ABT-670, an Orally BioaVailable Treatment for ED
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25 7461
1H), 4.18 (d, J ) 6 Hz, 2H), 7.21 (d, J ) 9 Hz, 1H), 7.29 (m, 2H),
7.39 (m, 1H), 7.62 (d, J ) 9 Hz, 1H), 7.68 (s, 1H), 8.23 (dd, J )
6 and 1.5 Hz, 1H), 8.64 (t, J ) 6 Hz, 1H); MS (DCI/NH3) m/e 324
(M + H - 16)+; 340 (M + H)+; Anal. (C20H25N3O2‚0.3H2O) C,
H, N.
3-Chloro-4-fluoro-N-(1-oxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′-bi-
pyridine]-1′-ylmethyl)benzamide (6l) was prepared in the same
manner as compound 6b but with substitution of 3-chloro-4-
fluorobenzamide in place of 3-methylbenzamide (85 mg, 89%
yield). 1H NMR (300 MHz, DMSO-d6) δ 1.52 (m, 2H), 1.89 (d, J
) 12 Hz, 2H), 2.36 (m, 2H), 2.95 (d, J ) 12 Hz, 2H), 3.20 (m,
1H), 4.18 (d, J ) 6 Hz, 2H), 7.24 (m, 2H), 7.39 (dd, J ) 6 and 1.5
Hz, 1H), 7.53 (t, J ) 9 Hz, 1H), 7.93 (m, 1H), 8.13 (dd, J ) 6 and
1.5 Hz, 1H), 8.23 (dd, J ) 6 and 1.5 Hz, 1H), 8.90 (t, J ) 6 Hz,
1H); MS (DCI/ NH3) m/e 348 (M + H - 16)+; 364 (M + H)+;
Anal. (C18H19N3O2ClF‚0.8H2O) C, H, N.
6-Chloro-N-(1-oxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′-bipyridine]-
1′-ylmethyl)nicotinamide (6q) was prepared in the same manner
as compound 6b but with substitution of 6-chloronicotinamide in
1
place of 3-methylbenzamide (20 mg, 25% yield). H NMR (300
MHz, DMSO-d6) δ 1.52 (m, 2H), 1.89 (d, J ) 12 Hz, 2H), 2.36
(m, 2H), 2.98 (d, J ) 12 Hz, 2H), 3.22 (m, 1H), 4.19 (d, J ) 6 Hz,
2H), 7.29 (m, 2H), 7.30 (dd, J ) 6 and 1.5 Hz, 1H), 7.65 (d, J )
9 Hz, 1H), 8.26 (m, 2H), 8.88 (d, J ) 3 Hz, 1H), 9.02 (t, J ) 6 Hz,
1H); MS (DCI/NH3) m/e 331 (M + H - 16)+; Anal. (C17H19N4O2-
Cl‚0.4H2O) C, H, N.
Pyridine-2-carboxylic Acid (1-Oxy-3′,4′,5′,6′-tetrahydro-2′H-
[2,4′-bipyridine]-1′-ylmethyl)amide (6r) was prepared in the same
manner as compound 6b but with substitution of pyridine-2-
carboxylic acid amide in place of 3-methylbenzamide (51 mg, 57%
yield). 1H NMR (300 MHz, DMSO-d6) δ 1.52 (m, 2H), 1.89 (d, J
) 12 Hz, 2H), 2.36 (m, 2H), 2.98 (d, J ) 12 Hz, 2H), 3.18 (m,
1H), 4.22 (d, J ) 6 Hz, 2H), 7.27 (m, 2H), 7.28 (dd, J ) 6 and 1.5
Hz, 1H), 7.63 (m, 1H), 8.03 (m, 1H), 8.22 (dd, J ) 6 and 1.5 Hz,
1H), 8.23 (dd, J ) 6 and 1.5 Hz, 1H), 8.68 (dd, J ) 6 and 1.5 Hz,
1H), 9.02 (t, J ) 6 Hz, 1H); MS (DCI/NH3) m/e 297 (M + H -
16)+; 313 (M + H)+; Anal. (C17H20N4O2‚0.3H2O) C, H, N.
