The First Selective Nonpeptide AT2 Receptor Agonist
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24 6003
(15 mL), ethanol (1.3 mL), NaOH (1.3 mL, 1 M), and Pd(PPh3)4
(10.9 mg, 9 µmol) were mixed together under a N2(g) atmo-
sphere. The mixture was heated to reflux and stirred for 3 h.
After dilution with EtOAc (20 mL), the reaction mixture was
washed with water and brine. The organic phase was dried
and concentrated under vacuum. The crude product was
purified by column chromatography (hexane:acetone 2:1) to
give the title compound in 76% yield (115.8 mg, 0.240 mmol).
1H NMR (CDCl3), δ, ppm: 8.43 (d, J ) 4.9 Hz, 1H), 8.12-8.10
(m, 2H), 7.58 (d, J ) 8.1 Hz, 2H), 7.38 (d, J ) 8.1 Hz, 2H),
7.28 (m, 1H), 6.71 (s, 1H), 5.53 (s, 2H), 4.09 (brs, 1H), 2.64 (d,
J ) 7.1 Hz, 2H), 1.90 (sep, J ) 6.7 Hz, 1H), 0.95 (d, J ) 6.7
Hz, 6H), 0.93 (s, 9H). 13C NMR (CDCl3), δ, ppm: 148.7, 147.0,
144.8, 143.8, 142.5, 136.8, 136.3, 135.2, 135.1, 129.8, 128.9,
128.2, 128.0, 118.8, 54.7, 47.0, 39.3, 30.6, 29.6, 22.3. IR
(compression cell), cm-1: 3095, 2954, 2872. Anal. (C25H30N4O2S2)
C, H, N.
3-(4-Imidazol-1-ylmethylphenyl)-5-isobutyl-N-tert-bu-
tylthiophene-2-sulfonamide (14). Compound 2 (200.5 mg,
0.628 mmol), 7 (98.8 mg, 0.416 mmol), toluene (15 mL), ethanol
(1.5 mL), NaOH (1.5 mL, 1 M), and Pd(PPh3)4 (14.5 mg, 12.5
µmol) were mixed together under a N2(g) atmosphere. The
mixture was heated to reflux and stirred for 3 h. After dilution
with EtOAc (50 mL), the reaction mixture was washed with
water and brine. The organic phase was dried and concen-
trated under vacuum. The crude product was purified by
column chromatography (CHCl3:MeOH 20:1) to give the title
compound in 63% yield (113.9 mg, 0.264 mmol).
Alternatively, a dried heavy-walled Pyrex tube was charged
with 2 (49.2 mg, 0.154 mmol), 7 (21.9 mg, 92.4 µmol), toluene
(1.56 mL), ethanol (0.22 mL), Na2CO3 (2.0 M, 0.22 mL), and
Pd(PPh3)4 (8 mg, 7 µmol). The reaction mixture was flushed
with nitrogen and the cap tightened thoroughly. The reaction
mixture was exposed to microwave heating (150 °C, 5 min).
The reaction mixture was diluted with EtOAc (15 mL), washed
with water and brine, and dried. The solvent was removed
and the residue was separated by column chromatography
(CH2Cl2:MeOH 20:1) to give the title compound in 75% yield
(30.0 mg, 0.0695 mmol). 1H NMR (CDCl3), δ, ppm: 7.60-7.57
(m, 3H), 7.22 (d, J ) 8.1 Hz, 2H), 7.08 (s, 1H), 6.90 (s, 1H),
6.73 (s, 1H), 5.15 (s, 2H), 4.35 (m, 1H), 2.66 (d, J ) 7.3 Hz,
2H), 1.90 (m, 1H), 0.98 (s, 9H), 0.96 (d, J ) 6.6 Hz, 6H).
13C NMR (CDCl3), δ, ppm: 148.7, 142.5, 137.5, 136.8, 136.5,
135.1, 130.0, 129.8, 129.0, 127.5, 119.3, 54.7, 50.6, 39.3, 30.6,
3-[4-(2-Ethylbenzoimidazol-1-ylmethyl)phenyl]-5-isobu-
tyl-N-tert-butylthiophene-2-sulfonamide (11). Compound
2 (151.0 mg, 0.473 mmol), 4 (131.4 mg, 0.417 mmol), toluene
(15 mL), ethanol (1.5 mL), NaOH (1.7 mL, 1 M), and Pd(PPh3)4
(14.5 mg, 12 µmol) were mixed together under a N2(g)
atmosphere. The mixture was heated to reflux and stirred for
3 h. After dilution with EtOAc (20 mL), the reaction mixture
was washed with water and brine. The organic phase was
dried and concentrated under vacuum. The crude product was
purified by column chromatography (hexane:acetone 4:1) to
give the title compound in 54% yield (114.8 mg, 0.225 mmol).
