Ether derivatives of 3-piperidinopropan-1-ol as non-imidazole histamine H3 receptor antagonists

Article abstract of DOI:10.1016/j.bmc.2006.01.013

A series of aliphatic and aromatic ether derivatives of 3-piperidinopropan-1-ol has been prepared by four different methods. The ethers obtained were evaluated for their affinities at recombinant human histamine H₃ receptor, stably expressed in CHO-K1 or HEK 293 cells. All compounds investigated show from moderate to high in vitro affinities in the nanomolar concentration range. Selected compounds were investigated under in vivo conditions after oral administration to mice. Some proved to be highly potent and orally available histamine H₃ receptor antagonists. The most potent antagonists in this series have been in vitro the 4-(1,1-dimethylpropyl)phenyl ether 19 (hH₃R K_i = 8.4 nM) and in vivo the simple ethyl ether 2 (ED₅₀ = 1.0 mg/kg).

Full text of DOI:10.1016/j.bmc.2006.01.013

Bioorganic & Medicinal Chemistry 14 (2006) 3522–3529
Ether derivatives of 3-piperidinopropan-1-ol as
non-imidazole histamine H3 receptor antagonists
a
b
b
c
_
Dorota Łazewska, Xavier Ligneau, Jean-Charles Schwartz, Walter Schunack,
d
a,
*
´
Holger Stark and Katarzyna Kiec-Kononowicz
aJagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs,
Medyczna 9, 30-688 Krako´w, Poland
bBioprojet-Biotech, 4 rue du Chesnay Beauregard, BP 96205, 35762 Saint-Gre´goire, France
cInstitut fu¨r Pharmazie, Freie Universita¨t Berlin, Ko¨nigin-Luise-Strasse 2+4, 14195 Berlin, Germany
dInstitut fu¨r Pharmazeutische Chemie, Biozentrum/ZAFES, Johann Wolfgang Goethe-Universita¨t,
Marie-Curie-Strasse 9, 60439 Frankfurt/Main, Germany
Received 21 September 2005; revised 29 December 2005; accepted 6 January 2006
Available online 8 February 2006
Abstract—A series of aliphatic and aromatic ether derivatives of 3-piperidinopropan-1-ol has been prepared by four different meth-
ods. The ethers obtained were evaluated for their affinities at recombinant human histamine H3 receptor, stably expressed in CHO-
K1 or HEK 293 cells. All compounds investigated show from moderate to high in vitro affinities in the nanomolar concentration
range. Selected compounds were investigated under in vivo conditions after oral administration to mice. Some proved to be highly
potent and orally available histamine H3 receptor antagonists. The most potent antagonists in this series have been in vitro the
4-(1,1-dimethylpropyl)phenyl ether 19 (hH3R Ki = 8.4 nM) and in vivo the simple ethyl ether 2 (ED50 = 1.0 mg/kg).
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
including attention-deficit hyperactivity disorder
(ADHD), Alzheimer’s disease, schizophrenia, epilepsy
as well as sleep disorders (narcolepsy) or obesity.6–9
Numerous histamine H3R ligands have been preclinical-
ly evaluated and may be some, at least one, have even
entered clinical stages, for example, GT-2331 (ciprali-
sant formerly perceptin; entered phase II clinical studies
for ADHD).9,10 So far, none of the H3R antagonists has
been brought into the market. Thus, much effort is fo-
cused on understanding H3 receptor (patho)physiology
and on the design of selective and potent H3R ligands.
Histamine is a biogenic amine with multiple physiologi-
cal activities and since 1907, when it was first synthe-
sized, is still in the centre of general interest.1 Its
important physiological role is attributed to four known
receptor subtypes: H1–H4. The third histamine receptor
(H3R) acts as an autoreceptor inhibiting the synthesis
and the release of histamine upon activation. The H3R
occurs also as heteroreceptor modulating the release of
a number of neurotransmitters including acetylcholine,
dopamine, glutamate, noradrenaline and others.2 The
molecular structure of this receptor was unknown until
1999 when it was published by Lovenberg et al.3 The
H3R shows functional constitutive activity in vivo, poly-
morphisms and multiple splice variants that differ across
species (for review, see4,5).
The first H3R antagonists were 4(5)-substituted imidaz-
oles (for review, see9,11). However, due to well-known
unfavourable imidazole-based properties (CYP 450
binding,12 potential lack of selectivity towards histamine
H3/H4 receptors,13 and lower affinity for cloned human
H3R than that for, e.g., rodent14) the actual focus is
on the development of non-imidazole compounds (for
review, see11a,15).
H3R antagonists could be useful for the treatment of a
wide range of central nervous system (CNS) disorders
The aromatic imidazole moiety was successfully re-
placed among others by an aliphatic piperidine, pyrrol-
idine or piperazine ring (for review, see11a,15). Such
compounds (different to endogenous ligand) may give
Keywords: Histamine; H3 receptor; Non-imidazole ligands; Binding;
Antagonists.
*
Corresponding author. Tel.: +48 12 657 04 88; fax: +48 12 657 04
88; e-mail: mfkonono@cyf-kr.edu.pl
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.01.013

D. Łaz_ewska et al. / Bioorg. Med. Chem. 14 (2006) 3522–3529
3523
a chance for enhanced selectivity, that is, for low bind-
2. Chemistry
ing at H4 receptors. This could be confirmed by other
investigations and there are known non-imidazole H3R
ligands inactive at the H4 receptor.13,18a
The novel ether derivatives 2–19 were synthesized by
four different methods as outlined in Scheme 1. 3-Piperi-
dinopropan-1-ol (1) was obtained from piperidine
and 3-chloropropan-1-ol by the method described
previously.20
Some of the non-imidazole H3R antagonists have en-
tered clinical trials, for example, Abbott Laboratories
ABT-239, which has been described as a promising
agent for the treatment of a variety of CNS disorders
(ADHD, Alzheimer’s disease and schizophrenia)16,17
(Fig. 1).
Ethers 2, 4–6 and 14–17 were synthesized by the John-
stone and Rose procedure.23 The alcohol 1 and appro-
priate alkyl halide were added to powdered KOH
stirred in dimethylsulfoxide (DMSO) and usually heated
in an oil bath (50 or 90 ꢁC).
Among classical approaches industrial high-throughput
screenings (HTS) led to the identification of new non-
imidazole ligands possessing the 3-piperidinylpropyloxy
motif.18 This motif is also present in the compound cho-
sen as the lead structure (FUB 637) for the work pre-
sented here (Fig. 2). In 2001, Meier et al. published
the results of ring replacements in piperidine analogues
of the known imidazole-based H3R antagonists.19 Com-
pound FUB 637 was one of the most interesting ligands
with comparable in vitro and in vivo potency to its imid-
azole analogue, FUB 153 (Fig. 2).
