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G.C. González-Muñoz et al. / European Journal of Medicinal Chemistry 46 (2011) 2224e2235
1H, J ¼ 2.8 Hz), 7.45 (dd, 1H, J ¼ 7.6 Hz, J ¼ 1.5 Hz), 7.39 (m, 1H), 7.02
(dd, 1H, J ¼ 9.0 Hz, J ¼ 2.8 Hz), 6.94e6.79 (m, 3H), 6.79 (s, 1H, NH),
3.82 (s, 3H), 2.68 (t, 2H, J ¼ 5.8 Hz), 2.65e2.55 (m, 8H), 2.47 (t, 2H,
as a yellow solid of m.p.: 179e181 ꢃC. ESI-MS m/z 370 [MH]þ. 1H
NMR (CDCl3):
d
¼ 10.69 (s, 1H, NH), 7.17 (m, 1H, H8), 7.06 (dd, 1H,
J ¼ 7.2 Hz, J ¼ 2.5 Hz, H9), 6.89 (t, 1H, J ¼ 7.2 Hz, H7), 6.82e6.72 (m,
2H, H1,6), 6.66 (d, 1H, J ¼ 2.6 Hz, H4), 6.62 (dd, 1H, J ¼ 8.9 Hz,
J ¼ 2.6 Hz, H2), 3.78 (s, 3H, CH3), 3.21 (t, 2H, J ¼ 5.7 Hz, H30), 2.86 (m,
J ¼ 5.8 Hz), 2.31 (s, 3H). 13C NMR (CDCl3):
d
¼ 172.4, 157.8, 150.9,
146.1, 138.9, 132.5, 129.6, 128.4, 122.4, 121.5, 114.4, 113.1, 109.9, 56.3,
55.4 (2C), 53.7, 52.9 (2C), 46.3, 31.6. Purity: 100% (by HPLC). Anal.
C21H27N5O4S (C, H, N, S).
6H, H20 and 2CH2), 1.63 (m, 4H, 2CH2). 13C NMR (CDCl3):
d
¼ 170.9
(CO), 156.0 (C3), 143.6 (C9a), 136.8 (C10a), 127.3 (C8), 126.9 (C9),
123.1 (C7), 121.1 (C4a), 119.3 (C5a), 113.6 (C1), 112.8 (C6), 112.6
(C2,4), 55.6 (C, CH3), 53.8 (2C, 2CH2), 51.1 (C3), 33.0 (C20), 23.5 (2C,
2CH2). Purity: 97% (by HPLC). Anal. C20H23N3O2S (C, H, N, S).
4.3.7. N0-{2-[(2,4-Dinitrophenyl)thio]phenyl}-3-(4-
methylpiperazin-1-yl)propanehydrazide (32)
Reagents were 23 (125 mg, 0.41 mmol), 25 (70 mg, 0.41 mmol),
and EDC (63 mg, 0.41 mmol). Intermediate 32 was obtained as
a yellow solid (70 mg, 37% yield) of m.p.: 65e67 ꢃC. ESI-MS m/z 461
4.4.4. 3-(4-Methylpiperazin-1-yl)-N-(10H-phenothiazin-10-yl)
propanamide (16)
From 29 (60 mg, 0.14 mmol) and K2CO3 (20 mg, 0.14 mmol),
compound 16 was obtained (16 mg, 30% yielþd) as a yellow solid of
m.p.: 177e178 ꢃC. ESI-MS m/z 369 [MH] . 1H NMR (CDCl3):
[MH]þ. 1H NMR (CDCl3):
d
¼ 9.99 (s, 1H, NH), 9.06 (d, 1H, J ¼ 2.4 Hz),
8.18 (dd, 1H, J ¼ 9.0 Hz, J ¼ 2.4 Hz), 7.46 (td, 1H, J ¼ 8.1 Hz,
J ¼ 1.4 Hz), 7.43 (dd,1H, J ¼ 8.1 Hz, J ¼ 1.4 Hz), 7.12 (d,1H, J ¼ 9.0 Hz),
6.95e6.99 (m, 2H), 6.69 (s, 1H, NH), 2.68 (t, 2H, J ¼ 5.8 Hz),
2.61e2.51 (m, 8H), 2.45 (t, 2H, J ¼ 5.8 Hz), 2.30 (s, 3H). 13C NMR
d
¼ 10.48 (s, 1H, NH), 7.06 (m, 4H, H2,4,6,8), 6.90 (td, 2H, J ¼ 7.9 Hz,
J ¼ 1.0 Hz, H3,7), 6.75 (dd, 2H, J ¼ 7.9 Hz, J ¼ 1.0 Hz, H1,9), 2.86 (t,
(CDCl3):
d
¼ 172.4, 150.8, 145.9, 144.9, 144.6, 137.8, 133.4, 129.6,
2H, J ¼ 5.8 Hz, H30), 2.70 (t, 2H, J ¼ 5.8 Hz, H20), 2.64e2.29 (m, 8H,
127.4, 121.8, 121.7, 113.3, 111.6, 55.2 (2C), 53.4, 52.6 (2C), 46.0, 31.3.
