New 1-benzyl-4-hydroxypiperidine derivatives as non-imidazole histamine H3 receptor antagonists

Article abstract of DOI:10.1002/ardp.200800070

A series of 1-benzyl-4-(3-aminopropyloxy)piperidine and 1-benzyl-4-(5-aminopentyloxy)piperidine derivatives has been prepared. The 1-benzyl-4-hydroxypiperidine derivatives obtained were evaluated for their affinities at recombinant human histamine H₃ receptor, stably expressed in HEK 293T cells. All compounds investigated show moderate to pronounced in-vitro affinities. The most potent antagonists in this series 9b2 (hH₃R, pK_i = 7.09), 9b1 (hH₃R, pK_i = 6.78), 9b5 (hH₃R, pK_i = 6.99), and 9b6 (hH₃R, pK_i = 6.97) were also tested in vitro as H₃ receptor antagonists - the electrically evoked contraction of the guinea-pig jejunum. The histaminergic H₁ antagonism of selected compounds 9b1, 9b2, and 9b4-9b6 was established on the isolated guinea-pig ileum by conventional methods; the pA₂ values were compared with the potency of pyrilamine. The compounds did not show any H₁ antagonistic activity (pA ₂ < 4; for pyrilamine pA₂ = 9.53).

Full text of DOI:10.1002/ardp.200800070

762
Arch. Pharm. Chem. Life Sci. 2008, 341, 762–773
Full Paper
New 1-Benzyl-4-hydroxypiperidine Derivatives as Non-
imidazole Histamine H3 Receptor Antagonists
Iwona Maslowska-Lipowicz1, Marek Figlus1+, Obbe P. Zuiderveld2, and Krzysztof Walczynski1
1 Department of Synthesis and Technology of Drugs, Medical University, Lꢀdz, Poland
2 Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Vrije Universiteit,
Amsterdam, The Netherlands
A series of 1-benzyl-4-(3-aminopropyloxy)piperidine and 1-benzyl-4-(5-aminopentyloxy)piperidine
derivatives has been prepared. The 1-benzyl-4-hydroxypiperidine derivatives obtained were eval-
uated for their affinities at recombinant human histamine H3 receptor, stably expressed in HEK
293T cells. All compounds investigated show moderate to pronounced in-vitro affinities. The
most potent antagonists in this series 9b2 (hH3R, pKi = 7.09), 9b1 (hH3R, pKi = 6.78), 9b5 (hH3R, pKi
= 6.99), and 9b6 (hH3R, pKi = 6.97) were also tested in vitro as H3 receptor antagonists – the electri-
cally evoked contraction of the guinea-pig jejunum. The histaminergic H1 antagonism of
selected compounds 9b1, 9b2, and 9b4–9b6 was established on the isolated guinea-pig ileum by
conventional methods; the pA2 values were compared with the potency of pyrilamine. The com-
pounds did not show any H1 antagonistic activity (pA2 a 4; for pyrilamine pA2 = 9.53).
Keywords: 1-Benzyl-4-(3-aminopropyloxy)piperidine / 1-Benzyl-4-(5-aminopentyloxy)piperidine derivatives / H3 antag-
onists / Histamine H3 receptor /
Received: April 8, 2008; accepted: July 15, 2008
DOI 10.1002/ardp.200800070
sidered to be potential drugs for the treatment of Alz-
Introduction
heimer's disease [9, 10], attention deficit-hyperactive dis-
order (ADHD) [11], memory and learning deficits [12–14],
and epilepsy [15].
The cloning [1] of the H3 receptor has provided fresh
impetus to the development of drug-like ligands of this
receptor. Homology analysis of the H3 receptor showed it
to be significantly different from the previously cloned
H1 and H2 receptors [1, 2]. The H3 receptors are located pre-
synaptically and, upon stimulation by histamine or
another H3 agonist, inhibit synthesis and release of hista-
mine [3, 4]. They are also known to play an important
role as heteroreceptors involved in the regulation of the
release of several other important neurotransmitters
such as acetylcholine [5], dopamine [6], noradrenaline [7],
and serotonin [8]. Antagonists to the H3 receptor are con-
During the years, following number of H3 antagonists
belonging to different chemical classes, subsequently div-
ided between classical imidazole-based [16–18] and non-
imidazole series have been described [19, 20]; the imida-
zole derivatives were considered to be less attractive for
pharmacokinetic as well as for toxicological reasons.
An early description of a systematic design of non-imi-
dazoles was reported by Ganellin et al. [21]. Based on the
SAR of a novel series of homologues O- and S-isosteric ter-
tiary amines of N-ethyl-N-(4-phenylbutyl)amine, it was dis-
covered that some activity was retained upon replace-
ment of the imidazole moiety with cyclic amines. Selec-
tion of these amines as the preferred group, by optimiz-
ing the chain length, by replacing a chain methylene
Correspondence: Krzysztof Walczynski, Department of Synthesis and
Technology of Drugs, Medical University, Muszynskiego street 1, 90-151
Lꢀdz, Poland.
E-mail: kwalczynski@pharm.am.lodz.pl
Fax: +48 42 6779159
+
From 2005 to 2006, Marek Figlus was employed in the Department of
Synthesis and Technology of Drugs, Medical University, Muszynskiego
street 1, 90-151 Lꢀdz, Poland.
Abbreviations: formic acid-acetic anhydride (FAM); structure-activity re-
lationship (SAR)
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Arch. Pharm. Chem. Life Sci. 2008, 341, 762–773
Non-imidazole Histamine H3 antagonists
763
Figure 1. Structures of some known histamine H3-recep-
tor antagonists and target molecules of this study.
with oxygen, and by attaching a nitro group to the phe- non-imidazole H3-histamine receptor antagonists, for
nyl ring led to the UCL 1972 (1; Fig. 1) – the most potent example compounds 4 [26] and 5 [27] (Fig. 1). Based on
compound of this series.
these results, it may be concluded that compounds carry-
Later on, the successful replacement of the imidazole ing a piperidine ring are more likely to be successful in
moiety with piperidine and other basic tertiary amines ethereal analogs than in the other series, especially in
was demonstrated with a variety of analogs [22–24]. As compounds, where the oxygen is directly connected to
might have been expected, the effect of replacement of an aromatic group. With ABT-239 [28] 6 and 7 [29] (Fig. 1),
the imidazole by basic tertiary amines affected the H3 it has been shown that the highly flexible propyloxy link
inhibitor potency to different degrees, depending on the can be successfully replaced by the partially rigid 2-ami-
chemical series. Many compounds showed large losses in noethylbenzofuran substructure or the 4-phenoxypiperi-
potency upon replacement of imidazole by piperidine. dine moiety. Another example of this theme (8; Fig. 1)
However, some of them such as ciproxifan analog UCL [30] shows that not only rigidification of propyloxy link
2190 [23] (2; Fig. 1) retained high potency, although not leads to active compounds, but also replacement of the
so much as the parent imidazole–ciproxifan [25] (3; oxygen and proximal methylene of 4 with an acetylene
Fig. 1). UCL 2190 was one of the first representatives of giving a more conformationally restricted analog, yields
piperidine-based ligands that contain the aminopropoxy- a derivative retaining the potency of the parent com-
phenyl group, which later appeared in several potent pound. This latter example suggests that the oxygen
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Arch. Pharm. Chem. Life Sci. 2008, 341, 762–773
Table 1. Antagonist potencies of 1-benzyl-4-hydroxypiperidine derivatives at histamine H3 receptor.
