Journal of Medicinal Chemistry
ARTICLE
starting material and 1,1-dichlorodimethyl ether was heated for 3 days at
50 °C in CDCl3. The volatile products (HCl and methyl formate) were
removed. Then 2 (1 equiv) in CDCl3 and NEt3 (2 equiv) were added to
the corresponding acid chloride. The new reaction mixture was stirred at
room temperature, and the reaction was complete within 5ꢀ10 min.
3-Iodo-N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-N-(pyridin-2-yl)
adamantane-1-carboxamide (6a). Starting with 5a (307 g, 1 mmol) and 2
(312 mg, 1 mmol) gave 212 mg (35%) of 6a as a colorless glass after column
chromatography (MeOH/CH2Cl2/NEt3, 1:1:0.01). 1H NMR (200.13
MHz, CDCl3): δ 1.60 (t, J = 15.7 Hz, 2H, 2 ꢁ CH), 1.80 (s, 4H, 2 ꢁ
CH2), 1.88 (bs, 2H, CH2), 2.42 (q, J = 11 Hz, 4H, 2 ꢁ CH2), 2.55ꢀ2.7 (m,
8H, N(CH2)3 and CH2), 2.83ꢀ2.90 (m, 4H, N(CH2)2), 3.72ꢀ3.92 (m,
5H, CH3 and NCH2), 6.75ꢀ6.98 (m, 4H, 2 ꢁ CH2), 7.18ꢀ7.32 (m, 2H, 2
ꢁ CH), 7.75 (dt, J = 7.6 Hz, 1H, CH), 8.45 (dd, J = 4.9 Hz, 1H, CH). 13C
NMR (50.32 MHz, CDCl3):δ32.29, 34.28, 37.87, 48.10, 48.19, 48.95, 50.44,
50.94, 53.34, 53.70, 55.18, 55.52, 110.98, 117.94, 120.75, 122.69, 122.86,
138.33, 141.10, 148.77, 152.04, 156.43, 176.03. HRMS (EI) m/z calcd for
C29H37IN4O2, 600.1961; found, 601.2028 (M þ H).
138.15, 141.02, 149.03, 152.03, 155.30, 173.25. HRMS (EI) m/z calcd
for C26H33IN4O2, 560.1648; found, 561.1720 (M þ H).
General Procedure for Synthesis of Compounds 7a, 7b, 7c,
7d. The acid chlorides of 5a, 5b, 5c, and 5d were synthesized as
mentioned above. Then 4 (0.5 equiv) and NEt3 (2 equiv) were dissolved
in CDCl3 or MeCN and added to the corresponding acid chloride. This
new mixture was stirred at room temperature for 10 min followed by
aminolysis in dioxane with 40% methylamine, unless otherwise indi-
cated. This reaction mixture was stirred at room temperature overnight.
N-(2-(4-(2-Hydroxyphenyl)piperazin-1-yl)ethyl)-4-iodo-N-(pyridin-
2-yl)adamantane-1-carboxamide (7a). Starting with 5a (612 mg, 2
mmol) and 4 (298 mg, 1 mmol) in CDCl3 (8 mL) gave a double
substituted compound. Then 40% methylamine (1 mL) in dioxane
(5 mL) was added, and this reaction mixture was stirred at room
temperature overnight to give 164 mg (28%) of 7a as a colorless glass
after column chromatography (CH2Cl2/AcOEt/NEt3, 2:1:0.01). 1H
NMR (250.13 MHz, CDCl3): δ 1.60 (t, J = 15.7 Hz, 2H, 2 ꢁ CH), 1.80
(s, 4H, 2 ꢁ CH2), 1.88 (bs, 2H, CH), 2.42 (q, J = 11 Hz, 4H, 2 ꢁ
NCH2), 2.55ꢀ2.70 (m, 8H, N(CH2)3 and CH2), 2.85ꢀ2.90 (m, 4H,
N(CH2)2), 3.85 (t, J = 7 Hz, 2H, NCH2), 6.80ꢀ6.98 (m, 2H, 2 ꢁ CH),
7.02ꢀ7.18 (m, 2H, 2 ꢁ CH), 7.26ꢀ7.37 (m, 2H, 2 ꢁ CH), 7.81 (dt, J =
7.6 Hz, 1H, CH), 8.54 (d, J = 4.9 Hz, 1H, CH). 13C NMR (50.32 MHz,
CDCl3): δ 32.28, 34.27, 37.88, 48.03, 48.21, 48.94, 50.93, 52.32,
53.77, 55.47, 113.86, 119.82, 121.19, 122.55, 122.91, 126.20, 138.40,
138.78, 148.84, 151.27, 156.39, 176.26. HRMS (EI) m/z calcd for
C28H35IN4O2, 586.1805; found, 587.1870 (M þ H).
