Pyrroloquinolone PDE5 inhibitors with improved pharmaceutical profiles for clinical studies on erectile dysfunction

Article abstract of DOI:10.1021/jm0401098

We previously reported a series of potent and selective pyrimidinyl pyrroloquinolone PDE5 inhibitors such as 2a for potential use in male erectile dysfunction (MED) (Sui, Z.; Guan, J.; Macielag, M. J.; Jiang, W.; Zhang, S.; Qiu, Y.; Kraft, P., Bhattacharj

Full text of DOI:10.1021/jm0401098

2126
J. Med. Chem. 2005, 48, 2126-2133
Pyrroloquinolone PDE5 Inhibitors with Improved Pharmaceutical Profiles for
Clinical Studies on Erectile Dysfunction
Weiqin Jiang, Jihua Guan, Mark J. Macielag, Suying Zhang, Yuhong Qiu, Patricia Kraft, Sheela Bhattacharjee,
T. Matthew John, Donna Haynes-Johnson, Scott Lundeen, and Zhihua Sui*
Johnson & Johnson Pharmaceutical Research and Development, 1000 Route 202, Raritan, New Jersey 08869
Received June 1, 2004
We previously reported a series of potent and selective pyrimidinyl pyrroloquinolone PDE5
inhibitors such as 2a for potential use in male erectile dysfunction (MED) (Sui, Z.; Guan, J.;
Macielag, M. J.; Jiang, W.; Zhang, S.; Qiu, Y.; Kraft, P., Bhattacharjee, S.; John, T. M.; Craig,
E.; Haynes-Johnson, D.; Clancy, J. J. Med. Chem. 2002, 45, 4094-4096). Unfortunately, the
low aqueous solubility and poor oral bioavailability rendered them undesirable development
candidates. To address this issue, we designed a series of analogues using two approaches:
increasing the overall basicity and reducing molecular weight of the lead. Through earlier SAR
studies, we discovered that the PDE5 potency of the pyrroloquinolones is insensitive to
substitution on the pyrrole nitrogen. Basic functional groups such as pyridines and benzimi-
dazoles were appended via the aromatic ring connected to the pyrrole nitrogen. Several
truncated analogues were also designed and synthesized to improve oral absorption. These
modifications allowed us to identify analogues with good oral bioavailability in rats, dogs, and
monkeys while the high potency against PDE5 and desirable selectivity versus other PDE
isozymes were maintained. Compounds R-11e and R-11l were selected as development
candidates for MED and other indications.
Introduction
clase, which catalyzes the cyclization of guanosine
triphosphate (GTP), generating cGMP. Increased cGMP
levels eventually cause a decrease in intracellular
calcium concentration, leading to relaxation of smooth
muscle in the corpus cavernosum. This allows increased
arterial blood flow to the penis, resulting in tumescence.
PDE5 inhibition blocks cGMP degradation, facilitating
cGMP accumulation.
Previously, we described the discovery of a series of
pyrimidine pyrroloquinolones as potent and selective
inhibitors of PDE5.8a The lead compound (2a, Chart 1)
was a highly potent inhibitor of PDE5, selective versus
other phosphodiesterases, capable of increasing intra-
cellular cGMP levels in RFL-6 cells, and efficacious in
a dog model for erectile dysfunction. However, its
physical and chemical properties proved unsuitable for
clinical studies. The poor aqueous solubility of the
compound not only affected the pharmacokinetic profile
but also significantly increased the difficulty in creating
formulations. Systematic modifications of this lead were
successful in achieving suitable pharmacokinetic (PK)
properties and solubility profile for clinical development
while the potency against PDE5 and selectivity versus
other PDE isozymes were maintained.
Male erectile dysfunction (MED or ED)1 was a largely
unmet medical need prior to the introduction of sildena-
fil in 1998. Sildenfil, a potent inhibitor of phosphodi-
esterase type 5 (PDE5),2 was originally studied for the
treatment of angina before its effectiveness in treating
ED was serendipitously discovered.3 Despite its success,
sildenafil has several notable side effects, such as
headache, nausea, cutaneous flushing, and visual dis-
turbances. These side effects may be attributed to the
limited selectivity of sildenafil versus other PDE
isozymes, most notably PDE1 and PDE6. Thus, the need
exists for PDE5 inhibitors possessing improved PDE
isozyme selectivities and therefore demonstrating fewer
side effects, as evidenced by the recent launches of
tadalafil4 and vardenafil.5,6 In addition, the potential
use of PDE5 inhibitors in other indications such as
pulmonary hypertension, stroke, and cardiac protection
is also fueling interest in this field.
PDE5 belongs to the superfamily of phosphodiesteras-
es that catalyze hydrolysis of the cyclic phosphate bond
in the second messengers cAMP and cGMP.2c To date,
the 21 mammalian PDE genes cloned thus far are
organized into 11 families on the basis of their sequence
homology and biochemical properties.7 Among the 11
families, PDE5, initially discovered in lung tissues, is
the first recognized cGMP-binding PDE. In the human
corpus carvernosum, PDE5 is the major enzyme to
facilitate the hydrolysis of cGMP to GMP, thus playing
an important role in penile erection.6b Upon sexual
stimulation, release of nitric oxide from nonadrenergic,
noncholinergic neurons activates soluble guanylyl cy-
Chemistry
Pyrimidinyl pyrroloquinolones were synthesized ei-
ther via Winterfeldt oxidation9 of â-carboline precursors
(Scheme 1) or via coupling reactions of the key pyrrolo-
quinolone precursor 1a (Scheme 2). Compounds 11a,
11b, 11c, and 11d were respectively synthesized from
â-carbolines 10a, 10b, 10c, and 10d by oxidation with
KOtBu/O2 (Scheme 1). The â-carboline intermediates 8a
and 10a were synthesized through coupling of â-carbo-
lines 6a with chloropyrimidine 7a and of â-carboline 6b
* Corresponding author. Phone: (908) 704-5778. Fax: (908) 526-
6469. E-mail: zsui@prdus.jnj.com.
10.1021/jm0401098 CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/08/2004

Pyrroloquinolone PDE5 Inhibitors for Use in MED
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 2127
Scheme 1. Pyrroloquinolones via Winterfeldt Oxidations of â-Carbolines
Chart 1. Identification of Lead Compound 11e
11g were respectively synthesized by direct substitution
of pyrroloquinolone 1a with chloropyrimidines 7a, 7b,
and 7d in the presence of KF/DIEA; analogous treat-
ment of 1b produced 11p. Pyrroloquinolone 11f was
converted to 11h and 11i by Suzuki coupling reactions
of the appropriate boronic acids. Buchwald amination
of the pyrrole nitrogen of 1a utilizing a combination of
Pd(OAc)2 and 2-(dicyclohexylphosphino)biphenyl as the
catalyst system delivered compounds 11j and 11k. A
different catalyst mixture (Pd2dba3/BINAP) proved more
efficient when amine 1a was coupled with 2-bromopy-
ridine. For relatively unreactive substrates 7h and 7i,
a more active, bulkier ligand 2-(dicyclohexylphosphino)-
biphenyl was used to prepare compounds 11m, 11n, and
11o from 1a or 1b, respectively (Scheme 2).
