Structure-activity relationships of new 1-substitutedmethyl-4-[5-(N-methyl- N-propylamino)pentyloxy]piperidines and selected 1-[(N-substituted-N-methyl)-3- propyloxy]-5-(N-methy-l-N-propyl)-pentanediamines as H3-antagonists

Article abstract of DOI:10.1111/cbdd.12206

Novel, potent non-imidazole histamine H₃ receptor antagonists have been prepared and in vitro tested as H₃-receptor antagonists (the electrically evoked contraction of the guinea-pig jejunum). The present compounds contain a 4-hydroxypiperidine core, which behaves as a conformationally restricted version of the 3-amino-1-propanol moiety common to the many previously described non-imidazole H₃ ligands. Detailed structure-activity studies revealed that 1-(2-benzofuranylmethyl)- 5c (pA ₂ = 8.47 ± 0.05) and 1-(3-benzofuranylmethyl)-4-[5-(N-methyl- N-propyl)pentyloxy]piperidine 5d (pA₂ = 8.15 ± 0.07) exhibit high potency for the H₃ histamine receptor. In addition, the potency of selected 1-[(N-substituted-N-methyl)-3-propyloxy]-5-(N-methyl-N-propyl) pentanediamines as antagonist of the H₃ histamine receptor was also evaluated. Replacement of the 4-hydroxypiperidine of the leads 7 and 5c by a highly flexible 3-(methylamino)propyloxy chain yields compounds 6a (pA ₂ = 8.02) and 6b (pA₂ = 6.23) with higher and lower potency than their piperidine analogues (7, pA₂ = 7.79; 5c, pA ₂ = 8.47), respectively. The histaminergic H₁ antagonism of selected compounds 5c, 5d and 6a has been established on the isolated guinea-pig ileum by conventional methods; the pA₂ values have compared with the potency of pyrilamine. None of them showed any H ₁-antagonistic activity (pA₂ < 4; for pyrilamine pA₂ = 8.5). The present compounds contain a 4-hydroxypiperidine core, which behaves as a conformationally restricted version of the 3-amino-1-propanol moiety common to the many previously described non-imidazole H₃ ligands. Detailed structure-activity studies revealed that 1-(2-benzofuranylmethyl)- 5c (pA₂ = 8.47 ± 0.05) and 1-(3-benzofuranylmethyl)-4-[5-(N-methyl-N-propyl)pentyloxy]piperidine 5d (pA₂ = 8.15 ± 0.07) exhibit high potency for the H₃ histamine receptor. Replacement of the 4-hydroxypiperidine of the leads 7 and 5c by a highly flexible 3-(methylamino)propyloxy chain yields compounds 6a (pA₂ = 8.02) and 6b (pA₂ = 6.23) with higher and lower potency than their piperidine analogues (7, pA₂ = 7.79; 5c, pA ₂ = 8.47), respectively.

Full text of DOI:10.1111/cbdd.12206

Chem Biol Drug Des 2014; 83: 106–118
Research Article
Structure–Activity Relationships of New
1-substitutedmethyl-4-[5-(N-methyl-N-propylamino)
pentyloxy]piperidines and Selected 1-[(N-substituted-
N-methyl)-3-propyloxy]-5-(N-methy-l-N-propyl)-
pentanediamines as H3-Antagonists
Histamine is a biogenic amine involved in a large variety of
physiological functions. It exerts its actions through four dis-
tinct G protein-coupled receptors, named H1, H2, H3 and
H4 (1,2). H1 and H2 receptor antagonists are well-known
therapeutic agents and are in use for the treatment of aller-
gic disease (3) and peptic ulcer (4), respectively. H4 recep-
tor is involved in inflammatory processes and takes an
immunomodulatory role. Ligands of these receptors could
be effective in the regulation of the immune response (5).
Iwona Masłowska-Lipowicz and Krzysztof
ꢀ
Walczynski*
Department of Synthesis and Technology of Drugs,
ꢀ
ꢀ
ꢀ
Medical University, Muszynskiego Street 1, 90-151 Łodz,
Poland
ꢀ
*Corresponding author: Krzysztof Walczynski,
krzysztof.walczynski@umed.lodz.pl
Novel, potent non-imidazole histamine H3 receptor
antagonists have been prepared and in vitro tested as
H3-receptor antagonists (the electrically evoked
contraction of the guinea-pig jejunum). The present
compounds contain a 4-hydroxypiperidine core, which
behaves as a conformationally restricted version of the
3-amino-1-propanol moiety common to the many
previously described non-imidazole H3 ligands. Detailed
structure-activity studies revealed that 1-(2-benzofura-
nylmethyl)- 5c (pA2 = 8.47 Æ 0.05) and 1-(3-benzofura-
nylmethyl)-4-[5-(N-methyl-N-propyl)pentyloxy]piperidine
5d (pA2 = 8.15 Æ 0.07) exhibit high potency for the
H3 histamine receptor. In addition, the potency of
selected 1-[(N-substituted-N-methyl)-3-propyloxy]-5-(N-
methyl-N-propyl)pentanediamines as antagonist of the
H3 histamine receptor was also evaluated. Replacement
of the 4-hydroxypiperidine of the leads 7 and 5c by a
highly flexible 3-(methylamino)propyloxy chain yields
compounds 6a (pA2 = 8.02) and 6b (pA2 = 6.23) with
higher and lower potency than their piperidine ana-
logues (7, pA2 = 7.79; 5c, pA2 = 8.47), respectively. The
histaminergic H1 antagonism of selected compounds
5c, 5d and 6a has been established on the isolated gui-
nea-pig ileum by conventional methods; the pA2 values
have compared with the potency of pyrilamine. None of
them showed any H1-antagonistic activity (pA2 < 4; for
pyrilamine pA2 = 8.5).
The histamine H3 receptor was discovered in 1983 by
Arrang et al. (6) as a presynaptic autoreceptor, and the
gene was successively cloned in 1999 by Lovenberg et al.
(7). Based on tissue distribution analysis, it has been
proved that the expression of the receptor is predomi-
nantly restricted to the brain (8). The H3 receptor does not
only mediate the inhibition of synthesis and release of his-
tamine from histaminergic neurons via a negative feedback
loop (9,10), but also exerts modulatory effects on other
neurotransmitter systems, for example, the cholinergic
(11,12), dopaminergic (13), noradrenergic (14) and seroto-
ninergic (15) systems, in both the central and peripheral
nervous system. A variety of potential therapeutic applica-
tion for H3 receptor antagonists/inverse agonists has been
proposed to be potential drugs for the treatment of several
CNS disorders, such as attention-deficit hyperactivity dis-
order (ADHD) (16,17), Alzheimer’s disease (18), epilepsy
(19), schizophrenia (20) and obesity (21). However, emerg-
ing novel therapeutic concepts have been introduced and
some indication in the H3 receptor field, for example,
migraine, pain or allergic rhinitis, might take advantage of
peripherally acting ligands. For example, kojic acid ana-
logues of benzyl-1-(4-(3-(piperidine-1-yl)propoxy)phenyl)-
methanamine derivatives might act peripherally (22).
Another approach for the treatment of allergic rhinitis is the
search of new dual H1H3 receptor antagonists (23).
Recently, scientists at the GlaxoSmithKlein Medicines
Research Centre have published dual H1H3 receptor
antagonists based on phthalazinone core (24).
Key words: histamine H3-receptor, H3 non-imidazole antago-
nists, 1-substitutedmethyl-4-[5-(N-methyl-N-propylamino)pen-
tyloxy]piperidines, 1-[(N-substituted-N-methyl)-3-propyloxy]-5-
(N-methyl-N-propyl)pentanediamines
Received 28 March 2013, revised 14 June 2013 and
accepted for publication 12 August 2013
The physiological and pathophysiological implications of
histamine H3 receptors increase the need for potent and
106
ª 2013 John Wiley & Sons A/S. doi: 10.1111/cbdd.12206

