Synthesis and structure-activity relationships of fused imidazopyridines: A new series of benzodiazepine receptor ligands

Article abstract of DOI:10.1021/jm9600609

2-Arylimidazo[4,5-c]quinolines and analogous fused imidazopyridines were synthesized and evaluated as benzodiazepine receptor ligands. Affinity to the receptors was greatly affected by the bulkiness of the aryl group at the 2- position, compared to the pyrazoloquinolines such as CGS-9896. Derivatives with an isoxazole moiety at the 2-position showed high binding affinity and in vivo activity. In the imidazo[4,5-c]quinoline series, substitution at the 6-position decreased or abolished activity. Most derivatives with an unsubstituted isoxazolyl group showed antagonist or inverse agonist activity except for the 7-halo analogues, which exhibited agonist activity. On the other hand, 5-methylisoxazol-3-yl or 3-methylisoxazol-5-yl derivatives generally exhibited agonist activity. A similar substitution effect on the isoxazole moiety was observed in the imidazopyridines fused with a nonaromatic ring. From the detailed pharmacological evaluation, S-8510, 2- (3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridine monophosphate, possessing weak inverse agonist activity was selected as a therapeutic candidate for the treatment of some symptoms of senile dementia.

Full text of DOI:10.1021/jm9600609

2844
J . Med. Chem. 1996, 39, 2844-2851
Syn th esis a n d Str u ctu r e-Activity Rela tion sh ip s of F u sed Im id a zop yr id in es: A
New Ser ies of Ben zod ia zep in e Recep tor Liga n d s
Susumu Takada,* Takashi Sasatani, Nobuo Chomei, Makoto Adachi, Toshio Fujishita, Masami Eigyo,
Shunji Murata, Kazuo Kawasaki, and Akira Matsushita
Shionogi Research Laboratories, Shionogi & Company, Ltd., Sagisu, Fukushima-ku, Osaka 553, J apan
Received J anuary 18, 1996X
2-Arylimidazo[4,5-c]quinolines and analogous fused imidazopyridines were synthesized and
evaluated as benzodiazepine receptor ligands. Affinity to the receptors was greatly affected
by the bulkiness of the aryl group at the 2-position, compared to the pyrazoloquinolines such
as CGS-9896. Derivatives with an isoxazole moiety at the 2-position showed high binding
affinity and in vivo activity. In the imidazo[4,5-c]quinoline series, substitution at the 6-position
decreased or abolished activity. Most derivatives with an unsubstituted isoxazolyl group showed
antagonist or inverse agonist activity except for the 7-halo analogues, which exhibited agonist
activity. On the other hand, 5-methylisoxazol-3-yl or 3-methylisoxazol-5-yl derivatives generally
exhibited agonist activity. A similar substitution effect on the isoxazole moiety was observed
in the imidazopyridines fused with a nonaromatic ring. From the detailed pharmacological
evaluation, S-8510, 2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridine mono-
phosphate, possessing weak inverse agonist activity was selected as a therapeutic candidate
for the treatment of some symptoms of senile dementia.
Sch em e 1a
In tr od u ction
Benzodiazepines and related ligands are generally
believed to interact with a specific site (“benzodiazepine
receptor”) that is allosterically coupled with a neuro-
inhibitory, postsynaptic GABAA receptor and a chloride
ionophore channel.1-3 These ligands exert a continuum
of intrinsic efficacy, from positive efficacy (agonists;
anxiolytic/anticonvulsant/sedative) through nil efficacy
(receptor antagonists) to negative efficacy (inverse ago-
nists; anxiogenic/proconvulsant/convulsant). Partial
agonists and partial inverse agonists exist between
these three categories. Although numerous agonists
and one antagonist (Flumazenil) have been used thera-
peutically,4 the inverse agonists have not. It is believed
that partial inverse agonists may be useful as cognition
enhancers.5-7
Previously we reported that variation of the size of
the alkyl substituent on a series of thienylpyrazolo-
quinolines results in a shift from their being inverse
agonists to antagonists to agonists.8 In order to refine
the structure-related shifts in functional activity and
to develop more efficacious ligands, chemical manipula-
tion of the ring system was investigated. In this report,
we describe the synthesis and structure-activity rela-
tionships of imidazo[4,5-c]quinolines and the analogous
fused imidazopyridines, which comprise a new series of
benzodiazepine (BZ) receptor ligands with positive and
negative functional effects.
a
(a) POCl3; (b) NH3; (c) H2/Pd-C; (d) ArCOOH, HMPA/CH3CN,
SOCl2; (e) HMPA/AcOH, reflux.
in turn were treated with various aromatic carboxylic
acids (ArCOOH) and thionyl chloride in a mixture of
hexamethylphosphoramide (HMPA) and acetonitrile to
afford the corresponding amides, which were cyclized
by heating in a mixture of HMPA and acetic acid to
provide the desired imidazoquinolines 3-5.
The preparation of [e]-fused 2-arylimidazo[4,5-c]py-
ridines 14 and 15 is illustrated in Scheme 2. A fused
3-nitropyridine (8) was prepared by heating a cyclic
ketone (7) and 3,5-dinitro-1-methyl-2-pyridone in meth-
anolic ammonia in the manner reported by Tohda and
co-workers.10 Hydrogenation of 8 and protection of the
resulting amino group with trichloroacetyl chloride
afforded the amide 10. Oxidation of 10 with 3-chloro-
peroxybenzoic acid gave the N-oxide 11, which was
treated with fuming nitric acid followed by concentrated
ammonium hydroxide to provide 3-amino-4-nitropyri-
dine 1-oxide 12. Reduction of 1-oxo and 4-nitro groups
in 12 was accomplished in a single step by hydrogena-
tion with Raney nickel to give the fused 3,4-diaminopy-
ridine 13. Finally, monoacylation of 13 with an appro-
priate aroyl chloride and subsequent thermal cyclization
Ch em istr y
Scheme 1 outlines our synthetic routes to arylimidazo-
[4,5-c]quinolines 3-5 via the diaminoquinolines 2. The
3-nitroquinolin-4-ones series 1 were prepared from
corresponding anthranilic acids in a manner similar to
that described by Bacheman et al.9 Successive treat-
ment of 1 with phosphorus oxychloride and ammonia
gave 4-amino-3-nitroquinolines, which were converted
into the 3,4-diaminoquinolines 2 in good yield. These
X Abstract published in Advance ACS Abstracts, J une 1, 1996.
S0022-2623(96)00060-X CCC: $12.00 © 1996 American Chemical Society

Synthesis and SAR of Fused Imidazopyridines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2845
Sch em e 2a
F igu r e 1. Superimposition of pyrazoloquinoline 6a (black
lines) and imidazoquinoline 3a (5H-tautomer; gray lines).
a
(a) 1-Methyl-3,5-dinitro-2-pyridone/NH3/MeOH; (b) H2/5% Pd-
C/MeOH; (c) Et3N/CH2Cl2, Cl3CCOCl; (d) MCPBA/CH2Cl2; (e)
fuming HNO3, aq NH4OH; (f) H2/Raney Ni/MeOH; (g) DMF,
ArCOCl/CH2Cl2, AcONa/HOCH2CH2OH, 150 °C.
F igu r e 2. Superimposition of 6a (black lines) and 4a (5H-
tautomer; gray lines).
provided the desired fused 2-arylimidazo[4,5-c]pyridines
14 and 15 in good yield.
Resu lts a n d Discu ssion
The role of the hydrogen atom at the 5-position of the
pyrazolo[4,3-c]quinolines as the hydrogen bond donor
is well-defined for high affinity to BZ receptors.11,13,14
We thought that an imidazo[4,5-c]quinoline might be a
bioisostere of an pyrazolo[4,3-c]quinoline because a
tautomer with a hydrogen atom at the 5-position of the
former may exist when it interacts with the receptor
protein. Compounds initially synthesized in this series
exhibited a broad range of affinities (Ki ) 1.7-270 nM)
in comparison to their corresponding pyrazoloquinolines
(Ki ) 0.22-0.83 nM) as shown in Table 1.
