Diether derivatives of homo- or substituted piperidines as non-imidazole histamine H3 receptor ligands

Article abstract of DOI:10.1016/j.bmc.2009.03.014

Synthesis and biological activities of a series of homo- or substituted piperidine unsymmetrical diethers are described. The novel compounds were evaluated for histamine H₃ receptor binding affinities at recombinant human H₃ receptor

Full text of DOI:10.1016/j.bmc.2009.03.014

Bioorganic & Medicinal Chemistry 17 (2009) 3037–3042
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Diether derivatives of homo- or substituted piperidines as non-imidazole
histamine H3 receptor ligands
a
a
b
b
c
_
Dorota Łazewska , Kamil Kuder , Xavier Ligneau , Jean-Claude Camelin , Walter Schunack ,
d
a,
*
´
Holger Stark , Katarzyna Kiec-Kononowicz
a Jagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, 30-688 Kraków, Poland
b Bioprojet-Biotech, 4 rue du Chesnay Beauregard, BP 96205, 35762 Saint-Grégoire, France
c Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2+4, 14195 Berlin, Germany
d Institut für Pharmazeutische Chemie, Biozentrum, ZAFES/LiFF/CMP, Johann Wolfgang Goethe-Universität, Max-von-Laue-Strasse 9, 60438 Frankfurt/Main, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis and biological activities of a series of homo- or substituted piperidine unsymmetrical diethers
are described. The novel compounds were evaluated for histamine H3 receptor binding affinities at
recombinant human H3 receptor stably expressed in HEK-293 cells. All diethers showed in vitro affinities
in nanomolar concentration range. The most potent compounds are 1-[3-(3-(4-chlorophenoxy)pro-
poxy)propyl]-3-methylpiperidine 11 (Ki = 3.2 nM) and 1-[3-(3-(4-chlorophenoxy)propoxy)propyl]aze-
pane 13 (Ki = 3.5 nM).
Received 17 December 2008
Revised 4 March 2009
Accepted 7 March 2009
Available online 14 March 2009
Keywords:
Histamine receptor, H3
Non-imidazole ligands
Ó 2009 Elsevier Ltd. All rights reserved.
Homopiperidine
Methylpiperidine
1. Introduction
O
N
Cl
Histamine H3 receptors, as autoreceptors, control the histamine
synthesis and the release from histaminergic neurons. Histamine
as neurotransmitter in the mammalian brain regulates numerous
brain functions and plays an important role in vigilance, attention,
sleep/wake and feeding/weight regulation.1–3 Histamine H3 recep-
tors act also as heteroreceptors modulating the release of various
neurotransmitters such as acetylcholine, dopamine, norepineph-
rine, glutamate or serotonin.4–10 These neurotransmitters are in-
volved in cognition, mood and sensory gating.
So far, histamine H3 receptor inverse agonists/antagonists are
the preferred class for the development of potential therapeutic
drugs for the treatment of sleep disorders (narcolepsy), obesity
and cognition disorders (attention-deficit hyperactivity disorder,
Alzheimer’s disease, schizophrenia).11–15
BF2.649
KiRC
:
17 nMa
Gp
pA2
:
8.25b
hKi:
EC50
2.4 0.5 nMc
1.5 0.1 nMd
:
h’Ki: : 0.16 0.03 nMe
h”Ki: : 2.7 0.5 nMf
ED50MsC: 1.6 0.9 mg/kg p.o.g
Figure 1. The structure and potency profile of BF2.649 (tiprolisant).22–24 (a) Rat
cerebral cortex; (b) isolated guinea pig ileum; (c) [125I]iodoproxyfan binding assay
at human H3R stably expressed in CHO-K1 cells; (d) [35S]GTP
c
S binding assay at
human H3R stably expressed in CHO-K1 cells; (e) [35S]GTP
cS binding assay at
human H3R stably expressed in HEK-293 cells; (f) [125I]iodoproxyfan binding assay
at human H3R stably expressed in C6 cells; (g) central H3R receptor assay in vivo
after p.o. administration to mice.
Many pharmaceutical companies and academic research groups
have synthesized a large variety of highly potent histamine H3
receptor antagonists/inverse agonists (for review see Refs. 16–
21). Within non-imidazole histamine H3 receptor ligands,
BF2.649 (tiprolisant) has been reported recently as a potent, selec-
tive and valuable drug candidate (Fig. 1).21 BF2.649 showed signif-
icant inhibitory potency in several rodent models of schizophrenia
and efficiency in treating excessive daytime sleepiness in narcolep-
tic patients as a first confirmation in proof-of-concept.25,26 Pres-
ently, BF2.649 is under clinical investigation in Phase II trials for
the treatment of schizophrenia and dementia among other drug
candidates24,26 (for review on clinical developments see Ref. 27).
This report is an extension of our previous work in the non-imid-
azoleresearcharea,28,29 inwhichcompoundFUB637, (1-[3-(phenyl-
propoxy)propyl]piperidine), the analogue of BF2.649, was taken as a
* Corresponding author. Tel.: +48 12 620 5581; fax: +48 12 620 55 96.
E-mail address: mfkonono@cyf-kr.edu.pl (K. Kiec´-Kononowicz).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.03.014

_
3038
D. Łazewska et al. / Bioorg. Med. Chem. 17 (2009) 3037–3042
R1
R1
lead structure. Recentlywe reportedon thesubstitutionof the piper-
idine moiety by different moieties mainly in 4-position (4-propyl, 4-
butyl, 4-benzyl), replacement by other related nitrogen-containing
bicycles (decahydroisoquinoline, 1,2,3,4-tetrahydroisoquinoline)
or by the replacement of the 3-(piperidino)propyloxy fragment with
bipiperidine.29 Here, a second ether moiety has been introduced and
a series of double-ether derivatives of substituted piperidines (3-
methyl, 4-methyl) and azepanes has been prepared. The obtained li-
gands were screened for their binding affinities at recombinant hu-
man histamine H3 receptor.
K2CO3, CH3CN
-HCl
OH
NH
N
Cl
OH
+
1a-1c
m
m
m=1, R: 3-CH3; m=1, R: 4-CH3; m=2, R:H
Scheme 2. The synthesis of 3-aminopropan-1-ols 1a–c.
R2
R2
CH3(CH2)2ONa
Br
O
n
+
Br
Br
n
2a, 2c, 3a-3c
HO
n: 2, 3
2. Results
R: a: 3-OCH3, b: 4-Cl, c: 4-tert-butyl
2.1. Chemistry
Scheme 3. The synthesis of 2-phenoxyethyl bromides (2a, 2c) and 3-phenoxypro-
pyl bromides (3a–c).
