Synthesis and biological evaluation of 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimdin-5(6H)-ones as functionally selective ligands of the benzodiazepine receptor site on the GABAA receptor

Article abstract of DOI:10.1021/jm0202019

Benzodiazepines are allosteric modulators of the GABA_A receptor. The traditionally prescribed benzodiazepines are nonselective and suffer from numerous side effects. Upon the identification of receptor subtypes, we set out to discover selective agents with the anticipation that these agents would have superior therapeutic potential. Herein, we describe the synthesis and biological evaluation of substituted 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-ones and disclose that these compounds exhibit functional selectivity at the benzodiazepine receptor of GABA_A receptor subtypes. The α₂/α₃-selective partial agonist 42 exhibited potent in vivo activity.

Full text of DOI:10.1021/jm0202019

J . Med. Chem. 2002, 45, 5043-5051
5043
Syn th esis a n d Biologica l Eva lu a tion of
7,8,9,10-Tetr a h yd r oim id a zo[1,2-c]p yr id o[3,4-e]p yr im d in -5(6H)-on es a s
F u n ction a lly Selective Liga n d s of th e Ben zod ia zep in e Recep tor Site on th e
GABAA Recep tor
Pamela A. Albaugh,*,† Lu Marshall,‡ J ames Gregory,§ Geoff White,§ Alan Hutchison,† Phil C. Ross,#
Dorothy W. Gallagher,‡ J ohn F. Tallman,# Matt Crago,| and J ames V. Cassella|
Neurogen Corporation, 35 Northeast Industrial Road, Branford, Connecticut 06405
Received May 13, 2002
Benzodiazepines are allosteric modulators of the GABAA receptor. The traditionally prescribed
benzodiazepines are nonselective and suffer from numerous side effects. Upon the identification
of receptor subtypes, we set out to discover selective agents with the anticipation that these
agents would have superior therapeutic potential. Herein, we describe the synthesis and
biological evaluation of substituted 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimidin-
5(6H)-ones and disclose that these compounds exhibit functional selectivity at the benzodi-
azepine receptor of GABAA receptor subtypes. The R2/R3-selective partial agonist 42 exhibited
potent in vivo activity.
In tr od u ction
GABA is the major inhibitory neurotransmitter in the
central nervous system (CNS). There are three phar-
macological classes of GABA receptors: GABAA, GABAB,
and GABAC. GABAA and the less well-known GABAC
are ligand-gated ion channels, whereas GABAB is a
G-protein-coupled receptor. For GABAA, postsynaptic
F igu r e 1. Known benzodiazepine receptor ligands 1 and 2
that are reported to exhibit behavioral selectivity. Benzodi-
azepine receptor ligand 3 is presented here.
responses to GABA are mediated by altered chloride
conductance, which typically hyperpolarizes the mem-
brane. Benzodiazepines have long been known to bind
in an allosteric manner to the GABAA receptor, and this
site has been termed the benzodiazepine receptor (BZR).
Binding by ligands at this site modulates the effects of
GABA. There is a continuous range of effects, from
positive allosteric modulators (agonists) that enhance
the GABAergic inhibition to negative allosteric modula-
tors (inverse agonists) that reduce the GABAergic
inhibition and lead to excitation of the neuron. Antago-
nists bind to this site and block the action of both
agonists and inverse agonists. Full agonists that act at
the benzodiazepine site are known to exhibit anxiolytic,
sedative, anticonvulsive, and hypnotic effects, while
compounds that act as inverse agonists elicit anxiogenic,
cognition enhancing, and proconvulsant effects. Al-
though benzodiazepines have a long history of pharma-
ceutical use as anxiolytics and hypnotics, they often
exhibit a number of unwanted side effects. These may
include cognitive impairment, sedation, ataxia, and
potentiation of ethanol. Tolerance and withdrawal are
problems with repeated use. No inverse agonists are
marketed.
At the time our research began, it was thought that
partial agonist activity at the GABA receptor would
reduce the side effects of the benzodiazepines. In addi-
tion, studies1 with CL218,872, a triazolopyridazine,
identified two distinct receptor binding sites that were
called BZ-1 and BZ-2. Multiple subunits that comprise
the GABAA receptor were being cloned, and the pos-
sibility of multiple receptor subtypes was just emerging
as we began our studies. It then became apparent that
improvement over existing benzodiazepine agonists
could arise from selective and/or partial agonisim at the
benzodiazepine receptor binding site. Indeed, as the
identity and location of the subtypes became known,
interest in designing selective benzodiazepine receptor
agonists grew. Now, the Bz-1 type is known to be the
R1 subtype, whereas the Bz-2 type comprises R2, R3, and
R5 subtypes. During the time of our work, two agents
with higher affinity for the Bz-1 receptor have come to
the market as hypnotics [Ambien (zolpidem) and Sonata
(zaleplon)]. Although these newer hypnotic agents have
some advantages over the older class of benzodiaze-
pines, improvement on the side effect profile of these
agents has been in debate. This could be due to targeting
of the wrong receptor subtype and/or lack of functional
selectivity (see Discussion below).
* To whom correspondence should be addressed. Current address:
Eli Lilly & Co., Drop Code 0548, Lilly Corporate Center, Indianapolis,
IN 46285. Phone: (317) 433-1610. Fax: (317) 277-3652. E-mail:
albaugh_pamela@lilly.com.
† Department of Chemistry.
Analogues derived from aryl-fused pyrazolo[4,3-c]-
quinolin-3-ones (1, Figure 1) have been claimed2 to
exhibit behavioral selectivity. Various fused pyrazolo-
[4,3-c]quinolin-3-ones3,4 have been disclosed, as have
‡ Department of Pharmacology.
§ Department of Electrophysiology.
#
Department of Molecular Biology.
| Department of Behavioral Biology.
10.1021/jm0202019 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/15/2002

5044 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23
Ta ble 1. Effect of Aryl Modification on Binding Affinity
Albaugh et al.
R1
R2
R3
R5
a
compd
aryl
Ki (nM)
maxb (%) EC50 (nM) max (%) EC50 (nM) max (%) EC50 (nM) max (%) EC50 (nM)
9
H
8.7 ( 0.1
1.3 ( 0.4
11.3 ( 2.8
21 ( 11
67
56
92
17
18
120
136
179
76
81
184
20
154
245
10
11
12
13
14
15
16
17
18
19
20
21
22
23
2-F
3-F
4-F
3-Cl
4-Cl
2-OMe
3-OMe
4-OMe
4-Me
2,4-diF
2,5-diF
3,4-diF
120
20
31
74
186
155
71 ( 22
121 ( 27
797 ( 242
2.3 ( 0.3
2.6 ( 0.5
43 ( 8
2.0 ( 0.6
11.4 ( 0.6
72 ( 16
123
122
62
63
59
81
28
266
92
115
142
94
184
82
268
143
1179
210
174
95
3826
500
17
30
650
323
36
188
2-F-4-OMe 0.6 ( 0.1
2-thienyl
3.0 ( 0.2
48
128
3.3
108
322
236
327
208
198
295
37
194
291
879
737
zolpidem
zaleplon
alprazolam
700
>280
774
>3000
>1000
69
<20
>77
206
>3000
>1000
10
∼352
∼1626
333
12
a
b
Determined by radioligand binding assay as described.8,9 Values represent the average ((SD). Measured as described by White et
al.12,13
Sch em e 1a
displace 3H-Ro 15-1788 in rat cortical tissue as described
by Thomas and Tallman.8,9 The results are shown in
Tables 1-5.
Currently there are at least 6R, 3â, 3γ, 1δ, and 2F
subunits identified. Since the GABAA receptor is a
pentameric complex, numerous combinations are pos-
sible. However, it is generally accepted that the pre-
dominant native receptors comprise 2R, 2â, and 1γ
subunits. Various evidence10,11 suggests that the major
naturally occurring combinations are R1â2γ2, R2â3γ2,
R3â3γ2, and R5â3γ2. Selected compounds were screened
for functional efficacy and selectivity using electrophysi-
ological recordings carried out on Xenopus oocytes
expressing the appropriate constructs, as described by
White et al.12,13 After addition of GABA to the oocyte
(benzodiazepine receptor ligands are active only in the
presence of GABA), the test compound was added. Any
potentiation of the current is recorded over a dose range
of the test compound. The fitted curve yields the
maximum percent potentiation along with the EC50. The
results are shown in Tables 1-5.
For the initial studies, the N-benzyl moiety was used
as the common structural feature in order to investigate
the impact of the aryl group (see Table 1). The unsub-
stituted phenyl (9) has a Ki of 8.7 nM, but affinity is
enhanced 7-fold by an ortho fluoro substituent (10).
