1-Phenoxyalkyl-4-[(N,N-disubstitutedamino)alkyl]piperazine derivatives as non-imidazole histamine H3-antagonists

Article abstract of DOI:10.1007/s00044-012-0090-2

In this study, a series of 1-phenoxyalkyl-4-[(N,N-disubstitutedamino)alkyl] piperazine derivatives has been prepared and in vitro tested as H ₃-receptor antagonists (electrically evoked contraction of the guinea pig jejunum). All compounds inve

Full text of DOI:10.1007/s00044-012-0090-2

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:1287–1304
DOI 10.1007/s00044-012-0090-2
ORIGINAL RESEARCH
1-Phenoxyalkyl-4-[(N,N-disubstitutedamino)alkyl]piperazine
derivatives as non-imidazole histamine H3-antagonists
•
Marek Staszewski Krzysztof Walczynski
´
Received: 18 February 2011 / Accepted: 14 May 2012 / Published online: 12 June 2012
Ó Springer Science+Business Media, LLC 2012
Abstract In this study, a series of 1-phenoxyalkyl-4-
[(N,N-disubstitutedamino)alkyl]piperazine derivatives has
been prepared and in vitro tested as H3-receptor antagonists
(electrically evoked contraction of the guinea pig jejunum).
All compounds investigated show moderate in vitro affin-
ities. The most potent antagonists in this series are the
compounds 9b, 1b, 1f, and 1l, which exhibit, independently
of the substituent at the end of -N- moiety, almost the same
level of affinity (pA2 = 7.18, pA2 = 7.27, pA2 = 7.13,
pA2 = 7.12, respectively). The histaminergic H1 antago-
nism of the aforementioned four products was established
on the isolated guinea pig ileum by conventional methods;
the pA2 values were compared with the potency of pyril-
amine. None of them shows any H1-antagonistic activity
(pA2 \ 4; for pyrilamine pA2 = 9.35).
autoreceptor regulating the synthesis and release of hista-
mine from histaminergic neurons (Arrang et al., 1985), as
well as a heteroreceptor regulating the release of acetyl-
choline (Clapham and Kilpatrick, 1992), noradrenaline
(Schlicker et al., 1989), serotonin (Schlicker et al., 1988),
and dopamine from non-histaminergic neurons (Schlicker
et al., 1994). Its involvement in different brain functions, like
learning process, tremor (Parkinson’s disease), and regula-
tion of food intake, has led to the H3 antagonists being pro-
posed for different therapeutic applications (Leurs et al.,
1998; Berlin et al., 2011), especially in the treatment of
Alzheimer’s disease (Witkin and Nelson, 2004), attention
deficit hyperactivity disorder (Glase et al., 2002), epilepsy
(Vohora et al., 2001), and obesity (Yoshimatsu et al., 1999).
So far, a variety of H3-receptor antagonists have been
synthesized and most of the early compounds were imid-
azole derivatives. Thioperamide (Arrang et al., 1987),
ciproxifan (Ligneau et al., 1998), and clobenpropit (Van
der Goot et al., 1992) (Chart 1), originally defined as
highly selective and potent antagonists at rat and guinea pig
H3 receptors, were later proved to have lower affinity for
the human H3 receptor (Ligneau et al., 2000; Lovenberg
et al., 2000; Stark et al., 2001; Wulff et al., 2002). Further
investigation revealed that these imidazole-containing
antagonists possessed a limited H3 selectivity/specificity
(Leurs et al., 1995; Liu et al., 2001). In most cases,
antagonists of histamine H3 receptor carrying an imidazole
ring have been proven to be undevelopable as therapeutic
agents for humans because of a number of liabilities,
including cytochrome P450 inhibition, low affinity for
human compared with rat H3 receptors, lack of selectivity,
or suboptimal brain penetration (Alves-Rodrigues et al.,
1996; Labella et al., 1992). For this reason, efforts have
been directed toward the discovery of H3 antagonists
without an imidazole moiety (Leurs et al., 2005). For a
Keywords Histamine H3-receptor ꢀ H3 antagonists ꢀ
1-Phenoxyalkyl-4-[(N,N-disubstitutedamino)alkyl]
piperazine derivatives
Introduction
It has been over 25 years since the pioneering study of Arrang
and co-workers, who demonstrated that histamine inhibited
its own release, from rat brain cortical slices via a novel
receptor that is pharmacologically distinct from both the H1
and H2 receptors (Arrang et al., 1983). It is now well rec-
ognized that this third histamine receptor, namely H3, is a
G-protein-coupled receptor that functions both as an
´
M. Staszewski ꢀ K. Walczynski (&)
Department of Synthesis and Technology of Drugs, Medical
´
University, Muszynskiego Street 1, 90-151 Lodz, Poland
e-mail: krzysztof.walczynski@umed.lodz.pl
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Chart 1 Representative histamine H3 receptor antagonists and the target molecules of this study
long time, attempts to replace the imidazole moiety with
other nitrogen-containing aromatic heterocycle resulted in
2-aminoethylbenzofurans (Cowart et al., 2005)—have been
characterized as potent and selective brain-penetrating H3
antagonists.
´
weak H3 antagonists (Kiec-Kononowicz et al., 1995;
´
Walczynski et al., 1999a).
Previously, our laboratory has described several non-
imidazole piperazine-based histamine H3 antagonists with
moderate-to-pronounced affinity for the receptor. These
antagonists consist of 1-(2-thiazolobenzo)-, 1-(2-thiazolo-
pyridine)-, and 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-pro-
pyl- piperazines (Walczynski et al., 1999a, b, 2005;
After the successful cloning of the human histamine H3
receptor in 1999 (Lovenberg et al., 1999), the interest in
non-imidazole H3 receptor antagonists as potential thera-
peutic agents has been reignited. In the recent studies, the
replacement of the imidazole ring of known H3 receptor
antagonists by alicyclic amines such as piperidine or
piperazine, resulted in the obtaining of promising candi-
dates such as UCL 2190 (Chart 1) (Ki = 4 nM) (Meier
et al., 2001), a potent non-imidazole analog of ciproxifan
(Chart 1). Several classes of novel potent and selective
non-imidazole histamine H3 receptor antagonists are rep-
resented, among others, by 1-[4-(phenoxymethyl)benzyl]
´
Frymarkiewicz and Walczynski, 2009). Together, they can
be generalized as consisting of piperazine ring flanked by
thiazolyl moieties and short alkyl chain. With the infor-
mation gained from these studies, we turned our attention
to the replacement of the thiazolyl components with a
range of 1–7-membered alkylamine chains and the short
alkyl residue with a range of 1–9-membered phenoxyalkyl
chains. Therefore, in the first step, to optimize the structure,
we prepared a series of 1-phenoxyalkyl-4-(amino)alkyl-
piperazines and functionally determined the H3 antagonist
activity in an in vitro test system using guinea pig jejunum
preparations. By elongating the alkyl chain between the
nitrogen at position 1 of piperazine and the phenoxy moiety
from 2 to 9 methylene groups, retaining the constant
`
piperidines (Miko et al., 2003, 2004), 4-(aminoalk-
oxy)benzylamines (Apodaca et al., 2003), and 1-arylox-
yalkyl-4-amidepiperazines e.g. A-3179020 (Chart 1)
(Zaragoza et al., 2005). They share common structural
features of the amine-alkoxy-phenyl pharmacophore. Very
recently, new classes of imidazole-free molecules—2-(4-
alkylpiperazin-1yl)quinolines (Zaragoza et al., 2005) and
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Scheme 1 Synthesis of
1-phenoxyalkyl-4-
(amino)propylpiperazines
7a–h and 1-phenoxyheptyl-
4-(amino)alkylpiperazines 9a–e
distance (3 methylene groups) between nitrogen at position
4 of the piperazine and the primary amine functionality, we
studied the influence of the chain length of the alkyl spacer
in the structure of 1-phenoxyalkyl-4-(amino)propylpipera-
zines (7a–h) (Scheme 1) on the H3 antagonistic activity. It
appeared that the most potent antagonist in this series was
1-phenoxyheptyl-4-(amino)propylpiperazine (7f). In the
next step, based on the obtained data, the alkyl chain
between the nitrogen at position 4 of piperazine and the
primary amine functionality was elongated from 2 to 7
methylene groups (7f and 9a–e) (Scheme 1), retaining the
phenoxyheptyl substituent at position 1 in the piperazine
ring. 1-Phenoxyheptyl-4-(amino)butylpiperazine (9b)
proved to be the most potent antagonist of this series, and
was chosen as the lead compound for further structural
modification. In the final step, the primary amino function
of 9b was disubstituted with several alkyl-, phenylalkyl-,
hetrocycle-, and corresponding amide moieties.