Furthermore, the steric requirements for the 2-sub-
stituent in the former appear to be much greater than
that in the latter series. This may be rationalized by
the binding site model proposed by Cook et al.14 Thus,
in a bioactive form (5H-tautomer) of the imidazoquino-
lines, the imidazole N3 nitrogen atom may interact at
the hydrogen-bond-donor site on the binding protein.
Therefore, the aryl substituent at the 2-position may
be closer to the surface of the lipophilic pocket than that
of pyrazoloquinolines in which the carbonyl oxygen has
been suggested to interact with the hydrogen-bond-
donor site as shown in Figure 1.15
Although thienyl compounds 3c,d showed relatively
high in vitro affinities for the receptor, neither exhibited
activity in vivo. Therefore, a number of analogues with
a variety of 5-membered heteroaromatic substituents
at the 2-position were synthesized and tested. Among
them, isoxazolyl compounds were found to exhibit both
high in vitro affinity and in vivo activity. The isoxazole
moiety is considered to be small enough to be accom-
modated by BZ receptor in its lipophilic area (Figure
2).
P h a r m a cologica l Meth od s
Affin ity to th e BZ Recep tor . This was measured
by displacement of [3H]diazepam to receptor preparation
obtained from the cerebral cortex of Wistar rats. The
procedure is given in our previous paper.11
Agon ist Activity. This was evaluated by inhibition
of pentylenetetrazole (PTZ)-induced convulsions. Groups
of 8-16 male mice were challenged with a convulsive
dose (125 mg/kg, sc) of PTZ 1 h after oral administration
of the test compounds. The dose required to prevent
tonic convulsions and death in 50% of the animals
during a 2-h observation period was calculated by the
probit method.
In ver se Agon ist Activity. This was evaluated by
potentiation of PTZ-induced convulsions. Groups of
8-16 male mice were challenged with a subconvulsive
dose (75 or 90 mg/kg, sc) of PTZ 1 h after oral
administration of the test compounds. The dose re-
quired to produce tonic convulsions and death in 50%
of the animals during a 2-h observation period was
calculated by the probit method. Both the agonist and
inverse agonist activities seemed to be mediated via BZ
receptors because these effects were completely antago-
nized by the BZ antagonist Ro-15-1788.12
An ta gon ist Activity. This was assessed by disrup-
tion of the anticonvulsant actions of diazepam against
PTZ. Groups of 8-16 male mice were challenged with
an effective dose (1 mg/kg, sc) of diazepam, which offers
100% protection against the convulsions induced by PTZ
(125 mg/kg, sc). Thirty minutes later, the animals were
administered a convulsive dose (125 mg/kg) of PTZ
immediately after intravenous injection of the test
compounds. The dose required to produce tonic convul-
sions and death in 50% of the animals during a 2-h
observation period was calculated by the probit method.
Table 2 shows the pharmacological activities of com-
pounds having an isoxazol-3-yl moiety at the 2-position
when the inverse agonist activities were assessed by

2846 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Takada et al.
Ta ble 1. Affinities of 2-Arylimidazo[4,5-c]quinolines and 2-Arylpyrazolo[4,3-c]quinolin-3-ones
compd
Ki (nM)a (mean ( SD)
compd
Ki (nM)a (mean ( SD)
Ar
3a
3b
3c
3d
270 ( 67
22.0 ( 9.9
4.5 ( 1.5
1.7 ( 0.5
6a (CGS-9896)b,c
6b (CGS-8216)b,c
6c (S-135)c
6d c
0.83 ( 0.15
0.22 ( 0.01
0.32 ( 0.02
0.41 ( 0.18
p-chlorophenyl
phenyl
5-methylthien-3-yl
thien-2-yl
a
b
Displacing potential to [3H]diazepam binding in rat cerebral cortex. See ref 13. c See ref 8.
Ta ble 2. Pharmacological Activities of 2-(Isoxazol-3-yl)imidazo[4,5-c]quinolines
inverse agonist actc
Kia (nM)
(mean ( SD)
agonist actb
ED50 (mg/kg po)
PTZ ) 90 mg/kg sc,
PTZ ) 75 mg/kg sc,
R1
R2
ED50 (mg/kg po)
ED50 (mg/kg po)
d
d
d
compd
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
Me
Et
H
H
H
H
H
H
H
H
H
H
6-F
6-Cl
7-F
7-Cl
7-MeO
8-F
8-Cl
8-MeO
9-F
0.6 ( 0.2
0.9 ( 0.4
1.1 ( 0.4
40.0 ( 18.6
524 ( 138
0.9 ( 0.4
3.5 ( 1.5
7.2 ( 2.0
0.8 ( 0.2
0.8 ( 0.3
0.5 ( 0.2
3.4 ( 0.9
7.8 ( 4.1
10.11 (6.70-16.70)
inactive to 10 iv
16.42 (10.50-29.44)
19.23 (13.53-26.49)
37.5% (10 iv)e
inactive to 10 iv
inactive to 10 iv
39.93 (23.35-)
27.22 (17.54-46.06)
8.77 (3.64-18.22)
16.46 (7.70-119.81)
14.21 (9.76-20.68)
31.53 (22.39-75.90)
21.19 (14.60-34.51)
5.95 (3.53-11.93)
16.17 (11.71-22.28)
64.12 (28.18-)
4j
4k
4l
25% (50 po)e
H
H
H
25% (50 po)e
35.73 (25.87-58.54)
7.21 (4.54-12.28)
4m
9-Cl
a
b
Displacing potential to [3H]diazepam binding in rat cerebral cortex. Mouse pentylenetetrazole anticonvulsant test. See text for
schedule details. c Mouse pentylenetetrazole proconvulsant activity. See text for schedule details. ED50 values and their 95% confidence
d
limits were calculated by the probit method. e Percentage of the animals affected at that dose.
potentiation of the convulsions induced by two subcon-
vulsive doses (75 and 90 mg/kg, sc) of PTZ. Since a
higher intrinsic activity of inverse agonists is defined
as the ability to potentiate the convulsant action of the
lower dose of PTZ, the assay using 75 mg/kg PTZ
indicates higher negative efficacy than the one using
90 mg/kg PTZ. Compound 4a having no substituent on
both the isoxazole and benzene ring showed high affinity
and moderate inverse agonist activity, as judged by its
potentiation of the proconvulsions caused only by 90 mg/
kg PTZ.
Substitution at the 5′-position with an alkyl group
(4b,c) led to a shift from inverse agonist to agonist
profile of activity. The similar substitution effect has
been observed for the series of 2-(thien-2-yl)pyrazolo-
[4,3-c]quinolines.8 In order to examine the structure-
activity relationships in detail, compounds with a
halogen or a methoxy on the benzene ring were syn-
thesized in which the isoxazole ring was kept unsub-
stituted. Substitution at the 6-position resulted in
marked loss of affinity and in vivo activity (4d ,e). The
affinities and inverse activities were retained in the
8-substituted compounds 4i-k . Halogenation at the
9-position moderately decreased affinity but increased
inverse activity showing potentiation of proconvulsions
caused by 75 mg/kg PTZ (4l,m ). Interestingly, substitu-
tion with a halogen at the 7-position altered the intrinsic
activity from an inverse agonist to an agonist type (4f,g),
while substitution with a methoxy group at the same
position enhanced the inverse agonist activity (4h ).
Table 3 summarizes the biological data of compounds
having an isoxazol-5-yl moiety at the 2-position. Com-
pound 5a with no substituent on the ring exhibited high
affinity comparable to 4a . Although 5a did not possess
either agonist or inverse agonist activity, it exhibited
antagonist activity (zero efficacy). The 3′-methyl ana-
logue 5b displayed more potent agonist activity than
the corresponding isoxazol-3-yl analogue 4b. With 3′-
methylisoxazole fixed at the 2-position, the effects of the
substituent on the benzene ring were investigated.