Thiazole-2-carboxylic Acid (1-Oxy-3′,4′,5′,6′-tetrahydro-2′H-
[2,4′-bipyridine]-1′-ylmethyl)amide (6s) was prepared in the same
manner as compound 6b but with substitution of thiophene-2-
carboxylic acid amide in place of 3-methylbenzamide (100 mg,
56.6% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.52 (m, 2H), 1.89
(d, J ) 12 Hz, 2H), 2.36 (m, 2H), 2.98 (d, J ) 12 Hz, 2H), 3.18
(m, 1H), 4.12 (d, J ) 6 Hz, 2H), 7.18 (dd, J ) 4.5 and 3.0, 1H),
7.28 (m, 2H), 7.39 (dd, J ) 9.0 and 3 Hz, 1H), 7.78 (dd, J ) 4.5
and 1.5 Hz, 1H), 7.85 (dd, J ) 4.5 and 1.5 Hz, 1H), 8.22 (dd, J )
6 and 1.5 Hz, 1H), 8.79 (t, J ) 6 Hz, 1H); MS (DCI/NH3) m/e 297
(M + H - 16)+; 313 (M + H)+. HRMS Calcd for C16H19N3O2-
SNa: 340.1096 (M + H)+. Found: 340.1090
General Procedure for Compounds 7a-z: 2-(1-Oxy-3′,4′,5′,6′-
tetrahydro-2′H-[2,4′-bipyridine]-1′-yl)-N-(m-tolyl)acetamide (7a).
A mixture of 2-bromo-N-(m-tolyl)acetamide (8.903 g, 39.03 mmol),
and 1′,2′,3′,4′,5′,6′-hexahydro-[2,4′-bipyridine] N-oxide (8.38 g,
39.03 mmol) and K2CO3 (10.78 g, 78.06 mmol) in DMF (100 mL)
was stirred at rt for 20 h. The reaction mixture was checked by
TLC. Both starting materials were present along with the product;
therefore, the reaction mixture was heated at 40 °C for 4 h. TLC
still showed starting materials 1 and 2, but to avoid any side
reactions due to prolonged heating, the reaction mixture was worked
up. DMF was removed on the rotary evaporator. The residue was
extracted between brine and EtOAc. The aqueous layer was
extracted with EtOAc (3 × 200 mL). Combined organics were dried
over MgSO4 and concentrated. The residue was purified by flash
chromatography with 4% MeOH in CH2Cl2 to give the desired
product as an off-white solid (8.065 g, 63.5%). 1H NMR (300 MHz,
DMSO-d6) δ 1.80 (m, 2H), 1.91 (m, 2H), 2.30 (m, 5H), 2.99 (m,
2H), 3.14 (s, 2H), 3.25 (m, 1H), 6.88 (d, J ) 7.5 Hz, 1H), 7.19 (t,
J ) 7.5 Hz, 1H), 7.31 (m, 2H), 7.45 (m, 2H), 8.24 (m, 1H), 9.6 (br
s, 1H); MS (DCI-NH3) m/e 310 (M + H - 16)+; 326 (M + H)+.
Anal. (C19H23N3O2) C, H, N.
3,5-Dimethyl-N-(1-oxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′-bipyri-
dine]-1′-ylmethyl)benzamide (6m) was prepared in the same
manner as compound 6b but with substitution of 3,5-dimethylben-
1
zamide in place of 3-methylbenzamide (140 mg, 60% yield). H
NMR (300 MHz, CD3OD) δ 1.76 (dd, J ) 12.4 and 3.6 Hz, 2H),
2.11 (d, J ) 12.6 Hz, 2H), 2.36 (s, 6H), 2.66 (m, 2H), 3.23 (d, J
) 12.2 Hz, 2H), 3.47 (m, 1H), 4.38 (s, 2H), 7.22 (s, 1H), 7.41 (m,
1H), 7.52 (m, 2H), 7.56 (m, 2H), 8.34 (d, J ) 6.4 Hz, 1H); MS
(ESI) m/e 340 (M + H)+. HRMS Calcd for C20H25N3O2Na:
362.1844. Found: 362.1839
3-Methoxy-2-methyl-N-(1-oxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′-
bipyridine]-1′-ylmethyl)benzamide (6n): 3-Methoxy-2-methyl-
benzamide. A reaction mixture containing 3-methoxy-2-methyl-
benzoic acid (2 g, 12.04 mmol), 1-[3-(dimethylamino)propyl]-3-
ethylcarbodiimidehydrochloride(2.76g,14.4mmol),and1-hydroxybenzo-
triazole hydrate (1.95 g, 14.4 mmol) in chloroform was stirred at
rt for 1 h. The reaction was quenched with 30% ammonium
hydroxide solution (35 mL), and stirring was continued for another
1.5 h. The layers were separated, and the organic phase was dried
over MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica gel
(50% EtOAc/hexanes) to afford a white powder (1.2 g, 60% yield).
1H NMR (300 MHz, CDCl3) δ 2.3 (s, 3H), 3.82 (s, 3H), 6.9 (d, J
) 9 Hz, 1H), 7.02 (d, J ) 9 Hz, 1H), 7.18 (t, J ) 9 Hz, 1H); MS
(DCI/NH3) m/e 166 (M + H)+.