Affinity drops for the meta fluoro group (11) and even
more so for the para fluoro (12). However, the presence
of a 4-fluoro is well tolerated in the 2,4-difluoro analogue
(19). The affinity of the 3,4-difluoro analogue 20 is even
worse than either the 3- or 4-fluoro substituent alone,
whereas the affinity of the 2,5-difluoro analogue 21 is
the same as the 3-fluoro analogue. Both the 3-chloro (13)
and 4-chloro (14) analogues have 6-fold lower affinity
than the analogous fluoro analogues. In contrast to
fluorine, an ortho methoxy group (15) significantly
reduces affinity, but affinity improves in the meta (16)
a
Reagents: (a) (PhCO)2O, pyridine; (b) urea, 2-(2-ethoxyeth-
oxy)ethanol; (c) ArCOCH2Br, DMF; (d) aqueous NaOH, EtOH; (e)
RX or RCOX, Et3N, DMF; (f) RCHO, NaCNBH3, HCl/MeOG; (g)
(i) RCOX, Et3N, DMF, (ii) BH3, CH2Cl2.
various fused [1,2,3]triazolo[1,5-c]pyrimidin-5(6H)-ones5,6
(2, Figure 1), all of which reportedly gave a range of
behavioral activities. Herein, we disclose our efforts
around a related template, 7,8,9,10-tetrahydroimidazo-
[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-ones (3, Figure 1).
We disclose here functional selectivity of these com-
pounds based on electrophysiology studies.
Ch em istr y
The known enaminonitrile 47 was protected as the
benzoyl amide 5 and then condensed with urea to give
aminopyrimidone 6. Various bromoacetophenones were
reacted with 6 to give in one step imidazopyrimidinones
7. Deprotection of 7 followed by alkylation, acylation,
or reductive amination afforded the desired final prod-
ucts 3 (Scheme 1).
Resu lts
Affinity of test compounds for the benzodiazepine
receptor was determined in vitro by their ability to

Pyrimidin-5(6H)-ones
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23 5045
Ta ble 2. Effect of Various N-Substitution on Binding Affinity
R1
R2
R3
R5
comd
N-R
Ki (nM)
max (%) EC50 (nM) max (%) EC50 (nM) max (%) EC50 (nM) max (%) EC50 (nM)
24
25
26
27
28
29
30
31
32
33
34
H
Me
Et
allyl
i-Pr
n-Bu
c-PrCH2
c-Hex-CH2
PhCH2CH2
PhCH2CH2CH2
pyrimidy-2-yl
NA
202 ( 90
0
0
5
0
0
18
56 ( 7
14
20
935
344
0
0
26 ( 0.5
51 ( 6
170
284
7.3 ( 3.6
30 ( 2
70
31
114
258
135
127
86
36
71
247
1162
202
72
28
115
394
424
213
4
7
101
291
94
231
0.9 ( 0.3
83 ( 20
147 ( 40
133 ( 78
0
44
84
35
117
0
Ta ble 3. Effect of N-Arylmethyl Substituents on Binding Affinity
R1
R2
R3
R5
compd
N-R
Ki (nM)
max (%) EC50 (nM) max (%) EC50 (nM) max (%) EC50 (nM) max (%) EC50 (nM)
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
2-F-Bz
3-F-Bz
4-F-Bz
0.2 ( 0.1
0.5 ( 0.1
1.7 ( 1
66
130
31
94
156
28
30
29
17
40
93
69
41
133
544
303
2200
56
53
82
38
59
90
62
38
78
42
58
54
26
256
70
55
238
134
327
383
101
99
39
59
242
65
21
67
346
38
3,4-diF-Bz
3.2 ( 0.8
1.5 ( 0.2
13.6 ( 4
6.6 ( 0.7
1.4 ( 0.2
0.9 ( 0.2
10.1 ( 2.1
0.5 ( 0.2
2.9 ( 0.9
6.5 ( 2.7
42
87
33
43
81
58
49
96
148
119
265
375
23
33
425
367
74
47
11
19
0
0
44
49
491
111
90
2-Me-Bz
4-Me-Bz
4-OMe-Bz
112
(Pyrid-3-yl)CH2
(Pyrid-4-yl)CH2
4/5-imidazyl-CH2
2-thienyl-CH2
Ph-(()-(Me)CH
Ph-(S)-(-)-(Me)CH
53
118
107
60
459
67
75
439
375
50
47
2-F-Ph-(()-(Me)CH 1.7 ( 0.1
3-F-Ph-(()-(Me)CH 8.3 ( 5.4
4-F-Ph-(()-(Me)CH 14.9 ( 5.7
and para (17) positions. The impact on affinity by an
ortho fluoro is again seen with the 2-fluoro-4-methoxy
analogue 22, which shows a 4-fold increase in affinity
over the 4-methoxy (17) alone. A para methyl group (18)
leads to a 5-fold drop in affinity. A thienyl group (23)
in lieu of phenyl leads to a 3-fold enhancement in
affinity.
Substitution on the aryl ring of the N-benzyl moiety
(see Table 3) with halo (35-38), alkyl (39-40), or alkoxy
(41) has only modest impact on affinity. Heteroaryl
replacement (42-45) is well tolerated. Branching on the
benzylic carbon is tolerated as demonstrated by ana-
logues (46-50). Stereochemical preference at this center
is not dramatic as shown by only a 2-fold difference
between the racemate 46 and the (S) isomer 47.
The aryl was then held constant as the ortho fluo-
rophenyl while exploring the impact of the tetrahydro-
pyridine substituent (Tables 2-4). An unsubstitued NH,
compound (24, Table 2) is inactive. Small alkyl groups
(25-28, 30) reduce affinity by 10- to 30-fold compared
to benzyl. Larger lipophilic alkyl groups (29, 31) sig-
nificantly improve affinity, comparable to that of N-
benzyl (10). Extension of the carbon chain from benzyl
to phenethyl (32) or phenpropyl (33) results in a
dramatic loss in affinity. Pyrimidyl substitution (34) also
results in significant loss in affinity.
Acylation (51-56) and carbamoylation (57-62) of the
tetrahydropyridine affords mostly weak or inactive
compounds (see Table 4).
The lead compound 9 exhibits 2.5-fold selectivity for
R2 vs R1 in maximum potentiation (efficacy) in electro-
physiology studies, although the EC50 (potency) is
shifted to the right (Table 1). All the fluoro analogues
(10-12) have lost this selectivity except for the 2,4-
difluoro analogue 19, of which is comparable. The
fluorine substituents also have dramatic differences on

5046 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23
Ta ble 4. Effect of N-Acyl Substituents on Binding Affinity
Albaugh et al.
R1
R2
EC50 (nM)
R3
EC50 (nM)
R5
compd
N-R
Me
Et
n-Pr
n-pentyl
Ph
Bz
2-pyridyl
3-pyridyl
4-pyridyl
OEt
Ki (nM)
max (%)
EC50 (nM)
max (%)
max (%)
max (%)
EC50 (nM)
51
52
53
54
55
56
57
58
59
60
61
62
41 ( 9
0
12
0
22
11
9
71
116
0
0
216 ( 29
261 ( 41
NA
95
110
83 ( 5
388 ( 155
73 ( 1
92 ( 0.2
123 ( 47
64 ( 5
230 ( 76
39 ( 8
O-n-Bu
OBz
5
<100
8
<100
0
∼3
∼1000
Ta ble 5. Effect of Substituents on Binding Affinity
the maximum potentiation of both R1 and R2, increasing
as the fluorine is moved from the ortho to the meta and
then to the para position, albeit all with EC50 shifts to
the right. The ortho fluoro analogue 10 is more effica-
cious on R3 and maintains potency. The para methyl
analogue 18 also has R3 selective efficacy but with
reduced potency. The meta (16) and para (17) methoxy
analogues have lost selectivity because of increased R1
efficacy, as has the thienyl analogue 23.
Small N-alkyl groups on the tetrahydropyridine (25-
27, 30) tend to exhibit antagonist or low partial agonist
characteristics in electrophysiology studies (Table 2).
The larger alkyl groups (29, 31) give much larger partial
agonist character. Despite differences in the maximum
potentiation between these N-alkyl analogues, none
exhibit any selectivity. The 2- (35) and 4-fluorobenzyl
(37) analogues (Table 3) exhibit no selectivity and are
partial agonists. In contrast, the 3-fluorobenzyl ana-
logue 36 and to some degree the 3,4-difluorobenzyl
analogue 38 are more R1-selective. The 2-methyl ana-
logue 39 also has enhanced R1 selectivity, whereas the
4-methyl (40) and 4-methoxy (41) analogues exhibit
much lower agonism with modest R2 selectivity. The
heteroarylmethyl analogues 42-44 are all partial ago-
nists. The 3- (42) and 4- (43) pyridylmethyl analogues
have R2/R3 selectivity. The thienylmethyl analogue (45)
and the racemic R-methyl analogue (46) exhibit signifi-
cantly less R2 activity than the corresponding benzyl
analogue 9. The acyl (51-52) and carbamoyl (62)
derivatives are essentially antagonists (Table 4).
a
compd
N-R
aryl
Ki (nM)
63
9
COPh
COPh
COPh
COPh
Me
Me
COEt
COEt
Ph
2-F-Ph
3-Cl-Ph
301
1.3
64
65
66
67
52
68
NAb
NA
240
45
4-OMe-Ph
4-OMe-Ph
2-F-4-OMe-Ph
2-F-Ph
216
NA
4-OMe-Ph
a
Analogues 63-68 were run only once as a set of triplicates.
NA ) not achieved for IC50 at the highest dose tested.
b
withdrawing groups in the para position are disfavored
(12, 14), especially compared to the corresponding meta
(11, 13) and ortho (10) analogues. There is no strong
correlation of the aryl substituent effect on functional
activity in electrophysiology studies. Both electron-
deficient and electron-rich aryl rings can be small
partial agonists or fuller agonists. Neither does size
seem to play a role on the functional activity in elec-
trophysiology.