Halogenation at the 6-position led to low affinity and a
loss of in vivo activity (5d ,c). Analogues substituted at

Synthesis and SAR of Fused Imidazopyridines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2847
Ta ble 3. Pharmacological Activities of 2-(Isoxazol-5-yl)imidazo[4,5-c]quinolines
inverse agonist actc
antagonist actd
Ki,a (nM)
(mean ( SD)
agonist actb
PTZ ) 90 mg/kg sc,
compd
R1
R2
ED50e (mg/kg po)
ED50e (mg/kg iv)
ED50e (mg/kg iv)
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
Me
Et
H
H
H
6-F
6-Cl
7-F
7-Cl
7-MeO
8-F
8-Cl
8-MeO
9-F
1.0 ( 0.3
0.9 ( 0.3
1.2 ( 0.3
302 ( 104
3354 ( 535
1.4 ( 0.4
18.8 ( 6.0
9.5 ( 1.9
1.1 ( 0.3
0.5 ( 0.2
0.9 ( 0.2
4.9 ( 1.7
13.7 ( 4.2
inactive to 10 iv
5.89 (3.79-8.57)
13.53 (9.99-19.58)
inactive to 50 pof
inactive to 10 iv
5.15 (3.54-7.18)
29.83 (22.06-42.65)
inactive to 10 iv
5.41 (2.96-12.99)
10.56 (4.78-17.08)
21.55 (11.44-77.99)
4.86 (3.24-7.03)
8.53 (5.08-16.82)
inactive to 10 iv
1.94 (1.35-2.77)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
inactive to 10 iv
inactive to 10 iv
46.2% (10 iv)g
5j
5k
5l
5m
9-Cl
d
a-c See the corresponding footnotes in Table 2. Antagonist activity. See text for schedule details. e ED50 values and their 95% confidence
g
limits were calculated by the probit method. f ED50 ) 8.42 mg/kg iv. Percentage of the animals affected at that dose.
Ta ble 4. Pharmacological activities of Fused Imidazopyridines
inverse agonist actc
Ki,a (nM)
(mean ( SD)
agonist actb
ED50 (mg/kg po)
PTZ ) 90 mg/kg sc,
PTZ ) 75 mg/kg sc,
d
d
d
compd
14a
14b
14c
14d
15a
15b
15c
X
ED50 (mg/kg po)
ED50 (mg/kg po)
CH2CH2
CH2
5.2 ( 2.9
1.2 ( 0.4
2.7 ( 0.9
5.3 ( 1.8
15.6 ( 5.3
2.2 ( 0.3
3.3 ( 1.4
14.6 ( 6.9
5.0 ( 0.4
inactive to 10 iv
inactive to 10 iv
inactive to 10 iv
inactive to 10 iv
19.63 (11.92-34.02)
4.72 (2.69-7.22)
antagoniste
antagonistf
O
25% (50 po)g
9.22 (6.76-12.51)
bond
CH2CH2
CH2
12.37 (6.01-25.87)
8.12 (5.85-10.65)
11.21 (7.81-16.06)
5.97 (4.41-8.53)
0.67 (0.47-0.94)
1.17 (1.06-2.93)
O
15d
bond
diazepam
CGS-9896
CGS-8216
0.83 ( 0.15
0.22 ( 0.01
12.77 (5.43-33.74)
25% (50 po)g
a-d
See the corresponding footnotes in Table 2. e Antagonist activity: ED50 ) 4.61 (3.78-6.29) mg/kg iv. See text for schedule details.
f Antagonist activity: ED50 ) 0.55 (0.26-2.04) mg/kg iv. Percentage of the animals affected at that dose.
g
the 8-position retained affinity and agonist activity (5i-
k ). The 9-halo derivatives 5l,m exhibited moderately
low affinities and retained agonist activities. Substitu-
tion at the 7-position resulted in diverse effects. Fluoro
compound 5f maintained its affinity and agonist activ-
ity, while chloro compound 5g displayed reduced affinity
but retained moderate agonist activity. Introduction of
a methoxy group at the 7-position (5h ) lowered the
affinity by 10-fold and abolished agonist activity result-
ing in a very weak antagonist activity.As mentioned
above, substitution on ring A has a pronounced effect
on affinity and a lesser effect on efficacy. This observa-
tion led us to try further structural modification in
which the benzene ring was replaced by a nonaromatic
ring. For comparison with imidazoquinolines 4a and
5b, [e]-fused imidazo[4,5-c]pyridines 14a -d and 15a -d
were prepared, respectively. Compounds 14a-d showed
lower binding affinities by 2-10-fold than 4a , but all of
them exhibited in vivo activities. 14a ,b with a 7- or
6-membered carbocyclic ring showed antagonist activity
(zero efficacy), while 14d with a 5-membered carbocyclic
ring exhibited strong inverse activity. Pyrano derivative
14c displayed moderate inverse agonist activity with
efficacy lying in between those of 14b,d . These findings

2848 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Takada et al.
8.0-8.6 (4H, m) 9.26 (1H, br s), 13.85 (1H, br s). Anal.
(C16H10N3Cl) C, H, N, Cl.
suggest that decreasing the size of ring A enhances
inverse agonist activity in the compounds with an
isoxazol-3-yl group at the 2-position. On the other hand,
compounds 15a -d with a 3-methylisoxazol-5-yl group
exhibited agonist activity regardless of the difference
of ring A. It is worth noting that all the 3-methylisox-
azol-5-yl derivatives possessed considerably high agonist
activity although their affinities were lower than that
of 5b.
Finally, several members of these series were selected
for further pharmacological and toxicological evalua-
tions as drug candidates. For example, the partial
agonists 5b and 15b are potential anxiolytics which
could be free of muscle relaxation or other sedative
effects.16 Antagonists such as 5a and 14b are expected
to be useful as antidotes to sedative overdose. Partial
inverse agonists 4b and 14c were evaluated as cognition
enhancers. Presently, compound 14c (S-8510) is under
clinical investigation for the treatment of senile demen-
tia. The detailed pharmacological results will be re-
ported in due course.
2-P h en yl-3H-im id a zo[4,5-c]qu in olin e (3b): mp 298-300
°C (EtOH); 1H-NMR (DMSO-d6) 7.50-7.80 (5H, m), 8.05-8.65
(4H, m), 9.25 (1H, s). Anal. (C16H11N3‚1/3H2O) C, H, N.
2-(5-Meth ylth ien -2-yl)-3H-im id a zo[4,5-c]qu in olin e (3c):
mp 293-295 °C (EtOH); 1H-NMR (DMSO-d6) 2.55 (3H, s),
7.57-7.80 (3H, m), 8.05-8.25 (2H, m), 8.39-8.59 (1H, m), 9.21
(1H, s). Anal. (C15H11N3S) C, H, N, S.
2-(Th ien -2-yl)-3H-im idazo[4,5-c]qu in olin e (3d): mp 304-
305 °C (EtOH); 1H-NMR (DMSO-d6) 7.25-7.40 (1H, m), 7.55-
7.90 (3H, m), 7.95-8.30 (2H, m), 8.40-8.55 (1H, m), 9.20 (1H,
s). Anal. (C14H9N3S) C, H, N, S.
2-(5-Met h ylisoxa zol-3-yl)-3H -im id a zo[4,5-c]q u in olin e
(4b): mp 273-274 °C (AcOEt); 1H-NMR (DMSO-d6) 2.57 (3H,
s), 6.92 (1H, s), 7.61-7.82 (2H, m), 8.10-8.17 (1H, m), 8.53-
8.68 (1H, m), 9.26 (1H, s). Anal. (C14H10N4O) C, H, N.