Cpd.
n
m
R
R1
pKi (s.e.m) N
Cpd.
n
m
R
R1
pKi (s.e.m) N
pA2 (s.e.m) N
caviae)
12
3
3
3
0
0
0
H
H
6.42 (0.02) 3
6.47 (0.02) 3
6.01 (0.04) 3
18
5
5
5
0
0
0
H
H
5.66 (0.05) 3
6.24 (0.06) 3
6.78 (0.08) 3
14
CH3
CH3
H
20
CH3
CH3
H
9a1
CH3
9b1
CH3
7.06 (0.04) 10 (3)
7.79 (0.06) 12 (4)
9a2
3
2
CH3
CH3
CH3
6.73 (0.05) 3
9b2
5
2
CH3
CH3
CH3
7.09 (0.03) 3
9a3
9a4
9a5
3
3
3
4
1
3
CH3
CH3
CH3
6.25 (0.02) 3
6.02 (0.04) 3
6.08 (0.02) 3
9b3
9b4
9b5
5
5
5
4
1
3
CH3
CH3
CH3
6.59 (0.03) 3
6.76 (0.13) 3
6.99 (0.03) 3
7.45 (0.05) 11 (4)
7.32 (0.04) 11 (4)
9a6
3
5
CH3
6.44 (0.02) 3
9b6
5
5
CH3
6.97 (0.08) 3
Controls
Cpd
pKi (s.e.m)
N
pA2 (s.e.m)
8.61 (0.07)
N (caviae)
12 (4)
Histamine (agonist)
Thioperamid (antagonist or inverse agonist)
Imetit (agonist)
7.65 (0.01)
7.29 (0.01)
8.89 (0.05)
8.85 (0.04)
3
3
3
3
Clobenpropit (antagonist or inverse agonist)
N – number of different animal preparation; caviae – number of animals.
atom in the link is not absolutely essential for high H3- amine binding at human histamine H3 receptor
histamine receptor binding affinity.
expressed in HEK 239T cell membranes.
In the present work, we report the synthesis and pre-
The presented 1-benzyl-4-(3-aminopropyloxy)- and 1-
liminary pharmacological investigation of a new series benzyl-4-(5-amino)pentyloxypiperi-dine derivatives all
of 1-benzyl-4-hydroxypiperidine-based H3-histamine possess, moderate to pronounced H3-receptor antagonist
receptor antagonists 9 (Fig. 1) in which two concepts –
potency (Table 1).
rigidification of aminopropyloxy link by incorporation it
It appeared that by comparison of homologous pairs,
into 4-hydroxypiperidine ring and replacement of phe- the 1-benzyl-4-(5-aminopentyloxy)piperidines (9b1–9b6)
nyl (present in aminopropyloxyphenyl archetypal H3 have a slightly higher potency than their 1-benzyl-4-(3-
pharmacophore) by aminoalkyl and aminophenylalkyl aminopropyloxy)piperidines analogues 9a1–9a6. The dif-
chain. In this series, we varied the length of the N-alkyl ference is observed for compounds 12, 14 and 18, 20 where
spacer from one to five methylene groups and, in addi- the 1-benzyl-4-(3-aminopropyloxy)piperidine (12; pKi =
tion, replaced the alkyl chain by phenylalkyl substitu- 6.42) and its N-methyl derivative (14; pKi = 6.47) have a
ents. We also studied the influence of the replacement of slightly higher activity than their 1-benzyl-4-(5-aminopen-
the N-aminopropyloxy chain by a N-aminopentyloxy one tyloxy)piperidine analogous (18;pKi =5.66; 20;pKi =6.24).
on the H3-receptor antagonist activity.
In the N-aminopropyloxy series (compounds 12, 14 and
9a1–9a6) there is no significant difference in hH3R poten-
cies among the aminopropyloksy derivative (12; pKi =
6.42) and N-methylaminopropyloxy derivative (14; pKi =
6.47). Replacement of hydrogen in the N-methyl group by
a second methyl group results in a decrease of potency
Results and discussion
In-vitro binding assay at cloned human histamine H3
receptors
The affinities of all compounds were determined by for compound 9a1 (pKi = 6.01); a further increase in the
measuring the displacement curves of [3H]Na-methylhist-
alkyl chain length to three methylene groups results in
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Arch. Pharm. Chem. Life Sci. 2008, 341, 762–773
Non-imidazole Histamine H3 antagonists
765
an increase of potency for compound 9a2 (pKi = 6.73) H1 histamine receptor antagonist potency in
reaching the maximum for this series. Elongation of contraction of the guinea-pig ileum
alkyl chain to five methylene groups again results in a Additionally, selected compounds 9b1, 9b2 and 9b4–9b6
decrease of potency for compound 9a3 (pKi = 6.25). were also tested for H1 antagonistic effects in vitro, follow-
Replacement of hydrogen by a phenyl group at the end of ing standard methods, using the guinea pig ileum. They
N-alkyl chain leads to compounds 9a4–9a6 (pKi = 6.02; pKi did not show any H1-antagonistic activity (pA2 a 4; for pyr-
= 6.08; pKi = 6.44, respectively) with moderate potency, ilamine pA2 = 9.53).
with slightly higher potency for compound 9a6.
In the N-aminopentyloxy series (compounds 18, 20 and
9b1–9b6) the highest activity is again seen in the com-
pound with the N-methyl-N-propyl substituent 9b2 (pKi =
Chemistry
7.09). In this series, similar results were observed, as in The general synthetic procedures used in this study are
the N-methyl-N-alkylaminopropyloxy derivatives, inde- illustrated in Scheme 1 and Scheme 2.
pendently on an increase in the alkyl chain length to five
The 1-benzyl-4-[3-(N-methyl-N-propylamino)propyloxy]-
methylene groups 9b3 or a decrease in the alkyl chain and 1-benzyl-4-[3-(N-methyl-N-pentylamino)propyloxy]pi-
length to one methyl group 9b1 results in an increase of peridines 9a2, 9a3 (Scheme 1, Procedure A), were synthe-
potency (pKi = 6.59) and (pKi = 6.78), respectively.
sized by standard methods. Compound 14 was acetylated
In the N-phenylalkyl derivatives of 1-benzyl-4-[5-(N- with an appropriate acid anhydride and next, obtained
methylaminopentyloxy)]piperidine there is no signifi- amides 15a2 and 15a3 were reduced with LiAlH4 in dry
cant difference in hH3R potencies, particularly among ethyl ether followed by purification with column chro-
the compounds 9b5 and 9b6 (pKi = 6.99; pKi = 6.97, respec- matography.
tively). This is in contrary to the N-phenylalkyl derivatives
The
1-benzyl-4-[3-(N-methylamino)propyloxy]piperi-
of 1-benzyl-4-[5-(N-methylamino-propyloxy)]piperidine dine 14 was prepared from compound 10 by a four-step
9a4-9a6 where the N-methyl-N-phenylpentylaminopropy- reaction (Scheme 1; Procedure A) including: O-alkylation
loxy derivative 9a6 shows a slightly higher potency than with acrylonitrile in the presence of small amount of Tri-
its N-methyl-N-phenylalkyl analogues 9a4, 9a5.
ton B to compound 11, reduction with LiAlH4 in dry ethyl
Clearly, 1-benzyl-4-[5-(N-methyl-N-subsitutedaminopen- ether to compound 12 [31–33] (CAS RN 200868-41-3), for-
tyloxy)]-piperidine 9b1-9b6 display a higher potency than mylation with formic acid-acetic anhydride (FAM) [34] to
their N-methyl-N-propyloxy 9a1-9a6 analogues. The high- compound 13, and, finally, reduction with LiAlH4 in dry
est potency for both homologous series is seen in the ethyl ether to compound 14, each step was followed by
compound with the N-methyl-N-propylaminopentyloxy purification with column chromatography.
substituent 9b2 (pKi = 7.09) and with slightly lower poten-
The 1-benzyl-4-[3-(N,N-dimethylamino)propyloxy]piper-
cies for compounds 9b5 (pKi = 6.99) and 9b6 (pKi = 6.97) idine 9a1 (Scheme 1, Procedure B) was synthesized by the
carrying on N-methyl-N-phenylpropylaminopentyloxy- reaction of 1-benzyl-4-(3-aminopropyloxy)piperidine 12
and N-methyl-N-phenylpentylaminopentyloxy-substitu- with formaldehyde in formic acid and separated by col-
ent, respectively.
umn chromatography.
