Benzobistriazinones and related heterocyclic ring systems as potent, orally bioavailable positive allosteric AMPA receptor modulators

Article abstract of DOI:10.1016/j.bmcl.2011.09.132

AMPA receptors (AMPARs) are an important therapeutic target in the CNS. A series of substituted benzobistriazinone, benzobispyrimidinone and related derivatives have been prepared with high potency and selectivity for the allosteric binding site of AMPARs

Full text of DOI:10.1016/j.bmcl.2011.09.132

Bioorganic & Medicinal Chemistry Letters 21 (2011) 7455–7459
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Bioorganic & Medicinal Chemistry Letters
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Benzobistriazinones and related heterocyclic ring systems as potent, orally
bioavailable positive allosteric AMPA receptor modulators
⇑
Rudolf Mueller , Stanislaw Rachwal, Mark A. Varney, Steven A. Johnson, Kashinatham Alisala,
Sheng Zhong, Yong-Xin Li, Peter Haroldsen, Todd Herbst, Leslie J. Street
Cortex Pharmaceuticals Inc., 15231 Barranca Parkway, Irvine, CA 92618, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
AMPA receptors (AMPARs) are an important therapeutic target in the CNS. A series of substituted
benzobistriazinone, benzobispyrimidinone and related derivatives have been prepared with high potency
and selectivity for the allosteric binding site of AMPARs. Further improvements have been made to pre-
viously reported series of positive AMPAR modulators and these compounds exhibit excellent in vivo
activity and improved in vivo metabolic stability with up to 100% oral bioavailability in rat.
Ó 2011 Published by Elsevier Ltd.
Received 10 August 2011
Revised 29 September 2011
Accepted 30 September 2011
Available online 8 October 2011
Keywords:
AMPA
Positive allosteric modulator
CNS
Triazinone
(
L
)-Glutamic acid, the main excitatory neurotransmitter in the
triazinone ring in these compounds improved metabolic stability
and plasma half-life over a similar series of bisbenzoxazinone
based AMPAKINEÒs.23 We now report on the further optimization
of these compounds by replacement of the second oxazinone ring
with the metabolically more favourable triazinone and pyrimidi-
one rings (Fig. 1) resulting in compounds with the general struc-
ture 2.
CNS, operates through two main groups of postsynaptic receptors:
metabotropic Glu receptors (mGluRs) and ionotropic Glu receptors
(iGluRs). Each of these receptor families is further divided into sub-
groups, with the iGluRs consisting of N-methyl-
(NMDA), kainic acid (KA), and -amino-3-hydroxy-5-methyl-4-
D-aspartic acid
a
isoxazole-propionic acid (AMPA) receptors. The AMPA subtype
mediates fast excitatory neurotransmission in the mammalian cen-
tral nervous system. Multiple series of small molecules
(AMPAKINEÒs) have been identified that positively modulate the
activity of AMPA receptors (AMPARs).1–7 Instead of affecting gluta-
mate binding itself, these molecules modulate the rate constants
for transmitter binding, channel opening and/or deactivation and
desensitisation. The therapeutic potential of positive allosteric
modulators of AMPARs is considered to be significant.8–15 Psychiat-
ric and neurologic disorders such as attention deficit hyperactivity
disorder (ADHD), schizophrenia, Huntington’s disease, Parkinson’s
disease, and Alzheimer’s disease have been targeted by positive
AMPAR modulators. AMPAKINEÒs have also been shown to upreg-
ulate the production of brain derived neurotrophic factor16–19
(BDNF), promoting synaptic plasticity and neuronal survival in ani-
mal models of brain injury and neurodegeneration. Several series
of positive allosteric AMPAR modulators20–23 have been synthe-
sized as potential drug candidates in our laboratories. AMPAKINEÒ
compounds of general structure 1 were previously shown to have
good activity in an in vivo electrophysiology assay.23 The
In our preceding paper, we demonstrated that the lead
compound (3) is able to facilitate the induction of long term poten-
tiation (LTP) in vivo, which is considered to be a key element in
learning and memory formation, and therefore might allow the
development of a treatment for disorders with cognitive defi-
cits.24–32 A summary of the AMPAR activity of the lead compounds
3 and 4 from the previously reported triazinonebenzoxazinone
O
N
N
N
N
Ar
O
O
1
O
N
N
X
N
Y
X, Y = C, N
N
Ar
O
2
⇑
Corresponding author.
