Anthranilic Sulfonamides as NoVel Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 21 6387
8.22 (d, J ) 8.8 Hz, 1H), 7.75 (d, J ) 1.9 Hz, 1H), 7.72 (dd, J )
8.7, 7.3 Hz, 1H), 7.42-7.27 (m, 5H), 7.23 (d, J ) 8.5 Hz, 1H),
6.92 (dd, J ) 8.4, 1.7 Hz, 1H), 6.26-6.17 (br m, 1H), 4.56 (d, J
) 5.6 Hz, 2H). Anal. (C20H15ClN4O3S2) C, H, N.
2-[(2,1,3-Benzothiadiazol-4-ylsulfonyl)amino]-4-chloro-N-meth-
yl-N-(phenylmethyl)-benzamide (24r). The compound was pre-
pared according to the general procedure for HATU-mediated
peptide coupling using 16d (18 mg, 0.05 mmol), pyridine (0.012
mL, 0.15 mmol), HATU (38 mg, 0.1 mmol), N-methylbenzylamine
(0.013 mL, 0.1 mmol), and DMF (0.4 mL) to give 24r (8 mg, 0.02
4-[4-Fluoro-2-[(5-quinoxalinylsulfonyl)amino]benzoyl]-mor-
pholine (26a). The compound was prepared from morpholine (12
µL, 0.14 mmol), 17g (24 mg, 0.07 mmol), HATU (53 mg, 0.14
mmol), pyridine (17 µL, 0.21 mmol), and DMF (400 µL) as
described in the general procedure for the HATU-mediated prepara-
tion of amides to give 26a as a white amorphous solid (15 mg,
0.036 mmol, 52%). HPLC-A: tR ) 7.76 min (>99%). HPLC-B:
tR ) 3.32 min (>99%). MS (ESI): m/z 417 [M + H]+, 439 [M +
1
Na]+. H NMR (400 MHz, CDCl3; rotameric broadening): δ 9.22
(s, 1H), 9.07 (d, J ) 1.8 Hz, 1H), 9.01 (d, J ) 1.8 Hz, 1H), 8.53
(dd, J ) 7.3, 1.4 Hz, 1H), 8.37 (dd, J ) 8.5, 1.4 Hz, 1H), 7.90 (dd,
J ) 8.5, 7.4 Hz, 1H), 7.35 (dd, J ) 10.7, 2.4 Hz, 1H), 7.05 (dd, J
) 8.5, 6.1 Hz, 1H), 6.74-6.69 (m, 1H), 3.60-3.39 (br m, 8H).
HRMS (ESI): calcd for C19H18FN4O4S [M + H]+, 417.1027; found,
417.1048.
mmol, 30%). HPLC-A: tR ) 9.94 min (>99%). HPLC-B: tR
)
1
4.33 min (>99%). MS (ESI): m/z 471 [M - H]-. H NMR (400
MHz, CDCl3; rotameric broadening): δ 9.15 (br s, 1H), 8.32 (br d,
J ) 6.8 Hz, 1H), 8.29-8.18 (br m, 1H), 7.79-7.63 (br m, 2H),
7.48-7.26 (br m, 4H), 7.15-6.83 (br m, 2H), 7.02 (br d, J ) 8.2
Hz, 1H), 4.65-4.37 (br s, 1.3H), 4.37-4.00 (br s, 0.7H), 3.15-
2.70 (br s, 1.1H), 2.70-2.35 (br s, 1.9H). HRMS (ESI): calcd for
C21H17ClN4O3S2 [M + H]+, 473.0503; found, 473.0529.
4-[4-Chloro-2-[(5-quinoxalinylsulfonyl)amino]benzoyl]-mor-
pholine (26b). The compound was prepared according to the
general procedure for HATU-mediated peptide coupling using 17d
(17 mg, 0.050 mmol), pyridine (0.012 mL, 0.15 mmol), HATU
(38 mg, 0.1 mmol), morpholine (0.009 mL, 0.1 mmol), and DMF
(0.4 mL) to provide 26b (20 mg, 0.046 mmol, 92%). MS (ESI):
m/z 431 [M - H]-. HPLC-A: tR ) 8.14 min. HPLC-B: tR ) 3.52
4-[2-[(2,1,3-Benzothiadiazol-4-ylsulfonyl)amino]benzoyl]-mor-
pholine (25a). The compound was prepared from morpholine (18
mL, 0.20 mmol), 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-
benzoic acid (16b; Fluorchem, Ltd., U.K.; 38 mg, 0.10 mmol),
HATU (76 mg, 0.20 mmol), pyridine (24 mL, 0.30 mmol), and
DMF (700 mL) as described in the general procedure for HATU-
mediated amide preparation to give 25a as a white solid (20 mg,
0.049 mmol, 49%). Mp 150-154 °C. HPLC-A: tR ) 7.66 min
(>99%). HPLC-B: tR ) 3.33 min (>99%). MS (ESI): m/z 405
[M + H]+, 427 [M + Na]+. 1H NMR (400 MHz, CDCl3; rotameric
broadening): δ 8.67 (s, 1H), 8.27-8.24 (m, 2H), 7.70 (dd, J )
8.8, 7.0 Hz, 1H), 7.47 (d, J ) 8.2 Hz, 1H), 7.31-7.27 (m, 1H),
7.10-7.08 (m, 2H), 3.63 (br s, 8H). HRMS (ESI): calcd for
C17H17N4O4S2 [M + H]+, 405.0686; found, 405.0716.
