R. Al Hussainy et al. / European Journal of Medicinal Chemistry 46 (2011) 5728e5735
5733
The reaction mixture was refluxed at 70 ꢁC in MeCN for 45 min to
1 h and the excess of thionyl chloride was totally evaporated at
room temperature (because of volatility of the acid chlorides)
under reduced pressure, then co-evaporated with MeCN. After-
ward, WAY-100634 (1 equivalent) in MeCN and NEt3 (2 equiva-
lents) were added to the corresponding acid chloride and stirred at
room temperature for 1 h. The solvent was evaporated and the
residue was dissolved in water and extracted with CH2Cl2. The
organic phase was collected, dried over anhydrous Na2SO4 and
evaporated to dryness.
J ¼ 48 Hz, 2H, CH2F), 6.78e7.08 (m, 4H, 4ꢃ CH), 7.20e7.40 (m, 2H,
2ꢃ CH), 7.75 (dt, J ¼ 7.4 Hz, 1H, CH), 8.52 (dd, J ¼ 4.9 Hz, 1H, CH). 13C
NMR (50.32 MHz, CDCl3):
d 31.42, 31.50, 34.15, 44.77, 44.85, 46.98,
47.29, 50.36, 53.24, 55.16, 55.48, 55.69, 84.92, 88,53, 110.98, 117.93,
120.75, 122.72, 122.89, 123.56, 137.97, 141.05, 148.98, 152.03, 155.53,
175.42. HRMS (EI) m/z calcd for C27H35FN4O2; 466.2744; found:
467.2811 (M þ H), tR: 16.6 min.
8.1.2. General procedure for synthesis of compounds 7a, 7b, 7c and
7d
The acid chlorides of 5aed were synthesized as mentioned
above. Then O-desmethyl WAY-100634 (0.5 equivalent) and NEt3
(2 equivalents) were dissolved in MeCN and added to the corre-
sponding acid chloride. This new reaction mixture was stirred at
room temperature for 30 min. Then the solvent was evaporated, the
residue was dissolved in a mixture of MeOH/saturated NaHCO3/
H2O (2/1/1) and heated at 50 ꢁC for 2 h, unless stated otherwise. The
solution was evaporated and the residue was dissolved in water,
extracted with EtOAc, unless noted otherwise, dried over Na2SO4,
filtered and evaporated to dryness.
8.1.1.1. 4-(Fluoromethyl)-N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)
ethyl)-N-(pyridin-2-yl)adamantane-1-carboxamide
(6a). Starting
with 5a (50 mg, 0.24 mmol) and WAY-100634 (73.8 mg, 0.24 mmol)
gave 116 mg (95%) of 6a as colorless glass after column chroma-
tography (EtOAc/NEt3, 1/0.01). 1H NMR (400.13 MHz, CDCl3):
d
1.28e1.44 (m, 4H, 2ꢃ CH2), 1.48e1.55 (m, 4H, 2ꢃ CH2), 1.67 (q,
J ¼ 12 Hz, 4H, 2ꢃ CH2), 1.95 (s, 2H, 2ꢃ CH), 2.64 (m, 6H, N(CH2)3),
2.90e3.10 (m, 4H, N(CH2)2), 3.80e3.86 (m, 5H, CH3, NCH2), 3.84 (d,
J ¼ 49 Hz, 2H, CH2F), 6.81e7.01 (m, 4H, 4ꢃ CH), 7.23e7.37 (m, 2H,
2ꢃ CH), 7.75 (dt, J ¼ 7.6 Hz, 1H, CH), 8.50 (d, J ¼ 4.9 Hz, 1H, CH). 13C
NMR (100.61 MHz, CDCl3):
d
28.07, 34.62, 34.79, 35.74, 37.02, 37.06,
8.1.2.1. 4-(Fluoromethyl)-N-(2-(4-(2-hydroxyphenyl)piperazin-1-yl)
39.34, 40.56, 40.61, 44.27, 49.06, 50.61, 53.51, 55.33, 55.76, 91.33,
93.05, 111.25, 118.08, 120.94, 122.79, 123.13, 126.11, 138.23, 141.35,
148.85,152.24,156.88,178.13. HRMS (EI) m/z calcd for C30H39FN4O2;
506.3057; found: 507.3127 (M þ H), tR: 48.8 min.
