S. Schwarthoff et al.
Bioorganic & Medicinal Chemistry 46 (2021) 116355
–
yl)propane-1-one (200 mg, 600
μ
mol, 1 equiv.), the reaction mixture
O). 13C NMR (126 MHz, CDCl3) δ = 169.56,
–
H), 2.97 (br s, 2H, CH2 C
–
was stirred for another 4 h and then poured into water (16 mL). The
solution was extracted with chloroform (2 × 10 mL). The organic phase
was concentrated under reduced pressure. The resulting green oil was
lyophilized and purified by chromatography on silica gel (SiO2 40–63
155.00, 144.55, 144.22, 142.22, 137.99, 134.70, 128.00, 127.08,
122.03, 119.70, 116.27, 110.09, 104.41, 103.52, 56.06, 39.72, 32.99.
HPLC/HRMS [M+H]+ for C27H21N3O2S calculated 452.1427, found
452.1435.
μ
m, CH2Cl2-MeOH 11:1) to furnish 7a (105 mg, 249.3 μmol, 42%) as
pale-yellow crystalline solid, Rf 0.50 (CH2Cl2-MeOH, 11:1). tR 8.53 min
(Method B). 1H NMR (CDCl3, 300 MHz) δ = 9.3–9.3 (m, 1H, H-1), 8.54
(d, 1H, J = 5.9 Hz, H-3), 8.17 (d, 1H, J = 7.7 Hz, H-6), 7.4–7.6 (m, 1H, H-
4), 7.1–7.4 (m, 11H, H-7, H-8, H-9, phenothiazine-H), 4.68 (br s, 2H,
4.1.6. Synthesis of compounds series 8
General procedure. All derivatives except compound 8e were pre-
pared according to the following procedure: To a solution of the corre-
sponding derivate 7 in THF, 10 equivalents of iodomethane were added.
The reaction solution was stirred for 12 h. The solvent was removed
under reduced pressure and the residue was washed with ice-cold
diethyl ether. The yellow crystalline solid was dried under reduced
pressure.
N
O). 13C NMR (126 MHz, CDCl3)
–
–
C
–
– –
CH2 CH2), 3.00 (br s, 2H, CH2
δ = 169.54, 144.66, 144.27, 142.38, 139.87, 137.99, 128.00, 127.09,
127.04, 121.53, 120.93, 120.84, 119.79, 109.23, 104.34, 39.59, 32.94.
HPLC/HRMS [M+H]+ for C26H19N3OS calculated 422.1322, found
422.1325.
2-Methyl-5-(3-oxo-3-(10H-phenothiazine-10-yl)propyl)-5H-pyrido
[4,3-b]indole-2-ium iodide (8a).Yield 89%. tR 8.71 min (Method B). 1H
NMR (DMSO‑d6, 300 MHz) δ = 9.77 (s, 1H, H-1), 8.67 (dd, 1H, J = 1.2,
7.1 Hz, H-3), 8.35 (d, 1H, J = 7.7 Hz, H-9), 8.16 (d, 1H, J = 7.1 Hz, H-6),
7.68–7.8 (m, 2H, H-7, H-8), 7.2–7.6 (m, 9H, H-4, phenothiazine-H), 4.82
3-(8-Fluoro-5H-pyrido[4,3-b]indole-5-yl)-1-(10H-phenothiazine-10-yl)
propane-1-one (7b). A solution of 6b (300 mg, 1.60 mmol, 1 equiv.) and
potassium 2-methylpropane-2-olate (180 mg, 1.6 mmol, 1 equiv.) in
THF (40 mL) was stirred for 1 h. After addition of 3-bromo-1-(10H-
phenothiazine-10-yl)propane-1-one (535 mg, 1.6 mmol, 1 equiv.), the
reaction mixture was stirred for 48 h. The solvent was removed under
reduced pressure, and the crude product was purified by chromatog-
– –
(br t, 2H, J = 6.1 Hz, N CH2 CH2), 4.34 (s, 3H, methyl-H), 3.12 (br s,
2H, CH2
C
O). 13C NMR (126 MHz, CD3CN) δ = 170.49, 146.87,
–
–
–
142.88, 139.63, 139.11, 130.79, 128.82, 128.32, 128.17, 124.40,
122.95, 121.63, 121.47, 112.57, 108.72, 47.87, 41.68, 33.20. HPLC/
HRMS [M]+ for C27H22N3OS+ calculated 436.1478, found 436.1483.