2-(5-Eth ylisoxazol-3-yl)-3H-im idazo[4,5-c]qu in olin e (4c):
1
mp 268-269 °C (AcOEt); H-NMR (DMSO-d6) 1.33 (3H, t, J
) 7 Hz), 2.91 (2H, q, J ) 7 Hz), 6.92 (1H, s), 7.58-7.83 (2H,
m), 8.09-8.20 (1H, m), 8.53-8.65 (1H, m), 9.24 (1H, s). Anal.
(C15H12N4O) C, H, N.
6-F lu or o-2-(isoxa zol-3-yl)-3H -im id a zo[4,5-c]q u in o-
lin e (4d ): mp 329-332 °C dec (MeOH-CH2Cl2); 1H-NMR
(DMSO-d6) 7.29 (1H, d, J ) 2 Hz), 7.43-7.81 (2H, m), 8.32-
8.43 (1H, m), 9.25 (1H, d, J ) 2 Hz), 9.31 (1H, s). Anal.
(C13H7N4FO) C, H, N.
Exp er im en ta l Section
Melting points were determined on a Yanagimoto hot plate
micromelting point apparatus and are uncorrected. IR spectra
were recorded on a Hitachi 260-10 infrared spectrophotometer.
1H-NMR spectra were recorded on a Varian VXR-200 spec-
trometer. Chemical shifts are given in parts per million
relative to tetramethylsilane as the internal standard.
3,4-Dia m in oqu in olin es (2). 3-Nitro-4-hydroxyquinolines
1 (prepared by condensation9 of anthranilic acids with meth-
azonic acid or by nitration17 of quinolin-4-ones) were heated
with phosphorus oxychloride to give 4-chloroquinolines which
were treated with ammonia followed by hydrogenation of the
resulting 4-amino-3-nitroquinolines, affording the title com-
pounds: 2a (R ) H), mp 168-170 °C dec; 2b (R ) 5-F), mp
168-169.5 °C dec; 2c (R ) 5-Cl), mp 157-159 °C (lit.17 mp
158-159 °C); 2d (R ) 6-F), mp 196-198 °C dec; 2e (R ) 6-Cl),
mp 206-209 °C; 2f (R ) 6-MeO), mp 181-182 °C dec; 2g (R
) 7-F), mp 185-188 °C dec; 2h (R ) 7-Cl), mp 193-195 °C
dec (lit.17 mp 191-192 °C); 2i (R ) 7-MeO), mp 136-139 °C
dec; 2j (R ) 8-F), mp 167-169 °C dec; 2k (R ) 8-Cl), mp 159-
161 °C dec.
6-Ch lor o-2-(isoxa zol-3-yl)-3H -im id a zo[4,5-c]q u in o-
lin e (4e): mp 284-287 °C dec (AcOEt-CH2Cl2); 1H-NMR
(DMSO-d6) 7.30 (1H, d, J ) 2 Hz), 7.60-7.98 (2H, m), 8.53-
8.63 (1H, m), 9.22 (1H, d, J ) 2 Hz), 9.39 (1H, s). Anal.
(C13H7N4ClO‚7/8H2O) C, H, N.
7-F lu or o-2-(isoxa zol-3-yl)-3H -im id a zo[4,5-c]q u in o-
lin e (4f): mp 297-299 °C (AcOEt-MeOH); 1H-NMR (DMSO-
d6) 7.26 (1H, d, J ) 2 Hz), 7.50-7.93 (2H, m), 8.57-8.73 (1H,
m), 9.19 (1H, d, J ) 2 Hz), 9.29 (1H, s). Anal. (C13H7N4FO‚
1/6H2O) C, H, N.
7-Ch lor o-2-(isoxa zol-3-yl)-3H -im id a zo[4,5-c]q u in o-
lin e (4g): mp 302-306 °C dec (MeOH-CHCl3); 1H-NMR
(DMSO-d6) 7.25 (1H, d, J ) 2 Hz), 7.65-7.79 (1H, dd, J ) 8,
2 Hz), 8.17 (1H, d, J ) 2 Hz), 8.60 (1H, d, J ) 8 Hz), 9.17 (1H,
d, J ) 2 Hz), 9.29 (1H, s). Anal. (C13H7N4ClO‚1/8H2O) C, H,
N.
2-(Isoxa zol-3-yl)-7-m et h oxy-3H -im id a zo[4,5-c]q u in o-
lin e (4h ): mp 293-296 °C dec (MeOH-AcOEt); 1H-NMR
(DMSO-d6) 3.94 (3H, s), 7.28 (1H, d, J ) 2 Hz), 7.37 (1H, dd,
J ) 9, 2 Hz), 7.57 (1H, d, J ) 2 Hz), 8.48 (1H, d, J ) 9 Hz),
9.21 (1H, s), 9.23 (1H, d, J ) 2 Hz). Anal. (C14H10N4O2) C, H,
N.
8-F lu or o-2-(isoxa zol-3-yl)-3H -im id a zo[4,5-c]q u in o-
lin e (4i): mp 308-310 °C dec (MeOH-AcOEt); 1H-NMR
(DMSO-d6) 7.30 (1H, d, J ) 2 Hz), 7.50-7.73 (1H, m), 8.14-
8.37 (2H, m), 9.25 (1H, d, J ) 2 Hz), 9.27 (1H, s). Anal.
(C13H7N4FO) C, H, N.
8-Ch lor o-2-(isoxa zol-3-yl)-3H -im id a zo[4,5-c]q u in o-
lin e (4j): mp 299-302 °C dec (AcOEt-MeOH); 1H-NMR
(DMSO-d6) 7.30 (1H, d, J ) 2 Hz), 7.74 (1H, dd, J ) 8, 2 Hz),
8.17 (1H, d, J ) 8 Hz), 8.66 (1H, d, J ) 2 Hz), 9.20 (1H, d, J
) 2 Hz), 9.30 (1H, s). Anal. (C13H7N4ClO) C, H, N.
2-(Isoxa zol-3-yl)-8-m et h oxy-3H -im id a zo[4,5-c]q u in o-
lin e (4k ): mp 279-281 °C dec (MeOH-AcOEt); 1H-NMR
(DMSO-d6) 3.96 (3H, s), 7.26 (1H, d, J ) 2 Hz), 7.38 (1H, d, J
) 2 Hz), 7.99-8.09 (2H, m), 9.10 (1H, s), 9.22 (1H, d, J ) 2
Hz). Anal. (C14H10N4O2‚1/4H2O) C, H, N.
9-F lu or o-2-(isoxa zol-3-yl)-3H -im id a zo[4,5-c]q u in o-
lin e (4l): mp 277-279 °C (MeOH-AcOEt); 1H-NMR (DMSO-
d6) 7.33 (1H, d, J ) 2 Hz), 7.43-7.85 (2H, m), 7.96-8.06 (1H,
m), 9.22 (1H, d, J ) 2 Hz), 9.32 (1H, s). Anal. (C13H7N4FO)
C, H, N.
9-Ch lor o-2-(isoxa zol-3-yl)-3H -im id a zo[4,5-c]q u in o-
lin e (4m ): mp 210-212 °C (MeOH); 1H-NMR (DMSO-d6) 7.31
(1H, d, J ) 2 Hz), 7.57-7.90 (2H, m), 8.13-8.19 (1H, m), 9.24
(1H, d, J ) 2 Hz), 9.33 (1H, s). Anal. (C13H7N4OCl‚1/2CH3-
OH) C, H, N, Cl.