The desired ethers 4–16 were prepared by Williamson type O-
alkylation under solvent-free conditions using microwave irradia-
tion according to the procedure described by Bogdał et al.30
(Scheme 1). The alcohol (1a, 1b or 1c) was mixed with the appro-
priate (aryloxy)alkyl bromide (2a, 2c, 3a–c) and a catalytic amount
of tetrabutylammonium bromide (TBAB). The mixture was ab-
sorbed on a mixture of powdered potassium carbonate and potas-
sium hydroxide and then irradiated in an open vessel in a domestic
microwave oven.
3-Amino substituted propan-1-ols (1a–c) were obtained from
appropriate secondary amines and 3-chloropropan-1-ol by the
method described earlier with small modifications (equal volume
of reagents) (Scheme 2).31
Table 1
Affinities of compounds 4–16 at human histamine H3 receptor
R2
R1
nO
N
m
O
Compounds
R1
m
n
R2
Ki SEa (nM)
4
5
6
7
8
3-CH3
4-CH3
H
3-CH3
3-CH3
4-CH3
H
3-CH3
4-CH3
H
3-CH3
4-CH3
H
1
1
2
1
1
1
2
1
1
2
1
1
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3-OCH3
3-OCH3
3-OCH3
4-C(CH3)3
3-OCH3
3-OCH3
3-OCH3
4-Cl
14.8 2.8
12.5 1.6b
7.2 1.1b
The required (aryloxy)alkyl bromides (2a, 2c, 3a–c; Scheme 3)
were prepared in propan-1-ol from suitable phenols and a,x-dib-
62
27.3 2.7
49
5
romoalkanes. The desired products were obtained as free bases.
The final compounds 4–16 were isolated as salts of oxalic acid
(hydrogen oxalates). Their purity was checked by TLC and their
structures were confirmed by standard spectral techniques (1H
NMR, IR) and elemental analysis (Table 3). Some preparative and
physicochemical properties of the ethers 4–16 are presented in
Table 2.
9
4
10
11
12
13
14
15
16
BF2.649
18.6 2.3b
3.2 0.1
27.9 5.9
3.5 0.5b
12.8 2.1b
51 5b
4-Cl
4-Cl
4-C(CH3)3
4-C(CH3)3
4-C(CH3)3
7.7 0.6
2.40c,d
2.2. Pharmacology
125I]Iodoproxyfan binding assay at human H3R stably expressed in HEK-293
a
[
cells.
b
Histamine H3 receptor affinities of the newly synthesized com-
pounds were evaluated at the human receptor. Displacement of
Ref. 40.
Ref. 22.
Ref. 28.
c
d
[
125I]iodoproxyfan from human histamine H3 receptor expressed
in HEK-293 cells, was measured as described previously.32,33 Re-
sults of the pharmacological screening are summarized in Table 1.
In the benzene ring three different substituents were intro-
duced in the para-position: methoxy (compounds 4–6 and 8–10),
tert-butyl (compounds 7 and 14–16) and chlorine (compounds
11–13). In the methoxy series (4–6, 8–10), elongation of the alkyl
chain from two to three carbon atoms (Scheme 1) exhibited a de-
crease in H3 receptor affinity. Compounds 8–10 (n = 3, Ki values of
27.3 nM, 49 nM and 18.6 nM, respectively) are about half as potent
as the related compounds 4–6 (n = 2, Ki values of 14.8 nM, 12.5 nM
and 7.2 nM, respectively).
3. Discussion
Two series of compounds were prepared with two or three
methylene groups between both ether functionalities: (i) deriva-
tives of substituted (2-bromoethoxy)benzenes (4–7) and (ii) deriv-
atives of substituted (3-bromopropoxy)benzenes (8–16). Results of
the displacement assay are shown in Table 1. All tested compounds
exhibited pronounced to high affinities for human histamine H3
receptor (Ki values from 3 to 62 nM).
It seems that steric hindrance limited histamine H3 receptor
affinity. The bulky tert-butyl residue in the para-position (com-
R2
R2
R1
KOH / K2CO3 / TBAB
mw (60-240s)
R1
nO
N
m
O
OH
Br
O
N
+
n
4-16
1a-1c
2a, 2c, 3a-3c
n=2 or 3
m
Scheme 1. The synthesis of ethers 4–16.

_
D. Łazewska et al. / Bioorg. Med. Chem. 17 (2009) 3037–3042
3039
Table 2
exhibit considerable affinities as that of BF2.649. Thus, it seems
that the piperidine moiety can be successfully replaced by the 3-
methylpiperidine or the homopiperidine ring while the second
ether group is introduced to the structure. However, further inves-
tigations are proceeding to confirm these results and to check what
kinds of structural variations are further acceptable for maintain-
ing H3 receptor affinity.
Physicochemical data of novel compounds 4–16
No.
Formula
MW
Mp (°C)
4
5
6
7
8
9
10
11
12
13
14
15
16
C18H29NO3ÁC2H2O4Á0.25H2O
C18H29NO3ÁC2H2O4
C18H29NO3ÁC2H2O4
C21H35NO2ÁC2H2O4
C19H31NO3ÁC2H2O4
C19H31NO3ÁC2H2O4
C19H31NO3ÁC2H2O4
C18H28NO2ClÁ0.9C2H2O4
401.99
397.45
397.45
423.53
411.48
411.48
411.48
406.92
415.91
415.91
451.09
437.56
437.56
89–91
99–101
88–90
145–148
94–96
88–90
88–91
5. Experimental
5.1. Chemistry
132–134
135–138
126–129
101–104
125–128
120–122
C
18H28NO2ClÁC2H2O4
C18H28NO2ClÁC2H2O4
C22H37NO2Á1.1C2H2O4Á0.25H2O
C22H37NO2ÁC2H2O4
Melting points were determined on a MEL-TEMP II apparatus
and are uncorrected. 1H NMR spectra were recorded on a Varian-
Mercury 300 MHz spectrometer in DMSO-d6 or CDCl3. Chemical
shifts are expressed in ppm downfield from internal tetramethyl-
silane as reference. Data are reported in the following order: mul-
tiplicity (br, broad; def, deformed; s, singlet; d, doublet; t, triplet;
m, multiplet; Azep, azepanyl; Ph, phenyl; Pip, piperidino), approx-
imate coupling constants J in hertz (Hz), number of protons. Mass
spectra (MS) were obtained on an EI-MS Finnigan MAT CH7A
(70EV, EI spectra). IR spectra were recorded with a Perkin–Elmer
297 spectral photometer or FT Jasco IR spectrometer from KBr discs
(s, strong). Elemental analyses (C, H, N) were measured on Perkin–
Elmer 240B or Elemental Vario-EL III instrument and are within
0.4% of the theoretical values. Column chromatography (CC)
was performed using silica gel 60 (0.063–0.20 mm; Merck). TLC
was carried out using silica gel F254 plates (Merck). The spots were
visualized with Dragendorff’s reagent or by UV absorption at
254 nM. The following abbreviations are used: CH2Cl2, dichloro-
methane; Et2O, diethyl ether; EtOH, ethanol; TBAB, tetrabutyl
ammonium bromide; W, Watt.