Ethers 3, 7, 8 and 10–13 were prepared under solvent-free
conditions using microwave irradiation according to the
procedure described by Bogdał et al.24 (Table 1). Alcohol
1 was mixed with appropriate alkyl halide and a cat-
alytic amount of tetrabutylammonium bromide
(TBAB). The mixture was absorbed on a mixture of
powdered potassium carbonate and potassium hydrox-
ide and then irradiated in an open vessel in the domes-
tic microwave oven.
As an extension of our previous work in the non-imidaz-
20–22
ole field
we have prepared a series of ether deriva-
tives of 3-piperidinopropan-1-ol with general structure
presented in Figure 3. All compounds were screened
for their affinities at the human histamine H3 receptor
stably expressed in CHO-K1 cells or HEK 293. The
in vivo potencies of selected compounds were also
investigated.
KOH /DMSO
2, 4-6, 14-17
KOH / K2CO3 / TBAB
CN
3, 7, 8, 10-13
mw (60 -120s)
pKih : 9.4a
pKir : 8.9b
N
O
pKbRC : 7.7c
pA2Gpi : 8.7d
+
R X
N
OH
ABT-239
1
X : Cl, Br or OH
Figure 1. Structure and histamine H3 potencies of ABT-239.15,17 (a)
Binding assay to recombinant human H3 receptor versus [3H]Na-
methylhistamine. (b) Binding assay to recombinant rat H3 receptor
versus [3H]Na-methylhistamine. (c) Functional assay on rat brain
cortical synaptosomes. (d) Functional assay on guinea pig ileal
segments.
NaH / 15-crown-5 / TBAI
toluene
9
Ph3P / DIAD
THF
18, 19
N
N
O
O
Scheme 1. General methods of synthesis of ethers 2–19.
N
H
FUB 637
FUB 153
KiRC : 15a nM
KiRC : 17a nM
pA2Gpi : 8.1b
pA2Gpi : 7.3b
ED50MsC : 3.7c mg/kg
ED50MsC : 1.4c mg/kg
Table 1. Conditions of the synthesis of ethers under microwave
irradiation
Figure 2. In vitro and in vivo histamine H3 receptor antagonist
potencies of FUB 153 and FUB 637.19 (a) Functional assay on rat
cerebral cortex. (b) Functional assay on guinea pig ileum. (c)
Histamine H3 receptor screening after po administration to mice.
Compound
Microwave oven powera [W]
Time [s]
3
7
100
300
100
300
300
300
100
2 · 60
60
8
2 · 60
60
60
10
11
12
13
R
N
O
60
60
R: alkyl, alkenyl or aryl
Figure 3. General structure of prepared ethers 2–19.
a Domestic microwave oven Samsung M1618.

3524
D. Łaz_ewska et al. / Bioorg. Med. Chem. 14 (2006) 3522–3529
The target ether 9 was obtained by classical Williamson
ether synthesis.25 The alcohol 1 was transformed into its
sodium alcoholate to which (bromomethyl)cyclopro-
pane was added. Compounds 18 and 19 were synthe-
sized by a Mitsunobu type ether formation from 1 and
the appropriate phenol.26
thioperamide, which is one of the reference imidazole-
containing H3R antagonists (ED50 = 1 mg/kg, po).29 In
contrast to this high in vivo potency, compound 2
showed moderate affinity in vitro only (Table 2). The
observed discrepancy may be connected with species dif-
ferences, improvement in absorption or formation of ac-
tive metabolites. These astonishing divergent effects
between in vivo and in vitro potencies were also noticed
in the whole series of alkyl derivatives (compounds 2, 3,
and 8). The gradual loss of oral activity with elongation
of the carbon chain was revealed, whereas in in vitro
studies the opposite tendency was observed. In contrast
to the comparable in vitro results of ethers 10 and 11,
compound 11 enhanced Ns-methylhistamine level with
only weak antagonist potency. Ether 12 did not retain
good in vitro potency, was only moderately potent in vi-
vo (ED50 = 7.7 mg/kg, po) and less potent than 10.
Remarkably, the aromatic derivatives tested showed
high antagonist potencies, but did not reach the potency
of compound 2. Compounds 2, 10, 13 and 17–19 re-
vealed in vivo potencies higher than that of the parent
lead structure FUB 637 (ED50 6 3.7 mg/kg, po).
Compounds were purified by column chromatography
and isolated as salts of oxalic acid. Their purity was
checked by TLC. Structures and purity of final com-
pounds were confirmed by standard techniques (1H
NMR, MS, IR and elemental analysis) (cf. Section 5
and Table 2).
3. Pharmacological results and discussion
3.1. In vitro binding assay at cloned human histamine H3
receptors
The affinities of compounds were determined by measur-
ing the displacement curves of [125I]iodoproxyfan bind-
ing at human histamine H3 receptors expressed in
CHO-K1 or HEK 293 cells stably transfected with the
full-length coding sequence of the hH3R, as described
previously (Table 2).27,28
4. Conclusions
In this study, we report on novel potent histamine H3
receptor ligands. These compounds are ether derivatives
of 3-piperidinopropan-1-ol. They proved to be hista-
mine H3 receptor ligands investigated in [125I]iodoproxy-
fan binding studies on the human histamine H3 receptor
and showed affinities from high to low nanomolar con-
centration range. In vivo screening of selected com-
pounds showed the highest antagonist potency for the
ethyl ether derivative 2.
Tested compounds showed different affinities from high
(2 and 3) to low (19) nanomolar concentration range. In
the aliphatic series (compounds 2–4 and 8) elongation of
the carbon chain led to an increase in H3R potencies
from hKi values of 743 nM (3) to 342 nM (8). The intro-
duction of alkyl substituents (methyl or ethyl) in b-posi-
tion within the butyl series 4–6 did not influence the
activities (hKi > 700 nM), whereas branching at the
end of the chain showed a slight increase in affinity
(7). In the cycloalkyl series (9–12) the size of the ring
(cyclopropyl, cyclobutyl and cyclohexyl) did not change
the potencies opposite to elongation of the carbon skel-
eton. Compound 12 (2-cyclohexylethyl derivative; Ki
40 nM) is about 8-fold more potent than the corre-
sponding cycloalkylmethyl ethers 9–11 (hKi > 300 nM).
