Pyrido[2,3-b]pyrazines, discovery of TRPV1 antagonists with reduced potential for the formation of reactive metabolites

Article abstract of DOI:10.1016/j.bmcl.2010.06.069

The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a non-selective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. During pre-clinical development, the 1,8-naphthyridine 2 demonstrated unacceptably high levels of irreversible covalent binding. Replacement of the 1,8-naphthyridine core by a pyrido[2,3-b]pyrazine led to the discovery of compound 26 which was shown to have significantly lower potential for the formation of reactive metabolites. Compound 26 was characterized as an orally bioavailable TRPV1 antagonist with moderate brain penetration. In vivo, 26 significantly attenuated carrageenan-induced thermal hyperalgesia (CITH) and dose-dependently reduced complete Freund's adjuvant (CFA)-induced chronic inflammatory pain after oral administration.

Full text of DOI:10.1016/j.bmcl.2010.06.069

Bioorganic & Medicinal Chemistry Letters 20 (2010) 4359–4363
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Pyrido[2,3-b]pyrazines, discovery of TRPV1 antagonists with reduced potential
for the formation of reactive metabolites
a
a
a
a
Kevin J. Hodgetts a, , Charles A. Blum , Timothy Caldwell , Rajagopal Bakthavatchalam , Xiaozhang Zheng ,
Scott Capitosti a, James E. Krause a, Daniel Cortright a, Marci Crandall a, Beth Ann Murphy b, Susan Boyce b,
A. Brian Jones b, Bertrand L. Chenard a
*
a Neurogen Corporation, 35 N. E. Industrial Road, Branford, CT 06405, USA
b Merck Sharp & Dohme Limited, Hertford Road, Hoddesdon Herts EN11 9BU, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a non-selective cation
channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat.
Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify
novel agents for pain treatment. During pre-clinical development, the 1,8-naphthyridine 2 demonstrated
unacceptably high levels of irreversible covalent binding. Replacement of the 1,8-naphthyridine core by a
pyrido[2,3-b]pyrazine led to the discovery of compound 26 which was shown to have significantly
lower potential for the formation of reactive metabolites. Compound 26 was characterized as an orally
bioavailable TRPV1 antagonist with moderate brain penetration. In vivo, 26 significantly attenuated
carrageenan-induced thermal hyperalgesia (CITH) and dose-dependently reduced complete Freund’s
adjuvant (CFA)-induced chronic inflammatory pain after oral administration.
Received 21 May 2010
Revised 10 June 2010
Accepted 11 June 2010
Available online 17 June 2010
Keywords:
TRPV1 antagonist
Analgesia
1,8-Naphthyridine
Pyrido[2,3-b]pyrazine
Ó 2010 Elsevier Ltd. All rights reserved.
The transient receptor potential cation channel, subfamily V,
member 1 (TRPV1) is a non-selective cation channel that can be
activated by a wide range of noxious stimuli, including capsaicin,
acid, and heat.1 Blockade of TRPV1 activation by selective antago-
nists is under investigation in an attempt to identify novel agents
for pain treatment.2 We have previously disclosed the evolution
of TRPV1 antagonists from ureas 13 and biarylamides4 to quinazo-
lines5 and ultimately 1,8-naphthyridines 26 (Fig. 1). Compound 2
was superior to many of its forerunners in a number of respects
including solubility, oral exposure and hERG inhibition. Further-
more, 2 demonstrated efficacy in both acute carrageenan-induced
thermal hyperalgesia (CITH) and sub-chronic complete Freund’s
adjuvant (CFA) models, completely blocking the effects of CFA at
10 mg/kg po in rodents. In addition, 2 did not incorporate the 4-tri-
fluoromethylaniline (TFMA) D-ring, which is known to be both
mutagenic and clastogenic in vitro,7 and was common to many
of the more-potent early compounds. In 2, the TFMA is replaced
by the Ames negative 2-amino-5-trifluoromethyl pyridine without
a significant loss in potency.6
toxicity.8 Because these toxicities may not manifest themselves
until the later stages of development or after the launch of a drug,
it is prudent to minimize the potential for formation of reactive
metabolites during the lead optimization stage. During preclinical
investigations, compound 2 was [14C]-labeled at the 7-position,
incubated with rat and human liver microsomes and afforded
levels of irreversible binding of radioactivity (121 and 169 pmol -
equiv/mg protein, respectively).9 These levels exceeded our criteria
for a compound to advance into development (<50 pmol/mg).8a
Presumably, one of the aromatic rings of 2 was oxidized to an
intermediate capable of reacting with a nucleophilic species on
microsomal proteins, resulting in the formation of covalent
adducts. Herein, we report on our efforts to improve the covalent
binding profile of this series while maintaining the overall favor-
able properties exhibited by 2.
