Antagonists of Melanin-Concentrating Hormone
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 24 7103
6-[4-(Methyloxy)phenyl]-3-[2-(4-morpholinylmethyl)-6-quino-
linyl]thieno[3,2-d]pyrimidin-4(3H)-one (22). 1H NMR (300 MHz,
DMSO-d6): δ 8.62 (s, 1H), 8.47 (d, J ) 8.5 Hz, 1H), 8.24 (s, 1H),
8.17 (d, J ) 8.9 Hz, 1H), 8.13-8.07 (m, 3H), 7.96-7.90 (m, 2H),
7.80 (d, J ) 8.5 Hz, 1H), 7.59 (m, 2H), 3.84 (s, 2H), 3.65 (m, 2H),
2.53 (m, 2H). Elemental analysis was performed for C, H, and N.
6-[4-(1-Methylpropyl)phenyl]-3-[2-(4-morpholinylmethyl)-6-
quinolinyl]thieno[3,2-d]pyrimidin-4(3H)-one (23). 1H NMR (300
MHz, DMSO-d6): δ 8.59 (s, 1H), 8.46 (d, J ) 8.5 Hz, 1H), 8.23
(s, 1H), 8.16 (d, J ) 8.9 Hz, 1H), 7.95-7.76 (m, 5H), 7.20 (m,
2H), 3.84 (s, 2H), 3.65 (m, 2H), 2.53 (m, 2H). Elemental analysis
was performed for C, H, and N.
6-[4-(1,1-Dimethylethyl)phenyl]-3-[2-(4-morpholinylmethyl)-
6-quinolinyl]thieno[3,2-d]pyrimidin-4(3H)-one (24). 1H NMR
(300 MHz, DMSO-d6): δ 8.60 (s, 1H), 8.47 (d, J ) 8.5 Hz, 1H),
8.24 (s, 1H), 8.17 (d, J ) 8.9 Hz, 1H), 7.96-7.77 (m, 6H), 7.59
(d, J ) 8.5 Hz, 1H), 3.84 (s, 2H), 3.66 (m, 2H), 2.54 (m, 2H).
Elemental analysis was performed for C, H, and N.
(d, J ) 9.0 Hz, 1H), 8.03-7.90 (m, 5H), 7.60 (d, J ) 8.4 Hz, 1H),
7.35-7.21 (m, 6H), 4.76 (s, 2H), 3.61-3.49 (m, 2H), 3.28-3.15
(m, 2H), 2.87 (m, 1H), 2.22-1.96 (m, 4 H). Elemental analysis
was performed for C, H, and N.
6-(4-Chlorophenyl)-3-(2-{[4-(4-fluorophenyl)-1-piperidinyl]-
1
methyl}-6-quinolinyl)thieno[3,2-d]pyrimidin-4(3H)-one (34). H
NMR (300 MHz, DMSO-d6): δ 8.66 (s, 1H), 8.36 (s, 1H), 8.29
(d, J ) 9.0 Hz, 1H), 8.07-7.91 (m, 8H), 7.65 (d, J ) 8.7 Hz, 1H),
7.33 (m, 1H), 7.17 (m, 2H), 3.87 (s, 2H), 3.04 (m, 3H), 2.80 (m,
2H), 2.26 (m, 2H), 1.84 (m, 2H). Elemental analysis was performed
for C, H, and N.
6-(4-Chlorophenyl)-3-[2-({4-[4-(trifluoromethyl)phenyl]-1-
piperidinyl}methyl)-6-quinolinyl]thieno[3,2-d]pyrimidin-4(3H)-
1
one (35). H NMR (300 MHz, DMSO-d6): δ 8.62 (s, 1H), 8.48
(d, J ) 8.6 Hz, 1H), 8.24 (s, 1H), 8.18 (d, J ) 9.0 Hz, 1H), 8.11-
7.81 (m, 8H), 7.83 (d, J ) 8.6 Hz, 1H), 7.70-7.38 (m, 2H), 3.89
(s, 2H), 3.03 (m, 3H), 2.75 (m, 2H), 2.24 (m, 2H) 1.81 (m, 2H).
