ꢀ
I. Sosic et al. / European Journal of Medicinal Chemistry 46 (2011) 2880e2894
2892
Naph-H), 8.02 (d, J ¼ 9.0 Hz, 1H, Naph-H), 8.34 (d, J ¼ 1.8 Hz, 1H,
Naph-H), 12.09 (br s, 1H, COOH); HRMS (ESI) m/z calcd for
H), 7.59 (dd, J ¼ 8.1, 1.5 Hz, 1H, Ar-H), 7.68 (dd, J ¼ 8.7, 1.8 Hz, 1H,
Ar-H), 7.90e7.93 (m, 2H, Ar-H), 8.03 (d, J ¼ 9.0 Hz, 1H, Ar-H), 8.11 (d,
J ¼ 1.5 Hz, 1H, Ar-H), 8.44 (d, J ¼ 1.8 Hz, 1H, Ar-H), 11.14 (br s, 1H,
NH), 13.20 (br s, 2H, 2 ꢁ COOH); 13C NMR (100 MHz, DMSO-d6):
C21H28NO5S [M
þ
H]þ 406.1688, found 406.1674; Anal.
(C21H27NO5S) C, H, N.
d
13.61, 18.67, 30.48, 67.51, 106.71, 119.17, 120.39, 120.68, 122.19,
5.6.3.21. (1R,2R)-2-(6-butoxynaphthalene-2-sulfonamido)cyclo-
123.59, 126.65, 128.27, 128.35, 130.87, 131.80, 132.64, 135.50, 136.44,
139.67, 159.17, 165.91, 169.03; HRMS (ESI) m/z calcd for C22H20NO7S
[MeH]ꢃ 442.0960, found 442.0962; Anal. (C22H21NO7S) C, H, N.
hexanecarboxylic acid (31c). White solid (85 mg, 91%); mp:
178.0e179.5 ꢀC; [
a
]
20: þ4.1 (c 0.231, DMSO); 1H NMR (300 MHz,
D
DMSO-d6):
d
0.96 (t, J ¼ 7.4 Hz, 3H, CH2CH3), 0.99e1.16 (m, 3H,
cyclohexyl-H), 1.28e1.57 (m, 6H, CH2CH3 and cyclohexyl-H),
1.70e1.87 (m, 3H, OCH2CH2 and cyclohexyl-H), 2.17 (td, J ¼ 10.5,
3.6 Hz, 1H, cyclohexyl-H), 3.28e3.41 (m, 1H, cyclohexyl-H, overlaps
with water), 4.13 (t, J ¼ 6.5 Hz, 2H, OCH2), 7.27 (dd, J ¼ 9.0, 2.4 Hz,
1H, Naph-H), 7.42 (d, J ¼ 2.4 Hz, 1H, Naph-H), 7.70 (br d, J ¼ 8.9 Hz,
1H, NH), 7.74 (dd, J ¼ 8.7, 1.8 Hz, 1H, Naph-H), 7.93 (d, J ¼ 8.7 Hz, 1H,
Naph-H), 8.03 (d, J ¼ 9.0 Hz, 1H, Naph-H), 8.31 (d, J ¼ 1.8 Hz, 1H,
Naph-H), 12.08 (br s, 1H, COOH); 13C NMR (100 MHz, DMSO-d6):
5.6.3.26. 5-(6-Butoxynaphthalene-2-sulfonamido)isophthalic acid
(31h). White solid (96 mg, 98%); mp: 233.5e235.0 ꢀC; 1H NMR
(300 MHz, DMSO-d6):
d
0.94 (t, J ¼ 7.4 Hz, 3H, CH2CH3), 1.39e1.52
(m, 2H, CH2CH3), 1.68e1.81 (m, 2H, OCH2CH2), 4.10 (t, J ¼ 6.5 Hz,
2H, OCH2), 7.26 (dd, J ¼ 9.0, 2.4 Hz, 1H, Ar-H), 7.39 (d, J ¼ 2.4 Hz,
1H, Ar-H), 7.69 (dd, J ¼ 8.7, 1.8 Hz, 1H, Ar-H), 7.90e7.97 (m, 3H, Ar-
H), 8.02 (d, J ¼ 9.0 Hz, 1H, Ar-H), 8.07 (dd, J ¼ 1.5, 1.5 Hz, 1H, Ar-H),
8.35 (d, J ¼ 1.8 Hz, 1H, Ar-H), 10.75 (br s, 1H, NH), 13.23 (br s, 2H,
2 ꢁ COOH); HRMS (ESI) m/z calcd for C22H20NO7S [MeH]ꢃ
442.0960, found 442.0968; Anal. (C22H21NO7S) C, H, N.