In contrast, the substituent on the tetrahydropyridine
plays a more significant role. Small alkyl as well as the
acyl and carbamoyl substituents all possess reduced
affinity. Groups occupying about the same space as
benzyl are optimal for affinity. Less lipophilic substit-
uents [small alkyl (25-28, 30) or those containing a
heteroatom (34, 41-47, 51, 52, 62)] tend to exhibit
lower, partial agonist characteristics in electrophysiol-
ogy studies. Both of the pyridylmethyl analogues (42,
43) exhibit R2/R3 selectivity. More lipophilic substituents
(31, 36, 38, 39) tend to have increased efficacy, espe-
cially on R1, but a few have selectivity for the others
(e.g., 45 for R3). Both the 4-Me (40) and the 4-OMe (41)
substituted benzyl analogues have reduced potency such
that combined with the low efficacy, they would be
considered bordering on antagonism.
Discu ssion
The effect of the aryl substituent has only modest
impact on affinity except in the case of ortho fluoro
substitution. The ortho fluoro can enhance affinity,
especially when combined with another substituent. For
example, compare 12 (21 nM) to 19 (2 nM) and compare
66 (240 nM) to 67(45 nM) (see Tables 1 and 5). Note
that for the tetrahydropyridine N-benzoyl analogues
(Table 5), essentially only the ortho fluoro analogue (55)
maintains potency. Only small substituents in the ortho
position of the aryl are tolerated (10 vs 15). Electron-

Pyrimidin-5(6H)-ones
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23 5047
Ta ble 6. Rat Behavioral Spontaneous Locomotor Activity
Studies
OMNI meda
(mg/kg)
OMNI meda
(mg/kg)
compd
compd
11
12
17
42
2
1
0.06
0.5
43
zolpidem
zaleplon
NSb
0.25
0.25
0.125
alprazolam
a
Compared with that administered in 50% aqueous PEG-400,
b
iv, used as dosing and control vehicle. NS ) not significant.
For the most part, the affinity SAR for the closely
related triazolopyrimidones reported previously6 is simi-
lar to the imidazopyridiones reported here. However,
the same SAR is not observed with respect to efficacy.
No electrophysiology data had been reported for the
triazolopyrimidone templates, only GABA shifts. His-
torically it was thought that the shift in affinity of a
ligand in the absence of GABA vs in the presence of
GABA reflected the amount of agonist character of the
ligand. The amount of shift was reported as the ratio of
the IC50 values. Thus, a ratio of 1 was deemed an
antagonist, those with a ratio less than 1 an inverse
agonist, and those with a ratio greater than or equal to
2 an agonist. The corresponding triazolopyrimidone
analogues6 of 9 and 42 reportedly have the same GABA
shift (1.4), yet the efficacy of 9 is twice that of 42.
Similarly, the corresponding triazolo analogues6 of 11
and 12 reportedly have comparable GABA shifts (1.6
and 1.7 respectively), yet 12 has twice the efficacy of
11. Thus, either there are significant differences in
efficacies between these two templates or the use of
GABA shifts is not accurate. The latter seems most
likely because GABA shifts were typically run on rat
brain and thus cannot distinguish between receptor
subtypes.
Several compounds were selected to run in rat be-
havioral locomotor studies. Reduction of spontaneous
locomotor activity is often used as a measure of sedation.
The results of these studies are shown in Table 6. The
observed minimum efficacious doses (med) correlate
with the potency (EC50) in electrophysiology. The degree
of GABA potentiation in electrophysiology also cor-
relates with efficacy in locomotor behavior. In electro-
physiology, 12 is about 2 times more efficacious than
11 and is twice as potent in vivo. In electrophysiology
studies, 17 has efficacy equivalent to that of 12, but 17
is 7-fold more potent. This is reflected in the significant
increase in potency of 17 in locomotor activity studies.
There are two compounds (zolpidem and zaleplon)
that have higher affinity for the R1 receptor and are now
marketed as hypnotics. However, they can still exhibit
the classical side effects such as memory impairment
and rebound insomnia.14 We felt that a true hypnotic
agent with a cleaner side effect profile would have
minimal activity on R1 and R5 subtypes.15 The R1 subtype
is found predominantly in the cortex, thalamus, and
brainstem, while R5 is the major subtype in the hippo-
campus, a site known to be involved with memory. In
fact, recent studies16 on R1 mutant mice, in which GABA
still binds but benzodiazepine receptor ligands do not,
demonstrate that the sedative component of diazepam
is due to R1 receptors but not to the hypnotic activity,
the latter being a measure of latency to fall asleep.
Furthermore, in these same R1 mutant mice studies,
F igu r e 2. Overlay of 9 (black) with alprazolam (green) and
zaleplon (blue). H1 and H2 denote hydrogen donor sites on
the receptor. A1 denotes a hydrogen acceptor site on the
receptor. L1, L2, and L3 denote lipophilic pockets on the
receptor.
some amnestic abilities were attributed to efficacy on
the R1 subytpe. This would explain the memory impair-
ment sometimes reported14 for these two marketed
hypnotics that are R1-preferring, despite lacking activity
on the hippocampal R5 subtype.
Here, we note that sedation is still observed with a
lower intrinsic partial agonist bearing R2/R3 selectivity
(42). It is notable that even though 42 is significantly
less efficacious in electrophysiology studies17 than either
the marketed hypnotics zolpidem or zaleplon (see Table
1), or even the marketed anxiolytic Xanax (alprazolam;
see Table 1), the minimum efficacious doses in locomotor
activity are not all that different. Because 42 has
minimal functional activity in electrophysiology studies
on R1 and R5, memory side effects would not be antici-
pated for this analogue. Also noteworthy is that al-
though analogue 17 is about half as efficacious as the
marketed anxiolytic alprazolam in electrophysiology
studies (see Table 1), analogue 17 is over twice as potent
in vivo (see Table 6). Because no exposure studies were
conducted with the analogues reported here, differences
in the in vivo efficacy could also possibly be due to
differences in plasma and/or brain levels.
In summary, we have shown here the achievement
of functional selectivity in ligands that bind to the
benzodiazepine receptor. These selective agents such as
42 would be expected to have reduced propensity in a
clinical setting for negative side effects such as memory
impairment as the classical benzodiazepines. Unfortu-
nately, many of the analogues were too insoluble to run
either in electrophysiology studies or in behavioral
studies. Furthermore, modeling of our template in the
emerging pharmacophore model (see Figure 2) indicated
that we were approaching the full agonist pocket of
benzodiazepines (“L3” in Cook18 nomenclature). This
pocket is considered to be lipophilic, and we believe it
to be predominantly an R1 pocket. The lower intrinsic
activity of the basic heteroarylmethyl analogues (42-
44) adheres to this hypothesis. Efforts were shifted to
other templates that we had been investigating that
seemed to possess better biopharmaceutical properties.
Indeed, these other templates ultimately led to further

5048 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23
Albaugh et al.
4.56-4.62 (m, 2H), 4.24-4.41 (m, 2H), 3.53-3.65 (m, 1H),
3.35-3.47 (m, 1H), 3.0-3.12 (m, 1H), 2.76-2.88 (m, 1H).
LCMS, m/z: MH+ 393.3, MH- 391.2. Anal. (C22H18F2N4O‚HCL‚
H2O) C, H, N.
The following compounds were prepared in a fashion similar
to that of 35, starting with the appropriate 1-bromoacetophe-
none.
refinement of our understanding the importance of the
GABAA subtypes in many CNS disorders, and multiple
clinical candidates. Data on the other series and findings
will be reported in the future.
Exp er im en ta l Section
9-Ben zyl-2-p h en yl-7,8,9,10-t et r a h yd r oim id a zo[1,2-c]-
p yr id o[3,4-e]p yr im id in -5(6H)-on e Hyd r och lor id e (9). 1H
NMR (DMSO-d6): δ 8.34 (s, 1H), 7.93 (d, J ) 8.52 Hz, 2H),
7.65-7.76 (m, 2H), 7.47-7.59 (m, 3H), 7.40 (t, J ) 7.42 Hz,
2H), 7.31 (d, J ) 7.35 Hz, 1H), 4.54 (s, 2H), 4.18-4.29. HPLC
purity in Supporting Information.
9-(2-Ben zyl)-2-(2-flu or op h en yl)-7,8,9,10-tetr a h yd r oim -
idazo[1,2-c]pyr ido[3,4-e]pyr im idin -5(6H)-on e (10). 1H NMR
(DMSO-d6): δ 8.12 (t, J ) 7.76 Hz, 1H), 7.94 (d, J ) 4.23 Hz,
1H), 7.29-7.47 (m, 8H), 3.78 (s, 2H), 3.56 (s, 2H), 2.81-2.84
(m, 2H), 2.66 (s, 2H). LCMS, m/z: MH+ 375.3, MH- 373.3.
Anal. (C22H19FN4O‚2HCl‚0.5H2O) C, H, N.
