Structure-Activity Relationships of Potent, Selective Inhibitors of Neuronal Nitric Oxide Synthase Based on the 6-Phenyl-2-aminopyridine Structure

Article abstract of DOI:10.1021/jm030519g

The synthesis and structure-activity relationships of a series of 6-phenyl-2-aminopyridines that potently and selectively inhibit the neuronal isoform of nitric oxide synthase (nNOS) are described. Compound 14bi from this series exhibits potent in vivo activity in harmaline-induced cGMP formation in rat cerebellum, a functional model of nNOS inhibition, and in the PCP-induced hypermotility model in the rat. These results suggest that 14bi may be a useful reagent for evaluating potential therapeutic applications of nNOS inhibitors in the central nervous system.

Full text of DOI:10.1021/jm030519g

J . Med. Chem. 2004, 47, 1575-1586
1575
Str u ctu r e-Activity Rela tion sh ip s of P oten t, Selective In h ibitor s of Neu r on a l
Nitr ic Oxid e Syn th a se Ba sed on th e 6-P h en yl-2-a m in op yr id in e Str u ctu r e
J ohn A. Lowe, III,* Weimin Qian, Susan E. Drozda, Robert A. Volkmann, Deane Nason, Robert B. Nelson,
Charles Nolan, Dane Liston, Karen Ward, Steve Faraci, Kim Verdries, Pat Seymour, Michael Majchrzak,
Anabella Villalobos, and W. Frost White
Pfizer Global Research and Development, Pfizer Inc., Eastern Point Road, Groton Connecticut 06340
Received October 13, 2003
The synthesis and structure-activity relationships of a series of 6-phenyl-2-aminopyridines
that potently and selectively inhibit the neuronal isoform of nitric oxide synthase (nNOS) are
described. Compound 14bi from this series exhibits potent in vivo activity in harmaline-induced
cGMP formation in rat cerebellum, a functional model of nNOS inhibition, and in the PCP-
induced hypermotility model in the rat. These results suggest that 14bi may be a useful reagent
for evaluating potential therapeutic applications of nNOS inhibitors in the central nervous
system.
In tr od u ction
Nitric oxide synthase (NOS), the enzyme that pro-
duces the neurotransmitter and cytotoxic agent nitric
oxide (NO), has long been recognized as a potentially
important target for new therapeutic agents.1,2 NOS
consists of three isoforms, including the inducible
(iNOS) enzyme which produces large quantities of NO
during bacterial infection or tumor cell cytolysis and the
endothelial isoform (eNOS), a constitutive, calcium-
dependent enzyme which produces vasorelaxant NO to
balance the vasoconstrictor adrenaline. The third iso-
form, neuronal NOS (nNOS), is also constitutive and
calcium-dependent, and is thought to play a role in
neurotransmission in the brain and spinal cord, and in
skeletal muscle by virtue of its localization to these
tissues. There is evidence from studies in transgenic
mice3 and with selective nNOS inhibitors4 for a role of
nNOS in producing cytotoxic levels of NO following
cerebral ischemia and reperfusion, such as might occur
during a stroke.
F igu r e 1. NOS inhibitor literature standards.
complicate the interpretation of these studies: (1) 1 is
actually a nonselective inhibitor of both nNOS and
eNOS (see below), and (2) 1 is an inhibitor of monoamine
oxidase B (MAO-B).10 The latter property was shown
to contribute to the neuroprotective activity of 1 in a
model of Parkinson’s disease,11 which had originally
been ascribed to nNOS inhibition.12
In addition, several reports have presented evidence
for the role of nNOS in spinal transmission of pain
sensation. For example, upregulation of nNOS in the
spinal cord has been demonstrated following formalin
injection in the rat hindpaw.5 In addition, formalin
injection also upregulates spinal levels of cGMP-de-
pendent protein kinase I alpha, which propagates the
pain signal initiated by spinally produced NO.6 The
selective nNOS inhibitor 7-nitroindazole, 1 (Figure 1),
blocks this upregulation. Compound 1 has been used
extensively in studies addressing the role of nNOS in
pain.7 Specifically, 1 was shown to inhibit carrageenin-
induced mechanical and thermal hyperalgesia in the rat
paw without affecting pain perception in the nontreated
paw.8 Another study with compound 1 indicated nNOS
plays a role throughout the hyperalgesic response, in
contrast to iNOS, which was suggested to play a role in
the later stages only.9 Two limitations of 1, however,
Nevertheless, there seems to be sufficient evidence
to suggest that centrally acting nNOS inhibitors might
prove therapeutically useful in the treatment of pain,
stroke, and/or Parkinson’s disease, provided they are
adequately selective to avoid interfering with the im-
portant functions of iNOS and eNOS. Finding the
required reagent for proof-of-concept studies, however,
has been challenging. There are several classes of
compounds currently under investigation for this po-
tential,13 among them the 2-aminopyridine class, ex-
emplified by 2-amino-4-methylpyridine, 2 (Figure 1).
Compound 2 is reported to be a potent, nonselective
inhibitor of all three NOS isoforms, with potent inhibi-
tion of NO production in vivo.14 We recently reported a
new series of NOS inhibitors with modest selectivity for
nNOS from the 6-phenyl-2-aminopyridine structural
class, exemplified by compound 3 (Figure 1).15 Com-
pound 3 exhibits good selectivity for nNOS over other
* To whom correspondence should be addressed. Phone: 860-441-
4248. Fax: 860-686-0013. E-mail: john_a_lowe@groton.pfizer.com.
10.1021/jm030519g CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/04/2004

1576 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 6
Lowe et al.
Sch em e 1
enzyme and receptor targets, as well as promising
pharmacokinetic properties suggesting its utility in
examining the role of nNOS in vivo. In searching for
analogues with improved nNOS selectivity, we exam-
ined: (1) substitution on the 6-phenyl ring, and (2)
adding an oxygen atom to the linking group to the
terminal amine function. We report herein the synthesis
and SAR of a series of 6-phenyl-2-aminopyridines that
led to the selection of compound 14bi, a potent, selective
nNOS inhibitor that may be useful for elucidating the
therapeutic potential of nNOS inhibition.
aromatic substitution reaction, followed by deblocking
to afford the final products 23i,ii. In Scheme 4, the more
conventional approach using displacement of a mesylate
leaving group by the sodium salt of a suitable phenol
precursor, followed by deblocking, affords the desired
products 25i,ii.
Biology
The NOS inhibitory activity of the compounds re-
ported herein was measured in vitro using human NOS
isoforms derived from the cloned genes expressed in
baculovirus in Sf9 cells. The assay was based on one
reported earlier.16 The in vitro activity of 14bi was
confirmed by measuring the functional inhibition of
cGMP formation, which is dependent on NO stimulation
of guanylate cyclase, induced by the proconvulsant
alkaloid harmaline in the rat.17 The activity of a
standard NOS inhibitor, L-nitroarginine, in this test
reflects its in vitro activity against nNOS. Inhibition of
PCP-induced hypermotility18 was then used to measure
the in vivo behavioral efficacy of 14bi.
Ch em istr y
The compounds in series 14, 18, 23, and 25 were
prepared as shown in Schemes 1 through 4. In Scheme
1, the key carbon-carbon bond is formed by a pal-
ladium-mediated Suzuki coupling reaction between a
suitably substituted boronic acid, 7a -d , and the 2,5-
dimethylpyrrolyl protected derivative of 2-amino-6-
bromopyridine. Attachment of the dialkylamino group
is achieved by water soluble carbodiimide-mediated
coupling to a suitable carboxylic acid precursor followed
by reduction. Deblocking using hydroxylamine hydro-
chloride affords the final products 14a -d . Scheme 2
illustrates an abbreviated synthesis in which the dimeth-
ylaminoethoxy side chain is installed near the beginning
of the route, followed by boronic acid formation, Suzuki
coupling, and deprotection. This route was used to
produce larger quantities of compound 14bi for in vivo
study, as well as analogue 18ei. Appending side groups
more highly substituted around the dialkylamino group
proved challenging and was dealt with as shown in
Schemes 3 and 4. In Scheme 3, an aromatic fluoro
precursor 21 was reacted with a dialkylamine-contain-
ing alcohol as the sodium alkoxide in a nucleophilic
Resu lts a n d Discu ssion
Table 1 displays the in vitro activity of the compounds
in the 2-amino-6-phenylpyridine series, determined as
IC50 values against the three NOS isoforms. While all
new compounds reported here show improved selectivity
over literature standards 1 and 2, as well as our
previously reported compound 3, some important trends
within the new series are evident. For example, the
inhibitory potency and selectivity for human nNOS
inhibitory activity increases in going from the naphthyl
series (14a ) to the tetralin (14b) and indane (14c) series.
This may indicate that nNOS prefers a more electron

Inhibitors of Neuronal Nitric Oxide Synthase
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 6 1577
Sch em e 2
Sch em e 3
rich ring at the 6-phenyl position of the pyridine group.
There are more subtle differences among the various
terminal amine side chains, but the simple dimethyl-
amino group generally affords good nNOS inhibitory
activity. On the basis of compound 14bi’s combination
of inhibitory human nNOS potency and selectivity over
human eNOS, it was selected for further profiling.
The NOS inhibitory activity of 14bi was confirmed
in vivo using the harmaline-induced formation of cGMP
in rat cerebellum. Harmaline is a neurotoxin known to
stimulate cGMP formation via opening of NMDA chan-
nels, followed by calcium influx, activation of nNOS and
subsequent NO-activation of guanylate cyclase. Thus
measuring cGMP levels following a harmaline chal-
lenge, in the presence and absence of an nNOS inhibitor,
is a measure of in vivo functional efficacy. As shown in
Figure 2, 14bi gave an ED50 value of 7 mg/kg when
administered subcutaneously in the rat harmaline test.
As a control compound, 1 gave an ED50 value of 30 mg/
kg sc. This increase in in vivo potency of 14bi relative
to 1 may result from both increased in vitro potency and
improved aqueous solubility, although distribution and
elimination of these compounds may also play a role.
Inhibition of PCP-induced hypermotility18 was then
used as another assessment of the in vivo activity of
14bi. As shown in Figure 3, 14bi gave an ED50 value of

1578 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 6
Lowe et al.
Sch em e 4
Ta ble 1. In Vitro NOS Inhibitory Data for Compounds 14, 18, 23, and 25
a
Inhibition of human neuronal nitric oxide synthase activity given as an IC50 value in nM units followed by the SEM value. N in the
b
following column indicates the number of determinations. Inhibition of human endothelial nitric oxide synthase activity given as an
IC50 value in nM units followed by the SEM value. N in the following column indicates the number of determinations. c Inhibition of
human inducible nitric oxide synthase activity given as an IC50 value in nM units followed by the SEM value. N in the following column
d
indicates the number of determinations. Inhibition of rat neuronal nitric oxide synthase activity given as an IC50 value in nM units
followed by the SEM value. N in the following column indicates the number of determinations. e Values for compound 2 are taken from
ref 14, and values for compound 3 are taken from ref 15.
2.8 mg/kg administered subcutaneously. This result is
in contrast to that reported for compound 3, which does
not appreciably inhibit the hypermotility response to
PCP in the rat. The greater in vitro potency and
selectivity of 14bi may contribute to this difference.
Although the PCP-induced hypermotility model is used
to test antipsychotic agents such as dopamine D2
receptor antagonists, the activity of 14bi in the model
is not a guarantee of clinically effective antipsychotic
activity. The significance of the result is rather that the
potent in vivo activity of 14bi makes it a useful reagent
for investigating the role of nNOS in the central nervous
system and the eventual unraveling of the therapeutic
potential of nNOS inhibitors.