Histamine H3-Receptor; H3 Non-Imidazole Antagonists
4-(3-aminopropyloxy)- and 1-benzyl-4-(5-amino)pent-
selective ligands as pharmacological tools and potential
drugs development. The first generation of H3 antagonists
was characterized by the presence of an imidazole ring as
in histamine, many of which have found utility as pharma-
cological tools (25,26). In contrast to the early work in the
field, most chemical series of current interest appear to be
non-imidazole compounds because of major disadvan-
tages of 4-substituted imidazole moiety, including poor
brain penetration and issue related to hepatic cytochrome
P450 enzymes inhibition, such as drug–drug interactions,
liver toxicity and inhibition of adrenal synthesis (27–30).
Additionally, non-imidazoles H3 antagonists/inverse agon-
ists tend to be more selective versus H1, H2 and H4 recep-
tors (31).
yloxypiperidine derivatives (37). It appeared that by com-
parison of homologous pairs, the 1-benzyl-4-(5-
aminopentyloxy)piperidines have slightly higher potency
than their 1-benzyl-4-(3-aminopropyloxy)piperidines ana-
logues. 1-Benzyl-4-[5-(N-methyl-N-propylaminopentyloxy)]
piperidine was the most potent compound of theses ser-
ies (pA2 = 7.79) and was chosen as the lead compound
for further structural modification. As the H3 receptor
antagonist potency could not be increased by modifying
the N-substituent of 1-benzyl-4-[5-(N-methyl-N-substitut-
edaminopentyloxy)]piperidine, attention was paid to
replacement benzene ring by various substituents consist
of benzene fused six-, five-membered heterocycles con-
taining carbonyl group and oxygen or only oxygen atom
and benzene fused six-, five-membered hydrocarbons
rings like 3,4-dihydro-4-oxo-2H-chromen-2-yl- and -3-yl-,
4-oxo-2H-chromen-2-yl- and -3-yl-, 2- and 3-benzofura-
nyl, 2-indenyl or 2-naphthyl one. With the aim of investi-
gation the effect of increased flexibility of the central core
on antagonistic potency, the 4-hydroxypiperidine was
replaced by 3-(methylamino)propyloxy chain, and two of
the most active analogues of both 4-hydroxypiperidine
series, that is, benzyl (6a) and 2-benzofuranyl (6b) deriva-
tive were synthesized and pharmacological evaluated. In
addition, structure–activity relationships (SAR) resulting
from variation of the position of 4-[5-(N-methyl-N-propyl-
aminopentyloxy)]piperidinyl moiety attached by methylene
linker in benzene fused six-, five-membered heterocyclic
and the presence or absence of double bond at hetero-
cycle ring are discussed.
Since 1994, when the marine natural product aplysamine-
1 was patented as a weak H3 histamine receptor antago-
nist (32), diamine-based ligands, containing the character-
istic aminopropoxyphenyl structural pharmacophore, have
become an important chemical class of H3 histamine
receptor antagonists. This motif has been repeated in a
number of different series of compounds from several lab-
oratories, for example, compounds 1 (33) and 2 (34)
(Chart 1). Later on, the successful replacement of the
highly flexible propyloxy link with 4-phenoxypiperidine moi-
ety
3 (35) (Chart 1) or the partially rigid 2-amin-
oethylbenzofuran substructure
demonstrated.
4
(36) (Chart 1) was
Previously, we reported the synthesis and preliminary
pharmacological investigation of new series of 1-benzyl-
H
N
N
N
O
N
O
1
2
O
H3C
N
NC
N
O
O
3
4
N
CH3
H3C
The target molecules of this study
Chart 1: Representative non-
imidazole H3-histamine receptor
antagonists containing the
characteristic aminopropoxyphenyl
structural pharmacophor, its rigid
analogues and the target molecules
of this study.
R
N
CH3
CH3
R
N
N
N
O
2
O
2
C3H7
C3H7
6a, b
CH3
5a-h
Chem Biol Drug Des 2014; 83: 106–118
107

ꢀ
Masłowska-Lipowicz and Walczynski
In the present work, we report the synthesis and prelimin-
ary pharmacological investigation [functionally on in vitro
test system using guinea-pig jejunum preparations (38)] of
new series of 1-[(substitutedmethyl)]-4-[5-(N-methyl-N-pro-
pyl)pentyloxy]piperidines and selected 1-[(N-substituted-N-
methyl)-3-propyloxy]-5-(N-methyl-N-propyl)pentandiamines
as H3 histamine receptor antagonists.
for H1 antagonistic effects in vitro, following standard
methods, using the guinea-pig ileum (39).
Chemistry
The general synthetic procedures used in this study are
illustrated in Schemes 1 and 2. The key intermediate for all
novel synthesized 4-hydroxypiperidines 5a–h is 4-[5-(N-
methyl-N-propyl)pentyloxy]piperidine 8, which was pre-
pared by hydrogenation of 1-benzyl4-[5-(N-methyl-N-pro-
Furthermore, to determine whether the most active com-
pounds of both series are or are not dual H1H3 receptor
antagonists, compounds 5c, 5d and 6a have been tested
Procedure
A
CH3
N
CH3
CH3
N
O
CH3
CH2Cl2
or
5
2
O
N
CH3
O
CH3
5
2
H2 /Pd/C
C2H5OH
5
2
N
CH3CN
R
X
+
N
HN
R
7
9a, c-f for X=Cl
5a-f
8
and 9b for X=OSO2CH3
O
O
O
O
where R=
O
9a
9d
9c
9b
O
9e
9f
Procedure
B
CH3
N
CH3
N
O
N
O
O
CH3
O
O
CH3
5
2
5
2
+
O
HN
H
H
5g
9g
8
O
Procedure
C
CH3
N
CH3
N
O
O
CH3
O
O
CH3
5
2
5
2
+
N
C2H5OH
HN
5h
CH2
8
9h
O
O
Scheme 1: Synthesis of 1-substitutedmethyl-4-[5-N-methyl-N-propylamino]piperidines 5a–h.
108
Chem Biol Drug Des 2014; 83: 106–118

Histamine H3-Receptor; H3 Non-Imidazole Antagonists
CH3
CH3
CH3OCH2CH2OCH3
N(C2H5)3
N
H
H2/Pd/C
CH3OH
N
+
Cl
OH
11
10
12
OH
H
CH3
N
CH3OCH2CH2OCH3
+
N(C2H5)3
O
Cl
O
N
CH3
9c
13
14
OH
OH
CN
R
N
CH3
R
NaH
LiAlH4
N
O
2
+
Br
CN
2
Toluene
(C2H5)2O
CH3
12 or 14
15
16a or 16b
OH
where:
R=
for a and R=
for b
O
H
O
R
NH2
FAM
R
N
LiAlH4
N
O
2
N
O
2
H
CH3
CH2Cl2
(C2H5)2O
CH3
17a or 17b
18a or 18b
O
CH3
CH3
R
N
(CH3CH2CO)2O
CH2Cl2
LiAlH4
N
R
N
O
2
H
N
O
CH3
2
CH3
(C2H5)2O
19a or 19b
CH3
20a or 20b
CH3
N
R
N
O
CH3
2
CH3
6a or 6b
Scheme 2: Synthesis of 1-[N-substituted-N-methyl)-3-propyloxy]-5-(N-methyl-N-propyl)- pentanediamines 6a and 6b.
pyl)pentyloxy]piperidine 7 with a catalytic amount of palla-
dium on charcoal in ethanol.
thane or acetonitrile followed by purification with column
chromatography. The product 5g (Scheme 1; Procedure
B) was synthesized by Mannich reaction involving the con-
densation of 1,4-benzopyrone 9g with formaldehyde and
8 in ethanol. The compound 9h in ethanol solution was
treated with 8 to yield 5h.
The 4-hydroxypiperidines 5a–f (Scheme 1; Procedure A)
were obtained from 8 by alkylation with the corresponding
mesyl chloride 9b and chlorides 9a, c–f in dichlorome-
Chem Biol Drug Des 2014; 83: 106–118
109