Ch em istr y. Reagents and solvents were used from com-
mercial sources without purification. Melting points were
determined on
a Thomas-Hoover capillary melting point
apparatus and are uncorrected. 1H NMR spectra were recorded
on a Varian Gemini 300 or a Varian Unity 400 MHz spec-
trometer. Electron ionization mass spectra (MS) were recorded
on a Hewlett-Packard 5890 mass spectrometer. Elemental
analyses were performed at Robertson Microlabs, Madison, NJ ,
and are within 0.4% of theoretical value. For those that did
not give satisfactory results from elemental analyses, the
purity was established via HPLC as provided in the Support-
ing Information.
9-Ben zyl-2-(3-flu or oph en yl)-7,8,9,10-tetr ah ydr oim idazo-
[1,2-c]pyr ido[3,4-e]pyr im idin -5(6H)-on e (11). 1H NMR (DM-
SO-d6): δ 8.37 (d, J ) 2.88 Hz, 1H), 7.79 (d, J ) 7.71 Hz, 1H),
7.73 (d, J ) 10.86 Hz, 1H), 7.30-7.46 (m, 5H), 7.29 (d, J )
4.07 Hz, 1H), 7.14 (t, J ) 8.48 Hz, 1H), 3.75 (s, 2H), 3.52 (s,
2H), 2.79 (s, 2H), 2.63 (s, 2H). LCMS, m/z: MH+ 375.3, MH-
373.3. Anal. (C20H19FN4O‚2HCl‚0.25H2O) C, H, N.
9-Ben zoyl-2-(2-flu or op h en yl)-7,8,9,10-tetr a h yd r oim id -
azo[1,2-c]pyr ido[3,4-e]pyr im idin -5(6H)-on e (55). To a stirred
suspension of 4-amino-3-cyano-1,2,5,6-tetrahydropyridine7 (95.51
g, 775 mmol) in pyridine (500 mL), benzoic anhydride (274 g,
1.20 mol) was added in portions over 1-2 h. After the mixture
was stirred an additional 0.5 h, the precipitate was collected,
washed with toluene and then ether, and dried to give
9-Ben zyl-2-(4-flu or oph en yl)-7,8,9,10-tetr ah ydr oim idazo-
1-benzoyl-4-amino-3-cyano-1,2,5,6,-tetrahydropyridine as
a
[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e Dih yd r och lor id e
white solid, mp 178-181 °C.
1
(12). H NMR (DMSO-d6): δ 8.35 (s, 1H), 7.97(dd, J ) 4.04,
A slurry of 1-benzoyl-4-amino-3-cyano-1,2,5,6-tetrahydro-
pyridine (35.23 g, 155 mmol) and urea (46.55 g, 775 mmol) in
2-(2-ethoxyethoxy)ethanol (75 mL) was gradually heated to 205
°C and maintained for 1.5 h. Heating was ceased and hot water
was carefully added while shaking the mixture. The mixture
was vacuum-filtered to collect the precipitate while hot. The
precipitate was washed with hot water until the filtrate was
colorless. The precipitate was then washed with ethanol until
the filtrate was colorless and then finally washed with EtOAc
and allowed to dry to afford 6-benzoyl-4-amino-6,7,8,9-tet-
rahydropyrido[3.4-e]pyrimidin-2-one as a light-yellow solid.
8.79 Hz, 2H), 7.71-7.74 (m, 2H), 7.47-7.49 (m, 3H), 7.23 (t,
J ) 8.79 Hz, 2H), 4.54 (s, 2H), 4.23 (s, 2H), 3.59-3.71 (m, 1H),
3.29-3.41 (m, 1H), 3.06-3.18 (m, 1H), 2.76-2.88 (m, 1H).
LCMS, m/z: MH+ 375.3, MH- 373.3. Anal. (C18H17FN4O2‚H2O‚
2HCl) C, H, F, N.
9-Ben zyl-2-(3-ch lor oph en yl)-7,8,9,10-tetr ah ydr oim idazo-
[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e Mesyla te (13). 1H
NMR (DMSO-d6): δ 8.47-8.53 (m, 1H), 7.88-7.94 (m, 1H),
7.76-7.82 (m, 1H), 7.65-7.71 (m, 2H), 7.41-7.65 (m, 5H), 4.6-
4.71 (m, 2H), 4.41-4.53 (m, 2H), 3.65-3.68 (m, 2H), 3.18-
3.24 (m, 2H), 2.68 (s, 6H). LCMS, m/z: MH+ 391.2, MH- 389.2.
HPLC purity in Supporting Information.
9-Ben zyl-2-(4-ch lor oph en yl)-7,8,9,10-tetr ah ydr oim idazo-
[1,2-c]pyr ido[3,4-e]pyr im idin -5(6H)-on e (14). 1H NMR (DM-
SO-d6): δ 8.06 (s, 1H), 7.84 (d, J ) 8.8 Hz, 2H), 7.34-7.44 (m,
6H), 3.81 (s, 2H), 3.68 (s, 2H), 2.87-2.99 (m, 2H), 2.70-2.73
(m, 2H). LCMS, m/z: MH+ 391.2, MH- 389.2. HPLC purity in
Supporting Information.
9-Ben zyl 2-(2-Meth oxyp h en yl)-7,8,9,10-tetr a h yd r oim -
id a zo[1,2-c]p yr id o[3,4-e] p yr im id in -5(6H)-on e (15). 1H
NMR (DMSO-d6): δ 8.12 (d, J ) 7.7 Hz, 1H), 8.04 (d, J ) 7.7
Hz, 1H), 7.25-7.46 (m, 6H), 7.12 (d, J ) 7.7 Hz, 1H), 7.0 (t,
J ) 11 Hz, 1H), 3.96 (s, 3H), 3.75 (s, 2H), 3.5 (s, 2H), 2.73-2.8
(m, 2H), 2.54-2.62 (m, 2H). LCMS, m/z: MH+ 387.3, MH-
385.3.
9-Ben zyl-2-(3-m eth oxy)p h en yl)-7,8,9,10-tetr a h yd r oim -
idazo[1,2-c]pyr ido[3,4-e]pyr im idin -5(6H)-on e (16). 1H NMR
(DMSO-d6): δ 8.25 (s, 1H), 7.25-7.44 (m, 6H), 6.92 (d, J )
8.79 Hz, 1H), 3.75 (s, 3H), 3.72 (s, 2H), 3.48 (s, 2H), 2.74 (s,
2H), 2.59 (s, 2H). LCMS, m/z: MH+ 387.3, MH- 385.3. Anal.
(C23H18N4O2‚0.25H2O) C, H, N.
A mixture of 6-benzoyl-4-amino-6,7,8,9-tetrahydropyrido-
[3.4-e]pyrimidin-2-one (1 g, 3.7 mmol) and 1-bromo-2′-fluoro-
acetophenone (0.74 g, 3.7 mmol) in DMF (8 mL) was heated
at 150 °C. The reaction mixture was poured into ice/water and
the precipitate was collected to give 55. Later, a second crop
1
was isolated as a cream solid. H NMR (DMSO-d6): δ 7.88-
8.18 (m, 2H), 7.24-7.53 (m, 8H), 4.41-4.71 (m, 2H), 3.59-
3.94 (m, 2H), 2.68 (s, 2H). LCMS, m/z: MH+ 389.2, MH- 387.
Mp 269-271 °C. HPLC purity in Supporting Information.
2-(2-F lu or op h en yl)-7,8,9,10-tetr a h yd r oim id a zo[1,2-c]-
p yr id o[3,4-e]p yr im id in -5(6H)-on e (24). To a solution of 55
(435 mg, 1.1 mmol) in ethanol (5 mL) was added 5 mL of 50%
aqueous sodium hyroxide. The mixture was refluxed for 1 h,
poured into saturated aqueous ammonium chloride, and
extracted 2× with 10% methanol/EtOAc. The combined organic
layers were dried (MgSO4), filtered, concentrated, and tritu-
1
rated with methanol/ether to give 24, mp >310 °C. H NMR
(DMSO-d6): δ 8.21 (t, J ) 7.13 Hz, 1H), 8.01 (d, J ) 4.02 Hz,
1H), 7.34-7.46 (m, 2H), 4.17 (s, 2H), 2.75-2.77 (m, 2H), 2.54-
2.59 (m, 2H). LCMS, m/z: MH- 283.3. HPLC purity in
Supporting Information.
9-Ben zyl-2-(4-m eth oxyp h en yl)-7,8,9,10-tetr a h yd r oim -
idazo[1,2-c]pyr ido[3,4-e]pyr im idin -5(6H)-on e (17). 1H NMR
(DMSO-d6): δ 8.11-8.16 (m, 1H), 7.82-7.89 (m, 2H), 7.33-
7.34 (m, 5H), 6.95-7.0 (m, 2h), 3.74-3.82 (m, 5H), 3.51 (s, 2H),
2.78-2.85 (m, 2H), 2.59-2.65 (m, 2H). LCMS, m/z: MH+
387.2, MH- 385.3. Anal. (C23H22N4O2) C, H, N.
9-Ben zyl-2-(4-m eth ylp h en yl)-7,8,9,10-tetr a h yd r oim id -
a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e (18). 1H NMR
(DMSO-d6): δ 8.12-8.24 (m, 1H), 7.80 (d, J ) 7.69 Hz, 2H),
7.35-7.59 (m, 5H), 7.19 (d, J ) 7.96 Hz, 2H), 4.1-4.6 (m, 2H),
3.4-3.9 (m, 2H), 2.6-2.9 (m, 2H), 2.35 (s, 3H). LCMS, m/z:
MH+ 371.3, MH- 369.3. HPLC purity in Supporting Informa-
tion.
