Synthesis and biological activity of piperazine and diazepane amides that are histamine H3 antagonists and serotonin reuptake inhibitors

Article abstract of DOI:10.1016/j.bmcl.2007.11.016

The synthesis and biological activity of a new series of piperazine and diazepane amides is described. The new compounds are high affinity histamine H₃ ligands and serotonin reuptake inhibitors.

Full text of DOI:10.1016/j.bmcl.2007.11.016

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 39–43
Synthesis and biological activity of piperazine and diazepane amides
that are histamine H3 antagonists and serotonin reuptake inhibitors
Kiev S. Ly, Michael A. Letavic,* John M. Keith, Jennifer M. Miller, Emily M. Stocking,
Ann J. Barbier, Pascal Bonaventure, Brian Lord, Xiaohui Jiang, Jamin D. Boggs,
Lisa Dvorak, Kirsten L. Miller, Diane Nepomuceno,
Sandy J. Wilson and Nicholas I. Carruthers
Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA
Received 17 October 2007; revised 5 November 2007; accepted 7 November 2007
Available online 13 November 2007
Abstract—The synthesis and biological activity of a new series of piperazine and diazepane amides is described. The new compounds
are high affinity histamine H3 ligands and serotonin reuptake inhibitors.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Selective serotonin reuptake inhibitors (SSRIs) are the
current first line treatments for depression, a disease that
affects millions of people worldwide.1 While effective in
many cases, SSRIs typically have a slow onset of action
and also have little effect on cognitive impairment and
fatigue, conditions that are reported by many depressed
patients.2,3 In order to address some of these issues
many physicians now co-prescribe stimulants with
SSRIs for the treatment of depression.4 While this ap-
proach appears to be useful in some instances, there
are a variety of reasons why stimulants are not the ideal
choice for the treatment of depression, including the fact
that many stimulants increase dopamine levels which
can lead to unwanted behavioral effects.
recently detailed the in vitro and in vivo pharmacology
of JNJ-28583867 (1), a potent histamine H3 antagonist
and serotonin reuptake inhibitor.13
Initial leads for the histamine H3/serotonin reuptake
inhibitor program included the hexahydropyrrolo-iso-
quinoline 2. Removal of the pyrrole ring led to the
simplified 4-aryltetrahydroisoquinolines, including
JNJ-28583867. These efforts eventually led to the discov-
S
O
O
4
3
We recently reported on several classes of histamine H3
antagonists with serotonin reuptake inhibitor activity as
possible alternative approaches for the treatment of
depression.5–9 Histamine H3 antagonists have been
shown to increase wakefulness10,11 in preclinical models
without showing nonspecific stimulant effects,12 thus we
hypothesized that histamine H3 antagonists with SSRI
activity might provide an improved therapy for the
treatment of depression. As part of these efforts we
N
N
N 2
O
N
1
O
1 (JNJ-28583867)
hH3 Ki= 10.6 nM
hSERT Ki= 3.7 nM
2, hH3 Ki= 0.7 nM
hSERT Ki= 3.3 nM
S
R1
O
N
R2
O
O
H
N
N
Keywords: Histamine H3 antagonist; Serotonin reuptake inhibitor;
Histamine; Serotonin.
H
N
N
n
*
Corresponding author. Tel.: +1 858 450 2302; e-mail: mletavic@
prdus.jnj.com
O
4 (n=1,2)
3, hH3 Ki= 11 nM
hSERT Ki= 0.8 nM
Present address: Shire Human Genetic Therapies, 700 Main street,
Cambridge MA 02139, UK.
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.11.016

40
K. S. Ly et al. / Bioorg. Med. Chem. Lett. 18 (2008) 39–43
ery of the even less complicated but related alkyne-based
benzyl amines, represented by 3.
alkyl and cycloalkyl substituents were likely to be pre-
ferred on the piperazine (for H3 affinity) and the com-
pounds in Table 1 confirmed our earlier findings by
affording high affinity H3 ligands.19 The preferred piper-
azine substituents in Table 1 are isopropyl and cyclobu-
tyl. Cyclopropyl groups generally reduced H3 affinity for
this series.
The alkyne subunit of 3 represents one of the many H3
pharmacophores14,15 that have been reported in the lit-
erature over the past few years. We now report on a re-
lated series of piperazine and diazepane amides 4 that
are also dual H3 antagonists/serotonin reuptake
inhibitors.