ꢀ
Masłowska-Lipowicz and Walczynski
The 3-(methylamino)propyloxy derivatives 6a,
b
were
hydroxy-benzaldehyde, 3-bromo-1-propene, 2H-1-Benzo-
pyran-2-one, 2-hydroxyacetophenone, ethyl chloroacetate
and indan-1-one were all purchased from commercial
source - (Sigma-Aldrich Corp, St. Louis, MO, USA).
obtained from compound 12 or 14 by a six-step synthesis
(Scheme 2) including the following: O-alkylation with 5-
bromopentanenitrile in dry toluene in the presence of
sodium hydride and 1,4,7,10,13-pentaoxycyclopentade-
cane (15-crown-5 ether) to compounds 16a or 16b, reduc-
tion with LiAlH4 in dry ethyl ether to compound 17a or 17b,
formylation with formic acid-acetic anhydride (FAM) to yield
18a, b, reduction with LiAlH4 in dry diethyl ether to obtain
19a or 19b, acetylated with propionic anhydride to amides
20a or 20b and reduction with LiAlH4 in dry diethyl ether to
the desired compounds 6a or 6b, each step was followed
by purification with column chromatography. 3-Benzylm-
ethylamino-1-propanol 10 was N-alkylated with 11 in 1,2-
dimethoxyethane (DME) in the presence of triethylamine
(TEA) to 3-(N-benzyl-N-methylamino)-1-propanol 12 (40).
Hydrogenation of (12) with a catalytic amount of palladium
on charcoal in methanol yield to 13 (40). The compound 14
was prepared from 2-chloromethylbenzofuran 9c through
nucleophilic substitution of the chlorine atom by 3-methyla-
mino-1-propanol 13 in DME in the presence of TEA. All
obtained final free bases were treated with methanolic oxa-
lic acid solution, and oxalic acid salts were precipitated
with dry diethyl ether and crystallized twice from ethanol.
Synthesis of 4-[5-(N-methyl-N-propyl)pentyloxy]
piperidine 8
A mixture of 7 (0.007 mol) and Pd/C (10%; 70 mg) in
100 mL of ethanol was shaken in autoclave under 3 atm.
of hydrogen at 50 °C temperature for 5 h. The catalyst was
filtered off, and the solvent was removed in vacuo. The resi-
due was purified by column chromatography with ethyl
acetate:methanol:TEA: 9:4:1 to give 8 as colourless oil.
8. C14H30N2, (M = 242.4); yield 98.0%; 1H NMR(CDCl3) d
p.p.m.: 0.863–0.912 (t, 3H, CH2CH3, J = 7.33 Hz); 1.315–
1.635 (m, 11H, alifCH2, pipCH2, NH); 1.84–1.88 (m, 2H,
pipCH2); 2.077–2.17 (m, 2H, pipCH2); 2.2 (s, 3H, NCH3);
2.246–2.335 (m, 4H, alifCH2); 2.722–2.759 (m, 2H, pipCH2);
3.223–3.306 (m, 1H, pipCHO); 3.394–3.438 (t, 2H,
alifCH2O, J = 6.6 Hz); 3.485 (s, 2H, CH2Ph); Rf = 0.17.
Elemental analysis for dioxalic acid salt C14H30N2
2C2H2O4 (M = 422,48); mpdioxalic acid salt = 110–111 °C.
Á
Experimental Section
C (%)
H (%)
N (%)
Calculated
Found
51.17
51.07
8.11
8.45
6.63
6.54
General methods
All melting points (mp) were taken in open capillaries on
an electrothermal apparatus and are uncorrected. For all
compounds, 1H NMR spectra were recorded on Varian
Gemini 200 MHz, Varian Mercury VX 300 MHz. Chemical
shifts are expressed in p.p.m. downfield from internal TMS
General method for the preparation of 1-
substitutedmethyl-4-[5-(N-methyl-N-propylamino)
pentyloxy]piperidines 5a–f
1
as reference. H NMR data are reported in order: multiplic-
ity (br, broad; s, singlet; d, doublet; t, triplet; m, multiplet;
*, exchangeable by D2O) number of protons and approxi-
mate coupling constant in Hertz. Elemental analysis (C, H,
N) for all compounds was measured on Perkin Elmer Ser-
ies II CHNS/O Analyzer 2400 (PerkinElmer, Inc., Waltham,
MA, USA) and are within Æ0.4% of the theoretical values.
TLC was performed on silica gel 60 F254 plates (Merck,
Darmstadt, Germany). Flash column chromatography was
To a solution of 4-[5-(N-methyl-N-propyl)pentyloxy]piperi-
dine 8 (0.0024 mol) in 60 mL of dichloromethane (for 5a)
or in 120 mL of acetonitrile (for 5b) was added the corre-
sponding chloride 9a or mesyloxide 9b (0.0012 mol). In
case of compounds 5c–f to solution of compound 8
(0.0011 mol) in 10 mL of acetonitrile, in the presence of
potassium carbonate (0.0011 mol), was added the corre-
sponding chloride 9c–f (0.0011 mol). The mixture was stir-
red at room temperature for 72–96 h and next 24 h at
40 °C. The solvent was evaporated and residue was
washed with saturated aqueous solution of potassium car-
bonate and extracted with ethyl acetate (3 9 50.0 mL).
The organic extracts were dried (Na2SO4) and filtered. The
solvent was evaporated to give the crude products as a
sticky oil, which was purified by column chromatography.
ꢁ
carried out using silica gel 60 A 50 lm (J. T. Baker B. V.),
employing the same eluent as was indicated by TLC. All
obtained final free bases were treated with methanolic ox-
alic acid solution, and oxalic acid salts were precipitated
with dry diethyl ether and crystallized twice from ethanol.
Description of the synthetic methods for preparing inter-
mediates 9a–e and 9h has been given in Appendix S1 also
graphic illustrations of synthetic pathways for these inter-
mediates (Schemes 3 and 4) have been presented in sup-
porting information section.
5a. C24H36N2O3, (M = 400.52); yield 24%; 1HNMR(CDCl3)
d p.p.m.: 0.87–0.89 (t, 3H, CH2CH3, J = 7.35 Hz); 1.31–
1.36 (m, 2H, alifCH2); 1.46–1.54 (m, 4H, alifCH2); 1.55–1.59
(m, 2H, alifCH2); 1.61–1.67 (m, 2H, pipCH2); 1.86–1.89 (m,
2H, pipCH2); 2.23 (s, 3H, NCH3); 2.31–2.37 (m, 6H, alifCH2,
pipCH2); 2.79–2.82 (m, 2H, pipCH2); 3.28–3.31 (m, 1H,
The 1,4-benzopyrone, 5-bromopentanonitrile, propionic
anhydride, 3-benzylmethylamino-1-propanol, 3-chloro-1-
propanol, 4-oxo-4H-1-benzopyran-2-carboxylic acid, 2-
110
Chem Biol Drug Des 2014; 83: 106–118

Histamine H3-Receptor; H3 Non-Imidazole Antagonists
pipCHO); 3.39–3.42 (t, 2H, OCH2, J = 6.6 Hz); 3.46 (s, 2H,
NCH2); 6.41 (s, 1H, CO-CH); 7.29–7.38 (m, 1H, aromCH);
7.4–7.45 (m, 1H, aromCH); 7.62–7.64 (m, 1H, aromCH); TLC
pipCH2); 2.13-2.17 (m, 2H, pipCH2); 2.21 (s, 3H, NCH3);
2.26–2,35 (m, 4H, alifCH2); 2.79–2.83 (m, 2H, pipCH2);
3.22–3.29 (m, 1H, pipCHO); 3.39–3.43 (t, 2H, J = 6.6,
OCH2); 3.63 (s, 2H, NCH2); 7.20–7.32 (m, 2H, aromCH);
7.44–7.48 (m, 1H, aromCH); 7.52 (s, 1H, 2-H); 7.70–7.73
(m, 1H, aromCH); TLC (ethyl acetate:methanol:concentrated
ammonium hydroxide: 9:1:1) Rf = 0.29.
(dichloromethane:methanol:concentrated
ammonium
hydroxide: 89:10:1) Rf = 0.37.
Elemental analysis for dioxalic acid salt C24H36N2O3
2C2H2O4 (M = 580.06); mpdioxalic acid salt = 155–158 °C.
Á
Elemental analysis for dioxalic acid salt C23H36N2O2
2C2H2O4 (M = 554.64); mpdioxalic acid salt = 155–157 °C.
Á
C (%)
H (%)
N (%)
Calculated
Found
57.92
58.10
6.94
7.06
4.83
4.85
C (%)
H (%)
N (%)
Calculated
Found
58.68
58.53
7.30
7.42
5.07
4.93
5b. C24H38N2O3, (M = 402.57); yield 74%; 1HNMR(CDCl3)
d p.p.m.: 0.88–0.90 (t, 3H, CH2CH3, J = 7.5 Hz); 1.32–
1.38 (m, 2H, alifCH2); 1.46–1.52 (m, 4H, alifCH2); 1.56–1.63
(m, 4H, alifCH2, pipCH2); 1.84–1.86 (m, 2H, pipCH2); 2.22 (s,
3H, NCH3); 2.27–2.35 (m, 6H, alifCH2, pipCH2); 2.72–2.77
(m, 2H, CO-CH2); 2.78–2.83 (m, 4H, alifCH2, pipCH2);
3.26–3.29 (m, 1H, pipCHO); 3.41–3.43 (t, 2H, OCH2,
J = 6.6 Hz); 4.58–4.62 (m, 1H, OCHCH2); 6.97–7.01 (m,
2H,aromCH); 7.44–7.47 (m, 1H, aromCH); 7.87–7.88 (m, 1H,
aromCH); TLC (dichloromethane:methanol:concentrated
ammonium hydroxide: 39:10:1) Rf = 0.39.
5e. C24H38N2O, (M = 370.54); yield 29%; H1NMR,
CDCl3, d p.p.m.: 0.88–0.93 (t, J = 7.2, 3H, CH2CH3);
1.30–1.40 (m, 2H, CH2); 1.45–1.66 (m, 8H, CH2); 1.86–
1.91 (m, 2H, CH2pip.); 2.09–2.16 (m, 2H, CH2pip.); 2.25
(s, 3H, NCH3); 2.31–2.40 (m, 4H, CH2); 2.75–2.79 (m,
2H, CH2pip.); 3.24–3.33 (m, 1H, CHOpip.); 3.37–3.45 (m,
6H, OCH2alif., =C-CH2-N, CH2inden); 6.67 (s, 1H, CH=Cin-
den); 7.11–7.16 (m, 1H,
CHarom); 7.21–7.31 (m, 2H, CHarom);
7.4–7.42 (m, 1H, CHarom); TLC (dichloromethane:metha-
nol:concentrated
ammonium
hydroxide:
18:1:0.5)
Elemental analysis for dioxalic acid salt C24H38N2O3
2C2H2O4 (M = 582.65); mpdioxalic acid salt = 135–137 °C.
Á
Rf = 0.31.
Elemental analysis for dioxalic acid salt C24H38N2O Á
2C2H2O4 (M = 554.58); mpdioxalic acid salt = 169–172 °C.
C (%)
H (%)
N (%)
Calculated
Found
57.72
57.80
7.27
7.34
4.81
4.74
C (%)
H (%)
N (%)
Calculated
Found
60.64
60.47
7.65
7.36
5.05
4.89
5c. C23H36N2O2, (M = 372.51); yield 41.48%; 1H NMR,
(CDCl3), d p.p.m.: 0.90–0.95 (t, 3H, J = 7.35, CH2CH3);
1.31–1.76 (m, 10H, alifCH2, pipCH2); 1.90–1.96 (m, 2H,
pipCH2); 2.24 (s, 3H, NCH3); 2.26–2.37 (m, 6H, alifCH2,
5f. C25H38N2O, (M = 382.65); yield 21%;1HNMR, CDCl3, d
p.p.m.: 0.86–0.91 (t, 3H, J = 7.5, CH2CH3); 1.31–1.67 (m,
10H, CH2alif., CH2pip); 1.85–1.92 (m, 2H, CH2pip); 2.13–2.17
(m, 2H, CH2pip); 2.21 (s, 3H, NCH3); 2.26–2.35 (m, 4H,
CH2alif); 2.75–2.82 (m, 2H, CH2pip); 3.27–3.30 (m, 1H, CHO-
pip-
pipCH2); 2.83–2.87 (m, 2H, pipCH2); 3.28–3.36 (m, 1H,
CHO); 3.43–3.47 (t,2H, J = 6.6, OCH2); 3.72 (s, 2H, NCH2);
6.61 (s, 1H, 3-H); 7.21–7.32 (m, 2H, aromCH); 7.50–7.58 (m,
2H, aromCH); TLC (ethyl acetate:methanol:TEA: 9:1:4)
Rf = 0.27.
pip); 3.40–3.44 (t, 2H, J = 6.6, OCH
2); 3.65 (s, 2H); 7.41–7.50 (m,
3H, CHarom); 7.72 (s, 1H, CHarom); 7.79–7.83 (m, 3H,
CHarom); TLC (eluents:dichloromethane:ethyl acetate and di-
chloromethane:methanol:concentrated ammonium hydrox-
ide – gradient from 4:1 to 9:1:1) Rf = 0.47.
Elemental analysis for dioxalic acid salt C23H36N2O2
2C2H2O4 (M = 554.64); mpdioxalic acid salt = 168–169 °C.
Á
C (%)
H (%)
N (%)
Elemental analysis for dioxalic acid salt C24H38N2O Á
2C2H2O4 (M = 562.73); mpdioxalic acid salt = 161–162 °C.
Calculated
Found
58.68
58.46
7.30
7.33
5.07
5.04
C (%)
H (%)
N (%)
5d. C23H36N2O2, (M = 372.51); yield 53.68%; 1H NMR,
(CDCl3), d p.p.m.: 0.86–0.91 (t, 3H, J = 7.5, CH2CH3);
1.24–1.65 (m, 10H, alifCH2, pipCH2); 1.86–1.90 (m, 2H,
Calculated
Found
61.9
61.57
7.53
7.84
4.98
4.71
Chem Biol Drug Des 2014; 83: 106–118
111

