Novel naphthyridines are histamine H3 antagonists and serotonin reuptake transporter inhibitors

Article abstract of DOI:10.1016/j.bmcl.2007.02.006

A series of novel tetrahydronaphthyridine-based histamine H₃ ligands that have serotonin reuptake transporter inhibitor activity is described. The 1,2,3,4-tetrahydro-2,6-naphthyridine scaffold is assembled via the addition of a nitrostyrene to a metalated pyridine followed by reduction and cyclization to form the naphthyridine. In vitro biological data for these novel compounds are discussed.

Full text of DOI:10.1016/j.bmcl.2007.02.006

Bioorganic & Medicinal Chemistry Letters 17 (2007) 2566–2569
Novel naphthyridines are histamine H3 antagonists
and serotonin reuptake transporter inhibitors
Michael A. Letavic,* John M. Keith, Kiev S. Ly, Ann J. Barbier, Jamin D. Boggs,
Sandy J. Wilson, Brian Lord, Timothy W. Lovenberg and Nicholas I. Carruthers
Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121-1126, USA
Received 2 January 2007; revised 1 February 2007; accepted 2 February 2007
Available online 4 February 2007
Abstract—A series of novel tetrahydronaphthyridine-based histamine H3 ligands that have serotonin reuptake transporter inhibitor
activity is described. The 1,2,3,4-tetrahydro-2,6-naphthyridine scaffold is assembled via the addition of a nitrostyrene to a metalated pyr-
idine followed by reduction and cyclization to form the naphthyridine. In vitro biological data for these novel compounds are discussed.
Ó 2007 Elsevier Ltd. All rights reserved.
Depression is a major health issue that affects millions of
people worldwide.1 Many of these individuals also suffer
from cognitive impairment2 and fatigue.3 Selective sero-
tonin reuptake inhibitors (SSRIs) are the most frequently
prescribed antidepressant drugs, however these agents
often fail to improve the cognitive impairment and
fatigue observed in many patients even as mood
improves.4,5 Some treatments even induce fatigue and
excessive sleepiness.6,7 Co-administration of wake-pro-
moting agents such as modafinil8–10 with SSRIs repre-
sents one viable strategy to improve the efficacy of
SSRI therapy. However, although effective, modafinil
has not seen widespread use in part because it is a Sche-
dule IV compound11 and a P450 inhibitor.12
In this report, we describe the combination of a tetra-
hydronaphthyridine core 6 and previously described
H3 pharmacophores 1, 2,20 and 3 to produce a new class
of dual H3 antagonists/SERT inhibitors 6. Introduction
of the nitrogen in the core naphthyridine ring structure
was expected to alter the physical properties of these
dual ligands, however it was not clear at the outset of
this research what effect the nitrogen would have on
activity at either target. We now describe the prepara-
tion and biological activity of novel 2,6- and 2,5-tetra-
hydronaphthyridines 6.
O
N
O
O
N
N
N
Since H3 receptor antagonists are known to improve
cognition13 and increase wakefulness14,15 in animal
models without showing nonspecific stimulant effects16
we hypothesized that dual H3 antagonists/serotonin
reuptake inhibitors might be useful for the treatment
of depression. Toward this goal, we recently disclosed
the combination of our potent propyloxypiperidine-
based H3 pharmacophore 117 with tetrahydroisoquino-
line-based transporter inhibitors related to 4.18 This
work led to the discovery of potent dual H3 antago-
nists/serotonin reuptake transporter (SERT) inhibitors
exemplified by 5.19
1; hH3 Ki= 0.6 nM
2; hH3 Ki= 2.1 nM
O
N
N
3; hH3 Ki= 1.3 nM
O
O
O
X
N
Y
N
N
Keywords: Histamine H3 antagonists; Serotonin reuptake inhibitors;
Naphthyridines.
N
N
Z
O
*
Corresponding author. E-mail: mletavic@prdus.jnj.com
Present address: EnVivo Pharmaceuticals, 480 Arsenal Street,
Building 1,Watertown, MA 02472, USA.
6, X or Y=N
Z=O or CH2
4; rSERT Ki= 0.43 nM
5; hH3 Ki= 13 nM
hSERT Ki= 6.2 nM
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.02.006