The isopropyl diazepanes 10a–d are also high affinity
histamine H3 ligands and SERT inhibitors (Table 2).
We also prepared the cyclopropyl diazepanes 10e–w
(Table 3). These cyclopropyl diazepanes proved to
be very high affinity histamine H3 ligands and, with
the appropriate aryloxy substituent, they are also po-
tent SERT inhibitors. As was also observed in our
earlier work with tetrahydroisoquinolines, the substitu-
ent on the aryloxy ring had a large effect on the sero-
tonin reuptake transporter (SERT) affinity. The
highest affinity for SERT was observed when the aryl
ring was substituted in the 4-position. As examples,
unsubstituted analogs (e.g., 9o, 10k), or those substi-
tuted only in the 2- or 3-positions of the ring (e.g.,
9n, 9p, 10d, 10o, 10s), had much lower affinity for
Intermediates 8 were easily obtained via the procedures
previously described for the synthesis of the alkynes 39
from 5-bromo-2-fluorobenzaldehyde 5 by reaction with
a variety of phenols, followed by reductive amination
with methylamine and protection as the Boc amine 8
(Scheme 1).
Compounds 8 were then directly converted to the desired
compounds 9 and 10 by microwave assisted aminocarb-
onylation reactions16,17 followed by Boc deprotection.18
Our initial work focused on the piperazine compounds 9
(Table 1). Previous studies had demonstrated that small
Ar
O
Ar
O
Ar
O
F
H
N
(c)
(a)
(b)
N
H
H
Br
Boc
Br
R1
Br
Br
O
8
O
6
5
7
R2
R1
R2
N
N
R2
NH
R2
O
NH
O
N
N
H
N
H
N
11
12
(d,e)
N
N
8
(d,e)
O
9
O
10
Scheme 1. Synthesis of compounds 9 and 10. Reagents and conditions: (a) K2CO3, ArOH, DMF, 90 ꢁC, 18–72 h; (b) 40% aqueous MeNH2, MeOH,
0 ꢁC, 20 min, then NaBH4, 0 ꢁC, 0.5 h, then 23 ꢁC, 18–24 h; (c) di-tert-butyl dicarbonate, CH2Cl2, 23 ꢁC, 1 h; (d) 11 or 12, THF, DBU, Hermann’s
catalyst,18 t-Bu3PHBF4, Mo(CO)6, 125 ꢁC, microwave, 6 min; (e) TFA, CH2Cl2.
Table 1. Binding data for the rat and human serotonin reuptake transporters and for the human H3 receptor for compounds 9
a
Compound
R1
R2
Rat SERT Kia (nM)
Human SERT Kia (nM)
Human H3 Kia (nM)
Human H3pA2
8.57 ( 0.01)
9a
9b
9c
9d
9e
9f
4-MeS–
4-MeS–
4-MeS, 3-Me–
4-MeS, 3-Me–
3,4 diCl–
3,4 diCl–
3,4 diCl–
3,4 diCl–
4-Cl–
i-Pr
1.8 ( 0.1)
4.0 ( 0.5)
5.8 ( 0.6)
4.2 ( 2.2)
4.9 ( 0.7)
9.3 ( 0.7)
12 ( 2)
5.9 ( 1.5)
5.0 ( 0.6)
8.1 ( 2.7)
11 ( 3)
2.2 ( 0.6)
29 ( 5)
c-Prb
i-Pr
4.3 ( 1.8)
21 ( 5)
8.15 ( 0.08)
c-Pr
i-Pr
6.3 ( 2.9)
6.8 ( 0.3)
16 ( 3)
2.4 ( 1.1)
23 ( 4)
8.17 ( 0.05)
8.10 ( 0.00)
8.35 ( 0.14)
c-Pr
c-Bu
c-Pent
i-Pr
9g
9h
9i
7.7 ( 2.5)
20 ( 7)
11 ( 2)
15 ( 3)
24 ( 7)
8.2 ( 2.5)
9.7 ( 3.7)
10 ( 2)
1.1 ( 0.3)
11 ( 3)
8.63 ( 0.00)
9j
4-Cl–
4-Cl–
c-Pr
c-Bu
c-Pent
i-Pr
23 ( 9)
39 ( 2)
9k
9l
2.4 ( 0.2)
3.4 ( 1.0)
1.1 ( 0.2)
14 ( 5)
4-Cl–
3-MeO–
3-Cl–
8.1 ( 1.2)
18 ( 6)
24 ( 1)
28 ( 5)
9m
9n
9o
9p
9q
8.53 ( 0.09)
c-Pr
c-Pr
c-Pr
c-Pr
113 ( 18)
186 ( 132)
102 ( 28)
16 ( 2.5)
155 ( 68)
535 ( 203)
363 ( 95)
37 ( 18)
H
3-F–
6.8 ( 0.9)
15 ( 2)
37 ( 4)
4-F3C–
a Values are means of at least three experiments in triplicate, standard error of the mean is in parentheses.
b Cyclopropyl.