1H NMR (CDCl3), δ, ppm: 7.82 (d, J ) 7.6 Hz, 1H), 7.56 (d, J
) 8.3 Hz, 2H), 7.30-7.20 (m, 3H), 7.12 (d, J ) 8.3 Hz, 2H),
6.70 (s, 1H), 5.39 (s, 2H), 4.05 (s, 1H), 2.94 (q, J ) 7.4 Hz,
2H), 2.65 (d, J ) 6.9 Hz, 2H), 1.90 (m, 1H), 1.45 (t, J ) 7.4
Hz, 3H), 1.00 (s, 9H), 0.95 (d, J ) 6.9 Hz, 6H). 13C NMR
(CDCl3), δ, ppm: 155.9, 148.6, 142.3, 135.8, 134.8, 129.7, 129.1,
128.8, 126.4, 126.1, 122.8, 122.7, 122.5, 119.1, 109.5, 54.6, 47.0,
29.6, 22.3. IR (compression cell), cm-1
(C22H29N3O2S2·H2O) C, H, N.
: 3060, 2996. Anal.
3-(4-Cyanomethylphenyl)-5-isobutyl-N-tert-butyl-
thiophene-2-sulfonamide (15). Compound 2 (200.5 mg,
0.628 mmol), (4-bromophenyl)acetonitrile (81.7 mg, 0.416
mmol), toluene (15 mL), ethanol (1.5 mL), NaOH (1.5 mL, 1
M), and Pd(PPh3)4 (18.0 mg, 15.6 µmol) were mixed together
under a N2(g) atmosphere. The mixture was heated to reflux
and stirred for 3 h. After dilution with EtOAc (50 mL), the
reaction mixture was washed with water and brine. The
organic phase was dried and concentrated under vacuum. The
crude product was purified by column chromatography (hexa-
ne:acetone 4:1) to give the title compound in 57% yield (92.5
39.2, 30.5, 29.4, 22.1, 20.8, 11.8. IR (compression cell), cm-1
3056, 2980, 2868. Anal. (C28H35N3O2S2) C, H, N.
:
3-(4-Benzoimidazole-1-ylmethylphenyl)-5-isobutyl-N-
tert-butylthiophenesulfonamide (12). Compound 2 (88.8
mg, 0.278 mmol), 5 (53.2 mg, 0.185 mmol), toluene (10 mL),
ethanol (0.65 mL), NaOH (0.74 mL, 1 M) and Pd(PPh3)4 (6.4
mg, 5.5 µmol) were mixed together under a N2(g) atmosphere.
The mixture was heated to reflux and stirred for 3 h. After
dilution with EtOAc (20 mL), the reaction mixture was washed
with water and brine. The organic phase was dried and
concentrated under vacuum. The crude product was purified
by column chromatography (hexane:acetone 2:1) to give the
1
mg, 0.237 mmol). H NMR (CDCl3), δ, ppm: 7.65 (d, J ) 8.2
Hz, 2H), 7.42 (d, J ) 8.2 Hz, 2H), 6.75 (s, 1H), 4.05 (brs, 1H),
3.81 (s, 2H), 2.70 (d, J ) 7.1 Hz, 2H), 1.97 (m, 1H), 1.01 (s,
9H), 0.98 (d, J ) 6.9 Hz, 6H). 13C NMR (CDCl3), δ, ppm: 148.7,
142.3, 134.8, 130.1, 129.8, 128.8, 128.0, 119.9, 117.6, 54.6, 39.2,
30.6, 29.6, 23.5, 22.1. IR (compression cell), cm-1: 3291, 2996,
2243. Anal. (C20H26N2O2S2·1/2H2O) C, H, N.
1
title compound in 95% yield (84.7 mg, 0.176 mmol). H NMR
3-(4-Cyanophenyl)-5-isobutyl-N-tert-butylthiophene-2-
sulfonamide (16). Compound 2 (200.5 mg, 0.628 mmol),
4-bromobenzonitrile (75.8 mg, 0.416 mmol), toluene (15 mL),
ethanol (1.5 mL), NaOH (1.5 mL, 1 M), and Pd(PPh3)4 (18.0
mg, 15.6 µmol) were mixed together under a N2(g) atmosphere.
