Pyridinic Analogues of Nimesulide
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 27 6757
N-[3-(4-Chlorophenoxy)-4-pyridinyl]trifluoromethane-
4-Amino-3-(4-bromophenoxy)pyridine (8e). Yield: 82%.
1H NMR (DMSO-d6): δ 5.87 (bs exchangeable, 2H, NH2), 6.59-
6.84 (m, 3H, H-5 + H-2′ + H-6′), 7.36 (d, 2H, H-3′ + H5′), 7.82-
7.91 (m, 2H, H-2 + H-6).
4-Amino-3-(4-methoxyphenoxy)pyridine (8f). Yield: 75%.
4-Amino-3-(2,4-dichlorophenoxy)pyridine (8g). Yield:
41%.
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sulfonamide (12l). Yield: 63%. Mp: 222-223 °C. H NMR
(DMSO-d6): δ 6.92 (d, 2H, H′-2 + H′6), 7.35 (d, 2H, H′-3 +
H′-5), 7.75 (d, 1H, H-5), 8.27 (d, 1H, H-6), 8.48 (s, 1H, H-2).
Anal. (C12H8ClF3N2O3S) C, H, N, S.
N-[3-(4-Bromophenoxy)-4-pyridinyl]trifluoromethane-
sulfonamide (12m). Yield: 71%. Mp: 245-246 °C. 1H NMR
(DMSO-d6): δ 6.87 (d, 2H, H-2′ + H-6′), 7.48 (d, 2H, H-3′ +
H-5′), 7.75 (d, 1H, H-5), 8.26 (d, 1H, H-6), 8.46 (s, 1H, H-2).
Anal. (C12H8BrF3N2O3S) C, H, N, S.
N-[3-(4-Methoxyphenoxy)-4-pyridinyl]trifluorometh-
anesulfonamide (12n). Yield: 56%. Mp: 191-192 °C. 1H
NMR (DMSO-d6): δ 3.72 (s, 3H, OCH3), 6.91-6.96 (m, 4H,
H′aro), 7.72 (d, 1H, H-5), 8.17-8.23 (m, 2H, H-2 + H-6). Anal.
(C13H11F3N2O4S) C, H, N, S.
N-[3-(2,4-Dichlorophenoxy)-4-pyridinyl]trifluo-
romethanesulfonamide (12o). Yield: 71%. Mp: 171-172
°C. 1H NMR (DMSO-d6): δ 6.85 (d, 1H, H-6′), 7.33 (d, 1H, H-5′),
7.70 (m, 2H, H-5 + H-3′), 8.28 (d, 1H, H-6), 8.55 (s, 1H, H-2),
14.05 (bs, 1H, NH+). Anal. (C12H7Cl2F3N2O3S) C, H, N, S.
N-[3-(3,5-Dichlorophenoxy)-4-pyridinyl]trifluo-
romethanesulfonamide (12p). Yield: 67%. Mp: 219-220
°C. 1H NMR (DMSO-d6): δ 7.01 (m, 2H, H′-2 + H′-6), 7.29 (m,
1H, H′-4), 7.77 (d, 1H, H-5), 8.31 (d, 1H, H-6), 8.57 (s, 1H, H-2).
Anal. (C12H7Cl2F3N2O3S) C, H, N, S.
4-Amino-3-(3,5-dichlorophenoxy)pyridine (8h). Yield:
72%.
4-Amino-3-phenylsulfanylpyridine (9). Yield: 77%.
4-Amino-3-phenylaminopyridine (10). Yield: 52%.
4-Amino-N′-methyl-N′-phenyl-3-pyridinamine
Yield: 60%.
N-(3-Phenoxy-4-pyridinyl)methanesulfonamide (12a)
and N-(3-Phenoxy-4-pyridinyl)trifluoromethanesulfona-
mide (12i). 12a and 12i were synthesized following the
procedure previously described.28
N-(3-(2-Chlorophenoxy)-4-pyridinyl)methanesulfona-
mide (12b). Anhydrous potassium carbonate (8.29 g, 60 mmol)
was added to 4-amino-3-(2-chlorophenoxy)pyridine (2.20 g, 10
mmol) dissolved in dry acetonitrile (112 mL). The suspension
was stirred for 5 min, and methanesulfonyl chloride (3.11 mL,
60 mmol) was added. The suspension was stirred for 6 h and
filtered, and the solvent was evaporated under reduced pres-
sure. The residue was taken up with a 10% aqueous solution
of NaOH, and the resulting solution was neutralized with 1
N HCl to precipitate the title compound as a white solid.
Yield: 76%. Mp: 208-209 °C. 1H NMR (DMSO-d6): δ 2.50 (s,
3H, CH3), 6.86 (d, 1H, H-6′), 7.12 (t, 1H, H-5′), 7.28 (m, 1H,
H-4′), 7.41 (d, 1H, H-3′), 7.54 (dd, 1H, H-5), 8.01-8.07 (m, 2H,
H-2 + H6). Anal. (C12H11ClN2O3S) C, H, N, S.