K. S. Ly et al. / Bioorg. Med. Chem. Lett. 18 (2008) 39–43
41
administration. This provided a crude measure of bio-
availability and of brain exposure. Also, measurement
of receptor/transporter occupancy could be performed
in the same experiment, if warranted.
R1
R1
O
O
N
N
H
N
H
N
N
N
Compound 9f is representative of the more promising
analogs. Figure 1 shows the plasma and brain concen-
trations following a 10 mg/kg p.o. dose of 9f. Good
exposure (Cmax in excess of 1 lM) was obtained both
in plasma and in the brain. A pharmacokinetics experi-
ment was then performed in rats (Fig. 2). Consistent
with the earlier result, compound 9f has good rat phar-
macokinetic parameters (iv t1/2 = 16.1 0.9 h, F = 93%,
Cl = 10.2 1.0 mL/min/kg, and Vss = 13.0 1.2 L/kg).
An ex-vivo autoradiography13 experiment was also per-
formed using 9f in order to confirm receptor occupancy
at the histamine H3 receptor and at the serotonin trans-
porter. The results are shown in Figures 3 and 4. There
is a dose dependent increase in receptor/transporter
occupancy. In a similar experiment (data not shown),
no significant NET occupancy was measured. In con-
trast to the good exposure observed for 9f in rat, several
of the compounds with higher histamine H3 affinity had
poorer PK properties. For example 9a, 9e, 10e, and 10g
had very low exposure (both in plasma and brain tissue)
in similar experiments.
O
O
10a-d
10e-w
SERT than compounds that have a substituent in the
4-position of the ring.
Select compounds were tested in a histamine H3 func-
tional assay and in all cases the compounds were found
to be H3 antagonists (pA2 data, Tables 1–3). Com-
pounds 9a and 10h were also screened in a commercial
panel of 50 receptor, ion channel, and transporter assays
(CEREP, www.cerep.com). Both compounds have weak
affinity for the l-opiate receptor and 10h has weak mus-
carinic-3 receptor affinity.20 Compounds 9a and 10h also
have significant affinity for the norepinephrine trans-
porter (NET) and dopamine transporter (DAT) in this
assay. We confirmed this preliminary data by generating
Ki’s for select compounds against both of these targets.
The compounds generally have very weak affinity for the
dopamine transporter, however they variably have
moderate affinity for the norepinephrine transporter
(Table 4).
In conclusion, we have prepared and characterized a
new class of histamine H3 antagonists with serotonin
reuptake inhibitor activity. Members of this series have
acceptable preclinical pharmacokinetics, which enabled
Several of the compounds in Tables 1–3 were screened in
preliminary in vivo assays. Initially, plasma and brain
levels of the drug in rats were measured following oral
Table 2. Binding data for the rat and human serotonin reuptake transporters and for the human H3 receptor for compounds 10a–d
R1
Rat SERT Kia (nM)
Human SERT Kia (nM)
Human H3 Kia (nM)
Human H3 pA2
a
Compound
10a
10b
10c
10d
4-MeS–
3,4 diCl–
4-Cl–
1.0 ( 0.3)
1.9 ( 0.2)
1.4 ( 0.4)
14 ( 4)
5.0 ( 0.5)
14 ( 7)
1.1 ( 0.1)
1.2 ( 0.2)
0.5 ( 0.3)
1.0 ( 0.1)
9.95 (n = 1)
8.86 ( 0.04)
10.72 (n = 1)
9.98 ( 0.25)
6.4 ( 0.7)
116 ( 15)
3-Cl–
a Values are means of at least three experiments in triplicate except where indicated, standard error of the mean is in parentheses.