The unsaturated allyl ether 13 showed moderate hista-
mine H3 receptor affinity, whereas the aliphatic propyl
derivative 3 is weak (hKi 700 nM) one. Stiffening the
end of the carbon chain seems to be advantageous,
whereas in the different position (as in (E)-but-2-enyl
(14)) led to a slight drop in H3R affinity.
Ether derivatives 17–19 are highly potent both in vitro
and in vivo studies and may be interesting subjects for
further investigation and development.
5. Experimental
5.1. Chemistry
5.1.1. General procedures. Melting points were deter-
mined on
a MEL-TEMP II apparatus and are
1
uncorrected. H NMR spectra were recorded on a Var-
ian-Merkury 300 MHz spectrometer in DMSO-d6.
Chemical shifts are expressed in parts per million down-
field from internal tetramethylsilane as reference. Data
are reported in the following order: multiplicity (br,
broad; def, deformed; s, singlet; d, doublet; dd, doublet
The aromatic derivatives showed at least one to two or-
ders of magnitude higher affinities than those of the non-
aromatic compounds. The compounds with the highest
affinities in this series are 19 and 16.
of doublets; t, triplet; m, multiplet or massif
( , the
*
centre of the chemical shift is given and , the range of
** *
3.2. In vivo assay on Swiss mice
**
the whole signal is given); Cyclobut, cyclobutyl; Cyclo-
prop, cyclopropyl; Cyclohex, cyclohexyl; Ph, phenyl;
and Pip, piperidino), approximate coupling constants J
in Hertz (Hz) and number of protons. Mass spectra
(MS) were obtained on an EI-MS Finnigan MAT
CH7A (70 eV, EI spectra). IR spectra were recorded
with a Perkin-Elmer 297 spectral photometer or FT
Jasco IR spectrometer from KBr discs (s, strong).
Selected compounds were screened for modulating Ns-
methylhistamine level in the brain cortex of Swiss mice
after oral treatment (Table 2). All compounds tested
showed antagonist properties. Compounds 11 and 14
enhanced Ns-methylhistamine level with weak antago-
nist potency only if they do any at all. However, ether
2 showed antagonist behaviour equipotent to that of

D. Łaz_ewska et al. / Bioorg. Med. Chem. 14 (2006) 3522–3529
3525
Table 2. Antagonist potencies of ether derivatives of 3-piperidinopropan-1-ol at histamine H3 receptor (general structure cf. Fig. 3)
Compound
R
Formula
Mw (g/mol)
hKia (nM)
ED50 SEMc (mg/kg) po
2
C10H21NOÆC2H2O4
261.33
700 95
1.0 0.1
5.3 0.1
d
3
4
5
C11H23NOÆC2H2O4
275.35
302.90
305.21
743 50
C12H25NOÆC2H2O4Æ0.75H2O
C13H27NOÆC2H2O4Æ0.10H2O
719 126b
713 44b
d
d
6
7
C14H29NOÆC2H2O4Æ0.25H2O
C13H27NOÆC2H2O4ÆH2O
321.94
321.41
728 168b
557 56
10
1
8
9
C13H27NOÆC2H2O4
303.41
291.87
342
6.1 1.7
d
C12H23NOÆC2H2O4Æ0.25H2O
341b
10
11
C13H25NOÆC2H2O4Æ0.50H2O
310.40
383.46
309 36
376 38
4.2 0.4
C15H29NOÆ1.5C2H2O4Æ0.50H2O
ꢀ15
12
C16H31NOÆC2H2O4
343.47
40 13
7.7 0.2
13
14
C11H21NOÆC2H2O4Æ0.25H2O
C12H23NOÆC2H2O4Æ0.20H2O
277.85
290.96
387 57
521 69
3.1 0.4
>10
d
15
16
17
C13H25NOÆC2H2O4
301.39
349.44
380.43
339b
d
C17H25NOÆC2H2O4
5.6 1.0b
O
C16H24NO2FÆC2H2O4Æ0.50H2O
31
22
5
3
2.8 0.1
2.8 0.4
2.1 0.2
F
18
19
C18H29NOÆC2H2O4
C19H31NOÆC2H2O4
365.48
379.51
8.4 1.3
FUB 637
3.1 0.5e
60 12g
3.7 1.0f
1.0 0.5h
Thioperamide
125I]Iodoproxyfan binding assay at human H3 receptors stably expressed in CHO-K1 cells.
a
[
b
[
125I]Iodoproxyfan binding assay at human H3 receptors stably expressed in HEK 293 cells.
c Central histamine H3 receptor assay in vivo after po administration to mice.
d Not tested.
e [3H]-(R)-a-Methylhistamine binding assay at human H3 receptors stably expressed in C6 cells.
f Ref. 19.
g Ref. 27.
h Ref. 29.

3526
D. Łaz_ewska et al. / Bioorg. Med. Chem. 14 (2006) 3522–3529
Elemental analyses (C, H and N) were measured on a
Perkin-Elmer 240B or Elemental Vario-EL III instru-
ment and are within 0.4% of the theoretical values.
Column chromatography (CC) was performed using sil-
ica gel 60 (0.063–0.20 mm; Merck). TLC was carried out
using silica gel F254 plates (Merck). The spots were visu-
alized by Dragendorff’s reagent or by UV absorption at
254 nm. The following abbreviations are used: CH2Cl2,
dichloromethane; 15-crown-5,1,4,7,10,13-pentaoxacycl-
opentadecane; DIAD, diisopropyl azodicarboxylate;
DMSO, dimethyl sulfoxide; Et2O, diethyl ether; EtOH,
ethanol; MeOH, methanol; TBAB, tetrabutylammoni-
um bromide; TBAI, tetrabutylammonium iodide; and
THF, tetrahydrofuran.
1H, Pip-4-Ha), 1.15–1.06 (m, 1H, CH2CH(CH3)C2H5),
0.89–0.85 (m, 6H, 2CH3); MS (70 eV): m/z (%) = 213
([Mꢀ]+, 1), 142 ([Pip-(CH2)3O+], 10), 99 (7), 98
(½Pip-CHþ2 ꢁ, 100).