C22H37NO2ÁC2H2O4
Table 3
Data of elemental analysis for final compounds 4–16
No.
% C
% H
% N
Calcd
Found
Calcd
Found
Calcd
Found
4
5
6
7
8
59.76
60.43
60.43
65.22
61.29
61.29
61.29
58.44
57.75
57.75
64.43
65.87
65.87
59.64
60.48
60.18
65.15
60.88
61.46
60.97
58.22
57.74
57.62
64.56
65.46
65.70
7.90
7.86
7.86
8.80
8.08
8.08
8.08
7.38
7.27
7.27
8.87
8.98
8.98
7.74
7.87
7.90
8.75
8.03
8.03
8.02
7.47
7.16
7.28
8.46
9.01
8.88
3.48
3.52
3.52
3.31
3.40
3.40
3.40
3.44
3.37
3.37
3.11
3.20
3.20
3.53
3.52
3.52
3.34
3.66
3.39
3.32
3.37
3.41
3.37
3.08
3.24
3.14
9
10
11
12
13
14
15
16
5.1.1. General procedure for the preparation of 3-heterocyclic
substituted propan-1-ols (1a–c)
pounds 14–16; Ki = 12.8 nM, 51 nM and 7.7 nM, respectively)
caused a decrease in potency compared with that of the para-chlori-
nated compounds 11–13 (Ki = 3.2 nM, 27.9 nM and 3.5 nM, respec-
tively). Compounds 11 and 13 showed the highest histamine H3
receptor affinities with Ki values of 3.2 nM and 3.5 nM, respectively.
From these results for ethers 8–16, the order of the most toler-
able substituents in the phenyl ring (by the binding pocket of H3
receptor) is concluded: 4-Cl > 4-tert-butyl > 3-OCH3. In the ethoxy-
benzen series (4–7) the order of substituents seems to be different:
3-OCH3 > 4-tert-butyl. However, the small number of compounds
does not allow drawing of a final conclusion.
Introduction of a methyl group in the 4-position of the piperi-
dine ring resulted in a decrease in binding affinities, compared
with its constitutional 3-substituted isomers, as seen in com-
pounds: 9 (Ki = 49 nM) versus 8 (Ki = 27.3 nM); 12 (Ki = 27.9 nM)
versus 11 (Ki = 3.2 nM); 15 (Ki = 51 nM) versus 14 (Ki = 12.8 nM).
Interestingly, the extent of this decrease depends on the substitu-
ent on the phenyl ring and the largest one is for the 4-chloro deriv-
atives (12 vs 11). Replacement of the 3-methylpiperidine ring by a
homopiperidine moiety results in derivatives with improved (6 vs
4; 10 vs 8; 16 vs 14) or comparable (13 vs 11) H3 receptor affinities.
Compared to BF2.649 (Ki = 2.4 nM), compounds 11 (Ki = 3.2 nM)
and 13 (Ki = 3.5 nM) showed affinities in the same concentration
range.22 Thus, introduction of the second ether moiety and the
homo- or 3-methyl-piperidine ring resulted in a considerable his-
tamine H3 receptor affinity with presumed differences in pharma-
cokinetic behaviour.
x
-Aminoalkan-1-ols were prepared according to Ref. 34 as de-
scribed previously.31
5.1.1.1. 3-(3-Methylpiperidin-1-yl)propan-1-ol (1a). From 3-
methylpiperidine (0.2 mol, 19.84 g) and 3-chloropropan-1-ol
(0.2 mol, 18.91 g). The reaction mixture was heated to reflux for
10 h and evaporated under Claisen column. Yield: 59%. [bp
114 °C (16 mm Hg) from Ref. 35].
5.1.1.2. 3-(4-Methylpiperidin-1-yl)propan-1-ol (1b). From 4-
methylpiperidine (0.2 mol, 19.84 g) and 3-chloropropan-1-ol
(0.2 mol, 18.91 g). The reaction mixture was heated to reflux for
10 h and evaporated under Claisen column. Yield: 59%. [bp
110 °C (13 mm Hg) from Ref. 35].
5.1.1.3. 3-(Azepan-1-yl)propan-1-ol) (1c). From homopiperidine
(0.2 mol, 19.84 g) and 3-chloropropan-1-ol (0.2 mol, 18.91 g). The
reaction mixture was heated to reflux for 10 h and evaporated un-
der Claisen column. Yield: 60%. [bp 115–117 °C (12 mm Hg) from
Ref. 36].
5.1.2. General procedure for the synthesis of 2-phenoxyethyl
bromides (2a, 2c) and 3-phenoxypropyl bromides (3a–c)
To the solution of sodium (0.1 mol, 2.3 g) in 100 mL of propan-
1-ol an appropriate derivative of the phenol was added (0.1 mol)
and 1,2-dibromoethane or 1,3-dibromopropane (0.3 mol) was
dropped over 1 h. Then, the reaction mixture was heated at 60 °C
for 3 h and refluxed for the next 3 h. The propan-1-ol was evapo-
rated, and to the residue 25 mL of 10% NaOH was added and ex-
tracted with CH2Cl2 25 mL. The organic solution was dried
4. Conclusions
The described diethers are a new promising lead of potent his-
tamine H3 receptor ligands. The most active compounds 11 and 13

_
D. Łazewska et al. / Bioorg. Med. Chem. 17 (2009) 3037–3042
3040
(Na2SO4) and evaporated to give a pure oil or further purified by
CC.
3.71–3.67(m, 5H, OCH3 + O-CH2Á Á ÁPh), 3.50 (t, J = 5.9 Hz, 2H,
PipÁ Á ÁCH2-O), 3.40–3.30 (m, 2H, Pip-2,6-He), 3.05–2.95 (m, 2H,
Pip-CH2), 2.90–2.80 (m, 2H, Pip-2,6-Ha) 1.95–1.85 (m, 2H, Pip-
CH2-CH2), 1.80–1.67 (m, 2H, Pip-3,5-He), 1.56 (br s, 1H, Pip-4-H),
1.40–1.25 (m, 2H, Pip-3,5-Ha), 0.88 (d, J = 6.7 Hz, 3H, CH3); IR
5.1.2.1. 2-Bromo-1-(3-methoxyphenoxy)ethane (2a). From 3-
methoxyphenol (0.1 mol, 12.4 g). Yield 41%. [bp 95–96 °C
(0.35 mm Hg) from Ref. 37].