Elemental analysis was performed for C, H, and N.
6-(4-Chlorophenyl)-3-(6-quinolinyl)thieno[3,2-d]pyrimidin-
4(3H)-one (25). 1H NMR (400 MHz, CDCl3): δ 9.01 (s, 1H), 8.59
(s, 1H), 8.47 (d, J ) 8.0 Hz, 1H), 8.23 (s, 1H), 8.18 (d, J ) 8.9
Hz, 1H), 8.02 (s, 1H), 7.95 (d, J ) 8.5 Hz, 1H), 7.66 (m, 1H),
7.59 (d, J ) 8.5 Hz, 1H). Elemental analysis was performed for C,
H, and N.
6-(4-Chlorophenyl)-3-{2-[(4-methyl-1-piperazinyl)methyl]-6-
quinolinyl}thieno[3,2-d]pyrimidin-4(3H)-one (36). 1H NMR (300
MHz, DMSO-d6): δ 8.56 (s, 1H), 8.42 (d, J ) 8.6 Hz, 1H), 8.19
(s, 1H), 8.11 (d, J ) 9.0 Hz, 1H), 8.02 (s, 1H), 7.94-7.88 (m,
3H), 7.75 (d, J ) 8.5 Hz, 1H), 7.59 (m, 2H), 3.82 (s, 2H), 2.64-
2.37 (m, 11H). Elemental analysis was performed for C, H, and N.
6-(4-Chlorophenyl)-3-{2-[(4-ethyl-1-piperazinyl)methyl]-6-
quinolinyl}thieno[3,2-d]pyrimidin-4(3H)-one (37). 1H NMR (300
MHz, DMSO-d6): δ 8.62 (s, 1H), 8.48 (d, J ) 8.6 Hz, 1H), 8.25
(s, 1H), 8.17 (d, J ) 8.8 Hz, 1H), 8.06 (s, 1H), 8.0 (d, J ) 8.4 Hz,
2H), 7.95-7.92 (m, 1H), 7.78 (d, J ) 8.5 Hz, 1H), 7.65 (d, J )
8.4 Hz, 2H), 3.87 (s, 2H), 2.76-2.53 (m, 9H), 1.03 (t, J ) 7.2 Hz,
3H). Elemental analysis was performed for C, H, and N.
6-(4-Chlorophenyl)-3-[2-({4-[2-(4-morpholinyl)ethyl]-1-pipera-
zinyl}methyl)-6-quinolinyl]thieno[3,2-d]pyrimidin-4(3H)-one (38).
1H NMR (300 MHz, DMSO-d6): δ 8.63 (s, 1H), 8.43 (d, J ) 8.6
Hz, 1H), 8.27 (s, 1H), 8.17 (d, J ) 9.1 Hz, 1H), 8.05 (s, 1H), 8.0
(d, J ) 8.6 Hz, 2H), 7.94-7.90 (m, 1H), 7.78 (d, J ) 8.6 Hz, 1H),
7.67 (d, J ) 8.6 Hz, 2H), 3.81 (s, 2H), 3.61 (m, 4H), 2.58-2.11
(m, 16H). Elemental analysis was performed for C, H, and N.
6-(4-Chlorophenyl)-3-[2-({4-[3-(4-morpholinyl)propyl]-1-pipera-
zinyl}methyl)-6-quinolinyl]thieno[3,2-d]pyrimidin-4(3H)-one (39).
1H NMR (300 MHz, DMSO-d6): δ 8.61 (s, 1H), 8.46 (d, J ) 8.5
Hz, 1H), 8.24 (s, 1H), 8.16 (d, J ) 9.0 Hz, 1H), 8.06 (s, 1H), 8.0
(d, J ) 8.5 Hz, 2H), 7.95-7.91 (m, 1H), 7.77 (d, J ) 8.5 Hz, 1H),
7.64 (d, J ) 8.5 Hz, 2H), 3.83 (s, 2H), 3.60 (m, 4H), 2.60-2.10
(m, 16H), 1.63 (m, 2H). Elemental analysis was performed for C,
H, and N.