Results and discussion
In the presented series of 1-phenoxyalkyl-4-[(N,N-disubsti-
tutedamino)- alkyl]piperazine derivatives, all of them pos-
sess moderate H3-receptor antagonist potency (Table 3). In
the 1-(x-phenoxyalkyl)-4-(3-aminopropyl)piperazines ser-
ies (compounds 7a–h; Table 1), the highest activity is seen
for the compound 7f (pA2 = 7.04), in which the alkyl chain
length between the nitrogen at position 1 of piperazine and
the phenoxy moiety consists of seven methylene groups. In
the next series (compounds 9a–e; Table 2), where the alkyl
chain is elongated between the nitrogen at position 4 of
piperazine and the primary amine functionality, retaining the
phenoxyheptyl substituent at position 1 in the piperazine
ring, the highest activity is seen for the compound 9b
(pA2 = 7.18). A further increase in the alkyl chain length to
seven methylene groups results in a decrease of antagonist
activity reaching the minimum for compounds 9d and 9e
(pA2 = 6.67 and pA2 = 6.67, respectively).
In the present study, we report the synthesis and pre-
liminary pharmacological investigation (functionally in the
in vitro test system using guinea pig jejunum preparations) of
a new series of 1-phenoxyalkyl-4-[(N,N-disubstitutedami-
no)alkyl]-piperazines 1 (Chart 1) as histamine H3 receptor
antagonists.
Based on the obtained data, 1-phenoxyheptyl-4-(amino)
butylpiperazine (9b) (pA2 = 7.18) was chosen as the lead
compound for further structural modification.
Replacement of hydrogen by an alkyl substituent at the
end of N-methyl chain leads to the compounds 1a–1e
(Table 3), while replacement of hydrogen in the N-methyl
group by a second methyl group results in the analog 1a
(pA2 = 7.01) with a slightly lower activity compared with
In addition, selected compounds were tested for H1
antagonistic effects in vitro, following standard methods,
using the guinea pig ileum.
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Table 1 H3 Antagonist potencies of 1-phenoxyalkyl-4-(amino)pro-
pylpiperazines 7a–h at histamine H3 receptor
Table 3 H3 Antagonist potencies of 1-phenoxyheptyl-4-[(N,N-di-
substitutedamino)butyl]piperazines 1a–j at histamine H3 receptor
R1
N
N
NH2
N
O
N
3
3 HCl
m
R2
N
O
m HCl
7
7a-h
1a-j
Cpd.
m
pA2 (SEM)
N (caviae)
Cpd.
m
R1
R2
pA2 (SEM)
N
(caviae)
7a
7b
7c
7d
7e
7f
0
1
2
3
4
5
6
7
6.75 (0.14)
6.29 (0.17)
6.62 (0.12)
6.80 (0.04)
6.72 (0.17)
7.04 (0.12)
6.84 (0.08)
6.99 (0.08)
10 (3)
10 (3)
10 (3)
12 (4)
10 (3)
12 (4)
11 (4)
11 (4)
1a
1b
1c
1d
1e
1f
3
3
3
3
3
3
3
3
2
2
2
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
7.01 (0.07) 12 (4)
7.27 (0.13) 12 (4)
7.05 (0.07) 10 (3)
6.85 (0.09) 12 (4)
6.60 (0.07) 10 (3)
7.13 (0.15) 12 (4)
7.04 (0.10) 12 (4)
6.95 (0.06) 11 (4)
7.16 (0.03) 11 (4)
7.00 (0.20) 12 (4)
6.98 (0.07) 11 (4)
CH3CH2–
CH3(CH2)2–
CH3(CH2)3–
CH3(CH2)4–
C6H5CH2–
C6H5(CH2)3–
C6H5(CH2)5–
CH3CO–
7g
7h
1g
1h
1i
SEM standard error of the mean, N number of different animal
preparation, cavie number of animals
1j
CF3CO–
1k
C6H5CO–
Table 2 H3 Antagonist potencies of 1-phenoxyheptyl-4-(amino)al-
kylpiperazines 9a–e at histamine H3 receptor
1l
3
7.12 (0.12) 11 (4)
N
NH2
N
n
1m
3
7.03 (0.18) 10 (3)
N
O
N
O
5
Thioperamid (antagonist or inverse agonist) 8.66 (0.05) 12 (4)
3 HCl
9a-e
Replacement of the methylalkylamine or meth-
yphenylalkylamine substituents by the corresponding meth-
ylalkyl or methylphenyl amide group yields the analogs 1i
and 1k (pA2 = 7.16, pA2 = 6.98, respectively), which have a
somewhat lower activity than their alkyl or phenylalkyl
counterparts.
Cpd.
n
pA2 (SEM)
N (caviae)
9a
9b
9c
9d
9e
1
3
4
5
6
6.42 (0.18)
7.18 (0.08)
6.99 (0.07)
6.67 (0.08)
6.67 (0.06)
10 (3)
12 (4)
10 (3)
10 (3)
10 (3)
With the aim of decreasing the basicity of the N-methyl
group nitrogen, the acetyl substituent was replaced with
trifluoroacetyl to obtain the compound 1j (pA2 = 7.0) with
a slightly lower affinity compared to the 1i derivative.
Because of the lower affinity of 1j compared to 1i, we
may conclude that the decreasing basicity of this nitrogen
has effect on blocking histamine H3 receptors.
SEM standard error of the mean, N number of different animal
preparation, cavie number of animals
the unsubstituted derivative 9b (pA2 = 7.18). A further
increase in the alkyl chain length to two methylene groups
results in an increase of potency for the compound 1b
(pA2 = 7.27), reaching a maximum for this series. Elon-
gation of the alkyl chain to five methylene groups results in
a decrease of potency for the compound 1e (pA2 = 6.60).
Replacement of hydrogen by a phenylalkyl group at the
end of N-methyl group leads to the compounds 1f–1h
(pA2 = 7.13, pA2 = 7.04, and pA2 = 6.95, respectively)
with 1f being slightly more potent.
In addition, besides the derivatives carrying the
N-methyl-, N-alkyl-, N-phenylalkyl-, and N-amide moie-
ties, two compounds containing an N-heterocycle sub-
stituent (1l and 1m) have been synthesized. A slightly
higher affinity was exhibited by 1l (pA2 = 7.12), compared
to its morpholino analog 1m (pA2 = 7.03).
To sum up, no definite structure–activity relationships
can be drawn from the present series as an influence of the
type of substituent at the end of -N-group, because there is
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no significant difference in H3 -receptor affinity among the
primary amine derivative 9b (Table 2) and the tertiary
amine series 1a–m (Table 3).
acetonitrile, followed by purification with column
chromatography.
1-Phenoxyheptyl-4-(N-methylamino)butylpiperazine N-amides
(1j, k) were obtained by standard methods. The compound
11 was acetylated with trifluoracetic anhydride and benzoyl
chloride in dichloromethane, respectively. 1-(7-Phenoxy-
heptyl)-4-[4-(piperidn-1-yl)butyl]piperazine 1l and 1-(7-
phenoxy-heptyl)-4-[4-(morpholin-4-yl)butyl]piperazine 1m
(Scheme 3) were synthesized from 14a and 14b, respec-
tively, by a three step reaction including acetylation with
succinic anhydride 13, yielding 15a and 15b, followed by
their acetylation with 1-(x-phenoxyheptyl)piperazine (5f) in
the presence of N,N-dicyclohexylo-carbodiimide (DCC) to
obtain 16a and 16b, and finally reduction with LiAlH4 in
dry diethyl ether, leading to the formation of 1l and 1m,
respectively.
Histaminergic H1 antagonism of the selected com-
pounds 9b, 1b, 1f, and 1l was established on the isolated
guinea pig ileum by conventional methods; the pA2 values
were compared with the potency of pyrilamine. None of
the examined compounds exhibited any H1-antagonistic
activity (pA2 \ 4; for pyrilamine pA2 = 9.50).
Experimental
Chemistry
The general synthetic procedures used in this study are
illustrated in Schemes 1, 2, and 3.
FAM was obtained according to Van Es and Stevens
(1965) by the treatment of acetic anhydride with formic acid.
5-Phenylpentyl bromide was synthesized according to Col-
lins and Davis (1961). 5-Phenoxypentyl-, 6-phenoxyhexyl-,
7-phenoxyheptyl-, 8-phenoxyoctyl-, and 9-phenoxynonyl
bromides were obtained by the reaction of the appropriate
dibromoalkane with sodium phenoxide in anhydrous ethanol
1-(2-phenoxyethyl)piperazine which was obtained accord-
1-Phenoxyalkyl-4-(amino)propylpiperazines (7a–h) and
1-phenoxyheptyl- 4-(amino)alkylpiperazines (7f and 9a–e)
(Scheme 1) were synthesized by standard methods. The
compounds 5a–h were N-alkylated with acrylonitrile in
methanol. The product 5f was N-alkylated with the corre-
sponding primary x-bromoalkanenitriles in acetonitrile, and
the obtained nitriles 6a–h and 8a–e were reduced with
LiAlH4 in dry diethyl ether.