CF3
CF3
D
N
HN
HN
The in vivo formation of reactive metabolites and subsequent
formation of covalent adducts with biological macromolecules is
recognized as a potential mediator of drug-induced idiosyncratic
CF3
N
O
CF3
A
B
N
C
N
7
N
N
N
1
2
* Corresponding author. Address: Galenea Corporation, 300 Technology Square,
Cambridge, MA, USA. Tel.: +1 203 675 7540.
hTRPV1 = 17 nM
hTRPV1 = 2.2 nM
E-mail address: kjhodgetts@aol.com (K.J. Hodgetts).
Figure 1. Evolution of TRPV1 antagonists.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.06.069

4360
K. J. Hodgetts et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4359–4363
Ar1
Table 2
1,8-Naphthyridine A-ring analogsa
Cl
N
Cl
N
HN
N
OHC
H2N
CF3
i
ii
Ar1
Ar2
N
Ar2
N
H2N
6
HN
N
Ar2
O
3
5
7-19
4
Ar2
N
N
Scheme 1. Synthesis of 1,8-naphthyridines. Reagents and conditions: (i) tBuOK,
THF, À20 °C (65–87%); (ii) Pd2dba3, Cs2CO3, xantphos, dioxane, 100 °C (43–84%).
2, 14-19
Compd
Ar2
hTRPV1-capb
IC50 (nM)
rTRPV1-pHc
IC50 (nM)
Table 1
1,8-Naphthyridine D-ring analogsa
CF3
Ar1
HN
2
2.2
3.2
na
N
CF3
CF3
N
N
14
161
N
N
N
4, 9-16
CF3
Compd
Ar1
hTRPV1-capb
IC50 (nM)
rTRPV1-pHc
IC50 (nM)
15
8.4
7.1
N
N
CF3
CF3
CF3
CF3
CF3
2
7
2.2
3.2
6.3
4.6
na
16
17
18
134
13
na
na
na
N
N
N
CF3
5.5
H2NOC
N
N
N
N
N
N
N
N
N
N
N
N
CF3
8
4.4
HO2C
607
N
9
81
N
S
Cl
19
12
na
CF3
CF3
10
11
12
25.4
48.7
1450
na
CN
a
b
c
Values are means of P3 experiments.
Human TRPV1 receptor activated by capsaicin.
Rat TRPV1 receptor activated by low pH (5.0–5.5).
CF3
na
CONH2
CF3
na
CF3
CF3
CO2H
Cl
N
N
CF3
HN
N
HN
N
N
O2N
H2N
H2N
H2N
N
N
N
i, ii
13
47
na
iii
S
Ar2
CH(OH)2
20
21
23-27
Ar2
a
b
c
O
22
Values are means of P3 experiments.
Human TRPV1 receptor activated by capsaicin.
Rat TRPV1 receptor activated by low pH (5.0–5.5).
Scheme 2. Synthesis of pyrido[2,3-b]pyrazines 23–27. Reagents and conditions: (i)
2-amino-5-trifluoromethyl pyridineÁHCl, MeCN (48%); (ii) Pd/C, H2 (50 psi), MeOH,
(87%); (iii) NaHCO3, EtOH (43–63%).
As the site of metabolic activation was unknown, we initially
chose to keep the 1,8-naphthyridine core constant and target
replacement of the A- or D-rings by a more electron deficient
surrogate that we hypothesized would be less prone to oxidation.
A two-step synthesis of the 1,8-naphthyridines described in this
study is outlined in Scheme 1. Friedlander10 reaction between
the aldehyde 36 and the ketone 4 gave the 7-substituted-4-
chloro-1,8-naphthyridines 5 in good yields. In the second step,
the D-ring was introduced using a palladium-catalyzed coupling
reaction11 between 5 and an aryl-amine 6 to provide compounds
7–19. The compounds were then assayed for their ability to inhibit
capsaicin activation of human TRPV1 receptors using fluorometric
imaging plate reader (FLIPR) technology as well as their ability to
inhibit the rat TRPV1 receptor upon activation by low pH (5.0–
5.5).12
Changes to the D-ring were investigated first and the introduc-
tion of a second nitrogen atom to the ring gave pyrazine 7 and
pyrimidine 8 and only a small loss in potency relative to 2 (Table 1).
