New COX-2/5-LOX Inhibitors
1545, 1478 cm-1
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25 6203
;
1H NMR (CDCl3) δ 7.54 (d, J ) 2.5, 1H),
bromide 9f (172 mg, 0.5 mmol) and phenol 6 by procedure C
and purification by FC with cyclohexane/AcOEt 8:2: mp 108-
110 °C; IR 3054, 2956, 2929, 2866, 1612, 1597, 1517 cm-1; 1H
NMR (CDCl3) δ 7.32-7.21 (m, 7H), 6.91 (m, 1H), 6.89-6.84
(m, 2H), 6.75 (m, 1H), 6.72 (m, 1H), 6.62 (s, 1H), 5.17 (s, 2H),
3.82 (s, 3H), 2.99 (s, 3H), 2.04-1.90 (m, 4H); LC-MS (APCI+)
m/z 489 (MH+). Anal. (C29H29FN2O4) C, H, N.
7.43-7.23 (m, 6H), 7.03 (dd, J ) 8.6, J ) 2.5, 1H), 6.60 (s,
1H), 4.69 (s, 2H).
3-[3-Fluoro-5-(4-methoxytetrahydropyran-4-yl)phe-
noxymethyl]-1-(4-methanesulfonylphenyl)-5-phenyl-1H-
pyrazole (10a). A solution of phenol 6 (4.45 g, 19.7 mmol) in
35 mL of DMF was stirred while cesium carbonate (6.7 g, 20.6
mmol) was added rapidly at room temperature. The mixture
was stirred for 0.5 h and then alkyl bromide 9a (7.0 g, 19.9
mmol) was added in one batch. The reaction mixture was
stirred at 90 °C for 2 h, concentrated under reduced pressure,
and extracted with ethyl acetate. The organic phase was
washed with brine, dried (MgSO4), and concentrated under
vacuum. Purification was performed by FC (cyclohexane/
AcOEt 1:1) to yield, after vacuum-drying, pyrazole 10a (8.5 g,
88% yield): mp 70-72 °C; IR 3062, 2951, 2865, 1614, 1593
1-(4-Trifluoromethoxyphenyl)-3-[3-fluoro-5-(4-methoxy-
tetrahydropyran-4-yl)phenoxymethyl]-5-phenyl-1H-pyra-
zole (10g) was synthesized in 74% yield (200 mg) from alkyl
bromide 9g (200 mg, 0.5 mmol) and phenol 6 by procedure C
and purification by FC with cyclohexane/AcOEt 8:2: mp 71-
1
73 °C; IR 3071, 2950, 2873, 1613, 1600, 1514 cm-1; H NMR
(CDCl3) δ 7.37-7.34 (m, 5H), 7.26-7.19 (m, 4H), 6.91 (m, 1H),
6.77-6.70 (m, 2H), 6.64 (s, 1H), 5.17 (s, 2H), 3.88-3.82 (m,
4H), 3.00 (s, 3H), 2.04-1.95 (m, 4H); LC-MS (APCI+) m/z 543
(MH+). Anal. (C29H26F4N2O4) C, H, N.
1
cm-1; H NMR (CDCl3) δ 7.91 (d, J ) 8.9, 2H), 7.52 (d, J )
8.6, 2H), 7.41-7.34 (m, 3H), 7.27-7.24 (m, 2H), 6.90 (s, 1H),
6.77-6.70 (m, 2H), 6.67 (s, 1H), 5.18 (s, 2H), 3.85-3.81 (m,
4H), 3.10 (s, 3H), 3.07 (s, 3H), 2.00 (m, 4H); LC-MS (APCI+)
m/z 537 (MH+). Anal. (C29H29FN2O5S) C, H, N.
1-(4-Aminosulfonylphenyl)-3-[3-fluoro-5-(4-methoxytet-
rahydropyran-4-yl)phenoxymethyl]-5-phenyl-1H-pyra-
zole (10h) was synthesized in 72% yield (190 mg) from alkyl
bromide 9h (196 mg, 0.5 mmol) and phenol 6 by procedure C
and purification by FC with cyclohexane/AcOEt 1:1: mp 68-
General Procedure for the Synthesis of Ethers 10b-j
(Procedure C). The 1-arylpyrazoles 9b-j (0.5 mmol) were
added in a multiblock reactor to a suspension of phenol 6 (1.1
mL, 0.5 M in DMF, 0.55 mmol) and cesium carbonate (0.21 g,
0.58 mmol) in DMF (0.5 mL). The reaction mixture was stirred
at 90 °C for 1 h before the solvent was removed. After cooling
to 20 °C, the residue was taken up in brine (3 mL) and the
aqueous mixture was extracted with ethyl acetate (2 × 10 mL).
