Non-Peptide Antagonists for Human NK-3 Receptor
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6 1063
in the presence of dicyclohexylcarbodiimide (DCC) and 1-hy-
droxybenzotriazole (HOBT) (method B of ref 9).
3H); EI-MS (source 180 °C, 70 eV, 200 mA) m/z 380 (M+•), 337,
232, 204. Anal. (C25H20N2O2) C, H, N.
(R,S)-N-[r-(2-Hydr oxyeth yl)ben zyl]-2-ph en ylqu in olin e-
4-ca r boxa m id e (33). (R,S)-N-[R-(Methoxycarbonylmethyl)-
benzyl]-2-phenylquinoline-4-carboxamide (16; 0.70 g, 1.7 mmol)
was dissolved under nitrogen atmosphere in t-BuOH (50 mL)
and MeOH (2 mL). NaBH4 (0.06 g, 1.6 mmol) was added in 15
min to the refluxing solution. The reaction mixture was
refluxed for 6 h, quenched with a saturated solution of NH4Cl
(5 mL), and then evaporated to dryness. The residue was
dissolved in CH2Cl2 and washed with brine; the organic layer
was separated, dried over Na2SO4, and evaporated to dryness.
The crude product was flash chromatographed on 230-400
mesh silica gel, eluting with Et2O containing 0.5% of 28% NH4-
OH, and then crystallized from i-PrOH/i-Pr2O to yield 33 (0.19
g, 0.5 mmol, 29%): mp 167-169 °C; IR (KBr) 3360, 1650, 1592
cm-1;1H NMR (DMSO-d6) δ 9.30 (d, J ) 6.1 Hz, 1H), 8.31 (d,
J ) 8.5 Hz, 2H), 8.13 (d, J ) 8.3 Hz, 1H), 8.10 (s, 1H), 8.03 (d,
J ) 8.4 Hz, 1H), 7.81 (dd, J ) 8.4, 8.3 Hz, 1H), 7.64-7.51 (m,
4H), 7.46 (d, J ) 8.5 Hz, 2H), 7.39 (dd, J ) 8.5, 8.5 Hz, 2H),
7.29 (dd, J ) 8.5, 8.5 Hz, 1H), 5.30 (dt, J ) 6.1, 6.1 Hz, 1H),
4.61 (t, J ) 4.5 Hz, 1H), 3.61-3.41 (m, 2H), 2.11-1.86 (m, 2H);
EI-MS (source 180 °C, 70 eV, 200 mA) m/z 382 (M+•), 337, 232,
204. Anal. (C25H22N2O2) C, H, N.
As an example, spectroscopic data of compound 14 are
20
reported: mp 180-181 °C (from i-PrOH); [R]D (c ) 0.5,
1
MeOH) ) - 42.0; IR (Nujol) 3300, 1750, 1640 cm-1; H NMR
(DMSO-d6) δ 9.72 (d, J ) 6.9 Hz, 1H), 8.28 (dd, J ) 8.3, 1.8
Hz, 2H), 8.20 (dd, J ) 8.3, 0.8 Hz, 1H), 8.13 (dd, J ) 8.5, 0.5
Hz,1H), 8.11 (s, 1H), 7.83 (ddd, J ) 7, 7, 1.6 Hz, 1H), 7.66
(ddd, J ) 7, 7, 1.2 Hz, 1H), 7.60-7.50 (m, 5H), 7.47-7.37 (m,
3H), 5.78 (d, J ) 6.9 Hz, 1H), 3.72 (s, 3H); EI-MS (source 180
°C, 70 eV, 200 mA) m/z 396 (M+•), 337, 232, 204. Anal.
(C25H20N2O3) C, H, N.
(R)-N-(r-Ca r boxyben zyl)-2-p h en ylqu in olin e-4-ca r box-
a m id e Hyd r och lor id e (15). (R)-N-[R-(Methoxycarbonyl)-
benzyl]-2-phenylquinoline-4-carboxamide (14; 0.20 g, 0.5 mmol),
10% HCl (10 mL), and 1,4-dioxane (3 mL) were refluxed under
stirring for 30 min. The solvent was evaporated to dryness,
and the residue was triturated with EtOAc/Et2O 1:1 first and
then with warm acetone to yield 15 as a white solid (0.17 g,
20
0.4 mmol, 86%): mp 203-205 °C; [R]D (c ) 0.5, MeOH) )
1
-40.0; IR (KBr) 1740, 1670, 1635, 1610, 1540 cm-1; H NMR
(DMSO-d6) δ 9.64 (d, J ) 7.6 Hz, 1H), 8.28 (d, J ) 7.8 Hz,
2H), 8.22 (d, J ) 7.7 Hz, 1H), 8.16 (d, J ) 7.7 Hz, 1H), 8.13 (s,
1H), 7.84 (dd, J ) 7.7, 7.7 Hz, 1H), 7.66 (dd, J ) 7.7, 7.7 Hz,
1H), 7.62-7.51 (m, 5 H), 7.46-7.34 (m, 3H), 5.70 (d, J ) 7.6
Hz, 1H); EI-MS (source 200 °C, 70 eV, 200 mA) m/z 382 (M+•),
337, 204. Anal. (C24H18N2O3‚HCl) C, H, N, Cl.