Enantiomers (R)-11e and (R)-11l were synthesized
via the same route as racemic 11e and 11l, starting from
enantiomerically pure (R)-1a.8b
Results and Discussion
In general, compounds in this series were found to
be extremely potent and selective PDE5 inhibitors. They
exhibit excellent selectivities versus PDE1-4/PDE5 and
good selectivity versus PDE6 (Table 1). It is worth
mentioning that, consistent with our earlier observation,
both potency and PDE6/5 selectivity are sensitive to the
C-1 aromatic substituents, and dihydrobenzofuranyl at
this position is more selective than methylenedioxy-
phenyl.8a For example, compound 11h and 11m are
more selective than 11p and 11o, respectively. Further-
more, replacing dihydrobenzofuran in 11e with benzo-
furan (11a) did not have profound effects on potency.
Identification of Lead Compound 11e. Although
our previous lead compound phenylpyrimidine pyrrolo-
quinolone derivative (R)-2a (JNJ-10258859)8c showed
very good potency against PDE5, superior selectivity in
the in vitro studies, and demonstrated in vivo efficacy
in the dog model for erectile dysfunction, its poor
solubility precluded its further development (Chart 1).
During our systematic SAR studies, we identified that
with chloropyrimidine 7b using the KF/DIEA condition.
Compound 8b was synthesized by palladium-catalyzed
coupling reaction of 6b with bromopyridine 7c. To
install the imidazole functionality in 11b and 11c,
â-carboline intermediates 10b and 10c were synthesized
by a modified literature protocol10 through coupling
reactions of either N-methyl (9a) or N-benzylimidazole
(9b) to bromide 8a. Intermediate 10d was synthesized
by Stille coupling reaction of 2-tributylstannanylpyri-
dine 9c with bromide 8b.
In some cases, the Winterfeldt oxidation of fully
elaborated â-carbolines proceeded with relatively low
yield. To address this problem, we utilized a more
divergent synthetic route via unsubstituted pyrroloqui-
nolones 1a and 1b for further analogue synthesis
(Scheme 2). Pyrimidinyl pyrroloquinolones 11e, 11f, and

2128 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Jiang et al.
Scheme 2. Pyrroloquinolones via Coupling Reactions of Pyrroloquinolone Precursor 1
the right portion of the molecule tolerates a wide range
of substituents on the pyrrole nitrogen. We took advan-
tage of this finding to improve the physical and chemical
properties by modifying this area of the scaffold through
introduction of solubilizing groups such as the basic
chain in 2b. While the PDE5 inhibition and isozyme
selectivity were maintained, these analogues were not
orally bioavailable. We reasoned that the increase in
molecular weight of 2b relative to 2a might have
decreased the absorption. Other approaches such as
replacing the methoxy group in 2a with carboxylic acid
and hydroxy groups proved unsuccessful in improving
bioavailability, possibly due to increased in vivo conju-
gation. We then focused our efforts on pyridine ana-
logues with molecular weight similar to 2a. While the
potency against PDE5 slightly increased, the PDE6/5
selectivity remained the same. Moving the pyridine
nitrogen from ortho (11e) to meta (11h) or to para (11i)
did not significantly impact the PDE5 potency. Even
though PDE6/5 selectivity of 11h seems to be better
than that of 11e and 11i, we selected 11e as the lead
compound, since the steric environment of the o-pyridine
might render it less prone to P450 oxidation.
Biological studies demonstrated that 11e has excel-
lent potency and selectivity in our in vitro studies and
31% oral bioavailibility in male rats with a half-life
about 6 h, though its bioavailability in monkeys was
poor. Even though the aqueous solubility of 11e was
sufficient for developing suitable formulations for fur-
ther development, we decided to further modify the
nonpharmacorphore part of the molecule in order to
improve the PK profile across different species. Phar-
macokinetic and in vitro metabolism studies on (R)-11e
indicated that neither fast metabolite formation nor
rapid elimination is the major reason for its relatively
moderate bioavailability. We decided to focus on im-
proving the absorption of this series by two ap-
proaches: adjusting the pKa and decreasing the molec-
ular weight (MW).
Modification of 11e. The acidic quinolone proton in
(R)-11e has a pKa of 9.24, and the pyridine has a basic
pKa of 4.43. Earlier studies indicated that the quinolone
proton is essential for PDE5 inhibition,8d so we focused
our efforts on increasing the basic pKa without increas-
ing the molecular weight. First, we replaced pyridine
with more basic imidazole moieties (11b and 11c, pKa

Pyrroloquinolone PDE5 Inhibitors for Use in MED
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 2129
Table 1. PDE5 Inhibition and Selectivity versus Other PDE Isozymes
Kia(SD) for
PDE6/5
cone
PDE6/5
rod
compd
PDE5 (nM)
PDE1/5
PDE2/5
PDE3/5
PDE4/5
sildenafil
tadalafil
11a
1.80(0.15)
5.00
180
12 750
12 790
2 920
9.0
3.2
>2 000
>2 000
>2 000
>2 000
>2 500
>2 500
>2 500
>2 500
>2 500
>2 500
>2 500
>2 500
>2 500
>2 500
>2 500
>2 500
>2 500
>2 500
>2 500
>2 500
>2 500
>2 500
1 000
22.3
219.4
359.2
69.2
-
-
0.19(0.06)
0.24(0.03)
0.24(0.04)
0.15(0.07)
0.40
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
4 870
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
>15 000
4 560
>15 000
>15 000
>15 000
10 270
>15 000
>15 000
>15 000
22.6
236.8
366.2
93.0
-
35.7
754.7
127.2
10.5
2.6
57.6
219
499
328.6
20.1
9.3
11b
11c
11d
11eb
11fb
1.90
39.2
309.9
66.5
12.1
10.3
68.9
237
1837
148.7
13.2
7.6
11g
1.05(0.09)
0.36(0.06)
0.22(0.06)
0.33(0.17)
0.17(0.09)
0.65
11h
11i
11j
11k
11lc
11m
11n
0.51(0.04)
6.43(2.45)
1.75
0.29(0.15)
0.019
0.12
11ob
11p
>15 000
>15 000
>15 000
(R)-11e
(R)-11l
67
106
99
173
a Ki was the mean of three tests for PDE5 and at least two tests for PDE1-4 and PDE6 (cone/rod). b IC50 was used. c Ki was tested one
time. d Reference 4b,c.
