N-Acyl Pyrroloquinolone PDE-5 Inhibitors
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 661
DMSO) δ (*mixture of rotamers) 3.68-3.85 (m, 2 H)
4.64-4.92 (m, 2 H) 5.98-6.31 (series of s, 3 H), 6.81-
7.64 (series of m, 11 H), 8.13 (d, J ) 7.9 Hz, 1 H), 11.73/
11.81* (br s, 1 H)). HRMS calcd MH+ for C26H20N2O4 is
425.1502; found 425.1494.
3-Ben zo[1,3]d ioxol-5-yl-2-ben zoyl-1,2,3,4-tetr a h y-
d r o-p yr r olo[3,4-b]qu in olin -9-on e (12). Prepared us-
ing benzoyl chloride as the electrophile. Yield: 61% MS
(m/z): 409 (M - H); 1H NMR (400 MHz, DMSO)
(*mixture of rotamers) δ 4.71/4.98* (d, J ) 12.8 Hz, 1
H), 4.92/5.09* (d, J ) 11.0 Hz, 1 H), 5.91-6.40 (series
of s, 3 H), 6.65-7.66 (series of m, 11 H), 8.10 (d, J ) 9
Hz, 1 H), 11.70/11.90* (br s, 1 H). HRMS calcd MH+ for
C25H18N2O4 is 411.1345; found 411.1347.
3-Ben zo[1,3]d ioxol-5-yl-2-(3-p h en yla llyl)-1,2,3,4-
tetr a h yd r o-p yr r olo[3,4-b]qu in olin -9-on e (13). Pre-
pared using cinnamyl bromide as the electrophile. Yield
45 % MS (m/z): 422 (M - H); 1H NMR (400 MHz,
CDCl3) δ 3.37 (dd, J ) 13.7, 7.7 Hz, 1 H), 3.58 (dd, J )
13.6, 4.6 Hz, 1 H), 3.83 (dd, J ) 12.3, 3.7 Hz, 1 H), 4.49
(dd, J ) 12.3, 2.8 Hz, 1 H), 4.92 (br s, 1 H), 5.97 (s, 1
H), 5.98 (s, 1 H), 6.17-6.25 (m, 1 H), 6.55 (d, J ) 15.9
Hz, 1 H), 6.82 (d, J ) 7.8 Hz, 1 H), 6.91 (dd, J ) 7.8, 1.2
Hz, 1 H), 6.97 (nd, J ) 1.2 Hz, 1 H), 7.20-7.33 (m, 5
H), 7.50 (t, J ) 8.5 Hz, 1 H), 7.92 (br s, 1 H), 8.38 (d, J
) 8.0, 1 H) HRMS calcd MH+ for C27H22N2O3 is
423.1714; found 423.1714.
3-Be n zo[1,3]d ioxol-5-yl-2-(2-p h e n yle t h e n e su l-
fonyl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one
(14). Prepared using 2-phenylethenesulfonyl chloride as
the electrophile. Yield 38 % MS (m/z): 471 (M - H); 1H
NMR (400 MHz, CDCl3) δ 4.68 (dd, J ) 12.6, 3.4 Hz, 1
H), 4.76 (d, J ) 11.5 Hz, 1 H), 5.68 (s, 1 H), 5.82 (s, 1
H), 5.90 (br s, 1 H), 6.36 (d, J ) 15.4 Hz, 1 H), 6.67 (d,
J ) 5.3 Hz, 1 H), 6.69 (s, 1 H), 6.83 (dd, J ) 8.1, 1.7 Hz,
1 H), 7.21-7.60 (m, 9H), 8.29 (d, J ) 7.1, 1 H), 9.45 (br
s, 1 H). HRMS calcd MH+ for C26H20N2O5S is 473.1171;
found 473.1195.
(m/z): 452 (M - H); 1H NMR (400 MHz, CDCl3) δ 2.83
(s, 3 H), 4.13 (d, J ) 15.3 Hz, 1 H), 4.54 (d, J ) 12.4 Hz,
1H), 4.70 (d, J ) 15.3 Hz, 1 H), 4.92 (dd, J ) 12.5, 3.4
Hz, 1 H), 5.86 (d, J ) 5.3 Hz, 2 H), 6.43 (nd, J ) 2.9 Hz,
1 H), 6.63 (d, J ) 7.9 Hz, 1 H), 6.69 (s, 1 H), 6.78 (d, J
) 7.9 Hz, 1 H), 7.15 (d, J ) 6.8 Hz, 2 H), 7.20-7.35 (m,
6 H), 7.52 (t, J ) 8.0 Hz, 1 H), 8.34 (t, J ) 8.0 Hz, 1 H),
9.62 (br s, 1 H); HRMS calcd MH+ for C27H23N3O4 is
454.1772; found 454.1775.
3-Ben zo[1,3]d ioxol-5-yl-9-oxo-1,3,4,9-tetr a h yd r o-
p yr r olo[3,4-b]qu in olin e-2-ca r boxylic Acid Ben zyl
Ester (18). Prepared using benzyl chloroformate as the
electrophile. Yield 31% MS (m/z): 439 (M - H); 1H NMR
(400 MHz, CDCl3) δ 4.62-4.75 (m, 2 H), 4.92-5.25
(series of m, 2 H), 5.76-5.82 (m, 3 H), 6.50-6.67 (m, 3
H), 6.98-7.57 (series of m, 9 H), 8.25-8.30 (m, 1 H),
10.40 and 10.68* (br s, 1 H); HRMS calcd MH+ for
C26H20N2O5 is 441.1469; found 441.1482.