(R)-N-[r-(Am in om eth yl)ben zyl]-2-p h en ylqu in olin e-4-
ca r boxa m id e (35). (R)-N-[R-(Phthalimidomethyl)benzyl]-2-
phenylquinoline-4-carboxamide (34; 1.0 g, 2.0 mmol) was
suspended in 96% EtOH (100 mL) and heated to reflux.
Hydrazine hydrate (0.15 g, 2.9 mmol) was added, and the
reaction mixture was refluxed for 4 h. Additional hydrazine
hydrate (0.41 g, 8.2 mmol) was added together with 1,2-
dichloroethane (20 mL) to dissolve completely the reagents,
and the reaction was refluxed for 3.5 h. The reaction mixture
was then evaporated to dryness, dissolved in H2O (20 mL),
cooled, and acidified with 37% HCl (10 mL). The mixture was
refluxed for 45 min and cooled; the phthalhydrazide was
filtered off. The aqueous layer was made alkaline with 40%
NaOH and extracted with CH2Cl2; the organic layer was
washed with brine, separated, dried over Na2SO4, and evapo-
rated to dryness. The residue was flash chromatographed on
230-400 mesh silica gel, eluting with CH2Cl2/MeOH (95:5)
containing 0.5% of 28% NH4OH to afford a purified product
which was crystallized from i-Pr2O/i-PrOH (95:5) to yield 35
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
17-19 in Sch em e 4. (R,S)-N-[R-(Methoxycarbonyl)benzyl]-2-
phenylquinoline-4-carboxamide (12) (0.44 g, 1.1 mmol) was
dissolved in 40 mL of 33% MeNH2/EtOH (to obtain 17) or 33%
Me2NH/EtOH (to obtain 18) or 16% NH3/MeOH (to obtain 19);
a catalytic amount of NaCN was added, and the reaction
mixture was heated at 70-120 °C for 1-6.5 h in a Parr
apparatus. The internal pressure rose to about 40 psi. The
solution was evaporated to dryness, and the residue was
triturated with water, filtered, dried, and recrystallized from
a mixture of i-PrOH/EtOH (2:1) to yield the title compounds
17-19. Typically, yields were in the range of 45-60%. As an
example, spectroscopic data for compound 17 are reported: mp
261-263 °C (from i-PrOH/EtOH); IR (KBr) 3300, 3270, 1660,
1635 cm-1 1H NMR (DMSO-d6) δ 9.48 (d, J ) 6.3 Hz, 1H),
;
20
8.33-8.25 (m, 3H), 8.18-8.10 (m, 3H), 7.8 (ddd, J ) 7.9, 7.9,
1.1 Hz, 1H), 7.68-7.50 (m, 6H), 7.40-7.28 (m, 3H), 5.75 (d, J
) 6.3 Hz, 1H), 2.63 (d, J ) 7.6 Hz, 3H); EI-MS (source 200 °C,
70 eV, 200 mA) m/z 395 (M+•), 337, 232, 204, 77. Anal.
(C25H21N3O2) C, H, N.
as a white solid (0.29 g, 0.8 mmol, 40%): mp 139-141 °C; [R]D
(c ) 0.5, MeOH) ) -6.9; IR (KBr) 3300, 1635, 1590, 1530,
1495, 770 cm-1; 1H NMR (DMSO-d6) δ 9.18 (d br, J ) 7.2 Hz,
1H), 8.35 (d, J ) 7.6 Hz, 2H), 8.20 (s, 1H), 8.13 (d, J ) 7.9 Hz,
1H), 8.07 (d, J ) 7.9 Hz, 1H), 7.81 (dd, J ) 7.9, 7.9 Hz, 1H),
7.63-7.51 (m, 4H), 7.44 (d, J ) 7.0 Hz, 2H), 7.38 (dd, J ) 7.2,
7.2 Hz, 2H), 7.28 (dd, J ) 7.2, 7.2 Hz, 1H), 5.08 (dt br, J )
7.2, 7.2 Hz, 1H), 2.89 (d, J ) 7.2 Hz, 2H), 1.60 (s br, 2H); EI-
MS (source 180 °C, 70 eV, 200 mA) m/z 338, 337, 255, 233,
232, 204. Anal. (C24H21N3O) C, H, N.