E-mail address: rudolfmueller@yahoo.com (R. Mueller).
Figure 1. Benzobistriazinone and related heterocycles as AMPAR modulators.
0960-894X/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2011.09.132

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R. Mueller et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7455–7459
Table 1
O
O
H
N
Influence of triazinone substitution on AMPAR activity
O
H2N
i
O
O
ii
O
O
O
N
N
N
N
O
O
10
11
O
Z
R
O
O
a
O
Z
T1/2 (rat)
R
EC2x
[lM]
A(%) [concn]b
H
N
H
N
O
O
iii
or iv
O
3
4
Tetrazol-2-yl
Tetrazol-1-yl
0.27 h
NT
Methyl
Methyl
0.46
0.19
33 [5]
7 [5]
O
O
O
NH2
NO2
EC2x values21 are defined as the concentration of compound required to double
a
O
O
the steady-state current induced by glutamate.
12
5
b
In vivo amplitude increase (%) from baseline, using [x] mg/Kg ip.
Scheme 1. Synthesis of intermediate 5. Reagents and conditions: (i) 100 ml
Ac2O/30 mL HCOOH, 10 min, rt, 150 mL CHCl3, 25 g 10, 20 min, 20 °C, 11 quant.;
(ii) 150 mL H2SO4, À10 °C, 15 mL 90% HNO3, 2.5 h ꢀ90% 9:1 mixture, cryst
CH2Cl2/MTBE ꢀ60–70% 12; (iii) CH2Cl2/MeOH, Pd/C 10%, H2, 50 PSI, 20 °C, 30 min
(90%); (iv) THF/MeOH 1:1, excess Zn/Cu, excess HCOOH, 15 min, 20 °C (90%) 5.
series23 is shown in Table 1. The 2-tetrazole 3 was the first ana-
logue from the series to show good activity in the in vivo electro-
physiology assay23 following intraperitoneal (ip) dosing,
suggesting some improvement in oral availability. However, since
compound 3 has a short plasma half-life in rat (0.27 h), our goal
was to further improve metabolic stability in the series. The 1-tet-
razole, compound 4, has poor in vivo activity following both ip and
iv dosing, even though it is more potent in vitro than 3, likely due
to lower brain penetration. Analogues of compound 3 were there-
fore targeted for further optimization studies.
We envisioned that potentially four new scaffolds could be gen-
erated by replacement of the oxazinone ring of 3, and the pyrimid-
inone analogue thereof, with either a triazinone or a pyrimidinone
ring (Fig. 2). To our surprise, only the synthesis of a bispyrimidi-
none scaffold, required to prepare derivatives 7, has been reported
in the literature.33,34
In order to synthesize all four possible combinations of these
tricyclic heterocyclic ring systems we needed a partially protected
intermediate, for example the bisester 5, which would allow us to
selectively close one ring independent from the other in a con-
trolled way to generate the structures 6, 7, 8 and 9 as shown in
Figure 2. The synthesis of intermediate 5 was accomplished by pro-
tecting the nitrogen of the commercially available dimethyl amino
terephthalate 10, as formate 11, followed by nitration, which re-
sulted in a 9:1 mixture of nitration products (Scheme 1). The main
isomer 12 could be crystallized as a single isomer. The reduction of
the nitro group to the aniline 5 was accomplished using Zn/Cu on a
smaller scale or H2/Pd on a larger scale.
deprotected (Scheme 2). Treatment of 13 with potassium hydrox-
ide yielded acid 14 which was coupled to an enantiomerically pure
tetrazole substituted prop-2-ylamine35 using standard conditions
to give the amide 15. Treatment of this aniline derivative with
iso-amyl nitrite yielded the bistriazinone 16 in good overall yield.
We were delighted to see that 16 maintained excellent AMPAR
activity (see Table 2) demonstrating that both oxazinone rings
can be replaced with triazinone rings without loss in activity. A
rat pharmacokinetic study with 16 showed it has 100% oral bio-
availability and a plasma half-life of 1.7 hours. In cynomolgus
monkey 16 has 100% oral bioavailability and a plasma half-life of
9.5 h. Thus, compound 16 has significantly improved pharmacoki-
netic stability over compound 3, achieved by replacing the meta-
bolically unstable oxazinone ring with a triazinone ring.