2-Ar yl-3H-im id a zo[4,5-c]qu in olin es 3-5. 2-(Isoxa zol-
3-yl)-3H-im id a zo[4,5-c]qu in olin e (4a ). Gen er a l P r oce-
d u r e. To a stirred solution of isoxazole-3-carboxylic acid (249
mg, 2.2 mmol) in a mixture of hexamethylphosphoramide
(HMPA) (4 mL) and acetonitrile (0.4 mL) was added, dropwise,
thionyl chloride (250 mg, 2.1 mmol) at -5-0 °C under
nitrogen. After stirring at the same temperature for 30 min,
3,4-diaminoquinoline 2a (318 mg, 2 mmol) was added and the
mixture was stirred at 0-5 °C for 4 h. The mixture was
diluted with ice-water and neutralized with saturated aque-
ous sodium bicarbonate. The resulting precipitate was filtered,
washed with water, and dried to give 4-amino-3-[(isoxazol-3-
ylcarbonyl)amino]quinoline as a crude product. This was
suspended in a mixture of HMPA (6 mL) and acetic acid (1.5
mL) and heated at 180 °C for 20 min under nitrogen. The
cooled mixture was diluted with water and neutralized with
saturated aqueous sodium bicarbonate. The resulting solid
was chromatographed on silica gel with chloroform/methanol
(10:1, v/v) as eluent followed by crystallization from ethyl
acetate to give 4a as white crystals (382 mg, 82%): mp 271-
1
274 °C dec (AcOEt); H-NMR (DMSO-d6) 7.28 (1H, d, J ) 2
Hz), 7.60-7.85 (2H, m), 8.10-8.27 (1H, m), 8.52-8.70 (1H,
m), 9.19 (1H, d, J ) 2 Hz), 9.29 (1H, s). Anal. (C13H8N4O‚1/
8H2O) C, H, N.
Compounds 3a -d , 4b-m , and 5a -m in Tables 1-3 were
prepared in the same way as 4a using the corresponding 3,4-
diaminoquinolines 2 and the appropriate carboxylic acids.
2-(4-Ch lor oph en yl)-3H-im idazo[4,5-c]qu in olin e (3a): mp
335-337 °C dec (EtOH); 1H-NMR (DMSO-d6) 7.6-7.9 (4H, m),
2-(Isoxa zol-5-yl)-3H-im id a zo[4,5-c]q u in olin e (5a ): mp
280-285 °C dec (AcOEt-MeOH); 1H-NMR (DMSO-d6) 7.26

Synthesis and SAR of Fused Imidazopyridines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2849
3-Nit r o-6,7,8,9-t et r a h yd r o-5H -cycloh ep t a [b]p yr id in e
(1H, d, J ) 2 Hz), 7.73 (2H, m), 8.15 (1H, m), 8.55 (1H, m),
8.81 (1H, d, J ) 2 Hz), 9.28 (1H, s). Anal. (C13H8N4O) C, H,
N.
2-(3-Met h ylisoxa zol-5-yl)-3H -im id a zo[4,5-c]q u in olin e
(5b): mp 303-305 °C (EtOH-AcOEt); 1H-NMR (DMSO-d6)
2.40 (3H, s), 7.10 (1H, s), 7.73 (2H, m), 8.16 (1H, m), 8.54 (1H,
m), 9.26 (1H, s). Anal. (C14H10N4O) C, H, N.
1
(8a ): X ) CH2CH2; mp 86-87 °C (CH2Cl2-i-PrOH); H-NMR
(DMSO-d6) 1.67-1.93 (6H, m), 2.91 (2H, m), 3.16 (2H, m), 8.17
(1H, d, J ) 3 Hz), 9.12 (1H, d, J ) 3 Hz). Anal. (C10H12N2O2)
C, H, N.
Data for compounds 8b (X ) CH2) and 8d (X ) bond) are
described in the literature.10
2-(3-Eth ylisoxazol-5-yl)-3H-im idazo[4,5-c]qu in olin e (5c):
mp 254-256 °C (AcOEt-MeOH); 1H-NMR (DMSO-d6) 1.32
(3H, t, J ) 7 Hz), 2.81 (2H, q, J ) 7 Hz), 7.19 (1H, s), 7.75
(2H, m), 8.18 (1H, m), 8.56 (1H, m), 9.29 (1H, s). Anal.
(C15H12N4O‚1/8H2O) C, H, N.
6-F lu or o-2-(3-m et h ylisoxa zol-5-yl)-3H-im id a zo[4,5-c]-
qu in olin e (5d ): mp 275-277 °C dec (AcOEt-EtOH); 1H-NMR
(DMSO-d6) 2.38 (3H, s), 7.14 (1H, s), 7.38-7.80 (3H, m), 8.23-
8.36 (1H, m), 9.28 (1H, s). Anal. (C14H9N4OF) C, H, N.
6-Ch lor o-2-(3-m eth ylisoxa zol-5-yl)-3H-im id a zo[4,5-c]-
qu in olin e (5e): mp 303-305 °C dec (AcOEt-CH2Cl2); 1H-
NMR (DMSO-d6) 2.40 (3H, s), 7.12 (1H, s), 7.59-7.95 (2H, m),
8.45-8.55 (1H, m), 9.36 (1H, s). Anal. (C14H9N4ClO) C, H,
N.
7-F lu or o-2-(3-m et h ylisoxa zol-5-yl)-3H-im id a zo[4,5-c]-
qu in olin e (5f): mp 308-310 °C dec (AcOEt-MeOH); 1H-NMR
(DMSO-d6) 2.40 (3H, s), 7.11 (1H, s), 7.52-7.92 (2H, m), 8.44-
8.63 (1H, m), 9.27 (1H, s). Anal. (C14H9N4OF) C, H, N.
7-Ch lor o-2-(3-m eth ylisoxa zol-5-yl)-3H-im id a zo[4,5-c]-
qu in olin e (5g): mp 319-321 °C dec (AcOEt-MeOH); 1H-
NMR (DMSO-d6) 2.38 (3H, s), 7.12 (1H, s), 7.70 (1H, dd, J )
8, 2 Hz), 8.15 (1H, d, J ) 2 Hz), 8.52 (1H, d, J ) 8 Hz), 9.27
(1H, s). Anal. (C14H9N4OCl‚CH3OH) C, H, N, Cl.
7-Meth oxy-2-(3-m eth ylisoxa zol-5-yl)-3H-im id a zo[4,5-c]-
qu in olin e (5h ): mp 280-282 °C dec (AcOEt-MeOH); 1H-
NMR (DMSO-d6) 2.38 (3H, s), 3.95 (3H, s), 7.08 (1H, s), 7.35
(1H, dd, J ) 8, 2 Hz), 7.55 (1H, d, J ) 2 Hz), 8.43 (1H, d, J )
8 Hz), 9.18 (1H, s). Anal. (C14H12N4O2‚1/8CH3COOC2H5) C,
H, N.
8-F lu or o-2-(3-m et h ylisoxa zol-5-yl)-3H-im id a zo[4,5-c]-
qu in olin e (5i): mp 293-295 °C (AcOEt); 1H-NMR (DMSO-
d6) 2.38 (3H, s), 7.11 (1H, s), 7.44-7.68 (12H, m), 8.10-8.27
(2H, m), 9.22 (1H, s). Anal. (C14H9N4OF‚1/4H2O) C, H, N.
8-Ch lor o-2-(3-m eth ylisoxa zol-5-yl)-3H-im id a zo[4,5-c]-
qu in olin e (5j): mp 310-311 °C dec (AcOEt-MeOH); 1H-NMR
(DMSO-d6) 2.41 (3H, s), 7.12 (1H, s), 7.69 (1H, dd, J ) 9, 2
Hz), 8.15 (1H, d, J ) 9 Hz), 8.52 (1H, d, J ) 2 Hz), 9.26 (1H,
s). Anal. (C14H9N4OCl‚5/6H2O) C, H, N.
8-Meth oxy-2-(3-m eth ylisoxa zol-5-yl)-3H-im id a zo[4,5-c]-
qu in olin e (5k ): mp 283-284 °C (AcOEt-MeOH); 1H-NMR
(DMSO-d6) 2.38 (3H, s), 3.93 (3H, s), 7.11 (1H, s), 7.33 (1H,
dd, J ) 9, 2 Hz), 7.89 (1H, d, J ) 2 Hz), 8.04 (1H, d, J ) 9 Hz),
9.09 (1H, s). Anal. (C15H12N4O2‚1/8H2O) C, H, N.