ꢀ
Masłowska-Lipowicz and Walczynski
Synthesis of 1-(4-oxo-2H-chromen-3-ylmethyl)-
4-[5-(N-methyl-N-propyl)pentyloxy]- piperidine
5g
A mixture of 1,4-benzopyrone 9g (0.045 mol), 4-[5-(N-
methyl-N-propyl)pentyloxy]piperidine 8 (0.05 mol), parafor-
maldehyde (0.09 mol) and 40 mL of absolute ethanol was
refluxed for 24 h. The solvent was evaporated to give the
crude product as a sticky oil, which was purified by col-
umn chromatography.
C (%)
H (%)
N (%)
Calculated
Found
57.72
58.09
7.27
7.09
4.81
4.74
General method for the preparation of 1-[(N-
substituted-N-methyl)-3-propyloxy]-5-(N-methyl-N-
propyl)pentanediamines 6a and 6b
Synthesis of 3-(N-benzyl-N-methylamino)-1-propanol
12. A mixture of 3-benzylmethylamine 10 (0.2 mol), 3-
chloro-1-propanol 11 (0.2 mol), triethylamine (0.2 mol) and
1,2-dimethoxyethane (150 mL) was heated at 93 °C for
20 h. The reaction mixture was cooled, and the trimethyl-
amine hydrochloride was filtered off. The solvent was
evaporated, and the residue was distillated under reduced
pressure to give 12 as colourless oil.
5g. C24H36N2O3, (M = 400.54); yield 27%; 1H NMR
(CDCl3):
d
p.p.m.: 0.87–0.92 (t, 3H, -CH2CH3,
J = 7.35 Hz); d = 1.26–1.45 (m, 2Hpip), d = 1.46–1.67
(m, 4H, -CH2-alif); d = 1.88–1.94 (m, 2Hpip); d = 2.25
(s, 3H, N-CH3), d = 2.31–2.4 (m, 4H, -CH2-), d = 2.81–
2.85 (m, 2Hpip); d = 3.25–3.34 (m, 1H, -CHO),
d = 3.40–3.45 (t, -CH2-alif, J = 6.45); d = 3.49 (s, 2H,
-CH2-); d = 7.37–7.47 (m, 2Hchromone); d = 7.63–7.69
(m, 1Hchromone); d = 8.02 (s, 1H, OCH = chromone);
d = 8.21–8.24 (m, 1Hchromon); TLC (ethyl acetate:meth-
anol:TEA: 9:1:4), Rf = 0.49.
12. C11H17NO, (M = 179.29); yield 51% bp = 152–
1
156 °C/15 torr [lit. bp = 98–100 °C/0.25 torr [40]]; HNMR
(CDCl3)d p.p.m.: 1.74–1.77 (m, 2H, CH2CH2CH2); 2.22 (s,
3H, NCH3); 2.61–2.64 (t, J = 6 Hz, 2H, CH2N); 3.51 (s,
2H, CH2Ph); 3.74–3.78 (t, J = 6 Hz, 2H, CH2OH); 4.50
(br, 1H, OH); 7.27–7.32 (m, 5H, Haromat.).
Elemental analysis for dioxalic acid salt C24H36N2O3
2C2H2O4 (M = 580.64); mpdioxalic acid salt = 165–167 °C.
Á
C (%)
H (%)
N (%)
Synthesis of 3-(methylamino)-1-propanol 13. A mix-
ture of 12 (0.1 mol) and Pd/C (10%; 110 mg) in 100 mL
of ethanol was shaken in autoclave under 20 atm. of
hydrogen at 60 °C temperature for 4 h. The catalyst was
filtered off, and the solvent was removed in vacuo. The
residue was distillated under reduced pressure to give 13
as colourless oil.
Calculated
Found
57.91
57.87
6.93
6.88
4.82
4.85
Synthesis of 1-(3,4-dihydro-4-oxo-2H-chromen-3-
ylmethyl)-4-[5-(N-methyl-N-propyl)- pentyloxy]
piperidine 5h
To a solution of 2,3-dihydro-3-methylene-4H-benzopyran-
4-on 9h (0.0033 mol) in 15 mL of ethanol was added 8
(0.0033 mol). The mixture was stirred for 168 h at room
temperature. The solvent was evaporated, and residue
was purified by column chromatography. The title products
were obtained as sticky oil.
13. C4H11NO, (M = 89.16); yield 61.0%; bp = 80–82 °C/
13 torr [lit.0 bp = 74–76 °C/10 torr [40]] 1HNMR(CDCl3) d
p.p.m.: 1.54–1.58 (m, 2H, CH2CH2CH2); 2.27 (s, 3H,
NCH3); 2.61–2.63 (t, J = 6 Hz, 2H, CH2N); 3.24 (br, 1H,
OH); 3.56–3.58 (t, J = 6 Hz, 2H, CH2OH).
Synthesis of 3-[[(benzofuran-2yl)methyl]amino]-1-
propanol 14. To a solution of 3-(methylamino)-1-pro-
panol 13 (0.022 mol) and TEA (0.022 mol) in 50 mL of
5h. C24H38N2O3, (M = 402.57); yield 30%; 1HNMR d
p.p.m.: 0.83–0.98 (t, 3H, J = 7.35, CH2CH3); 1.29–
1.65 (m, 8H, pipCH2, alifCH2); 1.85–1.99 (m, 2H,
pipCH2); 2.03–2.15 (m, 2H, pipCH2); 2.22 (s, 3H,
NCH3); 2.27–2.47 (m, 4H, alifCH2, pipCH2); 2.4–2.96 (m,
6H, alifCH2,pipNCH2); 3.23–3.25 (m, 1H, pipCH); 3.4–
3.45 (t, 2H, alifOCH2, J = 6.6 Hz); 4.36–4.43 (dd, 2H,
J = 8.7 Hz, J = 2.7 Hz, chromOCH2); 4.57–4.62 (dd, 1H,
J = 4.5 Hz, J = 7.2 Hz, chromCH); 6.95–7.03 (m, 2H,
aromCH); 7.44–7.51 (m, 1H, aromCH); 7.86–7.89 (dd,
1H, J = 1.8 Hz, J = 6 Hz, aromCH); TLC (dichlorome-
DME
was
added
2-chloromethylbenzofuran
9c
(0.22 mol). The reaction mixture was heated at 80 °C
for 24 h. After cooling, the resulting precipitate was fil-
tered off and solvent was evaporated to give the crude
product as a sticky oil, which was purified by column
chromatography.
14. C13H17NO2, (M = 219.31); yield 57%; 1HNMR (CDCl3)
d p.p.m.: 1.74–1.77 (m, 2H, CH2CH2CH2); 2.34 (s, 3H,
NCH3); 2.66–2.70 (t, J = 6 Hz, 2H, CH2N); 3.72 (s, 2H,
CH2benzofurane); 3.76–3.0 (t, J = 6 Hz, 2H, CH2OH); 4.77
(br, 1H, OH); 6.59 (s, 1H, Hbenzofurane); 7.17–7.27.); 7.45–
7.54 (m, 1H, Hbenzofurane); TLC (ethyl acetate:methanol:
TEA: 93:1:1), Rf = 0.22.
thane:methanol:concentrated
ammonium
hydroxide:
19:1:0.5), Rf = 0.4.
Elemental analysis for dioxalic acid salt C24H38N2O3
2C2H2O4 (M = 582.65); mpdioxalic acid salt = 129–132 °C.
Á
112
Chem Biol Drug Des 2014; 83: 106–118