9-(2-F lu or oben zyl)-2-(2-flu or op h en yl)-7,8,9,10-tetr a h y-
d r oim id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e (35).
2-Fluorobenzyl bromide (54 µL, 0.45 mmol) was added to a
solution of 24 (128 mg, 0.45 mmol) and triethylamine (76 µL,
0.54 mmol) in DMF (1 mL) at room temperature. The reaction
mixture was stirred and then concentrated. Aqueous sodium
bicarbonate was added, the aqueous layer was extracted 2×
with 10% methanol/EtOAc, and the combined organic layers
were dried (MgSO4), filtered, concentrated, and triturated with
methanol/ether to give 35 as an off-white solid, mp 270-273
1
°C. The HCl salt was prepared in ethanol. H NMR (DMSO-
d6): δ 8.10 (t, J ) 8.1 Hz, 1H), 7.97 (d, J ) 3.84 Hz, 1H), 7.83
(t, J ) 7.28 Hz, 1H), 7.55-7.58 (m, 1H), 7.31-7.41 (m, 5H),

Pyrimidin-5(6H)-ones
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23 5049
9-Ben zyl-2-(2,4-d iflu or op h en yl)-7,8,9,10-tetr a h yd r oim -
idazo[1,2-c]pyr ido[3,4-e]pyr im idin -5(6H)-on e (19). 1H NMR
(DMSO-d6): δ 8.04-8.09 (m, 1H), 7.86 (d, J ) 4.2 Hz, 1H),
7.27-7.38 (m, 5H), 7.14 (t, J ) 8.52 Hz, 2H), 3.72 (s, 2H), 3.49
(s, 2H), 2.77 (s, 2H), 2.60 (s, 2H). LCMS, m/z: MH+ 393.3, MH-
391.2. Anal. (C22H18F2N4O) C, H, F, N.
9-(4-Meth oxyben zyl)-2-(2-flu or op h en yl)-7,8,9,10-tetr a -
h ydr oim idazo[1,2-c]pyr ido[3,4-e]pyr im idin -5(6H)-on e (41).
1H NMR (DMSO-d6): δ 8.11 (t, J ) 3.85 Hz, 1H), 7.41 (d, J )
4.1 Hz, 1H), 7.27-7.43 (m, 5H), 6.92 (d, J ) 8.55 Hz, 2H), 3.75
(s, 3H), 3.68 (s, 2H), 3.5 (s, 2H), 2.77 (s, 2h), 2.62 (s, 2H). LCMS,
m/z: MH+ 405.3. HPLC purity in Supporting Information.19
9-Ben zyl-2-(2,5-d iflu or op h en yl)-7,8,9,10-tetr a h yd r oim -
id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e Dim eysla te
(20). H NMR (DMSO-d6): δ 8.03 (d, J ) 3.3 Hz, 1H), 7.75-
9-(2-Th ien ylm eth yl)-2-(2-flu or oph en yl)-7,8,9,10-tetr ah y-
d r oim id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e (45).
1H NMR (DMSO-d6): δ 8.09 (t, J ) 7.97 Hz, 1H), 7.89 (d, J )
4.12 Hz, 1H), 7.45 (d, J ) 5.22 Hz, 1H), 7.24-7.37 (m, 3H),
7.05 (s, 1H), 6.99 (d, J ) 4.12 Hz, 2H), 3.95 (s, 2H), 3.57 (s,
2H), 2.75-2.80 (m, 2H), 2.60 (s, 2H). LCMS, m/z: MH+ 381.2,
MH- 379.3. Anal. (C20H17FN4OS) C, H, F, N, S.
1
7.78 (m, 1H), 7.51-7.60 (m, 5H), 7.37-7.45 (m, 1H), 7.25-
7.28 (m, 1H), 4.42-4.78 (m, 3H), 4.27-4.32 (m, 1H), 3.76-3.8
(m, 1H), 3.40-3.43 (m, 1H), 2.91 (m, 2H), 2.31 (s, 6H). LCMS,
m/z: MH+ 393.3, MH- 391.2. Anal. (C22H18F2N4O‚MSOH‚H2O)
C, H, N, S.
9-Ben zyl-2-(3,4-d iflu or op h en yl)-7,8,9,10-tetr a h yd r oim -
idazo[1,2-c]pyr ido[3,4-e]pyr im idin -5(6H)-on e (21). 1H NMR
(DMSO-d6): δ 8.29-8.41 (m, 1H), 7.94 (t, J ) 9.75 Hz, 1 H),
7.71-7.82 (m, 1H), 7.35-7.53 (m, 6H), 4.1-4.7 (m, 2H), 3.6-
3.8 (m, 2H), 2.5-2.9 (m, 2H). LCMS, m/z: MH+ 393.4, MH-
391.2. Anal. (C22H187F2N4O‚2HCL‚H2O) C, H, N.
9-Ben zyl-2-(2-flu or o-4-m eth oxyph en yl)-7,8,9,10-tetr ah y-
d r oim id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e (22).
1H NMR (DMSO-d6): δ 7.95 (t, J ) 8.93 Hz, 1H), 7.76 (d, J )
4.4 Hz, 1H), 7.28-7.36 (m, 5H), 6.92 (d, J ) 13.5 Hz, 1H),
6.82-6.86 (m, 1H), 3.78 (s, 3H), 3.72 (s, 2H), 3.49 (s, 2H), 2.74-
2.76 (m, 2H), 2.59 (s, 2H). LCMS, m/z: MH+ 405.4, MH- 403.4.
HPLC purity in Supporting Information.
9-Ben zyl-2-(2-th ien yl)-7,8,9,10-tetr a h yd r oim id a zo[1,2-
c]p yr id o[3,4-e]p yr im id in -5(6H)-on e (23). 1H NMR (DMSO-
d6): δ 7.89 (s, 1H), 7.29-7.50 (m, 7H), 7.06-7.09 (m, 1H), 3.80
(s, 2H), 3.67 (s, 2H), 2.84-2.88 (m, 2H), 2.68-2.70 (m, 2H).
LCMS, m/z: MH+ 363.2, MH- 361.2. HPLC purity in Sup-
porting Information.
(+)-9-(r-Meth ylben zyl)-2-(2-flu or op h en yl)-7,8,9,10-tet-
r a h yd r oim id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H )-
1
on e (46). H NMR (DMSO-d6): δ 8.08-8.14 (m, 1H), 7.91 (d,
J ) 4.21 Hz, 1H), 7.28-7.42 (m, 8H), 3.97-4.05 (2H), 3.66 (d,
J ) 14.6 Hz, 1H), 3.5 (d, J ) 14.8 Hz, 1H), 2.56-2.76 (m, 3H),
1.41 (d, J ) 6.7 Hz, 3H). LCMS, m/z: MH+ 389.3, MH- 387.3.
Anal. (C23H21FN4O‚2HCl‚H2O) C, H, F, N.
(S)-(+)-9-(r-Meth ylben zyl)-2-(2-flu or op h en yl)-7,8,9,10-
t et r a h yd r oim id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H )-
on e (47). 1H NMR (DMSO-d6): δ 8.09 (t, J ) 7.42 Hz, 1H),
7.89 (d, J ) 2.47 Hz, 1H), 7.25-7.37 (m, 8H), 3.72 (d, J ) 5.77
Hz, 1H), 3.63 (d, J ) 15.38 Hz, 1H), 3.48 (d, J ) 14.28 Hz,
1H), 2.68-2.79 (m, 2H), 2.53-2.62 (m, 2H), 1.4 (d, J ) 6.1
Hz, 3H). LCMS, m/z: MH+ 389.2, MH- 387.3. HPLC purity
in Supporting Information.
(+) 9-(2-F lu or o-r-m et h ylb en zyl)-2-(2-flu or op h en yl)-
7,8,9,10-tetr a h yd r oim id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -
5(6H)-on e (48). 1H NMR (DMSO-d6): δ 8.07-8.14 (m, 1H),
7.89 (d, J ) 4 Hz, 1H), 7.22-7.46 (m, 5H), 7.11-7.21 (m, 2H),
3.70-3.79 (m, 1H), 3.61 (d, J ) 7.1 Hz, 1H), 3.49 (d, J ) 7.1
Hz, 1H), 2.61-2.71 (m, 2H), 1.43 (t, J ) 4 Hz, 3H). Anal.
(C23H20F2N4O‚2HCl) C, H, F, N.
(+) 9-(3-F lu or o-r-m et h ylb en zyl)-2-(2-flu or op h en yl)-
7,8,9,10-tetr a h yd r oim id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -
5(6H)-on e (49). 1H NMR (DMSO-d6): δ 8.12-8.24 (m, 1H),
7.94-8.0 (m, 2H), 7.69 (d, J ) 9.1 Hz, 1H), 7.57 (s, 2H), 7.26-
7.38 (m, 3H), 4.71-4.82 (m, 1H), 4.47-4.65 (m, 1H), 4.03 (s,
1H), 3.47-3.59 (m, 1H), 2.71-3.47 (m, 4H), 1.80 (d, J ) 4.9
Hz, 3H). LCMS, m/z: MH+ 407.3, MH- 405.3. HPLC purity
in Supporting Information.