The compounds 9a4–9a6 (Scheme 1, Procedure C) were
synthesized from 1-benzyl-4-[3-(N-methylamino)propylox-
y]piperidine 14 by alkylation with the corresponding pri-
mary phenylalkyl halides in the presence of K2CO3 in
H3 histamine receptor antagonist potency in
electrically-evoked contraction of the guinea-pig
jejunum
The most potent antagonists in this series 9b2 (hH3R pKi = DMF followed by purification with column chromatogra-
7.09), 9b1 (hH3R pKi = 6.78), 9b5 (hH3R pKi = 6.99), and 9b6 phy.
(hH3R pKi = 6.97) were in-vitro tested as H3-receptor antago-
The 1-benzyl-4-[3-(N-methyl-N-phenylalkylamino)penty-
nists by electrically-evoked contraction of the guinea-pig loxy]-piperidines 9b4–9b6 (Scheme 2, Procedure D) were
jejunum (Table 1). All compounds tested showed antago- obtained from 1-benzyl-4-[3-(N-methylamino)pentyloxy]-
nist properties. The highest activity is seen, as in-vitro piperidine 20 by alkylation with the corresponding pri-
binding assay at cloned human histamine H3 receptors, mary phenylalkyl halides in the presence of potassium
in the compound with the N-methyl-N-propyl substituent carbonate in DMF followed by purification with column
9b2 (pA2 = 7.79). Again, it appeared that compound 9b5 chromatography.
(pA2 = 7.45) has a slightly higher potency than its N-
The
1-benzyl-4-[3-(N-methylamino)pentyloxy]piperi-
methyl-N-phenylpentyl and N,N-dimethyl analogues 9b6 dine 20 was prepared from compound 10 by a four-step
(pA2 = 7.32) and 9b1 (pA2 = 7.06), respectively.
synthesis (Scheme 2; Procedure D) including: O-alkylation
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Arch. Pharm. Chem. Life Sci. 2008, 341, 762–773
Scheme 1. Synthesis of 1-benzyl-4-(3-aminopropyloxy)piperidine 12, 1-benzyl-4-[3-(N-methylamino)propyloxy]piperidine 14, 1-ben-
zyl-4-[3-(N-methyl-alkylamino)-propyloxy]piperidines 9a1–9a3 and 1-benzyl-4-[3-(N-methyl-N-phenylamino)-propyloxy]piperidines
9a4–9a6.
with 5-bromopentanenitrile in dry toluene in the pres- to compounds 9b1-9b3, each step was followed by purifi-
ence of sodium hydride and 1,4,7,10,13-pentaoxycyclo- cation with column chromatography.
pentadecane (15-crown-5 ether) to compound 17, reduc-
All obtained final free bases were treated with metha-
tion with LiAlH4 in dry ethyl ether to compound 18, for- nolic oxalic acid, and the oxalic acid salts were precipi-
mylation with formic acid-acetic anhydride (FAM) [34] to tated with dry diethyl ether.
compound 19 and, finally, reduction with LiAlH4 in dry
The formic acid-acetic anhydride (FAM) was obtained
ethyl ether to compound 20, each step was followed by according to van Es and Stewens [34] by the action of for-
purification with column chromatography.
mic acid on acetic anhydride.
The 1-benzyl-4-[3-(N-methyl-N-alkylamino)pentyloxy]pi-
The 1-chloro-5-iodopentane was obtained according to
peridines 9b1-9b3 were obtained from compound 10 by a Hass and Huffman [35] from 1,5-dichloropentane
two-step synthesis (Scheme 2; Procedure E) including: O- through nucleophilic mono-substitution of the chlorine
alkylation with 1-chloro-5-iodopentane in the presence of atom by iodide in dry acetone with sodium iodide. The 5-
KF/Al2O3 in acetonitrile to compound 21 and, finally, sub- phenylpentyl bromide was obtained according to Collins
stituted with the appropriate secondary amines in DMF and Davis [36]. The 5-phenyl-1-pentanol was converted
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Arch. Pharm. Chem. Life Sci. 2008, 341, 762–773
Non-imidazole Histamine H3 antagonists
767
Scheme 2. Synthesis of 1-benzyl-4-(5-aminopentyloxy)piperidine 18, 1-benzyl-4-[5-(N-
methylamino)pentyloxy]piperidine 20, 1-benzyl-4-[5-(N-methyl-N-alkylamino)-pentylox-
y]piperidines 9b1–9b3 and 1-benzyl-4-[5-(N-methyl-N-phenylalkylamino)-pentyloxy]pi-
peridines 9b4–9b6.
(60 MHz) spectrometer (Varian Inc., Palo Alto, CA, USA). Chemi-
cal shifts are expressed in ppm downfield from internal TMS as
reference. 1H-NMR data are reported in order: multiplicity (br,
broad; s, singlet; d, doublet; t, triplet; m, multiplet; *, exchange-
able by D2O) number of protons, and approximate coupling con-
stant in Hertz. Elemental analysis (C, H, N) for all compounds
were measured on Heraeus EA 415-0 (Heraeus, Hanau, Germany)
and are within l 0.4% of the theoretical values. TLC was perform-
ed on silica gel PF254 plates (Merck, Germany). Flash column chro-
matography was carried out using silica gel 30–60 lm (J. T.
Baker BV., Deventer, The Netherlands), employing the same elu-
ent as was indicated by TLC. In each case, the final free base was
treated with methanolic oxalic acid, and the oxalic acid salt
were precipitated with dry diethyl ether.
into the bromide by treatment with 50% aqueous hydro-
bromic acid and concentrated sulphuric acid. The 1-ben-
zyl-4-hydroxypiperidine, acetonitrile, 5-bromopentano-
nitrile, propionic anhydride, pentanoic anhydride, ben-
zyl bromide, 1-bromo-3-phenylpropane, 5-phenyl-1-pen-
tanol, benzoyl chloride, dimethylamine, methylpropyl-
amine, and methylpentylamine were all purchased from
commercial sources.
This work was supported by the Polish State Committee for Sci-
entific Research, Grant No. 502-13-410.
The authors have declared no conflict of interest.
Synthesis of 1-benzyl-4-(3-cyanopropyloxy)piperidine 11
To a solution of the 1-benzyl-4-hydroxypiperidine 10 (0.031 mol)
dissolved in 90 mL of acetonitrile was added dropwise Triton B
(2 mL). The mixture was heated at 808C for 25 h. After cooling,
the reaction mixture was poured out into 300 mL of ethyl ether.
The resulting precipitate was filtered off and the solvent was
evaporated to give the crude product as a sticky oil which was
purified by column chromatography.