F u sed 3-Am in op yr id in es 9. 3-Am in o-5,6,7,8-tetr a h y-
d r oqu in olin e (9b). Gen er a l P r oced u r e. A suspension of
3-nitro-5,6,7,8-tetrahydroquinoline (8b ) (15.8 g, 88.7 mmol)
and 5% palladium on carbon (1.6 g) in methanol (300 mL) was
hydrogenated at room temperature under atmospheric pres-
sure. The catalyst was filtered off, and the filtrate was
concentrated to afford a crude product which was recrystallized
from methylene chloride/isopropyl ether giving 9b (12.76 g,
97%): mp 97-98 °C; 1H-NMR (CDCl3) 1.80 (4H, m), 2.68 (2H,
t, J ) 6 Hz), 2.80 (2H, t, J ) 6 Hz), 3.30 (2H, br s), 6.70 (1H,
m), 7.88 (1H, d, J ) 3 Hz). Anal. (C9H12N2) C, H, N.
3-Am in o-6,7,8,9-t e t r a h yd r o-5H -cycloh e p t a [b]p yr i-
1
d in e (9a ): mp 79-80 °C (CH2Cl2-i-Pr2O); H-NMR (CDCl3)
1.61-1.83 (6H, m), 2.87 (2H, m), 2.93 (2H, m), 3.34 (2H, br s),
6.76 (1H, d, J ) 3 Hz), 7.79 (1H, d, J ) 3 Hz). Anal.
(C10H14N2) C, H, N.
3-Am in o-7,8-dih ydr o-5H-pyr an o[4,3-b]pyr idin e (9c): mp
1
138-139 °C (CH2Cl2-i-Pr2O); H-NMR (DMSO-d6) 2.67 (2H,
t, J ) 6 Hz), 3.89 (2H, t, J ) 6 Hz), 4.55 (2H, s), 5.10 (2H, br
s), 6.56 (1H, d, J )3 Hz), 7.76 (1H, d, J ) 3 Hz). Anal.
(C8H10N2O) C, H, N.
3-Am in o-6,7-d ih yd r o-5H-cyclop en ta [b]p yr id in e (9d ):
mp 114-115 °C (CH2Cl2-i-Pr2O); 1H-NMR (CDCl3) 2.08 (2H,
m), 2.84 (2H, t, J ) 8 Hz), 2.88 (2H, t, J ) 8 Hz), 3.30 (2H, br
s), 6.86 (1H, m), 7.85 (1H, m). Anal. (C8H10N2) C, H, N.
F u sed 3-[(Tr ich lor oa cet yl)a m in o]p yr id in es (10). 3-
[(Tr ich lor oa cet yl)a m in o]-5,6,7,8-t et r a h yd r oq u in olin e
(10b). Gen er a l P r oced u r e. To a stirred solution of 9b
(12.68 g, 85.6 mmol) and triethylamine (2.4 mL) in methylene
chloride (130 mL) was added, dropwise, a solution of trichlo-
roacetyl chloride (10.5 mL, 94.2 mmol) in methylene chloride
(30 mL) with ice cooling over a period of 7 min. The reaction
mixture was stirred at room temperature for 20 min, mixed
with saturated saline, and made weakly alkaline with aqueous
ammonia. The organic layer was separated, and the aqueous
layer was extracted with methylene chloride. The combined
organic extracts were washed (brine), dried (MgSO4), and
concentrated in vacuo. The residue was chromatographed on
silica gel with methanol/methylene chloride (1:9) as eluent.
The product was recrystallized from ethyl acetate to give 10b
(24.21 g, 95%): mp 157-159 °C; IR (Nujol) 1724 cm-1 1H-
;
NMR (CDCl3) 1.79-1.95 (4H, m), 2.84 (2H, t, J ) 6 Hz), 2.92
(2H, t, J ) 6 Hz), 7.86 (1H, m), 8.40 (1H, d, J ) 2 Hz). Anal.
(C11H11N2Cl3O) C, H, N, Cl.
9-F lu or o-2-(3-m et h ylisoxa zol-5-yl)-3H-im id a zo[4,5-c]-
qu in olin e (5l): mp 292-294 °C (AcOEt-MeOH); 1H-NMR
(DMSO-d6) 2.40 (3H, s), 7.31 (1H, s), 7.45-7.86 (2H, m), 7.97-
8.07 (1H, m), 9.35 (1H, s). Anal. (C14H9N4OF) C, H, N.
9-Ch lor o-2-(3-m eth ylisoxa zol-5-yl)-3H-im id a zo[4,5-c]-
3-[(Tr ich lor oa cet yl)a m in o]-6,7,8,9-t et r a h yd r o-5H -cy-
cloh ep ta [b]p yr id in e (10a ): mp 171-173 °C (MeOH-CHCl3-
AcOEt); IR (Nujol) 1712 cm-1; 1H-NMR (DMSO-d6) 1.58-1.83
(6H, m), 2.77 (2H, m), 2.96 (2H, m), 7.78 (1H, d, J ) 2 Hz),
8.47 (1H, d, J ) 2 Hz), 10.93 (1H, s). Anal. (C12H13N2Cl3O)
C, H, N, Cl.
3-[(Tr ich lor oa cetyl)a m in o]-7,8-d ih yd r o-5H-p yr a n o[4,3-
b]p yr id in e (10c): mp 137-138 °C (CH2Cl2-i-Pr2O); 1H-NMR
(CDCl3) 3.02 (2H, t, J ) 6 Hz), 4.08 (2H, t, J ) 6 Hz), 4.80
(2H, s), 7.89 (1H, d, J ) 3 Hz), 8.44 (1H, br s), 8.45 (1H, d, J
) 3 Hz). Anal. (C10H9N2Cl3O2) C, H, N.
1
qu in olin e (5m ): mp 243-245 °C (MeOH); H-NMR (DMSO-
d6) 2.40 (3H, s), 7.28 (1H, s), 7.73-7.90 (2H, m), 8.14-8.20
(1H, m), 9.35 (1H, s). Anal. (C14H9N4ClO) C, H, N, Cl.
F u sed 3-Nitr op yr id in es (8). Following the method re-
ported by Y. Tohda et al.,10 compounds 8 were prepared by
ring transformation of 1-methyl-3,5-dinitro-2-pyridone with
cyclic ketones in the presence of ammonia.
3-[(T r ic h lo r o a c e t y l)a m in o ]-6,7-d ih y d r o -5H -c y c lo -
p en ta [b]p yr id in e (10d ): mp 166-167 °C (CH2Cl2-i-Pr2O);
3-Nitr o-7,8-dih ydr o-5H-pyr an o[4,3-b]pyr idin e (8c). Gen -
er a l P r oced u r e. A suspension of 1-methyl-3,5-dinitro-2-
pyridone (3.98 g, 20 mmol) and tetrahydro-4H-pyran-4-one
(2.40 g, 24 mmol) in methanolic ammonia (1.1 M, 200 mL) was
heated at 55 °C for 5 h. The reaction mixture was concen-
trated in vacuo, and the residue was taken up in benzene. The
insoluble materials were removed by filtration, and the filtrate
was concentrated. The residue was subjected to chromatog-
raphy on silica gel with chloroform/toluene (1:1) as eluent. The
resulting product was recrystallized from methanol to yield
8c as crystals (2.22 g, 62%): mp 131-132°C; 1H-NMR (DMSO-
d6) 3.02 (2H, t, J ) 6 Hz), 4.02 (2H, t, J ) 6 Hz), 4.83 (2H, s),
8.39 (1H, d, J ) 2 Hz), 9.19 (1H, d, J ) 2 Hz). Anal.
(C8H8N2O3) C, H, N.
1
IR (Nujol) 1707 cm-1; H-NMR (DMSO-d6) 2.08 (2H, m), 2.88
(2H, t, J ) 8 Hz), 2.92 (2H, t, J ) 8 Hz), 7.85 (1H, m), 8.48
(1H, m), 10.94 (1H, s). Anal. (C10H9N2Cl3O) C, H, N, Cl.