Inhibitors of Neuronal Nitric Oxide Synthase
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 6 1579
sodium sulfate, and evaporated. The residue was chromato-
graphed on silica gel using methylene chloride/hexane as
eluant to afford 5.8 g (93%) of an oil. 1H NMR (δ, CDCl3): 5.22
(s, 2H), 6.74 (d, J ) 8, 1H), 7.4-7.7 (m, 8H), 8.21 (d, J ) 8,
1H), 8.39 (d, J ) 8, 1H). 13C NMR (δ, CDCl3): 70.3, 105.9,
113.6, 122.7, 126.1, 126.9, 127.0, 127.4, 127.9, 128.1, 128.7,
129.5, 132.6, 136.7, 154.3. MS (%): 314 (parent + 1, 100).
4-B r o m o -5,6,7,8-t e t r a h y d r o -1-b e n zy lo x y n a p h t h a -
len e, 6b. Prepared in 63% yield as an oil. 1H NMR (δ,
CDCl3): 1.77 (m, 4H), 2.75 (m, 4H), 5.045 (s, 2H), 6.62 (d, J )
9, 1H), 7.3-7.5 (m, 6H). 13C NMR (δ, CDCl3): 22.2, 22.9, 24.0,
30.7, 69.9, 109.8, 116.7, 127.1, 127.9, 128.6, 129.1, 129.3, 137.2,
137.5, 155.6.
4-Br om o-1-ben zyloxyin d a n e, 6c. Prepared in 96% yield
1
as an oil. H NMR (δ, CDCl3): 2.14 (m, 2H), 3.00 (t, J ) 7.5,
2H), 3.07 (t, J ) 7.5, 2H), 5.09 (s, 2H), 6.63 (d, J ) 8.5, 1H),
7.3-7.6 (m, 6H). 13C NMR (δ, CDCl3): 23.8, 30.9, 34.9, 70.0,
110.8, 111.5, 127.1, 157.8, 128.5, 130.0, 134.0, 137.1, 146.0,
154.4.
F igu r e 2. A representative dose-response curve depicting
reversal by 14bi of harmaline-induced cerebellar cGMP forma-
tion measured ex vivo by ELISA. 14bi was given 2 h before
harmaline, using 10 rats per dose group. The calculated ED50
from this experiment is 6.36 mg/kg sc, with an r value of 0.98.
The mean ED50 from this and two other experiments was 7 (
2 mg/kg. * p < 0.0005; @ p < 0.00005 difference from
harmaline; # p < 0.0005 difference from vehicle.
Bicyclo[2.2.1]cycloh exylp h en ol, 4d . A solution of 5.38 g
(48.0 mmol) of 2-hydroxypyrone (ref: Synth. Commun. 1975,
5, 461) and 18.1 g (190 mmol) norbornylene was heated at 125
°C for 28 h in a sealed tube and then cooled and chromato-
graphed on silica gel using hexane/ethyl acetate as eluant to
give a mixture of olefin isomers in 49% yield. This mixture
was treated with 500 mg of palladium oxide and 1.0 g of
magnesium sulfate in 80 mL of dry toluene at reflux for 18 h.
The reaction was cooled and filtered through Celite, and the
filtrate was concentrated and chromatographed on silica gel
using hexane/ethyl acetate as eluant to afford 2.65 g (71%) of
1
a yellow oil. H NMR (δ, CDCl3): 1.25 (m, 2H), 1.52 (m, 1H),
1.78 (m, 1H), 1.93 (m, 2H), 3.40 (m, 1H), 3.62 (m, 1H), 5.82
(bs, 1H), 6.65 (d, J ) 8, 1H), 6.86 (d, J ) 8, 1H), 7.00 (t, J )
8, 1H). 13C NMR (δ, CDCl3): 26.45,,27.0, 39.3, 44.0, 49.1, 113.2,
113.6, 126.8, 132.7, 148.5, 150.8. GC MS (%): 160 (parent,
100).
4-Br om o-5,6,7,8-t et r a h yd r o[2.2.1]b icyclo-1-b en zylox-
yn a p h th a len e, 6d . Prepared from 4d in 94% yield as an oil.
1H NMR (δ, CDCl3): 1.24 (m, 2H), 1.49 (m, 1H), 1.76 (m, 1H),
1.94 (m, 2H), 3.57 (m, 1H), 3.77 (m, 1H), 6.61 (d, J ) 8.5, 1H),
7.14 (d, J ) 8.5, 1H), 7.3-7.5 (m, 5H). 13C NMR (δ, CDCl3):
25.96, 26.23, 41.04, 44.72, 48.51, 70.57, 107.57, 112.64, 127.30,
127.94, 128.56, 128.59, 128.85, 137.24, 149.46, 151.50. MS
(%): 327/329 (100, parent + 1, Br79/Br81).
F igu r e 3. Dose-response curve depicting reversal by 14bi
of phencyclidine-induced hyperactivity. Data are combined
from three experiments, indicating an ID50 value of 2.8 mg/kg
sc and 95% confidence limits of 1.96-4.0.
1-Ben zyloxyn a p h th a len e-4-bor on ic Acid , 7a . To a 125
mL round-bottomed flask equipped with N2 inlet were added
5.95 g (19 mmol) of 4-bromo-1-benzyloxynaphthalene and 20
mL of dry tetrahydrofuran. The solution was cooled to -70
°C, 9.12 mL (22.89 mmol) of a 2.5 M solution of n-butyllithium
in hexane was added over 5 min, and the reaction was stirred
at -70 °C for 10 min. The solution was then treated with 3.88
mL (22.8 mmol) of triethyl borate, stirred 5 min at -70 °C,
and then warmed to room temperature and stirred 40 h. The
reaction was quenched with aqueous ammonium chloride
solution, poured into 0.5 N hydrochloric acid, and extracted
into ethyl acetate. The organic layer was washed with brine,
dried over sodium sulfate, and evaporated to a white solid after
trituration with hexane, mp 149-152 °C, 2.89 g (55%). 1H
NMR (δ, CDCl3): 5.18 (s, 2H), 6.82 (m, 1H), 7.2-7.8 (m, 8H),
8.28 (m, 2H). 13C NMR (δ, CDCl3): 69.9, 104.5, 104.7, 122.2,
122.4, 124.8, 125.0, 126.5, 126.6, 127.6, 127.7, 127.9, 128.0,
128.5, 130.9, 132.9, 136.9.
Exp er im en ta l Section
Melting points were obtained on a Hoover melting point
apparatus and are uncorrected. NMR spectra were obtained
on a Varian Unity 400 MHz NMR spectrometer. Low resolu-
tion mass spectra were obtained on a Fisons VG Platform
APCI mass spectrometer or a Micromass Platform LCZ LC
mass spectrometer under EI or CI conditions. GC mass spectra
were obtained on a Hewlett-Packard Model 5973 Mass Spec-
trometer coupled to a Hewlett-Packard Model 6890 GC Sys-
tem. High-resolution mass spectra were obtained on a VG
Analytical ZAB 2SE high field mass spectrometer by M-Scan,
Inc. in the FAB mode. Rotation data were obtained on a
Perkin-Elmer 241 MC Polarimeter. Tlc analyses were carried
out on EM Kieselgel 60 F254 5 × 20 cm plates. Elemental
analyses were carried out by Schwarzkopf Laboratories, Inc.
and are within (0.4% of theory unless otherwise noted.
6-[4-(2-Dim eth ylam in oeth oxy)n aph th alen -1-yl]pyr idin -
2-yla m in e, 14a i: Meth od A. 4-Br om o-1-ben zyloxyn a p h -
th a len e, 6a . The known19 4-bromo-1-naphthol, prepared from
2.88 g (20 mmol) of 1-naphthol with 1 equiv of tributylammo-
nium tribromide, was dissolved in 100 mL of acetonitrile,
treated with 3.57 mL (30 mmol) of benzyl bromide and 5.53 g
(40 mmol) potassium carbonate, and refluxed 14 h. TLC
showed a major spot at Rf ) 0.2 in 5% methylene chloride/
hexane. The reaction was cooled and poured into dilute
aqueous hydrochloric acid/ethyl acetate, and the organic layer
was separated, washed with water and brine, dried over
5,6,7,8-Tetr a h yd r o-1-ben zyloxyn a p h th a len e-4-bor on -
ic Acid , 7b. Prepared as a solid, mp 199-205 °C, in 72% yield.
1H NMR (δ, CDCl3): 1.72 (m, 4H), 2.70 (m, 4H), 5.005 (s, 2H),
6.66 (m, 1H), 7.01 (d, J ) 8, 1H), 7.2-7.4 (m, 5H). 13C NMR
(δ, CDCl3): 22.6, 22.9, 23.4, 30.0, 107.8, 125.9, 127.0, 127.6,
128.4, 131.1, 137.5, 140.8, 156.9.
1-Ben zyloxyin d a n e-4-bor on ic Acid , 7c. mp 222-223.5
1
°C, in 58.5% yield. H NMR (δ, CDCl3): 1.97 (m, 2H), 2.83 (t,
J ) 8.5, 2H), 3.03 (t, J ) 7.5, 2H), 5.04 (s, 2H), 6.65 (d, J ) 8,
1H), 7.2-7.5 (m, 6H). 13C NMR (δ, CDCl3): 24.7, 29.1, 34.25,
69.4, 108.7, 127.1, 127.7, 128.4, 131.7, 131.9, 133.9, 137.3,
156.9.