ethyl)-N-(pyridin-2-yl)adamantane-1-carboxamide
(7a). Starting
with 5a (50 mg, 0.24 mmol) and O-desmethyl WAY-100634 (35 mg,
0.12 mmol) in MeCN (4 mL) gave after column chromatography
(EtOAc/Hexane, 5/2) 47 mg (80%) of 7a as colorless glass. 1H NMR
(400.13 MHz, CDCl3):
d
1.30e1.80 (m, 12H, 6ꢃ CH2), 2.09 (s, 2H, 2ꢃ
8.1.1.2. 4-(Fluoromethyl)-N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)
ethyl)-N-(pyridin-2-yl)cubane-1-carboxamide (6b). Starting with
5b (300 mg, 1.09 mmol) and WAY-100634 (346 mg, 1.11 mmol)
gave 441 mg (84%) of 6b as colorless glass after column chroma-
tography (EtOAc/NEt3, 1/0.01). 1H NMR (200.13 MHz, CDCl3):
CH), 2.60e2.72 (m, 6H, N(CH2)3), 2.79e2.89 (m, 4H, N(CH2)2),
3.83e3.90 (m, 2H, N(CH2)), 3.86 (d, J ¼ 50 Hz, 2H, CH2F), 6.72e6.89
(m, 2H, 2ꢃ CH), 6.94e7.08 (m, 2H, 2ꢃ C), 7.17e7.25 (m, 2H, 2ꢃ CH),
7.70 (dt, J ¼ 7.6 Hz, 1H, CH), 8.44 (d, J ¼ 4.9 Hz, 1H, CH). 13C NMR
(62.90 MHz, CDCl3):
d 28.10, 34.61, 34.89, 35.91, 37.21, 37.28, 39.39,
d
2.46e3.20 (m, 10H, N(CH2)3 and N(CH2)2), 3.51e3.85 (m, 9H, 6ꢃ
40.62, 40.70, 44.33, 49.10, 52.54, 53.98, 55.73, 90.86, 93.59, 114.04,
119.99, 121.34, 122.85, 123.02, 126.39, 138.20, 139.02, 148.95, 151.52,
156.90, 178.27. HRMS (EI) m/z calcd for C29H37FN4O2; 492.2901;
found: 493.297 (M þ H), tR: 24.9 min.
CH and CH3), 3.90e4.12 (m, 2H, NCH2), 4.40 (d, J ¼ 48 Hz, 2H,
CH2F), 6.70e7.05 (m, 4H, 4ꢃ CH), 7.15e7.30 (m, 2H, 2ꢃ CH), 7.60
(dt, J ¼ 7.6 Hz, 1H, CH), 8.50 (dd, J ¼ 4.9 Hz, 1H, CH). 13C NMR
(50.32 MHz, CDCl3):
d 43.63, 43.83, 44.98, 47.34, 50.42, 53.18,
54.55, 54.96, 55.14, 56.01, 59.34, 81.13, 84.41, 110.96, 117.87, 119.93,
120.72, 121.61, 122.65, 137.96, 141.09, 148.79, 152.01, 155.23, 171.49.
HRMS (EI) m/z calcd for C28H31FN4O2; 474.2431; found: 475.2505
(M þ H), tR: 15.8 min.
8.1.2.2. 4-(Fluoromethyl)-N-(2-(4-(2-hydroxyphenyl)piperazin-1-yl)
ethyl)-N-(pyridin-2-yl)cubane-1-carboxamide (7b). Starting with 5b
(50 mg, 0.27 mmol) and O-desmethyl WAY-100634 (41 mg,
0.14 mmol) in MeCN (4 mL) gave after column chromatography
(EtOAc/MeOH,1/0.1 to only EtOAc) 38 mg (59%) of 7b as white solid.