Chart 2. Increasing Basic pKa of 11e
(11o, Κi ) 1.75 nM) or selectivity (11j showed lower
PDE6/5 selectivity than 11e; 11k showed lower PDE3/5
selectivity than 11e). Another approach to increasing
the basic pKa was to replace the pyrrolopyrimidine (pKa
∼ 3) with pyrrolopyridine (pKa ∼ 6). First, pyrrolopy-
ridine derivative 11d was synthesized for direct com-
parison with pyrimidine derivative 11e. While the
potency was maintained and the PDE 6/5 selectivity
slightly improved (3-fold), we were encouraged to note
that compound 11d showed slightly improved oral
bioavailability (39%), though not statistically significant.
To decrease the molecular weight, compound 11e was
truncated and two analogues, 11g and 11l, were gener-
ated with about 17% molecular weight (MW) reduction
(Chart 3). Both pyrimidinylpyrroloquinolone 11g and
pyridinylpyrroloquinolone 11l showed excellent potency
and PDE 6/5 selectivity. The slight increase in basicity
from 11g (pKa ) 4.4) to 11l (pKa ∼ 5) had a big influence
on their bioavailability. Compound 11l had an oral
bioavailability of 38% in male rats, while 11g had only
12% in a parallel study. The more active enantiomer,
compound (R)-11l was taken to male beagle dogs and
male cynomogolous monkeys for pharmacokinetic stud-
ies. To our delight, it was found to be 69% orally
bioavailable in dogs and 40% in monkeys, a significant
improvement in PK compared to (R)-11e. Thus, (R)-
11l was selected as one of the development candidates
for our PDE5 program.
Pharmacokinetic Studies
Phamacokinetic studies were conducted in male Spra-
gue-Dawly rats, male beagle dogs, and male rhesus
monkeys. Animals were separated into two groups for
oral (po) and intravenous (iv) dosing with three animals
per group. The oral group was dosed at 30 mg/kg using
0.5% methylcellulose as vehicle, while the intravenous
group was dosed at 3.0 mg/kg using 20% cyclodextrin
(HPBCD) as vehicle. The blood samples were collected
at 0, 0.5, 1, 2, 4, 6, and 24 h after the administration of
the drug. The plasma levels of the drug were quanti-
tatively determined by LC/MS. The results were calcu-
lated using WinNonlin Pro version 2.1. The average
6-7, Chart 2). To our delight, while the potency against
PDE5 was maintained, the selectivity versus PDE6 was
improved about 20-fold (Table 1). However, some imi-
dazole analogues were not orally bioavailable, e.g.
compound 11b has 0% bioavailability in rats. Other
imidazole-containing derivatives such as phenylimida-
zole analogues (11o and 11m) and pyridinylimidazole
analogues (11j and 11k) did not show desirable potency

2130 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Chart 3. Truncated Analogues of 11e
Jiang et al.
Table 2. Oral Bioavailability of Selected Compounds
compd
11b 11d 11e 11g 11l (R)-11l (R)-11l
oral bioavailability, %
standard deviatons, %
animal species
0
0
39.0 31.3 12.0 38.0 69.0 40.0
43.0 13.9 5.0 17.5 17.9 16.8
rat rat rat rat rat
dog
monkey
Figure 2. Effect on intracavernosal pressure after iv admin-
istration.
Figure 1. RFL-6 cell-based functional assay on (R)-11e and
(R)-11l.
Figure 3. Efficacy for (R)-11e and (R)-11l.
value and standard deviation of bioavailability of the
tested compounds from three animal species are re-
ported in Table 2.
Moreover, the more active enantiomers, (R)-11e and
(R)-11l, showed excellent in vivo efficacy in this model
(Figure 3).
Cell-Based Functional Assay. To further evaluate
the compounds, we tested selected compounds in vitro
in rat fetal lung fibroblast (RFL-6) cells. This assay uses
sodium nitroprusside-treated RFL-6 cells as a baseline
to facilitate the measurement of a compound’s ability
to elevate intracellular cGMP levels. Inhibition of PDE5
in these cells should raise cGMP levels in a dose-
dependent manner. As shown in Figure 1, both (R)-11e
(Ki ) 0.050 nM) and (R)-11l (Ki ) 0.12 nM) induced a
5-fold increase in intracellular cGMP concentration at
lower concentrations than sildenafil.
Conclusion
We have identified a series of heterocyclic analogues
of our earlier phenyl pyrimidine pyrroloquinolone PDE5
inhibitors. Most of the derivatives in this series are
extremely potent against PDE5 and highly selective
versus PDE1-4. Many analogues also showed very good
selectivity versus PDE6. Through adjusting pKa and
decreasing molecular weight, we were able to improve
the physical and chemical properties of the series. As a
consequence, preclinical pharmacokinetic studies on
these compounds showed that selected compounds such
as 11e, 11d, and 11l have oral bioavailibity of more than
30% in male rats. Among these compounds, (R)-11l has
very good bioavailability in dogs and monkeys. The in
vivo efficacy studies in anesthetized canines demon-
strated that many analogues are as efficacious in vivo
as sildenafil. Clinical studies of selected compounds are
ongoing and will be reported in due course.
In Vivo Efficacy. Selected analogues were studied
in the canine models in anesthetized male beagle dogs8c
(Figures 2 and 3). The intracavernosal blood pressure
(ICP) of the electrically stimulated dogs was measured
after administering the drug by the intravenous route.
PDE5 inhibitors increase ICP in this model as a result
of elevated cGMP levels and the subsequent engorged
penis. Figure 2 demonstrated that at dosage range of
1-100 µg/kg, many of our compounds (11b, 11d, 11l,
and 11o) showed comparable efficacy as sildenafil.

Pyrroloquinolone PDE5 Inhibitors for Use in MED
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 2131
1-(2,3-Dihydrobenzofuran-5-yl)-2-[5-(2,3-dimethyl-3H-
imidazol-4-yl)-pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-â-
carboline (10b).10 Bromide 8a (0.45 g, 1.00 mmol), 1,2-
dimethyl-1H-imidazole (0.18 g, 1.87 mmol), Pd(OAc)2 (12 mg,
0.050 mmol), PPh3 (26.0 mg, 0.10 mmol), and K2CO3 (0.28 g,
2.0 mmol) was stirred in DMF (3.5 mL) at 140 °C for 14 h.