1580 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 6
Lowe et al.
Bicyclo[2.2.1]-1-ben zyloxyn aph th alen e-4-bor on ic Acid,
7d . An oil in 100% yield. 1H NMR (δ, CDCl3): 1.2-1.9 (m, 6H),
3.7-3.8 (m, 2H), 6.83 (d, J ) 8.3, 1H), 7.2-7.5 (m, 5H), 7.92
(d, J ) 8.3, 1H).
1.77 (m, 2H), 2.16 (s, 6H), 2.63 (m, 2H), 2.73 (m, 2H), 5.89 (s,
2H), 6.3 (bs, 1H, OH), 6.51 (d, J ) 8, 1H), 7.02 (d, J ) 8, 1H),
7.13 (d, J ) 8, 1H), 7.35 (d, J ) 8, 1H), 7.83 (t, J ) 8, 1H). 13C
NMR (δ, CDCl3): 13.3, 22.3, 22.8 23.3, 28.6, 106.6, 112.1, 119.7,
123.3, 124.2, 127.8, 128.7, 131.9, 136.6, 138.1, 151.2, 154.4,
160.5. MS (%): 319 (parent + 1, 100).
2-(2,5-Dim et h ylp yr r olyl)-6-(4-b en zyloxy-1-n a p h t h yl)-
p yr id in e, 8a . To a 100 mL round-bottomed flask equipped
with condenser and N2 inlet were added 953 mg (3.795 mmol)
of N-(2,5-dimethylpyrrolyl)-6-bromopyridyl-2-amine, 1055 mg
(3.795 mmol) of 1-benzyloxynaphthalene-4-boronic acid, 1.61
g (15.2 mmol) of sodium carbonate, 44 mg (0.04 mmol) of
tetrakistriphenylphosphine palladium, 18 mL of ethanol, and
2 mL of water, and the reaction was heated at 80 °C for 13 h.
TLC showed a major spot at Rf ) 0.2 in 15% ethyl acetate in
hexane, and LCMS showed a major peak at P + 1 ) 319. The
reaction was cooled, poured into water, and extracted into ethyl
acetate. The organic layer was washed with water and brine,
dried over sodium sulfate, and evaporated. The residue was
chromatographed on silica gel using hexane/ethyl acetate as
2-(2,5-Dim eth ylp yr r olyl)-6-[4-h yd r oxyin d a n -1-yl]p yr i-
1
d in e, 9c. Prepared in 100% yield as an low melting solid. H
NMR (δ, CDCl3): 1.95 (m, 2H), 2.05 (s, 6H), 2.785 (t, J ) 7.5,
2H), 3.02 (t, J ) 7.5, 2H), 5.78 (s, 2H), 6.61 (d, J ) 8, 1H),
6.96 (d, J ) 7.5, 1H), 7.32 (d, J ) 8, 1H), 7.39 (d, J ) 8, 1H),
7.73 (t, J ) 8, 1H). 13C NMR (δ, CDCl3): 12.95, 25.30, 28.94,
33.85, 106.40, 113.31, 119.26, 121.43, 127.47, 128.43, 128.56,
130.71, 138.36, 144.68, 151.23, 153.85, 158.97. MS (%): 305
(parent + 1, 100).
2-(2,5-Dim et h ylp yr r olyl)-6-[4-h yd r oxyb icyclo[2.2.1]-
n a p h th a len -1-yl]p yr id in e, 9d . Prepared in 100% yield as
an low melting solid. 1H NMR (δ, CDCl3): 1.2-2.0 (m, 6H),
2.215 (s, 6H), 3.59 (m, 1H), 3.81 (m, 1H), 5.93 (s, 2H), 6.59 (d,
J ) 8.5, 1H), 7.11 (d, J ) 7.5, 1H), 7.38 (d, J ) 8.5, 1H), 7.50
(d, J ) 8, 1H), 7.85 (t, J ) 8, 1H). 13C NMR (δ, CDCl3): 13.4,
26.4, 26.6, 39.3, 43.0, 48.9, 106.8, 113.9, 119.2, 121.4, 127.6,
128.8, 133.5, 138.3, 148.6, 151.6, 150.0, 158.4, 163.8. MS (%):
329 (parent + 1, 100).
1
eluant to afford 1.53 g (∼100%) of an oil. H NMR (δ, CDCl3):
2.25 (s, 6H), 5.29 (s, 2H), 5.92 (s, 2H), 6.95 (d, J ) 8, 1H), 7.21
(d, J ) 7.5, 1H), 7.3-7.6 (m, 9H), 7.89 (t, J ) 8, 1H), 8.14 (m,
1H), 8.45 (m, 1H). 13C NMR (δ, CDCl3): 13.5, 70.1, 104.8, 106.8,
119.7, 122.5, 123.4, 125.2, 125.3, 125.9, 126.4, 126.9, 127.3,
127.9, 128.2, 128.6, 130.5, 132.0, 136.9, 138.0, 151.8, 155.0,
159.1. MS (%): 405 (parent + 1, 100).
2-(2,5-Dim e t h ylp yr r olyl)-6-(4-(2-ca r b oe t h oxym e t h -
yloxy)-1-n a p h th yl)p yr id in e, 10a . To a 125 mL round-
bottomed flask equipped with condenser and N2 inlet were
added 1.19 g (3.795 mmol) of 2-(2,5-dimethylpyrrolyl)-6-(4-
hydroxy-1-naphthyl)-pyridine, 0.505 mL (4.554 mmol) of ethyl
bromoacetate, 1.05 g (7.59 mmol) of potassium carbonate, and
25 mL of acetonitrile. The mixture was refluxed 12 h, cooled
(TLC Rf ) 0.6 in 1/1-ethyl acetate/hexane), poured into water,
and extracted into ethyl acetate. The organic layer was washed
with brine, dried over sodium sulfate, and evaporated. The
residue was chromatographed on silica gel using hexane/ethyl
2-(2,5-Dim eth ylpyr r olyl)-6-[4-ben zyloxy-5,6,7,8-tetr ah y-
d r on a p h th a len -1-yl]p yr id in e, 8b. Prepared in 100% yield
as an oil. 1H NMR (δ, CDCl3): 1.81 (m, 2H), 1.91 (m, 2H), 2.29
(s, 6H), 2.93 (m, 4H), 5.19 (s, 2h), 6.02 (s, 2H), 6.91 (d, J ) 8,
1H), 7.21 (d, J ) 8, 1H), 7.32 (d, J ) 8, 1H), 7.4-7.6 (m, 6H),
7.89 (t, J ) 8, 1H). 13C NMR (δ, CDCl3): 13.5, 22.5, 23.0, 24.0,
28.9, 69.8, 106.8, 108.2, 119.6, 123.1, 126.8, 127.2, 127.8, 12.9,
128.6, 128.7, 132.8, 136.8, 137.6, 138.0, 151.4, 156.8, 160.4.
MS (%): 409 (parent + 1, 100).
2-(2,5-Dim et h ylp yr r olyl)-6-[4-b en zyloxyin d a n -1-yl]-
p yr id in e, 8c. Prepared in 100% yield as an amorphous solid.
1H NMR (δ, CDCl3): 2.09 (m, 2H), 2.18 (s, 6H), 2.97 (t, J )
7.5, 2H), 3.20 (t, J ) 7.5, 2H), 5.15 (s, 2H), 5.90 (s, 2H), 6.83
(d, J ) 8, 1H), 7.08 (d, J ) 7.5, 1H), 7.2-7.6 (m, 7H), 7.82 (t,
J ) 8, 1H). 13C NMR (δ, CDCl3): 13.4, 25.3, 29.5, 34.3, 69.7,
106.5, 109.9, 119.1, 120.9, 127.1, 127.8, 128.5, 128.6, 133.2,
137.3, 138.0, 144.7, 151.4, 155.7, 158.6. MS (%): 395 (parent
+ 1, 100).
1
acetate as eluant to afford 2.05 g (∼100%) of an oil. H NMR
(δ, CDCl3): 1.31 (t, J ) 7, 3H), 2.26 (s, 6H), 4.29 (q, J ) 7,
2H), 4.82 (s, 2H), 5.94 (s, 2H), 6.78 (d, J ) 8, 1H), 7.20 (d, J )
8, 1H), 7.5-7.6 (m, 5H), 7.87 (t, J ) 8, 1H), 8.15 (m, 1H), 8.50
(m, 1H). 13C NMR (δ, CDCl3): 13.6, 14.2, 61.4, 65.7, 104.6,
107.0, 119.9, 122.6, 123.6, 125.3, 125.6, 125.8, 127.2, 128.0,
128.6, 131.4, 132.1, 138.3, 151.8, 154.3, 158.9, 168.6. MS (%):
401 (parent + 1, 100).
2-(2,5-Dim et h ylp yr r olyl)-6-[4-ca r b oet h oxym et h oxy-
5,6,7,8-t et r a h yd r on a p h t h a len -1-yl]p yr id in e, 10b . Pre-
2-(2,5-Dim eth ylp yr r olyl)-6-[4-ben zyloxybicyclo[2.2.1]-
1
n a p h th a len -1-yl]p yr id in e, 8d . Prepared in 94% yield as an
pared in 83.5% yield as an oil. H NMR (δ, CDCl3): 1.31 (t, J
1
amorphous solid. H NMR (δ, CDCl3): 1.2-2.0 (m, 6H), 2.22
) 7, 3H), 1.71 (m, 2H), 1.83 (m, 2H), 2.19 (s, 6H), 4.26 (q, J )
7, 2H), 4.66 (s, 2H), 5.90 (s, 2H), 6.64 (d, J ) 8, 1H), 7.12 (d,
J ) 8, 1H), 7.20 (d, J ) 8, 1H), 7.35 (d, J ) 8, 1H), 7.82 (t, J
) 8, 1H). 13C NMR (δ, CDCl3): 13.4, 14.2, 22.3, 22.9, 23.7, 28.7,
61.2, 65.5, 106.7, 107.8, 119.6, 123.0, 126.9, 127.7, 128.5, 133.4,
137.0, 138.1, 151.3, 156.0, 160.1, 169.0. MS (%): 405 (parent
+ 1, 100).
(s, 6H), 3.73 (m, 1H), 3.85 (m, 1H), 5.15 (s, 2H), 5.92 (s, 2H),
6.81 (d, J ) 8.5, 1H), 7.10 (d, J ) 7.5, 1H), 7.2-7.6 (m, 7H),
7.845 (t, J ) 8, 1H). 13C NMR (δ, CDCl3): 13.51, 26.40, 26.67,
39.72, 43.12, 48.95, 70.15, 106.70, 110.65, 119.01, 121.01,
126.34, 126.43, 127.82, 128.54, 128.71, 137.42, 138.05, 148.38,
151.59, 152.73, 158.05. MS (%): 421 (parent + 1, 100).
2-(2,5-Dim e t h ylp yr r olyl)-6-(4-h yd r oxy-1-n a p h t h yl-)
p yr id in e, 9a . To a 125 mL round-bottomed flask equipped
with condenser and N2 inlet were added 1.53 g (3.795 mmol)
of 2-(2,5-dimethylpyrrolyl)-6-(4-benzyloxy-1-naphthyl)pyridine,
1.20 g (18.975 mmol) of ammonium formate, 100 mg of 10%
palladium-on-carbon, and 30 mL of ethanol. The reaction was
refluxed 4 h, with additional catalyst and formate added at 2
and 3 h, and then cooled and filtered through Celite with
ethanol and methylene chloride. The filtrate was evaporated
and the residue taken up in ethyl acetate/aqueous sodium
bicarbonate solution. The organic layer was washed with brine,
dried over sodium sulfate, and evaporated to a light brown
solid, 1.21 g (∼100%). 1H NMR (δ, CDCl3): 2.105 (s, 6H), 5.775
(s, 2H), 6.66 (d, J ) 8, 1H), 7.04 (d, J ) 8, 1H), 7.29 (m, 2H),
7.38 (d, J ) 8, 1H), 7.72 (t, J ) 8, 1H), 7.95 (m, 1H), 8.18 (m,
1H). 13C NMR (δ, CDCl3): 13.8, 106.7, 106.8, 107.6, 119.6,
122.55, 124.5, 124.7, 125.0, 126.5, 128.4, 128.5, 128.7, 132.0,
138.2, 151.5, 153.9, 159.3. MS (%): 315 (parent + 1, 100).
2-(2,5-Dim eth ylp yr r olyl)-6-[4-ca r boeth oxym eth oxyin -
d a n -1-yl]p yr id in e, 10c. Prepared in 100% yield as an amor-
phous solid. 1H NMR (δ, CDCl3): 1.285 (t, J ) 7, 3H), 2.07
(m, 2H), 2.165 (s, 6H), 2.97 (t, J ) 7.5, 2H), 3.18 (t, J ) 7.5,
2H), 4.25 (q, J ) 7, 2H), 4.67 (s, 2H), 5.88 (s, 2H), 6.64 (d, J )
8.5, 1H), 7.07 (d, J ) 7.5, 1H), 7.50 (d, J ) 8, 1H), 7.58 (d, J
) 8.5, 1H), 7.81 (t, J ) 8, 1H). 13C NMR (δ, CDCl3): 13.38,
14.18, 21.04, 25.36, 29.43, 34.21, 61.32, 65.44, 106.57, 109.48,
112.49, 119.23, 120.90, 128.53, 128.63, 129.68, 133.35, 138.01,
145.09, 151.43, 154.86, 158.37, 169.00. MS (%): 391 (parent
+ 1, 100).
2-(2,5-Dim et h ylp yr r olyl)-6-[4-ca r b oet h oxym et h oxy-
bicyclo[2.2.1]n a p h th a len -1-yl]p yr id in e, 10d . Prepared in
1
80% yield as an oil. H NMR (δ, CDCl3): 1.29 (t, J ) 7, 3H),
1.3-1.4 (m, 2H), 1.51 (m, 1H), 1.74 (m, 1H), 1.97 (m, 2H), 2.20
(s, 6H), 3.73 (m, 1H), 3.83 (m, 1H), 4.25 (q, J ) 7, 2H), 4.67 (s,
2H), 5.89 (s, 2H), 6.63 (d, J ) 8.7, 1H), 7.09 (d, J ) 8, 1H), 7.5
(m, 2H), 7.835 (t, J ) 8, 1H).
13C NMR (δ, CDCl3): 13.4, 14.1, 26.25, 26.5, 39.7, 43.0, 48.8,
61.2, 65.8, 106.6, 110.1, 119.0, 120.9, 122.0, 127.4, 128.6, 136.3,
137.9, 148.5, 149.1, 151.8, 157.8, 169.0.
2-(2,5-Dim eth ylp yr r olyl)-6-[4-h yd r oxy-5,6,7,8-tetr a h y-
d r on a p h th a len -1-yl]p yr id in e, 9b. Prepared in 100% yield
as an low melting solid. 1H NMR (δ, CDCl3): 1.67 (m, 2H),