5.1.2.4. 1-[3-(2-Ethylbutoxy)propyl]piperidine hydro-
gen oxalate (6). From 3-bromomethylpentane (0.99 g,
6 mmol). Heated at 50 ꢁC for 48 h. Extracted with
Et2O, followed by purification by CC (eluent: CH2Cl2–
MeOH; 90:10). Yield: 3%. 1H NMR: d = 3.42 (t,
J = 5.8 Hz, 2H,CH2-O), 3.27 (d, J = 5.5 Hz, 2H, O-
CH2CH(C2H5)2), 3.20–3.04 (s, 2H, Pip-CH2), 3.04–
2.98 (m, 4H, Pip-2,6-H), 1.89 (m, 2H, PipCH2-CH2),
1.78–1.64 (m, 4H, Pip-3,5-H), 1.53 (br s, 2H, Pip-4-H),
1.42–1.27 (m, 5H, CH2CH(CH2CH3)2), 0.85 (t,
J = 7.2 Hz, 6H, 2CH3); MS (70 eV): m/z (%) = 227
([Mꢀ]+, 2), 142 ([Pip-(CH2)3O+], 15), 99 (7), 98
(½Pip-CHþ2 ꢁ, 100), 84 ([Pip+], 4).
5.1.2. General procedure for the preparation of ethers 2,
4–6 and 14–17. To 10 mL DMSO powdered KOH
(1.1 g, 20 mmol) was added and stirred for 5 min in
ambient temperature. Then 3-piperidinopropan-1-ol (1,
0.72 g, 5.0 mmol), TBAI (0.18 g, 0.5 mmol) and alkyl
halide (6 mmol) were added. Stirring was continued
for the proper time at ambient temperature or heated
(50 or 90 ꢁC). Then the mixture was poured into water
(25 mL) and extracted with CH2Cl2 or Et2O. The com-
bined organic extracts were purified by further extrac-
tion and/or CC. The extracts were dried over
anhydrous Na2SO4. The final products were crystallized
as salts of oxalic acid from EtOH/Et2O.
5.1.2.5.
1-{3-[(E)-But-2-enyloxy]propyl}piperidine
hydrogen oxalate (14). From (E)-1-bromobut-2-ene
(0.81 g, 6 mmol). Heated at 50 ꢁC for 15 h. Extracted
with Et2O, followed by purification by CC (eluent:
CH2Cl2–MeOH; 90:10). Yield: 30%. 1H NMR:
d = 5.71–5.59 (m, 1H, OCH2CH@CH), 5.58–5.44 (m,
1H, OCH2CH@CH), 3.83–3.81 (dd, J2 = 6.1 Hz, J2 =
2.3 Hz, 2H, OCH2CH@CH), 3.36 (t, J = 6.1 Hz, 2H,
Pip-(CH2)2CH2-O), 3.07–2.96 (m, 6H, Pip-CH2 + Pip-
2,6-H), 1.85 (m, 2H, PipCH2-CH2), 1.71–1.67 (m, 4H,
Pip-3,5-H), 1.65–1.63 (dd, J2 = 5,0 Hz, J2 = 1.4 Hz,
3H, CH3), 1.49 (br s, 2H, Pip-4-H); MS (70 eV): m/z
(%) = 197 ([Mꢀ]+, 1), 142 ([Pip-(CH2)3O+], 12), 99 (8),
98 (½Pip-CHþ2 ꢁ, 100), 84 ([Pip+], 5); IR (cmꢂ1): 1106s (m
[C–O–C]), 976s (c [@C–H]).
5.1.2.1. 1-(3-Ethoxypropyl)piperidine hydrogen oxa-
late (2). From 1-bromoethane (0.65 g, 6 mmol). Heated
at 50 ꢁC for 15 h. Extracted with Et2O, followed by puri-
fication by CC (eluent: CH2Cl2–MeOH; 90:10). Yield:
24%. 1H NMR: d = 3.42–3.35 (m, 4H, CH2OCH2),
3.16–2.95 (m, 6H, Pip-CH2 + Pip-2,6-H), 1.85 (m, 2H,
PipCH2-CH2), 1.73–1.67 (m, 4H, Pip-3,5-H), 1.49 (br
s, 2H, Pip-4-H), 1.08 (t, J = 7.2 Hz, 3H, CH3); MS
(70 eV): m/z (%) = 171 ([Mꢀ]+, 4), 142 ([Pip-(CH2)3O+],
15), 99 (15), 98 (½Pip-CHþ2 ꢁ, 100), 84 [Pip+], 6; IR
(cmꢂ1): 1134s (m [C–O–C]).
5.1.2.6. 1-{3-[3-Methylbut-2-enyloxy]propyl}piperidine
hydrogen oxalate (15). From 1-bromo-3-methylbut-2-
ene (0.89 g, 6 mmol). Heated at 50 ꢁC for 18 h. Extract-
ed with Et2O, followed by further washing with water
and 1% HCl. The acidic layer was alkalized by NaHCO3
and extracted to CHCl3. Organic layer was washed with
water, dried (Na2SO4) and after removal of the solvent
5.1.2.2. 1-(3-Butoxypropyl)piperidine hydrogen oxalate
(4). From 1-bromobutane (0.82 g, 6 mmol). Heated at
90 ꢁC for 47 h. Extracted with Et2O, followed by purifica-
tion by CC (eluent: CH2Cl2–MeOH; 90:10). Yield: 32%.
1H NMR: d = 3.41 (t, J = 5.8 Hz, 2H, CH2–O), 3.37 (t,
J = 6.6 Hz, 2H, O–CH2), 3.18–3.05 (m, 6H, Pip-2,6-
H + Pip-CH2), 1.90 (m, 2H, PipCH2-CH2), 1.80–1.60 (s,
4H, Pip-3,5-H), 1.53–1.44 (m, 4H, Pip-4-H + CH2C2H5),
1.38–1.26 (m, 2H, CH2CH3), 0.89 (t, J = 7.2 Hz, 3H,
CH3); MS (70 eV): m/z (%) = 199 ([Mꢀ]+, 2), 142 ([Pip-
1
in vacuo crystallized. Yield: 22%. H NMR: d = 5.27
(t, J = 6.9 Hz, 1H, CH@C(CH3)2), 3.91 (d, J = 6.9 Hz,
2H, OCH2), 3.41 (t, J = 6.1 Hz, 2H, CH2O), 3.10 (br
s, 4H, Pip-2,6-H), 3.05–2.99 (m, 2H, Pip-CH2), 1.89
(m, 2H, Pip-CH2CH2), 1.74–1.71 (m, 4H, Pip-3,5-H),
1.64 (s, 6H, 2CH3), 1.53 (br s, 2H, Pip-4-H); MS
(70 eV): m/z (%) = 211 ([Mꢀ]+, 1), 142 ([Pip-(CH2)3O+],
14), 124 (5), 99 (9), 98 (½Pip-CHþ2 ꢁ, 100), 96 (29), 84
([Pip+], 11), 69 (½ðCH3Þ C@CH–CHþꢁ, 9); IR (cmꢂ1):
2
2
(CH2)3O+], 10), 99 (7), 98 (½Pip-CHþꢁ, 100), 84 ([Pip+],
1102s (m [C–O–C]).