8.1.1.3. 4-(Fluoromethyl)-N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)
ethyl)-N-(pyridin-2-yl)bicyclo[2.2.2]octane-1-carboxamide
1H NMR (400.13 MHz, CDCl3):
d 2.50e2.90 (m, 10H, N(CH2)3 and
N(CH2)2), 3.60e3.89 (m, 6H, 6ꢃ CH), 4.05e4.12 (m, 2H, NCH2), 4.46
(d, J ¼ 4.9 Hz, 2H, CH2F), 6.80e7.30 (m, 6H, 6ꢃ CH), 7.81 (dt,
J ¼ 7.6 Hz, 1H, CH), 8.54 (d, J ¼ 4.9 Hz, 1H, CH). 13C NMR
(6c). Starting with 5c (25 mg, 0.13 mmol) and WAY-100634 (42 mg,
0.13 mmol) gave 38 mg (61%) of 6c after column chromatography
(EtOAc/MeOH, 1/0.07). 1H NMR (400.13 MHz, CDCl3):
d
1.23e1.40
(100.61 MHz, CDCl3): d 43.91, 44.01, 45.17, 47.58, 52.53, 53.81, 54.91,
(m, 6H, 3ꢃ CH2), 1.58e1.73 (m, 6H, 3ꢃ CH3), 2.60e2.70 (m, 6H,
N(CH2)3), 3.03 (bs, 4H, N(CH2)2), 3.82e3.91 (m, 5H, CH3 and NCH2),
3.93 (d, J ¼ 49 Hz, 2H, CH2F), 6.83e7.02 (m, 4H, 4ꢃ CH), 7.24e7.32
(m, 2H, 2ꢃ CH), 7.77 (dt, J ¼ 7.6 Hz, 1H, CH), 8.52 (d, J ¼ 4.9 Hz, 1H,
55.11, 56.16, 59.58, 82.15, 83.79, 114.04, 119.96, 121.28, 121.75,
126.37, 138.11, 138.98, 140.46, 149.07, 151.49, 155.48, 171.75. HRMS
(EI) m/z calcd for C27H29FN4O2; 460.2275; found: 461.2344 (M þ H),
tR: 11.6 min.
CH). 13C NMR (100.61 MHz, CDCl3):
d 26.95, 27.00, 28.60, 32.28,
32.46, 42.44, 48.88, 50.58 53.48, 55.35, 55.71, 89.85, 91.54, 111.27,
118.11, 120.96, 122.66, 122.82, 123.44, 138.20, 141.36, 149.00, 152.27,
156.88, 178.05. HRMS (EI) m/z calcd for C28H37FN4O2; 480.2901;
found: 481.2967 (M þ H), tR: 23.6 min.
8.1.2.3. 4-(Fluoromethyl)-N-(2-(4-(2-hydroxyphenyl)piperazin-1-yl)
ethyl)-N-(pyridin-2-yl)bicyclo[2.2.2]octane-1-carboxamide
(7c). Starting with 5c (50 mg, 0.27 mmol) and O-desmethyl WAY-
100634 (35 mg, 0.13 mmol) in MeCN (4 mL) gave after column
chromatography (EtOAc) 20 mg (33%) of 7c as colorless glass. 1H
8.1.1.4. 4-(Fluoromethyl)-N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)
ethyl)-N-(pyridin-2-yl)bicyclo[2.2.1]heptane-1-carboxamide
(6d). Starting with 5d (50 mg, 0.29 mmol) and WAY-100634
(90.48 mg, 0.29 mmol) gave 88 mg (65%) of 6c after column chro-
matography (EtOAc/MeOH, 1/0.07). 1H NMR (250.13 MHz, CDCl3):
NMR (400.13 MHz, CDCl3):
d
1.20e1.38 (m, 6H, 3ꢃ CH2), 1.59e1.74
(m, 6H, 3ꢃ CH2), 2.49e2.72 (m, 6H, N(CH2)3), 2.74e2.90 (m, 4H,
N(CH2)2), 3.83e3.90 (m, 2H, CH2), 4.00 (d, J ¼ 49 Hz, 2H, CH2F),
6.79e7.17 (m, 4H, 4ꢃ CH), 7.23e7.31 (m, 2H, 2ꢃ CH), 7.77 (dt,
J ¼ 7.6 Hz, 1H, CH), 8.50 (d, J ¼ 4.9 Hz, 1H, CH). 13C NMR
d
1.10e1.40 (m, 4H, 2ꢃ CH2), 1.40e1.70 (m, 4H, 2ꢃ CH2), 1.78e1.98
(100.61 MHz, CDCl3): d 26.95, 26.99, 28.62, 32.29, 32.47, 42.47,
(m, 2H, CH2), 2.50e2.75 (m, 6H, N(CH2)3), 2.80e3.10 (m, 4H,
N(CH2)2), 3.88 (s, 3H, CH3), 3.90e3.40 (m, 2H, NCH2), 4.33 (d,
48.94, 52.32, 53.95, 55.65, 89.83, 91.53, 114.02, 119.97, 121.34,
122.71, 123.31, 126.42, 138.26, 138.96, 149.08, 151.51, 156.86, 178.06.