8-Fluoro-2-methyl-5-(3-oxo-3-(10H-phenothiazine-10-yl)propyl)-5H-
pyrido[4,3-b]indole-2-ium iodide (8b). Yield 69%. tR 8.75 min (Method
B). 1H NMR (DMSO‑d6, 400 MHz) δ = 9.76 (s, 1H, H-1), 8.69 (br s, 1H,
H-3), 8.1–8.4 (m, 2H, H-6, H-9), 7.3–7.86 (m, 10H, H-4, H-7,
raphy on silica gel (SiO2 40–63 μm, CH2Cl2-MeOH 20/12:1) to furnish
7b (64 mg, 0.146 mmol, 9%) as pale-yellow crystalline solid, Rf 0.62
(CH2Cl2-MeOH, 10:1). tR 8.55 min (Method B). 1H NMR (CDCl3, 400
MHz) δ = 9.34 (s, 1H, H-1), 8.47 (br d, 1H, J = 6.4 Hz, H-3), 7.2–7.8 (m,
12H, H-4, H-6, H-7, H-9, phenothiazine-H), 4.7–4.9 (m, 2H,
N
CH2 CH2), 3.1–3.3 (m, 2H, CH2
O). 13C NMR (126 MHz,
–
–
C
–
– –
– –
phenothiazine-H), 4.83 (br s, 2H, N CH2 CH2), 4.35 (br s, 3H, methyl-
CDCl3) δ = 169.47, 159.21, 157.32, 145.04, 144.75, 142.49, 138.27,
137.93, 136.27, 128.03, 127.65, 127.59, 127.09, 126.97, 126.86,
126.64, 115.02, 114.82, 110.11, 110.03, 106.87, 106.82, 106.67,
104.60, 39.83, 32.85. HPLC/HRMS [M+H]+ for C26H18FN3OS calcu-
lated 440.1227, found 440.1229.
H), 3.15 (br s, 2H, CH2
C
O). 13C NMR (126 MHz, CD3CN) δ = 170.50,
–
–
–
161.12, 159.22, 147.47, 139.90, 139.33, 139.12, 128.80, 128.36,
128.17, 122.44, 122.35, 121.17, 121.13, 118.75, 118.54, 114.17,
114.10, 109.07, 109.03, 108.82, 47.95, 41.97, 33.14. HPLC/HRMS:
[M]+ for C27H21FN3OS+ calculated 454.1384, found 454.1386.
2,8-Dimethyl-5-(3-oxo-3-(10H-phenothiazine-10-yl)propyl)-5H-pyrido
3-(8-Methyl-5H-pyrido[4,3-b]indole-5-yl)-1-(10H-phenothiazine-10-
yl)propane-1-one (7c). A solution of 6c (419 mg, 2.30 mmol, 1 equiv.)
and potassium 2-methylpropane-2-olate (256 mg, 2.30 mmol, 1 equiv.)
in acetonitrile (250 mL) was stirred for 1 h. After addition of 3-bromo-1-
(10H-phenothiazine-10-yl)propane-1-one (770 mg, 2.3 mmol, 1 equiv.),
the reaction mixture was stirred for 24 h. Then, the reaction solution was
poured into water (250 mL) and extracted with chloroform (2 × 150
mL). The organic layer was concentrated under reduced pressure, and
the crude product purified by chromatography on silica gel (SiO2 40–63
[4,3-b]indole-2-ium iodide (8c). Yield 79%. tR 9.47 min (Method B). 1
H
NMR (DMSO‑d6, 250 MHz) δ = 9.72 (s, 1H, H-1), 8.65 (d, 1H, J = 6.4 Hz,
H-3), 8.1–8.2 (m, 2H, H-6, H-9), 7.69 (d, 1H, J = 8.4 Hz, H-4), 7.2–7.6
(m, 9H, H-7, phenothiazine-H), 4.81 (br t, 2H,
J = 6.2 Hz,
– –
CH2
N
CH2 CH2), 4.34 (s, 3H, N-CH3), 3.08 (br d, 2H, J = 18.3 Hz,
C
O), 2.5–2.6 (m, 3H, C-CH ). 13C NMR (126 MHz, CD3CN) δ =
–
–
–
170.51, 146.79, 141.12, 139.37,3138.83, 134.52, 132.16, 128.85,
128.17, 122.52, 121.64, 121.47, 112.29, 108.58, 47.82, 41.68, 33.20,
21.45. HPLC/HRMS [M]+ for C28H24N3OS+ calculated 450.1635, found
450.1634.