Inhibitors of Neuronal Nitric Oxide Synthase
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 6 1581
2-(2,5-Dim eth ylp yr r olyl)-6-(4-(2-ca r boxym eth yloxy)-1-
n a p h th yl)p yr id in e, 11a . To a 125 mL round-bottomed flask
equipped with condenser and N2 inlet were added 1.52 g (3.795
mmol) of 2-(2,5-dimethylpyrrolyl)-6-(4-(2-carboethoxymeth-
yloxy)-1-naphthyl)-pyridine, 15 mL of tetrahydrofuran, and
478 mg (11.385 mmol) of lithium hydroxide hydrate in 15 mL
water, with additional methanol to maintain a solution. The
reaction was stirred at room temperature for 12 h, (LCMS P
+ 1 ) 373), poured into dilute aqueous hydrochloric acid, and
extracted into ethyl acetate. The organic layer was washed
with brine, dried over sodium sulfate, and evaporated to a
123.5, 125.4, 125.5, 125.6, 127.0, 128.2, 128.6, 131.2, 132.0,
138.2, 151.8, 154.2, 159.0, 166.4. MS (%): 426 (parent + 1,
100).
2-(2,5-Dim et h ylp yr r olyl)-6-(4-((4-m et h ylp ip er a zin yl)-
car boxam ido)m eth yloxy)-1-n aph th yl)pyr idin e, 12aiii. Pre-
1
pared in 63.5% yield as a foam. H NMR (δ, CDCl3): 2.21 (s,
6H), 2.24 (s, 3H), 2.35 (m, 4H), 3.64 (m, 4H), 4.885 (s, 2H),
5.88 (s, 2H), 6.93 (d, J ) 8, 1H), 7.21 (d, J ) 7.5, 1H), 7.4-7.6
(m, 4H), 7.90 (t, J ) 8, 1H), 8.11 (m, 1H), 8.33 (m, 1H). 13C
NMR (δ, CDCl3): 13.54, 42.07, 45.37, 45.99, 54.56, 55.12, 68.01,
104.70, 106.87, 119.89, 122.05, 123.50, 125.40, 125.56, 125.62,
127.08, 128.11, 128.63, 131.31, 132.05, 138.24, 151.76, 154.04,
158.90, 166.16. MS (%): 455 (parent + 1, 100).
1
solid, 1.27 g (90%). H NMR (δ, CDCl3): 2.20 (s, 6H), 4.74 (s,
2H), 5.89 (s, 2H), 6.765 (d, J ) 8, 1H), 7.20 (d, J ) 8, 1H),
7.4-7.6 (m, 4H), 7.885 (t, J ) 8, 1H), 8.04 (m, 1H), 8.44 (m,
1H). 13C NMR (δ, CDCl3): 13.3, 65.3, 104.5, 106.9, 120.3, 122.6,
124.0, 125.0, 125.6, 125.7, 127.2, 128.0, 128.7, 130.8, 132.0,
138.6, 151.7, 154.3, 158.9, 170.9. MS (%): 373 (parent + 1,
100).
2-(2,5-Dim eth ylp yr r olyl)-6-(4-((4-d im eth yla m in op ip er -
id in e )ca r b oxa m id o)m e t h yloxy)-1-n a p h t h yl)p yr id in e ,
1
12a iv. Prepared in 45% yield as a foam. H NMR (δ, CDCl3):
1.37 (m, 2H), 1.82 (m, 1H), 2.20 (s, 6H), 2.21 (s, 6H), 2.32 (m,
1H), 2.7 (m, 1H), 3.06 (m, 1H), 4.1 (m, 1H), 4.6 (m, 1H), 4.89
(AB, 2H), 5.88 (s, 2H), 6.935 (d, J ) 8, 1H), 7.20 (d, J ) 8,
1H), 7.4-7.6 (m, 4H), 7.90 (t, J ) 8, 1H), 8.10 (m, 1H), 8.35
(m, 1H). 13C NMR (δ, CDCl3): 13.39, 27.84, 29.02, 41.43, 44.47,
61.72, 68.03, 104.65, 106.78, 119.77, 122.00, 123.36, 125.31,
125.48, 126.95, 127.99, 128.54, 131.20, 131.99, 138.08, 151.70,
154.02, 158.85, 165.90. MS (%): 483 (parent + 1, 100).
2-(2,5-Dim et h ylp yr r olyl)-6-[4-(N,N-d im et h ylca r b oxa -
m id o)m et h oxy-5,6,7,8-t et r a h yd r on a p h t h a len -1-yl]p yr i-
d in e, 12bi. Prepared in 100% yield as an oil. 1H NMR (δ,
CDCl3): 1.67 (m, 2H), 1.77 (m, 2H), 2.14 (s, 6H), 2.76 (m, 4H),
2.96 (s, 3H), 3.08 (s, 3H), 4.71 (s, 2H), 5.86 (s, 2H), 6.75 (d, J
) 8, 1H), 7.11 (d, J ) 8, 1H), 7.16 (d, J ) 8, 1H), 7.34 (d, J )
8, 1H), 7.82 (t, J ) 8, 1H). 13C NMR (δ, CDCl3): 13.3, 22.2,
22.8, 23.6, 28.6, 35.7, 36.7, 67.7, 106.5, 107.7, 119.6, 122.9,
126.5, 127.8, 128.6, 133.2, 136.8, 138.0, 151.2, 155.9, 160.2,
168.1. MS (%): 404 (parent + 1, 100).
2-(2,5-Dim eth ylp yr r olyl)-6-[4-ca r boxym eth oxy-5,6,7,8-
tetr a h yd r on a p h th a len -1-yl]p yr id in e, 11b. Prepared in
100% yield as a solid, mp 199-206 °C. 1H NMR (δ, CDCl3):
1.62 (m, 2H), 1.72 (m, 2H), 2.08 (s, 6H), 2.66 (m, 2H), 2.75 (m,
2H), 4.56 (s, 2H), 5.81 (s, 2H), 6.58 (d, J ) 8, 1H), 7.09 (m,
2H), 7.31 (d, J ) 8, 1H), 7.80 (t, J ) 8, 1H). 13C NMR (δ,
CDCl3): 12.95, 22.1, 22.6, 23.4, 28.4, 65.0, 106.5, 107.7, 119.9,
0.123.3, 126.7, 127.4, 128.5, 132.8 136.6, 138.3, 151.1, 155.9,
160.1, 171.2. MS (%): 377 (parent + 1, 100).
2-(2,5-Dim et h ylp yr r olyl)-6-[4-ca r b oxym et h oxyin d a n -
1-yl]p yr id in e, 11c. Prepared in 75% yield as an amorphous
1
solid. H NMR (δ, CDCl3): 2.09 (m, 2H), 2.16 (s, 6H), 2.97 (t,
J ) 7.5, 2H), 3.17 (t, J ) 7.5, 2H), 4.64 (s, 2H), 5.90 (s, 2H),
6.62 (d, J ) 8.5, 1H), 7.12 (d, J ) 8, 1H), 7.52 (d, J ) 8, 1H),
7.62 (d, J ) 8.5, 1H), 7.85 (t, J ) 8, 1H). 13C NMR (δ, CDCl3):
12.94, 25.05, 25.30, 29.10, 33.77, 64.46, 106.24, 109.13, 119.34,
121.07, 128.49, 129.96, 132.84, 138.05, 144.75, 147.40, 151.14,
154.39, 158.03, 172.84. MS (%): APCI positive 363 (parent +
1, 100). APCI negative 361 (100, parent - 1).
2-(2,5-Dim eth ylpyr r olyl)-6-[4-(pyr r olin ylcar boxam ido)-
m et h oxy-5,6,7,8-t et r a h yd r on a p h t h a len -1-yl]p yr id in e,
12bii. Prepared in 64.75% yield as an oil. 1H NMR (δ,
CDCl3): 1.66 (m, 2H), 1.77 (m, 2H), 1.82 (m, 2H), 1.92 (m, 2H),
2.13 (s, 6H), 2.75 (m, 4H), 3.51 (m, 4H), 4.64 (s, 2H), 5.85 (s,
2H), 6.73 (d, J ) 8, 1H), 7.11 (d, J ) 8, 1h), 7.15 (d, J ) 7.5,
1H), 7.33 (d, J ) 8, 1H), 7.81 (t, J ) 8, 1H). 13C NMR (δ,
CDCl3): 13.21, 22.14, 22.68, 23.56, 26.22, 28.50, 46.01, 46.14,
68.23, 106.44, 107.68, 119.54, 122.85, 126.34, 127.68, 128.51,
133.11, 136.73, 137.87, 151.14, 155.88, 160.09, 166.70. MS
(%): 430 (parent + 1, 100).
2-(2,5-Dim et h ylp yr r olyl)-6-[4-((4-m et h ylp ip er a zin yl)-
ca r boxa m id o)m eth oxy-5,6,7,8-tetr a h yd r on a p h th a len -1-
yl]p yr id in e, 12biii. Prepared in 90% yield as an oil. 1H NMR
(δ, CDCl3): 1.68 (m, 2H), 1.76 (m, 2H), 2.14 (s, 6H), 2.275 (s,
3H), 2.37 (m, 4H), 2.74 (m, 4H), 3.63 (m, 4H), 4.69 (s, 2H),
5.85 (s, 2H), 6.75 (d, J ) 8.5, 1H), 7.11 (d, J ) 8, 1H), 7.17 (d,
J ) 8, 1H), 7.33 (d, J ) 8, 1H), 7.81 (t, J ) 8, 1H). 13C NMR
(δ, CDCl3): 13.27, 22.14, 22.68, 23.60, 28.51, 41.91, 45.23,
45.96, 54.50, 55.07, 67.67, 106.49, 107.60, 119.55, 122.86,
126.23, 127.72, 128.48, 133.22, 136.79, 137.91, 151.12, 155.70,
160.02, 166.44. MS (%): 459 (parent + 1, 100).
2-(2,5-Dim eth ylp yr r olyl)-6-[4-ca r boxym eth oxybicyclo-
[2.2.1]n a p h th a len -1-yl]p yr id in e, 11d . Prepared in 65% yield
as an amorphous solid. 1H NMR (δ, CDCl3): 1.28 (m, 2H), 1.51
(m, 1H), 1.70 (m, 1H), 1.95 (m, 2H), 2.13 (s, 6H), 3.715 (m,
1H), 3.76 (m, 1H), 4.67 (s, 2H), 5.82 (s, 2H), 6.70 (d, J ) 8.5,
1H), 7.15 (d, J ) 8, 1H), 7.38 (d, J ) 8.5, 1H), 7.55 (d, J ) 8,
1H), 7.95 (t, J ) 8, 1H). 13C NMR (δ, CDCl3): 12.3, 25.9, 26.3,
39.6, 42.85, 65.0, 110.0, 119.7, 121.8, 126.5, 127.2, 128.15,
136.0, 138.8, 148.4, 151.6, 152.1, 158.1, 171.4. MS (%): 389
(parent + 1, 100).
2-(2,5-Dim et h ylp yr r olyl)-6-(4-(N,N-d im et h ylca r b oxa -
m id o)m eth yloxy)-1-n a p h th yl)p yr id in e, 12a i. To a 100 mL
round-bottomed flask equipped with condenser and N2 inlet
were added 150 mg (0.403 mmol) of 2-(2,5-dimethylpyrrolyl)-
6-(4-(2-carboxymethyloxy)-1-naphthyl)-pyridine, 33 mg (0.403
mmol) of dimethylamine hydrochloride, 77 mg (0.403 mmol)
of N-ethyl,N-3-dimethylaminopropylcarbodiimide, 0.185 mL
(1.33 mmol) of triethylamine, 10 mg of N-hydroxybenzotriazole,
and 7 mL of dry acetonitrile. The reaction was stirred at room
temperature 80 h (LCMS showed P + 1 ) 451 and TLC showed
Rf ) 0.3 in 10% methanol/methylene chloride) and evaporated
and the residue chromatographed on silica gel using methanol/
methylene chloride as eluant to afford 161 mg of the product
(100% yield) as an oil. 1H NMR (δ, CDCl3): 2.225 (s, 6H), 2.97
(s, 3H), 3.10 (s, 3H), 4.90 (s, 2H), 5.89 (s, 2H), 6.93 (d, J ) 8,
1H), 7.21 (d, J ) 8, 1H), 7.4-7.6 (m, 4H), 7.90 (t, J ) 8, 1H),
8.09 (m, 1H), 8.38 (m, 1H). 13C NMR (δ, CDCl3): 13.5, 35.8,
36.8, 67.9, 104.7, 106.8, 119.9, 122.2, 123.5, 125.4, 125.56,
125.63, 127.1, 128.1, 128.6, 131.2, 132.1, 138.2, 151.8, 154.1,
159.0, 167.7. MS (%): 400 (parent + 1, 100).
2-(2,5-Dim et h ylp yr r olyl)-6-[4-(N,N-d im et h ylca r b oxa -
m id o)m eth oxyin d a n -1-yl]p yr id in e, 12ci. Prepared in 93%
1
yield as an oil. H NMR (δ, CDCl3): 2.065 (m, 2H), 2.165 (s,
6H), 2.94 (m, 2H), 2.96 (s, 3H), 3.08 (s, 3H), 3.18 (t, J ) 7.5,
2H), 4.73 (s, 2H), 5.88 (s, 2H), 6.77 (d, J ) 8.5, 1H), 7.07 (d, J
) 8, 1H), 7.49 (d, J ) 8, 1H), 7.57 (d, J ) 8.5, 1H), 7.81 (t, J
) 8, 1H). 13C NMR (δ, CDCl3): 13.40, 25.28, 29.42, 34.16,
35.71, 36.65, 67.57, 106.56, 109.56, 119.21, 120.91, 128.64,
128.68, 129.50, 132.97, 138.08, 144.95, 151.38, 154.88, 158.46,
167.92. MS (%): 390 (parent + 1, 100).
2-(2,5-Dim eth ylp yr r olyl)-6-[4-(p yr r olid in ylca r boxa m i-
d o)m eth oxyin d a n -1-yl]p yr id in e, 12cii. Prepared in 64%
yield as an oil. 1H NMR (δ, CDCl3): 1.79 (m, 2H), 1.90 (m,
2H), 2.01 (m, 2H), 2.10 (s, 6H), 2.88 (t, J ) 7, 2H), 3.10 (t, J )
7, 2H), 3.4-3.6 (m, 4H), 4.62 (s, 2H), 5.82 (s, 2H), 6.70 (d, J )
8.5, 1H), 7.03 (d, J ) 8, 1H), 7.4-7.5 (m, 2H), 7.78 (t, J ) 8,
1H). 13C NMR (δ, CDCl3): 13.21, 23.66, 25.24, 26.16, 29.37,
33.98, 46.14, 46.29, 67.78, 106.45, 109.42, 119.39, 121.16,
2-(2,5-Dim eth ylp yr r olyl)-6-(4-(p yr r olid in ylca r boxa m i-
d o)m eth yloxy)-1-n a p h th yl)p yr id in e, 12a ii. Prepared in
93% yield as an oil. 1H NMR (δ, CDCl3): 1.80 (m, 2H), 1.90
(m, 2H), 2.22 (s, 6H), 3.54 (m, 4H), 4.84 (s, 2H), 5.88 (s, 2H),
6.93 (d, J ) 8, 1H), 7.21 (d, J ) 8, 1H), 7.4-7.6 (m, 4H), 7.90
(t, J ) 8, 1H), 8.10 (m, 1H), 8.38 (m, 1H). 13C NMR (δ, CDCl3):
13.5, 23.7, 26.3, 46.2, 46.3, 68.5, 104.7, 106.8, 119.9, 122.2,