Compound 6n was prepared in the same manner as compound
6b but with substitution of 3-methoxy-2-methylbenzamide in place
1
of 3-methylbenzamide (45 mg, 16% yield; white solid). H NMR
(300 MHz, CDCl3) δ 1.45-1.55 (m, 2H), 2.05-2.15 (m, 2H), 2.25
(s, 3H), 2.55-2.65 (m, 2H), 3.05-3.10 (m, 2H), 3.40-3.50 (m,
1H), 3.81 (s, 3H), 4.40 (d, J ) 6 Hz, 2H), 6.4 (br s, 1H), 6.85 (d,
J ) 9 Hz, 1H), 7.0 (d, J ) 9 Hz, 1H), 7.10-7.20 (m, 2H), 7.25-
7.32 (m, 2H), 8.20 (d, J ) 6 Hz, 1H); MS (DCI/NH3) m/e 356 (M
+ H)+; Anal. (C20H25N3O3) C, H, N.
3-Methoxy-4-chloro-N-(1-oxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′-
bipyridine]-1′-ylmethyl)benzamide (6o) was prepared in the same
manner as compound 6b but with substitution of 4-chloro-3-
methoxybenzamide in place of 3-methylbenzamide (75 mg, 17%
yield; yellow solid). 1H NMR (300 MHz, CDCl3) δ 1.6-1.68 (m,
2H), 2.05-2.20 (m, 2H), 2.50-2.65 (m, 2H), 3.05-3.20 (m, 2H),
3.42-3.55 (m, 1H), 3.98 (s, 3H), 4.40 (d, J ) 6 Hz, 2H), 6.65 (br
s, 1H), 7.15 (m, 1H), 7.2-7.35 (m, 3H), 7.40 (d, J ) 9 Hz, 1H),
7.45 (d, J ) 3 Hz, 1H), 8.22 (d, J ) 6 Hz, 1H); MS (DCI/NH3)
m/e 376 (M + H)+; Anal. (C19H22ClN3O3) C, H, N.
2-(1-Oxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′-bipyridine]-1′-yl)-N-
(3-trifluoromethylphenyl)acetamide (7b) was prepared in the
same manner as compound 7a but with substitution of 2-bromo-
N-(3-trifluoromethylphenyl)acetamide in place of 2-bromo-N-(3-
tolyl)acetamide (191 mg, 17% yield). This material was converted
to the maleate salt: 1H NMR (300 MHz, CD3OD) δ 8.39 (br d, J
) 6.5 Hz, 1H), 8.08 (br s, 1H), 7.77 (br d, J ) 8.1 Hz, 1H), 7.65-
7.44 (m, 5H), 6.26 (s, 2H), 4.12 (s, 2H), 3.77 (br d, J ) 11.9 Hz,
2H), 3.69 (ddd, J ) 12.2, 3.4, and 3.4 Hz, 1H), 3.30 (m, 2H), 2.35
(br d, J ) 13.9 Hz, 2H), 2.10 (m, 2H); MS (ESI) m/e 380 (M +
H)+; Anal. (C19H20F3N3O2‚1.2C4H4O4‚0.1H2O) C, H, N.
Naphthalene-2-carboxylic Acid (1-Oxy-3′,4′,5′,6′-tetrahydro-
2′H-[2,4′-bipyridine]-1′-ylmethyl)amide (6p) was prepared in the
same manner as compound 6b but with substitution of 2-naph-
thoylamide in place of 3-methylbenzamide (75 mg, 56% yield;
1
white solid). H NMR (300 MHz, DMSO-d6) δ 1.56 (q, J ) 12.2
Hz, 1H), 1.57 (q, J ) 11.9 Hz, 1H), 1.92 (d, J ) 11.2 Hz, 2H),
2.41 (t, J ) 11.2 Hz, 2H), 3.02 (d, J ) 11.5 Hz, 2H), 3.25 (m, J
) 12.9 Hz, 1H), 4.24 (d, J ) 5.8 Hz, 2H), 7.30 (m, 2H), 7.40 (dd,
J ) 7.5 and 2.4 Hz, 1H), 7.62 (m, 2H), 8.01 (m, 4H), 8.24 (d, J )
5.8 Hz, 1H), 8.51 (s, 1H), 8.97 (s, 1H); MS (DCI/ NH3) m/e 362
(M + H)+; Anal. (C22H23N3O2‚0.2CH2Cl2‚1.2H2O) C, H, N.
N-(3-Fluorophenyl)-2-(1-oxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′-
bipyridine]-1′-yl)acetamide (7c) was prepared in the same manner
as compound 7a but with substitution of 2-bromo-N-(3-fluorophe-
nyl)acetamide in place of 2-bromo-N-(m-tolyl)acetamide (157 mg,
68% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.68 (m, 2H), 1.92
(d, J ) 5.8 Hz, 2H), 2.30 (m, 2H), 3.01 (m, 2H), 3.19 (s, 2H), 3.25