The chloro-pyrimidine 9 was less active, but provided a handle to
introduce other electron withdrawing groups. However, the nitrile
10, amide 11 and acid 12 were less potent than 2. A number of
five-membered D-ring analogs were also prepared, for example
the thiazole 13, but a loss in potency was generally observed.
The pyrimidine 8 was evaluated in the rat CITH model13 of acute
inflammatory pain and gave 78% inhibition at 3 mg/kg po. On the
basis of this encouraging in vivo efficacy, the covalent binding lia-
bility of [14C]-labeled 814 in human liver microsomes was assessed.

K. J. Hodgetts et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4359–4363
4361
Table 3
activity as 14. Introduction of electron withdrawing groups to
the A-ring as in amide 17 or acid 18, led to a loss in potency. A lim-
ited number of 2-trifluoromethyl substituted five-membered het-
erocycles were evaluated and the thiazole 19 had encouraging
potency (hTRPV1 12 nM). The [14C]-labeled thiazole 1915 was incu-
bated with rat and human liver microsomes but afforded unaccept-
ably high levels of irreversible binding of radioactivity (340 and
356 pmol equiv/mg protein, respectively).
Pyrido[2,3-b]pyrazine analogsa
CF3
HN
N
N
N
Ar2
N
23-27
Replacement of the 1,8-naphthyridine by a more electron
deficient pyrido[2,3-b]pyrazine was investigated next and the syn-
thesis is outlined in Scheme 2. 4-Chloro-pyridine 2016 was treated
with 2-amino-5-trifluoromethyl pyridine and hydrogenation of the
nitro group yielded the diaminopyridine 21. Cyclization between
21 and 2217 was affected by treatment with NaHCO3 in ethanol
affording moderate yields of the desired pyrido[2,3-b]pyrazines
23–27.
Compd Ar2
hTRPV1-capb IC50
(nM)
rTRPV1-pHc IC50
(nM)
CF3
23
0.2
30
na
na
na
N
CF3
24
The parent compound 23 (Table 3) had excellent in vitro po-
tency and in in vivo fully inhibited CITH in rats following a 3 mg/
kg oral dose, with a significant effect at the 0.3 mg/kg dose.
5
N
Br
CF3
[
14C]-Labeled 23 was incubated in human liver microsomes and
25
15
N
encouragingly, afforded no irreversible binding of radioactivity.
In rat microsomes, however, 54 pmol equiv/mg protein of radioac-
tivity was observed, indicating that although the pyrido-pyrazine
core was a significant improvement over the 1,8-naphthyridine
core (compare 2 and 23, Table 4) there was still some risk of reac-
tive metabolite formation. We postulated that the residual cova-
lent binding might result from bioactivation of the A-ring and
chose to investigate electron-withdrawing groups at the 5-position
of the pyridine, a position that had not been investigated in the 1,8-
naphthyridine series. The bromo-24 and cyano-25 analogs were
several orders of magnitude less potent than 23. The amide 26,
however, was well tolerated (hTRPV1 0.8 nM and rTRPV1 1.3 nM)
while the corresponding acid was less active (hTRPV1 14 nM).
NC
CF3
26
0.8
27
1.3
na
N
H2NOC
CF3
27
N
HO2C
a
Values are means of P3 experiments.
Human TRPV1 receptor activated by capsaicin.
Rat TRPV1 receptor activated by low pH (5.0–5.5).
b
c
[
14C]-Labeled amide 26 was incubated with rat and human liver
However, the incubation afforded higher levels of irreversible
binding of radioactivity (204 pmol equiv/mg protein) than 2 and
the pyrimidine analog 8 was not pursued further.
A-ring modifications are compiled in Table 2. The pyridyl iso-
mer 14 was significantly less potent than 2, the pyridazine 15
was fourfold less active while the pyrimidine 16 was of similar
microsomes and afforded acceptable levels of irreversible binding
of radioactivity (19 and 8 pmol equiv/mg protein), respectively.