(KBr) (cmÀ1): 1204s (
m [C–O–Carom]), 1155s (m [C–O–C]).
5.1.2.2. 2-Bromo-1-(4-tert-butylphenoxy)ethane (2c). From 4-
tert-butylphenol (0.1 mol, 15.0 g). Yield: 27%. [bp 117 °C
(0.02 mm Hg) from Ref. 38].
5.1.3.3. 1–3-[2-(3-Methoxyphenoxy)ethoxy)propyl]azepane hy-
drogen oxalate (6). From 3-(azepan-1-yl)propan-1-ol (1c) (0.39 g,
2.5 mmol) and 2-bromo-1-(3-methoxyphenoxy)ethane (2a) (0.69 g,
3 mmol). Heated in the microwave oven for 120 s (2 Â 60 s). Yield of
50 mg (5%) of white solid. 1H NMR [DMSO-d6]: d = 7.16 (t, J = 8.0 Hz,
1H, Ph-5-H), 6.52–6.46 (m, 3H, Ph-2,4,6-H), 4.5 (def t, 2H, CH2-OPh),
3.75–3.67 (m, 5H, OCH3 + AzepÁÁ ÁO-CH2), 3.50 (t, J = 5.9 Hz, 2H,
AzepÁÁÁCH2-O), 3.25–3.10 (m, 4H, Azep-2-H2 + Azep-7-H2), 3.10–3.02
(m, 2H, Azep-CH2), 1.98–1.85 (m, 2H, Azep-CH2-CH2), 1.80–1.70 (m,
4H, Azep-3-H2 + Azep-6-H2), 1.64–1.50 (m, 4H, Azep-4-H2 + Azep-5-
5.1.2.3. 3-Bromo-1-(3-methoxyphenoxy)propane (3a). From 3-
methoxyphenol (0.1 mol, 12.4 g). The residue after the extraction
was purified by CC (CH2Cl2). Yield: 12%. [bp 113–114 °C (0.5 mm
Hg) from Ref. 37].
5.1.2.4. 3-Bromo-1-(4-chlorophenoxy)propane (3b). From 4-
chlorophenol (0.1 mol, 12.9 g). The residue after the extraction
was purified by CC (CH2Cl2). Yield: 84%. [bp 110–111 °C (0.3 mm
Hg) from Ref. 37].
H2); IR (KBr) (cmÀ1): 1205s (
m [C–O–Carom]), 1155s (m [C–O–C]).
5.1.3.4. 1-[3-(2-(-4-tert-Butylphenoxy)ethoxy)propyl]-3-meth-
ylpiperidine hydrogen oxalate (7). From 3-(3-methylpiperidin-
1-yl)propan-1-ol (1a) (0.39 g, 2.5 mmol) and 2-bromo-1-(4-tert-
butylphenoxy)ethane (2c) (0.77 g, 3 mmol).Heated in the micro-
wave oven for 240 s (4 Â 60 s). Yield of 150 mg (14%) of white so-
lid. 1H NMR [DMSO-d6]: d = 7.27 (d, J = 8.9 Hz, 2H, Ph-3,5-H), 6.84
(d, J = 8.7 Hz, 2H, Ph-2,6-H), 4.04 (t, J = 5.4 Hz, 2H, CH2-OPh), 3.68
(t, J = 5.4 Hz, 2H, O-CH2Á Á ÁPh), 3.50 (t, J = 6.2 Hz, 2H PipÁ Á ÁCH2-O),
3.40–3.20 (m, 2H, Pip-2,6-He), 3.05–2.95 (m, 2H, Pip-CH2), 2.72–
2.60 (m, 1H, Pip-6-Ha), 2.45–2.35(m, 1H, Pip-2-Ha), 1.95–1.60 (m,
6H, PipCH2-CH2 + Pip-4,5-H2), 1.23 (s, 9H, 3CH3), 1.10–0.90 (m,
1H, Pip-3-H), 0.85 (d, J = 6.7 Hz, 3H, CH3); IR (KBr) (cmÀ1): 1248s
5.1.2.5. 3-Bromo-1-(4-tert-butylphenoxy)propane (3c). From 4-
tert-butylphenol (0.1 mol, 15.0 g). The residue after the extraction
was purified by CC (CH2Cl2). The crude product contaminated with
4-tert-butylphenol was used without further purification. [bp 118–
120 °C (0.4 mm Hg) from Ref. 37].
5.1.3. General procedure for the preparation of ethers 4–16
A mixture of appropriate 3-aminopropan-1-ol (1a–c, 2.5 mmol),
an alkyl halide (3.0 mmol), TBAB (0.085 g, 0.25 mmol), K2CO3
(2.4 g, 10 mmol) and KOH (0.55 g, 10 mmol) was heated in a
domestic microwave oven (M = 100 W) in an open Erlenmeyer
flask for the appropriate time. After cooling, the reaction mixture
was extracted with CH2Cl2 (2 Â 20 mL). The solvent was removed
under reduced pressure, the residue dissolved in CH2Cl2 (20 mL)
and washed with 20 mL of 3% HCl. The acidic layer was alkalized
(10% NaOH) and extracted with Et2O. The organic layer was then
dried over anhydrous Na2SO4, filtered and concentrated in vacuo.
A colourless oil was dissolved in 2 mL of dry EtOH and then
1.1 equiv of oxalic acid were added. The solution was stirred in
the room temperature for 1 h. On addition of Et2O precipitation
took place and the white solid obtained was filtered. In some cases
re-crystallisation in the same solvents was necessary for
purification.
(m [C–O–Carom]), 1127s (m [C–O–C]).