F u sed 3-[(Tr ich lor oa cetyl)a m in o]p yr id in e 1-Oxid es
11. 3-[(Tr ich lor oa cetyl)a m in o]-5,6,7,8-tetr a h yd r oqu in o-
lin e 1-Oxid e (11b). Gen er a l P r oced u r e. To a solution of
10b (24.03 g, 81.9 mmol) in methylene chloride (40 mL) was
added 3-(chloroperoxy)benzoic acid (80% purity; 21.2 g, 98.3
mmol) at room temperature, and the mixture was stirred for
45 min. The mixture was mixed with isopropyl ether, and the
resulting crystals were filtered to give 11b (25.06 g, 99%): mp
244-246 °C dec; IR (Nujol) 1721 cm-1 1H-NMR (DMSO-d6)
;

2850 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Takada et al.
1.62-1.86 (4H, m), 2.69 (2H, d, J ) 6 Hz), 2.75 (2H, t, J ) 6
Hz), 7.43 (1H, d, J ) 2 Hz), 8.51 (1H, d, J ) 2 Hz), 11.06 (1H,
s). Anal. (C11H11N2Cl3O2) C, H, N, Cl.
F u sed 2-(Isoxa zol-3-yl)-3H-im d a zo[4,5-c]p yr id in es 14.
2-(Isoxa zol-3-yl)-3,6,7,9-tetr a h yd r oim id a zo[4,5-d ]p yr a n o-
[4,3-b]pyr idin e Mon oph osph ate Mon oh ydr ate (14c). Gen -
er a l P r oced u r e. To a stirred solution of 3,4-diamino-7,8-
dihydro-5H-pyrano[4,3-b]pyridine monohydrate (13c) (5.88 g,
32 mmol) in N,N-dimethylformamide (50 mL) was added a
solution of isoxazole-3-carbonyl chloride (4.43 g, 33.6 mmol)
in methylene chloride (4.7 mL) at ice-bath temperature. The
mixture was stirred at room temperature for 45 min, mixed
with triethylamine (4.7 mL), and stirred for 1 h. The resulting
crystals were collected by filtration, mixed with sodium acetate
(500 mg) and ethylene glycol (79 mL), and heated at 150 °C
for 5 h. The solvent was evaporated in vacuo, and the residue
was chromatographed on silica gel with methanol/chloroform
(1:9) as eluent. The product was treated with phosphoric acid
in aqueous 2-propanol to give 14c (8.60 g, 75%): mp 239-241
3-[(Tr ich lor oa cet yl)a m in o]-6,7,8,9-t et r a h yd r o-5H -cy-
cloh ep ta [b]p yr id in e 1-oxid e (11a ): mp 241-242 °C dec
1
(MeOH-AcOEt); IR (Nujol) 1723 cm-1; H-NMR (DMSO-d6)
1.53-1.81 (6H, m), 2.81 (2H, m), 3.23 (2H, m), 7.44 (1H, d, J
) 2 Hz), 8.51 (1H, d, J ) 2 Hz), 11.06 (1H, s). Anal. (C12H13N2-
Cl3O2) C, H, N, Cl.
3-[(Tr ich lor oa cetyl)a m in o]-7,8-d ih yd r o-5H-p yr a n o[4,3-
b]p yr id in e 1-oxid e (11c): mp 237-250 °C (MeOH-acetone);
1
IR (Nujol) 1728 cm-1; H-NMR (DMSO-d6) 2.76 (2H, t, J ) 6
Hz), 3.96 (2H, t, J ) 6 Hz), 4.68 (2H, s), 7.45 (1H, d, J ) 2
Hz), 8.56 (1H, d, J ) 2 Hz), 11,14 (1H, s). Anal. (C10H9N2-
Cl3O3) C, H, N, Cl.
3-[(T r ic h lo r o a c e t y l)a m in o ]-6,7-d ih y d r o -5H -c y c lo -
pen ta[b]pyr idin e 1-oxide (11d): mp 228-233 °C dec (MeOH-
i-PrOH); IR (Nujol) 1716 cm-1; 1H-NMR (DMSO-d6) 2.08 (2H,
m), 2.93 (2H, t, J ) 8 Hz), 2.99 (2H, t, J ) 8 Hz), 7.54 (1H, d,
1
°C dec (aqueous i-PrOH); H-NMR (DMSO-d6) 2.98 (2H, t, J
) 6 Hz), 4.05 (2H, t, J ) 6 Hz), 5.01 (2H, s), 7.24 (1H, d, J )
2
Hz), 8.84 (1H, s), 9.21 (1H, d, J ) 2 Hz). Anal.
(C12H10N4O2‚H3PO4‚H2O) C, H, N, P.
J
) 1 Hz), 8.43 (1H, d, J ) 1 Hz), 11.10 (1H, s). Anal.
(C10H9N2Cl3O2) C, H, N, Cl.
2-(Isoxa zol-3-yl)-3,6,7,8,9,10-h exa h yd r ocycloh ep t[b]im -
id a zo[4,5-d ]p yr id in e h yd r och lor id e (14a ): mp 191-193 °C
(MeOH-i-PrOH); 1H-NMR (D2O) 1.78-2.02 (6H, m), 3.24 (4H,
m), 7.15 (1H, m), 8.86 (1H, s), 8.96 (1H, m). Anal. (C14H14N4O‚
HCl) C, H, N, Cl.
F u sed 3-Am in o-4-n itr op yr id in e 1-Oxid es 12. 3-Am in o-
4-n itr o-5,6,7,8-tetr a h yd r oqu in olin e 1-Oxid e (12b). Gen -
er a l P r oced u r e. A suspension of 11b (1.00 g, 3.2 mmol) in
fuming nitric acid (d ) 1.52; 5 mL) was stirred at 55 °C for 5
h. The nitric acid was evaporated in vacuo, and the residue
was neutralized with aqueous ammonia and heated at 60 °C
for 2 h. The reaction mixture containing the resulting solid
was mixed with isopropyl ether/2-propanol (1:1, 10 mL), and
the precipitate was filtered. The filtrate was concentrated in
vacuo and extracted with methanol/chloroform (1:10). The
extract was concentrated and combined with the precipitate
obtained above and then chromatographed on silica gel with
methanol/chloroform (1:50) as eluent. The product was re-
crystallized from methylene chloride/2-propanol to give 12b
(525 mg, 78%): mp 199-201 °C dec; 1H-NMR (DMSO-d6):
1.55-1.97 (4H, m), 2.61 (2H, t, J ) 6 Hz), 2.74 (2H, t, J ) 6
Hz), 6.53 (2H, s), 7.96 (1H, s). Anal. (C9H11N3O3) C, H, N.
3-Am in o-4-n itr o-6,7,8,9-tetr a h yd r o-5H-cycloh ep ta [b]-
p yr id in e 1-oxid e (12a ): mp 188-194 °C dec (MeOH-i-
PrOH); 1H-NMR (DMSO-d6) 1.46-1.76 (6H, m), 2.66 (2H, m),
3.16 (2H, m), 6.22 (2H, s), 7.84 (1H, s). Anal. (C10H13N3O3)
C, H, N.
3-Am in o-4-n it r o-7,8-d ih yd r o-5H -p yr a n o[4,3-b]p yr i-
d in e 1-oxid e (12c): mp 200-201 °C (THF-i-PrOH); 1H-NMR
(DMSO-d6) 2.66 (2H, t, J ) 6 Hz), 3.88 (2H, t, J ) 6 Hz), 4.85
(2H, s), 7.23 (2H, s), 8.07 (1H, s). Anal. (C8H9N3O4) C, H, N.
3-Am in o-4-n it r o-6,7-d ih yd r o-5H -cyclop e n t a [b]p yr i-
d in e 1-oxid e (12d ): mp 225-226 °C dec (MeOH-i-PrOH); 1H-
NMR (DMSO-d6) 2.04 (2H, m), 2.84 (2H, t, J ) 7 Hz), 3.33
(2H, t, J ) 7 Hz), 7.23 (2H, s), 7.90 (1H, s). Anal. (C8H9N3O3)
C, H, N.