The following were prepared in a fashion similar to that for
55 starting from 24.
9-(2-P yr im id yl)-2-(2-flu or op h en yl)-7,8,9,10-tetr a h yd r o-
im id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H )-on e Dih y-
d r och lor id e (34). 1H NMR (DMSO-d6): δ 8.46 (d, J ) 4.66
Hz, 2H), 8.18-8.23 (m, 1H), 7.99 (d, J ) 4.12 Hz, 1H), 7.30-
7.43 (m, 3H), 6.74 (d, J ) 4.67 Hz, 1H), 4.85 (s, 2h), 4.11 (t,
J ) 5.77 Hz, 2H), 2.65-2.71 (m, 2H). LCMS, m/z: MH+ 363.2,
MH- 361.2. HPLC purity in Supporting Information.
9-(3-F lu or oben zyl)-2-(2-flu or op h en yl)-7,8,9,10-tetr a h y-
d r oim id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e (36).
1H NMR (DMSO-d6): δ 8.08 (t, J ) 7.69 Hz, 1H), 7.89 (d, J )
4.1 Hz, 1H), 7.07-7.43 (m, 7H), 3.75 (s, 2H), 3.53 (s, 2H), 2.77
(s, 2H), 2.61 (s, 2H). LCMS, m/z: MH+ 393.2, MH- 391.2.
HPLC purity in Supporting Information.
9-(4-F lu or oben zyl)-2-(2-flu or op h en yl)-7,8,9,10-tetr a h y-
d r oim id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e (37).
1H NMR (DMSO-d6): δ 8.11 (t, J ) 7.75 Hz, 1H), 7.92 (d, J )
4.2 Hz, 1H), 7.26-7.46 (m, 5h), 7.19 (t, J ) 8.89 Hz, 2H), 3.79
(s, 2H), 3.53 (s, 2H), 2.73-2.78 (m, 2H), 2.58-2.69 (m, 2H).
LCMS, m/z: MH+ 393.3, MH- 391.2. Anal. (C22H18F2N4O2‚
2HCl‚H2O) C, H, F, N.
9-(3,4-Diflu or ob en zyl)-2-(2-flu or op h en yl)-7,8,9,10-t et -
r a h yd r oim id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H )-
on e (38). 1H NMR (DMSO-d6): δ 8.08 (t, J ) 7.83 Hz, 1H),
7.89-7.90 (m, 1H), 7.24-7.45 (m, 6H), 3.72 (s, 2H), 3.53 (s,
2H), 2.76 (s, 2H), 2.60 (s, 2H). LCMS, m/z: MH+ 411.3, MH-
409.3. Anal. (C22H17F3N4O) C, H, F, N.
9-(2-Meth ylben zyl)-2-(2-flu or op h en yl)-7,8,9,10-tetr a h y-
d r oim id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e (39).
1H NMR (DMSO-d6): δ 8.08 (t, J ) 7.1 Hz, 1H), 7.89 (d, J )
4.1 Hz, 1H), 7.17-7.37 (m, 7H), 3.69 (s, 2H), 3.53 (s, 2H), 2.74-
2.79 (m, 2H), 2.59 (s, 2H), 2.33 (s, 3H). LCMS, m/z: MH+ 389.2,
MH- 387.2. Anal. (C23H21FN4O) C, H, F, N.
(+) 9-(4-F lu or o-r-m et h ylb en zyl)-2-(2-flu or op h en yl)-
7,8,9,10-tetr a h yd r oim id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -
5(6H)-on e (50). 1H NMR (DMSO-d6): δ 8.10 (t, J ) 7 Hz, 1H),
7.89 (d, J ) 4 Hz, 1H), 7.25-7.46 (m, 5H), 7.11-7.21 (m, 2H),
3.70-3.79 (m, 1H), 3.61 (d, J ) 7.1 Hz, 1H), 3.49 (d, J ) 7.1
Hz, 1H), 2.61-2.71 (m, 2H), 1.43 (t, J ) 4 Hz, 3H). LCMS,
m/z: MH+ 407.4, MH- 405.3. Anal. (C23H20F2N4O‚2HCl) C, H,
F, N.
9-P r op ion yl-2-(2-flu or op h en yl)-7,8,9,10-tetr a h yd r oim -
id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e (52). Pro-
pionyl chloride (39 µL, 0.4 mmol) was added to a solution of
24 (124 mg, 0.4 mmol) and triethylamine (74 µL, 0.5 mmoL)
in DMF (2 mL) at room temperature. The reaction mixture
was stirred for 1 h and then was poured into ice/water. The
precipitate was collected, washed with water and then with
95% ethanol and dried to yield 52 as a white solid, mp >310
°C. 1H NMR (DMSO-d6): δ 8.19-8.21 (m, 1H), 7.94 (d, J )
3.9 Hz, 1H), 7.31-7.41 (m, 3H), 4.59 (s, 2H), 3.74-3.79 (m,
2H), 2.65-2.7 (m, 2H), 2.55-2.6 (m, 2H), 1.03 (t, J ) 7.33 Hz,
3H). LCMS, m/z: MH+ 341.2, MH- 339.2. Anal. (C18H17FN4O2)
C, H, F, N.
The following compounds were prepared according to a
method similar to that of 52.
9-(4-Meth ylben zyl)-2-(2-flu or op h en yl)-7,8,9,10-tetr a h y-
d r oim id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e (40).
1H NMR (DMSO-d6): δ 8.03-8.12 (m, 1h), 7.88-7.94 (m, 1H),
7.12-7.35 (m, 7H), 3.59-3.76 (m, 2H), 3.41-3.76 (m, 2H),
2.71-2.82 (m, 2H), 2.53-2.71 (m, 2H), 2.29 (s, 3H). LCMS,
m/z: MH+ 389.4, MH- 387.2. HPLC purity in Supporting
Information.
9-Acetyl 2-(2-flu or oph en yl)-7,8,9,10-tetr ah ydr oim idazo-
[1,2-c]pyr ido[3,4-e]pyr im idin -5(6H)-on e (51). 1H NMR (DM-
SO-d6): δ 8.17-8.19 (m, 1H), 7.93-7.95 (m, 1H), 7.29-7.39
(m, 3H), 4.56-4.59 (m, 2H), 3.73-3.78 (m, 2H), 2.66-2.68 (m,
2H), 2.11-2.14 (m, 3H). LCMS, m/z: MH+ 327.2, MH- 325.2.
Anal. (C17H15FN4O2) C, H, F, N.

5050 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23
Albaugh et al.
9-Bu t a n oyl-2-(2-flu or op h en yl)-7,8,9,10-t et r a h yd r oim -
idazo[1,2-c]pyr ido[3,4-e]pyr im idin -5(6H)-on e (53). 1H NMR
(DMSO-d6): δ 8.20 (t, J ) 7.57 Hz, 1H), 7.95 (d, J ) 4.12 Hz,
1H), 7.31-7.39 (m, 3H), 3.76-3.78 (m, 2H), 2.67 (s, 2H), 2.56
(s, 2H), 2.37-2.46 (m, 2H), 1.53-1.58 (m, 2H), 0.92 (t, J )
7.33 Hz, 3H). LCMS, m/z: MH+ 355.2, MH- 353.3. HPLC
purity in Supporting Information.
9-Hexa n oyl-2-(2-flu or op h en yl)-7,8,9,10-tetr a h yd r oim -
idazo[1,2-c]pyr ido[3,4-e]pyr im idin -5(6H)-on e (54). 1H NMR
(DMSO-d6): δ 8.15-8.24 (m, 1H), 7.40 (s, 1H), 7.24-7.41 (m,
3H), 4.58 (s, 2H), 3.71-3.82 (m, 2H), 2.65 (s, 2H), 2.43-2.69
(m, 2H), 1.53-1.65 (m, 2H), 1.29-1.41 (m, 4H), 0.76-0.88 (m,
3H). LCMS, m/z: MH+ 383.3, MH- 381.3. Anal. (C21H23FN4O2)
C, H, F, N.
temperature was added n-butyraldehyde (53 µL, 0.6 mmol) and
sodium cyanoborohydride (38 mg, 0.6 mmol). The reaction
mixture was stirred for 6 h, and then concentrated HCl was
added until the mixture became homogeneous. The solution
was diluted with water (5 mL) and extracted 2× with ether.
The aqueous layer was made alkaline with aqueous am-
monium hydroxide, saturated with sodium chloride, and
extracted 2× with 10% methanol/EtOAc. The combined organic
layers were dried (MgSO4), filtered, and concentrated, and the
resulting solid was recrystallized from aqueous ethanol to give
1
29 as a white fluffy solid, mp 251-253 °C. H NMR (DMSO-
d6): δ 8.18 (t, J ) 7.76 Hz, 1H), 7.93 (d, J ) 4.12 Hz, 1H),
7.30-7.40 (m, 3H), 3.53 (s, 2H), 2.71-2.74 (m, 2H), 2.59 (s,
2H), 1.51-1.55 (m, 2H), 1.35 (q, J ) 7.52 Hz, 2H), 0.93 (t, J )
7.33 Hz, 3H). LCMS, m/z: MH+ 341.2, MH- 339.2. Anal.
(C19H21FN4O) C, H, N.