5.1.3.5. 1-[3-(3-(3-Methoxyphenoxy)propoxy)propyl]-3-meth-
ylpiperidine hydrogen oxalate (8). From 3-(3-methylpiperidin-1-
yl)propan-1-ol (1a) (0.39 g, 2.5 mmol) and 2-bromo-1-(3-
methoxyphenoxy)propane (3a) (0.74 g, 3 mmol). Heated in the
microwave oven for 180 s (3 Â 60 s). Yield of 330 mg (32%) of
white solid. 1H NMR [DMSO-d6]: d = 7.15 (t, J = 8.0 Hz, 1H, Ph-5-
H), 6.51–6.44 (m, 3H, Ph-2,4,6-H), 3.98 (t, J = 6.4 Hz, 2H, CH2-
OPh), 3.71 (s, 3H, OCH3), 3.50 (t, J = 6.2 Hz, 2H, O-CH2Á Á ÁPh), 3.42
(t, J = 5.9 Hz, 2H PipÁ Á ÁCH2-O), 3.36–3.20 (m, 2H, Pip-2,6-He),
3.05–2.90 (m, 2H, Pip-CH2), 2.70–2.55 (m, 1H, Pip-6-Ha), 2.45–
2.30(m, 1H, Pip-2-Ha), 1.96–1.60 (m, 8H, PipCH2-CH2 + CH2-
CH2OPh + Pip-4,5-H2), 1.10–0.90 (m, 1H, Pip-3-H), 0.85 (d,
5.1.3.1. 1-[3-(2-(3-Methoxyphenoxy)ethoxy]propyl-3-methylpi-
peridine hydrogen oxalate (4). From 3-(3-methylpiperidin-1-
yl)propan-1-ol (1a) (0.39 g, 2.5 mmol) and 2-bromo-1-(3-
methoxyphenoxy)ethane (2a) (0.69 g, 3 mmol). Heated in the
microwave oven for 120 s (2 Â 60 s). Yield of 70 mg (7%) of white
solid. 1H NMR [DMSO-d6]: d = 7.16 (t, J = 8.0 Hz, 1H, Ph-5-H),
6.52–6.46 (m, 3H, Ph-2,4,6-H), 4.07–4.04 (m, 2H, CH2-OPh), 3.71–
3.67 (m, 5H, OCH3 + O-CH2Á Á ÁPh), 3.50 (t, J = 6.2 Hz, 2H, PipÁ Á ÁCH2-
O), 3.40–3.25 (m, 2H, Pip-2,6-He), 3.05–2.90 (m, 2H, Pip-CH2),
2.95–2.80 (m, 1H, Pip-6-Ha), 2.48–2.35 (m, 1H, Pip-2-Ha), 1.95–
1.80 (m, 2H, PipCH2-CH2), 1.80–1.55 (m, 4H, Pip-4,5-H2), 1.10–
0.95 (m, 1H, Pip-3-H), 0.85 (d, J = 6.7 Hz, 3H, CH3); IR (KBr)
J = 6.7 Hz, 3H, CH3); IR (KBr) (cmÀ1): 1201s (
1149s ( [C–O–C]).
m [C–O–Carom]),
m
5.1.3.6. 1-[3-(3-(3-Methoxyphenoxy)propoxy)propyl]-4-meth-
ylpiperidine hydrogen oxalate (9). From 3-(4-Methylpiperidin-
1-yl)propan-1-ol (1b) (0.39 g, 2.5 mmol) and 2-bromo-1-(3-
methoxyphenoxy)propane (3a) (0.74 g, 3 mmol). Heated in the
microwave oven for 240 s (4 Â 60 s). Yield of 220 mg (21%) of
white solid. 1H NMR [DMSO-d6]: d = 7.15 (t, J = 8.0 Hz, 1H, Ph-5-
H), 6.51–6.45 (m, 3H, Ph-2,4,6-H), 3.98 (t, J = 6.4 Hz, 2H, CH2-
OPh), 3.70 (s, 3H, OCH3), 3.49 (t, J = 6.2 Hz, 2H, O-CH2Á Á ÁPh), 3.42
(t, J = 5.6 Hz, 2H, PipÁ Á ÁCH2-O), 3.35–3.25 (m, 2H, Pip-2,6-He),
3.03–2.90 (m, 2H, Pip-CH2), 2.83–2.70 (m, 2H, Pip-2,6-Ha) 1.97–
1.80 (m, 4H, PipCH2-CH2 + CH2–CH2OPh), 1.78–1.64 (m, 2H, Pip-
3,5-He), 1.55 (br s, 1H, Pip-4-H), 1.40–1.20 (m, 2H, Pip-3,5-Ha),
(cmÀ1): 1201s (
m [C–O–Carom]), 1156s (m [C–O–C]).
5.1.3.2. 1-[3-(2-(3-Methoxyphenoxy)ethoxy]propyl-4-methylpi-
peridine hydrogen oxalate (5). From 3-(4-methylpiperidin-1-
yl)propan-1-ol (1a) (0.39 g, 2.5 mmol) and 2-bromo-1-(3-
methoxyphenoxy)ethane (2a) (0.69 g, 3 mmol). Heated in the
microwave oven for 300 s (5 Â 60s). Yield of 50 mg (5%) of white
solid. 1H NMR [DMSO-d6]: d = 7.16 (t, J = 8.0 Hz, 1H, Ph-5-H),
6.52–6.46 (m, 3H, Ph-2,4,6-H), 4.07–4.04 (m, 2H, CH2-OPh),
0.88 (d, J = 6.4 Hz, 3H, CH3); IR (KBr) (cmÀ1): 1196s (
1154s ( [C–O–C]).
m [C–O–Carom]),
m
5.1.3.7. 1-[3-(3-(3-Methoxyphenoxy)propoxy)propyl]azepane
hydrogen oxalate (10). From 3-(azepan-1-yl)propan-1-ol (1c)
(0.39 g, 2.5 mmol) and 2-bromo-1-(3-methoxyphenoxy)propane

_
D. Łazewska et al. / Bioorg. Med. Chem. 17 (2009) 3037–3042
3041
(3a) (0.74 g, 3 mmol). Heated in the microwave oven for 180 s
(3 Â 60 s). Yield of 280 mg (27%) of white solid. 1H NMR [DMSO-
d6]: d = 7.15 (t, J = 8.0 Hz, 1H, Ph-5-H), 6.51–6.44 (m, 3H, Ph-
2,4,6-H), 3.98 (t, J = 6.4 Hz, 2H, CH2-OPh), 3.71 (s, 3H, OCH3), 3.50
(t, J = 6.2 Hz, 2H, AzepÁ Á ÁO-CH2), 3.42 (t, J = 6.2 Hz, 2H,
AzepÁ Á ÁCH2-O), 3.20–3.08 (m, 4H, Azep-2-H2 + Azep-7-H2), 3.08–
3.00 (m, 2H, Azep-CH2), 1.96–1.80 (m, 4H, Azep-CH2-CH2 + CH2-
CH2OPh), 1.80–1.70 (m, 4H, Azep-3-H2 + Azep-6-H2), 1.70–1.65
5.1.3.12. 1-[3-(3-(4-tert-Butylphenoxy)propoxy)propyl]-4-methyl
piperidine hydrogen oxalate (15). From 3-(4-methylpiperidin-1-
yl)propan-1-ol (1b) (0.39 g, 2.5 mmol) and 3-bromo-1-(4-tert-butyl-
phenoxy)propane (3c) (0.81 g, 3 mmol). Heated in the microwave
oven for 240 s (4 Â 60 s). Yield of 150 mg (14%) of white solid. 1H
NMR [DMSO-d6]: d = 7.26 (d, J = 8.7 Hz, 2H, Ph-3,5-H), 6.82 (d,
J = 8.7 Hz, 2H, Ph-2,6-H), 3.94 (t, J = 6.2 Hz, 2H, CH2-OPh), 3.50 (t,
J = 6.4 Hz, 2H, O-CH2Á ÁÁPh), 3.42 (t, J = 5.9 Hz, 2H, PipÁÁÁCH2-O),
3.37–3.25 (m, 2H, Pip-2,6-He), 3.03–2.93 (m, 2H, Pip-CH2), 2.85–
2.70 (m, 2H, Pip-2,6-Ha) 1.95–1.78 (m, 4H, PipCH2-CH2 + CH2-
CH2OPh), 1.78–1.68 (m, 2H, Pip-3,5-He), 1.55 (br s, 1H, Pip-4-H),
1.40–1.27 (m, 2H, Pip-3,5-Ha), 1.23 (s, 9H, 3CH3), 0.88 (d, J = 6.4 Hz,
(m, 4H, Azep-4-H2 + Azep-5-H2); IR (KBr) (cmÀ1): 1201s (
Carom]), 1162s ( [C–O–C]).