´
´
ing to Tkaczynski (Tkaczynski, 1966), and 1-(3-phenoxy-
propyl)piperazine was synthesized using the method of
Capuano et al. (2008), by the reaction of the appropriate
x-phenoxyalkyl bromide with piperazine. 1,5-Dibromobu-
tane, 1,6-dibromohexane, 1,7-dibromoheptane, 1,8-dibro-
mooctane, 1,9-dibromononane, 2-phenoxyethyl bromide,
3-phenoxypropyl bromide, 4-phenoxybutyl bromide, piper-
azine, acrylonitrile, bromoacetonitrile, 3-bromopropioni-
trile, 4-bromobutyronitrile, 5-bromovaleronitrile, 6-bromo-
hexanenitrile, 7-bromoheptanenitrile, acetic anhydride,
propionic anhydride, butyric anhydride, valeric anhydride,
phenylmethyl bromide, 1-bromo-3-phenylpropan, 5-phe-
nyl-1-pentanol, trifluoroacetic anhydride, benzoyl chloride,
succinic anhydride, piperidine, and morpholine, were all
purchased from commercial sources.
The 1-phenoxyalkylpiperazines 5a–h were synthesized
from piperazine (4) by alkylation with the corresponding
primary x-phenoxyalkyl bromides 3d–h in methanol fol-
lowed by purification with column chromatography. The
x-phenoxyalkyl bromides 3d–h were obtained from
sodium phenoxide (2) by alkylation with the appropriate
dibromoalkane in ethanol. 2-Phenoxyetyl-, 3-phenoxypro-
pyl-, and 4-phenoxybutyl-bromides 3a–c were all pur-
chased from commercial sources.
1-Phenoxyheptyl-4-(N-methylamino)butylpiperazine
(11) (Scheme 2) was synthesized from compound 9b by a
two step reaction (Scheme 2) including formylation with
formic acid–acetic anhydride (FAM) (Van Es and Stevens,
1965) to yield 10 and finally reduction with LiAlH4 in dry
diethyl ether to obtain 11. 1-Phenoxyheptyl-4-(N-methyl-
N-alkylamino)butylpiperazines 1b–e were prepared from
11 which was in the first step, acetylated with an appro-
priate acid anhydride. The obtained amides 1i and
12b–d were subsequently reduced with LiAlH4 in dry
diethyl ether.
Pharmacology
All the obtained final compounds were tested for H3
antagonistic effects in vitro, following standard methods,
using the electrically contracted guinea pig jejunum
(Vollinga et al., 1992). The potency is expressed by its pA2
value and calculated according to Arunlakshana and Schild
(1959) regression analysis, where at least three concen-
trations were used.
1-Phenoxyheptyl-4-(N,N-dimethylamino)butylpiper-
azine (1a) (Scheme 2) was synthesized by the reaction of
1-phenoxyheptyl-4-(N-methylamino)butylpiperazine (11)
with formaldehyde in formic acid. 1-Phenoxyheptyl-4-(N-
methyl-N-phenylalkylamino)butylpiperazines 1f–h were
obtained from 1-phenoxyheptyl-4-(N-methylamino)butyl-
piperazine (11) by alkylation with the corresponding pri-
mary phenylalkyl halides in the presence of K2CO3 in
Selected compounds were tested for H1 antagonistic
effects in vitro, following standard methods, using the
guinea pig ileum (Arunlakshana and Schild, 1959).
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Med Chem Res (2013) 22:1287–1304
Scheme 2 Synthesis of 1-phenoxyalkyl-4-[(N,N-disubstitutedamino)butyl]piperazine derivatives 1a–k
Experimental protocols
expressed in ppm downfield from internal TMS as a ref-
1
erence. H NMR data are reported in the following order:
General methods
multiplicity (br-broad, s singlet, d doublet, t triplet, m
multiplet, and dt double triplet; * exchangeable by D2O),
number of protons, and approximate coupling constant in
Hz. Elemental analysis (C, H, and N) for all compounds
were performed on Perkin Elmer Series II CHNS/O Ana-
lyzer 2400 and are within 0.4 % of the theoretical values.
All melting points (mp) were taken in open capillaries in an
electrothermal apparatus and are uncorrected. For all
1
compounds, H NMR spectra were recorded on a Varian
Mercury VX 300 MHz spectrometer. Chemical shifts are
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Med Chem Res (2013) 22:1287–1304
1293
Scheme 3 Synthesis of 1-(7-phenoxyheptyl)-4-[4-(piperidn-1-yl)butyl]piperazine 1l and 1-(7-phenoxyheptyl)-4-[4-(morpholin-4-yl)butyl]piper-
azine 1m
TLC was performed on silica gel 60 F254 plates (Merck).
Flash column chromatography was carried out using silica
gel 30–60 mm (J. T. Baker B. V.), employing the same
eluent as indicated by TLC. In each case, the final product
was treated with methanolic HCl and its hydrochloride acid
salt was recrystallized from ethanol.
6.95–6.86 (m, 3Harom); 3.98–3.94 (t, 2H, O–CH2;
J = 6.35 Hz); 3.44–3.39 (t, 2H, Br–CH2; J = 6.74 Hz);
1.94–1.71 (m, 4H, CH2–CH2–CH2); 1.61–1.40 (m, 4H,
CH2–CH2–CH2); TLC (hexane–dichloromethane 17:3)
Rf = 0.42.
3f. C13H19BrO (M = 271.19); yield 52.0 % [b.p.
1
154–157 °C/3 mmHg (Littmann and Marvel, 1930)]; H
Chemistry
NMR (d in ppm; CDCl3): 7.30–7.24 (m, 2Harom);
6.95–6.86 (m, 3Harom); 3.97–3.93 (t, 2H, O–CH2;
J = 6.45 Hz); 3.43–3.37 (t, 2H, Br–CH2; J = 6.74 Hz);
1.92–1.69 (m, 4H, CH2–CH2–CH2); 1.53–1.37 (m, 6H,
CH2–CH2–CH2); TLC (hexane–dichloromethane 17:3)
Rf = 0.4.
General method for the preparation of x-phenoxyalkyl
bromides 3d–h
To a solution of the appropriate dibromoalkane (0.05 mol)
in 100.0 mL of anhydrous ethanol, sodium phenoxide (2)
(0.05 mol) in 50.0 mL of anhydrous ethanol was added
dropwise at 65 °C. The mixture was stirred at 80 °C for
48 h. Then, organic solvent was evaporated, and residue
was dissolved in water (50.0 mL), alkalized with 10 %
aqueous NaOH (5.0 mL), and extracted with diethyl ether
(3 9 50.0 mL). The organic extracts were washed with
water (3 9 25.0 mL), dried (Na2SO4), filtered, and evap-
orated to give the respective products (3d–h) as a sticky
oil. In each case, the crude product was purified by column
chromatography.
3g. C14H21BrO (M = 285.23); yield 39.0 % [b.p.
178 °C/5 mmHg (Lehman et al., 1933)];1H NMR (d in
ppm; CDCl3): 7.31–7.24 (m, 2Harom); 6.95–6.86 (m,
3Harom); 3.97–3.92 (t, 2H, O–CH2; J = 6.55 Hz);
3.43–3.38 (t, 2H, Br–CH2; J = 6.84 Hz); 1.90–1.73 (m,
4H, CH2–CH2–CH2); 1.49–1.34 (m, 8H, CH2–CH2–CH2);
TLC (hexane–dichloromethane 17:3) Rf = 0.44.
3h. C15H23BrO (M = 299.25); yield 50.0 % [b.p.
141–143 °C/3 mmHg (Lehman et al., 1933), 1H NMR (d in
ppm; CDCl3): 7.30–7.24 (m, 2Harom); 6.95–6.87 (m,
3Harom); 3.97–3.92 (t, 2H, O–CH2; J = 6.55 Hz);
3.42–3.38 (t, 2H, Br–CH2; J = 6.84 Hz); 1.89–1.73 (m,
4H, CH2–CH2–CH2); 1.47–1.32 (m, 10H, CH2–CH2–CH2);
TLC (hexane) Rf = 0.22.
3d. C11H15BrO (M = 243.14); yield 47.6 % [b.p.
1
154–155 °C/5 mmHg (Littmann and Marvel, 1930)], H
NMR (d in ppm; CDCl3): 7.32–7.26 (m, 2Harom);
6.97–6.88 (m, 3Harom); 4.02–3.96 (t, 2H, O–CH2;
J = 6.35 Hz); 3.47–3.43 (t, 2H, Br–CH2; J = 6.74 Hz);
2.02–1.78 (m, 4H, CH2–CH2–CH2); 1.78–1.58 (m, 2H,
CH2–CH2–CH2); TLC (hexane–dichloromethane 8:2)
Rf=0.62.