The mixture was poured into 10% aqueous NaOH solution (50
mL). The aqueous layer was extracted with dichloromethane
(3 × 50 mL), dried, and concentrated. The crude product was
purified by preparative TLC (ethyl acetate/hexane 3:7 and then
5% methanol/dichloromethane) to provide product as a yellow
Experimental Section
General Information for Chemistry. NMR spectra were
obtained at 400 and 300 MHz on a Bruker AVANCE300 and
AVANCE400 spectrometer. Chemical shifts are reported in
ppm downfield from TMS as an internal standard. Thin-layer
chromatography was carried out using 2.5 × 7.5 -cm silica gel
60 (250 mM layer) plates with UV detection. Magnesium
sulfate was employed to dry organic extracts prior to concen-
tration by rotary evaporation. Flash chromatography was done
using EM science silical gel 60 (230-400 mesh). Standard
solvents from J. T. Baker were used as received. Anhydrous
solvents from J. T. Baker or Aldrich and all other commercially
available reagents were used without further purification.
Melting points were taken using a Thomas-Hoover MelTemp
apparatus without any correction. Quantitative Technologies
Inc., Whitehouse, NJ, delivered the results of elemental
analysis. Mass spectra were obtained on a Hewlett-Packard
5989A quadrupole mass spectrometer. Silica gel (E. Merck,
230-400 mesh) was used for all flash chromatography. Thin-
layer chromatography was performed on Analtech silica gel
GF prescored plates (250 µm). HPLC analysis was carried on
Agilent 1100 Series LC/MSD equipment.
1
powder (0.167 g, 36%); H NMR (CDCl3) δ 6.68-7.61 (m, 10
H), 4.91 (m, 1H), 4.52 (t, 2H, J ) 8.8 Hz), 3.35 (m, 1H), 3.10
(t, 2H, J ) 8.8.Hz), 2.90 (m, 2H), 2.35 (s, 3H), 2.21 (s, 3H); MS
(m/z) 463 (MH+), 461 (MH-); HRMS calcd MH+ for C28H26N6O
463.2246, found 463.2233.
2-[5-(3-Benzyl-2-methyl-3H-imidazol-4-yl)-pyrimidin-2-
yl]-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-
â-carboline (10c) was prepared the same as 10b in 40% yield
starting from 1-benzyl-2-methyl-1H-imidazole: 1H NMR (CDCl3)
δ 6.65-7.60 (m, 10 H), 4.92 (m, 1H), 4.52 (t, 2H, J ) 9.0 Hz),
2.85-3.45 (m, 7H), 2.21 (s, 3H); MS (m/z) 539 (MH+), 537
(MH-).
3-(2,3-Dihydrobenzofuran-5-yl)-2-[5-(2,3-dimethyl-3H-
imidazol-4-yl)pyrimidin-2-yl]-1,2,3,4-tetrahydropyrrolo-
[3,4-b]quinolin-9-one (11b) was prepared the same as 11a
in 24% yield starting from 10b: 1H NMR (CD3OD) δ 8.35 (m,
3H), 7.53 (s, 2H), 7.31 (m, 1H), 7.19 (m, 2H), 6.84 (s, 1H), 6.63
(m, 1H), 6.24 (s, 1H), 5.02 (br s, 2H), 4.42 (t, 2H, J ) 9.5 Hz),
3.50 (s, 3H), 3.28 (s, 3H), 3.08 (t, 2H, J ) 9.5 Hz); MS (m/z)
477, (MH+), 475 (MH-); HRMS calcd MH+ for C28H24N6O2
477.2039, found 477.2026.
2-[5-(3-Benzyl-2-methyl-3H-imidazol-4-yl)pyrimidin-
2-yl]-3-(2,3-dihydro-benzofuran-5-yl)-1,2,3,4-tetrahydro-
pyrrolo[3,4-b]quinolin-9-one (11c) was prepared the same
as 11a in 15% yield starting from 10c: 1H NMR (CD3OD) δ
8.85-6.61 (m, 15H), 6.15 (s, 1H), 5.12 (m, 2H), 4.48 (t, 2H, J
) 8.8 Hz), 3.12 (t, 2H, J ) 8.8 Hz), 2.21 (s, 2H), 1.90 (s, 3H);
MS (m/z) MH+ (553), MH- (551); HRMS calcd MH+ for
C34H28N6O2 553.2352, found 553.2357.
2-(5-Bromopyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-
yl)-2,3,4,9-tetrahydro-1H-â-carboline (8b). 1-(2,3-Dihydro-
5-benzofuranyl)-2,3,4,9-tetrahydro-1H-â-carboline 6b (2.90 g,
10.0 mmol), 2,5-dibromopyridine 7c (2.63 g, 11.0 mmol), Pd2-
dba3 (0.367 g, 0.40 mmol), dppp (0.33 g, 0.80 mmol), and
NaOtBu (1.35 g, 14 mmol) were stirred in DMF (60 mL) at 80
°C until the starting material was consumed, as monitored
by HPLC-MS. The reaction mixture was then filtered through
a plug of Celite with dichloromethane. The solution was
washed with brine (3 × 50 mL), dried with MgSO4 and filtered.
The filtrate was concentrated to a brown oil and then loaded
on silica gel column (110 g of silica gel) and eluted with ethyl
acetate/hexane (3:7). The product crystallized out in test tubes.
The fractions containing product were combined, concentrated,
and then recrystallized from THF to provide yellow crystals
as product (2.01 g, 45%): 1H NMR (THF-d8) δ 8.12 (s, 1H),
6.28 (s, 1H), 5.72 (m, 1H), 5.58 (m, 1H), 5.38 (m, 2H), 5.10
∼5.28 (m, 4H), 5.02 (d, 1H, J ) 7.6 Hz), 4.75 (d, 1H, J ) 7.6
H), 2.60 (t, 2H, J ) 9.5 Hz), 2.31 (m, 1H), 1.60 (m, 1H), 1.25
(t, 2H, J ) 9.5 Hz), 1.15 (m, 1H), 0.91 (m, 1H); MS (m/z) 446,
448 (MH+), 444, 446 (MH-).
2-[2,3′]Bipyridinyl-6′-yl-1-(2,3-dihydrobenzofuran-5-
yl)-2,3,4,9-tetrahydro-1H-â-carboline (10d). Bromide 8b
(0.446 g, 1.0 mmol), 2-tributylstannanylpyridine 9c (0.70 g,
1.90 mmol), and Pd(PPh3)4 (0.115 g, 0.10 mmol) were stirred
in 1,4-dioxane (3 mL) at 90 °C for 20 h. The reaction mixture
was filtered through a plug of Celite, washed with dichlo-
romethane, and then concentrated to a small volume. Prepara-
tive TLC (3:7 ethyl acetate/hexane; then 5% methanol/
dichloromethane) yielded the product (0.185 g, 42%) as a
yellow solid: 1H NMR (CDCl3) δ 6.85 (d, 1H, J ) 7.6 Hz), 6.71
(d, 1H, J ) 7.6 Hz), 4.53 (t, 2H, J ) 9.5 z), 4.31 (m, 1H), 3.58
(m, 1H), 3.10 (m, 3H), 2.82 (m, 1H); MS (m/z) 445, (MH+), 443
(MH-).
