Amidopropenyl Hydroxamates as HDAC Inhibitors
washed with H2O and brine. The organic phase was dried over
Na2SO4, evaporated to dryness, and the crude product was purified
by column chromatography (petroleum ether/EtOAc from 65:35 to
45:55) to give the tetrahydropyran-2-yl-protected acrylamide 27 as
a white powder (6.58 g, 81%). 1H NMR (300 MHz, [D6]DMSO): d=
11.39 (bs, 1H), 7.91 (t, J=7.63 Hz, 1H), 7.71 (d, J=7.34 Hz, 1H),
7.69 (d, J=15.85 Hz, 1H), 7.61 (d, J=7.63 Hz, 1H), 7.52 (d, J=
15.26 Hz, 1H), 7.10 (d, J=15.55 Hz, 1H), 7.00 (d, J=15.55 Hz, 1H),
4.94 (bs, 1H), 4.23 (q, J=7.04 Hz, 2H), 3.80–4.04 (m, 1H), 3.41–3.68
(m, 1H), 1.42–1.87 (m, 6H), 1.28 ppm (t, J=7.04 Hz, 3H).
mic acid 28 and 1-phenylpiperazine following the synthetic proce-
dure of the hydroxamic acid 29e. 1H NMR (300 MHz, [D6]DMSO):
d=7.93 (t, J=7.63 Hz, 1H), 7.80 (d, J=7.34 Hz, 1H), 7.66 (d, J=
15.26 Hz, 1H), 7.60 (d, J=8.22 Hz, 1H), 7.55 (d, J=15.55 Hz, 1H),
7.51 (d, J=15.26 Hz, 1H), 7.32 (t, J=8.07 Hz, 2H), 7.18 (d, J=
7.92 Hz, 2H), 7.04 (d, J=15.26 Hz, 1H), 6.93–7.01 (m, 1H), 3.67–4.06
(m, 4H), 3.17–3.45 ppm (m, 4H); 13C NMR (75 MHz, [D6]DMSO): d=
164.49, 162.31, 153.23, 153.04, 147.35, 140.63, 139.29, 136.71,
129.97 (2C), 124.91, 124.60 (2 C) 124.26, 123.20, 119.00 (2C), 51.51
(2C), 44.43, 40.85 ppm; HRMS-TOF (ESI): m/z [M+H]+ calcd for
C21H23N4O3: 379.1770, found: 379.1771; HPLC purity: 97%, tR =
1.81 min (Method 4).
NaOH (4n, 11.38 mL) was added dropwise to a stirred solution of
27 (6.58 g, 19.0 mmol) in THF (200 mL). The mixture was stirred at
room temperature for 2 h and was then brought to pH 5 with
citric acid (20% aqueous solution). The solution was concentrated
in vacuo, and the resulting slurry was acidified to pH 4 with citric
acid and extracted with EtOAc and CH2Cl2 several times. The col-
lected organic layers were dried over Na2SO4 and evaporated to
dryness. The crude mixture was triturated in EtOAc, THF, and petro-
leum ether to give the acrylic acid 28 as a white powder (5.7 g,
(ꢃ)-(E)-N-Hydroxy-3-{6-[(E)-3-(3-phenylpyrrolidin-1-yl)-3-oxo-1-
propen-1-yl]pyridin-2-yl}acrylamide hydrochloride (29c): Com-
pound 29c (yield 28%) was prepared by starting from the THP-
protected hydroxamic acid 28 and 3-phenylpyrrolidine according
to the procedure described for the synthesis of 29e. 1H NMR
(300 MHz, [D6]DMSO): d=7.90 (t, J=7.92 Hz, 1H), 7.76 (d, J=
7.19 Hz, 1H), 7.13–7.65 (m, 9H), 7.00 (d, J=15.55 Hz, 1H), 3.88–4.08
(m, 1H), 3.07–4.50 (m, 4H), 2.20–2.47 (m, 1H), 1.80–2.20 ppm (m,
1H); LC–MS (ESI): m/z: 364 [M+H]+; HPLC purity: 95%, tR =
1.64 min (Method 4).
