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S. El Kazzouli et al. / European Journal of Medicinal Chemistry 46 (2011) 4252e4257
(40 mg, 0.39 mmol) were added at 0 ꢀC then the reaction mixture
was stirred for 3 h at room temperature. The mixture was
hydrolysed with 10% solution of sodium bicarbonate then
extracted with dichloromethane. The organic layer was dried over
MgSO4, concentrated under vacuum then purified by column
chromatography on silica gel (MeOH/CH2Cl2, 2/98, v/v) to give
the desired product (72 mg) as a yellow solid in 52% yield after
three steps (starting from alcohol 10). mp: 197e198 ꢀC. IR (KBr,
62.6, 65.6, 105.8, 114.8, 117.8, 119.6, 127.6, 128.5, 128.9, 135.1, 142.4,
144.9, 148.9, 167.0, 170.6. HRMS calcd for
453.1900 found 453.1920.
C
24H27N3O6 (Mþ)
5.1.16. 3-[2-acetamido-2-ethoxycarbonylethyl]-6-methoxy-2-
phenylimidazoimidazo[1,2-a]pyridine 17
To a solution of diester 16 (270 mg, 0.60 mmol) in 10 ml of DMF,
H2O (200 ml) and LiBr (103 mg, 1.20 mmol) were added then the
cmꢂ1): 3216, 1163. 1H NMR (CDCl3)
d
1.94 (t, 3H, J ¼ 6.0, Hz,
reaction mixture was stirred at 150 ꢀC for 6 h. The solvent was
evaporated and the residue was dissolved in ethyl acetate, washed
with a solution of NaCl, dried over MgSO4 and concentrated. The
residue was purified by column chromatography on silica gel
(CH2Cl2/MeOH, 97/3, v/v) to give the desired product as a yellow oil
(150 mg, 66% yield). IR (KBr, cmꢂ1): 3370, 1746, 1662. 1H NMR
NHCOCH3), 3.28e3.33 (m, 2H, NHCH2CH2eAr), 3.44e3.50 (m, 2H,
NHCH2CH2eAr), 3.93 (s, 3H, OCH3), 6.06 (m, 1H, NH), 6.99 (dd,
J ¼ 2.2, 9.8 Hz, 1H, H7), 7.31e7.51 (m, 4H, HAr), 7.71e7.74 (m, 2H,
HAr), 8.04 (d, J ¼ 2.2 Hz, 1H, H5). 13C NMR (CDCl3)
d 23.3, 24.5, 37.7,
56.6, 105.7, 117.7, 118.2, 119.7, 127.6, 128.1, 128.8, 135.0, 142.1, 143.2,
149.7, 171.0. HRMS calcd for C18H19N3O2 (Mþ) 309.1477 found
309.1480.
(CDCl3)
d
0.90 (t, J ¼ 7.1 Hz, 3H, CH2CH3), 1.90 (s, 3H, COCH3), 3.52
(m, 1H, CH2ACH3), 3.65 (d, 2H, J ¼ 6.9 Hz, 3H, CH2), 3.88 (m, 1H,
CH2BCH3), 3.92 (s, 3H, OCH3), 4.78 (dd, J ¼ 6.8, 6.9 Hz, 2H, CH), 6.45
(d, J ¼ 6.8 Hz,1H, NH), 7.01 (dd, J ¼ 2.0,10,0 Hz,1H, HAr), 7.31 (m, 1H,
HAr), 7.41 (m, 2H, HAr), 7.50 (d, J ¼ 9.9 Hz, 1H, H8), 7.60 (m, 2H, HAr),
5.1.13. 3-(N,N-Dimethylaminomethyl)-6-methyl-2-phenylimidazo
[1,2-a]pyridine 14
To a solution of 3 (700 mg, 3.12 mmol) in 11 ml of acetonitrile,
Eschenmoser salt (751 mg, 4.06 mmol) was added then the reaction
mixture was stirred at 70 ꢀC for 1 h then one overnight at room
temperature. The solvent was evaporated then the residue was
dissolved in ethyl acetate, washed with a 1N solution of NaOH then
dried over MgSO4. The organic layer was evaporated to lead to
compound 15 as a yellow solid in 92% yield (810 mg). IR (KBr,
8.04 (d, J ¼ 2.0 Hz, 1H, H5). 13C NMR (CDCl3)
d 22.9, 27.5, 50.4, 56.3,
62.0, 105.8, 116.2, 117.6, 119.6, 127.5, 127.9, 128.6, 134.7, 141.9, 143.8,
149.5, 170.1, 171.2. HRMS calcd for C21H23N3O4 (Mþ) 381.1689 found
381.1691.
5.1.17. 3-[2-acetamido-3-hydroxypropyl]-6-methoxy-2-
phenylimidazoimidazo[1,2-a]pyridine 18
cmꢂ1): 3045, 1651. 1H NMR (CDCl3)
d
2.22 (s, 6H, N(CH3)2), 3.83 (s,
To a solution of 17 (120 mg, 0.32 mmol) in 10 ml of ethanol at
5H, OCH3 þ CH2), 6.98 (dd, J ¼ 2.2, 9.7 Hz, 1H, H7), 7.30 (m, 1H, HAr),
0
ꢀC, NaBH4 (36 mg, 0.94 mmol) was added then the reaction
7.40 (m, 2H, HAr), 7.50 (d, J ¼ 9.7 Hz, 1H, H8), 7.77 (m, 2H, HAr), 7.92
mixture was stirred for 6 h at room temperature. The solvent was
evaporated then dissolved in ethyl acetate and washed with
a saturated solution of Na2CO3. The organic layer was dried over
MgSO4, concentrated then purified by column chromatography on
silica gel (CH2Cl2/MeOH, 96/4, v/v) to give the desired product 18 as
a white solid (95 mg, 89% yield). mp. 95 ꢀC. IR (KBr, cmꢂ1): 3610,
(d, J ¼ 2.2 Hz, 1H, H5).13C NMR (CDCl3)
d 45.0, 53.0, 56.2, 107.5, 117.4,
118.2, 119.3, 127.5, 128.4, 128.7, 134.8, 142.1, 144.8, 148.7. HRMS calcd
for C18H22N3O (Mþ) 281.1528 found 281.1530.