The combined extracts were concentrated, and the crude
product was purified by FC (cyclohexane/AcOEt in adequate
proportions) to yield the phenoxymethylpyrazoles 10b-j.
3-[3-Fluoro-5-(4-methoxytetrahydropyran-4-yl)phe-
noxymethyl]-1,5-diphenyl-1H-pyrazole (10b) was synthe-
sized as an oil (210 mg, 91% yield) from alkyl bromide 9b (157
mg, 0.5 mmol) and phenol 6 by procedure C and purification
by FC with cyclohexane/AcOEt 8:2: IR 3060, 2923, 2853, 1616,
1592, 1506 cm-1; 1H NMR (CDCl3) δ 7.36-7.22 (m, 10H), 6.92
(m, 1H), 6.76 (m, 1H), 6.72 (m, 1H), 6.64 (s, 1H), 5.19 (s, 2H),
3.86-3.82 (m, 4H), 2.99 (s, 3H), 2.04-1.90 (m, 4H); LC-MS
(APCI+) m/z 459 (MH+). Anal. (C28H27FN2O3) C, H, N.
1
70 °C; IR 3415, 3076, 2923, 2853, 1616, 1593, 1506 cm-1; H
NMR (CDCl3) δ 7.90 (d, 2H), 7.50-7.35 (m, 5H), 7.30-7.25
(m, 4H), 6.91 (m, 1H), 6.75-6.70 (m, 2H), 6.65 (s, 1H), 5.18 (s,
2H), 3.84-3.81 (m, 4H), 2.99 (s, 3H), 2.04-1.90 (m, 4H); LC-
MS (APCI+) m/z 538 (MH+). Anal. (C28H28FN3O5S) C, H, N.
3-[3-Fluoro-5-(4-methoxytetrahydropyran-4-yl)phe-
noxymethyl]-1-(3,4-dimethylphenyl)-5-phenyl-1H-pyra-
zole (10i) was synthesized as an oil (170 mg, 70% yield) from
alkyl bromide 9i (171 mg, 0.5 mmol) and phenol 6 by procedure
C and purification by FC with cyclohexane/AcOEt 4:1: IR
1
3060, 2925, 2862, 1614, 1590, 1508 cm-1; H NMR (CDCl3) δ
7.35-7.22 (m, 6H), 7.05 (d, J ) 8.2, 1H), 6.92-6.87 (m, 2H),
6.75-6.71 (m, 2H), 6.62 (s, 1H), 5.18 (s, 2H), 3.86-3.82 (m,
4H), 2.99 (s, 3H), 2.27 (s, 3H), 2.24 (s, 3H), 2.04-1.91 (m, 4H);
LC-MS (APCI+) m/z 487 (MH+). Anal. (C30H31FN2O3) C, H,
N.
1-(3,4-Dichlorophenyl)-3-[3-fluoro-5-(4-methoxytetrahy-
dropyran-4-yl)phenoxymethyl]-5-phenyl-1H-pyrazole (10j)
was synthesized in 61% yield (160 mg) from alkyl bromide 9j
(191 mg, 0.5 mmol) and phenol 6 by procedure C and
purification by FC with cyclohexane/AcOEt: mp 79-81 °C; IR
3-[3-Fluoro-5-(4-methoxytetrahydropyran-4-yl)phe-
noxymethyl]-1-(4-fluorophenyl)-5-phenyl-1H-pyrazole
(10c) was synthesized in 55% yield (130 mg) from alkyl
bromide 9c (166 mg, 0.5 mmol) and phenol 6 by procedure C
and purification by FC with cyclohexane/AcOEt 8:2: mp 81-
1
3062, 2925, 2859, 1616, 1591, 1478 cm-1; H NMR (CDCl3) δ
7.56 (d, J ) 2.5, 1H), 7.40-7.34 (m, 4H), 7.27-7.23 (m, 2H),
7.05 (d, J ) 8.8, J ) 2.5, 1H), 6.91 (m, 1H), 6.77-6.69 (m,
2H), 6.63 (s, 1H), 5.16 (s, 2H), 3.86-3.82 (m, 4H), 3.00 (s, 3H),
2.00-1.90 (m, 4H); LC-MS (APCI+) m/z 528 (MH+). Anal.
(C28H25Cl2FN2O3) C, H, N, Cl.