d
13.64, 18.71, 23.65, 23.74, 28.17, 30.56, 31.62, 48.99, 53.23, 67.40,
106.68, 120.10, 122.84, 126.50, 126.77, 127.71, 130.67, 135.74, 137.19,
158.52, 174.74; HRMS (ESI) m/z calcd for C21H28NO5S [M þ H]þ
406.1688, found 406.1704; Anal. (C21H27NO5S) C, H, N.
5.6.3.27. 4-(6-Butoxynaphthalene-2-sulfonamido)isophthalic acid
(31i). White solid (102 mg, 86%); mp: 243.0e244.0 ꢀC; 1H NMR
5.6.3.22. 4-(6-Butoxynaphthalene-2-sulfonamido)cyclohexane-1,
(300 MHz, DMSO-d6):
d
0.93 (t, J ¼ 7.4 Hz, 3H, CH2CH3), 1.38e1.52
3-dicarboxylic acid, racemate (31d). White solid (54 mg, 87%);
(m, 2H, CH2CH3), 1.69e1.81 (m, 2H, OCH2CH2), 4.10 (t, J ¼ 6.5 Hz,
2H, OCH2), 7.29 (dd, J ¼ 9.0, 2.4 Hz, 1H, Ar-H), 7.41 (d, J ¼ 2.4 Hz,
1H, Ar-H), 7.66 (d, J ¼ 8.7 Hz, 1H, Ar-H), 7.77 (dd, J ¼ 8.7, 1.8 Hz, 1H,
Ar-H), 7.95 (d, J ¼ 8.7 Hz, 1H, Ar-H), 8.02 (dd, J ¼ 8.7, 2.1 Hz, 1H, Ar-
H), 8.08 (d, J ¼ 9.0 Hz, 1H, Ar-H), 8.43 (d, J ¼ 2.1 Hz, 1H, Ar-H), 8.58
(d, J ¼ 1.8 Hz, 1H, Ar-H), 11.55 (br s, 1H, NH), 12.89 (br s, 2H,
2 ꢁ COOH); HRMS (ESI) m/z calcd for C22H21NO7SNa [M þ Na]þ
466.0936, found 466.0932; Anal. (C22H21NO7S) C, H, N.
mp: 228.0e231.0 ꢀC; [
a
]
D
20: þ1.2 (c 0.115, DMSO); 1H NMR
(300 MHz, DMSO-d6):
d
0.96 (t, J ¼ 7.4 Hz, 3H, CH2CH3), 1.14e1.27
(m, 2H, cyclohexyl-H),1.33e1.56 (m, 4H, CH2CH3 and cyclohexyl-H),
1.68e1.87 (m, 4H, OCH2CH2 and cyclohexyl-H), 2.04e2.19 (m, 1H,
cyclohexyl-H), 2.45e2.52 (m, 1H, cyclohexyl-H, overlaps with
DMSO), 3.86e3.97 (m, 1H, cyclohexyl-H), 4.13 (t, J ¼ 6.5 Hz, 2H,
OCH2), 7.27 (dd, J ¼ 9.0, 2.4 Hz, 1H, Naph-H), 7.42 (d, J ¼ 2.4 Hz, 1H,
Naph-H), 7.70 (br d, J ¼ 9.0 Hz, 1H, NH), 7.81 (dd, J ¼ 8.7, 1.8 Hz, 1H,
Naph-H), 7.93 (d, J ¼ 8.7 Hz, 1H, Naph-H), 8.02 (d, J ¼ 9.0 Hz, 1H,
Naph-H), 8.31 (d, J ¼ 1.8 Hz, 1H, Naph-H), 12.06 (br s, 2H,
2 ꢁ COOH); HRMS (ESI) m/z calcd for C22H28NO7S [M þ H]þ
450.1586, found 450.1585; Anal. (C22H27NO7S) C, H, N.