2-(Isoxa zol-3-yl)-6,7,8,9-tetr a h yd r o-3H-im id a zo[4,5-c]-
qu in olin e h ydr och lor ide (14b): mp 263-267 °C dec (MeOH-
1
i-PrOH); H-NMR (DMSO-d6) 1.87-1.93 (4H, m), 3.08-3.14
(4H, m), 7.44 (1H, d, J ) 2 Hz), 9.32 (1H, s), 9.34 (1H, d, J )
2 Hz). Anal. (C13H12N4O‚HCl‚1/2H2O) C, H, N, Cl.
2-(Isoxazol-3-yl)-3,6,7,8-tetr ah ydr ocyclopen t[b]im idazo-
[4,5-c]p yr id in e h yd r och lor id e (14d ): mp 252-256 °C dec
(MeOH-i-PrOH); 1H-NMR (D2O) 2.46 (2H, m), 3.27 (2H, t),
3.31 (2H, t), 7.09 (1H, m), 8.94 (1H, m), 8.95 (1H, s). Anal.
(C12H10N4O‚HCl) C, H, N, Cl.
F u sed 2-(3-Meth ylisoxa zol-5-yl)-3H-im id a zo[4,5-c]p y-
r id in es 15. These compounds were prepared from 3-meth-
ylisoxazole-5-carbonyl chloride and the appropriate fused
diaminopyridine in a method analogous to that used for the
preparation of 14c.
2-(3-Meth ylisoxa zol-5-yl)-3,6,7,8,9,10-h exa h yd r ocyclo-
h ep t[b]im id a zo[4,5-d ]p yr id in e (15a ): mp 243-260 °C dec
(MeOH-i-PrOH); 1H-NMR (D2O) 1.77-2.03 (6H, m), 2.43 (3H,
s), 3.23 (4H, m), 7.14 (1H, s), 8.84 (1H, s). Anal. (C15H16N4O‚
HCl) C, H, N, Cl.
2-(3-Meth ylisoxazol-5-yl)-6,7,8,9-tetr ah ydr o-3H-im idazo-
[4,5-c]qu in olin e h yd r och lor id e (15b): mp 272-280 °C dec
(MeOH-i-PrOH); 1H-NMR (DMSO-d6) 1.91 (4H, br s), 2.41
(3H, s), 3.11 (4H, br s), 7.57 (1H, s), 9.29 (1H, s). Anal.
(C14H14N4O‚HCl) C, H, N, Cl.
2-(3-Met h ylisoxa zol-5-yl)-3,6,7,9-t et r a h yd r oim id a zo-
[4,5-d ]p yr a n o[4,3-b]p yr id in e h yd r och lor id e (15c): mp
266-272 °C dec (MeOH); 1H-NMR (D2O) 2.42 (3H, s), 3.24 (2H,
t, J ) 5 Hz), 4.24 (2H, t, J ) 5 Hz), 5.10 (2H, s), 7.11 (1H, s),
9.05 (1H, s). Anal. (C13H12N4O2‚HCl) C, H, N, Cl.
F u sed 3,4-Dia m in op yr id in es 13. 3,4-Dia m in o-5,6,7,8-
tetr a h yd r oqu in olin e (13b). Gen er a l P r oced u r e. A mix-
ture of 12b (5.00 g, 23.9 mmol) and Raney nickel (12.9 g) in
methanol was hydrogenated at room temperature under
atmospheric pressure. The catalyst was filtered off, and the
filtrate was concentrated in vacuo. The residue was chro-
matographed on alumina with methanol/chloroform (1:20) as
eluent. The product was recrystallized from methylene chloride/
ethyl acetate to give 13b (3.37g, 86%): mp 169-170 °C dec;
1H-NMR (DMSO-d6) 1.68 (4H, m), 2.38 (2H, t, J ) 6 Hz), 2.54
(2H, t, J ) 6 Hz), 4.26 (2H, s), 4.97 (2H, s), 7.47 (1H, s). Anal.
(C9H13N2) C, H, N.
2-(3-Meth ylisoxa zol-5-yl)-3,6,7,8-cyclop en t[b]im id a zo-
[4,5-c]p yr id in e h yd r och lor id e (15d ): mp 290-293 °C dec
1
(MeOH-i-PrOH); H-NMR (D2O) 2.42 (3H, s), 2.45 (2H, m),
3.25 and 3.33 (2H each, m), 7.05 (1H, s), 8.91 (1H, m). Anal.
(C13H12N4O‚HCl) C, H, N, Cl.
Molecu la r Mod elin g. These studies were carried out
using the Sybyl Molecular Modeling Software Package (version
6.10).18 Each structure was energy minimized within MOPAC
version 6.0 (PM3).19 In Figures 1 and 2, four atom pairs were
used to produce the least-squares superposition: (1) the N1
nitrogen atoms, (2) the carbonyl oxygen or N3 nitrogen atoms,
(3) the N5 nitrogen atoms, and (4) the centroids of the benzene
rings of the quinoline moieties.
3,4-Dia m in o-6,7,8,9-tetr a h yd r o-5H-cycloh ep ta [b]p yr i-
d in e (13a ): mp 167-168 °C (CHCl3-i-Pr2O); 1H-NMR (DMSO-
d6) 1.48-1.74 (6H, m), 2.58 (2H, m), 2.70 (2H, m), 4,26 (2H,
s), 5,02 (2H, s), 7.36 (1H, s). Anal. (C10H15N3) C, H, N.
3,4-Diam in o-7,8-dih ydr o-5H-pyr an o[4,3-b]pyr idin e (13c):
1
mp 196-200 °C dec (aqueous MeOH); H-NMR (CDCl3) 2.88
(2H, t), 3.05 (2H, br s), 3.84 (2H, s), 4.00 (2H, t), 4.63 (2H, s),
7.87 (1H, s). Anal. (C8H11N3O‚H2O) C, H, N.
Refer en ces
(1) Haefely, W.; Kyburz, E.; Gerecke, M.; Mohler, H. Recent
Advances in the Molecular Pharmacology of Benzodiazepine
Receptors and in the Structure-activity Relationships of Their
Agonists and Antagonists. In Advances in Drug Research; Testa,
B., Ed.; Academic Press: New York, 1985; Vol. 14, pp 165-322.
3,4-Dia m in o-6,7-d ih yd r o-5H -cyclop e n t a [b]p yr id in e
(13d ): mp 190-193 °C (AcOEt); 1H-NMR (DMSO-d6) 1.94 (2H,
m), 2.61 (2H, t, J ) 7 Hz), 2.63 (2H, t, J ) 7 Hz), 4.26 (2H, s),
5.08 (2H, s), 7.43 (1H, s). Anal. (C8H11N3) C, H, N.

Synthesis and SAR of Fused Imidazopyridines
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(15) Because the N3H imidazoquinolines are more stable than the
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imidazoquinolines as shown in the following figure (see below).
As the reviewer suggested, this alignment is consistent with
Fryer’s observation that substituents on ring A of pyrazolo-
quinolines can mimic the pharmacological effects of substituents
on ring D. Fryer had proposed that pyrazoloquinolines possess-
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BZR so that substituents on ring A occupy volumes comparable
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is needed to exhibit effects toward agonist in the inverted model.
Although some of our data (e.g., effects of the 7-halo substituents
of 4f,g) may be attributed to this model, the entire structure-
activity relationships can be well accounted for by the alignment
using the N5H imidazoquinolines shown in Figures 1 and 2.
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(18) Sybyl version 6.10; Tripos Inc., St. Louis, MO 63144.
(19) QCPE Program #455 (Quantum Chemistry Program Exchange,
Department of Chemistry, Indiana University, Bloomington, IN
47405); J . J . P. Stewart, Frank J . Seiler Research Laboratory,
U.S. Air Force Academy, CO 80840.
J M9600609