m [C–O–
m
5.1.3.8. 1-[3-(3-(4-Chlorophenoxy)propoxy)propyl]-3-methyl-
piperidine hydrogen oxalate (11). From 3-(3-methylpiperidin-
1-yl)propan-1-ol (1a) (0.39 g, 2.5 mmol) and 3-bromo-1-(4-chlo-
rophenoxy)propane (3b) (3 mmol, 0.75 g). Heated in the micro-
wave oven for 120 s (2 Â 60 s). Yield of 220 mg (22%) of white
solid. 1H NMR [DMSO-d6]: d = 7.31 (d, J = 9.2 Hz, 2H, Ph-3,5-H),
6.94 (d, J = 8.9 Hz, 2H, Ph-2,6-H), 4.00 (t, J = 6.4 Hz, 2H, CH2-
OPh), 3.49 (t, J = 6.2 Hz, 2H, O-CH2Á Á ÁPh), 3.42 (t, J = 5.9 Hz, 2H,
PipÁ Á ÁCH2-O), 3.35–3.20 (m, 2H, Pip-2,6-He), 3.03–2.90 (m, 2H,
Pip-CH2), 2.74–2.55 (m, 1H, Pip-6-Ha), 2.48–2.30 (m, 1H, Pip-2-
Ha), 1.98–1.55 (m, 8H, PipCH2-CH2 + CH2-CH2OPh + pip-4,5-H2),
1.10–0.90 (m, 1H, Pip-3-H), 0.86 (d, J = 6.4 Hz, 3H, CH3); IR
3H, CH3); IR (KBr) (cmÀ1): 1243s (
m [C–O–Carom]), 1124s (m [C–O–C]).
5.1.3.13. 1-[3-(3-(4-tert-Butylphenoxy)propoxy)propyl]azepane
hydrogen oxalate (16). From 3-(azepan-1-yl)propan-1-ol (1c)
(0.39 g, 2.5 mmol) and 3-bromo-1-(4-tert-butylphenoxy)propane
(3c) (0.81 g, 3 mmol). Heated in the microwave oven for 360 s
(6 Â 60 s). Yield of 280 mg (26%) of white solid. 1H NMR [DMSO-
d6]: d = 7.26 (d, J = 9.0 Hz, 2H, Ph-3,5-H), 6.82 (d, J = 9.0 Hz, 2H,
Ph-2,6-H), 3.96 (t, J = 6.4 Hz, 2H, CH2-OPh), 3.50 (t, J = 6.4 Hz, 2H,
O-CH2Á Á ÁPh), 3.42 (t, J = 5.9 Hz, 2H AzepÁ Á ÁCH2-O), 3.20–3.10 (m,
4H, Azep-2-H2 + Azep-7-H2), 3.10–2.97 (m, 2H, Azep-CH2), 1.95–
1.84 (m, 4H, Azep-CH2-CH2 + CH2-CH2OPh), 1.78–1.68 (m, 4H,
Azep-3-H2 + Azep-6-H2), 1.60–1.50 (m, 4H, Azep-4-H2 + Azep-5-
(KBr) (cmÀ1): 1248s (
m [C–O–Carom]), 1123s (m [C–O–C]).
5.1.3.9. 1-[3-(3-(4-Chlorophenoxy)propoxy)propyl]-4-methyl-
piperidine hydrogen oxalate (12). From 3-(4-methylpiperidin-1-
yl)propan-1-ol (1b) (0.39 g, 2.5 mmol) and 3-bromo-1-(4-chloro-
phenoxy)propane (3b) (3 mmol, 0.75 g). Heated in the microwave
oven for 180 s (3 Â 60 s). Yield of 180 mg (17%) of white solid. 1H
NMR [DMSO-d6]: d = 7.30 (d, J = 8.0 Hz, 2H, Ph-3,5-H), 6.94 (d,
J = 9.0 Hz, 2H, Ph-2,6-H), 3.99 (t, J = 6.4 Hz, 2H, CH2-OPh), 3.49
(t, J = 6.2 Hz, 2H, O-CH2Á Á ÁPh), 3.41 (t, J = 5.9 Hz, 2H, PipÁ Á ÁCH2-
O), 3.38–3.25 (m, 2H, Pip-2,6-He), 3.02–2.90 (m, 2H, Pip-CH2),
2.85–2.70 (m, 2H, Pip-2,6-Ha) 1.96–1.80 (m, 4H, PipCH2-
CH2 + CH2-CH2OPh), 1.78–1.60 (m, 2H, Pip-3,5-He), 1.55 (br s,
1H, Pip-4-H), 1.36–1.25 (m, 2H, Pip-3,5-Ha), 0.88 (d, J = 6.4 Hz,
H2), 1.22 (s, 9H, 3CH3); IR (KBr) (cmÀ1): 1185s (
1131s ( [C–O–C]).
m [C–O–Carom]),
m
5.2. Pharmacology
5.2.1. In vitro [125I]iodoproxyfan binding assay
Potency of the novel compounds 4–16 was investigated in
a
radioligand displacement assay described by Ligneau
et al.32 Briefly, stably transfected HEK-293 cells were washed
and harvested with
a PBS medium. They were centrifuged
(140g, 10 min, +4 °C) and then homogenized with a Polytron
in the ice-cold binding buffer (Na2HPO4/KH2PO4, c = 50 mmol/
L, pH 7.5). The homogenate was centrifuged (23,000g,
30 min, +4 °C) and the pellet obtained resuspended in the
binding buffer to constitute the membrane preparation used
for the binding assay. Aliquots of the membrane suspension
3H, CH3); IR (KBr) (cmÀ1): 1252s (
m [C–O–Carom]), 1107s (m [C–
O–C]).