M. A. Letavic et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2566–2569
2567
Br
The synthesis of the 2,5-naphthyridines (Scheme 2) pro-
ceeded smoothly from 2-hydroxynicotinic acid 14 via
bromination of the 5-position of the pyridine ring,
which was followed by chlorination of the hydroxypyri-
dine and reduction of the acid to form the (5-bromo-2-
chloropyridin-3-yl)-methanol 16 in 54% yield over three
steps. The alcohol was then converted to the mesylate
and treated with methylamine to form the benzyl amine
17 (47% for two steps), which was acylated to give the
acyclic amide 18. Treatment of the amide with NaH in
DMSO then gave a good yield of the lactam provided
the reaction was monitored closely. Allowing the ring
closure reaction to proceed beyond the time required
to consume starting material consistently resulted in
diminished yields. Borane reduction of the lactam then
gave the desired 2,5-naphthyridine ring system 20. Palla-
dium-catalyzed coupling of 1-but-3-ynylpiperidine
formed the alkyne 21 in good yield. The alkyne was then
reduced to the alkane via hydrogenation.
Br
H
Br
N
N
N
(a)
(b)
R1
O
R1
Br
O
O
7
8
9
R2
NO2
Br
(f or g, h)
(d, e)
(c)
N
N
R1
O
R1
O
O
O
O
R2
O
10
R2
11
(i)
N
N
R1
N
R1
NH
O
O
12
13
Scheme 1. Synthesis of 2,6-naphthyridines. Reagents and conditions:
(a) NaH, DMF, R1OH, 23 °C, 16 h, 37–84%; (b) diisopropylamine,
n-butyl lithium, THF, À78 °C, then DMF, À78 °C, 0.5 h, then 23 °C,
0.5 h; (c) H2SO4, MeOH, 23 °C, 18 h, 38–89% for two steps; (d) n-butyl
lithium, THF, À78 °C, 0.5 h; (e) various nitrostyrenes, À78 °C, 0.5 h,
then HOAc, 21–65%; (f) Zn, HOAc, 40 °C, 18 h; (g) Zn, 6 N HCl, 18 h;
(h) NaBH4, EtOH, 23 °C, 1 h, 21–96% for three steps; (i) (CH2O)n,
MeOH, 55 °C, then NaBH4, 23 °C, 1 h, 14–51%.
Rat and human SERT data, human histamine H3 bind-
ing data, and functional antagonist data for the 2,6-
naphthyridines 12 and 13 are shown in Table 1.16,19,20
N
OH
OH
N
OH
OH
N
Cl
(b, c)
Br
(a)
OH
Br
O
O
14
15
16
O
The synthesis of the 2,6-naphthyridines began with the
preparation of the trisubstituted pyridine 9 from 2,5-
dibromopyridine as shown in Scheme 1.
N
Cl
N
Cl
H
N
(f)
(d, e)
N
Br
Br
Reaction of 2,5-dibromopyridine with pre-formed
sodium alkoxides provided the 2-alkoxy-5-bromopyri-
dines 8 in good yield. Subsequent metalation of the
4-position of the pyridine ring with LDA21 was fol-
lowed by reaction with DMF to form the unstable
aldehydes 9, which were converted directly to the
dimethoxy acetals 10 in reasonable overall yields.
The key step in the sequence was the low temperature
lithium-halogen exchange on the bromopyridines 10,
followed by reaction with a nitrostyrene22 to form
the nitroalkanes 11. It was important to maintain
the temperature of this reaction at À78 °C in order
to obtain reasonable yields. Yields dropped precipi-
tously when the reaction temperatures were higher.
For this reason the nitrostyrene was typically added
as a pre-cooled solution in tetrahydrofuran and the
reaction was quenched with acetic acid at À78 °C
prior to work-up. Reduction of the nitroalkane to
an alkyl amine was then accomplished by reaction
with zinc in acetic acid. As this procedure variably
produced a small amount of cyclized imine product,
it was generally best to treat the crude mixture direct-
ly with zinc in 6 N HCl to form the imines, which
were then reduced with sodium borohydride to form
12. Alternatively, zinc in 6 N HCl could be used to
form the imines directly from 11. Reductive amination
of 12 then produced the N-methyltetrahydronaphthyri-
dines 13 in moderate yields.
17
O
18
O
O
(g)
Br
(i)
N
O
(h)
Br
N
N
N
19
20
O
O
N
N
N
(j)
N
N
N
21
22
Scheme 2. Synthesis of 2,5-naphthyridines. Reagents and conditions:
(a) Br2, 50% NaOH, H2O, 0–50 °C, 18 h, 78%; (b) thionyl chloride,
DMF, 70 °C, 4 h, 99%; (c) isobutyl chloroformate, Et3N, THF, 0 °C,
then NaBH4, 0–23 °C, 18 h, 70%; (d) MeSO2Cl, DIPEA, THF, 0 °C;
(e) 40% aqueous MeNH2, 23 °C, 2 h, 47% two steps; (f) 4-methoxyph-
enylacetyl chloride, N-methylmorpholine, DCM, 0–23 °C, 18 h, 94%;
(g) NaH, DMSO, 23 °C, 2 h, 65%; (h) BH3THF, THF, 60 °C, 2 h,
71%; (i) PPh3, 1-but-3-ynyl-piperidine, CuI, (Ph3P)2PdCl2, DMF,
Et2NH, 120 °C, 75 min, 67%; (j) H2, Pd/BaSO4, EtOH, 23 °C, 4 h,
96%.