5.6.3.28. 1-(6-(4-Cyano-2-fluorobenzyloxy)naphthalen-2-ylsulfonyl)
piperidine-4-carboxylic acid (32a). White solid (38 mg, 65%); mp:
217.0e218.0 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d 1.47e1.65 (m, 2H,
piperidyl-H), 1.80e1.94 (m, 2H, piperidyl-H), 2.17e2.31 (m, 1H,
piperidyl-H), 2.48 (td, J ¼ 11.1, 1.8 Hz, 2H, piperidyl-H), 3.52 (dt,
J ¼ 11.8, 3.9 Hz, 2H, piperidyl-H), 5.43 (s, 2H, OCH2), 7.43 (dd, J ¼ 9.0,
2.4 Hz, 1H, Ar-H), 7.65 (d, J ¼ 2.4 Hz, 1H, Ar-H), 7.71 (dd, J ¼ 8.7,
1.8 Hz, 1H, Ar-H), 7.81e7.88 (m, 2H, Ar-H), 7.95 (dd, J ¼ 9.9, 1.2 Hz,
1H, Ar-H), 8.04 (d, J ¼ 8.7 Hz, 1H, Ar-H), 8.16 (d, J ¼ 9.0 Hz, 1H, Ar-H),
8.36 (d, J ¼ 1.2 Hz, 1H, Ar-H), 12.22 (br s, 1H, COOH); HRMS (ESI) m/z
calcd for C24H20FN2O5S [MeH]ꢃ 467.1077, found 467.1068; Anal.
(C24H21FN2O5S) C, H, N.
5.6.3.23. 2-(4-(6-Butoxynaphthalene-2-sulfonamido)phenyl)acetic acid
(31e). White solid (70 mg, 91%); mp: 192.0e193.0 ꢀC; 1H NMR
(300 MHz, DMSO-d6):
d
0.95 (t, J ¼ 7.4 Hz, 3H, CH2CH3), 1.39e1.54 (m,
2H, CH2CH3), 1.70e1.82 (m, 2H, OCH2CH2), 3.40 (s, 2H, CH2COO), 4.11
(t, J ¼ 6.5 Hz, 2H, OCH2), 7.00e7.11 (m, 4H, Ar-H), 7.26 (dd, J ¼ 9.0,
2.4 Hz, 1H, Ar-H), 7.39 (d, J ¼ 2.4 Hz, 1H, Ar-H), 7.70 (dd, J ¼ 8.7, 1.8 Hz,
1H, Ar-H), 7.92 (d, J ¼ 8.7 Hz, 1H, Ar-H), 8.00 (d, J ¼ 9.0 Hz, 1H, Ar-H),
8.32 (d, J ¼ 1.8 Hz, 1H, Ar-H), 10.23 (br s, 1H, NH), 12.18 (br s, 1H,
COOH); HRMS (ESI) m/z calcd for C22H24NO5S [M þ H]þ 414.1375,
found 414.1358; Anal. (C22H23NO5S) C, H, N.