General method for the preparation of 1-(x-
phenoxyalkyl)piperazines 5a–h
To a solution of piperazine (4) (0.25 mol) in 150.0 mL of
methanol was added the corresponding x-phenoxyalkyl
bromide (3a–h) (0.05 mol). The mixture was stirred at
70 °C for 20 h. Then, organic solvent was evaporated, and
3e. C12H17BrO (M = 257.16); yield 35.5 % [b.p.
1
155–156 °C/3 mmHg (Littmann and Marvel, 1930)]; H
NMR (d in ppm; CDCl3): 7.31–7.24 (m, 2Harom);
123

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Med Chem Res (2013) 22:1287–1304
residue was dissolved in water (50.0 mL), alkalized with
10 % aqueous NaOH (5.0 mL), and extracted with diethyl
ether (3 9 50.0 mL). The organic extracts were washed
with water (3 9 25.0 mL), dried (Na2SO4), filtered, and
evaporated to give the respective products (5a–h) as a
sticky oil or light yellow solid. In each case, the crude
product was purified by column chromatography.
(dichloromethane–methanol–concentrated
hydroxide 189:10:1) Rf = 0.23.
5g. C18H30N2O; (M = 290.45); yield 69.6 %; mp =
ammonium
1
40.2–41.5 °C; H NMR (d in ppm; CDCl3): 7.30–7.23 (m,
2Harom); 6.95–6.86 (m, 3Harom); 3.96–3.92 (t, 2H, O–CH2;
J = 6.55 Hz); 2.92–2.89 (m, 4Hpip); 2.42–2.28 (m, 7H:
4Hpip, N–CH2; *, NH); 1.82–1.72 (m, 2H, CH2–CH2–CH2);
1.54–1.22 (m, 10H, CH2–CH2–CH2); TLC (dichlorometh-
ane–methanol–concentrated ammonium hydroxide 189:
10:1) Rf = 0.2.
5a. C12H18N2O; (M = 206.28); yield 73.4 %; sticky oil;
1
´
[b.p. 175–190 °C/20 mmHg (Tkaczynski, 1966)]; H NMR
(d in ppm; CDCl3): 7.31–7.24 (m, 2Harom); 6.97–6.88 (m,
3Harom); 4.12–4.08 (t, 2H, O–CH2; J = 5.83 Hz); 2.93–2.89
(m, 4Hpip); 2.81–2.77 (t, 2H, N–CH2; J = 5.83 Hz);
2.57–2.55 (br, 4Hpip); 2.09 (s*, 1H, NH); TLC (dichloro-
methane–methanol–concentrated ammonium hydroxide
189:10:1) Rf = 0.25.
5h. C19H32N2O; (M = 304.47); yield 74.6 %; mp =
1
59.8–61.8 °C; H NMR (d in ppm; CDCl3): 7.31–7.24 (m,
2Harom); 6.95–6.87 (m, 3Harom); 3.97–3.92 (t, 2H, O–CH2;
J = 6.55 Hz); 2.93–2.89 (m, 4Hpip); 2.42–2.28 (m, 6H:
4Hpip, N–CH2); 2.02 (s, *, 1H, NH); 1.82–1.73 (m, 2H,
CH2–CH2–CH2); 1.54–1.31 (m, 12H, CH2–CH2–CH2);
TLC (dichloromethane–methanol–concentrated ammonium
hydroxide 139:10:1) Rf = 0.37.
5b. C13H20N2O; (M = 220.31); yield 48.5 %; mp =
50.5–52 °C; [b.p. 225 °C/2.5 mmHg (Capuano et al.,
2008)]; 1H NMR (d in ppm; CDCl3): 7.31–7.24 (m,
2Harom); 6.96–6.87 (m, 3Harom); 4.03–3.97 (t, 2H, O–CH2;
J = 6.35 Hz); 2.92–2.89 (m, 4Hpip); 2.53–2.40 (m, 6H,
N–CH2; 4Hpip); 2.28 (s, *, 1H, NH); 2.02–1.92 (m, 2H,
CH2–CH2–CH2); TLC (dichloromethane–methanol–con-
centrated ammonium hydroxide 189:10:1) Rf = 0.19.
5c. C14H22N2O; (M = 234.34); yield 78.4 %;
mp = 46.4–47.8 °C; 1H NMR (d in ppm; CDCl3):
7.29–7.24 (m, 2Harom); 6.95–6.86 (m, 3Harom); 3.99–3.94
(t, 2H, O–CH2; J = 6.35 Hz); 2.91–2.87 (m, 4Hpip);
2.42–2.35 (m, 6H: 4Hpip, N–CH2,); 1.80-1.69 (m, 5H,
CH2–CH2–CH2–CH2, *, NH); TLC (dichloromethane–
methanol–concentrated ammonium hydroxide 189:10:1)
Rf = 0.29.
General method for the preparation of 1-(x-phenoxyalkyl)-
4-(3-nitrilopropyl)piperazines 6a–h
To a solution of acrylonitrile (0.011 mol) in 50 mL of
methanol was added the corresponding 1-(x-pheno-
xyalkyl)piperazine (5a–h) (0.01 mol). The mixture was
stirred at room temperature for 24 h. Then, organic solvent
was evaporated, to give the respective product (6a–h) as a
sticky oil or colorless solid. In each case, the crude product
was purified by column chromatography.
6a. C15H21N3O (M = 259.36); yield 82.7 %; sticky oil;
1H NMR (d in ppm; CDCl3); 7.31–7.24 (m, 2Harom);
6.97–6.87 (m, 3Harom); 4.12–4.08 (t, 2H, O–CH2; J =
5.75 Hz); 2.84–2.80 (t, 2H, N–CH2–CH2–O; J = 5.75 Hz);
5d. C15H24N2O; (M = 248.37); yield 87.0 %;
mp = 58.0–59.9 °C; 1H NMR (d in ppm; CDCl3):
7.31–7.24 (m, 2Harom); 6.96–6.86 (m, 3Harom); 3.98–3.94
(t, 2H, O–CH2; J = 6.55 Hz); 2.92–2.85 (m, 4Hpip);
2.42–2.29 (m, 6H, N–CH2; 4Hpip); 1.85–1.78 (m, 3H, CH2–
CH2–CH2; *, NH); 1.62–1.42 (m, 4H, CH2–CH2–CH2);
TLC (dichloromethane–methanol–concentrated ammo-
nium hydroxide: 89:10:1) Rf = 0.41.
2.72–2.47 (m, 12H: 8Hpip
, N–CH2–CH2–CN). TLC
(dichloromethane–methanol 49:1) Rf = 0.24.
6b. C16H23N3O (M = 273.38); yield 96.6 %; mp =
1
47.2–49.2 °C; H NMR (d in ppm; CDCl3): 7.31–7.24 (m,
2Harom); 6.96–6.87 (m, 3Harom); 4.03–3.98 (t, 2H, O–CH2;
J = 6.35 Hz); 2.73–2.48 [m, 14H: 8Hpip, N–CH2–CH2–
CN, N–CH2–(CH2)2–O]; 2.01–1.92 (m, 2H, CH2–CH2–
CH2); TLC (dichloromethane–methanol 49:1) Rf = 0.21.
6c. C17H25N3O (M = 287.41); yield 95.1 %; mp =
5e. C16H26N2O; (M = 262.4); yield 75.0 %; mp =
1
49.6–50.6 °C; H NMR (d in ppm; CDCl3);): 7.29–7.24
(m, 2Harom); 6.95–6.87 (m, 3Harom); 3.97–3.93 (t, 2H, O–
CH2; J = 6.45 Hz); 2.98–2.93 (m, 5H;*,NH; 4Hpip);
2.48–2.32 (m, 6H: 4Hpip, N–CH2); 1.83–1.74 (m, 2H, CH2–
CH2–CH2);1.55–1.33 (m, 6H, CH2–CH2–CH2); TLC
(dichloromethane–methanol–concentrated ammonium hydrox-
ide 139:10:1) Rf = 0.16.
1
55–56.6 °C; H NMR (d in ppm; CDCl3): 7.31–7.24 (m,
2Harom); 6.96–6.86 (m, 3Harom); 4.00–3.96 (t, 2H, O–CH2;
J = 6,15 Hz); 2.73–2.68 [t, 2H, O–(CH2)3–CH2–N;
J = 6.94 Hz] 2.66–2.42 (m, 12H: 8Hpip, N–CH2–CH2–
CN); 1.83–1.67 (m, 4H, O–CH2–CH2–CH2–CH2–N); TLC
5f. C17H28N2O; (M = 276.42); yield 76.0 %; mp =
1
(dichloromethane–methanol–concentrated
ammonium
49.8–51.2 °C; H NMR (d in ppm; CDCl3): 7.31–7.24 (m,
hydroxide 189:10:1) Rf = 0.72.