4-Iodo-N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-N-(pyridin-2-yl)
bicyclo[2.2.2]octane-1-carboxamide (6c). Starting with 5c (280 mg, 1
mmol) and 2 (312 mg, 1 mmol) gave 151 mg (26%) of 6c as a colorless
glass after column chromatography (MeOH/CH2Cl2/NEt3, 1:1:0.01). 1H
NMR (250.13 MHz, CDCl3): δ 1.75ꢀ1.81 (m, 6H, 3 ꢁ CH2), 2.28ꢀ2.34
(m, 6H, 3 ꢁ CH2), 2.55ꢀ2.68 (m, 6H, N(CH2)3), 2.90ꢀ3.09 (m, 4H,
N(CH2)2), 3.72ꢀ3.90 (m, 5H, CH3 and NCH2), 6.77ꢀ7.04 (m, 4H, 4 ꢁ
CH), 7.19ꢀ7.32 (m, 2H, 2 ꢁ CH), 7.74 (dt, J = 7.6 Hz, 1H, CH), 8.51 (d, J
= 4.9 Hz, 1H, CH). 13C NMR (62.90 MHz, CDCl3): δ 32.70, 38.90, 40.19,
43.93, 48.90, 50.51, 53.39, 55.25, 55.59, 111.19, 117.98, 120.85, 122.71,
122.99, 125.25, 138.25, 141.24, 148.90, 152.15, 156.61, 177.31. HRMS (EI)
m/z calcd for C27H35IN4O2, 574.1805; found, 575.1887 (M þ H).
General Procedure for Synthesis of Compounds 6b and
6d. Target compounds were synthesized in a two-step reaction using
thionyl chloride (1 equiv). The reaction mixture was refluxed at 70 °C in
dry MeCN (4 mL) under argon atmosphere for 45 min to 1 h, and the
excess thionyl chloride was totally evaporated under reduced pressure,
then coevaporated with MeCN (3 ꢁ 1 mL). Compound 2 (1 equiv) in
dry MeCN and NEt3 (2 equiv) was added to the corresponding acid
chloride. The new reaction mixture was stirred at room temperature
overnight. The residue was dissolved in water and extracted with
CH2Cl2. The organic phase was collected, dried over anhydrous
Na2SO4, and the solvent was evaporated under reduced pressure.
4-Iodo-N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-
N-(2-(4-(2-Hydroxyphenyl)piperazin-1-yl)ethyl)-4-iodo-N-(pyridin-
2-yl)cubyl-1-carboxamide (7b). Starting with 5b (200 mg, 0.730 mmol)
and 4 (238 mg, 0.798 mmol) in MeCN (8 mL) gave a double substituted
7b. This compound was then dissolved in water and basified MeCN
(4 mL) with NEt3 (1 equiv) and heated for 2 h at 50 °C. Then MeCN
was evaporated and the water layer was extracted with CH2Cl2 (3 ꢁ
1 mL). The collected organic layers were dried over Na2SO4, and the
solvent was evaporated in vacuo. Column chromatography (AcOEt/
NEt3, 99%, 0.01) gave 238 mg (54%) of 7b as a colorless glass. 1H NMR
(200.13 MHz, CDCl3): δ 2.20ꢀ3.00 (m, 10H, N(CH2)3 and N-
(CH2)2), 3.6ꢀ4.10 (m, 8H, 6 ꢁ CH and NCH2), 6.69ꢀ7.29 (m, 6H,
6 ꢁ CH), 7.7 (dt, J = 7.4, 1H, CH), 8.4 (dd, J = 4.9, 1H, CH). 13C NMR
(50.32 MHz, CDCl3) δ 36.10, 45.16, 51.10, 52.32, 53.65, 54.43,
55.89, 60.02, 113.87, 119.24, 119.82, 121.14, 121.74, 126.27, 138.16,
138.72, 148.91, 151.28, 154.60, 171.15. HRMS (EI) m/z calcd for
C26H27IN4O2, 554.1179; found, 555.1243 (M þ H).