5.1.2.7.
2
3); IR (cmꢂ1): 1113s (m [C–O–C]).
1-{3-{[(E)-3-Phenylprop-2-enyl]oxy}pro-
5.1.2.3. 1-[3-(2-Methylbutoxy)propyl]piperidine hydro-
gen oxalate (5). From 1-chloro-2-methylbutane (0.64 g,
6 mmol). Heated at 90 ꢁC for 48 h. Extracted with
Et2O, followed by purification by CC (eluent:
pyl}piperidine hydrogen oxalate (16). From (E)-1-bro-
mo-3-phenylprop-2-ene (1.19 g, 6 mmol). Heated at
50 ꢁC for 20 h. Extracted with Et2O, followed by further
washing with water and 1% HCl. The acidic layer was
alkalized by NaHCO3 and extracted to CHCl3. Organic
layer was washed with water, dried (Na2SO4) and after
removal of the solvent in vacuo purified by CC (eluent:
1
CH2Cl2–MeOH; 90:10). Yield: 7%. H NMR: d = 3.42
(t, J = 6.1 Hz, 2H, Pip-(CH2)2CH2-O), 3.27–2.98 (m,
8H, O-CH2CH(CH3) + Pip-CH2 + Pip-2,6-H), 1.89 (m,
2H, PipCH2-CH2), 1.74–1.70 (m, 4H, Pip-3,5-H),
1.64–1.40 (m, 3H, Pip-4-He + CH2CH3), 1.38–1.33 (m,
1
CH2Cl2–MeOH; 97:3). Yield: 15%. H NMR: d = 7.47
(d, J = 7.2 Hz, 2H, Ph-2,6-H), 7.36 (t, J = 6.9 Hz, 2H,

D. Łaz_ewska et al. / Bioorg. Med. Chem. 14 (2006) 3522–3529
3527
Ph-3,5-H), 7.28 (d, J = 7.4 Hz, 1H, Ph-4-H), 6.63 (d,
J = 15.9 Hz, 1H, CH@CH–Ph), 6.41–6.32 (dt,
J2 = 16.2 Hz, J3 = 5.8 Hz, 1H, CH2CH@CHPh), 4.11
(d, J = 5.8 Hz, 2H, CH2–CH@CH), 3.50 (t, J = 6.1 Hz,
2H, CH2O), 3.20–3.03 (m, 6H, Pip-CH2 + Pip-2,6-H),
1.94 (m, 2H, Pip-CH2CH2), 1.80–1.60 (m, 4H, Pip-3,5-
H), 1.53 (br s, 2H, Pip-4-H); MS (70 eV): m/z
(%) = 259 ([Mꢀ]+, 1), 142 ([Pip-(CH2)3O+], 11), 131 (6),
124 (10), 117 (½PhCH@CH–CHþ2 ꢁ, 14), 115 (10), 99 (8),
98 (½Pip-CHþ2 ꢁ, 100), 97 (11), 96 (50), 84 ([Pip+], 7), 77
([Ph+], 6); IR (cmꢂ1): 1637s (m [C@C]), 1227s (m [C–O–C]).
(m, 5H, Pip-3,5-H + CH(CH3)2), 1.49 (br s, 2H, Pip-4-
H), 1.36 (q, J = 6.6 Hz, 2H, CH2-CH(CH3)2), 0.84 (d,
J = 6.6 Hz, 6H, 2CH3); MS (70 eV): m/z (%) = 213
([Mꢀ]+, 1), 142 ([Pip(CH2)3O+], 15), 99 (7), 98
(½Pip-CHþ2 ꢁ, 100), 96 (10), 84 ([Pip+], 6); IR (cmꢂ1):
1113s (m [C–O–C]).
5.1.3.3. 1-(5-Pentyloxypropyl)piperidine hydrogen
oxalate (8). From 5-bromopentane (0.91 g, 6 mmol).
The extract after drying was further purified by CC (elu-
ent: CHCl3–MeOH; 70:30) and then crystallized. Yield:
13%. 1H NMR: d = 3.73 (t, J = 6.1 Hz, 2H, CH2-O),
3.32 (t, J = 6.4 Hz, 2H, O-CH2), 3.06 (br s, 2H, Pip-
CH2), 3.00–2.94 (m, 4H, Pip-2,6-H), 1.89–1.80 (m, 2H,
PipCH2-CH2), 1.75–1.60 (m, 4H, Pip-3,5-H), 1.49–1.42
(m, 4H, Pip-4-H + CH2(CH2)2CH3), 1.30–1.20 (m, 4H,
(CH2)2CH3), 0.84 (t, J = 6.9 Hz, 3H, CH3); MS
(70 eV): m/z (%) = 213 ([Mꢀ]+, 2), 142 ([Pip-(CH2)3O+],
12), 99 (8), 98 (½Pip-CHþ2 ꢁ, 100), 84 ([Pip+], 4); IR
(cmꢂ1): 1117s (m [C–O–C]).
5.1.2.8.
1-{3-[2-(4-Fluorophenoxy)ethoxy]pro-
pyl}piperidine hydrogen oxalate (17). From 1-bromo-
2(4-fluorophenoxy)ethane (2.19 g, 10 mmol). Room
temperature for 16 h. Extracted with CH2Cl2, followed
by further washing with 1% HCl. The organic layer
was dried (Na2SO4) and after removal of the solvent in
vacuo purified by CC (eluent: CHCl3: MeOH; 95: 5).
1
Yield: 7%. H NMR: d = 7.13–7.05 (m, 2H, Ph-2,6-H),
6.95–6.91 (m, 2H, Ph-3,5-H), 4.10–4.03 (m, 2H,
CH2-OPh), 4.02–3.66 (m, 2H, OCH2CH2Ph), 3.49
(t, J = 6.1 Hz, 2H, CH2-O), 3.39–2.97 (m, 6H,
Pip-CH2 + Pip-2,6-H), 1.88 (m, 2H, PipCH2-CH2),
1.70–1.60 (m, 4H, Pip-3,5-H), 1.49 (br s, 2H, Pip-4-H);
MS (70 eV): m/z (%) = 281 ([Mꢀ]+, 1), 150 (70), 142
([Pip-(CH2)3O+], 11), 135 (11), 133 (26), 105 (57), 99
(7), 98 (½Pip-CHþ2 ꢁ, 100); IR (cmꢂ1): 1208s (m [C–O–C]),
1124s (m [C–O–CAr]).