Table 3. Binding data for the rat and human serotonin reuptake transporters and for the human H3 receptor for compounds 10e–w
R1
Rat SERT Kia (nM)
Human SERT Kia (nM)
Human H3 Kia (nM)
Human H3 pA2
a
Compound
10e
10f
10g
10h
10i
4-MeS–
4-MeS, 3-Me–
3,4 diCl–
4-Cl–
2.2 ( 0.7)
9.5 ( 4.2)
9.1 ( 1.2)
3.8 ( 0.7)
4.5 ( 0.7)
9.7 ( 2.5)
37 ( 6)
2.9 ( 0.4)
12 ( 5)
1.4 ( 0.3)
4.1 ( 3)
9.76 ( 0.49)
9.06 ( 0.4)
9.76 ( 0.18)
10.1 ( 0.1)
10.37 ( 0.12)
10.4 ( 0.0)
10.7 ( 0.0)
9.0 ( 2.1)
10 ( 3)
13 ( 2)
1.8 ( 0.2)
1.1 ( 0.1)
1.0 ( 0.1)
0.9 ( 0.2)
0.8 ( 0.1)
1.0 ( 0.1)
1.0 ( 0.0)
0.8 ( 0.3)
2.0 ( 0.5)
2.0 ( 0.5)
1.5 ( 0.5)
1.4 ( 0.4)
1.0 ( 0.0)
0.7 ( 0.1)
1.1 ( 0.2)
2.1 ( 0.6)
5.5 ( 0.5)
3-MeO–
3-Cl–
10j
47 ( 19)
229 ( 91)
562 ( 43)
236 ( 94)
68 ( 6)
10k
10l
H
2-F–
117 ( 18)
39 ( 11)
6.7 ( 0.8)
900 ( 122)
11 ( 2)
10m
10n
10o
10p
10q
10r
10s
10t
10u
10v
10w
3-F–
4-F–
10.00 ( 0.52)
10.65 (n = 1)
9.41 (n = 1)
9.68 ( 0.12)
10.32 ( 0.06)
10.32 (n = 1)
10.37 ( 0.12)
10.44 ( 0.01)
10.3 ( 0.1)
2-F3C–
4-F3C–
4-F, 3-Cl–
4-Cl, 2-F–
2-CN
1400 ( 349)
17 ( 6)
36 ( 2)
8.5 ( 2.2)
7.9 ( 1.2)
238 ( 125)
13 ( 6.7)
24 ( 5)
41 ( 9)
797 ( 124)
122 ( 11)
94 ( 11)
702 ( 17)
95 ( 13)
3-CN
4-CN
2-F3CO–
4-F3CS–
299 ( 20)
11 ( 2)
9.60 ( 0.18)
9.23 ( 0.21)
a Values are means of at least three experiments in triplicate except where indicated, standard error of the mean is in parentheses.

42
K. S. Ly et al. / Bioorg. Med. Chem. Lett. 18 (2008) 39–43
Table 4. Binding data for human NET and DAT
100
90
80
70
60
50
40
30
20
10
0
3 mg/kg
Compound
Human NET Kia (nM)
Human DAT Kia (nM)
10 mg/kg
9a
9b
530 ( 150)
3700 ( 1500)
470 (n = 1)
4800 ( 350)
82 ( 32)
7300 ( 2000)
8300 ( 810)
4000 (n = 1)
7000 ( 1200)
330 ( 88)
30 mg/kg
9c
9d
9e
9f
3200 ( 720)
1300 ( 470)
730 (n = 1)
2000 (n = 1)
3300 ( 710)
140 ( 50)
490 ( 120)
3000 ( 690)
7000 (n = 1)
7000 ( 1200)
7700 ( 410)
330 ( 85)
9j
9m
9n
10f
10g
10h
10j
10k
10m
10p
112 ( 15)
420 ( 70)
770 ( 150)
2500 ( 320)
7300 ( 810)
8000 ( 1200)
9000 ( 0)
470 ( 150)
760 ( 220)
5700 ( 2000)
0
4
8
12
16
20
24
28
Time (hr)
a Values are means of at least three experiments in triplicate except
where indicated, standard error of the mean is in parentheses.
Figure 3. Ex-vivo histamine H3 receptor occupancy data in rat
striatum for compound 9f. Time-dependency and dose dependency
after oral administration (3, 10, and 30 mg/kg). Results are represented
as average SEM of n = 3.
