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A. Rodríguez-Sanz et al. / European Journal of Medicinal Chemistry 93 (2015) 83e92
were performed under an atmosphere of dry argon. Microwave-
assisted reactions were carried out in a 5 mL vial using a Synthe-
wave 402 microwave synthesizer (Prolabo). The reactions were
monitored by thin-layer chromatography (TLC) on silica-coated
aluminium sheets (60F254 Alugram) and chromatograms were
visualised with UV light (254 or 366 nm). Purification by column
chromatography was undertaken with Merck silica gel
(0.030e0.075 mm) and the solvents were used as received
(Scharlab). Infrared spectra (IR, KBr window) were recorded on a
give 1i as an orange solid. Yield: 85%; mp: 234e235 ꢀC (ethanol/
Et2O); 1H NMR (300 MHz, DMSO-d6):
(d, 1H, J ¼ 6.8 Hz), 8.58 (s, 1H), 8.47 (d, 1H, J ¼ 8.9 Hz), 7.68 (s, 1H),
7.17 (d, 1H, J ¼ 8.7 Hz), 5.96 (s, 2H), 3.97 (s, 3H), 3.15 (q, 2H,
J ¼ 7.2 Hz), 2.99 (q, 2H, J ¼ 7.2 Hz), 1.39 (t, 6H, J ¼ 6.8 Hz). Anal.
(C21H22N3O3Br$H2O) theoretical: C, 54.55; H, 5.23; N, 9.09. Found:
C, 55.72; H, 5.60; N, 8.77.
d
9.33 (d, 1H, J ¼ 6.8 Hz), 8.90
5.1.4. 14-Methoxy-16-(pent-4-ynyl)acenaphtho[100,200:30,40]
pyridazino[10,60:1,2]pyrido-[3,4-b]indol-9-inium mesitylensulfonate
(1j)
PerkineElmer FTIR 1725X instrument. The frequencies (n) of the
most intense bands are given in cmꢁ1. Nuclear magnetic resonance
spectra (1H and 13C NMR) were recorded using Varian Mercury-VX-
A mixture of 10 (see SD) (0.10 g, 0.2 mmol), acenaphthoquinone
(0.036 g, 0.2 mmol), anhydrous sodium acetate (0.016 g, 0.2 mmol)
and ethanol (10 mL) was heated under reflux for 1 h. The solid was
filtered when the mixture was still hot and was washed with hot
ethanol (5 mL) and hot acetone (5 mL). Crystallization from acetic
acid/acetone gave 1j as an orange solid. Yield: 67%; mp:
300 MHz (300 and 75 MHZ, respectively) and Varian-UNITYPLUS
-
500 (500 and 125 MHz, respectively) instruments. Chemical shifts
) are given in ppm and are referenced to the residual signal of the
(d
non-deuterated solvent. Coupling constants (J) are given in Hz. The
abbreviations s ¼ singlet, d ¼ doublet, dd ¼ doublet of doublets,
t ¼ triplet, td ¼ triplet of doublets, q ¼ quadruplet, m ¼ multiplet,
bs ¼ broad signal, appt ¼ apparent triplet are used throughout.
Elemental analyses (C, H, N) were carried out on a Heraeus CHN
Rapid Elemental Analyzer and were within 0.4% of the theoretical
values.
The supplementary data contains experimental procedures and
characterisation data for compounds 1aed, 1feg, 16 and their in-
termediates. 1H and 13C NMR spectra for 1e and its intermediates
are also provided as representative examples. The synthesis of new
compounds 1e, 1hek and 2aec is described below.