5.1.14. 1-(6-Methoxy-2-phenylimidazo[1,2-a]pyridin-3-yl)-N,N,N-
trimethyl methanaminium iodide 15
3274, 1660. 1H NMR (DMSO-d6)
d 1.80 (s, 3H, COCH3), 3.16 (dd,
Iodomethane (233
m
l, 3.76 mmol) was added to a solution of
J ¼ 5.3, 15.1 Hz, 1H, CH2), 3.36 (m, 3H, CH2, CH2OH), 3.89 (s, 3H,
OCH3), 4.00 (m, 1H, CH), 5.23 (s,1H, OH), 7.03 (dd, J ¼ 1.3, 9.7 Hz,1H,
HAr), 7.31 (m, 1H, HAr), 7.41 (m, 2H, HAr), 7.48 (d, J ¼ 9.7 Hz, 1H, H8),
7.91 (m, 2H, HAr), 8.37 (d, J ¼ 7.5 Hz, 1H, NH), 8.48 (d, J ¼ 1.3 Hz, 1H,
amine 14 (810 mg, 2.89 mmol) in 10 ml of methanol. The mixture
was stirred 8 h at room temperature then the solvent was evapo-
rated. The residue was washed several times with ether and led to
the desired product 14 (1 g) as a yellow solid in 82% yield. mp:
H5). 13C NMR (CDCl3)
d 22.6, 25.7, 50.2, 56.3, 61.6, 106.9, 116.9, 118.9,
156 ꢀC. IR (KBr, cmꢂ1): 3438, 1638. 1H NMR (CDCl3)
d
2.89 (s, 9H,
119.0, 126.9, 127.5, 128.4, 134.9, 140.8, 141.8, 148.5, 169.6. HRMS
Nþ(CH3)3), 3.91 (s, 3H, OCH3), 5.30 (s, 2H, CH2), 7.26 (dd, J ¼ 1.9,
9.7 Hz, 1H, H7), 7.40e7.69 (m, 3H, HAr), 7.67 (d, J ¼ 9.7 Hz, 1H, H8),
calcd for C19H21N3O3 (Mþ) 339.1583 found 339.1587.
7.82 (m, 2H, HAr), 8.47 (d, J ¼ 1.9 Hz, 1H, H5).13C NMR (CDCl3)
d 51.4,
5.2. Biological evaluation procedures
56.5, 57.1, 107.6, 110.3, 117.7, 121.2, 128.2, 128.6, 128.8, 134.0, 142.8,
148.4, 149.5. HRMS calcd for C18H22N3O (Mþ) 296.1763 found
296.1781.
The molecules were evaluated (Table 1) for their binding affinity
for membranes prepared from human MT1 and MT2 receptors
stably transfected in Human Embryonic Kidney (HEK 293) cells or
Chinese Hamster Ovarian (CHO) cells, using 2-[125I]iodomelatonin
as radioligand.
5.1.15. 3-[2-acetamido-2,2-di-(ethoxycarbonyl)-ethyl]-6-methoxy-
2-phenylimidazoimidazo[1,2-a]pyridine 16
A mixture of K2CO3 (281 mg, 2.04 mmol) and ethyl acet-
amidomalonate (883 mg, 4.06 mmol) in 40 ml of acetone was
stirred at 50 ꢀC for 30 min then the salt 15 (430 mg, 1.02 mmol) was
added. After 2 days in refluxing acetone, the solvent was evapo-
rated then the residue was dissolved in ethyl acetate and washed
two times with a 2N solution of NaOH and one time with a solution
of NaCl. The organic layer was dried over MgSO4 then evaporated.
The residue was purified by column chromatography on silica gel
(CH2Cl2/MeOH, 98/2, v/v) to give the desired product as an orange
oil (260 mg, 56% yield). IR (KBr, cmꢂ1): 3404, 1742, 1678. 1H NMR
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(CDCl3)
d
1.04 (t, J ¼ 7.1 Hz, 6H, CH2CH3), 1.69 (s, 3H, COCH3), 3.47
(m, 2H, CH2CH3), 3.80 (s, 3H, OCH3), 3.92 (m, 2H, CH2CH3), 4.27 ( s,
2H, CH2), 6.54 (s, 1H, NH), 6.92 (dt, J ¼ 2.2, 9.9 Hz, 1H, H7), 7.28 (m,
1H, HAr), 7.39 (m, 2H, HAr), 7.44 (d, J ¼ 9.9 Hz, 1H, H8), 7.63 (m, 2H,
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HAr), 7.65 (d, J ¼ 2.2 Hz, 1H, H5).13C NMR (CDCl3)
d 23.0, 26.8, 56.2,