10
Plasma
Brain
3 mg/kg
10 mg/kg
1
0.1
100
30 mg/kg
90
80
70
60
50
40
30
20
10
0
0.01
0
4
8
12
16
20
24
28
Time (hr)
Figure 1. Brain and plasma concentrations of compound 9f after oral
administration to the rat (10 mg/kg). Results are represented as
average SEM of n = 3.
10
0
4
8
12
16
20
24
28
PO
Time (hr)
IV
Figure 4. Ex-vivo SERT occupancy data in rat cortex for compound
9f. Time-dependency and dose dependency after oral administration
(3, 10, and 30 mg/kg). Results are represented as average SEM of
n = 3.
1
0.1
for a histamine H3 antagonist with serotonin reuptake
inhibitor activity for use as an alternative to the current
treatments for depression.
0.01
0
4
8
12
16
20
24
28
Time (hr)
Figure 2. Plasma concentrations of compound 9f in rat following po
(10 mg/kg) and iv (1 mg/kg) administration. Results are represented as
average SEM of n = 3.
References and notes
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and diluted with water and extracted into diethyl ether and
concentrated. Chromatography on silica gel (EtOAc/hex)
gave 6c (6.07 g, 71%). 7c: Compound 6c (6.07 g,
18.0 mmol) was dissolved in methanol (250 mL) and
treated with 40% aqueous methylamine (30 mL,
387 mmol). The mixture was stirred at 23 ꢁC for 20 min
until homogeneous then was cooled to 0 ꢁC prior to the
addition of sodium borohydride (in portions, 1.048 g,
27.7 mmol). The reaction mixture was then allowed to
warm to 23 ꢁC and was stirred at that temperature for
25 h. The mixture was diluted with 1 N NaOH and was
extracted with dichloromethane (3·). The organic layers
were dried over sodium sulfate and concentrated to give 7c
(5.76 g, 91%) as an oil. 8c: Compound 7c (5.76 g,
17.1 mmol) was dissolved in dichloromethane (250 mL)
and was treated with triethylamine (4.8 mL, 34.4 mmol)
and di-tert-butyl dicarbonate (4.51 g, 20.6 mmol). The
mixture was stirred at 23 ꢁC for 1 h, then was added to 1 N
NaOH and extracted with dichloromethane. The organic
layer was dried with sodium sulfate and concentrated to
give crude 8c (8.18 g, 106%) containing a small amount of
triethylamine as an oil. The material was used as it is for
the next step. 9c: 8c (0.292 g, 0.646 mmol) was dissolved in
tetrahydrofuran (2 mL) and treated with 1,8-diazabicy-
clo(5.4.0)undec-7-ene (DBU) (0.3 mL), isopropylpiper-
azine (0.3 mL), trans-di-l-acetatobis[2-(di-o-tolyl-phos-
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phino)benzyl]di-palladium(II)
(Hermann’s
catalyst)
(28.7 mg), tri-tert-butylphosphonium tetrafluoroborate
(26.9 mg), and molybdenum hexacarbonyl (177.4 mg)
were then sequentially added to the vial. The vial was
sealed and heated to 125 ꢁC in a microwave reactor for
6 min. The reaction mixture was allowed to cool to room
temperature and then concentrated under reduced pres-
sure. The resulting oil was applied directly to a silica gel
column and chromatographed using a mixture of dichlo-
romethane and 10% methanol containing 0.1% ammo-
nium hydroxide as eluent to give the Boc protected amine,
which was directly treated with dichloromethane (2 mL)
and TFA (1 mL), stirred for 1 h at 23 ꢁC, then concen-
trated and chromatographed using the above eluent to
give 9c (0.0958 g, 35% over 2 steps).
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18. Representative procedure for the synthesis of compounds
9 and 10. 6c: 5-bromo-2-fluorobenzaldehyde (5.13 g,
25.2 mmol) was dissolved in N,N-dimethylformamide
(25 mL) and treated with 4-(methylthio)-m-cresol (4.42 g,
28.7 mmol) and potassium carbonate (7.40 g, 53.5 mmol).
The mixture was heated to 90 ꢁC for 48 h and then cooled
19. A detailed description of the histamine H3 assay and the
histamine H3 functional assay can be found in Ref. 12. A
detailed description of the SERT, NET, and DAT assays
can be found in Ref. 13.
20. Compound 9a had 73% inhibition of the l-opiate receptor
at 1 lM and compound 10h had 66% inhibition of the l-
opiate receptor at 1 lM and 64% inhibition of the
muscarinic-3 receptor at 1 lM.