Experimental
General methods
All melting points (m.p.) were taken in open capillaries on an
electrothermal apparatus and are uncorrected. For all com-
pounds, 1H-NMR spectra were recorded on a Varian EM 360
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11: C15H20N2O, (M = 244.3); yield 60.6%; 1H-NMR (CDCl3), d:
1.57–1.68 (m, 2H, CH2CHO), 1.83–1.91 (m, 2H, CH2CHO), 2.11–
2.19 (m, 2H, NCH2), 2.56 (t, J = 6.3 Hz, 2H, CH2CN), 2.68–2.75 (m,
2H, NCH2), 3.35–3.43 (m, 1H, CHO), 3.48 (s, 2H, CH2Ph), 3.64–
3.68 (m, 2H, OCH2), 7.21–7.34 (m, 5H, CH); TLC (dichlorome-
The solvent was evaporated and the residue was purified by col-
umn chromatography on silicagel. The title products were
obtained as sticky oil.
14: C16H26N2O; (M = 262.4); yield 87.0%; 1H-NMR, CDCl3, d:
1.53–1.65 (m, 2H, CH2CHO), 1.7–1.79 (m, 2H, NCH2), 1.82–1.89
(m, 3H, CH2CHO, NH*), 2.08–2.16 (m, 2H, 9NCH2), 2.41 (s, 3H,
CH3), 2.62–2.67 (t, J = 6.9 Hz, 2H, OCH2), 2.69–2.76 (m, 2H, NCH2),
3.23–3.32 (m, 1H, HC-O-), 3.47–3.51 (m, 2H, OCH2), 3.48 (s, 2H,
PhCH2), 7.2–7.32 (m, 5H, CH); TLC (dichloromethane / methanol
/ concentrated ammonium hydroxide: 49 : 10 : 1) Rf = 0.45. Ele-
mental analysis for dioxalic acid salt C16H26N2O62 C2H2O4 (M =
442.5); m.p.dioxalic acid salt = 149.4–150.78C: calculated: C, 54.29; H,
6.83; N, 6.33. Found: C, 53.87; H, 6.72; N, 6.66.
thane
/ methanol / concentrated ammonium hydroxide:
394 : 5 : 1) Rf = 0.57.
Synthesis of 1-benzyl-4-(3-aminopropyloxy)piperidine 12
To a solution of 1-benzyl-4-(3-cyanopropyloxy)piperidine 11
(0.018 mol) in 50 mL of anhydrous ethyl ether was added LiAlH4
(0.06 mol). The mixture was stirred at room temperature for 1 h,
and quenched by dropwise addition of water (2.3 mL), 10% of
NaOH solution (2.3 mL), and water (2.3 mL). The suspension was
stirred for 30 min and filtered. The filter cake was washed with
ether (2650 mL). The combined organic extracts were washed
with water (3650 mL), dried (Na2SO4), and filtered. The solvent
was evaporated and residue was purified by column chromatog-
raphy on silicagel. The title products were obtained as sticky oil.
12: C15H24N2O, (M = 248.4); yield 60.0%; 1H-NMR (CDCl3), d:
11.56–1.77 (m, 4H, CH2CHO, NH2*), 1.67–1.75 (m, 2H, CH2), 1.84–
1.90 (m, 2H, CH2CHO), 2.09–2.17 (m, 2H, NCH2), 2.68–2.75 (m,
2H, NCH2), 2.80 (t, J = 6.9 Hz, 2H, CH2), 3,24–3,33 (m, 1H, HC-O-),
3.49 (s, 2H, PhCH2), 3.46–3.3 (m, 2H, CH2), 7.22–7.32 (m, 5H, CH);
TLC (dichloromethane / methanol / concentrated ammonium
hydroxide: 59 : 10 : 1) Rf = 0.43. Elemental analysis for dioxalic
General method for the preparation of 1-benzyl-4-[3-(N-
methyl-N-alkylcarbonylamino)propyloxy]piperidine
amides 15a2, 15a3
To a solution of 1-benzyl-4-[3-(N-methylamino)propyloxy]piperi-
dine 14 (0.003 mol) in 20.0 mL of anhydrous dichloromethane
was added the corresponding acid anhydride (0.009 mol). The
mixture was stirred at room temperature for 1 h. Then, water
(20 mL) was added, the mixture was neutralized with K2CO3, and
water layer was extracted with dichlorometane (2615 mL). The
combined organic extracts were washed with water (3630 mL),
dried (Na2SO4), filtered, and evaporated to give compounds 15a2,
15a3 as a sticky oil. In each case, the crude product was purified
by column chromatography.
acid salt C15H24N2O 6 2 C2H2O4 (M = 428.4); m.p.dioxalic
=
acid salt
166.5–167.28C: calculated: C, 53.27; H, 6.59; N, 6.54. Found: C,
53.45; H, 6.72; N, 6.76.
15a2
C19H30N2O2; (M = 318.5); yield 96.2%; 1H-NMR, CDCl3, d: 1.1–1.17
(m, 3H, CH2CH3), 1.55–1.65 (m, 2H, CH2CHO), 1.74–1.81 (m, 2H,
CH2), 1.83–1.90 (m, 2H, CH2O), 2.15–2.21 (m, 2H, NH2), 2.44–
2.52 (m, 2H, CH2), 2.72–2.75 (m, 2H, NCH2), 2.90–2.98 (m, 3H,
NCH3), 3.26–3.32 (m, 1H, HC-O-), 3.35–3.46 (m, 4H, CH2), 3.52–
3.54 (s, 2H, PhCH2), 7.21–7.31 (m, 5H, CH); TLC (dichloromethane
/ methanol / concentrated ammonium hydroxide: 89 : 10 : 1) Rf =
0.69.
Synthesis of 1-benzyl-4-[3-(N-
formylamino)propyloxy]piperidine 13
To a solution of 1-benzyl-4-(3-aminopropyloxy)piperidine 12
(0.01 mol) in 60 mL of anhydrous dichloromethane was added
FAM (18.0 mL). The mixture was stirred at 5–108C for 0.5 h.
Then, water (50.0 mL) and ethyl acetate (50.0 mL) were added
and the mixture was neutralized with K2CO3. The water layer
was extracted with dichloromethane (2650 mL). The combined
organic extracts were washed with water (3650 mL), dried
(Na2SO4), filtered, and evaporated; the residue was purified by
column chromatography on silicagel to give compound 13 as a
sticky oil.
15a3
C21H34N2O2; (M = 346.5); yield 94%;1H-NMR, CDCl3, d: 0.9–0.95 (t, J
= 6.9 Hz, 3H, CH2CH3), 1.29–1.42 (m, 2H, CH2), 1.53–1.67 (m, 4H,
CH2CHO, CH2), 1.74–1.88 (m, 4H, CH2CHO, CH2), 2.09–2.16 (m,
2H, NCH2), 2.26–2.37 (m, 2H, CH2), 2.71–2.75 (m, 2H, NCH2), 2.95
(s, 3H, NCH3), 3.26 (s, 1H, HC-O-), 3.37-3.47 (m, 4H, CH2, CH2), 3.49
(s, 2H, CH2Ph), 7.23–7.32 (m, 5H, CH); TLC (dichloromethane /
methanol / triethylamine: 89 : 10 : 1) Rf = 0.84.
13: C16H24N2O2; (M = 276.4); yield 89.0%; 1H-NMR CDCl3, d:
1.58–1.69 (m, 2H, CH2CHO), 1.72–1.82 (m, 2H, CH2CH2CH2),
1.86–1.95 (m, 2H, CH2CHO), 2.24–2.3 (m, 2H, NCH2), 2.72–2.76
(m, 2H, NCH2), 3.31–3.35 (m, 2H, CH2, NCH2), 3.35–3.45 (m, 1H,
HC-O-), 3.57 (s, 2H, CH2 Ph), 3.48–3.66 (m, 2H, OCH2), 6.24 (s*, br
1H, NH), 7.23–7.35 (m, 5H, CH), 8.11 (s, 1H, CHO); TLC (dichloro-
methane / methanol / concentrated ammonium hydroxide:
89 : 10 : 1) Rf = 0.51.