1582 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 6
Lowe et al.
128.62, 129.45, 132.92, 138.20, 144.90, 151.34, 154.84, 158.46,
167.02. MS (%): 416 (parent + 1, 100).
(t, J ) 6, 2H), 3.11 (m, 2H), 4.32 (t, J ) 6, 1H), 5.89 (s, 2H),
6.88 (d, J ) 8, 1H), 7.20 (d, J ) 8, 1H), 7.4-7.6 (m, 4H), 7.89
(t, J ) 8, 1H), 8.10 (m, 1H), 8.33 (m, 1H). 13C NMR (δ, CDCl3):
13.41, 28.37, 41.61, 53.61, 57.03, 62.02, 66.82, 104.29, 106.75,
119.61, 122.34, 123.36, 125.14, 125.78, 126.80, 128.24, 128.55,
130.28, 131.90, 137.95, 151.73, 155.12, 159.05. MS (%): 469
(parent + 1, 100).
2-(2,5-Dim e t h ylp yr r olyl)-6-[4-(N ,N -d im e t h yla m in o-
eth oxy)-5,6,7,8-tetr ah ydr on aph th alen -1-yl]pyr idin e, 13bi.
Prepared in 93% yield as an oil. 1H NMR (δ, CDCl3): 1.69 (m,
2H), 1.78 (m, 2H), 2.16 (s, 6H), 2.36 (s, 6H), 2.73 (t, J ) 7,
2H), 2.78 (m, 4H), 4.11 (t, J ) 7, 2H), 5.88 (s, 2H), 6.74 (d, J
) 8, 1H), 7.11 (d, J ) 8, 1H), 7.20 (d, J ) 8, 1H), 7.36 (d, J )
8, 1H), 7.81 (t, J ) 8, 1H). 13C NMR (δ, CDCl3): 13.3, 22.3,
22.9, 23.7, 28.7, 46.2, 58.4, 66.6, 106.6, 107.6, 119.5, 122.95,
126.5, 127.7, 128.6, 132.4, 136.6, 137.9, 151.2, 156.9, 160.35.
MS (%): 390 (parent + 1, 100).
2-(2,5-Dim et h ylp yr r olyl)-6-[4-((4-m et h ylp ip er a zin yl)-
ca r boxa m id o)m eth oxyin d a n -1-yl]p yr id in e, 12ciii. Pre-
pared in 78% yield as an oil. 1H NMR (δ, CDCl3): 2.07 (m,
2H), 2.16 (s, 6H), 2.72 (s, 3H), 2.38 (m, 4H), 2.91 (t, J ) 7,
2H), 3.18 (t, J ) 7, 2H), 3.61 (m, 4H), 4.72 (s, 2H), 5.88 (s,
2H), 6.78 (d, J ) 8.5, 1H), 7.07 (d, J ) 8, 1H), 7.49 (d, J ) 8,
1H), 7.57 (d, J ) 7.5, 1H), 7.805 (t, J ) 8, 1H). 13C NMR (δ,
CDCl3): 13.31, 25.19, 29.37, 34.06, 41.94, 45.21, 45.94, 54.53,
55.09, 67.60, 106.51, 109.37, 119.16, 120.81, 128.54, 128.65,
129.53, 132.75, 137.98, 144.90, 151.32, 154.66, 158.33, 166.29.
MS (%): 445 (parent + 1, 100).
2-(2,5-Dim et h ylp yr r olyl)-6-[4-(N,N-d im et h ylca r b ox-
a m id o)m eth oxybicyclo[2.2.1]n a p h th a len -1-yl]p yr id in e,
1
12d i. Prepared in 93.5% yield as an oil. H NMR (δ, CDCl3):
1.2-1.4 (m, 2H), 1.48 (m, 1H), 1.72 (m, 1H), 1.97 (m, 2H), 2.21
(s, 6H), 2.98 (s, 3H), 3.10 (s, 3H), 3.71 (m, 1H), 3.85 (m, 1H),
4.74 (s, 2H), 5.90 (s, 2H), 6.75 (d, J ) 8.7, 1H), 7.09 (d, J ) 8,
1H), 7.5 (m, 2H), 7.84 (t, J ) 8, 1H). 13C NMR (δ, CDCl3):
13.42, 26.36, 26.54, 35.65, 36.57, 39.61, 42.99, 48.85, 67.75,
106.62, 110.01, 118.99, 120.90, 126.90, 127.52, 128.58, 135.97,
138.00, 148.43, 151.52, 151.78, 157.87, 167.93. MS (%): 416
(parent + 1, 100).
2-(2,5-Dim e t h ylp yr r olyl)-6-[4-(p yr r olid in yle t h oxy)-
5,6,7,8-tetr a h yd r on a p h th a len -1-yl]p yr id in e, 13bii. Pre-
pared in 90% yield as an oil. 1H NMR (δ, CDCl3): 1.80 (m,
4H), 2.15 (s, 6H), 2.65 (m, 2H), 2.72 (m, 2H), 2.72 (m, 2H),
2.93 (t, J ) 6, 2H), 4.14 (t, J ) 6, 2H), 6.73 (d, J ) 8.5, 1H),
7.11 (d, J ) 8, 1H), 7.19 (d, J ) 7.5, 1H), 7.35 (d, J ) 8, 1H),
7.81 (t, J ) 8, 1H). 13C NMR (δ, CDCl3): 13.24, 22.25, 22.78,
23.50, 28.57, 30.23, 34.13, 54.87, 67.40, 106.44, 107.50, 119.36,
122.85, 125.43, 126.31, 127.63, 128.52, 132.29, 136.45, 137.74,
151.12, 156.80, 160.28. MS (%): 416 (parent + 1, 100).
2-(2,5-Dim eth ylp yr r olyl)-6-[4-((4-m eth ylp ip er a izin yl)-
eth oxy)-5,6,7,8-tetr ah ydr on aph th alen -1-yl]pyr idin e, 13biii.
Prepared in 65% yield as an oil. 1H NMR (δ, CDCl3): 1.67 (m,
2H), 1.75 (m, 2H), 2.15 (s, 6H), 2.29 (s, 3H), 2.5 (m, 4H), 2.7
(m, 4H), 2.70 (t, J ) 6, 2H), 2.76 (t, J ) 6, 2H), 2.85 (t, J ) 6,
2H), 4.13 (t, J ) 6, 2H), 5.86 (s, 2H), 6.72 (d, J ) 8.5, 1H),
7.10 (d, J ) 8, 1H), 7.18 (d, J ) 8.5, 1H), 7.35 (d, J ) 8, 1H),
7.81 (t, J ) 8, 1H). 13C NMR (δ, CDCl3): 13.25, 22.24, 22.77,
23.61, 28.56, 45.96, 53.55, 55.09, 57.13, 66.29, 106.45, 107.53,
119.38, 122.83, 126.34, 127.62, 128.51, 132.41, 136.50, 137.74,
151.14, 156.70, 160.22. MS (%): 445 (parent + 1, 100).
2-(2,5-Dim e t h ylp yr r olyl)-6-[4-(N ,N -d im e t h yla m in o-
eth oxy)in d a n -1-yl]p yr id in e, 13ci. Prepared in 100% yield
2-(2,5-Dim eth ylp yr r olyl)-6-(4-(2-(2-d im eth yla m in oeth -
yl)m eth yloxy)-1-n a p h th yl)p yr id in e, 13a i. To a 100 mL
round-bottomed flask equipped with condenser and N2 inlet
were added 160 mg (1.20 mmol) of aluminum chloride and 5
mL of dry tetrahydrofuran. The solution was cooled to 0 °C,
and 2.81 mL (2.81 mmol) of a 1.0 M solution of lithium
aluminum hydride in tetrahydrofuran was added. Stirring was
continued at room temperature for 20 min, the solution was
cooled to -70 °C, and a solution of 161 mg (0.403 mmol) of
2-(2,5-dimethylpyrrolyl)-6-(4-(2-(dimethylaminocarbonyl)-
methyloxy)-1-naphthyl)pyridine in 7 mL of dry tetrahydrofu-
ran was added. Stirring was continued 1 h at -70 °C and then
2 h at room temperature (LCMS showed P + 1 ) 386), followed
by careful quenching with 5 mL of 1 N hydrochloric acid. After
stirring for 20 min, the reaction was treated with 6 mL of 6 N
aqueous sodium hydroxide solution and extracted with several
portions of methylene chloride. The organic phase was dried
over sodium sulfate and evaporated to afford an oil, which was
converted to the hydrochloride salt using HCl in ether,
affording 164 mg of the product (∼100% yield) as an oil. 1H
NMR (δ, CDCl3): 2.24 (s, 6H), 2.42 (s, 6H), 2.915 (t, J ) 6,
2H), 4.30 (t, J ) 6, 2H), 5.91 (s, 2H), 6.90 (d, J ) 8, 1H), 7.20
(d, J ) 8, 1H), 7.5-7.7 (m, 4H), 7.89 (t, J ) 8, 1H), 8.13 (m,
1H), 8.37 (m, 1H). 13C NMR (δ, CDCl3): 13.5, 46.2, 58.2, 67.0,
104.3, 106.8, 119.7, 122.5, 123.5, 125.2, 125.3, 123.8, 126.9,
128.3, 138.6, 130.4, 132.0, 138.1, 151.8, 155.3, 159.1. MS (%):
386 (parent + 1, 100).
2-(2,5-Dim eth ylp yr r olyl)-6-(4-(2-(2-p yr r olid in yleth yl)-
m eth yloxy)-1-n a p h th yl)p yr id in e, 13a ii. Prepared in 100%
yield as an oil. 1H NMR (δ, CDCl3): 1.83 (m, 4H), 2.25 (s, 6H),
2.72 (m, 4H), 3.08 (t, J ) 6, 2H), 4.35 (t, J ) 6, 2H), 5.91 (s,
2H), 6.90 (d, J ) 8, 1H), 7.20 (d, J ) 8, 1H), 7.4-7.6 (m, 4H),
7.91 (t, J ) 8, 1H), 8.13 (m, 1H), 8.38 (m, 1H). 13C NMR (δ,
CDCl3): 13.6, 23.6, 54.9, 55.0, 68.0, 104.2, 106.8, 119.7, 122.5,
123.5, 125.2, 125.9, 126.9, 128.4, 128.7, 130.3, 132.0, 138.1,
151.8, 155.3, 159.2. MS (%): 412 (parent + 1, 100).
2-(2,5-Dim eth ylp yr r olyl)-6-(4-(2-(2-(4-m eth ylp ip er a zin -
yl)et h yl)m et h yloxy)-1-n a p h t h yl)p yr id in e, 13a iii. Pre-
pared in 35% yield as an oil. 1H NMR (δ, CDCl3): 2.225 (s,
6H), 2.30 (s, 3H), 2.5 (m, 4H), 2.7 (m, 4H), 2.99 (t, J ) 6, 2H),
4.33 (t, J ) 6, 2H), 5.89 (s, 2H), 6.88 (d, J ) 8, 1H), 7.20 (d, J
) 8, 1H), 7.4-7.6 (m, 4H), 7.90 (t, J ) 8, 1H), 8.11 (m, 1H),
8.33 (m, 1H). 13C NMR (δ, CDCl3): 13.44, 45.94, 53.57, 55.07,
57.03, 66.71, 104.23, 106.72, 119.64, 122.32, 123.39, 125.11,
125.20, 125.73, 126.85, 128.24, 128.58, 130.31, 131.86, 137.98,
151.70, 155.06, 159.01. MS (%): 441 (parent + 1, 100).
1
as an oil. H NMR (δ, CDCl3): 2.06 (m, 2H), 2.19 (s, 6H), 2.36
(s, 6H), 2.77 (t, J ) 6, 2H), 2.92 (t, J ) 7, 2H), 3.19 (t, J ) 7,
2H), 4.15 (t, J ) 6, 2H), 5.90 (s, 2H), 6.79 (d, J ) 8, 1H), 7.07
(d, J ) 8, 1H), 7.51 (d, J ) 8, 1H), 7.61 (d, J ) 8, 1H), 7.81 (t,
J ) 8, 1H). 13C NMR (δ, CDCl3): 13.41, 25.33, 29.49, 34.26,
46.16, 58.29, 66.60, 106.57, 109.42, 119.06, 120.84, 128.60,
128.75, 133.04, 137.97, 144.63, 151.40, 155.85, 158.61. MS
(%): 376 (parent + 1, 100).
2-(2,5-Dim eth ylp yr r olyl)-6-[4-(p yr r olid in yleth oxy)in -
d a n -1-yl]p yr id in e, 13cii. Prepared in 100% yield as an oil.
1H NMR (δ, CDCl3): 1.80 (m, 2H), 2.06 (m, 2H), 2.18 (s, 6H),
2.66 (m, 2H), 2.93 (m, 4H), 3.19 (t, J ) 7, 2H), 4.19 (t, J ) 6,
2H), 5.90 (s, 2H), 6.78 (d, J ) 8, 1H), 7.07 (d, J ) 8, 1H), 7.51
(d, J ) 8, 1H), 7.61 (d, J ) 8, 1H), 7.81 (t, J ) 8, 1H). 13C
NMR (δ, CDCl3): 13.41, 23.56, 25.31, 29.52, 30.33, 34.26, 54.94,
67.42, 106.54, 109.41, 119.05, 120.83, 125.53, 128.60, 128.66,
132.98, 137.96, 144.61, 151.40, 155.83, 158.63. MS (%): 402
(parent + 1, 100).
2-(2,5-Dim et h ylp yr r olyl)-6-[4-((4-m et h ylp ip er a zin yl)-
eth oxy)in d a n -1-yl]p yr id in e, 13ciii. Prepared in 91% yield
as an oil. 1H NMR (δ, CDCl3): 2.055 (m, 2H), 2.175 (s, 6H),
2.29 (s, 3H), 2.5 (m, 4H), 2.7 (m, 4H), 2.84 (m, 2H), 2.89 (t, J
) 7.5, 2H), 3.18 (t, J ) 7, 1H), 4.17 (t, J ) 6, 2H), 5.89 (s, 2H),
6.76 (d, J ) 8.5, 1H), 7.06 (d, J ) 8, 1H), 7.50 (d, J ) 8, 1H),
7.60 (d, J ) 8.5, 1H), 7.80 (d, J ) 8, 1H). 13C NMR (δ, CDCl3):
13.31, 25.19, 29.39, 34.16, 45.97, 53.57, 55.09, 57.08, 66.31,
106.48, 109.37, 118.96, 120.71, 128.52, 128.71, 132.94, 137.85,
144.54, 151.32, 155.67, 158.49. MS (%): 431 (parent + 1, 100).
2-(2,5-Dim e t h ylp yr r olyl)-6-[4-(N ,N -d im e t h yla m in o-
eth oxy)bicyclo[2.2.1]n a p h th a len -1-yl]p yr id in e, 13d i. Pre-
pared in 77% yield as an oil. 1H NMR (δ, CDCl3): 1.27 (m,
2H), 1.49 (m, 1H), 1.73 (m, 1H), 1.96 (m, 2H), 2.22 (s, 6H),
2.37 (s, 6H), 2.78 (t, J ) 6, 2H), 3.67 (m, 1H), 3.85 (m, 1H),
4.15 (t, J ) 6, 2H), 5.91 (s, 2H), 6.76 (d, J ) 8.5, 1H), 7.09 (d,
2-(2,5-Dim eth ylpyr r olyl)-6-(4-(2-(2-(4-dim eth ylam in opi-
p er id in yl)eth yl)m eth yloxy)-1-n a p h th yl)p yr id in e, 13a iv.
Prepared in 76% yield as an oil. 1H NMR (δ, CDCl3): 1.57 (m,
2H), 1.82 (m, 2H), 2.2 (m, 3H), 2.23 (s, 6H), 2.28 (s, 6H), 2.97