5.1.3.4.
1-[3-(Cyclobutylmethoxy)propyl]piperidine
hydrogen oxalate (10). From 1-bromomethylcyclobutane
(0.23 g, 3 mmol) and 3-piperidinopropan-1-ol (1, 0.36 g,
2.5 mmol). Yield: 9%. 1H NMR: d = 3.38 (t, J = 5.8 Hz,
2H, CH2-O), 3.31 (d, J = 6.6 Hz, 2H, O-CH2-Cyclobut),
3.24–2.94 (m, 6H, Pip-CH2 + Pip-2,6-H), 2.51–2.39 (m,
1H, Cyclobut-1-H), 1.98–1.63 (m, 12H, PipCH2-
CH2 + Pip-3,5-H + Cyclobut-2,3,4-H), 1.49 (br s, 2H,
Pip-4-H); MS (70 eV): m/z (%) = 211 ([Mꢀ]+, 1), 142
5.1.3. General procedure for the preparation of ethers 3, 7,
8 and 10–13. A mixture of 3-piperidinopropan-1-ol (1,
0.72 g, 5.0 mmol), an appropriate alkyl halide
(6.0 mmol), TBAB (0.17 g, 0.5 mmol), K2CO3 (4.8 g,
20 mmol) and KOH (1.1 g, 20 mmol) was heated in a
domestic microwave oven in an open Erlenmeyer flask
for the appropriate time (Table 1). After cooling, the
reaction mixture was extracted with CH2Cl2. The sol-
vent was removed under reduced pressure, the residue
dissolved in CH2Cl2 (or CHCl3) and washed with
H2O. The organic layer was then dried over anhydrous
Na2SO4, filtered and after concentration crystallized as
a salt of oxalic acid from EtOH/Et2O.
([Pip-(CH2)3O+], 12), 99 (7), 98 (½Pip-CHþꢁ, 100), 84
2
([Pip+], 4); IR (cmꢂ1): 1110s (m [C–O–C]).
5.1.3.5. 1-[3-(Cyclohexylmethoxy)propyl]piperidine
hydrogen oxalate (11). From 1-bromomethylcyclohex-
ane (1.06 g, 6 mmol). Yield: 41%. H NMR: d = 3.43
1
(t, J = 5.5 Hz, 2H, CH2-O), 3.13 (d, J = 6.6 Hz, 2H,
O-CH2), 3.06–2.93 (m, 7H, Pip-CH2 + Pip-2,6-
H + Cyclohex-1-H), 1.87–1.49 (m, 14H, PipCH2-CH2 +
Pip-3,4,5-H + Cyclohex-3,5-H), 1.29–1.13 (m, 2H,
Cyclohex-2,6-He), 1.07–0.80 (m, 2H, Cyclohex-2,6-Ha);
MS (70 eV): m/z (%) = 239 ([Mꢀ]+, 1), 142 ([Pip-
(CH2)3O+], 11), 99 (8), 98 (½Pip-CHþꢁ, 100), 96 (6), 84
2
([Pip+], 5); IR (cmꢂ1): 1120s (m [C–O–C]).
5.1.3.1. 1-(3-Propoxypropyl)piperidine hydrogen oxa-
late (3). From 1-bromopropane (0.74 g, 6 mmol). The
extract after drying was further purified by CC (eluent:
CHCl3–MeOH; 90:10) and then crystallized. Yield:
4%. 1H NMR: d = 3.38 (t, J = 5.8 Hz, 2H, O-CH2),
3.29 (t, J = 6.6 Hz, 2H, CH2O), 3.09–2.96 (m, 6H,
Pip-CH2 + Pip-2,6-H), 1.85 (m, 2H, PipCH2-CH2),
1.78–1.60 (m, 4H, Pip-3,5-H), 1.54–1.42 (m, 4H, Pip-4-
H + CH2CH3), 0.84 (t, J = 7.4 Hz, 3H, CH3); MS
(70 eV): m/z (%) = 185 ([Mꢀ]+, 1), 142 ([Pip(CH2)3O+],
23), 99 (13), 98 (½Pip-CHþ2 ꢁ, 100), 84 ([Pip+], 6); IR
(cmꢂ1): 1112s (m [C–O–C]).
5.1.3.6.
1-[3-(2-Cyclohexylethoxy)propyl]piperidine
hydrogen oxalate (12). From 2-bromoethylcyclohexane
(1.15 g, 6 mmol). The extract after drying was further
purified by CC (eluent: CHCl3–MeOH; 97:3) and then
crystallized. Yield: 7%. 1H NMR: d = 3.39–3.34 (m,
4H, CH2-O-CH2), 3.04–2.93 (m, 6H, Pip-CH2 + Pip-
2,6-H), 1.83 (m, 2H, PipCH2-CH2), 1.75–1.55 (m, 10H,
Pip-3,5-H + Cyclohex-3,4,5-H), 1.50 (br s, 2H, Pip-4-
H), 1.37 (q, J = 6.6 Hz, 2H, CH2-Cyclohex), 1.19 (m,
1H, Cyclohex-1-H), 1.15–1.05 (m, 2H, Cyclohex-2,6-
He), 0.91–0.84 (m, 2H, Cyclohex-2,6-Ha); MS (70 eV):
m/z (%) = 253 ([Mꢀ]+, 2), 142 ([Pip-(CH2)3O+], 19), 99
(7), 98 (½Pip-CH2þꢁ, 100), 84 ([Pip+], 5); IR (cmꢂ1):
1113s (m [C–O–C]).
5.1.3.2. 1-[3-(3-Methylbutoxy)propyl]piperidine hydro-
gen oxalate (7). From 1-bromo-3-methylbutane (0.45 g,
3 mmol) and 3-piperidinopropan-1-ol (1, 0.36 g,
1
2.5 mmol). Yield: 8%. H NMR: d = 3.40–3.33 (m, 4H,
CH2-O-CH2), 3.07 (br s, 4H, Pip-2,6-H), 3.00–2.96 (m,
2H, Pip-CH2) 1.85 (m, 2H, PipCH2-CH2) 1.70–1.55
5.1.3.7. 1-[3-(Allyloxy)propyl]piperidine hydrogen oxa-
late (13). From 1-bromoprop-2-ene (0.73 g, 6 mmol).