3-Ben zo[1,3]d ioxol-5-yl-9-oxo-1,3,4,9-tetr a h yd r o-
p yr r olo[3,4-b]qu in olin e-2-ca r boxylic Acid P yr id in -
4-ylm eth yl Ester (19). Prepared using the 4-nitrophe-
nyl carbonate of 4-pyridyl carbinol as the electrophile.
1
Yield 25% MS (m/z): 440 (M - H); H NMR (reported
for the (S)-enantiomer) (400 MHz, CDCl3) (*mixture of
rotamers) δ 4.72-5.25* (series of d, 4H), 5.85-5.91 (m, 3
H), 6.61-6.85* (series of m, 3 H), 7.19 (nd, J ) 5.0 Hz,
1 H), 7.31-7.61 (series of m, 5 H), 8.38 (q, J ) 10.9 Hz,
2 H), 8.53 (s, 1 H), 9.82 and 9.91* (br s, 1 H); HRMS
calcd MH+ for C25H19N3O5 is 442.1403; found 442.1383.
The enantiomers were separated using a Varian
PrepStar HPLC fitted with Chiral Technologies Chiral-
Pak AD 5 × 50, 20 µm column. Fractions were checked
for purity on the Agilent LC/MSD previously mentioned
but employing a Chiral Technologies ChiralPak AD 0.46
× 25 cm column. 2-Propanol was used as the mobile
phase on the preparative column while methanol was
utilized on the analytical column.
R-(-)-19. The first peak to elute from the preparative
column had a retention time of 3.581 min on the
analytical system. NMR and MS were the same as
3-Ben zo[1,3]dioxol-5-yl-2-ph en ylm eth an esu lfon yl-
1,2,3,4-tetr ah ydr o-pyr r olo[3,4-b]qu in olin -9-on e (15).
Prepared using phenylmethanesulfonyl chloride as the
electrophile. Yield 55% MS (m/z): 459 (M - H); 1H NMR
(400 MHz, CDCl3) δ 3.88 (d, J ) 13.9 Hz, 1 H), 4.02 (d,
J ) 13.9 Hz, 1 H), 4.23 (dd, J ) 12.6, 3.0 Hz, 1 H), 4.71
(d, J ) 12.7 Hz, 1 H), 5.80 (s, 1 H), 5.94 (s, 2 H), 6.61 (s,
1 H), 6.70-6.75 (m, 2 H), 7.15-7.37 (m, 8 H), 7.58 (t, J
) 8.0 Hz, 1 H), 8.28 (d, J ) 8.0 Hz, 1 H), 9.48 (br s, 1
H). HRMS calcd MH+ for C25H20N2O5S is 461.1171;
found 461.1179.
reported above. [R]23 ) -85, c ) 0.135 in methanol.
D
HRMS calcd MH+ for C25H19N3O5 is 442.1403; found
442.1379.
S-(+)-19. The second peak to elute from the prepara-
tive column had a retention time of 3.622 min on the
analytical system. NMR and MS were the same as
reported above. [R]23 ) +75, c ) 0.205 in methanol.
D
HRMS calcd MH+ for C25H19N3O5 is 442.1403; found
442.1382.
3-Ben zo[1,3]d ioxol-5-yl-9-oxo-1,3,4,9-tetr a h yd r o-
p yr r olo[3,4-b]qu in olin e-2-ca r boxylic Acid Ben zyl-
a m id e (16). Prepared using benzyl isocyanate as the
electrophile. Yield 61% MS (m/z): 438 (M - H); 1H NMR
(400 MHz, DMSO) δ 4.12 (dd, J ) 15.9, 5.6 Hz, 1 H),
4.32 (dd, J ) 15.9, 5.6 Hz, 1 H), 4.57 (d, J ) 12.9 Hz, 1
H), 4.71 (dd, J ) 12.9, 3.6 Hz, 1 H), 5.99 (nd, J ) 3.8
Hz, 2 H), 6.04 (nd, J ) 3.2 Hz, 1 H), 6.78-7.35 (series
of m, 10 H), 7.54-7.64 (m, 2 H), 8.13 (d, J ) 7.9 Hz, 1
H), 11.78 (s, 1H). HRMS calcd MH+ for C26H21N3O4 is
440.1610; found 440.1612.
3-Ben zo[1,3]dioxol-5-yl-4-m eth yl-9-oxo-1,3,4,9-tet-
r a h yd r o-p yr r olo[3,4-b]qu in olin e-2-ca r boxylic Acid
P yr id in -4-ylm eth yl Ester (20) A suspension of sodium
hydride (26 mg, 0.33 mmol, 60% dispersion in mineral
oil) in dry DMF (4 mL) was treated with 19 (140 mg,
0.29 mmol). Dimethyl sulfate (30 µL, 0.33 mmol) was
introduced via syringe and the resulting brown solution
stirred at ambient temperature for 1 h. Water (10 mL)
was added to the reaction mixture, and the emulsion
was washed with ethyl acetate (3 × 20 mL). The
combined organic extracts were washed with 10% LiCl
solution and brine, dried (MgSO4), and concentrated in
vacuo. Purification of the residue by flash chromatog-
raphy (SiO2, 5% MeOH/CH2Cl2) afforded 23 mg of the
product as a tan solid (15%). MS (m/z): 456 (MH+); 1H
3-Ben zo[1,3]d ioxol-5-yl-9-oxo-1,3,4,9-tetr a h yd r o-
p yr r olo[3,4-b]qu in olin e-2-ca r boxylic Acid Ben zyl-
m eth yla m id e (17). Prepared using benzyl methyl
carbamoyl chloride as the electrophile. Yield 31% MS