2568
M. A. Letavic et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2566–2569
Table 1. Binding data for the rat and human serotonin reuptake transporters and for the human histamine H3 receptor for compounds 12 and 13
N
N
Et2N
N
O
i-Pr
A
B
C
D
b
Compound
R1
R2
Rat SERT Kia (nM)
Human SERT Kia (nM)
Human H3 Kia (nM)
Human pA2
12a
13a
12b
13b
12c
13c
13d
13e
12d
13f
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
3,4-Dichloro
3,4-Dichloro
4-Chloro
4-Chloro
2-Chloro
3-Chloro
4-Chloro-3-fluoro
3-Methoxy
4-Methoxy
4-Methoxy
4-Fluoro
H
20 ( 7)
15 ( 3)
32 ( 23)
5 ( 1)
18 ( 8)
2 ( 1)
7.95 (n = 2)
7.74 (n = 3)
8.41
120 ( 66)
141 ( 12)
106 ( 7)
30 ( 5)
22 ( 2)
15 ( 3)
1 ( 1)
7 ( 3)
194 ( 51)
144 ( 68)
26 ( 1)
1333 ( 408)
826 ( 214)
147 ( 66)
302 ( 61)
147 ( 17)
107 ( 69)
362 ( 43)
1137 ( 548)
2333 ( 548)
768 ( 458)
26 ( 7)
8.98
8.01
7.78
7.59
8.23
7 ( 2)
8 ( 4)
4 ( 0)
59 ( 8)
46 ( 10)
34 ( 8)
12 ( 6)
9 ( 3)
5 ( 2)
13g
13h
12e
13i
186 ( 59)
569 ( 282)
1667 ( 408)
191 ( 57)
15 ( 2)
8.45
7.67
9.14
8.98
7.85
H
1 ( 0)
2 ( 0)
7 ( 0)
2-Fluoro
3,4-Dichloro
3,4-Dichloro
4-Methoxy
4-Methoxy
H
12f
13j
B
33 ( 11)
129 ( 51)
19 ( 3)
30 ( 15)
226 ( 104)
66 ( 12)
16 ( 2)
23 ( 5)
13 ( 1)
4 ( 2)
12g
13k
13l
B
B
B
583 ( 256)
53 ( 9)
2000 ( 0)
189 ( 19)
70 ( 5)
9.18
12h
13m
12i
C
C
C
D
D
D
D
4-Methoxy
4-Methoxy
H
43 ( 10)
90 ( 17)
13 ( 2)
13 ( 3)
13 ( 4)
4 ( 0)
29 ( 15)
2000 ( 707)
18 ( 3)
7.93 (n = 2)
4767 ( 286)
37 ( 12)
31 ( 5)
12j
3,4-Dichloro
3,4-Dichloro
4-Methoxy
4-Methoxy
13n
12k
13o
Fluoxetine
23 ( 8)
15 ( 6)
93 ( 31)
62 ( 4)
2.2 ( 0.6)
8.45
45 ( 19)
2.9( 0.6)
13 ( 1)
7300 ( 1100)
a Values are means of at least three experiments in triplicate, standard error of the mean is in parentheses.
b Unless indicated, this is the result of a single experiment.
All compounds in Table 1 were tested as racemic mix-
tures.23 Data for the more conformationally restricted
piperidinemethanol compounds 12j–k and 13n–o are
also detailed in Table 1. Most of the compounds in
the table are potent human histamine H3 ligands. Excep-
tions are the morpholine analogs 12h and 13m. In most
cases the N–H tetrahydronaphthyridines 12 have higher
affinity for the H3 receptor than the N-CH3 analogs 13.
All of the compounds tested were functional antagonists
of the histamine H3 receptor (pA2’s between 7.59 and
9.14).
ence against the presence of a nitrogen at this position
on the tetrahydronaphthyridine.24
In order to assess the brain-penetrating ability of a pro-
totype compound, 12i was dosed orally at 10 mg/kg in
rats and the brain and plasma concentrations were mea-
sured at 1, 6, and 24 h. In this experiment, the plasma
Cmax was 0.22 lM at 1 h and the brain Cmax was