Yield: 12%. 1H NMR: d = 5.92–5.79 (m, 1H,

3528
D. Łaz_ewska et al. / Bioorg. Med. Chem. 14 (2006) 3522–3529
–CH@CH2), 5.23 (dd, JE = 17.3 Hz, J2 = 1.7 Hz, 1H,
–CH@CH2), 5.13 (dd, JZ = 10.5 Hz, J2 = 1.9 Hz, 1H,
–CH@CH2), 3.90 (d, J = 5.3 Hz, 2H, O–CH2–CH@CH2),
3.41 (t, J = 6.1 Hz, 2H, –CH2O), 3.07–2.97 (m, 6H, Pip-
2,6-H + Pip-CH2), 1.87 (m, 2H, PipCH2-CH2), 1.71–
1.67 (m, 4H, Pip-3,5-H), 1.49 (m, 2H, Pip-4-H); MS
(70 eV): m/z (%) = 183 ([Mꢀ]+, 1), 142 ([Pip(CH2)3O+],
4), 99 (8), 98 (½Pip-CHþ2 ꢁ, 100), 96 (11), 84 ([Pip+], 7); IR
(cmꢂ1): 1102s (m [C–O–C]), 1626s (m [C@C]).
1.60–1.45 (m, 4H, Pip-4-H + CH2CH3), 1.18 (s, 6H,
C(CH3)2), 0.58 (t, J = 7.2 Hz, 3H, CH2CH3); MS
(70 eV): m/z (%) = 289 ([Mꢀ]+, 7), 124 (Pip-(CH2)3+],
7), 99 (7), 98 (½Pip-CHþ2 ꢁ, 100); IR (cmꢂ1): 1513s (m
[C@C]); 1248s (m [C–O–C]).
5.2. Pharmacology
5.2.1. In vitro [125I]iodoproxyfan binding assay. Affinities
of the novel compounds 2–19 were investigated in a
radioligand binding assay as described by Ligneau
et al.27 Stably transfected CHO-K1 (or HEK 293) cells
were washed and harvested with a PBS medium. They
were centrifuged (140g, 10 min, and +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, and
+4 ꢁC) and the pellet obtained resuspended in the bind-
ing buffer to constitute the membrane preparation used
for the binding assay. Aliquots of the membrane suspen-
sion (5–15 g protein) were incubated for 60 min at 25 ꢁC
with [125I]iodoproxyfan (c = 25 pmol/L) alone or togeth-
er with competing drugs dissolved in the same buffer to
give a final volume of 200 lL. Incubations were per-
formed in triplicate and stopped by four additions
(5 mL) of ice-cold medium, followed by rapid filtration
through glass microfibre filters (GF/B Whatman, Clif-
ton, 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 H3 receptor agonist.28
The corresponding Ki values were determined according
to the Cheng–Prusoff equation.30 Data are presented as
means of experiments performed at least in triplicate.
5.1.4. Synthesis of 1-[3-(cyclopropylmethoxy)propyl]pi-
peridine hydrogen oxalate (9). 15-Crown-5 (0.5 mmol,
0.1 mL) and 3-piperidinopropan-1-ol (1, 0.72 g, 5 mmol)
were added to NaH (0.24 g, 6 mmol) (60% suspension in
mineral oil) in dry toluene (10 mL). The reaction
mixture was stirred at room temperature for 24 h. Then
1-bromomethylcyclopropane (0.68 g, 5 mmol) and a cat-
alytic amount of TBAI were added and refluxed for
34 h. After cooling, the mixture was filtered and the fil-
trate concentrated in vacuo. The residue was purified by
CC (eluent: CH2Cl2–MeOH; 97:3). The pure fractions
were crystallized as a salt of oxalic acid from EtOH/
Et2O. Yield: 5%. 1H NMR: d = 3.45 (t, J = 6.1 Hz,
2H, Pip-(CH2)2CH2-O), 3.22 (d, J = 6.9 Hz, 2H,
O-CH2), 3.11–3.00 (m, 6H, Pip-2,6-H + Pip-CH2), 1.90
(m, 2H, PipCH2-CH2), 1.80–1.60 (m, 4H, Pip-3,5-H),
1.53 (br s, 2H, Pip-4-H), 1.02–0.95 (m, 1H, Cycloprop-
1-H), 0.47 (m, 2H, Cycloprop-2,3-He), 0.18 (m, 2H,
Cycloprop-2,3-Ha); MS (70 eV): m/z (%) = 197 ([Mꢀ]+,
1), 142 ([Pip-(CH2)3O+], 14), 124 (2), 99 (8), 98
(½Pip-CHþ2 ꢁ, 98), 84 ([Pip+], 6).
5.1.5. General procedure for Mitsunobu-type ether for-
mation (18 and 19). Triphenylphosphine (1.31 g,
5 mmol) was dissolved in 15 mL of freshly distilled
THF together with 3-piperidinopropan-1-ol (1, 0.72 g,
5 mmol) and 5 mmol of the phenol derivative and
cooled in an ice bath. Then DIAD (1.01 g, 5 mmol)
was added dropwise. The mixture was stirred for 72 h
(for 18) and 96 h (for 19) at ambient temperature. Then,
the solvent was removed under reduced pressure and the
crude product purified by CC, eluent: CHCl3–MeOH;
95:5. Pure fractions were crystallized as salts of oxalic
acid from EtOH/Et2O.
5.2.2. Histamine H3 receptor antagonist potency in vivo in
mice. In vivo testing was performed after oral administra-
tion to Swiss mice according to Garbarg et al.31 Brain his-
taminergic neuronal activity was assessed by measuring
the main metabolite of histamine, Ns-methylhistamine.
Mice were fasted for 24 h before po treatment. Animals
were decapitated 90 min after treatment and the cerebral
cortex was isolated. The cerebral cortex was homogenized
in 10 vol of ice-cold perchloric acid (0.4 M). The Ns-meth-
ylhistamine level was measured by radioimmunoassay.32
By treatment with 3 mg/kg ciproxifan the maximal in-
crease in Ns-methylhistamine level was obtained33 and
related to the level reached with the administered drug.
Each experiment was performed at least in triplicate.