Histamine H3-Receptor; H3 Non-Imidazole Antagonists
Synthesis
of
1-[(N-substituted-N-methylamino)-
a
TLC (dichloromethane:methanol:concentrated ammonium
hydroxide: 29:10:1), Rf = 0.16.
3-propyloxy]-5-pentanenitriles 16a and 16b. To
solution of the corresponding 3-(N-substituted-N-methyla-
mino)-1-propanol 12 or 14 (0.009 mol) in 100 mL of dry
toluene was added sodium hydride (0.018 mol). The resul-
tant suspension was stirred at room temperature for 1 h
and then was added dropwise 15-crown-5 ether
(0.054 mol) and then treated in a single portion with 5-
bromopentanonitrile (0.054 mol). The reaction mixture was
stirred at room temperature for 72 h, and excess of sodium
hydride was quenched by dropwise addition of ethanol
(30 mL). The solvent was evaporated under reduce pres-
sure, and water (50 mL) was added. The mixture was
extracted with dichloromethane (3 9 50.0 mL), and
organic layer was dried (Na2SO4) and filtered. The solvent
was evaporated, and residue was purified by column chro-
matography. The title products were obtained as sticky oil.
17b. C18H28N2O2, (M = 304.48); yield 42%; 1HNMR,
CDCl3, d: 1.21–1.59 (m, 8H, CH2alif, NH2Ã); 1.76–1.86 (m,
2H, CH2alif); 2.32 (s, 3H, NCH3); 2.50–2.55 (m, 2H,
CH2alif); 2.64–2.67 (t, 2H, J = 6.9, CH2alif); 3.35–3.40 (t,
2H, J = 6.6, OCH2); 3.43–3.47 (t, 2H, J = 6.6, OCH2);
3.69 (s, 2H, benzofuran-CH2-N); 6.57 (s, 1H, 3-
H
benzofurane); 7.16–7.27 (m, 2H, CHbenzofurane); 7.44–7.53
(m, 2H, CHbenzofurane); TLC (dichloromethane:methanol:
concentrated ammonium hydroxide: 9:1:1), Rf = 0.15.
Synthesis
of
1-[(N-substituted-N-methyl)-3-
propyloxy]-5-(N-formylo)-pentanediamines 18a and
18b. To a solution of the corresponding 17a or 17b
(0.004 mol) in 25 mL of anhydrous dichloromethane was
added FAM (10 mL). The mixture was stirred at 5–10 °C
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 dichlo-
romethane (2 9 50 mL). The organic layers were com-
bined, washed with water (3 9 50 mL), dried (Na2SO4),
filtered and evaporated, and residue was purified by col-
umn chromatography to give the desired compounds as
sticky oil.
16a. C16H24N2O, (M = 260.42); yield 50%; 1HNMR,
CDCl3,d: 1.66–1.82 (m, 6H, CH2alif); 2.19 (s, 3H, NCH3);
2.33–2.38 (t, 2H, J = 7.2, OCH2); 2.41–2.46 (t, 2H,
J = 7.2, OCH2); 3.40–3.47 (m, 4H, CH2alif); 3.48 (s, 2H,
PhCH2); 7.22–7.34 (m, 5H, CHarom); TLC (dichlorome-
thane:methanol:concentrated
ammonium
hydroxide:
29:10:1), Rf = 0.29.
16b. C18H24N2O2, (M = 300.44); yield 42%; 1HNMR,
CDCl3, d: 1.61–1.71 (m, 4H, CH2alif); 1.76–1.85 (m, 2H,
CH2alif); 2.27–2.32 (m, 2H, CH2CN); 2.34 (s, 3H, NCH3);
2.50–2.55 (t, 2H, J = 7.5, NCH2); 3.36–3.40 (t, 2H,
J = 5.7, OCH2); 3.42–3.46 (t, 2H, J = 6.3, OCH2); 3.71 (s,
2H, benzofuran-CH2-N); 6.59 (s, 1H, 3-Hbenzofurane); 7.17–
7.28 (m, 2H, CHbenzofurane); 7.45–7.54 (m, 2H, CHbenzofurane);
TLC (ethyl acetate:methanol:TEA: 39:1:1), Rf = 0.49.
18a. C17H28N2O2, (M = 292.47); yield 99%; 1HNMR,
CDCl3,d: 1.32–1.41 (m, 2H, CH2alif); 1.42–1.62 (m, 4H,
CH2alif); 1.74–1.83 (q, 2H, J = 6.9, CH2alif); 2.19 (s, 3H,
NCH3); 2.42–2.47 (t, 2H, J = 7.5, CH2alif); 3.25–3.32 (m,
2H, CH2alif); 3.37–3.41 (t, 2H, J = 6.6, OCH2); 3.43–3.47
(t, 2H, J = 6.6, OCH2); 3.48 (s, 2H, PHCH2); 7.21–7.34
(m, 5H, CHarom); 8.13–8.14 (s, 1H, COH); TLC (dichlorom-
ethane:methanol:concentrated
ammonium
hydroxide:
Synthesis of 1-[(N-substituted-N-methylamino)-3-
a
29:10:1), Rf = 0.42.
propyloxy]-5-pentanediamines 17a and 17b. To
solution of the corresponding 1-[(N-substituted-N-
methylamino)-3-propyloxy]-5-pentanenitrile 16a or 16b
(0.0046 mol) in 40 mL of anhydrous ethyl ether LiAlH4
(0.0092 mol) was added. The mixture was stirred at room
temperature for 1 h and quenched by dropwise addition
of water (0.35 mL), 10% of NaOH solution (0.35 mL) and
water (0.35 mL). The suspension was stirred for 30 min
and filtered. The filter cake was washed with ether
(2 9 30 mL). The organic layers were combined, washed
with water (3 9 30 mL), dried (Na2SO4) and filtered. The
solvent was evaporated, and residue was purified by col-
umn chromatography. The title products were obtained
as sticky oil.
18b. C19H28N2O3, (M = 332.67); yield 42%; 1HNMR,
CDCl3, d: 1.26–1.40 (m, 2H, CH2alif); 1.43–1.59 (m, 4H,
CH2alif); 1.70–1.85 (m, 2H, CH2alif); 2.33 (s, 3H, NCH3);
2.50–2.55 (t, 2H, J = 7.5, NCH2); 3.21–3.31 (m, 2H,
CH2NCOH); 3.34–3.39 (m, 2H, OCH2);3.43–3.47 (t, 2H,
J = 6.3, OCH2); 3.70 (s, 2H, benzofurane-CH2-N); 5.53 (br s,
1H, NH*); 6.58 (s, 1H, (s, 1H, 3-Hbenzofurane); 7.17–7.28
(m, 2H, CHbenzofurane); 7.44–7.54 (m, 2H, CHbenzofurane);
8.14 (s, 1H, NCOH); TLC (dichloromethane:methanol:con-
centrated ammonium hydroxide: 9:1:1), Rf = 0.49.
Synthesis
propyloxy]-5-(N-methyl)pentanediamines 19a and
19b. To solution of the appropriate 19a or 19b
of
1-[(N-substituted-N-methyl)-3-
a
17a. C16H28N2O, (M = 264.46); yield 87%; 1HNMR,
CDCl3,d: 1.32–1.61 (m, 8H, CH2alif, NH2Ã); 1.75–1.84 (q,
2H, J = 6.9, CH2alif); 2.18 (s, 3H, NCH3); 2.42–2.47 (t, 2H,
J = 7.5, CH2alif); 2.66–2.70 (t, 2H, J = 6.9, CH2alif); 3.37–
3.41 (t, 2H, J = 6.6, OCH2); 3.43–3.48 (t, 2H, J = 6.6,
OCH2); 3.48 (s, 2H, PHCH2); 7.22–7.32 (m, 5H, CHarom);
(0.004 mol) in 50 mL of anhydrous ethyl ether was added
LiAlH4 (0.008 mol). The mixture was stirred at room tem-
perature for 1 h and quenched by dropwise addition of
water (0.3 mL), 10% of NaOH solution (0.3 mL) and water
(0.3 mL). The suspension was stirred for 30 min and fil-
tered. The filter cake was washed with ether (2 9 25 mL).
Chem Biol Drug Des 2014; 83: 106–118
113