5.6.3.29. (1R,2S)-2-(6-(4-cyano-2-fluorobenzyloxy)naphthalene-2-sul-
fonamido)cyclohexanecarboxylic acid (32b). White solid (95 mg, 67%);
mp: 187.0e189.0 ꢀC; [
(300 MHz, DMSO-d6): d 1.05e1.31 (m, 3H, cyclohexyl-H), 1.37e1.62
a
]
D
20: þ25.8 (c 0.149, DMSO); 1H NMR
5.6.3.24. 2-(6-Butoxynaphthalene-2-sulfonamido)-5-hydroxybenzoic
acid (31f). Pale brown solid (116 mg, 84%); mp: 196.0e198.0 ꢀC; 1H
(m, 4H, cyclohexyl-H), 1.74e1.70 (m, 1H, cyclohexyl-H), 2.47e2.55 (m,
1H, cyclohexyl-H), 3.60e3.75 (m, 1H, cyclohexyl-H), 5.47 (s, 2H,
OCH2), 7.45 (dd, J ¼ 9.0, 2.1 Hz, 1H, Ar-H), 7.65 (d, J ¼ 2.1 Hz, 1H, Ar-H),
7.80e7.94 (m, 3H, Ar-H), 7.97e8.06 (m, 2H, Ar-H), 8.14 (d, J ¼ 9.0 Hz,
1H, Ar-H), 8.43 (d, J ¼ 1.2 Hz, 1H, Ar-H), resonance for NH missing,
12.09 (br s, 1H, COOH); HRMS (ESI) m/z calcd for C25H22FN2O5S
[MeH]ꢃ 481.1233, found 481.1220; Anal. (C25H23FN2O5S) C, H, N.
NMR (300 MHz, DMSO-d6):
d
0.94 (t, J ¼ 7.4 Hz, 3H, CH2CH3),
1.39e1.53 (m, 2H, CH2CH3), 1.69e1.82 (m, 2H, OCH2CH2), 4.10 (t,
J ¼ 6.5 Hz, 2H, OCH2), 6.95 (dd, J ¼ 9.0, 3.0 Hz, 1H, Ar-H), 7.16 (d,
J ¼ 3.0 Hz, 1H, Ar-H), 7.26 (dd, J ¼ 9.0, 2.4 Hz, 1H, Ar-H), 7.36e7.44
(m, 2H, Ar-H), 7.55 (dd, J ¼ 8.7, 1.8 Hz, 1H, Ar-H), 7.87 (d, J ¼ 8.7 Hz,
1H, Ar-H), 8.00 (d, J ¼ 9.0 Hz, 1H, Ar-H), 8.30 (d, J ¼ 1.8 Hz, 1H, Ar-H),
9.61 (s, 1H, OH), 10.44 (br s, 1H, NH), 13.56 (br s, 1H, COOH); HRMS
(ESI) m/z calcd for C21H20NO6S [MeH]ꢃ 414.1011, found 414.1013;
Anal. (C21H21NO6S) C, H, N.
5.6.3.30. (1R,2R)-2-(6-(4-cyano-2-fluorobenzyloxy)naphthalene-2-
sulfonamido)cyclohexanecarboxylic acid (32c). White solid (92 mg,
65%); mp: 212.0e214.5 ꢀC; [
(300 MHz, DMSO-d6): d 0.91e1.19 (m, 3H, cyclohexyl-H),
a
]
20: þ13.9 (c 0.024, DMSO); 1H NMR
D
5.6.3.25. 2-(6-Butoxynaphthalene-2-sulfonamido)terephthalic acid
(31g). White solid (149 mg, 87%); mp: 233.0e234.0 ꢀC; 1H NMR
1.28e1.59 (m, 4H, cyclohexyl-H), 1.73e1.86 (m, 1H, cyclohexyl-H),
2.17 (td, J ¼ 10.4, 3.6, 1H, cyclohexyl-H), 3.27e3.39 (m, 1H, cyclo-
hexyl-H, overlaps with water), 5.41 (s, 2H, OCH2), 7.39 (dd, J ¼ 9.0,
2.1 Hz, 1H, Ar-H), 7.59 (d, J ¼ 2.1 Hz, 1H, Ar-H), 7.74e7.89 (m, 3H,
(300 MHz, DMSO-d6):
d
0.94 (t, J ¼ 7.4 Hz, 3H, CH2CH3), 1.39e1.53
(m, 2H, CH2CH3),1.68e1.81 (m, 2H, OCH2CH2), 4.10 (t, J ¼ 6.5 Hz, 2H,
OCH2), 7.28 (dd, J ¼ 9.0, 2.4 Hz, 1H, Ar-H), 7.40 (d, J ¼ 2.4 Hz, 1H, Ar-