Benzofuran-5-carbaldehyde (5a) was synthesized in four
steps in 24% overall yield according to the procedure reported
by Hiroya et al. (Heterocycles 1994, 38, 2463-2472).
1-Benzofuran-5-yl-2,3,4,9-tetrahydro-1H-â-carboline
(6a). Benzofuran-5-carbaldehyde (5a) (0.096 g, 0.657 mmol)
and tryptamine (0.106 g, 0.661 mmol) were stirred in dichlo-
romethane (5 mL) with trifluoroacetic acid (0.090 mL) for 48
h. The reaction mixture was concentrated to a brown oil. The
crude mixture was purified by silica gel column (5% methanol/
chloroform) to provide product as an off-white solid (0.157 g,
83%): 1H NMR (CDCl3) δ 8.27 (s, 1H), 7.08-7.59 (m, 7H), 6.61
(s, 1H), 5.22 (s, 1H), 2.71-3.23 (m, 4H); MS (m/z) 289 (MH+),
287 (MH-).
1-(3,4-Methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-â-
carboline (6b) was prepared the same as 6a in 82% yield
starting from 2,3-dihydrobenzofuran-5-carbaldehyde.
1-Benzofuran-5-yl-2-(5-pyridin-2-ylpyrimidin-2-yl)-
2,3,4,9-tetrahydro-1H-â-carboline (10a). A mixture of chlo-
ropyrimidine 7a (0.175 g, 0.913 mmol) and KF (0.194 g, 3.33
mmol) in DMF (2 mL) was stirred at 90 °C for 2 h. A solution
of â-carboline (6a) (0.24 g, 0.833 mmol), DIEA (0.31 mL, 1.77
mmol), and DMF (2 mL) was added and the reaction mixture
was stirred at 80 °C for 16 h. The reaction mixture was
partitioned between water and dichloromethane (40 mL/40
mL). The organic layer was washed with water (2 × 100 mL),
dried, and concentrated. The residue was purified by silica gel
column (1% methanol/dichloromethane) to provide product as
off-white solid (0.36 g, 95%): 1H NMR (CDCl3) δ 7.08-9.21
(m, 14H), 6.68 (s, 1H), 5.08 (m, 1H), 3.48-2.81 (m, 4H); MS
(m/z) 444 (MH+), 442 (MH-).
3-Benzofuran-5-yl-2-(5-pyridin-2-ylpyrimidin-2-yl)-
1,2,3,4-tetrahydropyrrolo[3,4-b]quinolin-9-one (11a). â-Car-
boline 10a (300 mg, 0.68 mmol) was mixed with KOtBu (129
mg) in DMF (6 mL) at room temperature. The reaction mixture
was stirred under constant oxygen bubble for 10 h. The
reaction mixture was partitioned between ethyl acetate and
water (50 mL/50 mL). The organic layer was washed with
aqueous HCl (1 N) solution (50 mL) and brine (50 mL) and
then dried and concentrated. The crude product was purified
on a silica gel column (5% methanol/dichloromethane) to
provide product as an off-white solid (120 mg, 38%): 1H NMR
(CD3OD) δ 8.87 (m, 2H), 8.59 (br s, 1H), 8.37 (br s, 1H), 7.21-
7.79 (m, 10H), 6.80 (m, 1H), 6.60 (m, 1H), 5.21 (m, 2H); MS
(m/z) 458(MH+), 456 (MH-); HRMS calcd MH+ for C28H19N5O2
458.1617, found 458.1606.
2-(5-Bromopyrimidin-2-yl)-1-(2,3-dihydrobenzofuran-
5-yl)-2,3,4,9-tetrahydro-1H-â-carboline (8a) was prepared
the same as 10a in 24% yield starting from â-carboline 6b and
1
chloropyrimidine 7b. H NMR (CDCl3) δ 8.62 (s, 2H), 7.12-
7.55 (m, 7H), 6.83 (m, 1H), 4.87 (m, 1H), 4.55 (t, 2H, J ) 8.0
Hz), 2.82-3.32 (m, 5H); MS (m/z) 447 (MH-).

2132 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Jiang et al.
2-[2,3′]Bipyridinyl-6′-yl-3-(2,3-dihydrobenzofuran-5-
yl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinolin-9-one (11d)
was prepared the same as 11a in 11% yield starting from
10d: 1H NMR (CDCl3) δ 8.70-6.60 (15 H), 6.12 (s, 1H), 5.20-
4.98 (m, 2H), 4.43 (t, 2H, J ) 9.5 Hz), 3.16 (t, 2H, J ) 9.5 Hz);
MS (m/z) 459 (MH+), 457 (MH-); HRMS calcd MH+ for
C29H22N4O2 459.1821, found 459.1819.
from 4-pyridine boronic acid 12b: 1H NMR (CDCl3) δ 6.65-
8.95 (sets of m, 13 H), 6.32 (s, 1H), 4.41 (t, 2H, J ) 8.0 Hz),
3.12 (t, 2H, J ) 8.0 Hz); HRMS calcd MH+ for C28H21N5O2
460.1774, found 460.1763.
3-(2,3-Dihydrobenzofuran-5-yl)-2-[5-(3-methyl-3H-imi-
dazol-4-yl)pyridin-2-yl]-1,2,3,4-tetrahydropyrrolo[3,4-b]-
quinolin-9-one (11j). Pyrroloquinolone 1a (0.127 g, 0.372
mmol), 2-chloro-5-(3-methyl-3H-imidazol-4-yl)pyridine 7e [0.060
g, 0.31 mmol, prepared in 31% yield according to the procedure
reported by Kondo et al. (Org. Lett. 2000, 2, 3111-3113)], Pd-
(OAc)2 (3.5 mg, 0.0155 mmol), biphenyl-2-yldicyclohexylphos-
phane (5.43 mg, 0.0155 mmol), and NaOtBu (0.104 g, 1.085
mmol) were stirred in 1,4-dioxane (0.6 mL) at 90 °C until the
starting material was consumed as monitored by HPLC-MS.
Ethyl acetate (50 mL) and water (50 mL) were added to the
reaction mixture. The organic layer was separated, dried and
concentrated. Purification by preparative TLC (5% methanol
in dichloromethane) yielded the product as a yellow solid (18.8
mg, 12%): 1H NMR (CD3OD) δ 7.20-8.55 (m, 10 H), 6.70 (m,
2H), 6.08 (s, 1H), 5.12 (m, 2H), 3.60 (s, 3H), 3.50 (t, 2H, J )
8.0 Hz), 3.12 (t, 2H, J ) 8.0 Hz); MS (m/z) MH+ (462), MH-
(460); HRMS calcd MH+ for C28H23N5O2 462.1930, found
462.1917.