1
83 °C; IR 3081, 2922, 2859, 1612, 1598, 1513 cm-1; H NMR
(CDCl3) δ 7.34-7.21 (m, 7H), 7.08-7.02 (m, 2H), 6.91 (m, 1H),
6.76-6.71 (m, 2H), 6.63 (s, 1H), 5.17 (s, 2H), 3.86-3.82 (m,
4H), 3.00 (s, 3H), 2.04-1.95 (m, 4H); LC-MS (APCI+) m/z 477
(MH+). Anal. (C28H26F2N2O3) C, H, N.
General Procedure for the Synthesis of Ethers 10k-m
(Procedure D). A solution of pyrazole 8a (1 g, 3.05 mmol) in
DMA (3 mL) was stirred while sodium hydride (0.13 g, 60%
dispersion in mineral oil, 3.15 mmol) was added rapidly at 0
°C. The mixture was stirred for 0.5 h before a solution of
adequate substituted fluorobenzene (3 mmol) in DMA (1 mL)
was added in a multiblock reactor. The reaction mixture was
stirred at 20 °C for 15 h and the solvent was removed. The
residue was taken up in brine (3 mL) and the aqueous mixture
was extracted with ethyl acetate (2 × 10 mL). The combined
extracts were concentrated, and the crude product was purified
by FC (cyclohexane/AcOEt 7:3) to give the phenoxymeth-
ylpyrazoles 10k-m.
3-[(3-Fluoro-5-methoxy)phenoxymethyl]-1-(4-methane-
sulfonylphenyl)-5-phenyl-1H-pyrazole (10k) was synthe-
sized in 20% yield (195 mg) from primary alcohol 8a and 3,5-
difluoroanisole (441 mg, 3 mmol) by procedure D and
purification by FC: mp 96-98 °C; IR 3001, 2954, 2925, 2832,
1597, 1511 cm-1; 1H NMR (CDCl3) δ 7.91 (d, J ) 8.2, 2H), 7.52
(d, J ) 8.2, 2H), 7.39-7.34 (m, 3H), 7.27-7.23 (m, 2H), 6.65
(s, 1H), 6.43-6.38 (m, 2H), 6.30 (dd, J ) 10.2, J ) 2.0, 1H),
5.14 (s, 2H), 3.78 (s, 3H), 3.07 (s, 3H); LC-MS (APCI+) m/z
453 (MH+). Anal. (C24H21FN2O4S) C, H, N.
1-(4-Chlorophenyl)-3-[3-fluoro-5-(4-methoxytetrahy-
dropyran-4-yl)phenoxymethyl]-5-phenyl-1H-pyrazole
(10d) was synthesized in 50% yield (120 mg) from alkyl
bromide 9d (174 mg, 0.5 mmol) and phenol 6 by procedure C
and purification by FC with cyclohexane/AcOEt 8:2: mp 103-
105 °C; IR 3063, 2952, 2859, 1613, 1598, 1503 cm-1; 1H NMR
(CDCl3) δ 7.35-7.31 (m, 5H), 7.27-7.22 (m, 4H), 6.91 (m, 1H),
6.75-6.71 (m, 2H), 6.63 (s, 1H), 5.17 (s, 2H), 3.85-3.82 (m,
4H), 3.00 (s, 3H), 2.04-1.90 (m, 4H); LC-MS (APCI+) m/z 494
(MH+). Anal. (C28H26ClFN2O3) C, H, N.
3-[3-Fluoro-5-(4-methoxytetrahydropyran-4-yl)phe-
noxymethyl]-1-(4-methylphenyl)-5-phenyl-1H-pyrazole
(10e) was synthesized in 85% yield (200 mg) from alkyl
bromide 9e (164 mg, 0.5 mmol) and phenol 6 by procedure C
and purification by FC with cyclohexane/AcOEt 8:2: mp 90-
1
92 °C; IR 2951, 2923, 2858, 1612, 1598, 1518 cm-1; H NMR
(CDCl3) δ 7.33-7.13 (m, 9H), 6.91 (m, 1H), 6.75 (m, 1H), 6.71
(m, 1H), 6.62 (s, 1H), 5.17 (s, 2H), 3.88-3.79 (m, 4H), 2.99 (s,
3H), 2.37 (s, 3H), 2.04-1.90 (m, 4H); LC-MS (APCI+) m/z 473
(MH+). Anal. (C29H29FN2O3) C, H, N.
3-[3-Fluoro-5-(4-methoxytetrahydropyran-4-yl)phe-
noxymethyl]-1-(4-methoxyphenyl)-5-phenyl-1H-pyra-
zole (10f) was synthesized in 82% yield (200 mg) from alkyl
1-(4-Methanesulfonylphenyl)-3-[(3-nitro)phenoxy-
methyl]-5-phenyl-1H-pyrazole (10l) was synthesized in 23%