5.1.3.10. 1-[3-(3-(4-Chlorophenoxy)propoxy)propyl]azepane
hydrogen oxalate (13). From 3-(azepan-1-yl)propan-1-ol (1c)
(0.39 g, 2.5 mmol) and 3-bromo-1-(4-chlorophenoxy)propane
(3b) (3 mmol, 0.75 g). Heated in the microwave oven for 180 s
(3 Â 60 s). Yield of 200 mg (19%) of white solid. 1H NMR [DMSO-
d6]: d = 7.30 (d, J = 9.2 Hz, 2H, Ph-3,5-H), 6.94 (d, J = 9.0 Hz, 2H,
Ph-2,6-H), 3.99 (t, J = 6.4 Hz, 2H, CH2-OPh), 3.49 (t, J = 6.2 Hz, 2H,
O-CH2Á Á ÁPh), 3.41 (t, J = 5.9 Hz, 2H AzepÁ Á ÁCH2-O), 3.22–3.10 (m,
4H, Azep-2-H2 + Azep-7-H2), 3.10–2.96 (m, 2H, Azep-CH2), 1.97–
1.80 (m, 4H, Azep-CH2-CH2 + CH2-CH2OPh), 1.80–1.68 (m, 4H,
Azep-3-H2 + Azep-6-H2), 1.62–1.49 (m, 4H, Azep-4-H2 + Azep-5-
(5–15
125I]iodoproxyfan (c = 25 pmol/L) alone, or together with com-
peting drugs dissolved in the same buffer to give a final vol-
ume of 200 L. Incubations were performed in triplicate and
stopped by four additions (5 mL) of ice-cold medium, followed
by rapid filtration through glass microfiber filters (GF/B What-
lg protein) were incubated for 60 min at 25 °C with
[
l
man, Clifton, NJ) presoaked in polyethylene imine (
x = 0.3%).
Radioactivity trapped on the filters was measured with
a
LKB (Rockville, MD) gamma counter (efficiency: 82%). Specific
binding was defined as that inhibited by imetit (c = 1 mol/L),
a specific histamine H3 receptor agonist.33 The corresponding
Ki values were determined according to the Cheng-Prusoff
H2); IR (KBr) (cmÀ1): 1201s (
m [C–O–Carom]), 1121s (m [C–O–C]).
5.1.3.11. 1-[3-(3-(4-tert-Butylphenoxy)propoxy)propyl]-3-methyl
piperidine hydrogen oxalate (14). From 3-(3-methylpiperidin-1-
yl)propan-1-ol (1a) (0.39 g, 2.5 mmol) and 3-bromo-1-(4-tert-butyl-
phenoxy)propane (3c) (0.69 g, 3 mmol). Heated in the microwave
oven for 120 s (2 Â 60 s). Yield of 200 mg (18%) of white solid. 1H
NMR [DMSO-d6]: d = 7.26 (d, J = 8.7 Hz, 2H, Ph-3,5-H), 6.82 (d,
J = 8.7 Hz, 2H, Ph-2,6-H), 3.97 (t, J = 6.4 Hz, 2H, CH2-OPh), 3.50 (t,
J = 6.4 Hz, 2H, O-CH2Á ÁÁPh), 3.42 (t, J = 5.9 Hz, 2H PipÁÁÁCH2-O),
3.40–3.25 (m, 2H, Pip-2,6-He), 3.05–2.95 (m, 2H, Pip-CH2), 2.75–
2.60 (m, 1H, Pip-6-Ha), 2.46–2.30(m, 1H, Pip-2-Ha), 1.96–1.60 (m,
8H, PipCH2-CH2 + CH2-CH2OPh + Pip-4,5-H2), 1.05–0.93 (m, 1H, Pip-
equation.39
Data
are
presented
as
the
mean
of
experiments performed at least in triplicate with standard er-
ror (SE).
Acknowledgements
We gratefully thank Mrs. M. Kaleta for help in preparing com-
pounds 4–16. This work was supported by the Deutscher Akadem-
ischer Austauschdienst (D/06/25529), Germany, the Ministry of
Scientific Research and Information Technology, Poland DAAD/
55/2007 Program and by the ‘LOEWE Lipid Signalling Forschungs-
zentrum’ (LiFF, Frankfurt/Main).
3-H), 0.85 (d, J = 6.7 Hz, 3H, CH3); IR (KBr) (cmÀ1): 1246s (
om]), 1122s ( [C–O–C]).
m [C–O–Car-
m

_
3042
D. Łazewska et al. / Bioorg. Med. Chem. 17 (2009) 3037–3042
22. Meier, G.; Apelt, J.; Reichert, U.; Grassmann, S.; Ligneau, X.; Elz, S.; Leurquin, F.;
References and notes
Ganellin, C. R.; Schwartz, J.-C.; Schunack, W.; Stark, H. Eur. J. Pharm. Sci. 2001,
12, 249.
1. Schwartz, J.-C.; Arrang, J. M. In Neuropsychopharmacology: The Fifth Generation
of Progress; Davis, K. L. et al., Eds.; Lippinocott Williams: Wilkins, 2002; pp
179–190.
2. Brown, R. E.; Stevens, D. R.; Haas, H. L. Prog. Neurobiol. 2001, 63, 637.
3. Haas, H.; Panula, P. Nat. Rev. Neurobiol. 2004, 4, 121.
4. Arrang, J. M.; Garbarg, M.; Schwartz, J.-C. Nature 1983, 302, 832.
5. Blandina, P.; Giorgetti, M.; Bartolini, L.; Cecchi, M.; Timmerman, H.; Leurs, R.;
Pepeu, G.; Giovannini, M. G. Br. J. Pharmacol. 1996, 119, 1656.
6. Schlicker, E.; Fink, K.; Detzner, M.; Göthert, M. J. Neural. Trans. Gen. Sect. 1993,
93, 1.
7. Schlicker, E.; Fink, K.; Hinterthaner, M.; Göthert, M. Naunyn-Schmiedeberg’s
Arch. Pharmacol. 1989, 340, 633.