ꢀ
Masłowska-Lipowicz and Walczynski
The organic layers were combined, washed with water
(3 9 25 mL), dried (Na2SO4) and filtered. The solvent
was evaporated, and residue was purified by column
chromatography. The title products were obtained as
sticky oil.
romethane:methanol:concentrated ammonium hydroxide:
9:1:1), Rf = 0.57.
Synthesis
of
1-[(N-substituted-N-methyl)-3-
propyloxy]-5-(N-methyl-N-propyl)- pentanediamines
6a and 6b. To a solution of the appropriate amides 20a
or 20b (0.002 mol) in 50 mL of anhydrous ethyl ether
LiAlH4 (0.004 mol) was added. The mixture was stirred at
room temperature for 2 h and quenched by dropwise
addition of water (0.15 mL), 10% of NaOH solution
(0.15 mL) and water (0.15 mL). The suspension was stir-
red for 30 min and filtered. The filter cake was washed
with ether (2 9 25 mL). The combined organic layers were
washed with water (3 9 25 mL), dried (Na2SO4) and fil-
tered. The solvent was evaporated, and residue was puri-
fied by column chromatography. The title products were
obtained as sticky oil.
19a. C17H30N2O, (M = 279.49); yield 72%; 1HNMR,
CDCl3,d: 1.25–1.39 (m, 2H, CH2alif); 1.40–1.60 (m, 5H,
CH2alif, NH*); 1.62–1.84 (m, 2H, CH2alif); 2.18 (s, 3H
NCH3); 2.42 (s, 3H NCH3); 2.42–2.47 (t, 2H, J = 7.5,
NCH2); 2.54–2.58 (t, 2H, J = 7.2, NCH2); 3.37-3.41 (t, 2H,
J = 6.6, OCH2); 3.43–3.47 (t, 2H, J = 6.6, OCH2); 3.48 (s,
2H, PhCH2); 7.20–7.34 (m, 5H, CHarom); TLC (dichlorome-
thane:methanol:concentrated
ammonium
hydroxide:
29:10:1), Rf = 0.22.
19b. C19H30N2O2, (M = 318.69); yield 89%; 1HNMR,
CDCl3, d: 1.31–1.39 (m, 2H, CH2alif);1.43–160 (m, 5H,
CH2alif, NH*); 1.76–1.86 (m, 2H, CH2alif); 2.32 (s, 3H,
NCH3); 2.42 (s, 3H, NCH3); 2.50–2.57 (m, 4H, CH2alif);
3.35–3.40 (t, 2H, J = 6.6, OCH2); 3.43–3.47 (t, 2H,
J = 6.6, OCH2); 3.70 (s, 2H, benzofurane-CH2-N); 6.58 (s,
1H, 3-Hbenzofurane); 7.17–7.27 (m, 2H, CHbenzofurane); 7.45–
7.54 (m, 2H, CHbenzofurane); TLC (dichloromethane:metha-
nol:concentrated ammonium hydroxide: 4:1:1), Rf = 0.22.
6a. C20H36N2O, (M = 320.58); yield 51%; 1HNMR,
CDCl3,d: 0.86–0.91 (t, 3H, J = 7.5, CH2CH3); 1.30–
1.37 (m, 2H, CH2alif); 1.41–1.62 (m, 6H, CH2alif); 1.77–
1.84 (q, 2H, J = 6.9, CH2alif); 2.18 (s, 3H, NCH3); 2.20
(s, 3H, NCH3); 2.24–2.33 (m, 4H, CH2alif); 2.42–2.47 (t,
2H, J = 7.5, CH2alif); 3.36–3.41 (t, 2H, J = 6.6, OCH2);
3.43–3.47 (t, 2H, J = 6.6, OCH2); 3.48 (s, 2H, PhCH2);
7.22–7.32 (m, 5H, CHarom); TLC (dichloromethane:
Synthesis
propyloxy]-5-(N-methyl-N-propionylcarbonyl)-
of
1-[(N-substituted-N-methyl)-3-
methanol:concentrated
139:10:1), Rf = 0.38.
ammonium
hydroxide:
pentanediamine amides 20a and 20b. To an ice-
cooled solution of the appropriate 19a or 19b in 70 mL of
dichloromethane was slowly added propionic anhydride,
and reaction mixture was stirred at room temperature for
2 h. Saturated aqueous solution of sodium bicarbonate
was then added until pH 9, and the reaction mixture was
stirred for 24 h. The organic layer was separated, dried
(Na2SO4) and filtered. Dichloromethane was evaporated to
give the crude products 20a and 20b as sticky oil, which
was purified by column chromatography.
Elemental analysis for dioxalic acid salt C19H36N2O Á
2C2H2O4 (M = 494.66); mpdioxalic acid salt = 123–125 °C.
C (%)
H (%)
N (%)
Calculated
Found
57.58
57.42
8.05
7.91
5.58
5.66
6b. C22H36N2O2, (M = 360.58); yield 72%; 1HNMR,
CDCl3, d: 0.86–0.91 (t, 3H, J = 7.5, CH2CH3); 1.26–1.35
(m, 2H, CH2alif); 1.42–1.56 (m, 6H, CH2alif); 1.76–1.86 (q,
2H, J = 6.9, CH2alif); 2.12 (s, 3H, NCH3); 2.26–2.34 (m,
4H, CH2alif); 2.32 (s, 3H, NCH3); 2.50–2.55 (t, 2H, J = 7.5,
CH2alif); 3.35–3.39 (t, 2H, J = 6.6, OCH2); 3.42–3.47 (t,
2H, J = 6.6, OCH2); 3.67 (s, 2H, benzofurane-CH2-N); 6.57
(s, 1H, 3-Hbenzofurane); 7.16–7.27 (m, 2H, CHbenzofurane);
7.44–7.53 (m, 2H, CHbenzofurane). TLC (dichloromethane:
methanol:concentrated ammonium hydroxide: 9:1:1),
Rf = 0.35.
20a. C20H34N2O2, (M = 334.56); yield 93%; 1HNMR,
CDCl3,d: 1.11–1.18 (m, 3H, CH2CH3); 1.29–1.39 (m, 2H,
CH2alif); 1.43–1.62 (m, 4H, CH2alif); 1.74–1.84 (m, 2H,
CH2alif); 2.18–2.19 (d, 3H, J = 1.2, PhCH2NCH3); 2.27–
2.36 (m, 2H, CH2alif); 2.42–2.47 (t, 2H, J = 7.5, CH2alif);
2.91–2.95 (d, 3H, J = 12.9, CH3NCO); 3.33–3.47 (m, 6H,
CH2alif); 3.48 (s, 2H, PhCH2); 7.21–7.34 (m, 5H, CHarom);
TLC (dichloromethane:methanol:concentrated ammonium
hydroxide: 139:10:1), Rf = 0.67.
20b. C22H34N2O3, (M = 374.58); yield 83%; 1HNMR,
CDCl3, d: 1.10–1.16 (m, 3H, CH2CH3); 1.24–1.34 (m, 2H,
CH2alif); 1.43–1.59 (m, 4H, CH2alif); 2.23–2.35 (m, 5H,
NCH3, CH2alif); 2.49–2.54 (t, 2H, J = 7.5, CH2alif); 2.89–
2.93 (d, 3H, J = 9.9, CH3NCO); 3.31–3.38 (m, 4H, CH2alif);
3.42–3.47 (m, 2H, CH2alif); 3.69 (s, 2H, benzofuran-CH2-
N); 6.57 (s, 1H, 3-Hbenzofurane); 7.16–7.30 (m, 2H, CH
benzofurane); 7.44–7.53 (m, 2H, CHbenzofurane); TLC (dichlo-
Elemental analysis for dioxalic acid salt C22H36N2O2
2C2H2O4 (M = 520.66); mpdioxalic acid salt = 103–105 °C.
Á
C (%)
H (%)
N (%)
Calculated
Found
59.97
59.85
7.76
7.49
5.38
5.57
114
Chem Biol Drug Des 2014; 83: 106–118

Histamine H3-Receptor; H3 Non-Imidazole Antagonists
Pharmacology. The potency of all the obtained com-
pounds was tested for H3 antagonistic effects in vitro on
the guinea-pig jejunum (38).
NaCl (136.9); KCl (2.68); NaHPO4 (7.19). After flushing the
intraluminal contents, segments of about 2 cm long were
cut and mounted for isotonic contractions in water jacked
20 mL organ baths filled with oxygenated (O2:CO2 = 95:5,
v/v) Krebs buffer containing (mM) NaCl (117.5); KCl (5.6);
MgSO4 (1.18); CaCl2 (2.5); NaH2PO4 (1.28); NaHCO3 (25);
glucose (5.5) and indomethacin (1 9 10À6 M) at 37 °C
under a constant load of 0.5 g. After a 30-min equilibration
period with washings every 10 min, a submaximal priming
dose of histamine (1 lM) was given and washed out (stan-
dard washing procedure: three changes of buffer during
30 min). After washing out, the antagonistic activity of given
compounds was measured by recording a concentration-
response curve (CRC) for histamine in the presence of the
testing compounds 5c, 5d and 6a, which was added 5 min
before histamine. This procedure was repeated with higher
concentrations of the compounds. The antagonism was of
a competitive nature causing a parallel shift of the CRC. The
pA2-values were calculated according to Arunlakshana and
Schild (39). The pA2 values were compared with the potency
of pyrilamine.
Selected compounds 5c, 5d and 6a were also tested for
H1 antagonistic effects in vitro, following standard meth-
ods, using the guinea-pig ileum (39).
H3 antagonistic effects in vitro on the guinea-pig
jejunum for compounds 5a–h, 6a,b, 7 and 8
Male guinea-pigs weighing 300–400 g were killed by a
blow on the head. A portion of the small intestine, 20–
50 cm proximal to the ileocaecal valve (jejunum), was
removed and placed in Krebs buffer [composition (mM)
NaCl 118; KCl 5.6; MgSO4 1.18; CaCl2 2.5; NaH2PO4
1.28; NaHCO3 25; glucose 5.5 and indomethacin
(1 9 10À6 M)]. Whole jejunum segments (2 cm) were pre-
pared and mounted between two platinum electrodes
(4 mm apart) in 20 mL Krebs buffer, continuously gassed
with 95% O2:5% CO2 and maintained at 37 °C. Contrac-
tions were recorded isotonically under 1.0 g tension with
Hugo Sachs Hebel-Messvorsatz (Tl-2)/HF-modem (Hugo
Sachs Electronik, Hugstetten, Germany) connected to a
pen recorder. After equilibration for 1 h with washings
every 10 min, the muscle segments were stimulated maxi-
mally between 15 and 20 Volt and continuously at a fre-
quency of 0.1 Hz and a duration of 0.5 millisecond, with
rectangular-wave electrical pulses, delivered by a Grass
Stimulator S-88 (Grass Instruments Co., Quincy, MA,
USA). After 30 min of stimulation, 5 min before adding (R)-
Results and Discussion
The potency of all synthesized compounds was preliminary
in vitro tested as H3 receptor antagonists – electrically
evoked contraction of the guinea-pig jejunum. 1-Substitut-
edmethyl-4-[5-(N-methyl-N-propylamino)pentyloxy]piperi-
dines (5a–h) and selected 1-[(N-substituted-N-methyl)-3-
propyloxy]-5-(N-methyl-N-propyl)pentanediamines (6a, 6b)
all showed moderate to high antagonist activity at H3-
receptor, except of derivative 6b showing weak potency.
Results are presented in Table 1.
a-methylhistamine, pyrilamine (1 9 10À5
M concentration
in organ bath) was added, and then cumulative
concentration-response curves (half-log increments) of
(R)-a-methylhistamine, H3-agonist, were recorded until no
further change in response was found. Five minutes before
The
1-benzyl-4-[5-(N-methyl-N-propylaminopentyloxy)]
adding the tested compounds, the pyrilamine (1 9 10À5
M
piperidine 7 has been selected as the lead structure from
the previously examined compounds (37) to allow a direct
comparison of the changes in activity of the newly
designed compounds with the replacement of the benzyl
group of the N-piperidine moiety.
concentration in organ bath) was added, and after 20 min,
cumulative concentration-response curves (half-log incre-
ments) of (R)-a-methylhistamine, H3-agonist, were
recorded until no further change in response was found.
Statistical analysis was carried out with the Student’s t-
test. In all test, p < 0.05 was considered statistically signifi-
cant. The potency of an antagonist is expressed by its pA2
value, calculated from the Schild (39) regression analysis
where at least three concentrations were used. The pA2
values were compared with the potency of thioperamide.
It has appeared that by comparison of homologous pairs
that 5g and 5h have higher potency than their analogous
5a and 5b. The differences are observed inside of each
series. While it is quite a significant difference in H3-recep-
tor potency between derivative 5g (pA2 = 7.63) – with
double bond – and 5h (pA2 = 7.1) – without double bond
in 2,3-dihydro-4H-pyran-4-one ring – only very small differ-
ence in activity between the derivative 5a (pA2 = 7.2) and
5b (pA2 = 7.11) is observed. Moreover, comparing deriva-
H1 antagonistic activity for 5c, 5d and 6a
compounds
Selected compounds were tested for H1 antagonistic
effects in vitro, following standard methods, using the gui-
nea-pig ileum (39).
tives 5a and 5b with unsubstituted derivative
8
(pA2 = 7.31), it is seen that H3 antagonistic activity is
almost on the same level, independently on the presence
or absence of substituent 9a or 9b. These results suggest
that in the chromones (5a and 5g) and chromanones (5b
and 5h) series, the heterocyclic ring should contain a dou-
ble bond and 4-[5-(N-methyl-N-propyl)pentyloxy]piperidi-
Male guinea-pigs weighing 300–400 g were killed by a blow
on the head. The ileum was excised and placed in phos-
phate buffer at room temperature (pH 7.4) containing (mM)
Chem Biol Drug Des 2014; 83: 106–118
115