Based on the results with 16, the pyrimidinone analogues 19
and 20 were also prepared from compound 5 (Scheme 3). Heating
5 with commercially available (R)-2-amino propanol gave the
pyrimidinone analogue 17. Ester hydrolysis, followed by standard
amide formation and ring closure produced the bisazinone
O
N
O
H
N
H
N
O
(H, HCO)
O
i
N
N
O
In order to prepare the bistriazinone compounds, aniline 5 was
diazotized and the crude solution quenched with cyclopropyl-
amine (or any amine of choice) to give the cyclopropyltriazinone
derivative 13, as a mixture of components with the aniline partially
O
NH2
O
O
5
13
14
ii
O
N
N
O
N
H2N
HO
N
N
H2N
O
N
O
N
N
N
N
N
N
R2
R2
N
O
N
O
H
N
N
N
N
N
N
iii
N
R1
R1
O
O
15
7
6
iv
O
H2N
N
O
O
N
O
N
N
N
NH
N
N
N
N
O
5
O
N
O
O
R2
R2
O
N
N
16
N
N
N
N
N
N
R1
R1
N
N
Scheme 2. Synthesis of bistriazinones. Reagents and conditions: (i) THF/H2O,
NaNO2, HCl, 0 °C, 2 equiv amine, NEt3, 20 °C, 13 (76–86%); (ii) KOH, THF/MeOH/H2O,
30–60 min, 20 °C 14; (iii) 1 equiv amine, 3 equiv EDCI, 1 equiv HOBT, 1 equiv DMAP,
NEt3, DMF, 20–50 °C, 15 (50–72%); (iv) DMF, excess i-Amyl nitrite, AcOH, 20 °C,
3–18 h, 16 60%.
O
O
9
5 allows the selective synthesis of the
8
Figure 2. The versatile intermediate
heterocyclic ring systems 6–9.

R. Mueller et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7455–7459
7457
Table 2
Influence of triazinone and pyrimidinone units on AMPAR activity
O
N
N
O
X
N
N
Y
N
N
N
N
A(%) [concn]b
a
X
Y
T1/2 (rat)
F (rat)
T1/2 (dog)
T1/2 (monkey)
EC2x
[lM]
16
19
23
24
N
C
N
C
N
N
C
1.7 h
1.6 h
NT
100%
100%
NT
3 h
4.8 h
NT
9.5 h
NT
NT
0.28
0.6
1.0
37[5]
33 [5]
16 [5]
2 [5]
C
NT
NT
NT
NT
1.4
NT = not tested.
a
See Table 1.
b
In vivo amplitude increase (%) from baseline, using [x] mg/Kg ip.
O
O
O
N
N
O
H
N
R2
R2
O
N
O
N
O
N
O
O
O
N
N
i
N
N
OH
i
H
O
N
N
R1
R1
NH2
NH2
NH2
O
5
21
17
8
ii
iv
iii
O
N
N
O
R2
R2
O
N
N
N
N
O
i
H
N
N
OH
N
N
R1
R1
NH2
N
N
22
O
O
7
18
v
Scheme 4. Synthesis of triazinone–pyrimidinone derivatives and bispyrimidinones.
Reagents and conditions: (i) Toluene, TosOH, excess HC(OMe)3 or CH(OMe)2N(Me)2
110 °C (40–70%).
N
N
O
N
O
N
N
O
N
N
N
O
N
N
N
N
N
N
N
N
modulator both in vitro and in vivo, whereas the bispyrimidinone
24 is 5 times weaker in vitro and is essentially inactive in the
in vivo electrophysiology assay. When only one pyrimidinone unit
is present, the compounds are active in vitro and in vivo, however
analogue 19 exhibits better properties, compared to 23. Based on
the SAR results of our preceding work20–23 we prepared a series
of compounds based on the lead compounds 16 and 19 incorporat-
ing a range of side-chains (Tables 3 and 4).
N
N
19
20
Scheme 3. Synthesis of pyrimidinones/triazinones. Reagents and conditions:
(i) 1 equiv 5, 1.8 equiv (R)-2-amino propanol, 0.3 equiv NaCN, 110 °C, 30 min, 59%
17, (ii) 2.1 equiv KOH, MeOH/H2O, 1 h, 65 °C; (iii) 3.3 equiv cyclopropylamine,
2.7 equiv EDCI, 1 equiv HOBT, 2 equiv DMAP, 2 equiv NEt3, DMF, 40 °C, 6 h;
(iv) DMF, excess iso-butyl nitrite, AcOH, 22 °C, 16 h, 18; (v) 4.1 equiv tetrazole,
1.65 equiv Ph3P, 2 equiv DIAD, THF, 20 °C, 14 h, 19 (less polar) and 20.