273e274 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d 9.55 (s, 1H), 9.37 (d,
1H, J ¼ 6.9 Hz), 8.75 (d, 1H, J ¼ 6.9 Hz), 8.71 (d, 1H, J ¼ 6.9 Hz), 8.58
(d, 1H, J ¼ 7.3 Hz), 8.38 (d, 1H, J ¼ 8.4 Hz), 8.34 (d, 2H, J ¼ 8.0 Hz),
8.02 (t, 2H, J ¼ 7.4 Hz), 7.52 (d,1H, J ¼ 1.8 Hz), 7.18 (dd,1H, J ¼ 8.8 Hz,
J ¼ 2.2 Hz), 5.24 (t, 2H, J ¼ 7.3 Hz), 4.05 (s, 3H), 2.75 (s, 1H),
2.54e2.51 (m, 2H), 2.38e2.29 (m, 2H); IR (KBr): n 2932, 1621, 1574,
1544, 1409, 1250, 1223, 1161, 829, 678; Anal. (C39H33N3O4S$2H2O)
theoretical: C, 69.31; H, 5.52; N, 6.22. Found: C, 69.07; H, 5.19; N,
5.91.
5.1.5. 1,10-Bis-(1-methyl-7-methoxy-pyrido[3,4-b]indol-9-yl)-
deca-4,6-diyne (11)
5.1.1. 2,3-Dimethyl-12H-10-methoxy-pyridazino[10,60:1,2]pyrido
[3,4-b]indol-5-inium bromide (1e)
A mixture of 9 (see SD) (0.26 g, 1 mmol) and copper(II) acetate
(0.90 g, 5 mmol) in acetonitrile (20 mL) was heated under reflux for
48 h. Water (10 mL) and 25% ammonia (5 mL) were added. The
mixture was extracted with CH2Cl2 (30 mL) and the organic phase
was dried (MgSO4) and filtered. The solvent was removed under
reduced pressure and the residue was chromatographed on silica
gel using acetone/ethanol (8:2) as eluent. Crystallization from
acetone gave 11 as a pale yellow solid. Yield: 45%; mp: 184e185 ꢀC;
A solution of 6 (see SD) (51 mg, 0.1063 mmol) in 48% HBr (2 mL)
was stirred at room temperature for 1 h. The solvent was removed
under reduced pressure and the residue was dried under a vacuum.
The solid was treated with Et2O in an ultrasound bath and the
mixture was filtered. Compound 1e was obtained as a yellow solid
and this was recrystallized from ethanol/acetic acid. Yield: 31%;
mp: >280 ꢀC (dec.); 1H NMR (300 MHz, CD3OD):
d 9.09 (d, 1H,
J ¼ 7.0 Hz), 8.78 (s, 1H), 8.67 (d, 1H, J ¼ 7.0 Hz), 8.32 (d, 1H,
J ¼ 9.0 Hz), 7.29 (d, 1H, J ¼ 2.2 Hz), 7.17 (dd, 1H, J ¼ 9.0 Hz,
J ¼ 2.2 Hz), 4.03 (s, 3H), 2.84 (s, 3H), 2.73 (s, 3H). 13C NMR (125 MHz,
1H NMR (300 MHz; CDCl3):
d
8.9 (d, 2H, J ¼ 5.5 Hz), 7.97 (d, 2H,
J ¼ 8.8 Hz), 7.74 (d, 2H, J ¼ 5.1 Hz), 6.89 (d, 2H, J ¼ 2.2 Hz), 6.89 (dd,
2H, J ¼ 8.8 Hz, J ¼ 2.2 Hz), 4.64 (t, 4H, J ¼ 7.3 Hz), 3.94 (s, 6H), 3.04 (s,
CD3OD):
d
164.4, 162.1, 146.4, 139.6, 131.7, 131.2, 130.2, 128.6, 127.8,
6H), 2.38 (t, 4H, J ¼ 6.6 Hz), 2.13e2.04 (m, 4H); IR (KBr):
n
2966,
127.3, 124.4, 117.0, 115.7, 114.8, 100.9, 95.5, 56.4, 20.7, 19.4. HRMS
[ESI-TOF]: Calcd for C17H16N3O, [Mþ]: 278.1286. Found [Mþ]:
278.1288. Anal. (C17H16BrN3O) theoretical: C, 57.00; H, 4.50; N,
11.73. Found: C, 57.27; H, 4.82; N, 11.38.
2115, 1617, 1558, 1414, 1238, 1108, 839, 675 cme1
; Anal.
(C36H34N4O2) theoretical: C, 77.95; H, 6.18; N,10.10. Found: C, 77.71;
H, 6.33; N, 9.84.