In an in vivo study in rats, 26 (8.1 mg/kg po) demonstrated low
covalent binding to liver (<10 pmol equiv/mg protein at 2, 6 and
24 h) and plasma proteins (<10 pmol equiv/mg protein at 2, 6
and 24 h).
Table 4
Covalent binding to rat and human liver microsomal proteins obtained by incubation of [14C]-compounds9
CF3
CF3
CF3
CF3
CF3
N
HN
N
HN
N
HN
N
N
HN
N
HN
N
N
N
14
N
N
CF3
CF3
CF3
CF3
14
14
14
N
N
N
N
N
2
N
N
N
8
14
N
N
N
N
S
CF3
H2NOC
19
23
26
Compd
hTRPV1-capa
IC50 (nM)
rTRPV1-pHb
2IC50 (nM)
Rat liver
somesc
Rat
l
somes
Human
l
somes
CITH %inhib
(mpk, po)e
Plasma
concn (l
M)f
l
covalent bindingd
covalent bindingd
2
2.2
3.2
100
121 13
169
4
66 @ 1 mpk
115 @ 3 mpk
78% @ 3 mpk
na
85 @ 0.3 mpk
134 @ 3 mpk
49 @ 1 mpk
74 @ 3 mpk
0.30 0.14
1.40 0.69
na
8
19
23
4.4
12
0.2
4.6
na
na
100
100
100
20
3
204 15
356
<5
340 42
8
na
54
19
9
2
na
26
0.8
1.3
100
8
1
0.24 0.07
1.09 0.06
a
b
c
d
e
f
Human TRPV1 receptors activated by capsaicin.
Rat TRPV1 receptors activated by low pH (5.0–5.5).
Percentage of compound remaining after 10 min in rat liver microsomes.
pmol equiv/mg protein at 1 h of incubation.
Dosed as a suspension in 0.5% methocel.
Plasma samples taken immediately after CITH experiment.

4362
K. J. Hodgetts et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4359–4363
Table 5
Plasma PK data for 26
The amide 26 was profiled in the CITH model and gave 49% and
74% inhibition at 1 and 3 mg/kg po with associated plasma concen-
trations of 0.24 and 1.09 M, respectively, and was advanced into
l
Rat
Dog
Rhesus monkey
the CFA model. Compound 26 reversed mechanical hyperalgesia,
in this rat model of persistent inflammation. Rats received an intra-
planar injection of complete Freund’s adjuvant (CFA, 200 lL) into
Dose IVa (mg/kg)
T1/2 (h)
Cl (ml/min/kg)
Vd (l/kg)
Dose POb (mg/kg)
F (%)
1
2.3
25
1
1.5
7.4 1.3
1.3 0.1
1
4.4
2.8 0.7
1.0 0.2
3
4.3 0.1
the left hind paw. The next day the rats were dosed orally once a
day for three consecutive days with either 26 (1, 3, or 10 mg/kg),
vehicle or naproxen (20 mg/kg, positive control). Mechanical hyper-
sensitivity was recorded as a differential weight-bearing response,
measured 0, 1, 2, 4 and 24 h post-dosing. In a separate cohort, plasma
samples were taken each day, 2 h after dosing 26 (Table 6). Within
experimental errors, the plasma levels showed a close to linear rela-
tionship with increasing dose, and at the 10 mg/kg dose plasma con-
1
1
1
103 15
0.3 0.1
1.4 0.1
57 11
0.5 0.1
2.7 0.2
38 11
0.7 0.3
4.9 0.8
Cmax
(lM)
AUC0–24h
(lM h)
Dose POb (mg/kg)
Cmax M)
AUC0–24h
10
2.1 0.2
29.9 3.1
10
5.2 0.7
68 6.9
na
(
l
(lM h)
Dose POb (mg/kg)
Cmax M)
AUC0-24h
100
15 4.3
268 93
na
na
centrations reached 4.24 lM. Figure 2 shows the difference in
(
l
(l
M h)
weight bearing between ipsilateral (CFA-injected) and contralateral
hind paws over the course of the study. A single dose of 26 (1, 3 and
10 mg/kg po) produced a dose-dependent inhibition on day 1 of 39%,
a
Dosed as a solution in 3:1 PEG300:water.