9-P h en yla cetyl-2-(2-flu or op h en yl)-7,8,9,10-tetr a h yd r o-
1
im id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e (56). H
NMR (DMSO-d6): δ 8.23-8.27 (m, 1H), 7.94 (d, J ) 3.42 Hz,
1H), 7.23-7.40 (m, 8H), 4.63 (s, 2H), 3.82-3.9 (m 4H), 2.5 (m,
2H). LCMS, m/z: MH+ 403.4, MH- 401.3. HPLC purity in
Supporting Information.
9-P icolin oyl-2-(2-flu or op h en yl)-7,8,9,10-tetr a h yd r oim -
idazo[1,2-c]pyr ido[3,4-e]pyr im idin -5(6H)-on e (57). 1H NMR
(DMSO-d6): δ 8.63 (d, J ) 5.49 Hz, 1H), 7.66 (t, J ) 7.01 Hz,
1H), 7.88-7.96 (m, 2H), 7.66 (d, J ) 7.69 Hz, 1H), 7.52 (t, J )
6.32 Hz, 1H), 7.27-7.38 (m, 3H), 4.77 (s, 1H), 4.63 (s, 1H),
3.94-4.0 (m, 1H), 2.69 (s, 2H). LCMS, m/z: MH+ 390.2, MH-
388.2. HPLC purity in Supporting Information.
9-Nicotin oyl-2-(2-flu or op h en yl)-7,8,9,10-tetr a h yd r oim -
idazo[1,2-c]pyr ido[3,4-e]pyr im idin -5(6H)-on e (58). 1H NMR
(DMSO-d6): δ 8.71-8.73 (m, 2H), 8.24-8.26 (m, 1h), 7.87-
8.0 (m, 2h), 7.52-7.57 (m, 1H), 7.25-7.35 (m, 3H), 4.76-4.79
(m, 1h), 4.54-4.59 (m, 1H), 3.95-4.0 (m, 1H), 3.60-3.65 (m,
1h), 2.65-2.70 (m, 2H). LCMS, m/z: MH+ 390.2, MH- 388.2.
HPLC purity in Supporting Information.
9-Ison icotin oyl-2-(2-flu or op h en yl)-7,8,9,10-tetr a h yd r o-
im id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e Dim esyl-
a te (59). 1H NMR (DMSO-d6): δ 8.96 (s, 2h), 8.21-8.29 (m,
1H), 7.91-8.12 (m, 3H), 7.24-7.47 (m, 3h), 4.46 (s, 1H), 3.98
(s, 1H), 3.57 (s, 1H), 2.62-2.71 (m, 2H), 2.34 (s, 6H). LCMS,
m/z: MH+ 390.2, MH- 388.2. HPLC purity in Supporting
Information.
9-Ca r boben zyloxy-2-(2-flu or op h en yl)-7,8,9,10-tetr a h y-
d r oim id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e (62).
Benzyl chloroformate (57 µL, 0.4 mmol) was added to a solution
of 24 (124 mg, 0.4 mmol) and triethylamine (74 µL, 0.5 mmol)
in DMF (1 mL) at room temperature. The reaction mixture
was stirred for 1 h and then was poured into ice/water. The
precipitate was collected, washed with 95% ethanol and then
ether, dried, and recrystallized from aqueous ethanol to afford
62 as an off-white solid, mp 250 °C (dec). 1H NMR (DMSO-
d6): δ 8.12-8.21 (m, 1H), 7.93 (d, J ) 3.84 Hz, 1H), 7.29-
7.39 (m, 8H), 5.14 (s, 2H), 4.55 (s, 2H), 3.71-3.76 (m, 2H),
2.53-2.65 (m 2H). LCMS, m/z: MH+ 419.3, MH- 417.2. HPLC
purity in Supporting Information.
The following compounds were prepared in a fashion similar
to that for 29.
9-Meth yl-2-(2-flu or oph en yl)-7,8,9,10-tetr ah ydr oim idazo-
[1,2-c]pyr ido[3,4-e]pyr im idin -5(6H)-on e (25). 1H NMR (DM-
SO-d6): δ 8.16 (t, J ) 7.97 Hz, 1H), 7.92 (d, J ) 2.93 Hz, 1H),
7.29-7.39 (m, 3H), 3.51 (s, 2H), 2.65-2.7 (m, 2H), 2.61 (s, 2H),
2.42 (s, 3H). LCMS, m/z: MH- 297.3. HPLC purity in Sup-
porting Information.
9-Eth yl-2-(2-flu or op h en yl)-7,8,9,10-tetr a h yd r oim id a zo-
[1,2-c]pyr ido[3,4-e]pyr im idin -5(6H)-on e (26). 1H NMR (DM-
SO-d6): δ 8.14-8.17 (m, 1H), 7.90 (d, J ) 3.84 Hz, 1H), 7.18-
7.41 (m, 3H), 3.52 (s, 2H), 2.71 (s, 2H), 2.50-2.59 (m, 4H), 1.12
(t, J ) 5.77 Hz, 3H). LCMS, m/z: MH- 311.2. Anal. (C17H17
FN4O‚0.5NaCl) C, H, N.20
-
9-Allyl-2-(2-flu or op h en yl)-7,8,9,10-tetr a h yd r oim id a zo-
[1,2-c]pyr ido[3,4-e]pyr im idin -5(6H)-on e (27). 1H NMR (DM-
SO-d6): δ 8.12-8.15 (m, 1H), 7.91-7.93 (m, 1H), 7.21-7.37
(m, 3H), 5.82-5.94 (m, 1H), 5.30 (d, J ) 6.9 Hz, 1H), 5.21 (d,
J ) 9.9 Hz, 1H), 3.53 (s, 2H), 2.73 (s, 2H), 2.59 (s, 2H). LCMS,
m/z: MH- 323.3. Anal. (C18H17FN4O) C, H, F, N.
9-Isop r op yl-2-(2-flu or op h en yl)-7,8,9,10-tetr a h yd r oim -
idazo[1,2-c]pyr ido[3,4-e]pyr im idin -5(6H)-on e (28). 1H NMR
(DMSO-d6): δ 8.12-8.24 (m, 1H), 7.92 (d, J ) 4.4 Hz, 1H),
7.21-7.45 (m, 3H), 3.61 (s, 2H), 2.82-2.94 (m, 1H), 2.74 (s,
2H), 2.57 (s, 2H), 1.08 (s, 6H). LCMS, m/z: MH- 325.3. Anal.
(C18H19FN4O‚2HCl‚H2O) C, H, F, N.
9-Cyclop r op ylm eth yl-2-(2-flu or op h en yl)-7,8,9,10-tetr a -
h ydr oim idazo[1,2-c]pyr ido[3,4-e]pyr im idin -5(6H)-on e (30).
1H NMR (DMSO-d6): δ 8.15 (t, J ) 7.69 Hz, 1H), 7.87 (d, J )
4.12 Hz, 1H), 7.26-7.34 (m, 3H), 3.60 (s, 2H), 2.75-2.78 (m,
2H), 2.57 (s, 2H), 2.41 (d, J ) 6.6 Hz, 2H), 1.75 (s, 2H), 0.85-
0.97 (m, 1H), 0.48-0.52 (m, 2H). LCMS, m/z: MH- 337.2.
Anal. (C19H19FN4O‚2HCl)) C, H, F, N.
9-Cycloh exylm eth yl-2-(2-flu or oph en yl)-7,8,9,10-tetr ah y-
d r oim id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e (31).
1H NMR (DMSO-d6): δ 8.15 (t, J ) 7.55 Hz, 1H), 7.88-7.90
(m, 1H), 7.24-7.41 (m, 3H), 3.48 (s, 2H), 2.67 (s, 2H), 2.56 (s,
2H), 2.31 (d, J ) 6.32 Hz, 2H), 1.5-1.82 (m, 6H), 1.06-1.24
(m, 3H), 0.76-0.86 (m, 2H). LCMS, m/z: MH+ 381.3, MH-
379.4. HPLC purity in Supporting Information.
The following compounds were prepared in a fashion similar
to that for 62.
9-Ca r boeth oxy-2-(2-flu or op h en yl)-7,8,9,10-tetr a h yd r o-
1
im id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e (60). H
9-(3-P yr idylm eth yl)-2-(2-flu or oph en yl)-7,8,9,10-tetr ah y-
d r oim id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e (42).
A mixture of 58 (128 mg, 0.33 mmol), CH2Cl2 (3 mL), and 1 M
borane in THF (3.3 mL) was stirred at room temperature for
16 h. The reaction mixture was carefully acidifed with 6 N
HCl (5 mL) and heated at reflux. The reaction mixture was
made alkaline with 10% NaOH, and the aqueous layer was
extracted 2× with 10% methanol/ethyl acetate. The combined
organic layers were dried (MgSO4) and concentrated, and the
resulting solid was recrystallized from ethanol to afford 42 as
NMR (DMSO-d6): δ 8.20 (t, J ) 7.38 Hz, 1H), 7.95 (d, J )
4.02 Hz, 1H), 7.31-7.42 (m, 3H), 4.54 (s, 2H), 4.13 (q, J ) 7.05
Hz, 2H), 3.72 (s, 2H), 2.62 (s, 2H), 1.24 (t, J ) 7.08 Hz, 3H).