The ED50 value was calculated as mean with SEM.34
5.1.5.1. 1-[3-(4-tert-Butylphenoxy)propyl]piperidine
hydrogen oxalate (18). From 4-tert-butylphenol (0.76 g,
1
5 mmol). Yield: 56%. H NMR: d = 7.28–7.25 (m, 2H,
Ph-2,6-H), 6.84–6.81 (m, 2H, Ph-3,5-H), 3.97 (t,
J = 6.1 Hz, 2H, CH2-O), 3.11–3.06 (m, 6H, Pip-
CH2 + Pip-2,6-H), 2.11 (m, 2H, PipCH2-CH2), 1.75–
1.65 (m, 4H, Pip-3,5-H), 1.50 (br s, 2H, Pip-4-H), 1.22
(s, 9H, C(CH3)3); MS (70 eV): m/z (%) = 275 ([Mꢀ]+,
8), 126 (½Pip-ðCH2Þþꢁ, 4), 99 (8), 98 (½Pip-CHþꢁ, 100);
Acknowledgements
2
IR (cmꢂ1): 1514s (m3[C@C]); 1249s (m [C–O–C]).
We gratefully thank Mrs. M. Kaleta for help in prepar-
ing compounds 7, 10, 11 and 13. This work was support-
ed by the Biomedical and Health Research Programme
(BIOMED) of the European Union, the Fonds der
Chemischen Industrie, Verband der Chemischen Indust-
rie, Frankfurt am Main, Germany and the Polish State
Committee for Scientific Research, Grant No. 6 P05F
013 20, respectively.
5.1.5.2.
1-[3-(4-(1,1-Dimethylpropyl)phenoxy)pro-
pyl]piperidine hydrogen oxalate (19). From 4-(1,1-dim-
ethylpropyl)phenol (0.92 g, 5 mmol). Yield: 55%. 1H
NMR: d = 7.20 (d, J = 8.8 Hz, 2H, Ph-2,6-H), 6.83 (d,
J = 8.8 Hz, 2H, Ph-3,5-H), 3.97 (t, J = 6.1 Hz, 2H,
CH2-O), 3.12–3.06 (m, 6H, Pip-CH2 + Pip-2,6-H), 2.07
(m, 2H, PipCH2-CH2), 1.72–1.62 (m, 4H, Pip-3,5-H),

D. Łaz_ewska et al. / Bioorg. Med. Chem. 14 (2006) 3522–3529
3529
J.-M.; Ganellin, C. R.; Schwartz, J.-C.; Schunack, W.
Bioorg. Med. Chem. Lett. 2001, 11, 951.
Appendix A. Data of elemental analysis for final com-
pounds 2–19
15. Cowart, M.; Altenbach, R.; Black, L.; Faghih, R.; Zhao,
C.; Hancock, A. A. Mini-Rev. Med. Chem. 2004, 4, 979.
16. <http://www.pharma.org/newmedsdb/drugs/drugs.cfm/>.
17. (a) Esbenshade, T. A.; Fox, G. B.; Krueger, K. M.; Miller,
T. R.; Hee Kang, C.; Denny, L. I.; Witte, D.; Yao, B. B.;
Pan, L.; Wetter, J.; Marsh, K.; Bennani, Y.; Cowart, M.
D.; Sullivan, J. P.; Hancock, A. A. J. Pharmacol. Exp.
Ther. 2005, 313, 165; (b) Fox, G. B.; Esbenshade, T. A.;
Pan, J. B.; Radek, R. J.; Krueger, K. M.; Yao, B. B.;
Browman, K. E.; Buckley, M. J.; Ballard, M. E.; Komater,
V. A.; Miner, H.; Zhang, M.; Faghih, R.; Rueter, L. E.;
Bitner, R. S.; Drescher, K. U.; Wetter, J.; Marsh, K.;
Lemaire, M.; Porsolt, R. D.; Bennani, Y. L.; Sullivan, J.
P.; Cowart, M. D.; Decker, M. W.; Hancock, A. A.
J. Pharmacol. Exp. Ther. 2005, 313, 176.
18. (a) Shah, C.; McAtee, L.; Breitenbucher, J. G.; Rudolph,
D.; Li, X.; Lovenberg, T. W.; Mazur, C.; Wilson, J. S.;
Carruthers, N. I. Bioorg. Med. Chem. Lett. 2002, 12, 3309;
(b) Chai, C.; Breitenbucher, J. G.; Kwok, A.; Li, X.;
Wong, V.; Carruthers, N. I.; Lovenberg, T. W.; Mazur,
C.; Wilson, S. J.; Axe, F. U.; Jones, T. K. Bioorg. Med.
Chem. Lett. 2003, 13, 1767; (c) Apodaca, R.; Dvorak, C.
A.; Xiao, W.; Barbier, A. J.; Boggs, J. D.; Wilson, S. J.;
Lovenberg, T. W.; Carruthers, N. I. J. Med. Chem. 2003,
46, 3938; (d) Dvorak, C. A.; Apodaca, R.; Barbier, A. J.;
Berridge, C. W.; Wilson, S. J.; Boggs, J. D.; Xiao, W.;
Lovenberg, T. W.; Carruthers, N. I. J. Med. Chem. 2005,
48, 2229.
No.
% C
% H
% N
Calcd Found Calcd Found Calcd Found
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
55.15 54.84 8.87
56.71 56.47 9.15
55.52 55.53 9.48
59.03 58.93 9.64
59.69 59.71 9.86
56.05 56.24 9.72
59.38 59.16 9.63
57.61 57.78 8.81
58.04 57.93 9.09
56.38 56.41 8.67
62.95 62.59 9.68
56.20 56.20 8.53
57.79 57.69 8.80
59.78 59.50 9.03
65.31 65.57 7.79
56.83 56.91 7.15
65.73 65.54 8.55
66.46 66.33 8.76
8.83 5.36
8.85 5.09
9.23 4.62
9.89 4.59
10.16 4.35
9.49 4.36
9.87 4.62
8.67 4.80
8.82 4.51
8.91 3.65
9.81 4.08
8.24 5.04
8.76 4.81
9.01 4.65
7.88 4.01
6.80 3.68
8.66 3.83
8.95 3.69
5.28
5.23
4.38
4.61
4.34
4.13
4.58
4.75
4.67
4.81
4.04
5.05
4.85
4.61
4.02
3.66
3.86
3.67
19. Meier, G.; Apelt, J.; Reichert, U.; Grassmann, S.;
Ligneau, X.; Elz, S.; Leurquin, F.; Ganellin, C. R.;
Schwartz, J.-C.; Schunack, W.; Stark, H. Eur. J. Pharm.
Sci. 2001, 13, 249.
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_
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20. Łazewska, D.; Kiec-Kononowicz, K.; Pertz, H. H.; Stark,
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_
´
21. Łazewska, D.; Kiec-Kononowicz, K.; Pertz, H. H.; Elz, S.;
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_
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