(11).
N-(3-Phenoxy-4-pyridinyl)ethanesulfonamide (12q).
Yield: 63%. Mp: 128-129 °C. 1H NMR (DMSO-d6): δ 0.95 (t,
3H, CH3), 2.85 (bm, 2H, CH2), 6.91 (d, 2H, H-2′ + H-6′), 7.06
(t, 1H, H-4′), 7.33 (t, 2H, H-3′ + H-5′), 7.42 (d, 1H, H-5), 8.02
(bs, 1H, H-6), 8.08 (s, 1H, H-2). Anal. (C13H14N2O3S) C, H, N,
S.
N-[3-(4-Chlorophenoxy)-4-pyridinyl]ethanesulfona-
The following compounds were similarly were prepared.
N-[3-(3-Chlorophenoxy)-4-pyridinyl]methanesulfona-
mide (12c). Yield: 52%. Mp: 172-173 °C. 1H NMR (DMSO-
d6): δ 2.79 (s, 3H, CH3), 6.88 (dd, 1H, H-4′), 6.98 (s, 1H, H-2′),
7.13 (d, 1H, H-6′), 7.36 (t, 1H, H-5′), 7.44 (d, 1H, H-5), 8.06 (d,
1H, H-6), 8.18 (s, 1H, H-2). Anal. (C12H11ClN2O3S) C, H, N, S.
N-[3-(4-Chlorophenoxy)-4-pyridinyl]methanesulfona-
1
mide (12r). Yield: 79%. Mp: 133-134 °C. H NMR (DMSO-
d6): δ 0.95 (t, 3H, CH3), 2.80 (bm, 2H, CH2), 6.92 (d, 2H, H-2′
+ H-6′), 7.35-7.43 (m, 3H, H-5 + H-3′ + H-5′), 8.0 (m, 1H,
H-6), 8.16 (s, 1H, H-2). Anal. (C13H13ClN2O3S) C, H, N, S.
N-(3-Phenoxy-4-pyridinyl)propanesulfonamide (12s).
Yield: 61%. Mp: 191-192 °C. 1H NMR (DMSO-d6): δ 0.79 (t,
3H, CH3), 1.45 (m, 2H, CH2), 2.80 (bm, 2H, CH2), 6.91 (d, 2H,
H-2′ + H-6′), 7.06 (t, 1H, H-4′), 7.29-7.35 (t, 2H, H-3′ + H-5′),
7.42 (d, 1H, H-H-5), 8.02 (bs, 1H, H-6), 8.11 (s, 1H, H-2). Anal.
(C14H16N2O3S) C, H, N, S.
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mide (12d). Yield: 64%. Mp: 213-214 °C. H NMR (DMSO-
d6): δ 2.75 (s, 3H, CH3), 6.90-6.95 (m, 2H, H-2′ + H-6′), 7.20-
7.40 (m, 3H, H-5 + H-3′ + H-5′), 7.90-8.10 (m, 2H, H-2 +
H-6). Anal. (C12H11ClN2O3S) C H, N, S.
N-[3-(4-Chlorophenoxy)-4-pyridinyl]propanesulfona-
N-[3-(4-Bromophenoxy)-4-pyridinyl]methanesulfona-
mide (12e). Yield: 73%. Mp: 224-225 °C. 1H NMR (DMSO-
d6): δ 2.73 (s, 3H, CH3), 6.90-6.95 (d, 2H, H-2′ + H-6′), 7.25-
7.50 (m, 3H, H-5 + H-3′ + H-5′), 8.00-8.10 (m, 2H, H-2 +
H-6). Anal. (C12H11BrN2O3S) C, H, N, S.
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mide (12t). Yield: 47%. Mp: 121-122 °C. H NMR (DMSO-
d6): δ 0.80 (t, 3H, CH3), 1.35 (m, 2H, CH2), 2.75 (bm, 2H, CH2),
6.92 (d, 2H, H-2′ + H-6′), 7.33-7.42 (m, 3H, H-5 + H-3′ + H-5′),
8.01 (m, 1H, H-6), 8.16 (s, 1H, H-2). Anal. (C14H15ClN2O3S) C,
H, N, S.
N-[3-(4-Methoxyphenoxy)-4-pyridinyl]methanesulfona-
1
N-(3-Phenylsulfanyl-4-pyridinyl)methanesulfona-
mide (13a). Yield: 53%. Mp: 180-181 °C. 1H NMR (DMSO-
d6): δ 2.82 (s, 3H, CH3), 7.21 (d, 1H, H-5), 7.32 (s, 1H, H-2),
7.49 (m, 5H, H′aro), 7.92 (d, 1H, H-6), 13.60 (bs, 1H, H+). Anal.