4-[2-[(2,1,3-Benzothiadiazol-4-ylsulfonyl)amino]-4-fluoroben-
zoyl]-morpholine (25b). The compound was prepared from mor-
pholine (18 µL, 0.20 mmol), 16g (35 mg, 0.10 mmol), HATU (76
mg, 0.20 mmol), pyridine (24 µL, 0.30 mmol), and DMF (700 µL)
and purified as described in the general procedure for HATU-
mediated amide preparation to give 22b as a white solid (25 mg,
0.059 mmol, 59%). Mp 165-168 °C. HPLC-A: tR ) 8.14 min
(>99%). MS (ESI): m/z 423 [M + H]+, 445 [M + Na]+. 1H NMR
(400 MHz, CDCl3; rotameric broadening): δ 9.21 (s, 1H), 8.33 (dd,
J ) 7.0, 1.0 Hz, 1H), 8.26 (dd, J ) 8.4, 1.0 Hz, 1H), 7.73 (dd, J
) 8.8, 7.0 Hz, 1H), 7.37 (dd, J ) 10.6, 2.4 Hz, 1H), 7.09-7.05
(m, 1H), 6.75-6.71 (m, 1H), 3.61 (br s, 4H), 3.42 (br s, 4H). Anal.
(C17H15FN4O4S2) C, H, N.
1
min. H NMR (500 MHz, CDCl3; rotameric broadening): δ 9.11
(br s, 1H), 9.06 (d, J ) 1.8 Hz, 1H), 9.01 (d, J ) 1.8 Hz, 1H), 8.52
(dd, J ) 7.0, 1.5 Hz, 1H), 8.37 (dd, J ) 8.4, 1.4 Hz, 1H), 7.90 (dd,
J ) 8.4, 7.4 Hz, 1H), 7.63 (d, J ) 1.5 Hz, 1H), 7.00 (m, 2H), 3.55
(br m, 6H), 3.22 (br m, 2H). Anal. (C19H17ClN4O4S) C, H, N.
4-[4-Bromo-2-[(5-quinoxalinylsulfonyl)amino]benzoyl]-mor-
pholine (26c). The compound was prepared according to the general
procedure for HATU-mediated peptide coupling using 17e (21 mg,
0.051 mmol), pyridine (0.012 mL, 0.15 mmol), HATU (38 mg,
0.1 mmol), morpholine (0.009 mL, 0.1 mmol), and DMF (0.4 mL)
to provide 26c (22 mg, 0.046 mmol, 92%). MS (ESI): m/z 475/
477 [M - H]-. HPLC-A: tR ) 8.23 min. HPLC-B: tR ) 3.58
1
min. H NMR (500 MHz, CDCl3; rotameric broadening): δ 9.08
(br s, 1H), 9.06 (d, J ) 1.8 Hz, 1H), 9.01 (d, J ) 1.8 Hz, 1H), 8.52
(dd, J ) 7.0, 1.5 Hz, 1H), 8.37 (dd, J ) 8.4, 1.4 Hz, 1H), 7.90 (dd,
J ) 8.4, 7.4 Hz, 1H), 7.79 (d, J ) 1.5 Hz, 1H), 7.17 (dd, J ) 8.0,
1.6 Hz, 1H), 6.92 (d, J ) 8.0 Hz, 1H), 3.55 (br m, 6H), 3.22 (br
m, 2H). Anal. (C19H17BrN4O4S) C, H, N.
4-[4-Iodo-2-[(5-quinoxalinylsulfonyl)amino]benzoyl]-morpho-
line (26d). The compound was prepared according to the general
procedure for HATU-mediated peptide coupling using 17f (23 mg,
0.050 mmol), pyridine (0.012 mL, 0.15 mmol), HATU (38 mg,
0.1 mmol), morpholine (0.009 mL, 0.1 mmol), and DMF (0.4 mL)
to give 26d (22 mg, 0.042 mmol, 84%). MS (ESI): m/z 523 [M -
H]-. HPLC-A: tR ) 8.32 min. 1H NMR (500 MHz, CDCl3;
rotameric broadening): δ 9.06 (d, J ) 1.8 Hz, 1H), 9.02 (d, J )
1.8 Hz, 1H), 9.01 (br s, 1H), 8.51 (dd, J ) 7.0, 1.5 Hz, 1H), 8.37
(dd, J ) 8.4, 1.4 Hz, 1H), 7.96 (d, J ) 1.5 Hz, 1H), 7.90 (dd, J )
8.4, 7.4 Hz, 1H), 7.38 (dd, J ) 8.0, 1.6 Hz, 1H), 6.76 (d, J ) 8.0
Hz, 1H), 3.50 (br m, 6H), 3.15 (br m, 2H). Anal. (C19H17IN4O4S)
C, H, N.