Dosed as a suspension in 0.5% methocel.
b
65% and 85% at 2 h with plasma concentrations of 0.27
lM, 1.2 lM
and 2.4 M, respectively. Similar levels of inhibition were observed
l
following dosing on days 2 and 3 with an overall increase in the mag-
nitude of inhibition at 24 h post dose. On day 3 this equated to 42%,
64% and 70% inhibition at the three doses tested. The level of inhibi-
tion demonstrated by 26 at 10 mg/kg was equivalent to that
observed for rats treated with naproxen (20 mg/kg) in the same
study. It has been suggested in the literature that CNS penetration
is an important attribute for a TRPV1 antagonist in order to achieve
maximum efficacy in pain models that incorporate a component of
central sensitization (e.g., in the CFA-induced mechanical allodynia
model).18 In our hands, robust efficacy is achieved in the CFA weight-
bearing model when 26 is administered at 10 mg/kg po. This corre-
sponds to a Cmax in the brain of ꢀ300 nM, or about 100-fold over the
rat IC50 (rTRPV1pH 3.2 nM).
Table 6
Plasma concentrations of compound 26 for the CFA model (Fig. 1)
Dose of 26 (mg/kg)a
Plasma concentration 2 h post dose (lM)
Day 1
Day 2
Day 3
1
3
10
0.27 0.01
1.20 0.40
2.43 0.80
0.36 0.02
1.10 0.11
3.12 0.52
0.35 0.04
1.28 0.09
4.24 0.56
a
Dosed as a suspension in 0.5% methocel.
Compound 26 had acceptable PK parameters in three species; rat,
dog and rhesus monkey (Table 5) including excellent oral bioavail-
ability (38–103%) across all three species. At higher doses of 26
excellent exposures were also achieved in both rat (10 and
100 mg/kg po) and dog (10 mg/kg po). At the 10 mg/kg dose in both
species the exposure was ꢀ20-fold higher than those at 1 mg/kg
while at 100 mg/kg in rat a ꢀ10-fold increase was achieved. In vitro,
26 demonstrated high permeability in MDCK cells (Papp = 34 Â
10À6 cm/s) and a Pgp efflux ratio ((B?A)/(A?B)) of 3.1, indicating
moderate Pgp efflux liability. However, at the 10 mg/kg po dose in
rat, analysis of brain samples indicated a significant resistance to
To help demonstrate that the observed behavioral effects were
specific to blockade of TRPV1, compound 26 was tested for off-tar-
get activity against a panel of more than 160 receptors, ion chan-
nels, transporters and kinases (MDS Pharma Services). Significant
effects were only observed at the hERG channel (IC50 5.9
and monoamine oxidase MAO-A (IC50 2.4 M) and MAO-B (IC50
2.5 M). Cardiovascular effects were assessed in anaesthetized
lM)
l
l
dogs but no significant effects on cardiovascular parameters
(MAP, HR or ECG intervals) were observed at plasma concentra-
tions of up to 24 lM. Additional studies evaluating the inhibition
crossing the blood–brain barrier; AUC0–24h 3.4 lM h, Cmax 0.3 lM
and brain-to-plasma ratio ꢀ0.1.
Figure 2. Effect of compound 26 at 1, 3 and 10 mg/kg po in the CFA model of inflammation and spontaneous nociception.

K. J. Hodgetts et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4359–4363
4363
10. Cheng, C.-C.; Yan, S.-J. Org. React. 1982, 28, 37.
of MAO activity in vivo and the potential for tyramine interaction
may be required to fully assess the risk of hypertension from using
compound 26 in a clinical setting.
11. Yin, J.; Zhao, M. M.; Huffman, M. A.; McNamara, J. M. Org. Lett. 2002, 4, 3481.
12. Compounds were tested as previously described: Szallasi, A.; Blumberg, P. M.;
Annicelli, L. L.; Krause, J. E.; Cortright, D. N. Mol. Pharmacol. 1999, 56, 581.
13. Carrageenan-induced thermal hyperalgesia model of acute inflammatory pain
as described by: Field, M. J.; Oles, R. J.; Lewis, A. S.; McCleary, S.; Hughes, J.;
Singh, L. Br. J. Pharmacol. 1997, 121, 1513.
14. The brevity of the route to the 1,8-naphthyridine core allowed the introduction
of the [14C]-label at a late stage in the synthesis. The synthesis of the [14C]-
labeled ketone which was then used in the Friedlander cyclization (as outlined
in Scheme 1) is shown below.