LCMS, m/z: MH+ 357.2, MH- 355.2. HPLC purity in Sup-
porting Information.
9-Ca r bobu toxy-2-(2-flu or op h en yl)-7,8,9,10-tetr a h yd r o-
1
im id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e (61). H
NMR (DMSO-d6): δ 8.18 (t, J ) 2.99 Hz), 7.94 (d, J ) 3.95
Hz), 7.31-7.39 (m, 3H), 4.52 (s, 2H), 4.06-4.08 (m, 2H), 3.71
(s, 2H), 2.61 (s, 2H), 1.58-1.6 (m, 2H), 1.34-1.39 (m, 2h),
0.89-0.93 (m, 3H). LCMS, m/z: MH+ 385.2, MH- 383.3. Anal.
(C20H21FN4O3) C, H, N.
9-n -Bu tyl-2-(2-flu or oph en yl)-7,8,9,10-tetr ah ydr oim idazo-
[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e (29). To 24 (171
mg, 0.6 mmol) in pH 4-5 HCl/methanol (6 mL) at room
1
a pale-yellow solid, mp 290-292 °C. H NMR (DMSO-d6): δ
8.86 (s, 1H), 8.78 (d, J ) 5.5 Hz, 1H), 8.09 (t, J ) 7.97 Hz,
1H), 7.98 (d, J ) 4.1 Hz, 1H), 7.71-7.76 (m, 1H), 7.29-7.41
(m, 3H), 4.18-4.53 (m, 6H), 2.82-2.94 (m, 2H), 2.3 (s, 3H).
LCMS, m/z: MH+ 376.4, MH- 374.3. Anal. (C21H18FN5O) C,
H, F, N.

Pyrimidin-5(6H)-ones
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23 5051
(4) Forbes, I. T.; J ohnson, C. N.; J ones, G. E.; Loudon, J .; Nicholass,
J . M.; Thompson, M. Synthesis and evaluation of a series of aryl-
[e]fused pyrazolo[4,3-c]pyridines with potential anxiolytic activ-
ity. J . Med. Chem. 1990, 33, 2640-2645.
The following was prepared in a fashion similar to that for
42.
9-(2-P h en yleth yl)-2-(2-flu or op h en yl)-7,8,9,10-tetr a h y-
d r oim id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e (32).
1H NMR (DMSO-d6): δ 8.18 (t, J ) 7.56 Hz, 1H), 7.93 (d, J )
4.01 Hz, 1H), 7.17-7.42 (m, 8H), 3.64 (s, 2H), 3.32 (s, 2H),
2.78-2.84 (m, 4H), 2.58-2.64 (m, 2H). LCMS, m/z: MH+
389.2, MH- 387.2. HPLC purity in Supporting Information.
9-(3-P h en ylp r op yl)-2-(2-flu or op h en yl)-7,8,9,10-tetr a h y-
d r oim id a zo[1,2-c]p yr id o[3,4-e]p yr im id in -5(6H)-on e (33).
1H NMR (DMSO-d6): δ 8.18 (t, J ) 7.76 Hz, 1H), 7.93 (d, J )
4.07 Hz, 1H), 7.19-7.41 (m, 8H), 3.55 (s, 2h), 2.70-2.75 (m,
2H), 2.54-2.68 (m, 6H,), 1.83-1.87 (m, 3H). LCMS, m/z: MH+
403.5, MH- 401.4. Anal. (C24H23FN4O) C, H, F, N.
9-(4-P yr idylm eth yl)-2-(2-flu or oph en yl)-7,8,9,10-tetr ah y-
dr oim idazo[1,2-c]pyr ido[3,4-e]pyr im idin -5(6H)-on e Dim e-
syla te (43). 1H NMR (DMSO-d6): δ 8.94 (d, J ) 5.77 Hz, 1H),
7.97-8.11 (m, 4H), 7.27-7.38 (m, 3H), 4.63-4.65 (m, 2H),
4.27-4.29 (m, 2H), 3.35-3.52 (m, 2H), 2.82-2.93 (m, 2H), 2.32
(s, 6H). LCMS, m/z: MH+ 376.3. HPLC purity in Supporting
Information.
Biologica l P r oced u r es. 1. Ra d ioliga n d Bin d in g Assa y.
Binding affinities were determined by displacement of 3H-
flumazenil from rat cortex homogenates as described previ-
ously,8,9 with minor modifications. A competitive binding curve
is obtained with up to 11 points, potentially spanning the
compound concentration range from 10-12 to 10-5 M. Ki values
are calculated according to the Cheng-Prussof equation.
2. Electr op h ysiology. Xenopus laevis oocytes were injected
with human cRNA of the appropriate R, â, and γ subunits in
order to express the desired receptor subtype. After addition
of GABA to the oocyte, at least five concentrations of test drug
were then added, recording on at least two oocytes per test
drug. Percent potentiation values were averaged and fit to the
(5) Francis, J . E.; Cash, W. D.; Barbaz, B. S.; Bernard, P. S.; Lovell,
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walder, A. F.; Loo, P. S.; Bennett, D. A. Synthesis and benzo-
diazepine binding activity of a series of novel [1,2,4]triazolo[1,5-
c]quinazolin-5(6H)-ones. J . Med. Chem. 1991, 34, 281-290.
(6) Francis, J . E.; Bennett, D. A.; Hyun, J . L.; Rovinski, S. L.;
Amrick, C. L.; Loo, P. S.; Murphy, D.; Neale, R. F.; Wilson, D.
E. Anxiolytic properties of certain annelated [1,2,4]triazolo[1,5-
c]pyrimidin-5(6H)-ones. J . Med. Chem. 1991, 34, 2899-2906.
(7) Taub, D.; Kuo, C.-H.; Wendler, N. L. Transformations in the
1,2,5,6-tetrahydropyridine series. J . Chem. Soc. C 1967, 1558-
1564.
(8) Thomas, J . W.; Tallman, J . F. Characterization of photoaffinity
labeling of benzodiazepine binding sites. J . Biol. Chem. 1981,
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(10) Pritchett, D. B.; Seeburg, P. H. Type I and type II GABAA-
benzodiazepine receptors. Science 1989, 245, 1389-1392.
(11) Knight, A. R.; Hartnett, C.; Marks, C.; Brown, M.; Gallager, D.;
Tallman, J .; Ramabhadran, T. V. Molecular size of R1â1 and
R1â1γ2 GABAA receptors expressed in SF9 cells. Recept. Chan-
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(12) White, G.; Gurley, S. Benzodiazepine site inverse agonists can
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(13) Gurley, D.; Amin, J .; Ross, P. C.; Weiss, D. S.; White, G. Point
mutations in the M2 region of the R, â, or γ subunit of the GABAA
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3, 1-5.
(14) Some recent papers are the following. Hindmarch, I.; Patat, A.;
Stanley, N.; Paty, I.; Rigney, U. Residual effects of zaleplon and
zolpidem following middle of the night administration five hours
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logistic equation, which gave a maximal potentiation, an EC50
,
and a Hill number (not shown but typically ranging from 0.8
to 1.2). Details of the procedure have been described.12,13
3. Sp on ta n eou s Locom otor Activity.17 Male Sprague-
Dawley rats were injected iv with the test drug in a vehicle of
50% aqueous PEG-400. The animals were then placed in an
automated activity monitor in which movement time, total
distance, and vertical activity were assessed over a 15 min
period. The minimum efficacious dose is defined as that needed
to give a statistically significant (P < 0.05) value from control
in at least two of the three measurements.
Su p p or t in g In for m a t ion Ava ila b le: Purity of com-
pounds established from HPLC analysis. This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) Tallman, J . F.; Cassella, J . V.; White, G.; Gallager, D. W. GABAA
receptors: Diversity and its implications for CNS disease.
Neuroscientist 1999, 5, 351-361.
(18) Diaz-Aurauzo, H.; Koehler, K. F.; Hagen, T. J .; Cook, J . M.
Synthetic and computer assisted analysis of the pharmacophore
for agonist at benzodiazepine receptors. Life Sci. 1991, 49, 207-
216.
(19) Subsequent HPLC analysis indicated the presence of starting
material 24. Because 24 is inactive up to the concentrations
tested here, the presence of it was deemed relatively unimpor-
tant with regard to the binding affinity of 41, since 41 is already
potent.
Refer en ces
(1) Klepner, C. A.; Lippa, A. S.; Benson, D. I.; Sano, M. C.; Beer, B.
Resolution of two biochemically and pharmacologically distinct
benzodiazepine receptors. Pharmacol. Biochem. Behav. 1979, 11,
457-462.
(2) Yokoyoma, N.; Ritter, G.; Neubert, A. D. 2-Arylpyrazolo[4,3-c]-
quinoline-3-ones: Novel agonist, partial agonist, and antagonist
of benzodiazepines. J . Med. Chem. 1982, 25, 337-339.
(3) Shindo, H.; Takada, S.; Murata, S.; Masami, E.; Matsushita, A.
Thienylpyrazolquinolines with high affinity to benzodiazepine
receptors: Continuous shift from inverse agonist to agonist
properties depending on the size of the alkyl substituent. J . Med.
Chem. 1989, 32, 1213-1217.
(20) HPLC analysis confirmed the purity of organic material. Thus,
subsequent analogues with various fractionals in the elemental
analysis were not cross-validated.
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