Inhibitors of Neuronal Nitric Oxide Synthase
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 6 1583
J ) 8, 1H), 7.5 (m, 2H), 7.83 (t, J ) 8, 1H). 13C NMR (δ,
CDCl3): 13.52, 26.42, 26.66, 39.69, 43.10, 46.13, 48.91, 58.32,
66.89, 106.68, 110.21, 118.93, 120.94, 125.55, 126.28, 127.48,
128.66, 136.12, 137.98, 148.29, 151.63, 152.78, 158.10. MS
(%): 402 (parent + 1, 100).
NMR (d, CDCl3): 22.4, 22.9, 23.5, 23.7, 28.2, 54.9, 55.0, 67.4,
106.1, 107.5, 114.4, 126.3, 126.9, 133.5, 136.3, 137.7, 156.4,
157.7, 158.9. MS (%): 338 (parent + 1, 100). Anal. (C21H27N3O‚
2HCl‚3H2O) C, H, N.
6-{4-[2-(4-Meth yl-p ip er a zin -1-yl)eth oxy]5,6,7,8-tetr a h y-
d r on a p h th a len -1-yl}p yr id in -2-yla m in e, 14biii. Prepared
by Method A in 100% yield, as an amorphous solid, as the
hydrochloride salt. 1H NMR (δ, CDCl3): 1.62 (m, 2H), 1.72 (m,
2H), 2.26 (s, 3H), 2.4-2.8 (m, 12H), 2.81 (t, J ) 6, 2H), 4.09
(t, J ) 6, 2H), 4.50 (bs, 2H), 6.35 (d, J ) 8, 1H), 6.63 (m, 2H),
7.07 (d, J ) 8, 1H), 7.39 (t, J ) 8, 1H). 13C NMR (δ, CDCl3):
22.4, 22.9, 23.37, 28.2, 46,1, 53.37, 55.2, 57.3, 66.3, 106.1, 107.6,
114.4, 126.3, 126.9, 133.6, 136.3, 137.7, 156.3, 157.7, 158.9.
MS (%): 367 (parent + 1, 100). Anal. (C22H30N4O‚3HCl‚H2O‚
1/2(C4H10O)) C, H, N.
6-[4-(2-Dim eth ylam in oeth oxy)n aph th alen -1-yl]pyr idin -
2-yla m in e, 14a i. To a 100 mL round-bottomed flask equipped
with condenser and N2 inlet were added 155 mg (0.403 mmol)
of 2-(2,5-dimethylpyrrolyl)-6-(4-(2-(2-dimethylaminoethyl)-
methyloxy)-1-naphthyl)pyridine, 500 mg of hydroxylamine
hydrochloride, 9 mL of ethanol, and 1 mL of water. The
solution was refluxed 40 h (LCMS P + 1 ) 308), cooled, poured
into dilute aqueous hydrochloric acid, and washed with ethyl
acetate. The aqueous layer was adjusted to pH 12 with 6 N
aqueous sodium hydroxide solution and extracted with several
portions of methylene chloride. The organic layer was dried
over sodium sulfate and evaporated to a solid, 81 mg (65%),
mp 98-106 °C. 1H NMR (δ, CDCl3): 2.395 (s, 6H), 2.89 (t, J )
6, 2H), 4.27 (t, J ) 6, 2H), 4.65 (bs, 2H, NH2), 6.43 (d, J ) 8,
1H), 6.84 (m, 2H), 7.4-7.6 (m, 4H), 8.10 (m, 1H), 8.32 (m, 1H).
13C NMR (δ, CDCl3): 46.2, 58.2, 66.9, 104.2, 106.6, 115.2,
122.2, 125.1, 125.7, 125.8, 126.7, 127.2, 131.4, 132.2, 138.0,
154.7, 157.8, 158.2. MS (%): 308 (parent + 1, 100). Anal.
(C19H21N3O‚1/4H2O) C, H, N.
6-[4-(2-P yr r olid in -1-yleth oxy)n a p h th a len -1-yl]p yr id in -
2-yla m in e, 14a ii. Prepared by Method A in 69% yield, mp
245-255 °C, as the hydrochloride salt. 1H NMR (δ, CDCl3):
1.79 (bs, 4H), 2.685 (bs, 2H), 3.035 (t, J ) 6, 2H), 4.30 (t, J )
6, 2H), 4.68 (bs, 2H, NH2), 6.41 (d, J ) 8, 1H), 6.82 (m, 2H),
7.4-7.6 (m, 4H), 8.10 (m, 1H), 8.31 (m, 1H). 13C NMR (δ,
CDCl3): 23.6, 54.9, 55.0, 67.8, 104.2, 106.6, 115.1, 122.2, 125.0,
125.7, 125.8, 126.6, 127.3, 131.4, 132.2, 138.0, 154.7, 157.7,
158.2. MS (%): 334 (parent + 1, 100). Anal. (C21H23N3O‚
2HCl): C, H; N: calcd, 10.34; found, 9.56.
6-{4-[2-(4-Meth yl-p ip er a zin -1-yl)eth oxy]n a p h th a len -1-
yl}p yr id in -2-yla m in e, 14a iii. Prepared by Method A in 74%
yield, as an amorphous solid as the hydrochloride salt. 1H NMR
(δ, CDCl3): 2.26 (s, 3H), 2.5 (m, 4H), 2.7 (m, 4H), 2.955 (t, J )
6, 2H), 4.29 (t, J ) 6, 2H), 4.55 (bs, 2H), 6.44 (d, J ) 8, 1H),
6.82 (m, 2H), 7.4-7.6 (m, 4H), 8.08 (m, 1H), 8.27 (m, 1H). 13C
NMR (δ, CDCl3): 45.97, 53.61, 55.11, 57.10, 66.69, 104.31,
106.41, 115.20, 122.09, 125.00, 125.62, 125.82, 126.55, 127.11,
131.50, 132.11, 137.86, 154.63, 157.79, 157.99. MS (%): 363
(parent + 1, 100). Anal. (C22H26N4O‚3HCl‚7/4H2O) C, H, N.
6-{4-[2-(4-Dim eth yla m in op ip er id in -1-yl)eth oxy]n a p h -
th a len -1-yl}p yr id in -2-yla m in e, 14a iv. Prepared by Method
A in 73% yield, as an amorphous solid as the hydrochloride
salt. 1H NMR (δ, CDCl3): 1.56 (m, 2H), 1.80 (m, 2H), 2.18 (m,
3H), 2.26 (s, 6H), 4.28 (t, J ) 6, 2H), 3.10 (m, 2H), 4.28 (t, J )
6, 2H), 4.58 (bs, 2H), 6.43 (d, J ) 8, 1H), 6.83 (m, 2H), 7.44
(m, 4H), 8.09 (m, 1H), 8.29 (m, 1H). 13C NMR (δ, CDCl3): 28.33,
41.61, 53.65, 57.12, 62.11, 66.77, 76.76, 104.33, 106.51, 115.22,
122.15, 125.09, 125.70, 125.85, 126.64, 127.23, 131.49, 132.15,
137.97, 154.65, 157.80, 158.08. MS (%): 391 (parent + 1, 100).
Anal. (C24H30N4O‚3HCl‚3H2O‚1/2(C4H10O)) C, H, N. HRMS
Calcd for C24H31N4O: 391.2498. Found: 391.2485.
6-[7-(2-Dim et h yla m in oet h oxy)in d a n -4-yl]p yr id in -2-
yla m in e, 14ci. Prepared by Method A starting with 1-indanol,
in 57% yield, mp 215-218 °C, as the hydrochloride salt. 1H
NMR (δ, CDCl3): 2.00 (quin, J ) 6, 2H), 2.32 (s, 6H), 2.72 (t,
J ) 6, 2H), 2.86 (t, J ) 7, 2H), 3.06 (t, J ) 7, 2H), 4.10 (t, J )
6, 2H), 4.63 (bs, 2H), 6.32 (d, J ) 8, 1H), 6.71 (d, J ) 8, 1H),
6.76 (d, J ) 8, 1H), 7.39 (m, 2H). 13C NMR (δ, CDCl3): 25.31,
29.56, 33.78, 46.07, 58.24, 66.46, 106.02, 109.34, 112.88,
127.97, 129.99, 132.66, 137.80, 144.30, 155.24, 157.34, 158.08.
MS (%): 298 (parent + 1, 100). Anal. (C18H23N3O‚2HCl‚1/2H2O)
C, H, N.
6-[7-(2-P yr r olid in -1-yle t h oxy)in d a n -4-yl]p yr id in -2-
yla m in e, 14cii. Prepared by Method A in 72% yield, mp 113-
117 °C, as the hydrochloride salt. 1H NMR (δ, CDCl3): 1.77
(m, 4H), 2.01 (uqin, J ) 7, 2H), 2.62 (m, 4H), 2.89 (m, 4H),
3.08 (t, J ) 7, 2H), 4.15 (t, J ) 6, 2H), 4.52 (bs, 2H), 6.34 (d,
J ) 8, 1H), 6.73 (d, J ) 8, 1H), 6.79 (d, J ) 8, 1H), 7.40 (m,
4H). 13C NMR (δ, CDCl3): 23.53, 25.30, 29.57, 33.78, 54.88,
54.98, 67.37, 105.94, 109.36, 112.99, 127.97, 129.94, 132.65,
137.80, 144.28, 155.27, 157.45, 157.95. MS (%): 324 (parent
+ 1, 100). Anal. (C20H25N3O‚2HCl‚3/2H2O) C, H, N.
6-{7-[2-(4-Me t h ylp ip e r a zin -1-yl)e t h oxy]in d a n -4-yl}-
p yr id in -2-yla m in e, 14ciii. Prepared by Method A in 81%
yield, as a tan solid, mp > 205 °C, as the hydrochloride salt.
1H NMR (δ, CDCl3): 2.00 (quin, J ) 7, 2H), 2.26 (s, 3H), 2.4-
2.7 (m, 8H), 2.8-2.9 (m, 4H), 3.08 (t, J ) 7, 2H), 4.13 (t, J )
6, 2H), 4.49 (bs, 2H), 6.34 (d, J ) 8, 1H), 6.71 (d, J ) 8, 1H),
6.79 (d, J ) 8, 1H), 7.40 (t, J ) 8, 1H). 13C NMR (δ, CDCl3):
25.20, 29.46, 33.72, 45.96, 53.55, 55.04, 57.08, 66.24, 105.85,
109.32, 112.86, 127.86, 129.97, 132.61, 137.69, 144.23, 155.08,
157.31, 157.87. MS (%): 353 (parent + 1, 100). HRMS Calcd
for C21H29N4O: 353.2345. Found: 353.2341.
6-[7-(2-Dim eth ylam in oeth oxy)bicyclo[2.2.1]n aph th alen -
1-yl]p yr id in -2-yla m in e, 14d i. Prepared by Method A in 78%
1
yield, mp 130 °C (dec), as the hydrochloride salt. H NMR (δ,
CDCl3): 1.1-1.3 (m, 2H), 1.43 (m, 1H), 1.68 (m, 1H), 1.89 (m,
2H), 2.34 (s, 6H), 2.74 (t, J ) 6, 2H), 3.61 (m, 1H), 3.74 (m,
1H), 4.11 (t, J ) 6, 2H), 4.52 (bs, 2H), 6.35 (d, J ) 8, 1H), 6.70
(d, J ) 8.5, 1H), 6.80 (d, J ) 7.5, 1H), 7.36 (d, J ) 8.5, 1H),
7.42 (t, J ) 8, 1H). 13C NMR (δ, CDCl3): 26.49, 26.73, 39.79,
42.90, 46.06, 48.84, 58.29, 66.89, 105.92, 110.24, 113.24,
126.94, 127.51, 135.82, 137.78, 148.00, 152.22, 156.88, 158.20.
MS (%): 324 (parent + 1, 100). Anal. (C20H25N3O‚2HCl‚3/
2H2O‚(1/2C4H10O)) C, H, N.
6-[4-(N,N-Dim et h yla m in oet h oxy)-5,6,7,8-t et r a h yd r o-
n a p h t h a len -1-yl]p yr id in -2-yla m in e, 14b i. Prepared by
Method A in 57% yield as the hydrochloride salt, mp 239-
242 °C from methanol/isopropyl ether. 1H NMR (δ, CDCl3):
1.64 (m, 2H), 1.71 (m, 2H), 2.33 (s, 6H), 2.67 (m, 4H), 2.74 (t,
J ) 6, 2H), 4.07 (t, J ) 6, 2H), 4.55 (bs, 2H), 6.36 (d, J ) 8,
1H), 6.62 (d, J ) 8, 1H), 6.67 (d, J ) 8, 1H), 7.07 (d, J ) 8,
1H), 7.40 (t, J ) 8, 1H). 13C NMR (δ, CDCl3): 22.3, 22.8 23.6,
28.1, 46.0, 58.2, 66.4, 106.0, 107.4, 114.3, 126.2, 126.8, 133.5,
136.2, 137.6, 156.3, 157.6, 158.8. MS (%): 312 (parent + 1,
100). Anal. (C19H25N3O‚2HCl‚1/4H2O) C, H, N.
6-[4-(2-P yr r olid in -1-yleth oxy)-5,6,7,8-tetr a h yd r on a p h -
th a len -1-yl]p yr id in -2-yla m in e, 14bii. Prepared by Method
A in 58% yield, as a hygroscopic solid as the hydrochloride
salt. 1H NMR (d, CDCl3): 1.64 (m, 2H), 1.74 (m, 2H), 1.77 (m,
4H), 2.62 (m, 4H), 2.68 (m, 4H), 2.89 (t, J ) 6, 2H), 4.10 (t, J
) 6, 2H), 4.52 (bs, 2H), 6.37 (d, J ) 8, 1H), 6.63 (d, J ) 8, 1H),
6.65 (d, J ) 8, 1H), 7.07 (d, J ) 8, 1H), 7.40 (t. J ) 8, 1H). 13C
Method B. 4-Bromo-1-(N,N-dimethylaminoethoxy)-5,6,7,8-
tetrahydronaphthalene, 15b. To a 1 L round-bottomed flask
equipped with condenser and N2 inlet were added 10.0 g (44
mmol) of 4-bromo-5,6,7,8-tetrahydro-naphthalen-1-ol, 19 g (130
mmol) of 2-dimethylaminoethyl chloride hydrochloride, 30.3
g (220 mmol) of powdered potassium carbonate, and 600 mL
of acetonitrile. The reaction was refluxed 60 h, followed by an
additional portion of the chloride, and then refluxed for an
additional 24 h. The reaction was cooled, filtered, and concen-
trated. The residue was chromatographed on silica gel using
methanol/methylene chloride as eluant to afford 8.55 g (65%)
of a light brown oil. 1H NMR (δ, CDCl3): 1.72 (m, 4H), 2.33 (s,
6H), 2.63 (m, 2H), 2.68 (m, 2H), 2.73 (t, J ) 6, 2H), 4.01 (t, J
) 6, 2H), 6.53 (d, J ) 8, 1H), 7.28 (d, J ) 8, 1H). 13C NMR (δ,