6-(4-Chlorophenyl)-3-{2-[(dimethylamino)methyl]-6-quinolin-
1
yl}thieno[3,2-d]pyrimidin-4(3H)-one (26). H NMR (400 MHz,
CDCl3): δ 8.26 (d, J ) 7.9 Hz, 1H), 8.25 (s, 1H), 8.21 (d, J ) 8.2
Hz, 1H), 7.91 (d, J ) 2.3 Hz, 1H), 7.76 (dd, J ) 2.4 and 9.0 Hz,
1H), 7.72 (d, J ) 8.4 Hz, 1H), 7.68 (d, J ) 8.8 Hz, 2H), 7.57 (s,
1H), 7.46 (d, J ) 8.8 Hz, 2H), 3.83 (s, 2H), 2.37 (s, 6H). EI-LCMS
m/z: 447 (M + H).
6-(4-Chlorophenyl)-3-(2-{[methyl(phenyl)amino]methyl}-6-
quinolinyl)thieno[3,2-d]pyrimidin-4(3H)-one (27). 1H NMR (300
MHz, DMSO-d6): δ 8.57 (s, 1H), 8.43 (d, J ) 8.5 Hz, 1H), 8.39
(s, 1H), 8.31 (d, J ) 9.0 Hz, 1H), 8.20 (s, 1H), 8.16 (m, 3H), 7.57
(m, 2H), 7.47 (d, J ) 8.5 Hz, 1H), 7.15 (m, 2H), 6.77 (m, 2H),
6.62 (m, 1H), 4.87 (s, 2H), 3.17 (s, 3H).
6-(4-Chlorophenyl)-3-[2-(1H-imidazol-1-ylmethyl)-6-quinoli-
nyl]thieno[3,2-d]pyrimidin-4(3H)-one (28). 1H NMR (300 MHz,
DMSO-d6): δ 9.33 (s, 1H), 8.55 (m, 2H), 8.25 (s, 1H), 8.02 (s,
1H), 8.00 (s, 1H), 7.93 (m, 3H), 7.83 (s, 1H), 7.75 (s, 1H), 7.68 (d,
J ) 8.6 Hz, 1H), 7.58 (d, J ) 8.6 Hz, 2H), 5.84 (s, 2H). Elemental
analysis was performed for C, H, and N.
6-(4-Chlorophenyl)-3-[2-(1-pyrrolidinylmethyl)-6-quinolinyl]-
thieno[3,2-d]pyrimidin-4(3H)-one (29). 1H NMR (400 MHz,
CDCl3): δ 8.25-8.23 (m, 2H), 8.18 (d, J ) 8.4 Hz, 1H), 7.88 (d,
J ) 2.4 Hz, 1H), 7.75-7.70 (m, 2H), 7.67 (d, J ) 8.4 Hz, 2H),
7.56 (s, 1H), 7.45 (d, J ) 8.8 Hz), 3.99(s, 2H), 2.63 (br s, 4H),
1.85-1.82 (m, 4H). ES-LCMS m/z: 473 (M + H).
6-(4-Chlorophenyl)-3-[2-(1-piperidinylmethyl)-6-quinolinyl]-
thieno[3,2-d]pyrimidin-4(3H)-one (30). 1H NMR (300 MHz,
DMSO-d6): δ 8.64 (s, 1H), 8.63 (d, J ) 9.1 Hz, 1H), 8.36 (s, 1H),
8.28 (d, J ) 9.0 Hz, 1H), 8.07 (m, 5H), 7.65 (m, 2H), 3.50 (s, 2H),
2.53 (m, 4H), 1.86-1.49 (m, 6H). Elemental analysis was per-
formed for C, H, and N.