5.56 lM at 6 h postdose. Significant brain concentra-
tions (>0.6 lM) were also observed at 24 h, indicating
that this prototype compound should be expected to
have a long duration of action.
Substituents on the aromatic ring (R2) have a dramatic
effect on rat and human SERT activity. Substitution in
the 3- or 4-position is preferred for SERT activity.
SERT activity is practically eliminated when the 3-
and 4-positions of the aromatic ring are not substituted
(e.g., 13h and 12e). The most potent analogs at the
SERT are the 3,4-dichloro- or 4-methoxy derivatives.
Noticeable differences between the rat and human SERT
potency are observed in many cases. Typically these
compounds are less potent at the human SERT than
at the rat SERT, reinforcing the need to screen at the
human transporter. The 2,5-naphthyridines 21 (hSERT
Ki = 1800 nM, hH3 Ki = 38 nM) and 22 (hSERT
Ki = 2500 nM, hH3 Ki = 57 nM) are significantly less po-
tent ligands for either target, suggesting a strong prefer-
In conclusion, we have developed viable synthetic routes
to novel 4-aryl-2,6-tetrahydronaphthyridines and 4-aryl-
2,5-tetrahydronaphthyridines. The 4-aryl-2,6-tetra-
hydronaphthyridines represent a novel class of potent
dual H3 antagonists/SERT inhibitors. A prototype com-
pound in this series was shown to readily penetrate the
brain of a rat indicating that these compounds may be
viable leads for CNS targets. We have also demonstrated
that the 2,5 tetrahydronaphthyridine core, at least in the
case of the 7-alkyl analogs shown, is not favored for
SERT affinity. Further studies detailing the pharmacology
of dual histamine H3 antagonists and serotonin
reuptake inhibitors will be the subject of future
disclosures.

M. A. Letavic et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2566–2569
2569
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demonstrated that the (R)- and (S)-enantiomers of those
compounds are nearly equipotent at both targets. In this
study, the enantiomers of compound 12a were also found
to be essentially equipotent at the human H3 receptor and
the rat SERT.
24. The direct tetrahydroisoquinoline comparator to com-
pound 21, that is, 4-(4-methoxyphenyl)-2-methyl-7-(4-
piperidin-1-yl-but-1-ynyl)-1,2,3,4-tetrahydroisoquinoline,
is reported to have the following Ki’s; human H3
Ki = 3 nM, human SERT Ki = 4 nM (see Carruthers, N.
I.; Gomez, L. A.; Jablonowski, J. A.; Keith, J. M.; Letavic,
M. A.; Ly, K. S.; Miller, J. M. B.; Stocking, E. M.; Wolin,
R. L. PCT Int. Appl. 2006, WO 2006066197 A1), also
indicating that there is a preference against the presence of
the nitrogen atom in the 2,5-naphthyridine structure,
particularly with respect to SERT affinity.