It is apparent from the data in Tables 3 and 4 that R1 = methyl is
the best group for AMPAR activity. Variation of R2 on the triazinone
ring is tolerated, but small substituents are preferred, for example,
methyl and cyclopropyl. All the tetrazol-1-yl substituted com-
pounds are more active in vitro than the tetrazol-2-yl derivatives,
but are less active in vivo which may be due to lower CNS penetra-
tion of the more polar tetrazol-1-yl derivatives. In general, the
bistriazinone and pyrimidinone/triazinone derivatives in Tables 3
and 4 exhibit similar in vivo activities, when compounds with
the same substitution pattern are compared. Compound 16 was
tested in a large series (ꢀ100 targets) of in vitro CNS and nonCNS
receptor binding and enzymatic assays (NovaScreenÒ, Caliper Life
derivative 18. The hydroxyl group of 18 could be replaced by a
range of N-linked heterocycles.
For example, replacement with tetrazole under Mitsunobu con-
ditions generated a mixture of tetrazoles 19 and 20 which could be
easily separated by column chromatography. We were pleased to
see that compound 19 exhibited similar in vitro and in vivo AMPAR
activity to compound 16 (Table 2). A rat pharmacokinetic study
with 19 showed it to have excellent oral bioavailability, similar
to 16 (see Table 2).
In the preceding examples the triazinone ring was closed as the
last step to form the tricyclic scaffold. The final step can also be
ring closure to form a pyrimidinone ring. This route gave us access
to the two remaining bisazinone scaffolds (Scheme 4). From
intermediate 21 we were able to make the derivatives 8, and from
intermediate 22 we were able to form the bispyrimidinone deriv-
atives 7.
Using these routes, the additional analogues of 16 and 19, com-
pounds 23 and 24, were prepared35,36 for comparison studies (see
Table 2).
Sciences) and showed no ‘off target’ activity up to 10
ing good selectivity for the AMPA receptor.
lM suggest-
The improvement made in these newer series of compounds is
best demonstrated by comparing compounds 3 and 16 (see Figs. 3
and 4) in our in vivo electrophysiology model. The effect of both
compounds on evoked EPSP in the dentate gyrus of anesthetized
rats after ip dosing is similar, comparing the increase in amplitude.
However the duration of the effect is significantly prolonged with
16, and this correlates with the longer plasma half-life of this
compound.
A comparison of this short series of bisazinones shows that the
bistriazinone 16 is the most active positive allosteric AMPAR
Since the azole side-chains of the compounds in Tables 3 and 4
contribute significantly to the AMPAR activity, we wanted to see if

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R. Mueller et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7455–7459
Table 3
AMPAR activity of a series of substituted bistriazinones
O
N
O
R2
N
N
N
N
X
N
R1
R1
R2
EC2x [lM]
A(%) [concn]b
a
X
25
26
27
16
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
3-F-Phenyl
Ethynyl
Ethynyl
H
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Methyl
Methyl
Methyl
Methyl
Ethyl
2-Propyl
Allyl
Propargyl
But-2-ynyl
Methoxyethyl
0.45
NT
NT
0.28
0.07
1.3
0.37
1.1
1 [5]
4 [5]
1 [5]
Tetrazol-2-yl
Tetrazol-2-yl
Tetrazol-2-yl
Tetrazol-1-yl
Triazol-2-yl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
37 [5]
11 [5]
12 [10]
24 [10]
7 [5]
17 [5]
7 [5]
8 [5]
Triazol-1-yl
1,2,4-Triazol-1-yl
4-Cyano-triazol-2-yl
Methyltetrazol-2-yl
Methyltetrazol-1-yl
Methanesulfonamide
Tetrazol-2-yl
Tetrazol-1-yl
Triazol-2-yl
NT
3.1
0.25
0.7
0.28
0.08
2.1
0.09
0.3
0.44
NT
NA
46 [5]
19 [5]
7 [5]
Triazol-1-yl
7 [5]
Tetrazol-2-yl
Tetrazol-2-yl
Tetrazol-2-yl
Tetrazol-2-yl
Tetrazol-2-yl
Tetrazol-2-yl
34 [5]
26 [5]
12 [5]
20 [5]
43 [5]
34 [5]
0.57
NT
NT
NT = not tested; NA = not active.
a
See Table 1.
b
In vivo amplitude increase (%) from baseline, using [x] mg/Kg, ip.