6-(4-chlorophenyl)-3-(2-{[4-(1-pyrrolidinyl)-1-piperidinyl]-
methyl}-6-quinolinyl)thieno[3,2-d]pyrimidin-4(3H)-one (31). 1H
NMR (300 MHz, DMSO-d6): δ 8.60 (s, 1H), 8.32 (s, 1H), 8.25
(d, J ) 8.9 Hz, 1H), 8.04 (m, 2H), 7.94 (m, 2H), 7.87 (d, J ) 8.6
Hz, 1H), 7.29 (m, 1H), 7.19 (m, 2H), 3.42 (s, 2H), 2.98 (m, 1H),
2.09-1.54 (m, 16H). Elemental analysis was performed for C, H,
and N.
6-(4-Chlorophenyl)-3-[2-({4-[2-(1-pyrrolidinyl)ethyl]-1-piperi-
dinyl}methyl)-6-quinolinyl]thieno[3,2-d]pyrimidin-4(3H)-one (32).
1H NMR (300 MHz, DMSO-d6): δ 8.59 (m, 2H), 8.31 (s, 1H),
8.22 (d, J ) 8.9 Hz, 1H), 8.03-7.89 (m, 5H), 7.60 (m, 2H), 3.44
(s, 2H), 2.92 (m, 2H), 1.98 (m, 2H), 1.87-1.26 (m, 17H). Elemental
analysis was performed for C, H, and N.
6-(4-Chlorophenyl)-3-{2-[(4-phenyl-1-piperidinyl)methyl]-6-
quinolinyl}thieno[3,2-d]pyrimidin-4(3H)-one (33). 1H NMR (300
MHz, DMSO-d6): δ 8.61 (s, 1H), 8.59 (s, 1H), 8.32 (s, 1H), 8.25
6-(4-Chlorophenyl)-3-{2-[(4-phenyl-1-piperazinyl)methyl]-6-
quinolinyl}thieno[3,2-d]pyrimidin-4(3H)-one (40). 1H NMR (300
MHz, DMSO-d6): δ 8.62 (s, 1H), 8.60 (s, 1H), 8.32 (s, 1H), 8.25
(d, J ) 9.0 Hz, 1H), 8.03-7.94 (m, 4H), 7.84 (d, J ) 8.4 Hz, 1H),
7.60 (m, 2H), 7.28 (m, 1H), 7.16 (m, 1H), 7.00 (d, J ) 8.2 Hz,
1H), 6.87 (t, J ) 7.2 Hz, 1H), 6.74 (d, J ) 7.7 Hz, 1H), 4.84 (s,
2H), 3.54 (m, 4H), 2.07 (m, 4H). Elemental analysis was performed
for C, H, and N.
6-(4-Chlorophenyl)-3-[2-(hydroxymethyl)-6-quinolinyl]thieno-
[3,2-d]pyrimidin-4(3H)-one (41). (a) 6-Nitroquinoline-2-carbal-
dehyde. To a hot solution of selenium dioxide (41.6 g, 375 mmol)
in dioxane (185 mL) and water (35 mL) was added 2-methyl-6-
nitroquinoline (47.0 g, 250 mmol). The mixture was refluxed for
30 min. The selenium black was filtered off, and the filtrate was
concentrated by rotary evaporation. The resulting solid was washed
with a saturated solution of sodium bicarbonate. The solid was
filtered, washed with water, and dried to give the product as a tan
1
solid (44.8 g, 89%). H NMR (300 MHz, DMSO-d6): δ 10.17 (s,
1H), 9.21 (d, J ) 2.6 Hz, 1H), 8.97 (d, J ) 8.5 Hz, 1H), 8.59 (dd,
J ) 2.6 and 9.2 Hz, 1H), 8.44 (d, J ) 9.2 Hz, 1H), 8.16 (d, J )
8.5 Hz, 1H).
(b) (6-Nitro-2-quinolinyl)methanol. To 6-nitro-2-quinolinecarb-
aldehyde (500 mg, 2.47 mmol) in a 50% mixture of ethyl alcohol
and 1,4-dioxane (30 mL) at 0 °C was added sodium borohydride
(188 mg, 4.95 mmol). After stirring for 10 min, the reaction mixture