1
95%). H NMR (300 MHz, [D6]DMSO): d=12.30 (bs, 1H), 11.41 (bs,
1H), 7.90 (t, J=7.63 Hz, 1H), 7.67 (d, J=7.34 Hz, 1H), 7.60 (d, J=
7.63 Hz, 1H), 7.61 (d, J=15.55 Hz, 1H), 7.54 (d, J=15.26 Hz, 1H),
7.09 (d, J=15.55 Hz, 1H), 6.93 (d, J=15.55 Hz, 1H), 4.95 (bs, 1H),
3.84–4.11 (m, 1H), 3.36–3.74 (m, 1H), 1.28–2.01 ppm (m, 6H).
(ꢃ)-(E)-N-Hydroxy-3-{6-[(E)-3-(2-phenylpiperidin-1-yl)-3-oxo-1-
propen-1-yl]pyridin-2-yl}acrylamide hydrochloride (29d): Com-
pound 29d (yield 36%) was prepared by starting from the THP-
protected hydroxamic acid 28 and 2-phenylpiperidine according to
the synthetic procedure of the hydroxamic acid 29e. 1H NMR
(300 MHz, [D6]DMSO, 353 K): d=7.84 (t, J=7.63 Hz, 1H), 7.64 (d,
J=7.63 Hz, 1H), 7.56 (d, J=15.55 Hz, 1H), 7.48–7.56 (m, 1H), 7.49
(d, J=15.55 Hz, 1H), 7.47 (d, J=15.55 Hz, 1H), 7.33–7.43 (m, 2H),
7.20–7.34 (m, 3H), 7.00 (d, J=15.55 Hz, 1H), 5.44–5.95 (m, 1H),
3.90–4.48 (m, 1H), 2.79–3.13 (m, 1H), 2.29–2.47 (m, 1H), 1.81–2.08
(m, 1H), 1.35–1.81 ppm (m, 4H); LC–MS (ESI): m/z: 378 [M+H]+;
HPLC purity: 95%, tR =1.79 min (Method 4).
3-Phenylpiperidine (42.5 mg, 0.264 mmol) was added to a stirred
solution of 28 (70 mg, 0.22 mmol), TEA (0.061 mL, 0.44 mmol), EDC
(63 mg, 0.33 mmol), and HOBt (45 mg, 0.33 mmol) in CH2Cl2 (3 mL).
The mixture was stirred at room temperature for 8 h and then
washed with 1m K2CO3. The layers were separated by a phase sep-
arator cartridge and the organic layer was shaken overnight in the
presence of PS-isocyanate (240 mg, loading: 1.58 mmolgꢂ1). The
resin was filtered off and the solvent was evaporated in vacuo. The
crude product was purified using a SiO2 cartridge (CH2Cl2/MeOH/
NH4OH 98:2:0.2) and the resulting product was dissolved in CH2Cl2
and treated with HCl/Et2O for 2 h. The precipitate was filtered off
(E)-N-Hydroxy-3-{6-[(E)-3-(4-phenylpiperidin-1-yl)-3-oxo-1-
propen-1-yl]pyridin-2-yl}acrylamide hydrochloride (29 f): Com-
pound 29 f (yield 49%) was prepared by starting from the THP-
protected hydroxamic acid 28 and 4-phenylpiperidine according to
1
to give the title compound as its HCl salt (44.4 mg, 53%). H NMR
(300 MHz, [D6]DMSO, 353 K+TFA): d=7.86 (t, J=7.63 Hz, 1H), 7.70
(d, J=7.04 Hz, 1H), 7.55 (d, J=15.85 Hz, 1H), 7.48–7.54 (m, 1H),
7.48 (d, J=15.55 Hz, 1H), 7.46 (d, J=15.26 Hz, 1H), 7.27–7.38 (m,
4H), 7.16–7.28 (m, 1H), 7.01 (d, J=15.85 Hz, 1H), 4.12–4.45 (m,
2H), 3.04 (bs, 1H), 2.62–2.82 (m, 2H), 1.92–2.13 (m, 1H), 1.69–1.92
(m, 2H), 1.40–1.69 ppm (m, 1H); 13C NMR (75 MHz, [D6]DMSO): d=
164.24, 162.13, 152.96, 143.95, 139.99, 128.93 (4C), 127.68, 127.46,
127.03, 124.50, 124.30, 52.07, 48.60, 46.24, 43.69, 42.56, 31.98,
26.76, 25.43 ppm; HRMS-TOF (ESI): m/z [M+H]+ calcd for
C22H24N3O3: 378.1817, found: 378.1850; HPLC purity: 98%, tR =
1.83 min (Method 4).