General method for the preparation of 1-benzyl-4-[3-(N-
methyl-N-alkylamino)propyloxy]piperidines 9a2, 9a3
To a solution of the appropriate 1-benzyl-4-[3-(N-methyl-N-alkyl-
carbonylamino)propyloxy]piperidine amides 15a2 and 15a3
(0.002 mol) in 10 mL of anhydrous ethyl ether was added LiAlH4
(0.0087 mol). The mixture was stirred at room temperature for
1 h, and quenched by dropwise addition of water (0.33 mL), 10%
of NaOH solution (0.33 mL), and water (0.33 mL). The suspension
was stirred for 30 min, and filtered. The filter cake was washed
with ether (2610 mL). The combined organic extracts were
washed with water (3610 mL), dried (Na2SO4), and filtered. The
solvent was evaporated and residue was purified by column
chromatography on silicagel. The title products were obtained
Synthesis of 1-benzyl-4-[3-(N-
methylamino)propyloxy]piperidine 14
To a solution of 1-benzyl-4-[3-(N-formylamino)propyloxy]piperi-
dine 13 (0.01 mol) in 30 mL of anhydrous ethyl ether was added
LiAlH4 (0.037 mol). The mixture was stirred at room temperature
for 1 h, and quenched by dropwise addition of water (1.4 mL),
10% of NaOH solution (1.4 mL), and water (1.4 mL). The suspen-
sion was stirred for 30 min, and filtered. The filter cake was
washed with ether (2630 mL). The combined organic extracts
were washed with water (3630 mL), dried (Na2SO4), and filtered.
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2008, 341, 762–773
Non-imidazole Histamine H3 antagonists
769
as sticky oil. Free base was treated with methanolic oxalic acid
and oxalic acid salt were precipitated with dry diethyl ether.
thane (3625 mL), dried (Na2SO4), and filtered. The solvent was
evaporated to give the crude products which were purified by
column chromatography. The title products were obtained as
sticky oil. Free bases were treated with methanolic oxalic acid
and oxalic acid salt were precipitated with dry diethyl ether.
9a2
C19H32N2O; (M = 304.5); yield 51.7%; 1H-NMR, CDCl3, d: 0.86–0.91
(t, J = 3.9 Hz, 3H, CH2CH3), 1.41–1.51(m, 2H, CH2), 1.53–1.65 (m,
2H, CH2CHO), 1.68–1.77 (m, 2H, CH2), 1.84–1.89 (m, 2H,
CH2CHO), 2.07–2.15 (m, 2H, NCH2), 2.2 (s, 3H, NCH3), 2.25–2.3
(m, 2H, CH2), 2.37–2.42 (m, 2H, CH2), 2.72–2.76 (m, 2H, NCH2),
3.23–3.32 (m, 1H, HC-O-), 3.44–3.5 (m, 2H, CH2), 3.48 (s, 2H,
PhCH2), 7.21–7.32 (m, 5H, CH); TLC (dichloromethane/methanol/
concentrated ammonium hydroxide: 89 : 10 : 1) Rf = 0.55. Ele-
mental analysis for dioxalic acid salt C19H32N2O62 C2H2O4 (M =
484.55); m.p.dioxalic acid salt = 147.8–149.88C: calculated: C, 57.01; H,
7.49; N, 5.78. Found: C, 57.23; H, 7.81; N, 5.69.
9a4
C23H32N2O (M = 352.5); yield 27.8%; 1H-NMR, CDCl3, d: 1.56–1.62
(m, 4H, CH2CHO, CH2), 1.73–1.82 (m, 4H, CH2CHO, CH2), 2.08–
2.15 (m, 2H, NCH2), 2.18 (s, 3H, NCH3), 2.44 (t, J = 7Hz, 2H, CH2),
2.70–2.75 (m, 2H, NCH2), 3.25–3.32 (m, 1H, HC-O-), 3.45–3.47
(m, 4H, =N-CH2Ph, CH3-N-CH2Ph), 7.19–7.37 (m, 10H, CH); TLC
(dichloromethane/methanol/concentrated ammonium hydrox-
ide: 189 : 10 : 1) Rf = 0.30. Elemental analysis for dioxalic acid
salt C23H32N2O62 C2H2O4 (M = 532.6); m.p.dioxalic
= 185–
acid salt
1878C: calculated: C, 60.89; H, 6.81; N, 5.26. Found: C, 60.55; H,
6.52; N, 4.96.
9a3
C21H36N2O; (M = 332.5); yield 59.7%; 1H-NMR, CDCl3, d: 0.87–0.91
(t, J = 6.9 Hz, 3H; CH2CH3), 1.23–1.36 (m, 4H, CH2, CH2), 1.40–1.50
(m, 2H, CH2), 1.52-1.64 (m, 2H, CH2CHO), 1.67–1.77 (m, 2H, CH2),
1.83–1.89 (m, 2H, CH2CHO), 2.07–2.14 (m, 2H, NCH2), 2.20 (s, 3H,
NCH3), 2.28–2.33 (t, J = 7.6 Hz, 2H, CH2), 2.37–2.41 (t, J = 7.3 Hz,
2H, CH2), 2.71–2.75 (m, 2H, NCH2), 3.23–3.32 (m, 1H, HC-O-),
3.44–3.48 (m, 4H, CH2, CH2Ph), 7.22–7.31 (m, 5H, CH); TLC
(dichloromethane/methanol / concentrated ammonium hydrox-
ide: 189 : 10 : 1) Rf = 0.34. Elemental analysis for dioxalic acid salt
C21H36N2O62 C2H2O4 (M = 512.6); m.p.dioxalic acid salt = 146.8–1488C:
calculated: C, 58.58; H, 7.86; N, 5.46. Found: C, 58.34; H, 7.71; N,
5.69.
9a5
1
C25H36N2O (M = 380.6); yield 57.3%; H-NMR, CDCl3, d: 1.52-1.64
(m, 2H, CH2CHO), 1.67-1.88 (m, 6H, CH2CHO, CH2, CH2), 2.06-2.13
(m, 2H, NCH2), 2.21 (s, 3H, NCH3), 2.24-2.42 (m, 4H, CH2, CH2), 2.62
(t, J = 7.8 Hz, 2H, CH2), 2.71-2.75 (m, 2H, NCH2), 3.23-3.29 (m, 1H,
HC-O-), 3.44-3.48 (m, 4H, CH2Ph, CH2), 7.14-7.31 (m, 10H, CH); TLC
(dichloromethane/methanol / concentrated ammonium hydrox-
ide: 139 : 10 : 1) Rf = 0.25. Elemental analysis for dioxalic acid
salt C25H36N2O62 C2H2O4 (M = 560.6); m.p.dioxalic
182.28C: calculated: C, 62.13; H, 7.19; N, 5.00. Found: C, 61.87; H,
6.91; N, 4.74.