2-[5-(3-Benzyl-3H-imidazol-4-yl)pyridin-2-yl]-3-(2,3-di-
hydrobenzofuran-5-yl)-1,2,3,4-tetrahydropyrrolo[3,4-b]-
quinolin-9-one (11k) was prepared the same as 11j in 14%
yield starting from chloride 7f: 1H NMR (CD3OD) δ 6.45-
8.54 (m, 12H), 6.05 (s, 1H), 5.10 (m, 2H), 4.55 (t, 2H, J ) 8.3
Hz), 3.60 (m, 2H), 3.12 (t, 2H, J ) 8.3 Hz); MS (m/z) MH+
(538), MH- (536); 446123; HRMS calcd MH+ for C34H27N5O2
538.2243, found 538.2239.
3-(2,3-Dihydrobenzofuran-5-yl)-2-pyridin-2-yl-1,2,3,4-
tetrahydropyrrolo[3,4-b]quinolin-9-one (11l). Pyrrolo-
quinolone‚HCl (1a‚HCl) (0.30 g, 0.88 mmol), 2-bromopyridine
7g (2 mL), Pd2dba3 (0.23 g, 0.25 mmol), (()-BINAP (0.47 g,
0.75 mmol), and NaOtBu (0.66 g, 6.87 mmol) were stirred in
1,4-dioxane (4 mL) at 90 °C for 1 h. The resulting mixture was
concentrated and then filtered on a plug of Celite with
dichloromethane. Ethyl acetate (50 mL) and water (50 mL)
were added to the reaction mixture. The organic layer was
separated, dried and concentrated. Purification by preparative
TLC (5% methanol/dichloromethane) yielded the product as a
yellow solid (0.185 g, 55%): 1H NMR (CD3OD) δ 8.30 (d, 1H,
J ) 9.3 Hz), 8.02 (m, 1H), 7.35 (m, 4H), 7.10 (m, 3H), 6.55 (m,
2H), 4.85 (d, 1H, J ) 22.0 Hz), 4.54 (d, 1H, J ) 22.0 Hz), 4.40
(t, 2H, J ) 9.5 Hz), 2.92 (t, 2H, J ) 9.5 Hz); MS (m/z) 382,
(MH+), 380 (MH-); HRMS calcd MH+ for C24H19N3O2 382.1556,
found 382.1552.
1,2,3,4-Tetrahydro-2-[5-(2-pyridinyl)pyrimidin-2-yl]-3-
(3,4-dihydrobenzofuranyl)-9H-pyrrolo[3,4-b]quinolin-9-
one (11e). Anhydrous KF (1.80 g, 0.031 mmol), chloropyrim-
idine 7a (1.60 g, 8.36 mmol), and DMF (8.3 mL) was stirred
at 80 °C for 3 h. After cooling, a solution of amine 1a (2.60 g,
7.60 mmol) and DIEA (2.9 mL, 0.017 mmol) in DMF (11 mL)
was added. After stirring at 55 °C for 4 h, the reaction mixture
was partitioned between ethyl acetate and water (220 mL/220
mL). While the solid was collected, the organic layer was
washed with water (2 × 220 mL), dried, and concentrated. The
residue was combined with the solid obtained before and the
mixture was triturated with ethyl acetate to yield the product
as a white solid (2.61 g, 75%): mp 201-203 °C; 1H NMR
(DMSO-d6) δ 11.90 (s, 1 H), 9.12 (s, 2 H), 8.98 (s 1H), 8.60 (d,
J ) 4.5 Hz, 1 H), 8.16 (d, J ) 7.9 Hz, 1 H), 7.91 (d, J ) 7.7 Hz,
1 H), 7.84 (d, J ) 7.1 Hz, 1 H), 7.59 (t, J ) 8.6 Hz, 2 H), 7.31
(m, 4H), 6.73 (d, J ) 8.1 Hz, 1H), 6.34 (s, 1H), 4.91 (m, 2H),
4.46 (t, J ) 8.5 Hz, 2H), 3.11 (t, J ) 8.5 Hz, 2H); MS (m/z) 460
(MH+), 458 (MH-); HRMS calcd MH+ for C28H21N5O2 460.1774,
found 460.1785.
(R)-1,2,3,4-Tetrahydro-2-[5-(2-pyridinyl)pyrimidin-2-
yl]-3-(3,4-dihydrobenzofuranyl)-9H-pyrrolo[3,4-b]quino-
lin-9-one [(R)-11e] was prepared the same as 11e in 85%
yield starting from (R)-1a: mp 231-233 °C; [R]22D -237.9 ° (c
0.1883, methanol). Anal. Calcd for C28H21N5O2.CH4O3S‚
1.5H2O: C, 59.78; H, 4.84; N, 12.02; S, 5.50. Found: C, 59.50;
H, 4.78; N, 11.87; S, 5.19.
2-(5-Bromopyrimidin-2-yl)-3-(2,3-dihydrobenzofuran-
5-yl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinolin-9-one (11f)
was prepared the same as 11e in 41% yield starting from 7b:
1H NMR (DMSO-d6) δ 12.05 (s, 1H), 8.81-7.29 (sets of m, 9H),
6.82 (s, 1H), 6.36 (s, 1H), 4.92 (m, 2H), 4.62 (t, 2H, J ) 8.0
Hz), 3.21 (t, 2H, J ) 8.0 Hz); HRMS calcd MH+ for C23H17-
BrN4O2 461.0613, found 461.0616.
3-(2,3-Dihydrobenzofuran-5-yl)-2-pyrimidin-2-yl-1,2,3,4-
tetrahydropyrrolo[3,4-b]quinolin-9-one (11g) was pre-
pared the same as 11e in 24% yield starting from 2-chloropy-
rimidine 7d: 1H NMR (CDOD3) δ 8.38-6.59 (m, 10 H), 6.31
(s, 1H), 4.95 (m, 2H), 4.48 (t, 2H, J ) 9.0 Hz), 3.12 (t, 2H, J )
9.0 Hz); MS (m/z) 383 (MH+), 381 (MH-); HRMS calcd MH+
for C23H18N4O2 383.1508, found 383.1506.