1584 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 6
Lowe et al.
1
CDCl3): 22.1, 22.8, 23.7, 30.5, 46.0, 538.2, 66.6, 109.2, 116.4,
128.8, 129.2, 137.2, 155.6. MS: 298/300 (parent + 1).
p yr id in e, 17e. Prepared in 40% yield as an oil. H NMR (δ,
CDCl3): 1.63 (m, 4H), 1.82 (m, 2H), 2.17 (s, 6H), 2.35 (s, 6H),
2.77 (t, J ) 6, 2H), 2.80 (m, 2H), 2.96 (m, 2H), 4.09 (t, J ) 6,
2H), 5.87 (s, 2H), 6.79 (d, J ) 8, 1H), 7.13 (d, J ) 7.5, 1H),
7.18 (d, J ) 8.5, 1H), 7.30 (d, J ) 8, 1H), 7.81 (t, J ) 8, 1H).
13C NMR (δ, CDCl3): 13.33, 25.51, 27.29, 27.74, 31.28, 32.41,
46.10, 58.38, 67.45, 106.61, 109.87, 119.38, 123.09, 128.30,
128.57, 132.68, 132.89, 137.68, 142.93, 151.40, 155.87, 160.77.
MS (%): 404 (parent + 1, 100).
1-(N,N-Dim eth yla m in oeth oxy)-5,6,7,8-tetr a h yd r on a ph -
t h a len e-4-b or on ic Acid , 16b . To a 1 L three-neck round-
bottomed flask equipped with septum and N2 inlet were added
8.55 g (28.7 mmol) of 4-bromo-1-(2-dimethylaminoethoxy)-
5,6,7,8-tetrahydro-naphthalene and 300 mL of dry tetrahy-
drofuran. The solution was cooled to -70 °C, and 13.8 mL (34.4
mmol) of a 2.5 M solution of butyllithium in hexanes was
added. The reaction was stirred at -70 °C for 1 h, 5.9 mL (34.4
mmol) triethyl borate was added, and the reaction was stirred
at -70 °C for 2 h and warmed to room-temperature overnight.
The reaction was quenched with aqueous saturated am-
monium chloride solution and extracted three times with ethyl
acetate. The organic layer was washed with brine, dried over
sodium sulfate, and evaporated. The residue was triturated
with hexane to a white solid, 6.3 g (83.5%). 1H NMR (δ,
CDCl3): 1.79 (m, 4H), 2.44 (s, 6H), 2.68 (m, 2H), 2.89 (m, 2H),
3.32 (m, 2H), 4.19 (m, 2H), 6.74 (d, J ) 8, 1H), 8.03 (d, J ) 8,
1H).
2-(2,5-Dim e t h ylp yr r olyl)-6-[4-(N ,N -d im e t h yla m in o-
eth oxy)-5,6,7,8-tetr a h yd r on a p h th a len -1-yl]p yr id in e, 13b.
To a 500 mL round-bottomed flask equipped with condenser
and N2 inlet wereadded 6.3g(23.4mmol)of1-(N,N-dimethylamino-
ethoxy)-5,6,7,8-tetrahydro-naphthalene-4-boronic acid, 6.0 g
(23.4 mmol) of 6-bromo-2-(2,5-dimethylpyrrolyl)pyridine, 10.1
g (95.6 mmol) of sodium carbonate, 552 mg of tetrakistri-
phenylphosphine palladium, 200 mL of ethanol, and 20 mL of
water. The reaction was refluxed 20 h, cooled, and filtered.
The filtrate was concentrated, taken up in 1 N sodium
hydroxide solution, and extracted into ethyl acetate 3×. The
organic layer was washed with saturated aqueous sodium
bicarbonate solution and brine, dried over sodium sulfate, and
evaporated. The residue was chromatographed on silica gel
using methanol/methylene chloride as eluant to afford 7.67 g
(82%) of the product as an oil, which matched 13b prepared
previously. This material was converted to 14b as described
above.
4-H y d r o x y -6,7,8,9-t e t r a h y d r o -5H -b e n zo c y c lo h e p -
ten e, 4e. Prepared in analogy with 4d by reaction of 8 g (71.4
mmol) of 2-hydroxypyrone (ref: Synth. Commun. 1975, 5, 461)
and 20 mL cycloheptene in a sealed tube at 150 °C for 24 h,
followed by chromatography on silica gel using hexane/ethyl
acetate as eluant, to give 1-oxo-3,4,6,7,8,9-hexahydro-5H-
benzocycloheptene in 49.5% yield, followed by reaction with
isopropenyl acetate to afford the enol acetate and treatment
with 2,3-dichloro-5,6-dicyanobenzoquinone at 90 °C for 1.5 h
(ref: J . Med. Chem. 1994, 37, 3803) to afford 4-acetoxy-6,7,8,9-
tetrahydro-5H-benzocycloheptene in 69% yield as an oil.
Hydrolysis with 3.7 equiv of powdered potassium hydroxide
in ethanol at room temperature for 2 h gave a 44% yield of
the desired 4-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohep-
tene after purification by column chromatography as a white
solid. 1H NMR (δ, CDCl3): 1.64 (m, 4H), 1.85 (m, 2H), 2.79
(m, 2H), 2.86 (m, 2H), 6.64 (d, J ) 8, 1H), 6.72 (d, J ) 7, 1H),
6.94 (t, J ) 8, 1H). 13C NMR (δ, CDCl3): 25.8, 27.6, 28.2, 32.8,
36.6, 113.4, 121.6, 126.2, 129.6, 146.0, 152.4. GC MS: 162
(parent + 1, 100).
6-[4-(2-Dim et h yla m in oet h oxy)-6,7,8,9-t et r a h yd r o-5H-
ben zocycloh ep ten -1-yl]p yr id in -2-yla m in e, 18ei. Prepared
in 89% yield to give the product as an amorphous solid as the
hydrochloride salt from ether, mp 90 °C (dec). 1H NMR (δ,
CDCl3): 1.58 (m, 4H), 1.79 (m, 2H), 2.34 (s, 6H), 2.75 (m, 4H),
2.93 (m, 2H), 4.06 (t, J ) 6, 2H), 4.48 (bs, 2H), 6.39 (d, J ) 8,
1H), 6.62 (d, J ) 8, 1H), 6.74 (d, J ) 8, 1H), 7.10 (d, J ) 8,
1H), 7.41 (d, J ) 8, 1H). 13C NMR (δ, CDCl3): 25.51, 27.36,
27.75, 31.21, 32.46, 46.03, 58.35, 67.43, 105.94, 109.95, 114.72,
127.58, 132.85, 133.74, 137.54, 142.88, 155.43, 157.74, 159.32.
MS (%): 326 (parent + 1, 100). FAB HRMS: Calcd for
C
20H28N3O: 326.2232. Found: 326.2229.
Meth od C. 6-[4-(1-Meth ylpyr r olidin -2-ylm eth oxy)-n aph -
th alen -1-yl]pyr idin -2-ylam in e, 23i: 4-Br om o-1-flu or on aph -
th a len e, 19. To a 50 mL round-bottomed flask equipped with
condenser and N2 inlet were added 3.75 mL (5.0 g, 34.25 mmol)
of 1-fluoronaphthalene and 10 mL of carbon tetrachloride,
followed by dropwise addition of 1.7 mL (5.5 g., 34.375 mmol)
of bromine over 3 min. The reaction was heated to 50-60 °C
as HBr was evolved for 2 h and then cooled and concentrated.
The residue was dissolved in methanol and kept overnight at
0 °C. After filtration with cold methanol, the product, with mp
close to room temperature, was 4.62 g (60%) of a yellow oil.
1H NMR (δ, CDCl3): 7.02 (t, J ) 8, 1H), 7.6-7.7 (m, 3H), 8.10
(d, J ) 8.5, 1H), 8.20 (d, J ) 8.5, 1H). GCMS (%): 224/226
(parent, Br79/Br81 100).
4-F lu or on a p h th a len e-1-bor on ic Acid , 20. To a 250 mL
three-necked round-bottomed flask equipped with septum and
N2 inlet were added 4.62 g (20.53 mmol) of 4-bromo-1-
fluoronaphthalene and 100 mL of dry tetrahydrofuran. The
solution was cooled to -70 °C, and 15.4 mL (24.64 mmol) of a
1.6 M solution of butyllithium in hexane was added dropwise
over 5 min. The reaction was stirred at -70 °C for 10 min, 4.2
mL (3.59 g, 24.64 mmol) triethyl borate was added, and the
reaction was stirred at -70 °C for 20 min and warmed to room
temperature. After stirring overnight at room temperature,
the reaction was quenched with saturated aqueous ammonium
chloride solution, acidified with 1 N hydrochloric acid, and
extracted into ethyl acetate (twice). The combined organic layer
was washed with brine, dried over sodium sulfate, and
evaporated. The residue was triturated with hexane to give
an off-white powder, 1.97 g (51%), as a mixture of monoaryl
and diaryl boronic acids. 1H NMR (δ, CDCl3): 7.2-7.4 (m, 1H),
7.5-7.7 (m, 3H), 8.0-8.5 (m, 1H), 8.5 and 9.2 (m, 1H). APCI
(-) (%): 189 (parent-1, 60).
2-(2,5-Dim eth ylp yr r olyl)-6-(4-flu or on a p h th -1-yl)p yr i-
d in e, 21. To a 50 mL round-bottomed flask equipped with
condenser and N2 inlet were added 404 mg (2.13 mmol) of
4-fluoronaphthalene-1-boronic acid, 534 mg (2.13 mmol) of
2-(2,5-dimethylpyrrolyl)-6-bromopyridine, 902 mg (8.51 mmol)
of sodium carbonate, 150 mg of tetrakistriphenylphosphine,
10 mL of ethanol, and 2 mL of water. The reaction was refluxed
overnight, cooled, poured into water, and extracted into ethyl
acetate. After being combined with another run on a larger
scale, the organic layer was washed with brine, dried over
sodium sulfate, and evaporated. The residue was chromato-
graphed on silica gel using hexane/ethyl acetate as eluant to
afford 4.72 g (85%) of an oil. 1H NMR (δ, CDCl3): 2.25 (s, 6H),
5.92 (s, 2H), 7.1-7.2 (m, 2H), 7.4-7.6 (m, 4H), 7.95 (t, J ) 8,
1H), 8.12 (d, J ) 8, 1H), 8.19 (d, J ) 8, 1H). 13C NMR (δ,
CDCl3): 13.41, 106.97, 108.82, 109.02, 120.18, 120.78, 120.84,
123.42, 123.81, 123.96, 125.48, 126.20, 127.32, 127.68, 127.76,
128.56, 132.35, 133.90, 138.22, 151.87, 157.82, 158.30, 160.34.
MS (%): 317 (parent + 1, 100). HRMS Calcd for C21H18N2F
(parent + 1): 317.1454. Found: 317.1462.
4-Br om o-1-(N,N-dim eth ylam in oeth oxy)-6,7,8,9-tetr ah y-
d r o-5H-ben zocycloh ep ten e, 15e. Prepared in 25% yield as
1
a light brown oil. H NMR (δ, CDCl3): 1.54 (m, 4H), 1.79 (m,
2H), 2.32 (s, 6H), 2.72 (t, J ) 6, 2H), 2.91 (m, 2H), 3.01 (m,
2H), 3.99 (t, J ) 6, 2H), 6.57 (d, J ) 9, 1H), 7.27 (d, J ) 9,
1H). 13C NMR (δ, CDCl3): 25.9, 26.5, 27.1, 32.1, 34.2, 46.0,
58.2, 67.5, 111.7, 115.5, 130.0, 134.4, 143.7, 154.9. MS: 312/
314 (parent + 1, 100, Br79/Br81).
1-(N,N-Dim eth yla m in oeth oxy)-6,7,8,9-tetr a h yd r o-5H-
ben zocycloh ep ten e-4-bor on ic Acid , 16e. Prepared in 49.5%
1
yield as a tan amorphous solid. H NMR (δ, CDCl3): 1.57 (m,
4H), 1.71 (m, 2H), 1.83 (m, 2H), 2.38 (s, 6H), 2.83 (t, J ) 6,
2H), 2.94 (m, 2H), 3.39 (m, 2H), 4.13 (t, J ) 6, 2H), 6.75 (d, J
) 8, 1H), 7.90 (d, J ) 8, 1H).
2-(2,5-Dim e t h ylp yr r olyl)-6-[4-(N ,N -d im e t h yla m in o-
et h oxy)-6,7,8,9-t et r a h yd r o-5H -b en zocycloh ep t en -1-yl]-