(C12H12N2O3S2) C, H, N, S.
mide (12f). Yield: 68%. Mp: 188-189 °C. H NMR (DMSO-
d6): δ 2.91 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 6.90-7.0 (m, 4H,
H
aro′), 7.41 (d, 1H, H-5), 7.88 (s, 1H, H-2), 8.03 (d, 1H, H-6),
11.5 (bs, 1H, N-H). Anal. (C13H14N2O4S) C, H, N, S.
N-[3-(2,4-Dichlorophenoxy)-4-pyridinyl]methane-
1
N-(3-Phenylsulfanyl-4-pyridinyl)trifluoromethane-
sulfonamide (12g). Yield: 57%. Mp: 205-206 °C. H NMR
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sulfonamide (13b). Yield: 59%. Mp: 188-189 °C. H NMR
(DMSO-d6): δ 2.75 (s, 3H, CH3), 6.75 (d, 1H, H-6′), 7.15-7.60
(m, 3H, H-5 + H-3′ + H-5′), 7.90-8.10 (m, 2H, H-2 + H-6).
Anal. (C12H10Cl2N2O3S) C, H, N, S.
N-[3-(3,5-Dichlorophenoxy)-4-pyridinyl]methane-
sulfonamide (12h). Yield: 78%. Mp: 126-127 °C. H NMR
(DMSO-d6): δ 2.60 (s, 3H, CH3), 6.90 (s, 2H, H-2′ + H-6′), 7.2
(s, 1H, H-4′), 7.35 (d, 1H, H-5), 8.00 (d, 1H, H-6), 8.20 (s, 1H,
H-2). Anal. (C12H10Cl2N2O3S) C, H, N, S.
N-[3-(2-Chlorophenoxy)-4-pyridinyl]trifluoromethane-
sulfonamide (12j). Yield: 51%. Mp: 204-205 °C. H NMR
(DMSO-d6): δ 6.80 (dd, 1H, H′-6), 7.09-7.14 (m, 1H, H′-5),
7.22-7.27 (m, 1H, H′-4), 7.54 (dd, 1H, H′-3), 7.75 (d, 1H, H-5),
8.30 (d, 1H, H-6), 8.45 (s, 1H, H-2). Anal. (C12H8ClF3N2O3S)
C, H, N, S.
N-[3-(3-Chlorophenoxy)-4-pyridinyl]trifluoromethane-
sulfonamide (12k). Yield: 59%. Mp: 198-199 °C. H NMR
(DMSO-d6): δ 7.52-7.59 (m, 3H, H-2′ + H-4′ + H-6′), 7.70 (t,
2H, H-3′ + H-5′), 7.93 (d, 1H, H-5), 8.35 (d, 1H, H-6), 9.03 (s,
1H, H-2). Anal. (C12H9F3N2O3S) C, H, N, S.
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N-(3-Phenylamino-4-pyridinyl)trifluoromethane-
1
sulfonamide (14b). Yield: 42%. Mp: 188-189 °C. H NMR
(DMSO-d6): δ 7.05 (t, 1H, H-4′), 7.28-7.42 (m, 5H, H′aro + NH),
7.62 (d, 1H, H-5), 7.97 (d, 1H, H-6), 8.05 (s, 1H, H-2), 13.60
(bs, 1H, N-H+). Anal. (C12H10F3N3O2S) C, H, N, S.
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N-[3-(N′-Methyl-N′-phenylamino)-4-pyridinyl]trifluo-
romethanesulfonamide (15b). Yield: 59%. Mp: 218-219
1
°C. H NMR (DMSO-d6): δ 3.12 (s, 3H, N-CH3), 6.58 (d, 2H,
H-2′ + H-6′), 6.72 (t, 1H, H-4′), 7.11-7.18 (m, 2H, H-3′ + H-5′),
7.76 (d, 1H, H-5), 8.25 (d, 1H, H-6), 8.35 (s, 1H, H-2). Anal.
(C13H12F3N2O2S) C, H, N, S.
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N-(3-Phenylsulfinyl-4-pyridinyl)trifluoromethane-
sulfonamide (16b). N-(3-Phenylsulfanyl-4-pyridinyl)trifluo-
romethanesulfonamide (0.1 g, 0.29 mmol) was dissolved in
dichloromethane (10 mL). Then m-chloroperbenzoic acid (0.056
g, 0.32 mmol) was added and the solution was stirred for 2 h.
(DMSO-d6): δ 6.87-7.95 (m, 2H, H-2′ + H-6′), 7.13 (d, 1H,
H-4′), 7.30 (t, 1H, H-5′), 7.75 (d, 1H, H-5), 8.10 (d, 1H, H-6),
8.55 (s, 1H, H-2), 13.90 (bs, 1H, NH). Anal. (C12H8ClF3N2O3S)
C, H, N, S.