(R,S)-N-(r-Acetylben zyl)-2-p h en ylqu in olin e-4-ca r box-
a m id e (31). Oxalyl chloride (0.27 mL, 3.1 mmol) was dissolved
under nitrogen atmosphere in dry CH2Cl2 (2.3 mL). The
solution was cooled to -55 °C, and DMSO (0.22 mL, 3.1 mmol),
dissolved in dry CH2Cl2 (0.7 mL), was added dropwise while
maintaining the temperature below -50 °C. The reaction was
stirred at -55 °C for 7 min; then (R,S)-N-[R-(1-hydroxyethyl)-
benzyl]-2-phenylquinoline-4-carboxamide (30; 0.96 g, 2.5 mmol),
dissolved in dry CH2Cl2 (25 mL), was added keeping the
temperature between -50 and -55 °C. After 30 min at -55
°C, TEA (1.9 mL) was added without exceeding -40 °C; then
the reaction mixture was allowed to reach room temperature
and stirred for an additional 15 min. The reaction was
quenched with H2O (5 mL) and extracted with CH2Cl2; the
organic layer was washed with H2O, 20% citric acid, 5%
NaHCO3, and brine; the organic layer was separated, dried
over Na2SO4, and evaporated to dryness. The residual oil was
flash chromatographed on 230-400 mesh silica gel, eluting
with a mixture of hexane/EtOAc (7:3) containing 0.5% of 28%
NH4OH to afford a compound which was crystallized from
i-PrOH/i-Pr2O (1:2) to yield 31 (0.50 g, 1.3 mmol, 53%): mp
(S)-N-(r-Eth ylben zyl)-3-a ceta m id o-2-p h en ylqu in olin e-
4-ca r boxa m id e (60). (S)-N-(R-Ethylbenzyl)-3-amino-2-phe-
nylquinoline-4-carboxamide (55; 0.38 g, 1.0 mmol) was heated
in acetic anhydride (25 mL) at 70 °C for 1 h and then at 100
°C for an additional 3 h. The reaction mixture was then
evaporated to dryness and the residue dissolved in EtOAc; the
solution was washed with water, 5% NaHCO3, and brine, dried
over Na2SO4, and evaporated to dryness. The crude product
was purified by silica gel flash column chromatography, eluting
with
a mixture of hexane/EtOAc/28% NH4OH, 70:30:0.5,
respectively, to afford a solid compound which was recrystal-
lized from acetone to yield 60 (0.14 g, 0.33 mmol, 33%): mp
20
268-269 °C; [R]D (c ) 0.5, MeOH) ) -71.4; IR (KBr) 3230,
1
1670, 1640, 1555, 1525 cm-1; H NMR (DMSO-d6) δ 9.77 (s,
1H), 8.94 (d, J ) 8.1 Hz, 1H), 8.09 (d, J ) 8.5 Hz, 1H), 7.81
(dd, J ) 8.5, 8.5 Hz, 1H), 7.71-7.59 (m, 4H), 7.50-7.25 (m,
8H), 5.02 (dt, J ) 8.1, 8.1 Hz, 1H), 1.83-1.67 (m, 2H), 1.60 (s,
3H), 0.96 (t, J ) 7.2 Hz, 3H); EI-MS (source 180 °C, 70 eV,
200 mA) m/z 423 (M+•), 381, 334, 289, 261, 247, 218. Anal.
(C27H25N3O2) C, H, N.
160-161 °C; IR (KBr) 3400, 3265, 1725, 1660, 1640, 1592 cm-1
;
1H NMR (DMSO-d6) δ 9.60 (d, J ) 7.3 Hz, 1H), 8.29 (d, 2H),
8.17 (d, J ) 7.5 Hz, 1H), 8.14 (d, 1H), 8.12 (s, 1H), 7.82 (dd, J
) 7.5, 7.5 Hz, 1H), 7.65 (dd, J ) 7.5, 7.5 Hz, 1H), 7.61-7.51
(m, 5H), 7.48-7.36 (m, 3H), 5.90 (d, J ) 7.3 Hz, 1H), 2.19 (s,
(S)-N-(r-Eth ylben zyl)-3-(d im eth yla m in oa ceta m id o)-2-