(R)-(-)-3-(2,3-Dihydrobenzofuran-5-yl)-2-pyridin-2-yl-
1,2,3,4-tetrahydropyrrolo[3,4-b]quinolin-9-one [(R)-11l]
was prepared the same as 11l in 50% yield starting from (R)-
1a. Karl Fisher analysis calcd %H2O 0.66, found %H2O 0.59;
3-(2,3-Dihydrobenzofuran-5-yl)-2-(5-pyridin-3-ylpyri-
midin-2-yl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinolin-9-
one (11h). A stirred mixture of Pd(OAc)2 (13.6 mg, 0.061
mmol) and dppf (42.1 mg, 0.076 mmol) in DMF (5 mL) was
warmed to 50 °C for 15 min. After cooling, pyrroloquinolone
11f (350 mg, 0.76 mmol), 3-pyridine boronic acid 12a (102 mg,
0.83 mmol), and Et3N (0.15 mL, 1.6 mmol) were heated to 90
°C for 30 h. The reaction mixture was diluted with ethyl ether
and filtered through a filter paper. The solution was washed
by 10% aqueous ammonium, brine, and water. After being
dried and concentrated, silica gel column chromatograph
purification provided the product as off-white solid (80.2 mg,
23%): 1H NMR (CDCl3) δ 6.75-8.95 (sets of m, 13H), 6.31 (s,
1H), 4.92 (m, 2H), 4.54 (t, 2H, J ) 8.0 Hz), 3.13 (t, 2H, J ) 8.0
Hz); HRMS calcd MH+ for C28H21N5O2 460.1774, found
460.1753.
[R]22 -199.0° (c 0.31, methanol); mp 251.0-253.0 °C. Anal.
D
Calcd for C24H19N3O2‚0.14H2O: C, 74.93; H, 5.05; N, 10.92.
Found: C, 74.57; H. 5.21; N, 10.59.
3-(2,3-Dihydrobenzofuran-5-yl)-2-(4-imidazol-1-yl-
phenyl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinolin-9-one
(11m).11c,d Pyrroloquinolone (1a) (34.1 mg, 0.1 mmol), 1-(4-
bromophenyl)-1H-imidazole 7h (22.3 mg, 0.10 mmol), Pd2dba3
(4.6 mg, 0.0050 mmol), biphenyl-2-yldi-tert-butylphosphane
(3.0 mg, 0.010 mmol), and NaOtBu (14 mg, 0.14 mmol) were
stirred in 1,4-dioxane (0.60 mL) at 89 °C for 17 h. Ethyl acetate
(50 mL) and water (50 mL) were added to the reaction mixture.
The organic layer was separated, dried and concentrated.
Purification by preparative TLC (5% methanol/dichloromethane)
provide product as yellow powder (12.3 mg, 24%): 1H NMR
(CD3OD) δ 6.67-8.58 (sets of m), 5.89 (s, 1H), 5.05 (d, 1H, J
) 16.0 Hz), 4.78 (d, 1H, J ) 16.0 Hz), 4.50 (t, 2H, J ) 8.0 Hz),
3.12 (t, 2H, J ) 8.0 Hz); MS (m/z) MH+ (447), MH- (445);
HRMS calcd MH+ for C28H22N4O2 447.1821, found 447.1816.
3-Benzo[1,3]dioxol-5-yl-2-(5-pyridin-3-ylpyrimidin-2-
yl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinolin-9-one (11p)
was prepared the same as 11h in two steps in 40% and 23%
1
yields starting from amine 1b: H NMR (DMSO-d6) δ 8.45-
8.95 (m, 4H); 8.12 (m, 2H), 7.28-7.62 (m, 4H), 6.95 (m, 3H),
6.31 (s, 1H), 5.95 (s, 2H), 4.91 (m, 2H); HRMS calcd MH+ for
C27H19N5O3 462.1566, found 462.1593.
3-Benzo[1,3]dioxol-5-yl-2-(4-imidazol-1-ylphenyl)-1,2,3,4-
tetrahydropyrrolo[3,4-b]quinolin-9-one (11o) was pre-
pared the same as 11m in 20% yield starting from amine 1b:
1H NMR (CD3OD) δ 6.75-8.32 (m, 14H), 5.88 (s, 2H), 5.48 (s,
3-(2,3-Dihydrobenzofuran-5-yl)-2-(5-pyridin-4-ylpyri-
midin-2-yl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinolin-9-
one (11i) was prepared the same as 11h in 25% yield starting

Pyrroloquinolone PDE5 Inhibitors for Use in MED
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 2133
(5) For Levitra (vardenafil), see: Sorbera, L. A.; Martin, L.; Ra-
basseda, J.; Castaner, J.; Vardenafil, Treatment of Erectile
Dysfunction, Phosphodiesterase 5 Inhibitor. Drugs Future 2001,
26 (2), 141-144 and references therein.
2H), 5.02 (d, 1H, J ) 13.8 Hz), 4.70 (d, 1H, J ) 13.8 Hz); MS
(m/z) MH+ (449), MH- (447); HRMS calcd MH+ for C27H20N4O3
449.1614, found 449.1617.
2-[2,2′]Bipyridinyl-5-yl-3-(2,3-dihydrobenzofuran-5-yl)-
(6) For comparison of the three launched PDE5 inhibitors, see: (a)
Gresser, U.; Gleiter, C. H. Erectile Dysfunction: Comparison of
Efficacy and Side Effects of the PDE-5 Inhibitors Sildenafil,
Vardenafil and Tadalafil. Eur. J. Med. Res. 2002, 7, 435-466.
(b) Sui, Z.; Phosphodiesterase-5 Inhibitors for Male Erectile
Dysfunction. Expert Opin. Ther. Pat. 2003, 13 (9), 1373-1388.
(7) Fawcett, L.; Baxendale, R.; Stacey, P.; McGrouther, C.; Harrow,
I.; Soderling, S.; Hetman, J.; Beavo, J. A.; Phillips, S. C.;
Molecular cloning and characterization of a distinct human
phosphodiesterase gene family: PDE11A. Proc. Natl. Acad. Sci.
U.S.A. 2000, 97, 3702-07.
(8) (a) Sui, Z.; Guan, J.; Macielag, M. J.; Jiang, W.; Zhang, S.; Qiu,
Y.; Kraft, P., Bhattacharjee, S.; John, T. M.; Craig, E.; Haynes-
Johnson, D.; Clancy, J. Pyrimidinyl Pyrroloquinolones as Highly
Potent and Selective PDE5 Inhibitors for Treatment of Erectile
Dysfunction. J. Med. Chem. 2002, 45, 4094-4096. (b) Jiang, W.;
Sui, Z.; Chen, X. Synthesis of Optically Pure Pyrroloquinolones
via Pictet-Spengler and Winterfeldt Reactions. Tetrahedron
Lett. 2002, 43 (49), 8941-8945. (c) Qiu, Y.; Bhattacharjee, S.;
Kraft, P.; John, T. M.; Craig, E.; Haynes-Johnson, D.; Guan, J.;
Jiang, W.; Macielag, M.; Sui, Z.; Clancy, J.; Lundeen, S.
Characterization of a novel phosphodiesterase type 5 inhibitor:
JNJ-10258859. Eur. J. Pharm. 2003, 472 (1-2), 73-80. (d)
Lanter, J. C.; Walsh, S. P.; Sui, Z.; Macielag, M. J.; Jiang, W.;
Fiordeliso, J. J.; Guan, J.; Qiu, Y.; Kraft, P.; Lombardi, E.; John,
T. M.; Clancy, J. Structure-Activity Relationships of N-Acyl
Pyrroloquinolone PDE-5 Inhibitors. J. Med. Chem. 2004, 47,
656-662.