The mixture was heated to reflux and stirred for 3 h. After
dilution with EtOAc (50 mL), the reaction mixture was washed
with water and brine. The organic phase was dried and
concentrated under vacuum. The crude product was purified
by column chromatography (hexane:acetone 5:1) to give the
title compound in 64% yield (100.1 mg, 0.266 mmol). 1H NMR
(CDCl3), δ, ppm: 7.74 (m, 4H), 6.75 (s, 1H), 4.12 (brs, 1H),
2.68 (d, J ) 7.1 Hz, 2H), 1.91 (m, 1H), 1.03 (s, 9H), 0.97 (d, J
) 6.6 Hz, 6H). 13C NMR (CDCl3), δ, ppm: 149.2, 141.2, 139.5,
137.6, 132.0, 129.9, 128.6, 118.5, 112.0, 54.9, 39.1, 30.6, 29.6,
(CDCl3), δ, ppm: 8.26 (d, J ) 6.9 Hz, 1H), 7.89 (d, J ) 8.6 Hz,
2H), 7.60-7.20 (m, 6H), 6.70 (s, 1H), 5.55 (s, 2H), 4.12 (s, 1H),
2.67 (d, J ) 7.1 Hz, 2H), 1.90 (m, 1H), 0.94 (m, 15H). 13C NMR
(CDCl3), δ, ppm: 148.7, 143.9, 143.2, 142.5, 136.8, 135.8, 135.2,
133.8, 129.9, 129.0, 127.3, 123.4, 122.6, 120.6, 110.1, 54.7, 48.8,
39.3, 30.7, 29.6, 22.3. IR (compression cell), cm-1: 3063, 2964.
Anal. (C26H31N3O2S2) C, H, N.
3-[4-(2-Methylimidazol-1-ylmethyl)phenyl]-5-isobutyl-
N-tert-butylthiophene-2-sulfonamide (13). Compound 2
(479 mg, 1.50 mmol), 6 (251 mg, 1.00 mmol), toluene (12 mL),
ethanol (3 mL), NaOH (160 mg, 4 mmol as pellets), PPh3 (16
mg, 60 µmol), and Pd(OAC)2 (6.7 mg, 0.03 mmol) were mixed
together under a N2(g) atmosphere. The mixture was heated
to 80 °C and stirred for 2 h. After dilution with EtOAc (20
mL), the reaction mixture was washed with water and brine.
The organic phase was dried and concentrated under vacuum.
The crude product was purified by column chromatography
(CH2Cl2:MeOH 25:1) to give the title compound in 83% yield
22.1. IR (compression cell), cm-1
: 3260, 2985, 2224. Anal.
(C19H24N2O2S2·1/3H2O) C, H, N.
N-Butyloxycarbonyl-3-(4-imidazo[4,5-b]pyridin-3-
ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide (17).
Compound 10 (150 mg, 0.311 mmol) and anisole (150 µL) were
dissolved in TFA (5 mL) and stirred overnight. The reaction
mixture was evaporated under vacuum and coevaporated with
acetonitrile twice. The residue was dissolved in pyridine (1.6
mL), and pyrrolidinopyridine (52.1 mg, 0.35 mmol) was added.
The solution was cooled on an ice bath and butyl chloroformate
(447 µL, 3.49 mmol) was added under a N2(g) atmosphere. The
reaction was stirred at ambient temperature overnight. The
1
(368.8 mg, 0.828 mmol). H NMR (CDCl3), δ, ppm: 7.59 (d, J
) 8.1 Hz, 2H), 7.13 (d, J ) 8.1 Hz, 2H), 6.98 (s, 1H), 6.86 (s,
1H), 6.73 (s, 1H), 5.09 (s, 2H), 4.06 (s, 1H), 2.67 (d, J ) 7.1
Hz, 2H), 2.34 (s, 3H), 1.91 (m, 1H), 0.99 (s, 9H), 0.97 (d, J )
6.6 Hz, 6H). 13C NMR (CDCl3), δ, ppm: 148.6, 144.8, 142.4,
136.7, 136.5, 134.8, 129.7, 128.9, 127.6, 126.7, 119.9, 54.6, 49.4,
39.2, 30.5, 29.5, 22.1, 13.1. IR (compression cell), cm-1: 3053,
2958. Anal. (C23H31N3O2S2) C, H, N.