6d. C18H27N3O (M = 301.43); yield 84.5 %; mp =
2Harom); 6.95–6.87 (m, 3Harom); 3.97–3.92 (t, 2H, O–CH2;
J = 6.45 Hz); 2.92–2.89 (m, 4Hpip); 2.42–2.28 (m, 6H:
4Hpip, N–CH2); 1.94 (s, *, 1H, NH); 1.82–1.73 (m, 2H,
CH2–CH2–CH2); 1.55–1.32 (m, 8H, CH2–CH2–CH2); TLC
1
53.5–54.2 °C; H NMR (d in ppm; CDCl3): 7.31–7.24 (m,
2Harom); 6.95–6.86 (m, 3Harom); 3.97–3.93 (t, 2H, O–CH2;
J = 6.45 Hz); 2.72–2.68 [t, 2H, O–(CH2)4–CH2–N;
123

Med Chem Res (2013) 22:1287–1304
1295
J = 6.94 Hz]; 2.53–2.34 (m, 12H: 8Hpip, N–CH2–CH2–
CN); 1.85–1.76 (m, 2H, CH2–CH2–CH2); 1.62–1.43 (m,
4H, CH2–CH2–CH2); TLC (dichloromethane–methanol
49:1) Rf = 0.24.
7a. C15H25N3O (M = 263.39); yield 87.0 %;1H NMR
(d in ppm, CDCl3): 7.31–7.25 (m, 2Harom); 6.97–6.89 (m,
3Harom); 4.13–4.08 (t, 2H, O–CH2; J = 5.85 Hz); 2.84–
2.80 (t, 2H, O–CH2–CH2–N; J = 5.95 Hz); 2.76–2.38 (m,
12H, 8Hpip, N–CH2–CH2–CH2–NH2;); 1.68–1.62 (m, 4H,
CH2–CH2–CH2, *, NH2); Rf = 0.40.
6e. C19H29N3O (M = 315.46); yield 74.5 %; mp =
1
37.8–38.8 °C; H NMR (d in ppm; CDCl3): 7.31–7.24 (m,
2Harom); 6.96–6.87 (m, 3Harom); 3.77–3.93 (t, 2H, O–CH2;
J = 6.45 Hz); 2.73–2.39 [m, 14H: 8Hpip, O–(CH2)5–CH2–
N, N–CH2–CH2–CN]; 1.83–1.74 (m, 2H, CH2–CH2–CH2);
1.62–1.32 (m, 6H, CH2–CH2–CH2); TLC (dichlorometh-
ane–methanol 49:1) Rf = 0.16.
Elemental analysis for three hydrochloride salt
C15H25N3O 3HCl (M = 372.77); mptrihydrochloric acid salt
235.0–236.8 °C.
=
C
H
N
6f. C20H31N3O (M = 329.49); yield 95.0 %; mp =
1
42.8–44.0 °C; H NMR (d in ppm; CDCl3): 7.31–7.25 (m,
Calculated
Found
48.32
48.11
7.57
7.88
11.27
11.12
2Harom); 6.96–6.88 (m, 3Harom); 3.97–3.93 (t, 2H, O–CH2;
J = 6.45 Hz); 2.72–2.32 [m, 14H: 8Hpip, O–(CH2)6–CH2–
N, N–CH2–CH2–CN]; 1.83–1.75 (m, 2H, CH2–CH2–CH2);
1.49–1.34 (m, 8H, CH2–CH2–CH2); TLC (dichlorometh-
ane–methanol 49:1) Rf = 0.18.
7b. C16H27N3O (M = 277.41); yield 98.6 %;.1H NMR
(d in ppm, CDCl3): 7.29–7.24 (m, 2Harom); 6.95–6.88 (m,
3Harom); 4.03–3.99 (t, 2H, O–CH2; J = 6.35 Hz);
2.79–2.38 (m, 14H, 8Hpip, O–CH2–CH2–N, N–CH2–CH2–
CH2–NH2); 2.02–1.93 (m, 2H, CH2–CH2–CH2); 1.69–1.59
(m, 2H, CH2–CH2–CH2); 1.11 (br*, 2H, NH2); Rf = 0.46.
Elemental analysis for three hydrochloride salt
6g. C21H33N3O (M = 343.51); yield 89.2 %; mp =
1
40.2–41.7 °C; H NMR (d in ppm; CDCl3): 7.31–7.24 (m,
2Harom); 6.95–6.86 (m, 3Harom); 3.97–3.92 (t, 2H, O–CH2;
J = 6.55 Hz); 2.72–2.32 [m, 14H: 8Hpip, O–(CH2)7–CH2–
N, N–CH2–CH2–CN]; 1.82–1.72 (m, 2H, CH2–CH2–CH2);
1.47–1.24 (m, 10H, CH2–CH2–CH2); TLC (dichlorometh-
ane–methanol 49:1) Rf = 0.16.
C16H27N3O 3HCl (M = 386.80); mptrihydrochloric acid salt
229.7–230.7 °C.
=
6h. C22H35N3O (M = 357.55); yield 94.2 %; mp =
1
C
H
N
55.3–56.9 °C; H NMR (d in ppm; CDCl3): 7.31–7.24 (m,
2Harom); 6.95–6.87 (m, 3Harom); 3.97–3.92 (t, 2H, O–CH2;
J = 6.55 Hz); 2.73–2.32 [m, 14H: 8Hpip, O–(CH2)8–CH2–
N, N–CH2–CH2–CN]; 1.82–1.73 (m, 2H, CH2–CH2–CH2);
1.47–1.25 (m, 12H, CH2–CH2–CH2) TLC (dichlorometh-
ane–methanol 49:1) Rf = 0.23.
Calculated
Found
49.68
49.49
7.82
7.95
10.86
11.02
7c. C17H29N3O (M = 291.44); yield 92.0 %;.1H NMR
(d in ppm; CDCl3): 7.30–7.23 (m, 2Harom); 6.95–6.86 (m,
3Harom); 4.00–3.95 (t, 2H, O–CH2; J = 6.25 Hz); 2.76–
2.72 [t, 2H, O–(CH–2)3–CH2–N; J = 6.74 Hz]; 2.48–2.37
(m, 12H: 8Hpip, N–CH2–CH2–CH2–NH2); 1.85–1.61 (m,
6H, –CH2–CH2–CH2–); 1.32–1,23 (br, *, 2H, CH2–NH2).;
Rf = 0.39.
General method for the preparation of 1-(x-phenoxyalkyl)-
4-(3-aminopropyl)piperazines 7a–h
To a solution of the corresponding 1-(x-phenoxyalkyl)-4-
(3-nitrilopropyl)piperazine (6a–h) (0.01 mol) in 50 mL of
anhydrous diethyl ether was added LiAlH4 (0.04 mol). The
mixture was stirred at room temperature for 2.5 h, and
quenched by dropwise addition of water (0.5 mL), 10 %
aqueous NaOH solution (0.5 mL), and water (0.5 mL). The
suspension was stirred for 30 min, and filtered. The filter
cake was washed with ether (2 9 50 mL). The combined
organic extracts were washed with water (3 9 50 mL),
dried (Na2SO4), and filtered. The solvent was evaporated
and all the title products were obtained as sticky oils. In
each case, the mixture of dichloromethane–methanol–
concentrated ammonium hydroxide 49:10:1 was used as
eluent.
7c. Elemental analysis for three hydrochloride salt
C17H29N3O 3HCl (M = 400.82); mptrihydrochloric acid salt
230.5–232.0 °C.
=
C
H
N
Calculated
Found
50.94
50.87
8.05
8.30
10.48
10.48
7d. C18H31N3O (M = 305.47); yield 76.5 %;.1H NMR
(d in ppm; CDCl3): 7.30–7.24 (m, 2Harom); 6.95–6.86 (m,
3Harom); 3.97–3.93 (t, 2H, O–CH2; J = 6.45 Hz); 2.76–
2.72 [t, 2H, O–(CH2)4–CH2–N; J = 6.74 Hz]; 2.48–2.28
(m, 12H: 8Hpip, N–CH2–CH2–CH2–NH2); 1.85–1.76 (m,
2H, CH2–CH2–CH2); 1.68–1.42 (m, 8H, CH2–CH2–CH2; *,
NH2); Rf = 0.46.
The free base was treated with methanolic HCl and the
obtained hydrochloride was precipitated. The solid was
recrystallized once from dry ethanol.
123

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Med Chem Res (2013) 22:1287–1304
Elemental analysis for three hydrochloride salt
C
H
N
C18H31N3O 3HCl (M = 414.85); mptrihydrochloric acid salt
232.7–234.0 °C.
=
Calculated
Found
55.20
55.33
8.82
9.07
9.20
8.90
C
H
N
7h. C22H39N3O (M = 361.58); yield 67.0 %;.1H NMR
(d in ppm; CDCl3): 7.31–7.24 (m, 2Harom); 6.96–6.87 (m,
3Harom); 3.97–3.93 (t, 2H, O–CH2; J = 6.64 Hz); 2.77–
2.73 [t, 2H, O–(CH2)8–CH2–N; J = 6.74 Hz]; 2.48–2.29
(m, 12H: 8Hpip, N–CH2–CH2–CH2–NH2); 1.83–1.73 (m,
2H, CH2–CH2–CH2); 1.69–1.60 (m, 2H, CH2–CH2–CH2);
1.50–1.22 (m, 14H, CH2–CH2–CH2; *, NH2); Rf = 0.46.
