ature and atmospheric pressure. After 3 h the reaction mixture
was filtered over celite and then evaporated in vacuo obtaining
a brown residue which was crystallized by EtOH/DMF giving 2
(0.05 g, 92%) as a brown solid: mp 329–330 °C; 1H NMR (DMSO
d6) d 1.10 (t, J = 7.0 Hz, 3H, CH2CH3), 3.10–3.15 and 3.35–3.40
(m, each 4H, piperazine CH2), 3.95–4.05 (m, 5H, CH3 and
CH2CH3), 5.50 (br s, 2H, NH2), 7.10 (dd, J = 5.0 and 8.0 Hz, 1H,
H-30), 7.20 (s, 1H, H-8), 7.45 (dd, J = 2.0 and 8.0 Hz 1H, H-40),
7.55 (s, 1H, H-5), 7.60 (d, J = 3.0 Hz, 1H, H-70), 8.10 (dd, J = 2.0
and 5.0 Hz, 1H, H-20), 8.25 (d, J = 3.0 Hz, 1H, H-90), 8.75 (s, 1H,
H-2), 10.40 (br s, 1H, NH), 16.00 (br s, 1H, COOH); 13C NMR
(DMSO d6) d 14.0, 41.0, 42.1, 49.6, 50.6, 105.9, 106.8, 107.5,
120.1, 121.2, 122.5, 126.6, 127.1, 130.1, 133.5, 139.8, 142.2,
143.8, 143.9, 145.8, 146.6, 151.3, 152.9, 167.5, 167.6, 176.5. Anal.
calcd for C28H28N8O4: C 62.21, H 5.22, N 20.73, found C 62.57, H
5.48, N 20.20.
To
a
solution of 11-ethyl-8-nitro-5,11-dihydro-6H-dipyr-
ido[3,2-b:20,30-e][1,4]diazepin-6-one 929 (0.03 g, 1.05 mmol) in
acetic acid (7 mL), a solution of SnCl2 (0.76 g, 3.36 mmol) in 12 N
HCl (3 mL) was added. The reaction mixture was maintained at
room temperature for 3 h and then poured into water, neutralized
with 10% NaOH, and extracted with EtOAc. The organic layers were
evaporated to dryness, to give a residue which was purified by
flash chromatography eluting with CH2Cl2, to give 10 (0.02 g,
84%): mp 220–221 °C; 1H NMR (DMSO d6) d 1.00 (t, J = 7 Hz, 3H,
CH2CH3), 4.00 (q, J = 7.0 Hz, 2H, CH2CH3), 5.10 (br s, 2H, NH2),
7.10 (dd, J = 5.0 and 8.0 Hz, 1H, H-3), 7.25 (d, J = 3.0 Hz, 1H, H-7),
7.45 (dd, J = 2.0 and 8.0 Hz, 1H, H-4), 7.60 (d, J = 3.0 Hz, 1H, H-9),
8.10 (dd, J = 2.0 and 5.0 Hz, 1H, H-2), 10.20 (br s, 1H, CONH).
C
13H13N5O: C 61.17, H 5.13, N 27.43, found C 61.25, H 5.20, N
27.43 HRMS calcd for [C13H13N5O+H+] 256.1193, found 256.1194.
6.1.6. 11-Ethyl-8-(piperazin-1-yl)-5,11-dihydro-6H-
dipyrido[3,2-b:20,30-e][1,4]diazepin-6-one (11)
To a suspension of 10 (0.3 g, 1.33 mmol) in diethylene glycol
monomethyl ether (8 mL), 2-chloro-N-(2-chloroethyl)ethanamine
hydrochloride (1.2 g, 6.6 mmol) was added, and the reaction mix-
ture was maintained at reflux for 72 h. After cooling the mixture
was poured into water, neutralized with a saturated solution of
NaHCO3, and extracted with EtOAc. The organic layer was dried
over anhydrous Na2SO4 and the filtrate was evaporated to dryness,
obtaining a residue which was dissolved in EtOH and triturated
with Et2O, giving a solid which was isolated by filtration. The solid
was purified by flash chromatography eluting with CHCl3/MeOH/
NH4OH (80:19.9:0.1), giving a solid which was then crystallized
by a mixture of EtOH/DMF, to give 11 (0.2 g, 46%): mp 182–
183 °C; 1H NMR (DMSO d6) d 1.10 (t, J = 7.0 Hz, 3H, CH2CH3),
3.05–3.10 and 3.40–3.45 (m, 4H, piperazine CH2), 4.00 (q,
J = 7.0 Hz, 2H, CH2CH3), 7.10 (dd, J = 6.0 and 8.0 Hz, 1H, H-3), 7.45
(dd, J = 2.0 and 8.0 Hz, 1H, H-4), 7.60 (d, J = 3.0 Hz, 1H, H-7), 8.10
(dd, J = 2.0 and 6.0 Hz, 1H, H-2), 8.25 (d, J = 3.0 Hz, 1H, H-9), 9.30
(br s, 1H, NH), 10.50 (1H, br s, CONH); 13C NMR (DMSOd6) d 14.1,
41.0, 42.7, 45.8, 120.0, 121.1, 127.3, 127.6, 130.0, 140.2, 142.8,
6.1.9. 8-[(2-Aminoethyl)amino]-11-ethyl-5,11-dihydro-6H-
dipyrido[3,2-b:20,30-e][1,4]diazepin-6-one hydrochloride (14)
A mixture of 10 (0.2 g, 0.88 mmol) and (2-chloroethyl)amine
hydrochloride (0.15 g, 1.32 mmol) in diethylene glycol mono-
methyl ether (1.5 mL), was irradiated in a microwave oven at
150 °C for 35 min. The reaction mixture was evaporated to dry-
ness, to give a residue which was purified by flash chromatogra-
phy eluting with CHCl3/MeOH/NH4OH (80:19.9:0.1), to give 14
(0.17 g, 47%): mp 163–165 °C; 1H NMR (DMSO d6) d 1.00 (t,
J = 7.6 Hz, 3H, CH2CH3), 2.85–2.95 and 3.20–3.25 (m, each 2H,
CH2), 4.00 (q, J = 7.6 Hz, 2H, CH2CH3), 6.20–6.25 (m, 1H, NH),
7.10 (dd, J = 5.0 and 7.7 Hz, 1H, H-3), 7.25 (d, J = 3.1 Hz, 1H, H-
7), 7.45 (dd, J = 1.6 and 7.6 Hz, 1H, H-4), 7.90 (d, J = 3.0 Hz, 1H,
H-9), 7.90–7.95 (m, 2H, NH2), 8.10 (dd, J = 1.6 and 5.7 Hz, 1H,
H-2), 10.20 (br s, 1H, CONH); 13C NMR (DMSO d6) d 14.0, 39.5,
40.9, 45.4, 119.7, 121.6, 122.0, 127.1, 129.8, 136.2, 142.0, 143.6,
148.8, 153.4, 167.8. C15H18N6O: C 60.39, H 6.08, N 28.17, found
C 60.45, H 6.10, N 28.29.