ꢀ
Masłowska-Lipowicz and Walczynski
Table 1: H3 antagonistic activity of 1-substituted-4-[5-(N-methyl-N-propylamino)pentyloxy]piperidines (5a–h, 7, 8) and 1-[(N-substituted-
N-methyl)-3-propyloxy]-5-(N-methyl-N-propyl)pentanediamines (6a, 6b) as tested on the in vitro test system on the guinea-pig jejunum
The concentrations of the tested
Cpd.
Structure
compound ci (M)
pA2 (sem) H3
7.2 (0.1)
N (caviae)
5a
1 9 10À7; 3 9 10À7; 1 9 10À6
9 (3)
O
CH3
N
O
O
CH3
2
5
5
N
N
O
O
CH3
CH3
1 9 10À7; 3 9 10À7; 1 9 10À6
3 9 10À9; 1 9 10À8; 3 9 10À8
1 9 10À8; 3 9 10À8; 1 9 10À7
7.11 (0.14)
8.47 (0.05)
8.15 (0.07)
9 (3)
12 (4)
12 (4)
O
N
CH3
5b
5c
2
O
CH3
N
O
CH3
CH3
5
2
N
O
CH3
N
O
O
5
2
5d
N
3 9 10À8; 1 9 10À7; 3 9 10À7
1 9 10À7; 3 9 10À7; 1 9 10À6
7.76 (0.09)
7.04 (0.11)
12 (4)
9 (3)
CH3
N
O
CH3
2
5
N
5e
5f
CH3
O
N
CH3
2
5
N
3 9 10À8; 1 9 10À7; 3 9 10À7
7.63 (0.08)
7.1 (0.15)
9 (3)
CH3
N
O
O
CH3
2
5
5g
5h
N
O
O
1 9 10À7; 3 9 10À7; 1 9 10À6
13 (4)
CH3
O
N
CH3
2
5
N
O
3 9 10À8; 1 9 10À7; 3 9 10À7
7.79 (0.06)
7.31 (0.1)
12 (4)
9 (3)
CH3
N
O
CH3
5
2
7
8
N
1 9 10À7; 3 9 10À7; 1 9 10À6
CH3
N
O
CH3
5
2
HN
1 9 10À8; 3 9 10À8; 1 9 10À7
8.06 (0.05)
12 (4)
CH3
N
O
CH3
5
5
2
6a
N
CH3
3 9 10À7; 1 9 10À6; 3 9 10À6
6.23 (0.12)
8.65 (0.07)
12 (4)
CH3
N
O
CH3
2
6b
N
CH3
O
Thioperamide
3 9 10À9; 1 9 10À8; 3 9 10À8
36 (12)
sem, standard error of the mean; N, number of different animal preparations; cavie, number of animals.
nyl substituent should be present at a favourable posi-
tion 3.
reduction of a heterocyclic ring with a six-membered to
five-membered ring and removal of the carbonyl group
lead to compound 5c (pA2 = 8.47) and 5d (pA2 = 8.15)
showing the highest potency for all presented 4-hydroxypi-
peridine derivatives. We observe that the 2-position of 4-
[5-(N-methyl-N-propylamino)pentyloxy]piperidinyl moiety in
the 2-methylbenzofuran ring (5c) is slightly favourable for
histamine H3-receptor antagonist activity than position 3.
Replacement of the benzyl substituent by 2-methylindenyl
To investigate the influence of the size of the heterocyclic
ring and the presence of the carbonyl group, on the
antagonistic activity on the histamine H3 receptor, two
methylbenzofuran derivatives containing 4-[5-(N-methyl-N-
propylamino)pentyloxy]piperidinyl moiety at position 2 (5c)
and 3 (5d) in benzofuran ring were synthesized. The
116
Chem Biol Drug Des 2014; 83: 106–118