4-[2-[(2,1,3-Benzothiadiazol-4-ylsulfonyl)amino]-4-bromoben-
zoyl]-morpholine (25c). The compound was prepared from mor-
pholine (18 µL, 0.20 mmol), 16e (41 mg, 0.10 mmol), HATU (76
mg, 0.20 mmol), pyridine (24 µL, 0.30 mmol), and DMF (700 µL)
and purified as described in the general procedure for HATU-
mediated amide preparation to give 25c as a white solid (23 mg,
0.048 mmol, 48%). Mp 185-188 °C. HPLC-A: tR ) 8.43 min
1
(>99%). MS (ESI): m/z 483/484/485 [M + H]+. H NMR (400
(S)-4-[4-Chloro-2-[(5-quinoxalinylsulfonyl)amino]benzoyl]-3-
methylmorpholine (26e). The title compound was prepared ac-
cording to the general procedure for HATU-mediated peptide
coupling using 17d (18 mg, 0.050 mmol), pyridine (0.012 mL, 0.15
mmol), HATU (38 mg, 0.1 mmol), (S)-3-methylmorpholine41 (0.010
mL, 0.1 mmol), and DMF (0.4 mL) to give 26e (5 mg, 0.01 mmol,
20%). MS (ESI): m/z 445 [M - H]-. HPLC-A: tR ) 8.44 min
MHz, CDCl3; rotameric broadening): δ 8.97 (s, 1H), 8.32 (dd, J )
7.0, 1.0 Hz, 1H), 8.27 (dd, J ) 8.8, 1.0 Hz, 1H), 7.78 (d, J ) 1.8
Hz, 1H), 7.74 (dd, J ) 8.8, 7.0 Hz, 1H), 7.18 (dd, J ) 8.2, 1.8 Hz,
1H), 6.94 (d, J ) 8.2 Hz, 1H), 3.7-3.18 (br m, 8H). Anal. (C17H15-
BrN4O4S2) C, H, N.
4-[2-[(2,1,3-Benzothiadiazol-4-ylsulfonyl)amino]-4-iodobenzoyl]-
morpholine (25d). The compound was prepared from morpholine
(9 µL, 0.05 mmol), 16f (23 mg, 0.05 mmol), HATU (38 mg, 0.10
mmol), pyridine (12 µL), and DMF (400 µL) and purified as
described in the general procedure HATU-mediated amide prepara-
tion to give 25d as a white amorphous solid (13 mg, 0.025 mmol,
50%). HPLC-A: tR ) 8.50 min (>99%). MS (ESI): m/z 531 [M
1
(>99%). HPLC-B: tR ) 3.60 min (>99%). H NMR (400 MHz,
CDCl3; rotameric broadening): δ 9.05 (br s, 1H), 9.05 (d, J ) 1.8
Hz, 1H), 9.00 (d, J ) 1.8 Hz, 1H), 8.56 (dd, J ) 7.3, 1.3 Hz, 1H),
8.37 (dd, J ) 8.5, 1.3 Hz, 1H), 7.91 (dd, J ) 8.5, 7.3 Hz, 1H),
7.57 (s, 1H), 7.03-6.98 (m, 2H), 4.70-3.40 (br m, 2H), 3.92-
3.80 (br m, 1H), 3.75-3.58 (br m, 1H), 3.51 (dd, J ) 11.7, 2.8
Hz, 1H), 3.40-3.15 (br m, 2H), 1.35-1.15 (br m, 3H). HRMS
(ESI): calcd for C20H19ClN4O4S [M + H]+, 447.0888; found,
447.0893.
1
+ H]+, 553 [M + Na]+. H NMR (400 MHz, CDCl3; rotameric
broadening): δ 8.91 (s, 1H), 8.31 (dd, J ) 7.0, 0.9 Hz, 1H), 8.27
(dd, J ) 8.8, 0.9 Hz, 1H), 7.97 (d, J ) 1.5 Hz, 1H), 7.74 (dd, J )
8.8, 7.0 Hz, 1H), 7.41 (dd, J ) 8.1, 1.6 Hz, 1H), 6.78 (d, J ) 8.1
Hz, 1H), 3.75-3.0 (br m, 8H). Anal. (C17H15IN4O4S2) C, H, N.
(R)-4-[4-Chloro-2-[(5-quinoxalinylsulfonyl)amino]benzoyl]-3-
methylmorpholine (26f). The title compound was prepared ac-