Recent reports have indicated that administration of TRPV1
antagonists causes hyperthermia in rodents19 and humans.20 None
of the compounds in the current study were assessed in this para-
digm, however, we have previously reported that compound 2 in
rodents caused a significant increase in initial core body tempera-
ture an effect that was tolerated upon repeat dosing.6 It remains to
be established if this undesirable effect can be disconnected from
analgesic activity.
CF3
N
CF3
N
CF3
N
O
14
14
i
ii
Cl
CN
In summary, the 1,8-naphthyridine 2 demonstrated levels of
irreversible binding of radioactivity that exceeded our criteria for
a compound to advance into development. Substitution of either
the A- or D-ring of 2 by a more electron deficient surrogate was
investigated but no improvement in covalent binding was
observed. Replacement of the 1,8-naphthyridine by a pyrido[2,3-
b]pyrazine core led to the identification of compound 23 and a
significant lowering of the potential for reactive metabolite forma-
tion. Finally, the incorporation of a primary amide at the 5-position
of the A-ring, afforded 26 (hTRPV1 0.8 nM and rTRPV1 1.3 nM) and
minimal potential for covalent protein binding both in vitro and in
vivo. The amide 26 had excellent oral exposure across three species
and at high doses (100 mg/kg) in rat. The pyrido[2,3-b]pyrazine 26
displayed a good selectivity profile in an off-target screen of over
160 receptors, ion channels and enzymes although MAO inhibition
was identified as a potential issue that would need to be further
evaluated in preclinical studies. The overall profile of 26 made it
an excellent candidate for additional in vivo studies to assess the
pharmacological effects of a TRPV1 antagonist with moderate brain
penetration. In rats, 26 significantly attenuated inflammatory pain
in both an acute (carrageenan) and a sub-chronic (CFA) model, fur-
ther supporting the utility of a TRPV1 antagonist for the treatment
of inflammatory pain states (e.g., osteo-arthritis).
Reagents and conditions: (i) Zn(14CN)2, Pd2(dba)3, dppf, DMF, 100 °C (87%); (ii)
CH3MgBr, THF, À20 °C, H3O+ (78%).
15. The synthesis of the [14C]-labeled thiazole is outlined below.
O
O
O
N
N
N
i, ii
iii, iv
OH
CF3
v, vi
H2N
OEt
OEt
S
S
S
I
O
O
N
N
14
vii
NMe(OMe)
CF3
S
S
CF3
Reagents and conditions: (i) NIS, DMF, 60 °C (73%); (ii) tBuONO, THF, 50 °C (49%); (iii)
methyl 2,2,-difluoro-2-(fluorosulfonyl)acetate, CuI, DMF, 85 °C (47%); (iv) 1 M NaOH,
dioxane, rt (93%); (v) (COCl)2, DMFcat, CH2Cl2 (99%); (vi) HN(OMe)MeÁHCl, NEt(iPr)2,
CH2Cl2 (61%); (vii) 14CH3MgBr, THF, À20 °C (84%).
16. Deady, L. W.; Korytsky, O. L.; Rowe, J. E. Aust. J. Chem. 1982, 35, 2025.
17. The dihydroxy-ketones used in the cyclization to pyrido[2,3-b]pyrazines were
prepared from the methyl ketone.
References and notes
1. Szallasi, A.; Cortright, D. N.; Blum, C. A.; Eid, S. R. Nat. Rev. Drug Disc. 2007, 6,
357.
2. Westaway, S. M. J. Med. Chem. 2007, 50, 2589; Gharat, L.; Szallasi, A. Drug Dev.
Res. 2007, 68, 477.
3. (a) DeSimone, R. W.; Hodgetts, K.; Krause, J. E.; White, G. PCT WO 02/08221.;
(b) Bakthavatchalam, R.; Hutchison, A.; DeSimone, R. W.; Hodgetts, K.; Krause,
J. E.; White, G. U.S. Patent 6,723,730, 2004.
CH2Br
O
CH(OH)2
O
ii, iii
i
Ar2
O
Ar2
Ar2
Reagents: (i) Br2, HBr, AcOH (67%); (ii) AgNO3, MeCN (93%); (iii) NaOAc, DMSO (95%).
18. Cui, M.; Honore, P.; Zhong, C.; Gauvin, D.; Mikusa, J.; Hernandez, G.; Chandran,
P.; Gomtsyan, A.; Brown, B.; Bayburt, E. K.; Marsh, K.; Bianchi, B.; McDonald, H.;
Niforatos, W.; Neelands, T. R.; Moreland, R. B.; Decker, M. W.; Lee, C.-H.;
Sullivan, J. P.; Faltynek, C. R. J. Neurosci. 2006, 26, 9385.
