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Y. Uto et al. / European Journal of Medicinal Chemistry 45 (2010) 4788e4796
strong enzymatic inhibitory activity (IC50 (mouse) ¼ 2 nM) and
good oral bioavailability (F >95%). Easier synthetic accessibility of
10e has turned it to an attractive alternative to 10c, which was
previously reported as a highly potent SCD1 inhibitor. With regard
to the pharmacological evaluation, 10e demonstrated striking
reduction of the desaturation index in a dose-dependent manner in
the plasma of C57BL/6J mice on a high carbohydrate diet after a 7-
day oral administration (q.d.). In addition, it did not cause noticeable
abnormalities in the skin up to the highest dose (10 mg/kg). Further
pharmacological evaluation and toxicological analysis of the spi-
ropiperidine-based SCD1 inhibitors will be reported in the future.
provided 84.8 mg of 10b (52%) as a colorless solid. Mp 192e193 ꢁC.
1H NMR (400 MHz, CDCl3):
8.67 (1H, d, J ¼ 2.0 Hz), 8.57 (1H, dd,
d
J ¼ 4.7 and 1.6 Hz), 8.03 (1H, d, J ¼ 9.4 Hz), 7.77 (1H, d, J ¼ 7.8 Hz),
7.30 (1H, dd, J ¼ 8.1 and 4.9 Hz), 7.02 (1H, d, J ¼ 9.8 Hz), 6.93e6.87
(1H, m), 6.57e6.52 (1H, m), 4.41e4.38(2H, m), 4.33 (2H, s),
3.63e3.55 (2H, m), 2.79 (2H, t, J ¼ 6.9 Hz), 2.03e2.00 (2H, m), 1.87
(2H, t, J ¼ 6.9 Hz), 1.76e1.68 (2H, m). IR (KBr, cmꢀ1): 3067, 2926,
2859, 1592, 1488, 1447, 1262, 1236. MS (ESI) m/z: 477(M þ H)þ;
HRMS (ESI) m/z: 477.1852 (calcd for C25H23F2N6O2 477.1851). Anal.
Calcd for C25H22F2N6O2: C, 63.02; H, 4.65; N, 17.64; F, 7.97. Found: C,
62.86; H, 4.66; N, 17.48; F, 8.04.
5. Experimental
5.1.2.3. 10-{6-[5-(Pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-
3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,40-piperidine]
(10c). In accordance with the general procedures (Section 5.1.2), 13c
(554 mg, 1.80 mmol) and 19b (465 mg, 1.70 mmol) provided 587 mg
(68%) of 10c as a white solid. Mp 217e218 ꢁC (iPrOH). 1H NMR
5.1. Chemistry
5.1.1. General procedures
All melting points were measured with a Mettler Toledo Thermo
System FP8HT and are uncorrected. The IR spectra were measured
with a JEOL FT/IR 6100 spectrophotometer, and the peaks were
(400 MHz, DMSO-d6):
d
8.65 (1H, d, J ¼ 2.4 Hz), 8.54 (1H, dd, J ¼ 4.7
and 1.5 Hz), 7.99 (1H, d, J ¼ 9.8 Hz), 7.84 (1H, d, J ¼ 7.8 Hz), 7.47 (1H, d,
J ¼ 9.8 Hz), 7.43 (1H, dd, J ¼ 7.8 and 4.7 Hz), 7.33 (1H, t, J ¼ 8.0 Hz),
7.27 (1H, d, J ¼ 6.7 Hz), 7.17 (1H, d, J ¼ 8.3 Hz), 4.47 (2H, s), 4.30e4.26
(2H, m), 3.54e3.48 (2H, m), 2.89 (2H, t, J ¼ 6.6 Hz), 1.91 (2H, t,
J ¼ 6.6 Hz), 1.86e1.83 (2H, m), 1.77e1.70 (2H, m). IR (KBr, cmꢀ1):
3065, 2958, 2851, 1594, 1463, 1431, 1320, 1258. MS (ESI) m/z: 509
(M þ H)þ; HRMS (ESI) m/z: 509.1915 (calcd for C26H24F3N6O2
509.1913). Anal. Calcd for C26H23F3N6O2: C, 61.41; H, 4.56; N, 16.53; F,
11.21. Found: C, 61.33; H, 4.62; N, 16.45; F, 11.37.
recorded in cmꢀ1 1H NMR spectra were recorded on a Varian
.
Mercury 400 or 500 spectrometer with tetramethylsilane as an
internal reference. The mass spectra (low- or high-resolution mass)
spectroscopy was carried out with a JEOL GCmate, JEOL JMS-700
mass spectrometer or JEOL T100LC (AccuTOF). Thin-layer chroma-
tography (TLC) was used routinely to monitor the progress and the
purity of the compounds and was performed on Merck Kieselgel 60
F254 plates (0.25 mm thickness). For the flash column chromatog-
raphy, silica gel (Kieselgel 60, 230e400 mesh) or pre-packed silica
gel column (KP-SilÔ silica) from Biotage was employed. The
o-hydroxyacetophenones (11eef) were commercially available. The
experimental procedures for the preparation of the intermediates
in Schemes 1 and 2 are described in Supplementary data.
5.1.2.4. 5-Methyl-10-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]
pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,40-piperidine]
(10d). In accordance with the general procedures (Section
5.1.2), 13d (254 mg, 1.00 mmol) and 19b (274 mg, 1.00 mmol)
provided 387 mg of 10d (58%) as a white solid. Mp 194e195 ꢁC.