N-(pyridin-2-yl)cubyl-1-carboxamide (6b). Starting with 5b (300 mg,
1.09 mmol) and 2 (346 mg, 1.11 mmol) gave 441 mg (70%) of 6b as a
colorless glass after column chromatography (AcOEt/NEt3, 1:0.01). 1H
NMR (200.13 MHz, CDCl3): δ 2.60ꢀ2.90 (m, 6H, N(CH2)3),
2.95ꢀ3.07 (m, 4H, N(CH2)2), 3.81 (s, 3H, CH3), 3.97ꢀ4.20 (m, 8H,
6 ꢁ CH and NCH2), 6.79ꢀ7.05 (m, 4H, 4 ꢁ CH), 7.15ꢀ7.30 (m, 2H, 2
ꢁ CH), 7.77 (dt, J = 7.6 Hz, 1H, CH), 8.4 (dd, J = 4.9, 1H, CH). 13C
NMR (50.32 MHz, CDCl3): δ 35.62, 44.62, 49.81, 51.08, 53.07, 54.42,
55.20, 55.58, 59.09, 110.98, 118.04, 119.35, 120.79, 121.87, 123.00,
138.31, 140.62, 148.83, 151.97, 154.85, 171.17. HRMS (EI) m/z calcd
for C27H29IN4O2, 568.1335; found, 569.1412 (M þ H).
N-(2-(4-(2-Hydroxyphenyl)piperazin-1-yl)ethyl)-4-iodo-N-(pyridin-
2-yl)bicyclo[2.2.2]octane-1-carboxamide (7c). Starting with 5c (440
mg, 1.57 mmol) and 4 (234 mg, 0.785 mmol) in CDCl3 (8 mL) gave a
double substituted compound. Then 40% methylamine (2.5 mL) in
dioxane (5 mL) was added, and this reaction mixture was stirred at room
temperature overnight to give 167 mg (38%) of 7c as a colorless glass
after column chromatography (CH2Cl2/AcOEt/NEt3, 5:1:0.01). 1H
NMR (250.13 MHz, CDCl3): δ 1.70ꢀ1.85 (m, 6H, 3 ꢁ CH2),
2.22ꢀ2.38 (m, 6H, 3 ꢁ CH2), 2.59ꢀ2.66 (m, 6H, N(CH2)3),
2.75ꢀ2.86 (m, 4H, N(CH2)2), 3.72ꢀ3.82 (m, 2H, NCH2),
6.79ꢀ6.96 (m, 2H, 2 ꢁ CH), 7.01ꢀ7.16 (m, 2H, 2 ꢁ CH),
7.20ꢀ7.33 (m, 2H, 2 ꢁ CH), 7.78 (dt, J = 7.6 Hz, 1H, CH), 8.53 (d,
J = 4.9 Hz, 1H, CH). 13C NMR (62.90 MHz, CDCl3): δ 32.70, 38.93,
40,16, 43.76, 48.93, 52.39, 53.82, 55.49, 113.94, 119.86, 121.17, 122.78,
122.86, 126.29, 138.34, 138.82, 148.98, 151.36, 156.54, 177.40. HRMS
(EI) m/z calcd for C26H33IN4O2, 560.1648; found, 561.1717 (M þ H).
N-(2-(4-(2-Hydroxyphenyl)piperazin-1-yl)ethyl)-4-iodo-N-(pyridin-
2-yl)bicyclo[2.2.1]heptane-1-carboxamide (7d). Starting with 5d (50
mg, 0.188 mmol) and 4 (28 mg, 0.094 mmol) in dry MeCN (5 mL) gave
a double acylated 7d. The double acylated product was then dissolved in
a mixture of MeOH (4 mL), saturated NaHCO3 (1 mL), and water
(1 mL). The reaction mixture was heated for 2 h at 50 °C. Then MeOH
4-Iodo-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, 0.19 mmol) and 2 (65 mg, 0.21 mmol) gave 94 mg
(80%) of 6d as a colorless glass after column chromatography (MeOH/
CH2Cl2/NEt3, 1:1:0.01). 1H NMR (200.13 MHz, CDCl3): δ1.00ꢀ1.35
(m, 2H, CH2), 1.62ꢀ2.25 (m, 8H, 4 ꢁ CH2), 2.4ꢀ2.79 (m, 6H,
N(CH2)3), 2.80ꢀ3.15 (m, 4H, N(CH2)2), 3.69ꢀ4.00 (m, 5H, CH3 and
NCH2), 6.75ꢀ7.05 (m, 4H, 4 ꢁ CH), 7.18ꢀ7.39 (m, 2H, 2 ꢁ CH),
7.75 (dt, J = 7.6 Hz, 1H, CH), 8.5 (dd, J = 4.9 Hz, 1H, CH). 13C NMR
(50.32 MHz, CDCl3): δ 34.95, 36.37, 43.46, 47.10, 50.36, 52.82, 53.22,
54.58, 55.18, 55.43, 110.98, 117.92, 120.75, 122.74, 123.06, 123.25,
3487
dx.doi.org/10.1021/jm1009956 |J. Med. Chem. 2011, 54, 3480–3491