= 178–
acid salt
9a6
Synthesis of 1-benzyl-4-[3-(N,N-
C27H40N2O (M = 398.6); yield 35.9%; 1H-NMR, CDCl3, d: 1.29–1.37
(m, 2H, CH2), 1.44–1.76 (m, 8H, CH2, CH2, CH2, CH2CHO), 1.84–
1.88 (m, 2H, CH2CHO), 2.08–2.15 (m, 2H, NCH2), 2.19 (s, 3H,
NCH3), 2.31 (t, J = 7.6 Hz, 2H, CH2), 2.39 (t, J = 7.3 Hz, 2H, CH2), 2.60
(t, J = 7.8 Hz, 2H, CH2), 2.71–2.75 (m, 2H, NCH2), 3.24–3.30 (m,
1H, HC-O-), 3.45 (t, J = 6.6 Hz, 2H, CH2), 3.48 (s, 2H, CH2Ph), 7.16–
7.31 (m, 10H, CH); TLC (dichloromethane/methanol/concen-
trated ammonium hydroxide: 89 : 10 : 1) Rf = 0.61. Elemental
analysis for dioxalic acid salt C27H40N2O62 C2H2O4 (M = 560.6);
dimethylamino)propyloxy]piperidine 9a1
The 1-benzyl-4-(3-aminopropyloxy)piperidine 12 (0.005 mol) was
dissolved in 11.5 g of 100% formic acid and 0.9 g of 36% formal-
dehyde was added. The mixture was heated for 10 h at 100–
1058C. After cooling, the mixture was alkalinized with sodium
hydroxide to pH 12 and extracted with diethyl ether
(3650.0 mL), dried (Na2SO4), and filtered. The solvent was evapo-
rated and the crude product was purified by column chromatog-
raphy on silicagel.
m.p.dioxalic
= 169–1708C: calculated: C, 66.42; H, 7.91; N,
acid salt
9a1: C17H29N2O; (M = 277.4); yield 61.4%; 1H-NMR, CDCl3, d:
1.56–1.77 (m, 4H, CH2CHO), 1.86–1.90 (m, 2H, CH2), 2.12–2.20
(m, 2H, NCH2), 2.24 (s, 6H, CH3), 2.36 (t, J = 6.9 Hz, 2H, CH2N),
2.27–2.76 (m, 2H, NCH2), 3.20–3.30 (m, 1H, HC-O-), 3.45–3.49
(m, 4H, OCH2, CH2Ph), 7.24–7.32 (m, 5H, CH); TLC (dichlorome-
5.00. Found: C, 66.07; H, 7.59; N, 4.68.
Synthesis of 1-benzyl-4-(4-nitrilopentyloxy)piperidine 17
To a solution of the 1-benzyl-4-hydroxypiperidine 10 (0.03 mol)
in 80 mL of dry toluene was added sodium hydride (0.06 mol),
and after stirred at room temperature for 1 h, to the suspension
was added dropwise 15-crown-5 ether (0.036 mol) and then 5-
bromopentanonitrile (0.036 mol). The reaction mixture was
stirred at room temperature for 72 h, and excess of sodium
hydride was quenched by dropwise addition of ethanol (10 mL).
The solvent was evaporated under reduce pressure, and water
(15 mL) was added. The mixture was extracted with dichlorome-
tane (3650.0 mL), organic layer dried (Na2SO4), and filtered. The
solvent was evaporated and remaining material was purified by
column chromatography on silicagel. The title products were
obtained as sticky oil.
thane/methanol/concentrated
189 : 10 : 1) Rf = 0.37. Elemental analysis for dioxalic acid salt
C17H29N2O62 C2H2O4 (M = 457.5); m.p.dioxalic = 160.0–
ammonium
hydroxide:
acid salt
162.08C: calculated: C, 55.13; H, 7.27; N, 6.12. Found: C, 54.86; H,
6.80; N, 6.33.
General method for the preparation of 1-benzyl-4-[3-(N-
methyl-N-phenylalkylamino)propyloxy]piperidines 9a4–
4a6
To a solution of 1-benzyl-4-[3-(N-methylamino)propyloxy]piperi-
dine 14 (0.0025 mol) with the presence of potassium carbonate
(0.0025 mol) in 10 mL of anhydrous DMF was added correspond-
ing phenylalkyl halide (0.0028 mol). The suspension was stirred
for 24 h at room temperature and filtered. The solution was
diluted with 20 mL of water and extracted with dichlorome-
17: C17H24N2O (M = 272.4); yield 32.4%; 1H-NMR, CDCl3, d: 1.52–
1.67 (m, 2H, CH2CHO), 1.68-1.81 (m, 4H, CH2CH2), 1.82–1.90 (m,
2H, CH2CHO), 2.09–2.17 (m, 2H, NCH2), 2.37 (t, J = 6.9 Hz, 2H,
CH2), 2.68–2.74 (m, 2H, NCH2), 3.23–3.32 (m, 1H, CHO ), 3.46 (t, J
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770
I. Masłowska-Lipowicz et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 762–773
= 5.7 Hz, 2H, CH2), 3.49 (s, 2H, CH2Ph), 7.21–7.33 (m, 5H, CH); TLC
20: C18H30N2O (M = 290.45); yield 76.2%; 1H-NMR, CDCl3, d:
1.34–1.42 (m, 2H, CH2), 1.48–1.64 (m, 6H, CH2, CH2, CH2CHO),
1.83–1.89 (m, 2H, CH2CHO), 2.07–2.15 (m, 2H, NCH2), 2.2 (s, 1H,
NH*), 2.44 (s, 3H, NCH3), 2.56–2.61 (t, J = 7.2 Hz, 2H, CH2), 2.72–
2.76 (m, 2H, NCH2), 3.22–3.31 (m, 1H, HC-O-), 3.39-3.44 (t, J =
6.6 Hz, 2H, CH2), 3.49 (s, 2H, CH2Ph), 7.22–7.31 (m, 5H, CH); TLC
(dichloromethane/methanol/concentrated ammonium hydrox-
ide: 89 : 10 : 1) Rf = 0.28. Elemental analysis for dioxalic acid salt
C18H30N2O x 2 C2H2O4 (M = 470.5); m.p.dioxalic acid salt = 148.3–49.78C:
calculated: C, 56.16; H, 7.28; N, 5.95. Found: C, 55.84; H, 6.95; N,
5.83.
(dichloromethane/methanol/triethylamine: 289 : 10 : 1) Rf
0.29.
=
Synthesis of 1-benzyl-4-(5-aminopentyloxy)piperidine 18
To a solution of 1-benzyl-4-(4-nitrilopentykoxy)piperidine 17
(0.01 mol) in 60 mL of anhydrous ethyl ether was added LiAlH4
(0.037 mol). The mixture was stirred at room temperature for
1 h, and quenched by dropwise addition of water (1.4 mL), 10%
of NaOH solution (1.4 mL), and water (1.4 mL). The suspension
was stirred for 30 min, and filtered. The filter cake was washed
with ether (2630 mL). The combined organic extracts were
washed with water (3630 mL), dried (Na2SO4), and filtered. The
solvent was evaporated and the residue was purified by column
chromatography on silicagel. The title products were obtained
as sticky oil.