19. (a) Honore, P.; Chandran, P.; Hernandez, G.; Gauvin, D. M.; Mikusa, J. P.; Zhong,
C.; Joshi, S. K.; Ghilardi, J. R.; Sevcik, M. A.; Fryer, R. M.; Segreti, J. A.; Banfor, P.
N.; Marsh, K.; Neelands, T.; Bayburt, E.; Daanen, J. F.; Gomtsyan, A.; Lee, C. H.;
Kort, M. E.; Reilly, R. M.; Surowy, C. S.; Kym, P. R.; Mantyh, P. W.; Sullivan, J. P.;
Jarvis, M. F.; Faltynek, C. R. Pain 2009, 142, 27; (b) Tamayo, N.; Liao, H.; Stec, M.
M.; Wang, X.; Chakrabarti, P.; Retz, D.; Doherty, E. M.; Surapaneni, S.; Tamir, R.;
Bannon, A. W.; Gavva, N. R.; Norman, M. H. J. Med. Chem. 2008, 51, 2744; (c)
Garami, A.; Shimansky, Y. P.; Pakai, E.; Oliveira, D. L.; Gavva, N. R.; Romanovsky,
A. A. J. Neurosci. 2010, 34, 1435.
4. Zheng, X.; Hodgetts, K. J.; Brielmann, H.; Hutchison, A.; Burkamp, F.; Jones, A.
B.; Blurton, P.; Clarkson, R.; Chandrasekhar, J.; Bakthavatchalam, R.; De
Lombaert, S.; Crandall, M.; Cortright, D.; Blum, C. A. Bioorg. Med. Chem. Lett.
2006, 16, 5217.
5. Blum, C. A.; Zheng, X.; Brielmann, H.; Hodgetts, K. J.; Bakthavatchalam, R.;
Chandrasekhar, J.; Krause, J. K.; Cortright, D.; Matson, D.; Crandall, M.; Ngo, C.
K.; Fung, L.; Day, M.; Kershaw, M.; De Lombaert, S.; Chenard, B. L. Bioorg. Med.
Chem. Lett. 2008, 18, 4573.
6. Blum, C. A.; Caldwell, T.; Zheng, X.; Bakthavatchalam, R.; Capitosti, S.;
Brielmann, H.; De Lombaert, S.; Kershaw, M. T.; Matson, D.; Krause, J. E.;
Cortright, D.; Crandall, M.; Jones, A. B.; Martin, W. J.; Murphy, B. A.; Boyce, S.;
Mason, G.; Rycroft, W.; Perrett, H.; Conley, R.; Burnaby-Davies, N.; Chenard, B.
L.; Hodgetts, K. J. J. Med. Chem. 2010, 53, 3330.
7. Brent, R. L. Teratology 2001, 63, 106.
20. Gavva, N. R.; Treanor, J. J. S.; Garami, A.; Fang, L.; Surapaneni, S.; Akrami, A.;
Alvarez, F.; Bak, A.; Darling, M.; Gore, A.; Jang, G. R.; Kesslak, J. P.; Ni, L.;
Norman, M. H.; Palluconi, G.; Rose, M. J.; Salfi, M.; Tan, E.; Romanovsky, A. A.;
Banfield, C.; Davar, G. Pain 2008, 136, 202.
8. (a) Evans, D. C.; Watt, A. P.; Nicoll-Griffith, D. A.; Baillie, T. A. Chem. Res. Toxicol.
2004, 17, 3; (b) Nassar, A. F.; Lopez, A. A. Curr. Opin. Drug Disc. Dev. 2004, 7, 126;
(c) Kalgutkar, A. S.; Soglia, J. R. Expert Opin. Drug Metab. Toxicol. 2005, 1, 91; (d)
Ju, C.; Uetrecht, J. P. Curr. Drug Metab. 2002, 3, 367.
9. Samuel, K.; Yin, W.; Stearns, R. A.; Tang, Y. S.; Chaudhary, A. G.; Jewell, J. P.;
Lanza, T., Jr.; Lin, L. S.; Hagmann, W. K.; Evans, D. C.; Kumar, S. J. Mass Spectrom.
2003, 38, 211.