Purity: 100% (by HPLC). Anal. C20H24N6O5S (C, H, N, S).
4CH2), 2.28 (s, 3H, CH3). 13C NMR (CDCl3):
d
¼ 170.8 (CO), 143.1
(C9a,10a), 127.3 (C2,8), 127.1 (C4,6), 123.5 (C3,7), 119.8 (C4a,5a),
112.6 (C1,9), 54.7 (2CH2), 53.4 (C30), 52.4 (2CH2), 45.7 (CH3), 31.4
(C20). Purity: 98% (by HPLC). Anal. C20H24N4OS (C, H, N, S).
4.4. Synthesis of new N-(10H-phenothiazin-10-yl)-3-(pyrrolidin-1-
yl)propanamides (13e19)
4.4.5. N-(3-Chloro-10H-phenothiazin-10-yl)-3-(4-
A mixture of the corresponding hydrazide (0.2 mmol) (26e32)
and potassium carbonate (28 mg, 0.2 mmol) in DMF (5 mL) was
refluxed for 10e15 min. After cooling to room temperature, the
solvent was removed under reduced pressure and the residue was
purified on silica gel, using a flash-chromatography column and
a mixture of CH2Cl2 and MeOH (9:1) as eluent.
methylpiperazin-1-yl)propanamide (17)
Using 30 (100 mg, 0.22 mmol) and K2CO3 (31 mg, 0.22 mmol) as
reagents, the N-acylaminophenothiane 17 was obtained (46 mg,
51% yield), as a yellow solid of m.p.: 188e189 ꢃC. ESI-MS m/z 403
[MH]þ, 405 [MH þ 2]þ, 425 [M þ Na]þ. 1H NMR (CDCl3):
¼ 10.41 (s,
d
1H, NH), 7.06 (m, 1H, H8), 7.03 (dd, 1H, J ¼ 7.7 Hz, J ¼ 1.3 Hz, H6),
7.01 (d, 1H, J ¼ 2.5 Hz, H4), 6.96 (dd, 1H, J ¼ 8.8 Hz, J ¼ 2.5 Hz, H2),
6.91 (td, 1H, J ¼ 7.7 Hz, J ¼ 1.3 Hz, H7), 6.72 (dd, 1H, J ¼ 7.7 Hz,
J ¼ 1.3 Hz, H9), 6.62 (d, 1H, J ¼ 8.8 Hz, H1), 2.80 (t, 2H, J ¼ 5.9 Hz,
H30), 2.64 (t, 2H, J ¼ 5.7 Hz, H20), 2.58e2.30 (m, 8H, 4CH2), 2.27 (s,
4.4.1. N-(10H-Phenothiazin-10-yl)-3-(pyrrolidin-1-yl)propanamide
(13)
From 26 (54 mg, 0.14 mmol) and K2CO3 (19 mg, 0.14 mmol), the
N-acylaminophenothiazine 13 was obtained (25 mg, 53% yield) as
a yellow solid of m.p.: 195e196 ꢃC. ESI-MS m/z 340 [MH]þ, 362
3H, CH3). 13C NMR (CDCl3):
d
¼ 170.9 (CO), 142.6 (C9a), 141.7 (C10a),
128.3 (C3), 127.5 (C8), 127.0 (C4), 126,9 (C6), 126.4 (C2), 123.5 (C7),
121.6 (C4a), 118.9 (C5a), 113.6 (C1), 112.8 (C9), 54.8 (2CH2), 53.4
(C30), 52.6 (2CH2), 45.8 (CH3), 31.4 (C20). Purity: 100% (by HPLC).
Anal. C20H23ClN4OS (C, H, N, S).
[M þ Na]þ, 701 [2M þ Na]þ. 1H NMR (CDCl3):
¼ 10.26 (s, 1H, NH),
d
7.03 (m, 4H, H2,4,6,8), 6.90 (t, 2H, J ¼ 7.6 Hz, H3,7), 6.79 (d, 2H,
J ¼ 7.6 Hz, H1,9), 3.07 (t, 2H, J ¼ 5.7 Hz, H30), 2.76 (m, 6H, 2CH2 and
H20), 1.81 (m, 4H, 2CH2). 13C NMR (CDCl3):
(C9a,10a), 126.6 (C2,C8), 126.3 (C4,C6), 122.4 (C3,7), 119.6 (C4a,5a),
111.8 (C1,9), 52.9 (2CH2), 50.2 (C30), 32.0 (C20), 22.4 (2CH2). Purity:
100% (by HPLC). Anal. C19H21N3OS (C, H, N, S).