Elemental analysis for tree hydrochloride salt C22H39
N3O 3HCl (M = 470.96); mptrihydrochloric acid salt = 239.6–
241.6 °C with decomposition.
Calculated
Found
52.11
51.92
8.26
8.55
10.13
10.24
7e. C19H33N3O (M = 319.49); yield 52.2 %;.1H NMR
(d in ppm; CDCl3): 7.31–7.24 (m, 2Harom); 6.95–6.86 (m,
3Harom); 3.97–3.92 (t, 2H, O–CH2; J = 6.45 Hz); 2.76–
2.72 [t, 2H, O–(CH2)5–CH2–N; J = 6.84 Hz]; 2.48–2.28
(m, 12H: 8Hpip, N–CH2–CH2–CH2–NH2); 1.83–1.74 (m,
2H, CH2–CH2–CH2); 1.68–1.33 (m, 10H, CH2–CH2–CH2;
*, NH2); Rf = 0.43.
Elemental analysis for three hydrochloride salt
C
H
N
C19H33N3O 3HCl (M = 428.88); mptrihydrochloric acid salt
233.0–235.0 °C.
=
Calculated
Found
56.11
56.27
8.99
9.31
8.92
8.65
C
H
N
Calculated
Found
53.21
53.27
8.46
8.32
9.80
9.82
General method for the preparation of 1-(7-
phenoxyheptyl)-4-(x-nitriloalkyl)piperazines 8a–e
7f. C20H35N3O (M = 333.52); yield 77.9 %;.1H NMR
(d in ppm; CDCl3): 7.30–7.24 (m, 2Harom); 6.95–6.87 (m,
3Harom); 3.96–3.92 (t, 2H, O–CH2; J = 6.55 Hz); 2.76–
2.72 [t, 2H, O–(CH2)6–CH2–N; J = 6.84 Hz]; 2.48–2.28
(m, 12H: 8Hpip, N–CH2–CH2–CH2–NH2); 1.82–1.73 (m,
2H, CH2–CH2–CH2); 1.68–1.32 (m, 12H, CH2–CH2–CH2;
*, NH2); Rf = 0.43.
To a suspension of the respective 1-(7-phenoxyhep-
tyl)piperazine (5f) (0.003 mol) and potassium carbonate
(0.012 mol) in 50 mL of acetonitrile was added the cor-
responding x-bromoalkylnitrile. The suspension was stir-
red for 24 h at room temperature, and filtered. The solvent
was evaporated to give the respective crude product
(8a–e) as a sticky oil or colorless solid which was purified
by column chromatography.
Elemental analysis for three hydrochloride salt
C20H35N3O 3HCl (M = 442.90); mptrihydrochloric acid salt
236.0–237.7 °C.
=
8a. C19H29N3O (M = 315.46); yield: 78.9 %; mp =
1
54.5–55.5 °C; H NMR (d in ppm; CDCl3): 7.31–7.26 (m,
2Harom); 6.96–6.88 (m, 3Harom); 3.98–3.94 (t, 2H, O–CH2;
J = 6.55 Hz); 3.51 (s, 2H, N–CH2–CN) 2.66–2.32 [m,
10H: 8Hpip, N–CH2–(CH2)6O]; 1.81–1.74 (m, 2H, CH2–
CH2–CH2); 1.60–1.35 (m, 8H, CH2–CH2–CH2); TLC
(dichloromethane–methanol 49:1) Rf = 0.38.
C
H
N
Calculate
Found
54.24
54.35
8.65
8.89
9.49
9.54
8b. C21H33N3O (M = 343.51); yield: 93.8 %; sticky oil;
1H NMR (d in ppm; CDCl3): 7.31–7.24 (m, 2Harom);
6.95–6.87 (m, 3Harom); 3.96–3.92 (t, 2H, O–CH2; J =
6.55 Hz); 2.61–2.29 [m, 14H: 8Hpip, N–CH2–CH2–CH2–
CN, N–CH2–(CH2)6O]; 1.86–1.73 (m, 4H, CH2–CH2–
CH2); 1.55–1.25 (m, 8H, CH2–CH2–CH2); TLC (dichlo-
romethane–methanol 49:1) Rf = 0.18.
7g. C21H37N3O (M = 347.54); yield 76.8 %;.1H NMR
(d in ppm; CDCl3): 7.31–7.24 (m, 2Harom); 6.95–6.87 (m,
3Harom); 3.96–3.92 (t, 2H, O–CH2; J = 6.55 Hz); 2.77–
2.72 [t, 2H, O–(CH2)7–CH2–N; J = 6.84 Hz]; 2.48–2.29
(m, 12H: 8Hpip, N–CH2–CH2–CH2–NH2); 1.82–1.72 (m,
2H, CH2–CH2–CH2); 1.69–1.53 (m, 4H, CH2–CH2–CH2;
*, NH2); 1.47–1.26 (m, 10H, CH2–CH2–CH2); Rf = 0.43.
Elemental analysis for three hydrochloride salt
8c. C22H35N3O (M = 357.58); yield: 44.4 %; sticky oil;
1H NMR (d in ppm; CDCl3): 7.31–7.25 (m, 2Harom);
6.95–6.87 (m, 3Harom); 3.97–3.93 (t, 2H, O–CH2;
J = 6.45 Hz); 2.69–2.37 [m, 14H: 8Hpip, N–CH2–(CH2)2–
C21H37N3O 3HCl (M = 456.93); mptrihydrochloric acid salt
236.6–238.5 °C with decomposition.
=
123

Med Chem Res (2013) 22:1287–1304
1297
CH2–CN, N–CH2–(CH2)6O]; 1.82–1.65 (m, 8H, CH2–
CH2–CH2); 1.48–1.35 (m, 6H, CH2–CH2–CH2); TLC
(dichloromethane–methanol 47:3) Rf = 0.71.
9b. C21H37N3O (M = 347.48); yield 92.6 %; mp =
1
47.7–49.2 °C; H NMR (d in ppm; CDCl3): 7.31–7.25 (m,
2Harom); 6.93–6.88 (m, 3Harom); 3.97–3.93 (t, 2H, O–CH2;
J = 6.55 Hz); 2.74–2.31 (m, 14H: 8Hpip, N–CH2–);
1.62–1.48 (m, 16H, CH2–CH2–CH2; *, NH2); TLC Rf =
0.48.
8d. C23H37N3O (M = 371.57); yield: 95.0 %; mp =
1
52.5–54.5 °C; H NMR (d in ppm; CDCl3): 7.31–7.24 (m,
2Harom); 6.95–6.86 (m, 3Harom); 3.97–3.92 (t, 2H, O–CH2;
J = 6.45 Hz); 2.57–2.32 [m, 14H: 8Hpip, N–CH2–(CH2)3–
CH2–CN, N–CH2–(CH2)6O]; 1.80–1.33 (m, 16H, CH2–
CH2–CH2); TLC (dichloromethane–methanol 47:3) Rf =
0.67.
Elemental analysis for trihydrochloric acid salt
C21H37N3O 3HCl (M = 456.93); mptrihydrochloric acid salt
242.2–244.2 °C.
=
C
H
N
8e. C24H39N3O (M = 385.60); yield: 88.9 %; mp =
1
53.9–55.5 °C; H NMR (d in ppm; CDCl3): 7.31–7.24 (m,
Calculated
Found
55.20
54.84
8.82
9.16
9.20
9.12
2Harom); 6.95–6.87 (m, 3Harom); 3.97–3.92 (t, 2H, O–CH2;
J = 6.55 Hz); 2.55–2.32 [m, 14H: 8Hpip, N–CH2–(CH2)4–
CH2–CN, N–CH2–(CH2)6O]; 1.82–1.62 (m, 4H, CH2–
CH2–CH2); 1.56–1.31 (m, 14H, CH2–CH2–CH2); TLC
(dichloromethane–methanol 47:3) Rf = 0.70.