General method for the preparation of 1-benzyl-4-[5-(N-
methyl-N-phenylalkylamino)pentyloxy]piperidines 9b4–
9b6
18: C17H28N2O (M = 276.4); 1H-NMR, CDCl3, d: 1.32–1.64 (m,
10H, CH2, CH2, CH2, CH2CHO, NH2*), 1.82-1.90 (m, 2H, CH2CHO),
2.07–2.15 (m, 2H, NCH2), 2.68 (t, J = 6.9 Hz, 2H, CH2), 2.72–2.77
(m, 2H, NCH2), 3.22–3.31 (m, 1H, HC-O-), 3.42 (t, J = 6.6 Hz, 2H,
CH2), 3.49 (s, 2H, CH2Ph), 7.21–7.31 (m, 5H, CH); TLC (dichlorome-
To a solution of 1-benzyl-4-[5-(N-methylamino)pentyloxy]piperi-
dine 20 (0.0007 mol) with the presence of potassium carbonate
(0.0007 mol) in 5 mL of anhydrous DMF was added correspond-
ing phenylalkyl halide (0.00083 mol). The suspension was stirred
for 24 h at room temperature and filtered. The solution was
diluted with 10 mL of water and extracted with dichlorome-
thane (3615 mL), dried (Na2SO4), and filtered. The solvent was
evaporated to give the crude products which were purified by
column chromatography. The title products were obtained as
sticky oil.
thane/methanol/concentrated
ammonium
hydroxide:
39 : 10 : 1) Rf = 0.45. Elemental analysis for dioxalic acid salt
C17H28N2O62 C2H2O4 (M = 456.5); m.p.dioxalic acid salt = 136.2–1388C:
calculated: C, 55.25; H, 7.06; N, 6.14. Found: C, 54.87; H, 6.89; N,
6.02.
9b4
Synthesis of 1-benzyl-4-[5-(N-
C25H36N2O (M = 380.8); yield 51.0%; 1H-NMR d: 1.25–1.40 (m, 2H,
CH2), 1.48–1.63 (m, 6H, CH2CH2CH2), 1.84–1.89 (m, 2H, CH2CH),
2.07–2.14 (m, 2H, CH2N-), 2.17 (s, 3H, NCH3), 2.33–2.38 (m, 2H,
NCH2), 2.72–2.76 (m, 2H, CH2-N-CH3), 3.23–3.29 (m, 1H, HC-O-),
3.41 (m, 2H, -O-CH2), 3.47 (s, 2H, CH2Ph), 3.49 (s, 2H, CH2Ph),
7.21–7.32 (m, 10H); TLC (dichloromethane/methanol/concen-
trated ammonium hydroxide: 164 : 10 : 1) Rf = 0.47. Elemental
analysis for dioxalic acid salt C25H36N2O62 C2H2O4 (M = 560.6);
m.p.dioxalic acid salt = 192-1938C: calculated: C, 62.13; H, 7.19; N, 5.00.
Found: C, 61.87; H, 7.01; N, 4.48.
formylamino)pentyloxy]piperidine 19
To a solution of 1-benzyl-4-(3-aminopropyloxy)piperidine 10
(0.004 mol) in 25 mL of anhydrous dichloromethane was added
FAM (10 mL). The mixture was stirred at 5–108C for 0.5 h. Then,
water (50.0 mL) and ethyl acetate (50.0 mL) were added and the
mixture was neutralized with K2CO3 and water layer was
extracted with dichlorometane (2650 mL). The combined
organic extracts were washed with water (3650 mL), dried
(Na2SO4), filtered, and evaporated, the residue was purified by
column chromatography on silicagel to give compound 19 as a
sticky oil.
9b5
19: C18H28N2O2 (M = 304.5); yield 85%; 1H-NMR, CDCl3, d: 1.38–
1.45 (m, 2H, CH2), 1.51–1.64 (m, 6H, CH2, CH2, CH2CHO), 1.84–
1.89 (m, 2H, CH2CHO), 2.12–2.17 (m, 2H, NCH2), 2.72–2.76 (m,
2H, NCH2), 3.21–3.34 (m, 3H, HC-O-, CH2), 3.43 (t, J = 6.3 Hz, 2H,
CH2), 3.49 (s, 2H, CH2Ph), 5.69 (s, 1H, NH*), 7.22–7.33 (m, 5H, CH),
8.16 (s, 1H, HN-CHO); TLC (dichloromethane/methanol/concen-
trated ammonium hydroxide: 189 : 10 : 1) Rf = 0.36.
C27H40N2O (M = 408.6); yield 35.0%; 1H-NMR, CDCl3, d: 1.25–1.38
(m, 2H, CH2), 1.44–1.64 (6H, CH2, CH2, CH2CHO), 1.76–1.89 (m,
4H, CH2, CH2CHO), 2.09–2.15 (m, 2H, NCH2), 2.23 (s, 3H, NCH3),
2.32-2.41 (m, 4H, CH2, CH2), 2.63 (t, J = 7.8 Hz, 2H, CH2), 2.72–2.76
(m, 2H, NCH2), 3.22–3.31 (m, 1H, HC-O-), 3.41 (t, J = 6.6 Hz, 2H,
CH2), 3.49 (s, 2H, CH2Ph), 7.15–7.32 (m, 10H, CH); TLC (dichloro-
methane/methanol/concentrated
ammonium
hydroxide:
89 : 10 : 1) Rf = 0.63. Elemental analysis for dioxalic acid salt
C27H40N2O62 C2H2O4 (M = 588.7); m.p.dioxalic acid salt = 177.2–1798C:
calculated: C, 63.25; H, 7.53; N, 4.76. Found: C, 63.09; H, 7.25; N,
4.37.
Synthesis of 1-benzyl-4-[5-(N-
methylamino)pentyloxy]piperidine 20
To a solution of 1-benzyl-4-[5-(N-formylamino)pentyloxy]piperi-
dine 19 (0.004 mol) in 25 mL of anhydrous ethyl ether was added
LiAlH4 (0.013 mol). The mixture was stirred at room temperature
for 1 h, and quenched by dropwise addition of water (0.5 mL),
10% of NaOH solution (0.5 mL), and water (0.5 mL). The suspen-
sion was stirred for 30 min, and filtered. The filter cake was
washed with ether (2625 mL). The combined organic extracts
were washed with water (3625 mL), dried (Na2SO4), and filtered.
The solvent was evaporated and the residue was purified by col-
umn chromatography on silicagel. The title products were
obtained as sticky oil.
9b6
C29H44N2O (M = 436.7); yield 40.70%; 1H-NMR, CDCl3, d: 1.25–1.37
(m, 4H, CH2, CH2), 1.42–1.68 (m, 10H, CH2, CH2, CH2, CH2,
CH2CHO), 1.83–1.89 (m, 2H, CH2CHO), 2.06–2.14 (m, 2H, NCH2),
2.19 (s, 3H, NCH3), 2.27–2.32 (m, 4H, CH2, CH2), 2.61 (t, J = 7.8 Hz,
2H, CH2), 2.72–2.76 (m, 2H, NCH2), 3.22–3.29 (m, 1H, CHO), 3.41
(t, J = 6.6 Hz, 2H, CH2), 3.48 (s, 2H, CH2Ph), 7.14–7.31 (m, 10H,
CH); TLC (dichloromethane/methanol/concentrated ammonium
hydroxide: 89 : 10 : 1) Rf = 0.65. Elemental analysis for dioxalic
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2008, 341, 762–773
Non-imidazole Histamine H3 antagonists
771
acid salt C29H44N2O62 C2H2O4 (M = 616.75); m.p.dioxalic
153.4–154.88C: calculated: C, 64.27; H, 7.84; N, 4.54. Found: C,
=
calculated: C, 58.58; H, 7.86; N, 5.46. Found: C, 58.75; H, 8.06; N,
5.43.
acid salt
63.96; H, 7.55; N, 4.32.