1H NMR (400 MHz, DMSO-d6):
d 8.63 (1H, s), 8.52 (1H, d,
5.1.2. General synthetic procedures to obtain spiropiperidine-based
SCD1 inhibitor (10aef, 22e24) from spiropiperidine (13aef) and
chloropyridazine (19aec, 21)
A mixture of spiropiperidine (13, 1 equiv), chloropyridazine (19
or 21,1 equiv), and triethylamine (2 equiv) in n-BuOH was heated at
100 ꢁC for 2 days, cooled to room temperature, and concentrated.
Chromatography of the residue on SiO2 (Chromatorex NH Fuji
Silysia Chemical Ltd. 200e300 mesh, CH2Cl2/EtOAc 1:0 to 3:1) gave
the desired product (10, 22, 23, or 24). The product was further
purified by recrystallization when necessary.
J ¼ 4.7 Hz), 7.95 (1H, d, J ¼ 9.4 Hz), 7.83e7.80 (1H, m), 7.43 (1H,
d, J ¼ 9.7 Hz), 7.41e7.39 (1H, m), 6.97 (1H, dd, J ¼ 7.6 and
7.6 Hz), 6.71 (1H, d, J ¼ 7.0 Hz), 6.66 (1H, d, J ¼ 8.2 Hz), 4.45(2H,
s), 4.28e4.21 (2H, m), 3.49e3.43 (2H, m), 2.60 (2H, t,
J ¼ 6.9 Hz), 2.17 (3H, s), 1.83 (2H, t, J ¼ 6.9 Hz), 1.82e1.78 (2H,
m), 1.69e1.62 (2H, m). IR (KBr, cmꢀ1): 3068, 2953, 2924, 2847,
1594, 1536, 1466, 1429, 1250; MS (ESI) m/z: 455 (M þ H)þ;
HRMS (ESI) m/z: 455.2189 (calcd for C26H27N6O2 455.2196).
Anal. Calcd for C25H22F2N6O2: C, 68.70; H, 5.77; N, 18.49.
Found: C, 68.42; H, 5.75; N, 18.42.
5.1.2.1. 5-Chloro-10-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]
pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,40-piperidine]
(10a). In accordance with the general procedures (Section 5.1.2),
13a (29.2 mg, 0.123 mmol) and 19b (28.0 mg, 0.102 mmol)
provided 31.0 mg of 10a (64%) as a yellow amorphous. 1H NMR
5.1.2.5. 5-Fluoro-10-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]
pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,40-piperidine] (10e). In
accordance with the general procedures (Section 5.1.2), 13e
(541 mg, 2.11 mmol) and 19b (547 mg, 2.00 mmol) provided
682 mg of 10e (74%) as a pale pink solid. Mp 183e185 ꢁC
(500 MHz, DMSO-d6):
d
8.64 (1H, d, J ¼ 2.0 Hz), 8.53 (1H, dd, J ¼ 4.3
(CH3CN/iPr2O). 1H NMR (400 MHz, DMSO-d6):
d 8.65 (1H, d,
and 1.4 Hz), 7.97 (1H, d, J ¼ 9.8 Hz), 7.82 (1H, d, J ¼ 7.8 Hz), 7.45 (1H,
d, J ¼ 9.7 Hz), 7.42 (1H, dd, J ¼ 7.8 and 4.8 Hz), 7.14 (1H, t, J ¼ 8.0 Hz),
7.00 (1H, d, J ¼ 7.8 Hz), 6.85 (1H, d, J ¼ 7.3 Hz), 4.46 (2H, s),
4.29e4.24 (2H, m), 3.52e3.45 (2H, m), 2.73 (2H, t, J ¼ 6.6 Hz), 1.89
(2H, t, J ¼ 6.8 Hz), 1.85e1.80 (2H, m), 1.74e1.68 (2H, m). IR (KBr,
cmꢀ1): 3064, 2953, 2846, 1595, 1446, 1430, 1248. MS (ESI) m/z: 475
(M þ H)þ; HRMS (ESI) m/z: 475.1646 (calcd for C25H24ClN6O2
475.1649). Anal. Calcd for C25H23ClN6O2: C, 63.22; H, 4.88; N, 17.69;
Cl, 7.46. Found: C, 63.08; H, 4.83; N, 17.55; Cl, 7.47.
J ¼ 2.0 Hz), 8.54 (1H, dd, J ¼ 4.9 and 1.3 Hz), 7.99 (1H, d,
J ¼ 9.8 Hz), 7.84 (1H, d, J ¼ 7.9 Hz), 7.47 (1H, d, J ¼ 9.3 Hz), 7.43
(1H, dd, J ¼ 7.7 and 4.9 Hz), 7.14 (1H, dd, J ¼ 15.3 and 7.8 Hz),
6.73e6.69 (2H, m), 4.47 (2H, s), 4.30e4.20 (2H, m), 3.52e3.42
(2H, m), 2.71 (2H, t, J ¼ 6.4 Hz), 1.87(2H, t, J ¼ 7.0 Hz), 1.87e1.83
(2H, m), 1.75e1.68 (2H, m). IR (KBr, cmꢀ1): 3057, 2948, 2866,
1593, 1467, 1446, 1254. MS (ESI) m/z: 459 (M þ H)þ; HRMS
(ESI) m/z: 459.1936 (calcd for C25H24FN6O2 459.1945). Anal.
Calcd for C25H23FN6O2: C, 65.49; H, 5.06; N, 18.33; F, 4.14.
Found: C, 65.31; H, 5.12; N, 18.23; F, 4.02.
5.1.2.2. 5,8-Difluoro-10-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-
2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,40-piperidine]
(10b). In accordance with the general procedures (Section 5.1.2),
13b (97.2 mg, 0.353 mmol) and 19b (93.7 mg, 0.342 mmol)
5.1.2.6. 10-{6-[5-(Pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyr-
idazin-3-yl}-3,4-dihydrospiro[chromene-2,40-piperidine]
(10f). In
accordance with the general procedures (Section 5.1.2),13f (791 mg,