μ
m, CH2Cl2-MeOH 20:1, 40:1) to furnish 7c (366.4 mg, 0.84 mmol,
36%) as light-brown crystalline solid, Rf 0.25 (CH2Cl2-MeOH, 20:1). tR
9.20 min (Method B). 1H NMR (CDCl3, 250 MHz) δ = 9.28 (s, 1H, H-1),
8.49 (br d, 1H, J = 5.7 Hz, H-3), 7.98 (s, 1H, H-6), 7.1–7.5 (m, 10H, H-7,
8-Methoxy-2-methyl-5-(3-oxo-3-(10H-phenothiazine-10-yl)propyl)-5H-
pyrido[4,3-b]indole-2-ium iodide (8d). Yield 77%. tR 8.77 min (Method
B). 1H NMR (CD3CN, 300 MHz) δ = 9.3–9.4 (m, 1H, H-1), 8.2–8.3 (m,
1H, H-3), 7.7–7.9 (m, 2H, H-6, H-9), 7.2–7.6 (m, 10H, H-4, H-7,
– –
H-9, phenothiazine-H), 4.66 (br s, 2H, N CH2 CH2), 2.9–3.2 (m, 2H,
–
–
–
C
CH2
O), 2.58 (s, 3H, methyl-H). 13C NMR (126 MHz, CDCl3) δ =
169.55, 144.50, 144.35, 142.32, 138.12, 138.02, 130.45, 128.30,
128.00, 127.08, 121.67, 120.77, 119.62, 108.91, 104.25, 39.56, 32.99,
21.33. HPLC/HRMS [M+H]+ for C27H21N3OS calculated 436.1478,
found 436.1477.
– –
phenothiazine-H), 4.6–4.8 (m, 2H, N CH2 CH2), 3.9–4.0 (m, 3H,
O). 13C
–
–
CH3), 3.9–4.0 (m, 3H, N CH3), 3.16 (br s, 2H, CH2 C
–
–
–
O
NMR (CD3CN, 126 MHz) δ = 170.52, 157.60, 146.62, 139.25, 139.17,
139.10, 137.36, 128.83, 128.33, 128.17, 122.39, 121.44, 119.83,
113.48, 108.64, 105.47, 56.87, 47.81, 41.77, 33.27. HPLC/HRMS [M]+
for C28H24N3O2S+ calculated 466.1589, found 466.1589.
3-(8-Methoxy-5H-pyrido[4,3-b]indole-5-yl)-1-(10H-phenothiazine-10-
yl)propane-1-one (7d). A solution of 6d (50 mg, 0.252 mmol, 1 equiv.)
and potassium 2-methylpropane-2-olate (28 mg, 0.252 mmol, 1 equiv.)
in acetonitrile (20 mL) was stirred for 1 h. After addition of 3-bromo-1-
2-Benzyl-5-(3-oxo-3-(10H-phenothiazine-10-yl)propyl)-5H-pyrido[4,3-
b]indole-2-ium bromide (8e). To a solution of 63 mg compound 7a (149
µmol, 1 equiv.) in acetone, 5 equivalents of benzyl bromide (127 mg,
754 µmol) were added. The reaction solution was stirred for 12 h, the
resulting white precipitate was filtered, washed with ice cold acetone
yielding 8e (39 mg, 65.8 µmol, 44%) as colorless crystalline solid, tR
10.69 min (Method B). 1H NMR (DMSO‑d6, 400 MHz) δ = 10.24 (s, 1H,
H-1), 8.89 (m, 1H, H-3), 8.22 (m, 1H, H-9), 8.17 (m, 1H, H-6), 7.19–7.77
(10H-phenothiazine-10-yl)propane-1-one (85 mg, 0.252 mmol,
1
equiv.), the reaction mixture was stirred for 24 h. Then, the reaction
solution was poured into water (10 mL) and extracted with chloroform
(2 × 6 mL). The organic layer was concentrated under reduced pressure,
and the crude product was purified by chromatography on silica gel
(SiO2 40–63 μm, CH2Cl2-MeOH 20:1) to furnish 7d (38 mg, 0.084 mmol,
33%) as a slightly pink oil, Rf 0.55 (CH2Cl2-MeOH, 20:1). tR 8.63 min
(Method B). 1H NMR (CDCl3, 300 MHz) δ = 9.28 (s, 1H, H-1), 8.50 (d,
(m, 16H, H-7, H-8, H-9, ph–enothi–azine-H, benzyl-H), 5.84 (br s, 2H,
–
C
–
1H,
J
=
5.8 Hz, H-3), 7.0–7.7 (m, 12H, H-4, H-6, H-7, H-9,
benzyl-H), 4.82 (br s, 2H, N CH2 CH2), 3.15 (br s, 2H, CH2
O).
–
13C NMR (126 MHz, CD3CN) δ = 170.61, 148.62, 147.19, 142.99,
– –
phenothiazine-H), 4.65 (br s, 2H, N CH2 CH2), 3.96 (s, 3H, methoxy-
8