Table 4
AMPAR activity of a series of pyrimidinone/triazinones
O
N
O
R2
N
N
N
N
X
R1
a
X
R1
H
R2
EC2x [lM]
A(%) [concn]b
46
19
20
47
48
49
50
51
52
53
54
55
56
57
58
Tetrazol-2-yl
Tetrazol-2-yl
Tetrazol-1-yl
Triazol-2-yl
4-Cyano-triazol-2-yl
Pyrazolyl
4-Cyanopyrazolyl
Tetrazol-2-yl
Triazol-2-yl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Methyl
Methyl
Methyl
Propargyl
Propargyl
NT
0.6
0.07
NT
NT
NT
NT
NT
NT
NT
0.5
0.25
NT
NT
NT
7 [5]
33 [5]
2 [5]
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
9 [10]
3 [10]
20 [10]
2 [5]
63 [5]
30 [20]
5 [20]
11 [5]
1 [5]
Triazol-1-yl
Tetrazol-2-yl
Tetrazol-1-yl
Tetrazol-2-yl
Tetrazol-2-yl
Tetrazol-2-yl
Fluoroethyl
Difluoroethyl
Trifluoroethyl
32 [10]
16 [20]
7 [10]
NT = not tested.
a
See Table 1.
b
In vivo amplitude increase (%) from baseline, using [x] mg/Kg, ip.
activity could be enhanced even further by the incorporation of two
azole substituted side-chains as shown by the compoundsin Table 5.
These compounds were prepared using the routes described in
Schemes 1–4. As anticipated, potency was enhanced by this modifi-
cation and the compounds in this series are some of the most potent
allosteric AMPAR modulators described to date. As in the preceding
series, the most potent compound in vivo is the bistriazinone com-
pound 59 with two tetrazol-2-yl units in the side-chains.
In summary, by replacing both oxazinone rings in previously re-
ported AMPAKINE series with either a triazinone or a pyrimidinone
ring removed the metabolic liability and resulted in compounds
having good in vivo activity, excellent oral bioavailability and in-
creased pharmacokinetic stability in rat and higher species. The
incorporation of two tetrazol-2-yl side-chains on to the bistriazi-
none scaffold gave the symmetrical compound 59, the most potent
AMPAKINE molecule in the in vivo electrophysiology assay

R. Mueller et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7455–7459
7459
180
160
140
120
100
80
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■
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■
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Figure 4. In vivo activity of 16 on the amplitude of the f-EPSP in rat dentate gyrus.
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Table 5
Effect of 2 chiral sidechains on AMPAR activity
O
30. Lamprecht, R.; LeDoux, J. Nat. Rev. Neurosci. 2004, 5, 45.
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32. Zivcovic, I.; Thompson, D. M.; Bertolino, M.; Uzunov, D.; Dibella, M.; Costa, E.;
Guidotti, A. Pharmacol. Exp. Ther. 2009, 272, 300.
R2
N
X
N
N
Y
R1
N
33. Skibo, E. B.; Gilchrist, J. H. J. Org. Chem. 1988, 53, 4209.
34. Skibo, E. B.; Huang, X.; Martinez, R.; Lemus, R. H.; Craigo, W. A. J. Med. Chem.
2002, 45, 5543.
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36. Mueller, R.; Lee, S. O’Hare, S.; Rogers, G.; Rachwal, S.; Street, L. US2010/
0041647 A1, 2010.
O
R1
X
Y
R2
EC2x [lM]
A(%) [concn]b
a
59
60
61
62
63
64
65
66
Tetrazol-2-yl
Tetrazol-2-yl
Triazol-2-yl
Triazol-1-yl
Tetrazol-2-yl
Tetrazol-2-yl
Tetrazol-2-yl
Pyrazolyl
N
N
N
N
C
C
C
C
N
N
N
N
N
N
C
Tetrazol-2-yl
Triazol-2-yl
Triazol-2-yl
Triazol-1-yl
Tetrazol-2-yl
Tetrazol-1-yl
Tetrazol-2-yl
Pyrazolyl
0.016
0.07
0.40
0.06
0.008
0.02
0.03
0.09
59 [1]
26 [3]
9 [5]
0 [3]
43 [1]
1 [5]
0 [5]
C
2 [5]
a
See Table 1.
b
In vivo amplitude increase (%) from baseline, using [x] mg/Kg, ip.
reported to date. The further biological evaluation of these com-
pounds will be reported in a separate publication.