9c. C22H39N3O (M = 361.58); yield 96.9 %; mp =
1
39.2–41.0 °C; H NMR (d in ppm; CDCl3):7.29–7.24 (m,
2Harom); 6.95–6.87 (m, 3Harom); 3.97–3.92 (t, 2H, O–CH2;
J = 6.55 Hz); 2.70–2.66 (t, 2H, H2N–CH2, J = 6.95 Hz);
2.48–2.29 (m, 12H: 8Hpip, CH2–N); 1.79–1.29 (m, 18H,
CH2–CH2–CH2; *, NH2); TLC Rf = 0.4
General method for the preparation of 1-(7-
phenoxyheptyl)-4-(x-aminoalkyl)piperazines 9a–e
Elemental analysis for trihydrochloric acid salt
To a solution of 1-(7-phenoxyheptyl)-4-(x-nitriloalkyl)
piperazine (5f) (0.01 mol) in 50 mL of anhydrous diethyl
ether was added LiAlH4 (0.04 mol). The mixture was
stirred at room temperature for 2.5 h, and quenched by
dropwise addition of water (0.5 mL), 10 % aqueous NaOH
solution (0.5 mL), and water (0.5 mL). The suspension was
stirred for 30 min, and filtered. The filter cake was washed
with ether (2 9 50 mL). The combined organic extracts
were washed with water (3 9 50 mL), dried (Na2SO4), and
filtered. The solvent was evaporated and the respective title
product was obtained as a sticky oil. In each case, the
mixture of dichloromethane–methanol–concentrated ammo-
nium hydroxide 49:10:1 was used as eluent.
C21H37N3O 3HCl (M = 470.96); mptrihydrochloric acid salt
243.6–245.6 °C (with decomposition).
=
C
H
N
Calculated
Found
56.11
55.79
8.99
9.27
8.92
8.86
9d. C23H41N3O (M = 375.60); yield 87.1 %; mp =
1
56.8–58.8 °C; H NMR (d in ppm; CDCl3):7.30–7.24 (m,
2Harom); 6.95–6.87 (m, 3Harom); 3.96–3.92 (t, 2H, O–CH2;
J = 6.45 Hz); 2.70–2.65 (t, 2H, H2N–CH2, J = 6.84 Hz);
2.48–2.30 (m, 12H: 8Hpip, CH2–N); 1.80–1.31 (m, 20H,
CH2–CH2–CH2; *, NH2); TLC Rf = 0.51.
The free base was treated with methanolic HCl and the
obtained hydrochloride was precipitated. The solid was
recrystallized once from dry ethanol.
Elemental analysis for trihydrochloric acid salt C23H41
N3O 3HCl (M = 484.98); mptrihydrochloric acid salt = 248.2–
250.0 °C (with decomposition).
9a. C19H33N3O (M = 319.49); yield 87.9 %; sticky oil;
1H NMR (d in ppm; CDCl3): 7.31–7.23 (m, 2Harom);
6.94–6.86 (m, 3Harom); 3.96–3.92 (t, 2H, O–CH2;
J = 6.55 Hz); 2.81–2.76 (t, 2H, H2N–CH2, J = 6.25 Hz);
2.48–2.29 (m, 12H: 8Hpip, CH2–N); 1.82–1.72 (m, 2H,
CH2–CH2–CH2); 1.64 (s*, 2H, NH2); 1.55–1.29 (m, 8H,
CH2–CH2–CH2); TLC Rf = 0.57.
C
H
N
Calculated
Found
56.96
56.96
9.14
9.26
8.66
8.62
Elemental analysis for trihydrochloric acid salt.
9e. C24H43N3O (M = 389.63); yield 86.7 %; mp =
1
C19H33N3O 3HCl (M = 428.88); mptrihydrochloric acid salt
245.3–247 °C (with decomposition).
=
59.6–61.8 °C; H NMR (d in ppm; CDCl3):7.30–7.24 (m,
2Harom); 6.95–6.87 (m, 3Harom); 3.97–3.92 (t, 2H, O–CH2;
J = 6.45 Hz); 2.70–2.65 (t, 2H, H2N–CH2, J = 6.94 Hz);
2.48–2.29 (m, 12H: 8Hpip, CH2–N); 1.80–1.73 (m, 2H,
CH2–CH2–CH2); 1.55–1.31 (m, 20H, CH2–CH2–CH2; *,
NH2); TLC Rf = 0.44.
C
H
N
Calculated
Found
53.21
53.04
8.46
8.78
9.80
9.67
123

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Med Chem Res (2013) 22:1287–1304
Elemental analysis for trihydrochloric acid salt C24H43
CH2–CH2–CH2; * NH); TLC (dichloromethane–methanol–
N3O 3HCl (M = 499.01); mptrihydrochloric acid salt = 250.2–
251.0 °C (with decomposition).
concentrated ammonium hydroxide 89:10:1) Rf = 0.5
General method for the preparation of 1-(7-
phenoxyheptyl)-4-[4-(N-methylamino)butyl]piperazine
N-amides 1i and 12b–d
C
H
N
Calculated
Found
55.77
56.09
9.29
9.56
8.42
8.21
To a solution of 1-(7-phenoxyheptyl)-4-[4-(N-methyl-
amino)butyl)piperazine (11; Scheme 2) (0.0005 mol) in
20.0 mL of anhydrous dichloromethane was added the
corresponding acid anhydride (0.0015 mol). The mixture
was stirred at room temperature for 1 h. Then, water
(20.0 mL) was added and the mixture was neutralized with
K2CO3, and the aqueous layer was extracted with dichlo-
romethane (2 9 15.0 mL). The combined organic extracts
were washed with water (3 9 30 mL), dried (Na2SO4),
filtered, and evaporated to give the respective products (1i
and 12b–d) as a sticky oil or white solid. In each case, the
crude product was purified by column chromatography.
1i. C24H41N3O (M = 403.61); yield 98.6 %; sticky oil;
1H NMR (d in ppm; CDCl3); 7.30–7.24 (m, 2Harom);
6.95–6.87 (m, 3Harom); 3.97–3.92 (t, 2H, O–CH2; J =
6.55 Hz); 3.39–3.25 (dt, 2H, CH2–N–CH3); 2.97–2.91 (ds,
3H, N–CH3); 2.53–2.37 (m, 12H: 8Hpip, CH2–piperazine);
2.09–2.06 [ds, 3H, C(O)–CH3]; 1.82–1.73 (m, 2H, CH2–
CH2–CH2); 1.53–1.26 (m, 12H, CH2–CH2–CH2); TLC
(dichloromethane–methanol–concentrated ammonium hydrox-
ide 189:10:1) Rf = 0.52.
Synthesis of 1-(7-phenoxyheptyl)-4-[4-(N-
formylamino)butyl]piperazine 10
To a solution of 1-[7-phenoxyheptyl)-4-(4-aminobutyl]
piperazine (9b; Scheme 2) (0.004 mol) in 30.0 mL of
anhydrous dichloromethane was added FAM (10 mL). The
mixture was stirred at 5–10 °C for 1.0 h. Then, water
(30.0 mL) was added and the mixture was neutralized with
K2CO3 and the aqueous layer was extracted with dichlo-
romethane (5 9 50 mL). The combined organic extracts
were washed with water (3 9 50 mL), dried (Na2SO4),
filtered, and evaporated; the residue was purified by col-
umn chromatography on silicagel to give 10 as a sticky oil.
10. C22H37N3O2 (M = 375.56); yield 88.81 %; mp =
55.6–57.6 °C;1H NMR (d in ppm; CDCl3): 8.16 (s, 1H, –
CHO); 7.32–7.25 (m, 2Harom); 6.96–6.88 (m, 3Harom); 6.84
(br, *, 1H, CH2–NH–CHO) 3.97–3.93 (t, 2H, O–CH2;
J = 6.55 Hz); 3.32–3.22 (m, 2H, CH2–NH–CHO);
2.53–2.33 (m, 12H: 8Hpip, CH2–N); 1.83–1.74 (m, 2H,
CH2–CH2–CH2); 1.62–1.26 (m, 12H, CH2–CH2–CH2):
TLC (dichloromethane–methanol–concentrated ammo-
nium hydroxide 189:10:1) Rf = 0.34.
Elemental analysis for dihydrochloric acid salt C24
H41N3O 2HCl (M = 476.54); decomposition tempera-
turedihydrochloric acid salt = 256.5–258.5 °C.
C
H
N
Calculated
Found
60.49
60.23
9.10
9.21
8.82
8.76
Synthesis of 1-(7-phenoxyheptyl)-4-[4-(N-
methylamino)butyl]piperazine 11
To a solution of 1-(7-phenoxyheptyl)-4-[4-(N-formylami-
no)butyl]piperazine (10; Scheme 2) (0.01 mol) in 30 mL
of anhydrous diethyl 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 %
aqueous 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 (2 9 30 mL). The combined
organic extracts were washed with water (3 9 30 mL),
dried (Na2SO4), and filtered. The solvent was evaporated to
give the title product as a sticky oil.
12b. C25H43N3O2 (M = 417.64); yield 96.2 %; sticky
1
oil; H NMR (d in ppm; CDCl3); 7.31–7.24 (m, 2Harom);
6.95–6.86 (m, 3Harom); 3.96–3.92 (t, 2H, O–CH2; J =
6.55 Hz); 3.40–3.25 (dt, 2H, –CH2–N–CH3); 2.95–2.91
(ds, 3H, N–CH3); 2.53–2.27 [m, 14H: 8Hpip, CH2–pipera-
zine,–C(O)–CH2–CH3]; 1.82–1.72 (m, 2H, CH2–CH2–
CH2); 1.58–1.35 (m, 12H, CH2–CH2–CH2); 1.19–1.10
(m, 3H, CH2–CH3); TLC (dichloromethane–methanol–
concentrated ammonium hydroxide 189:10:1) Rf = 0.43.