Histamine H3-Receptor; H3 Non-Imidazole Antagonists
Conflict of Interest
group 5e (pA2 = 7.76) reduced potency. Antagonistic
activity was further reduced when the 2-methylindenyl
substituent has been replaced by the most lipophilic 2-
methylnaphthyl moiety 5f (pA2 = 7.04).
The authors have declared no conflict of interest.
Surprisingly, replacement of the 4-hydroxypiperidine in the
leads 7 and 5c by a highly flexible 3-(methylamino)propyloxy
chain yields compounds 6a (pA2 = 8.02) and 6b (pA2 = 6.23)
with higher and lower affinity than their piperidine analogues
(7, pA2 = 7.79; 5c, pA2 = 8.47), respectively.
References
1. Hough L.B. (2001) Genomics meets histamine recep-
tors: new subtypes, new receptors. Mol Pharma-
col;59:415–419.
2. Parsons M.E., Ganellin C.R. (2006) Histamine and its
receptors. Br J Pharmacol;147(S1):S127–S135.
3. Leurs R., Church M.K., Taglialatela M. (2002) H1-anti-
histamines: inverse agonism, anti-inflammatory actions
and cardiac effects. Clin Exp Allergy;32:489–498.
4. Ganellin C.R. (1981) Medicinal chemistry and dynamic
structure-activity analysis in discovery of drug acting at
histamine H2 receptors. J Med Chem;24:913–920.
5. Zhang M., Thurmond R.L., Dunford P. (2007) The hista-
mine H4 receptor: a novel modulator of inflammatory and
immune disorders. Pharmacol Therap;113:594–606.
6. Arrang J.-M., Garbarg M., Schwartz J.-C. (1983) Auto-
inhibition of brain histamine release mediated by a
novel class (H3) of histamine receptor. Nature;302:
832–837.
In conclusion, it may be noticed that the spatial configura-
tions greatly decide on the activity of these series than the
others physico-chemical parameters.
Additionally, selected compounds 5c, 5d and 6a have also
been tested for H1 antagonistic effects in vitro, following
standard methods, using the guinea-pig ileum. None of
them showed any H1-antagonistic activity (pA2 < 4; for py-
rilamine pA2 = 8.5).
Due to the lack of antagonistic activity of selected com-
pounds at H1 receptor, we can conclude that the derivatives
of 5c, 5d and 6a are not double H1H3 receptor antagonists.
7. Lovenberg T.W., Roland B.L., Wilson S.J., Jiang X.,
Pyati J., Huvar A., Jackson M.R., Erlander M.G. (1999)
Cloning and functional expression of the human hista-
mine H3 receptor. Mol Pharmacol;55:1101–1107.
8. Lovenberg T.W., Pyti J., Chang H., Wilson S.J., Erland-
er M.G. (2000) Cloning of rat histamine H3 receptor
Conclusions and Future Directions
Novel, potent non-imidazole histamine H3 receptor antago-
nists have been prepared possessing either a highly flexi-
ble 3-(methylamino)propyloxy chain or 4-hydroxypiperidine
ring resulting in increased rigidity of these compounds.
Investigation of the compounds in an in vitro functional
assay on the guinea-pig ileum led to the identification of
5c and 5d as the most potent compounds in vitro in both
series (pA2 = 8.47 and pA2 = 8.15, respectively). By com-
paring pairs of homologous compounds 5c/6b versus 7/
6a, it was found that the 5c (pA2 = 8.47) has a higher
activity than its 3-(methylamino)propyloxy analogue 6b
(pA2 = 6.23), which is in contrast to a pair of homologues
7/6a, where 3-(methylamine)propyloxy derivative 6a
(pA2 = 8.02) has a higher activity than its 4-hydroxypiperi-
dine analogue 7 (pA2 = 7.79). For explanation of tentative
interpretation of the different SAR for the compounds 5c/
6b versus 7/6a, we will try to solve this problem by molec-
ular modelling. However, further structural modifications,
both in 4-hydroxypiperidine and 3-(methylamino)propyloxy
series, are required to explain these unexpected results. At
last, based on the SAR of all synthesized compounds, the
most active derivatives will be chosen and investigated for
their effects on central histaminergic neuron activity in vivo.
reveals distinct species pharmacological profiles.
J
Pharmacol Exp Therap;293:771–778.
9. Arrang J.-M., Garbarg M., Schwartz J.C. (1985) Auto-
regulation of histamine release in brain by presynaptic
H3-receptors. Neuroscience;15:553–562.
10. Arrang J.-M., Garbarg M., Schwartz J.-C. (1987) Au-
toinhibition of histamine synthesis mediated by presyn-
aptic H3-receptors. Neuroscience;23:149–157.
11. Clapham J., Kilpatrick G.J. (1992) Histamine H3 recep-
tors modulate the release of [3H]-acetylcholine from
slices of rat entorhinal cortex: evidence for the possible
existence of H3 receptor subtypes. Br J Pharma-
col;107:919–923.
12. Yokatoni K., Murakami Y., Okada S., Wang M., Na-
kamura K. (2000) Histamine H(3) receptor-mediated
inhibition of endogenous acetylcholine release from the
isolated, vascularly perfused rat stomach. Eur J Phar-
macol;392:23–29.
€
13. Schlicker E., Fink K., Detzner M., Gothert M. (1993)
Histamine inhibits dopamine release in the mouse stri-
atum via presynaptic H3 receptors. J Neural Transm
Gen Sect;93:1–10.
Acknowledgements
€
14. Schlicker E., Schunack W., Gothert M. (1990) Hista-
mine H3 receptor-mediated inhibition of noradrenaline
release in pig retina discs. Naunyn-Schmiedeberg’s
Arch Pharmacol;342:497–501.
This work was supported by the Polish State Committee
for Scientific Research, Grant No. N N405092140.
Chem Biol Drug Des 2014; 83: 106–118
117

ꢀ
Masłowska-Lipowicz and Walczynski
€
15. Schlicker E., Betz R., Gothert M. (1988) Histamine H3
antagonists reach out for the clinic. Drug Discovery
receptor-mediated inhibition of serotonin release in the
rat brain cortex. Naunyn-Schmiedeberg’s Arch Phar-
macol;337:588–590.
Today;10:1613–1627.
ꢀ
_
29. Łazewska D., Kiec-Kononowicz K. (2010) Recent
advances in histamine H3 receptor antagonists/inverse
agonists. Expert Opin Ther Pat;20:1147–1169.
30. Berlin M., Boyce C.W., De Lera Ruiz M. (2011) Hista-
mine H3 receptor as a drug discovery target. J Med
Chem;54:26–53.
16. Miyazaki S., Imaizumi M., Onodera K. (1995) Effects
of thioperamide, a histamine H3-receptor antagonist,
on a scopolamine-induced learning deficit using an
elevated plus-maze test in mice. Life Sci;57:2137–
2144.
17. Onodera K., Miyazaki S., Imaizumi M., Stark H., Schu-
nack W. (1998) Improvement by FUB 181, a novel his-
tamine H3-receptor antagonist, of learning and
memory in the elevated plus-maze test in mice. Nau-
nyn Schmiedebergs Arch Pharmacol;357:508–513.
18. Passani M.B., Cangioli I., Bocciottini L., Mannaioni P.F.
(2000) Thioperamide and cimetidine modulate acetyl-
choline release from the amygdala of freely moving
rats. Inflamm Res;49:S43–S44.
31. Hancock A.A. (2006) The challenge of drug discovery
of a GPCR target: analysis of preclinical pharmacology
of histamine H3 antagonists/inverse agonists. Biochem
Pharmacol;71:1103–1113.
32. Pomponi S.A., Gullo V.P., Horan A.C., Patel M.G.,
Coval S. (1994) Method for treating airway congestion.
U.S. Patent, 5,352,707 [Chem. Abstr. 1994, 121,
272,182n].
33. Apodaca R., Dvorak C.A., Xiao W., Barbier A.J., Bog-
gs J.D., Wilson S.J., Lovenberg T.W., Carruthers
N.I.A. (2003) A new class of diamine-based human
histamine H3 receptor antagonists: 4-(aminoalkoxy)
benzylamines. J Med Chem;46:3938–3944.
34. Gadski R.A., Hipskind P.A., Jesudason C.D., Pickard
R.T., Beavers L.S. (Lilly Co. Eli) (2004) Substituted aze-
pines as histamine H3 receptor antagonists, prepara-
tion and therapeutic uses. WO2004018432 [Chem.
Abstr. 2004, 140, P235617e].
35. 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. (2005) 4-phenoxypiperidines: potent,
conformationally restricted, non-imidazole histamine
H3 antagonists. J Med Chem;48:2229–2238.
36. Cowart M.D., Bennani Y.L., Faghih R., Gfesser G.
(2002) Novel amines as histamine-3 receptor ligands
and their therapeutic applications, (Abbott Laborato-
ries). WO 02074758. [Chem. Abstr. 137 (2002)
P247602x].
19. Yokoyama H., Onodera K., Maeyama K., Sakurai E., Ii-
numa K., Leurs R., Timmerman T., Watanabe H.
(1994) Clobenpropit (VUF-9153), a new histamine H3
receptor antagonist, inhibits electrically induced convul-
sions in mice. Eur J Pharmacol;260:23–28.
ꢀ
20. Pillot C., Ortiz J., Heron A., Ridray S., Schwartz J.-C.,
Arrang J.-M. (2002) Ciproxifan, a histamine H3-recep-
tor antagonist/inverse agonist, potentiates neurochemi-
cal and behavioral effects of haloperidol in the rat. J
Neurosci;22:7272–7280.
21. Takahashi K., Suwa H., Ishikawa T., Kotani H. (2002)
Targeted disruption of H3 receptors results in changes
in brain histamine tone leading to an obese phenotype.
J Clin Invest;110:1791–1799.
22. Sander K., Kottke T., Weizel L., Stark H. (2010) Kojic
acid derivatives as histamine H3 receptor ligands.
Chem Pharm Bull;58:1353–1361.
23. Beaton G., Moree W.J. (2010) The expanding role of
H1 antihistamines: a potent survey of selective and
dual activity compounds 2005–2010. Expert Opin Ther
Pat;20:1197–1218.
24. Procopiou P.A., Browning C., Buckley J.M., Clark
K.L., Fechner L., Gore P.M., Hancock A.P. et al.
(2011) The discovery of phthalazinone-based human
H1 and H3 single-ligand antagonists suitable for intra-
nasal administration for the treatment of allergic rhinitis.
J Med Chem;54:2183–2195.
37. Masłowska-Lipowicz I., Figlus M., Zuiderveld O.P.,
ꢀ
Walczynski K. (2008) New 1-benzyl-4-hydroxypiperi-
dine derivatives as non-imidazole histamine H3-antago-
nists. Arch Pharm;341:762–773.
38. Vollinga R.C., Zuiderveld O.P., Scheerens H., Bast A.,
Timmerman H. (1992) A simple and rapid in vitro test
system for the screening of histamine H3 ligands.
Methods Find Exp Clin Pharmacol;105:747–751.
39. Arunlakshana O., Schild H.O. (1959) Some quantitative
uses of drug antagonists Br. J Pharmacol;14:48–55.
40. Parcell R.F., Hauck F.P. JR (1963) Preparation of tetra-
25. Stark H., Schlicker E., Schunack W. (1996) Develop-
ments of histamine H3-receptor antagonists. Drugs
Future;21:507–520.
hydropyridines from enamines and imines.
J Org
26. Van der Goot H., Timmerman H. (2000) Selective
ligands as tools to study histamine receptors. Eur J
Med Chem;35:5–20.
Chem;28:3468–3473.
Supporting Information
27. Cowart M., Altenbach R., Black L., Faghih R., Zhao
C., Hanckok A.A. (2004) Medicinal chemistry and bio-
logical properties of non-imidazole histamine H3 antag-
onists. Mini Rev Med Chem;4:979–992.
Additional Supporting Information may be found in the
online version of this article:
28. Celanire S., Wijtmans M., Talaga P., Leurs R., de Esch
I.J.P. (2005) Keynote review: histamine H3 receptor
Appendix S1. Description of the synthetic methods for
preparing intermediates 9a–e and 9h.
118
Chem Biol Drug Des 2014; 83: 106–118