Inhibitors of Neuronal Nitric Oxide Synthase
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 6 1585
2-(2,5-Dim et h ylp yr r olyl)-6-(4-((1-m et h ylp yr r olid in -2-
ylm eth oxy)n a p h th -1-yl)p yr id in e, 22i. To a 20 mL round-
bottomed flask equipped with condenser and N2 inlet were
added 145 mg (1.266 mml) (S)-(-)-1-methyl-pyrrolidin-2-
ylmethanol and 8 mL of dry dimethylformamide, followed by
76 mg (1.989 mmol) of sodium hydride (60% in oil). The
reaction was heated to 70 °C to ensure complete formation of
the alkoxide, 200 mg (0.633 mmol) of 2-(2,5-dimethylpyrrolyl)-
6-(4-fluoro-naphth-1-yl)pyridine in 2 mL of dry dimethylfor-
mamide was added, and the reaction was heated at 80 °C for
2 h. The reaction was cooled, poured into water, and extracted
into ethyl acetate. The organic layer was washed with brine,
dried over sodium sulfate, and evaporated. The residue was
chromatographed on silica gel using methanol/methylene
washed three times with water and once with brine, dried over
sodium sulfate, and evaporated. The residue was chromato-
graphed on silica gel using methanol/methylene chloride as
eluant to afford 112 mg (43.5%) of the product as an oil. 1H
NMR (δ, CDCl3): 1.29 (m, 3H), 1.5 (m, 1H), 1.6-1.8 (m, 6H),
1.9 (m, 1H), 2.1 (m, 1H), 2.16 (s, 6H), 2.43 (s, 6H), 2.7 (m, 1H),
2.755 (dd, J ) 7, 10, 4H), 4.39 (m, 1H), 5.87 (s, 2H), 6.78 (d, J
) 8, 1H), 7.11 (d, J ) 8, 1H), 7.18 (d, J ) 8, 1H), 7.37 (d, J )
8, 1H), 7.82 (t, J ) 8, 1H). 13C NMR (δ, CDCl3): 13.32, 22.42,
22.86, 23.69, 24.11, 24.54, 27.84, 28.71, 30.26, 42.11, 66.03,
76.04, 106.50, 108.92, 119.46, 122.94, 127.57, 128.60, 132.17,
136.79, 137.81, 151.25, 155.37, 160.41. MS (%): 444 (parent
+ 1, 100).
2-(2,5-Dim et h ylp yr r olyl)-6-[4-(1-m et h ylp yr r olid in -3-
yloxy)-5,6,7,8-tetr a h yd r on a p h th a len -1-yl]p yr id in e, 24ii.
Prepared as for 24i, using N-methyl-3-pyrrolidinol, in 9% yield
1
chloride as eluant to afford 235 mg (90%) of an oil. H NMR
(δ, CDCl3): 1.83 (m, 2H), 1.90 (m, 1H), 2.15 (m, 1H), 2.23 (s,
6H), 2.38 (m, 1H), 2.585 (s, 3H), 2.89 (m, 1H), 3.17 (m, 1H),
4.17 (AB multiplet, J ) 60, 2H), 5.89 (s, 2H), 6.89 (d, J ) 8,
1H), 7.22 (m, 1H), 7.49 (m, 2H), 7.56 (m, 2H), 7.90 (t, J ) 8,
1H), 8.12 (m, 1H), 8.33 (m, 1H). 13C NMR (δ, CDCl3): 13.44,
22.97, 28.89, 41.80, 57.77, 64.36, 71.45, 104.11, 106.72, 119.64,
122.30, 123.42, 125.15, 125.68, 126.80, 128.29, 128.58, 130.21,
131.86, 138.00, 151.68, 155.24, 159.06. MS (%): 412 (parent
+ 1, 100). HRMS Calcd for C27H29N3O (parent + 1): 412.2389.
Found: 412.2377.
1
as an oil. H NMR (δ, CDCl3): 1.65 (m, 2H), 1.74 (m, 2H), 2.0
(m, 1H), 2.14 (s, 6H), 2.31 (m, 1H), 2.41 (s, 3H), 2.6 (m, 1H),
2.7-2.8 (m, 6H), 3.0 (m, 1H), 4.85 (m, 1H), 5.86 (s, 2H), 6.61
(d, J ) 8, 1H), 7.11 (d, J ) 7.5, 1H), 7.16 (d, J ) 8, 1H), 7.35
(d, J ) 8, 1H), 7.81 (t, J ) 8, 1H). 13C NMR (δ, CDCl3): 13.33,
22.72, 22.84, 23.79, 28.67, 32.66, 33.16, 42.33, 62.54, 106.50,
108.47, 119.50, 122.94, 126.89, 127.53, 128.62, 132.32, 136.74,
137.83, 151.23, 155.73, 160.28. MS (%): 402 (parent + 1, 100).
6-[4-(2-Dim eth yla m in o-cycloh exyloxy)-5,6,7,8-tetr a h y-
d r on a p h th a len -1-yl]p yr id in -2-yla m in e, 25i: Deblocked as
described for compound 7a , affording the product in 76% yield,
as an amorphous solid. 1H NMR (δ, CDCl3): 1.06 (m, 1H), 1.27
(m, 3H), 1.43 (m, 1H), 1.6-1.8 (m, 4H), 1.86 (m, 1H), 2.12 (m,
1H), 2.41 (s, 6H), 2.6-2.8 (m, 6H), 4.36 (m, 1H), 4.47 (bs, 2H),
6.38 (d, J ) 8, 1H), 6.66 (d, J ) 8, 1H), 6.72 (d, J ) 8, 1H),
7.07 (d, J ) 8, 1H), 7.42 (t, J ) 8, 1H). 13C NMR (δ, CDCl3):
22.41, 22.78, 23.63, 24.03, 24.53, 28.01, 28.20, 30.18, 42.01,
46.07, 65.91,75.88, 105.95, 108.66, 114.39, 126.63, 127.36,
133.18, 136.42, 137.64, 154.75, 157.54, 158.93. MS (%): 366
(parent + 1, 100). HRMS Calcd for C23H32N3O (parent + 1):
366.2545. Found: 366.2556.
2-(2,5-Dim eth ylp yr r olyl)-6-(4-(1-a za bicyclo[2.2.2]oct-2-
ylm eth oxy)n a p h th -1-yl)p yr id in e, 22ii. Prepared as for 22i,
using 1-azabicyclo[2.2.2]oct-2-ylmethanol, in 67% yield as a
tan oil. 1H NMR (δ, CDCl3): 1.4-1.6 (m, 5H), 1.90 (m, 2H),
2.24 (s, 6H), 2.84 (m, 1H), 3.0-3.2 (m, 3H), 3.43 (m, 1H), 4.23
(AB, ∆ν ) 87, 2H), 5.90 (s, 2H), 6.93 (d, J ) 8, 1H), 7.23 (d, J
) 8, 1H), 7.5-7.6 (m, 4H), 7.90 (t, J ) 8, 1H), 8.12 (m, 1H),
8.37 (m, 1H). 13C NMR (δ, CDCl3): 13.54, 21.60, 25.71, 26.76,
30.48, 42.87, 50.06, 55.15, 70.89, 104.56, 106.81, 119.72,
122.58, 123.52, 125.19, 125.23, 125.92, 126.92, 128.36, 128.67,
130.38, 131.96, 138.10, 151.77, 155.49, 159.14. HRMS Calcd
for C29H31N3O (parent + 1): 438.2545. Found: 438.2521.
6-[4-(1-Met h ylp yr r olid in -2-ylm et h oxy)n a p h t h a len -1-
yl]p yr id in -2-yla m in e, 23i: Deblocking was carried out as
described for compound 14a i in 88% yield to give the product
as a tan solid, mp 80-95 °C, RD ) -36.47° (c ) 1, CH2Cl2). 1H
NMR (δ, CDCl3): 1.8 (m, 2H), 1.9 (m, 1H), 2.12 (m, 1H), 2.34
(m, 1H), 2.56 (s, 3H), 2.83 (m, 1H), 3.13 (m, 1H), 4.13 (AB,
2H), 4.63 (bs, 2H), 6.41 (d, J ) 8, 1H), 6.83 (m, 2H), 7.46 (m,
4H), 8.10 (m, 1H), 8.31 (m, 1H). 13C NMR (δ, CDCl3): 23.00,
28.92, 41.87, 57.79, 64.27, 71.57, 104.06, 106.45, 115.09,
122.07, 124.97, 125.64, 125.73, 126.01, 126.53, 127.20, 131.29,
132.06, 137.89, 154.78, 157.69, 158.07. MS (%): 334 (parent
+ 1, 100). Anal. (C21H23N3O‚1/3H2O) C, H, N.
6-[4-(1-Met h ylp yr r olid in -3-yloxy)-5,6,7,8-t et r a h yd r o-
n a p h th a len -1-yl]p yr id in -2-yla m in e, 25ii: Prepared by de-
blocking 24ii as for 25i in 93.5% yield as an amorphous solid.
1H NMR (δ, CDCl3): 1.64 (m, 2H), 1.72 (m, 2H), 2.31 (m, 2H),
2.40 (s, 3H), 2.56 (m, 1H), 2.67 (m, 4H), 2.99 (m, 1H), 4.53 (bs,
2H), 4.83 (m, 1H), 6.39 (d, J ) 8, 1H), 6.57 (d, J ) 8, 1H), 6.64
(d, J ) 8, 1H), 7.06 (d, J ) 8, 1H), 7.42 (t, J ) 8, 1H). 13C
NMR (δ, CDCl3): 22.4, 22.9, 23.8, 25.8, 25.2, 33.1, 42.3, 55.2,
62.6, 106.2, 108.4, 112.5, 114.5, 126.7, 133.3, 136.5, 137.8,
155.3, 157.7, 158.8. MS (%): 366 (parent + 1, 100). HRMS
Calcd for C20H26N3O (parent + 1): 324.2076. Found: 324.2083.
Biologica l Assa ys. NOS En zym e Assa ys. NO synthase
activity was measured by a modification of the procedure
described in Bredt, D. S.; Snyder, S. H. Proc. Natl. Acad. Sci.,
U. S. A. 1990, 87, 714. Using this procedure, 10 µL of enzyme
solution and 10 µL of 3[H]-arginine were added to 80 µL of
buffer (contents of which varied depending on the NOS isoform
being tested). After incubation for 50 min at 30 °C, the reaction
was terminated by application to a 0.15 mL column containing
Biorex-60 cation-exchange resin, sodium form, and washed
with 90 µL water. 3[H]-Citrulline was quantified by liquid
scintillation spectroscopy of the eluant.
Har m alin e-In du ced cGMP P r otocol. Male Sprague Daw-
ley rats 75-85 g are administered the test compound subcu-
taneously in 5/5/90 DMSO/Emulphor/saline and then, 20 min
later, injected (ip) with 20 mg/kg harmaline‚HCl in saline
using an injection volume of 0.5 mL/100 g. Ten minutes after
injection, animals are sacrificed with focused microwave
irradiation to quench brain enzymatic activity. The cerebellum
is removed and frozen at -70 °C until assay. On the day of
assay, cerebellum is extracted with 0.5 mL of 0.5 N HCl.
Briefly, the tissue is probe-sonicated with 0.5 mL of the 0.5 N
HCl for 15 s using a Branson Sonifier 250 at a constant output
of 20. The resulting homogeneous mixture is centrifuged at
15 000g for 20 min at 4 °C. The supernatant is removed and
assayed immediately for cGMP by ELIZA (R and D systems).
A cGMP standard curve of 0.8-500 pg/mL was utilized. A 10
6-[4-(1-Aza bicyclo[2.2.2]oct-2-ylm eth oxy)n a p h th a len -
1-yl]p yr id in -2-yla m in e, 23ii. Prepared by Method C using
1-aza-bicyclo[2.2.2]oct-2-yl-methanol in 79% yield, mp 180-
190 °C as the free base and mp 145-155 °C, as the hydro-
1
chloride salt. H NMR (δ, CDCl3): 1.56 (m, 5H), 1.86 (m, 2H),
2.75 (m, 1H), 2.93 (m, 2H), 3.10 (m, 1H), 3.36 (m, 1H), 4.07
(AB multiplet, J ) 65, 2H), 6.43 (d, J ) 8, 1H), 6.74 (d, J ) 7,
1H), 6.83 (d, J ) 8, 1H), 7.39 (m, 4H), 7.93 (m, 1H), 8.28 (m,
1H). 13C NMR (δ, CDCl3): 21.21, 25.11, 26.10, 29.80, 42.44,
48.91, 49.13, 49.50, 55.08, 69.91, 104.23, 107.04, 115.02,
122.13, 125.15, 125.46, 125.63, 126.67, 127.07, 131.37, 132.10,
138.27, 154.70, 157.08, 158.30. MS (%): 360 (parent + 1, 100).
Anal. Calculated for a sample of the free base, which formed
the N-carboxy derivative from CO2 in the air, (C23H25N3O‚CO2)
C, H, N.
Meth od D. 2-(2,5-Dim eth ylp yr r olyl)-6-[4-(2-(d im eth yl-
am in o)cycloh exyloxy)-5,6,7,8-tetr ah ydr on aph th alen -1-yl]-
p yr id in e, 24i. To a 100 mL round-bottomed flask equipped
with condenser and N2 inlet were added 185 mg (0.58 mmol)
of 9b, 173 mg (0.58 mmol) of N,N-dimethyl (2-tosyloxycyclo-
hexyl)amine, 320 mg (2.3 mmol) of potassium carbonate, and
10 mL of dry dimethylformamide. The reaction was heated at
140 °C for 18 h, cooled, and poured into 1 N aqueous sodium
hydroxide solution. The aqueous phase was extracted three
times with ethyl acetate, and the combined organic layers were

1586 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 6
Lowe et al.
7-Nitro Indazole and Related Indazoles - Antinociceptive and
Cardiovascular Effects. Br. J . Pharmacol. 1993, 110, 219-224.
(c) Handy, R. L. C.; Moore, P. K. A comparison of the effects of
L-NAME, 7-NI and L-NIL on carrageenan-induced hindpaw
edema and NOS activity. Br. J . Pharmacol. 1998, 123, 1119-
1126.
µL aliquot of the supernatant was sufficient to cover the range
of expected cGMP levels. The pellet was solubilized with 1 mL
of 0.2% sodium sulfate in 0.5 N NaOH and protein content
determined by the BCA protein assay method. Results are
reported as pmol/mg protein. The induction of cGMP in
harmaline-treated rats was 5-10-fold over vehicle-injected
rats.
(8) Handy, R. L.; Moore, P. K. Effects of selective inhibitors of
neuronal nitric oxide synthase on carrageenan-induced mechan-
ical and thermal hyperalgesia. Neuropharmacology 1998, 37,
37-43.
(9) Osborne, M. G.; Coderre, T. J . Effects of intrathecal administra-
tion of nitric oxide synthase inhibitors on carrageenan-induced
thermal hyperalgesia. Br. J . Pharmacol. 1999, 126, 1840-1846.
(10) Castagnoli, K.; Palmer, S.; Anderson, A.; Bueters, T.; Castagnoli,
N. J r. The neuronal nitric oxide synthase inhibitor 7-nitroinda-
zole also inhibits the monoamine oxidase-B catalyzed oxidation
of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Chem. Res.
Toxicol. 1997, 10, 364-368.
(11) DiMonte, D. A.; Royland, J . E.; Anderson, A.; Castagnoli, K.;
Castagnoli, N. J r.; Langston, J . W. Inhibition of monoamine
oxidase contributes to the neuroprotective effect of 7-nitroinda-
zole against MPTP neurotoxicity. J . Neurochem. 1997, 69, 1771-
1773.
In h ibition of P CP -In du ced Hyper m otility. Three groups
of rats are used, vehicle-vehicle, 3.2 mg/kg PCP-vehicle, and
3.2 mg/kg PCP-drug. The drug was administered subcutane-
ously in 5/5/90 DMSO/Emulphor/saline followed by PCP. Rats
were placed in hypermotility boxes in which they had been
previously acclimated, and crossovers and rears were mea-
sured over a 2 h period. Results are expressed as inhibition of
mean crossovers, with SEM.
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