1
the methodology described for the hydroxamic acid 29e. H NMR
(300 MHz, [D6]DMSO): d=7.90 (t, J=7.78 Hz, 1H), 7.77 (d, J=
7.04 Hz, 1H), 7.63 (d, J=15.55 Hz, 1H), 7.57 (d, J=7.34 Hz, 1H),
7.51 (d, J=15.26 Hz, 1H), 7.50 (d, J=15.55 Hz, 1H), 7.14–7.38 (m,
5H), 7.01 (d, J=15.26 Hz, 1H), 4.54–4.83 (m, 1H), 4.21–4.46 (m,
1H), 3.05–3.40 (m, 1H), 2.67–2.96 (m, 2H), 1.77–2.05 (m, 2H), 1.41–
1.74 ppm (m, 2H); LC–MS (ESI): m/z: 378 [M+H]+; HPLC purity:
99%, tR =1.81 min (Method 4).
(ꢃ)-(E)-N-Hydroxy-3-{6-[(E)-3-(3-phenylpiperazin-1-yl)-3-oxo-1-
propen-1-yl]pyridin-2-yl}acrylamide hydrochloride (29g): Com-
pound 29g (yield 28%) was prepared by starting from the THP-
protected hydroxamic acid 28 according to the methodology de-
(E)-N-Hydroxy-3-{6-[(E)-3-(4-methylpiperazin-1-yl)-3-oxo-1-
propen-1-yl]pyridin-2-yl}acrylamide (29a): Compound 29a
(55 mg, yield 78%) was prepared by starting from the THP-protect-
ed hydroxamic acid 28 and 1-methylpiperazine following the syn-
thetic procedure of the hydroxamic acid 29e. 1H NMR (300 MHz,
[D6]DMSO+TFA): d=10.68 (bs, 1H), 7.91 (t, J=7.78 Hz, 1H), 7.77
(d, J=7.34 Hz, 1H), 7.60 (d, J=15.26 Hz, 1H), 7.57–7.61 (m, 1H),
7.54 (d, J=15.26 Hz, 1H), 7.50 (d, J=15.55 Hz, 1H), 7.03 (d, J=
15.55 Hz, 1H), 4.32–4.69 (m, 2H), 3.38–3.72 (m, 3H), 2.94–3.27 (m,
3H), 2.81 ppm (s, 3H); LC–MS (ESI): m/z: 317 [M+H]+; HPLC purity:
98%, tR =0.81 min (Method 6).
1
scribed for the hydroxamic acid 29e. H NMR (300 MHz, [D6]DMSO,
353 K+Na2CO3): d=10.76 (bs, 1H), 8.82 (bs, 1H), 7.86 (t, J=
7.78 Hz, 1H), 7.67–7.76 (m, 1H), 7.56–7.64 (m, 2H), 7.29–7.57 (m,
7H), 7.05 (d, 1H), 4.29–4.64 (m, 2H), 4.05 (dd, J=10.86, 2.64 Hz,
1H), 3.39 (dd, J=10.71, 4.55 Hz, 1H), 3.21–3.32 (m, 1H), 2.92–
3.03 ppm (m, 2H); LC–MS (ESI): m/z: 379 [M+H]+; HPLC purity:
98%, tR =1.01 min (Method 4).
(ꢃ)-(E)-N-Hydroxy-3-{6-[(E)-3-(4-methyl-3-phenylpiperazin-1-yl)-
(E)-N-Hydroxy-3-{6-[(E)-3-(4-phenylpiperazin-1-yl)-3-oxo-1-
propen-1-yl]pyridin-2-yl}acrylamide (29b): Compound 29b (yield
50%) was prepared by starting from the THP-protected hydroxa-
3-oxo-1-propen-1-yl]pyridin-2-yl}acrylamide
hydrochloride
(29h): Compound 29h (yield 38%) was prepared by starting from
the THP-protected hydroxamic acid 28 according to the synthetic
ChemMedChem 2010, 5, 1359 – 1372
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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