5.1.6. 9,90-(Deca-4,6-diyn-1,10-diyl)-bis-(2-amino-1-methyl-7-
methoxy-pyrido[3,4-b]indol-2-inium) dimesitylenesulfonate (12)
A solution of MSH (0.30 g, 1.4 mmol) in CH2Cl2 (2 mL) was added
dropwise to a slurry of 11 (0.55 g, 1 mmol) in CH2Cl2 (5 mL) at room
temperature. After 1 h, Et2O was added and the resulting solid was
filtered and washed with acetone and CH2Cl2. Crystallization from
ethanol gave 12 as a white solid. Yield: 90%; mp: 250e251 ꢀC; 1H
5.1.2. 2,3-Diethyl-10-methoxy-12-(3-iodopropyl)-pyridazino
[10,60:1,2]pyrido[3,4-b]indol-5-inium iodide (1h)
A slurry of 8 (see SD) (86.8 mg, 0.3 mmol) in 1,3-diiodopropane
(5 mL) was irradiated in a microwave synthesiser for 10 min (ꢂ2) at
300 W. The solid was filtered when the mixture was still hot and
was washed with acetone (2 ꢂ 5 mL) and Et2O (2 ꢂ 5 mL). Crys-
tallization from ethanol yielded 1h as an orange solid. Yield: 55%;
NMR (300 MHz, DMSO-d6):
d
8.54 (d, 2H, J ¼ 6.6 Hz), 8.43 (d, 2H,
mp: >300 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
9.18 (d, 1H,
J ¼ 6.9 Hz), 8.30 (d, 2H, J ¼ 9.2 Hz), 7.67 (s, 4H), 7.35 (d, 2H,
J ¼ 1.8 Hz), 7.05 (dd, 2H, J ¼ 8.8 Hz, J ¼ 1.8 Hz), 4.70 (t, 4H, J ¼ 7.3 Hz),
3.94 (s, 6H), 3.13 (s, 6H), 2.47e2.43 (m, 4H), 2.02e1.97 (m, 4H); IR
J ¼ 7.0 Hz), 9.04 (d, 1H, J ¼ 7.0 Hz), 8.87 (s, 1H), 8.37 (d, 1H,
J ¼ 8.8 Hz), 7.20 (s, 1H), 7.08 (d, 1H, J ¼ 9.0 Hz), 5.19 (bs, 2H), 3.94 (s,
3H), 3.35 (bs, 2H), 2.97 (q, 2H, J ¼ 7.2 Hz), 2.90 (q, 2H, J ¼ 7.2 Hz),
2.59 (bs, 2H),1.40 (t, 6H, J ¼ 7.0 Hz). Anal. (C22H25N3OI2) theoretical:
C, 43.95; H, 4.19; N, 6.99. Found: C, 44.27; H, 4.42; N, 7.17.
(KBr): n 3432, 3252, 3139, 2934, 2328, 1624, 1573, 1456, 1249, 1228,
1167, 1085, 1014, 816, 679; Anal. (C54H60N6O8S2) theoretical: C,
65.83; H, 6.14; N, 8.53. Found: C, 65.57; H, 6.22; N, 8.40.
5.1.3. 12-Carboxymethyl-2,3-diethyl-10-methoxy-pyridazino
[10,60:1,2]pyrido[3,4-b]indol-5-inium bromide (1i)
A mixture of 1f (see SD) (38.7 mg, 0.08 mmol) and 48% HBr
(1 mL) was heated under reflux for 3 h. The solvent was evaporated
under reduced pressure and the residue was treated with Et2O to
5.1.7. 12,120-(Deca-4,6-diyn-1,10-diyl)-bis-(2,3-diethyl-10-
methoxy-pyridazino[10,60:1,2]pyrido[3,4-b]indol-5-inium)
dimesitylenesulfonate (1k)
A mixture of 12 (0.10 g, 0.1 mmol), hexane-3,4-dione (0.025 g,
0.2 mmol), anhydrous sodium acetate (0.008 g, 0.1 mmol) and