d
¼ 169.7 (CO), 142.2
4.4.6. N-(3-Methoxy-10H-phenothiazin-10-yl)-3-(4-
methylpiperazin-1-yl)propanamide (18)
From 31 (70 mg, 0.16 mmol) and K2CO3 (22 mg, 0.16 mmol), the
N-acylaminophenothiazine 18 was obtained (30 mg, 48% yield) as
a yellow solid of m.p.: 202e203 ꢃC. ESI-MS m/z 399 [MH]þ. 1H NMR
4.4.2. N-(3-Chloro-10H-phenothiazin-10-yl)-3-(pyrrolidin-1-yl)
propanamide (14)
(CDCl3):
d
¼ 10.69 (s, 1H, NH), 7.16 (m, 1H, H8), 7.06 (dd, 1H,
From 27 (200 mg, 0.48 mmol) and K2CO3 (66 mg, 0.48 mmol),
the N-acylaminophenothiazine 14 was obtained (90 mg, 51%þyield)
as a yellow solid of m.p.: 186e187 ꢃC. ESI-MS m/z 374 [MH] , 376
J ¼ 7.2 Hz, J ¼ 2.5 Hz, H9). 6.91 (t, 1H, J ¼ 7.2 Hz, H7), 6.78e6.70 (m,
2H, H1,6), 6.67 (d, 1H, J ¼ 2.5 Hz, H4), 6.61 (dd, 1H, J ¼ 8.8 Hz,
J ¼ 2.5 Hz, H2), 3.78 (s, 3H, CH3), 2.85 (t, 2H, J ¼ 5.7 Hz, H30),
2.79e2.43 (m, 10H, H20 and 4CH2), 2.37 (s, 3H, CH3). 13C NMR
[MH þ 2]þ. 1H NMR (CDCl3):
¼ 10.87 (s, 1H, NH), 7.06 (m, 1H, H8),
d
7.03 (dd, 1H, J ¼ 7.9 Hz, J ¼ 1.2 Hz, H6), 7.01 (d, 1H, J ¼ 2.2 Hz, H4),
6.96 (dd, 1H, J ¼ 2.3, J ¼ 8.6 Hz, H2), 6.90 (td, 1H, J ¼ 7.9 Hz,
J ¼ 1.2 Hz, H7), 6.73 (dd, 1H, J ¼ 7.9 Hz, J ¼ 1.2 Hz, H9), 6.63 (d, 1H,
J ¼ 8.6 Hz, H1), 2.97 (t, 2H, J ¼ 5.9 Hz, H30), 2.73 (m, 6H, H20 and
(CDCl3):
d
¼ 171.3 (CO), 156.5 (C3), 143.9 (C9a), 137.2 (C10a), 127.9
(C8), 127.4 (C9), 123.6 (C7), 120.6 (C4a), 119.9 (C5a), 113.9 (C1), 113.0
(C6), 112.9 (C2,4), 56.1 (CH3), 55.2 (2CH2), 53.9 (C30), 52.4 (2CH2),
46.1 (CH3), 31.9 (C20). Purity: 99% (by HPLC). Anal. C21H26N4O2S (C,
H, N, S).
2CH2), 1.85 (m, 4H, 2CH2). 13C NMR (CDCl3):
d
¼ 171.4 (CO), 143.0
(C9a), 142.1 (C10a), 128.5 (C3), 127.8 (C8), 127.3 (C4), 127.2 (C6),
126.6 (C2), 123.9 (C7), 121.8 (C4a), 119.2 (C5a), 113.9 (C1), 113.0 (C9),
53.7 (2C, 2CH2), 51.3 (C30), 33.5 (C20), 23.8 (2C, 2CH2). Purity: 98%
(by HPLC). Anal. C19H20ClN3OS (C, H, N, S).
4.4.7. 3-(4-Methylpiperazin-1-yl)-N-(3-nitro-10H-phenothiazin-
10-yl)propanamide (19)
From 32 (50 mg, 0.11 mmol) and K2CO3 (15 mg, 0.11 mmol), the
N-acylaminophenothiazine 19 was obtained (30 mg, 67% yield) as
a yellow solid of m.p.: 192e193 ꢃC. ESI-MS m/z 414 [MH]þ. 1H NMR
4.4.3. N-(3-Methoxy-10H-phenothiazin-10-yl)-3-(pyrrolidin-1-yl)
propanamide (15)
From 28 (100 mg, 0.24 mmol) and K2CO3 (33 mg, 0.24 mmol),
the N-acylaminophenothiazine 15 was obtained (40 mg, 45% yield)
(CDCl3):
d
¼ 10.87 (s,1H, NH), 7.85 (d,1H, J ¼ 2.5 Hz, H4), 7.82 (m,1H,
H2), 7.06 (td, 1H, J ¼ 7.5 Hz, J ¼ 1.6 Hz, H8), 6.97 (m, 2H, H6,7), 6.69
(m, 2H, H1, H9), 2.84 (t, 2H, J ¼ 5.7 Hz, H30), 2.68 (t, 2H, J ¼ 5,7 Hz,