8. Di Carlo, G.; Ghi, P.; Orsetti, M. Prog. Neuropsychopharmacol. Biol. Psychiat. 2000,
24, 275.
9. Schlicker, E.; Betz, R.; Göthert, M. Naunyn-Schmiedeberg’s Arch. Pharmacol.
1988, 337, 588.
10. Threlfell, S.; Cragg, S. J.; Kalló, I.; Turi, G. F.; Coen, C. W.; Greenfield, S. A. J.
Neurosci. 2004, 24, 8704.
11. Arrang, J. M.; Morisset, S.; Gbahou, F. Trends Pharmacol. Sci. 2007, 28, 350.
12. Parmentier, R.; Anaclet, C.; Guhennec, C.; Brousseau, E.; Bricout, D.; Giboulot,
T.; Bozyczko-Coyne, D.; Spiegel, K.; Ohtsu, H.; Williams, M.; Lin, J. S. Biochem.
Pharmacol. 2007, 73, 1157.
13. Masaki, T.; Yoshimatsu, H. Recent Patents CNS Drug Discov. 2007, 2, 238.
14. Esbenshade, T. A.; Browman, K. E.; Bitner, R. S.; Strakhova, M.; Cowart, M. D.;
Brioni, J. D. Br. J. Pharmacol. 2008, 154, 1166.
15. Hajós, M.; Siok, C. J.; Hoffmann, W. E.; Li, S.; Kocsis, B. J. Pharmacol. Exp. Ther.
2008, 324, 391.
16. Celanire, S.; Wijtmans, M.; Talaga, P.; Leurs, R.; de Esch, I. J. P. Drug Discov.
23. Ligneau, X.; Perrin, D.; Landais, L.; Camelin, J.-C.; Calmels, T. P. G.; Berrebi-
Bertrand, I.; Lecomte, J.-M.; Parmentier, R.; Anaclet, C.; Lin, J.-S.; Bertaina-
Anglade, V.; Drieu la Rochelle, C.; d’Aniello, F.; Rouleau, A.; Gbahou, F.; Arrang,
J.-M.; Ganellin, C. R.; Stark, H.; Schunack, W.; Schwartz, J.-C. J. Pharmacol. Exp.
Ther. 2007, 320, 365.
24. www.stanleyresearch.org/programs/trialgrants.htm.
25. Ligneau, X.; Landais, L.; Perrin, D.; Piriou, J.; Uguen, M.; Denis, E.; Robert, P.;
Parmentier, R.; Anaclet, C.; Lin, J.-S.; Burban, A.; Arrang, J.-M.; Schwartz, J.-C.
Biochem. Pharmacol. 2007, 73, 1215.
26. Lin, J.-S.; Dauvilliers, Y.; Arnulf, I.; Bastuji, H.; Anaclet, C.; Parmentier, R.;
Kocher, L.; Yanagisawa, M.; Lehert, P.; Ligneau, X.; Perrin, D.; Robert, P.; Roux,
M.; Lecomte, J.-M.; Schwartz, J.-C. Neurobiol. Dis. 2008, 30, 74.
27. Sander, K.; Kottke, T.; Stark, H. Biol. Pharm. Bull. 2008, 31, 2163.
_
28. Łazewska, D.; Ligneau, X.; Schwartz, J.-C.; Schunack, W.; Stark, H.; Kiec´-
Kononowicz, K. Bioorg. Med. Chem. 2006, 14, 3522.
_
29. Łazewska, D.; Kuder, K.; Ligneau, X.; Schwartz, J.-C.; Schunack, W.; Stark, H.;
Kiec´-Kononowicz, K. Bioorg. Med. Chem. 2008, 16, 8729.
30. Bogdał, D.; Pielichowski, J.; Jaskot, K. Org. Prep. Proc. Int. 1998, 30, 427.
_
31. Łazewska, D.; Kiec´-Kononowicz, K.; Pertz, H. H.; Stark, H.; Schunack, W.; Elz, S.
Pharmazie 2001, 12, 927.
32. Ligneau, X.; Morisset, S.; Tardivel-Lacombe, J.; Gbahou, F.; Ganellin, C. R.; Stark,
H.; Schunack, W.; Schwartz, J.-C.; Arrang, J.-M. Br. J. Pharmacol. 2000, 131,
1247.
33. Ligneau, X.; Garbarg, M.; Vizuette, M. L.; Diaz, J.; Purand, K.; Stark, H.;
Schunack, W.; Schwartz, J.-C. J. Pharmacol. Exp. Ther. 1994, 271, 452.
34. Pandey, G.; Kumaraswamy, G.; Reddy, P. Y. Tetrahedron 1992, 48, 8295.
35. McElvain, S. M.; Carney, T. P. J. Am. Chem. Soc. 1946, 68, 2592.
36. Blicke, F. F.; Doorenbos, N. J. J. Am. Chem. Soc. 1954, 76, 2317.
37. Augstein, J.; Austin, W. C.; Boscott, R. J.; Green, S. M.; Worthing, C. R. J. Med.
Chem. 1965, 8, 356.
Today 2005, 10, 1613.
17. Esbenshade, T. A.; Fox, G. B.; Cowart, M. D. Mol. Interventions 2006, 6, 77.
18. Letavic, M. A.; Barbier, A. J.; Dvorak, C. A.; Carruthers, N. I. Prog. Med. Chem.
2006, 44, 181.
19. Wijtmans, M.; Leurs, R.; de Esch, J. Exp. Opin. Invest. Drugs 2007, 16, 967.
20. Berlin, M.; Boyce, C. W. Exp. Opin. Ther. Patents 2007, 17, 675.
21. Celanire, S.; Lebon, F.; Stark, H. In The Third Histamine H3 Receptor: Selective
Ligands as Potential Therapeutic Agents in CNS Disorders; Vohora, D. S., Ed.;
Taylor & Francis CRC: Boca Raton, Fla, 2009; pp 103–165.
38. Atkinson, J. M.; Boghai, D. M.; Lindoy, L. F.; Ghanbari, B.; Meehan, G. V.; Saini, V.
Aust. J. Chem. 1999, 52, 351.
39. Cheng, Y.-C.; Prussoff, W. H. Biochem. Pharmacol. 1973, 22, 3099.
_
40. Kuder, K.J.; Ligneau, X.; Camelin, J.-C.; Łazewska, D.; Schwartz, J.-C.; Schunack,
´
W.; Stark, H.; Kiec-Kononowicz, K. Abstract Book of the 37th Annual Meeting of
the EHRS, May 7–10; Stockholm/Sweden, 2008, p 56.