9b3
1
C23H40N2O (M = 360.6); yield 47%; H-NMR d: 0.87–0.91 (m, 3H,
Synthesis of 1-benzyl-4-(5-chloropentyloxy)piperidine 21
To a solution of the 1-benzyl-4-hydroxypiperidine 10 (0.021 mol)
in 30 mL of acetonitrile, with the presence of KF/Al2O3 (30 g/45 )
(0.14 mol) was added dropwise 1-chloro-5-iodopentane
(0.26 mol). The suspension was heated at 268C for 70 h, filtered,
and the solvent was evaporated. The residue was dissolved in
100 mL of dichloromethane and washed with 10% of NaOH solu-
tion (3610 mL). The organic layer was washed with water, dried
(Na2SO4), and filtered. The solvent was evaporated and the resi-
due was purified by column chromatography on silicagel. The
title products were obtained as sticky oil.
CH2CH3), 1.22–1.67 (m, 14H, CH2CH, CH2), 1.84–1.89 (m, 2H,
CH2CH), 2.07–2.15 (m, 2H, NCH2), 2.20 (s, 3H, NCH3), 2.27–2.33
(m, 4H, NCH2), 2.72–2.76 (m, 2H, NCH2), 3.23–3.29 (m, 1H, OCH),
3.42 (m, 2H, OCH2), 3.49 (s, 2H, CH2Ph), 7.23–7.32 (m, 5H, CH);
TLC (dichloromethane/methanol/concentrated ammonium
hydroxide: 89 : 10 : 1) Rf = 0.55. Elemental analysis for dioxalic
acid salt C23H40N2O62 C2H2O4 (M = 540.65); m.p.dioxalic acid salt = 145-
1468C: calculated: C, 59.98; H, 8.20; N, 5.18. Found: C, 59.63; H,
8.01; N, 5.12.
Pharmacology
21: C17H26ClNO (M = 295.85); yield 24%; 1H-NMR d: 1.46–1.89
(m, 10H, CH2CH, CH2), 2.11–2.17 (m, 2H, NCH2), 2.71–2.76 (m,
2H, NCH2), 3.25–3.31 (m, 1H, OCH), 3.43 (m, 2H, OCH2), 3.50 (s,
2H, CH2Ph), 3.51–3.56 (m, 2H, ClCH2), 7.22–7.32 (m, 5H); TLC
(dichloromethane/methanol/concentrated ammonium hydrox-
ide: 239: 10 : 1) Rf = 0.51.
The affinities of all compounds were determined by measuring
the displacement curves of [3H]Na-methylhistamine binding at
human histamine H3 receptor expressed in HEK 239T cell mem-
branes [37]. Selected compounds 9b1, 9b2, 9b5, and 9b6 were
tested for H3 antagonistic effects in vitro on the guinea pig jeju-
num [38]. Selected compounds 9b1, 9b2 and 9b4–9b6, were also
tested for H3-antagonist effects in vitro, following standard meth-
ods, using the guinea pig ileum [39].
General method for the preparation of 1-benzyl-4-[5-(N-
methyl-N-alkylamino)pentyloxy]piperidines 9b1–9b3
To a solution of the 1-benzyl-4-(5-chloropentyloxy)piperidine 21
(0.001 mol) in 5 mL of anhydrous DMF was added corresponding
methylalkylamine (0.01 mol). The reaction mixture was stirred
for 24 h at 1008C. In the case of dimethylamine, the methanolic
solution was used and the reaction was carried out in 358C. After
cooling, the solvent was evaporated under reduced pressure.
The residue was dissolved in 80 mL of dichloromethane, washed
with 10% NaOH solution (3610 mL). The organic layer was sepa-
rated, washed with water, dried (Na2SO4), and filtered. The sol-
vent was evaporated to give the crude products which were puri-
fied by column chromatography. The title products were
obtained as sticky oil.
In-vitro pharmacology
Radioligand displacement studies at the human H3
receptor
Cell culture and transfection: HEK 293T cells were maintained
in Dulbecco's modified Eagle medium (DMEM) supplemented
with 10% fetal bovine serum (FBS), 50 IU/mL penicillin, and
50 lg/mL streptomycin in 5% CO2 humidified atmosphere at
378C. Approximately 46106 cells were seeded in a 10-cm dish
and cultured overnight before transfection. The transfection
mixture (for transfection of a dish of cells) containing 5 lg of
human H3R receptor cDNA [37] and 20 lL of 1 mg/mL 25 kDa lin-
ear polyethyleneimine (Polyscience, Inc., USA) was prepared in
0.5 mL serum-free DMEM with incubation for 10–15 minutes at
room temperature before being added into the cell culture con-
taining 6 mL fresh cell culture medium. Two days after transfec-
tion, the cells were scraped, collected as pellet by centrifugation,
and stored at –208C until use.
9b1
C19H32N2O (M = 304.5); yield 40%;1H-NMR, CDCl3, d: 1.29–1.40 (m,
2H, CH2), 1.43–1.50 (m, 2H, CH2), 1.52–1.64 (m, 4H, CH2,
CH2CHO), 1.83–1.89 (m, 2H, CH2CHO), 2.06–2.14 (m, 2H, NCH2),
2.20 (s, 6H, NCH3, NCH3), 2.21–2.26 (m, 2H, CH2), 2.72–2.75 (m,
2H, NCH2), 3.22–3.30 (m, 1H, CHO), 3.39-3.44 (t, J = 6.6 Hz, 2H,
CH2), 3.48 (s, 2H, CH2Ph), 7.21–7.31 (m, 5H, CH); TLC (dichlorome-
thane/methanol/concentrated
ammonium
hydroxide:
[3H]Na-Methylhistamine binding assay
89 : 10 : 1) Rf = 0.35. Elemental analysis for dioxalic acid salt
C19H32N2O62 C2H2O4 (M = 484.55); m.p.dioxalic acid salt = 97.5–1008C:
calculated: C, 57.01; H, 7.49; N, 5.78. Found: C, 56.93; H, 7.55; N,
5.43.
Displacement radioligand binding assay was performed in
50 mM Tris-HCl buffer (pH 7.4 at 258C) containing homogenized
human H3R-transfected cells, with or without competing ligands
(10– 4 to 10– 11 M), in the presence of 2.5 nM [3H]Na-Methylhist-
amine (70,4 Ci/mmol; Perkin Elmer, USA) in a total volume of
200 lL. The binding reaction was incubated for 60 min at 258C,
and terminated by rapid filtration over Unifilter GF/C 96-well fil-
terplates (Perkin Elmer, USA) pretreated with 0.3% 750 kDa poly-
ethylenimine, followed by three washes with ice cold 50 mM
Tris-HCl (pH 7.4 at 48C). Radioactivity retained on the filter was
determined by liquid scintillation counting on the Microbeta
Trilux with 25 lL Microscint”O”TM (Perkin Elmer, USA). The
binding assay data were analyzed using Prism 4.0 (Graphpad
Software, Inc., USA).
9b2
C21H36N2O (M = 460.5); yield 52%;1H-NMR d: 0.88 (m, 3H, CH2CH3),
1.25–1.64 (m, 10H, CH2CH, CH2), 1.85–1.89 (m, 2H, CH2CH),
2.07–2.14 (m, 2H, NCH2), 2.20 (s, 3H, NCH3), 2.21–2.33 (m, 4H,
NCH2), 2.72–2.76 (m, 2H, NCH2), 3.23–3.29 (m, 1H, OCH), 3.42 (t,
2H, OCH2), 3.49 (s, 2H, CH2Ph), 7.22–7.32 (m, 5H, CH); TLC
dichloromethane/methanol/concentrated ammonium hydrox-
ide: 89 : 10 : 1) Rf = 0.44. Elemental analysis for dioxalic acid salt
C21H36N2O62 C2H2O4 (M = 512.6); m.p.dioxalic
salt = 163–1648C:
acid
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772
I. Masłowska-Lipowicz et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 762–773
H3 antagonistic effects in vitro on the guinea pig jejunum
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