1,2,3,4-tetrahydropyrrolo[3,4-b]quinolin-9-one
(11n).
Pyrroloquinolone‚HCl (1a‚HCl) (0.034 g, 0.1 mmol), 5-bromo-
[2,2′]bipyridinyl 7h [23.5 mg, 0.10 mmol; prepared according
to the procedure reported by Bomero and Ziessel (Tetrahedron
Lett. 1995, 36, 6471-6474)], Pd2dba3 (4.6 mg, 0.005 mmol),
biphenyl-2-yldi-tert-butylphosphane (3.0 mg, 0.01 mmol), and
NaOtBu (44 mg, 0.44 mmol) were stirred in 1,4-dioxane (0.6
mL) at 90 °C for 1 h. The resulting mixture was concentrated
and filtered on a plug of Celite with dichloromethane. Purifica-
tion by preparative TLC (5% methanol/dichloromethane)
yielded the product as a yellow solid (10.0 mg, 22%): 1H NMR
(CD3OD) δ 6.65-8.45 (sets of m, 14H), 5.92 (s, 1H), 5.10 (m,
2H), 4.45 (t, 2H, J ) 8.0 Hz), 3.15 (t, 2H, J ) 8.0 Hz); MS
(m/z) 459 (MH+), 457 (MH-); HRMS (ESI) calcd MH- for
C29H22N4O2 457.1665, found 457.1688.
Biological Assays. All assays used in this report were
discussed in our previous publication.8c
Acknowledgment. We thank Mary Evangelisto and
Dr. Nareshkumar Jain for HPLC analysis and Steve
Juzwin, William Jones, Patrick Sasso for PK studies.
Supporting Information Available: A table listing the
1
purity of 11a-p; H NMR of 6a,b, 8a,b, 10a-d, and 11a-p;
and HPLC of 11a-p. This material is available free of charge
via the Internet at http://pubs.acs.org.
(9) (a) Winterfeldt, E. Chinolon-Derivate durch autoxidation. Liebigs
Ann. Chem. 1971, 745, 23-30. (b) Warneke, J.; Winterfeldt, E.
Die autoxidative indol-chinolon-umwandlung eines camptoth-
ecin-modells. Chem. Ber. 1972, 105, 2120-2125. (c) Boch, M.;
Korth T.; Nelke, J. M.; Pike, D.; Radunz, H.; Winterfeldt, E.;
Die biogenetisch orientierte totalsynthese von DL-Camptoyhecin
und 7-chlor-camptothecin. Chem. Ber. 1972, 105, 2126-2142.
(d) Carniaux, J.-F.; Kan-Fan, C.; Royer, J.; Husson, H.-P.
Synthesis of a Novel Fused Tricyclic Quinolone system via
Oxidation of 1,2,3,4-Tetrahydro-â-Carbolines Tetrahedron Lett.
1997, 38, 2997-3000.
(10) Pivsa-Art, S.; Sato, T.; Kawamura, Y.; Miura, M.; Nomura, M.
Palladium-Catalyzed Arylation of Azolation of Azole Compounds
with Aryl Halides in the Presence of Alkali Metal Carbonates
and the Use of Copper Iodides in the Reaction. Bull. Chem. Soc.
Jpn. 1998, 71, 467-73.
(11) (a) Wolfe, J. P.; Buchwald, S. L.; Palladium-Catalyzed Amination
of Aryl Iodides, J. Org. Chem. 1996, 61, 1133-35. (b) Old, D.
W.; Harris, M. C.; Buchwald, S. L.; Efficient Palladium-
Catalyzed N-arylation of Indoles, Org. Lett. 2000, 2, 1403-1406.
(c) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald. S.
L. Simple, Efficient Catalyst System for the Palladium-Catalyzed
Amination of Aryl Chlorides, Bromides, and Triflates. J. Org.
Chem. 2000, 65, 1158-74. (d) Wolfe, J. P.; Buchwald, S. L. Scope
and Limitations of the Pd/BINAP-Catalyzed Amination of Aryl
Bromides. J. Org. Chem. 2000, 65, 1144-57.
References
(1) For MED, see: (a) Lue, T. F. Erectile Dysfunction. N. Engl. J.
Med. 2000, 342, 1802-1818. (b) Feldman, H. A.; Goldstein, I.;
Hatzichristou, D. G.; Krane, R. J.; McKinlay, J. B. Impotence
and Its Medical and Physiological Correlates: Results of the
Massachusetts Male Aging Study. J. Urol. 1994, 151, 54-56.
(2) (a) Corbin, J. D.; Francis, S. H. Cyclic GMP Phosphodiesterase-
5: Target of Sildenafil. J. Biol. Chem. 1999, 274, 13729-13732.
(b) Soderling, S. H.; Beavo, J. A. Regulation of cAMP and cGMP
signaling: New phosphodiesterases and new functions. Curr.
Opin. Cell Biol. 2000, 12, 174-179. (c) Conti, M.; Jin, S.-L. C.
The molecular Biology of Cyclic Nucleotide Phosphodiesterases.
Prog. Nucleic Acid Res. Mol. Biol. 2001, 65, 1-52.
(3) For Viagra (sildenafil), see: Brook, G. Sildenafil Citrate (Viagra).
Drugs Today 2000, 36 (2-3), 125-134 and references therein.
(4) For Cialis (tadalafil), see: (a) Sorbera, L A.; Martin, L.; Leeson,
P. A.; Casraner, J.; IC-351, Treatment of Erectile Dysfunction.
Treatment of Female Sexual Dysfunction, Phosphodiesterase 5
Inhibitor. Drugs Future 2001, 26 (1), 15-19 and references
therein. For discovery of tadalafil, see: (b) Daugan, A.; Grondin,
P.; Ruault, C.; Gouville, A.-C. L. M.; Coste, H.; Kirilovsky, J.;
Hyafil, F.; Labaudiniere, R. The Discovery of Tadalafil: A Novel
and Highly Selective PDE5 Inhibitor. 1: 5,6,11,11a-Tetrahydro-
1H-imidazole[1′,5′:1,6]pyrido[3,4-b]indole-1, 3(2H)-dione Ana-
logues. J. Med. Chem. 2003, 46, 4525-4532. (c) Daugan, A.;
Grondin, P.; Ruault, C.; Gouville, A.-C. L. M.; Coste, H.; Linget,
J. M.; Kirilovsky, J.; Hyafil, F.; Labaudiniere, R. The Discovery
of Tadalafil: A Novel and Highly Selective PDE5 Inhibitor. 2:
2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-
1,4-dione Analogues. J. Med. Chem. 2003, 46, 4533-4542.
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