12c. C26H45N3O2 (M = 431.67); yield 73.8 %; mp =
1
46.5–47.7 °C; H NMR (d in ppm; CDCl3); 7.30–7.25 (m,
2Harom); 6.95–6.87 (m, 3Harom); 3.97–3.92 (t, 2H, O–CH2;
J = 6.55 Hz); 3.32–3.29 (m, 2H, –CH2–N–CH3);
2.97–2.91 (ds, 3H, N–CH3); 2.58–2.27 [m, 14H:
8Hpip, CH2–piperazine,–C(O)–CH2–]; 1.82–1.73 (m, 4H,
CH2–CH2–CH2); 1.60–1.35 (m, 12H, CH2–CH2–CH2);
11. C22H39N3O (M = 361.58); yield 76.9 %; sticky oil;
1H NMR (d in ppm; CDCl3); 7.29–7.24 (m, 2Harom);
6.94–6.87 (m, 3Harom); 3.96–3.91 (t, 2H, O–CH2; J =
6.55 Hz); 2.66–2.29 (m, 17H: 8Hpip, CH2–N–, –CH3);
1.82–1.72 (m, 2H, CH2–CH2–CH2); 1.53–1.33 (m, 13H,
123

Med Chem Res (2013) 22:1287–1304
1299
0.98–0.92 (m, 3H, CH2–CH3); TLC (dichloromethane–
methanol–concentrated ammonium hydroxide 189:10:1)
Rf = 0.12.
(m, 12H, CH2–CH2–CH2); 0.91–0.86 (m, 3H, CH2–CH3,
J = 7.34 Hz); TLC (dichloromethane–methanol–concen-
trated ammonium hydroxide 189:10:1) Rf = 0.19.
Elemental analysis for trihydrochloric acid salt
C25H45N3O 3HCl (M = 513.04); decomposition tempera-
turetrihydrochloric acid salt = 249.0–251.0 °C.
12d. C27H47N3O2 (M = 445.69); yield 42.2 %; sticky
1
oil; H NMR (d in ppm; CDCl3); 7.31–7.24 (m, 2Harom);
6.95–6.86 (m, 3Harom); 3.96–3.92 (t, 2H, O–CH2; J =
6.45 Hz); 3.37–3.25 (m, 2H, –CH2–N–CH3); 2.97–2.91
(ds, 3H, N–CH3); 2.49–2.26 [m, 14H: 8Hpip, CH2–pipera-
zine, –C(O)–CH2–]; 1.82–1.73 (m, 4H, CH2–CH2–CH2);
1.67–1.34 (m, 14H, CH2–CH2–CH2); 0.95–0.91 (t, 3H,
CH2–CH3, J = 7.24 Hz); TLC (dichloromethane–metha-
nol–concentrated ammonium hydroxide 89:10:1) Rf = 0.55.
C
H
N
Calculated
Found
58.53
58.26
9.43
9.69
8.19
8.25
1d. C26H47N3O (M = 417.68); yield 79.81 %; sticky
1
oil; H NMR (d in ppm; CDCl3); 7.30–7.25 (m, 2Harom);
General method for the preparation of 1-(7-
phenoxyheptyl)-4-[4-(N-alkyl-N-
methylamino)butyl]piperazines 1b–e
6.95–6.88 (m, 3Harom); 3.97–3.92 (t, 2H, O–CH2;
J = 6.54 Hz); 2.61–2.29 (m, 16H: 8Hpip,–N–CH2–); 2.20
(s, 3H, N–CH3); 1.78–1.75 (m, 4H, CH2–CH2–CH2);
1.59–1.35 (m, 14H, CH2–CH2–CH2); 0.94–0.91 (m, 3H,
CH2–CH3, J = 7.34 Hz); TLC (dichloromethane–metha-
nol–concentrated ammonium hydroxide 89:10:1) Rf =
0.52.
To a solution of the appropriate 1-(7-phenoxyheptyl)-4-[4-
(N-methylamino)butyl]-piperazine N-amide (1i or 12b–d;
Scheme 2) (0.002 mol) in 10.0 mL of anhydrous diethyl
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 % aqueous
NaOH solution (0.33 mL), and water (0.33 mL). The sus-
pension was stirred for 30 min, and filtered. The filter cake
was washed with ether (2 9 10 mL). The combined
organic extracts were washed with water (3 9 10.0 mL),
dried (Na2SO4), and filtered. The solvent was evaporated to
give the respective title product as a sticky oil. The free
base was treated with methanolic HCl. The obtained solid
was recrystallized once from dry ethanol.
Elemental analysis for trihydrochloric acid salt C26
H47N3O 3HCl (M = 527.07); decomposition tempera-
turetrihydrochloric acid salt = 247.0–248.5 °C.
C
H
N
Calculated
Found
59.25
58.92
9.56
9.78
7.97
8.34
1e. C27H49N3O (M = 431.71); yield 82.64 %; sticky oil;
H NMR (d in ppm; CDCl3); 7.30–7.24 (m, 2Harom);
1
1b. C24H43N3O (M = 389.63); yield 91.30 %; sticky
1
6.95–6.87 (m, 3Harom); 3.96–3.92 (t, 2H, O–CH2;
J = 6.54 Hz); 2.48–2.17 (m, 19H: 8Hpip,–N–CH2–, N–
CH3); 1.80–1.73 (m, 4H, CH2–CH2–CH2); 1.50–1.34 (m,
16H, CH2–CH2–CH2); 0.92–0.87 (m, 3H, CH2–CH3,
J = 7.34 Hz); TLC (dichloromethane–methanol–concen-
trated ammonium hydroxide 89:10:1) Rf = 0.31.
oil; H NMR (d in ppm; CDCl3); 7.31–7.24 (m, 2Harom);
6.95–6.86 (m, 3Harom); 3.96–3.92 (t, 2H, O–CH2; J =
6.55 Hz); 2.51–2.29 (m, 16H: 8Hpip, –N–CH2–); 2.21 (s,
3H, N–CH3); 1.82–1.73 (m, 2H, CH2–CH2–CH2); 1.55–
1.31 (m, 12H, CH2–CH2–CH2); 1.08–1.03 (m, 3H, CH2–
CH3, J = 7.24 Hz); TLC (dichloromethane–methanol–
concentrated ammonium hydroxide 89:10:1) Rf = 0.25.
Elemental analysis for trihydrochloric acid salt C24
H43N3O 3HCl (M = 499.01); decomposition tempera-
turetrihydrochloric acid salt = 251.5–253.0 °C.
Elemental analysis for trihydrochloric acid salt
C27H49N3O 3HCl (M = 541.09); decomposition tempera-
turetrihydrochloric acid salt = 243.0–245.0 °C.
C
H
N
C
H
N
Calculated
Found
59.93
59.82
9.69
9.95
7.76
7.82
Calculated
Found
57.78
57.41
9.29
9.59
8.42
8.34
Synthesis of 1-(7-phenoxyheptyl)-4-[4-(N,N-
dimethylamino)butyl]piperazine 1a
1c. C25H45N3O (M = 403.66); yield 82.90 %; sticky oil;
1H NMR (d in ppm; CDCl3); 7.30–7.24 (m, 2Harom);
6.95–6.88 (m, 3Harom); 3.97–3.92 (t, 2H, O–CH2;
J = 6.55 Hz); 2.59–2.25 (m, 16H: 8Hpip,–N–CH2–); 2.20 (s,
3H, N–CH3); 1.82–1.73 (m, 4H, CH2–CH2–CH2); 1.52–1.34
1-(7-Phenoxyheptyl)-4-[4-(N-methylamino)butyl]pipera-
zine (11; Scheme 2) (0.003 mol) was dissolved in 0.15 mol
of 100 % formic acid and 0.55 g of 36 % formaldehyde
123

1300
Med Chem Res (2013) 22:1287–1304
was added. The mixture was heated for 10 h at
100–105 °C. After cooling, the mixture was alkalinized
with sodium hydroxide to pH 12 and extracted with diethyl
ether (3050.0 mL), dried (Na2SO4), and filtered. The sol-
vent was evaporated and the crude product was purified by
column chromatography on silicagel. The title product was
obtained as a sticky oil. The free base was treated with
methanolic HCl. The obtained solid was recrystallized once
from dry ethanol.
C
H
N
Calculated
Found
62.08
61.74
8.62
8.82
7.49
7.50
1g. C31H49N3O (M = 479.76); yield 57.70 %; sticky
1
oil; H NMR (d in ppm; CDCl3); 7.31–7.17 (m, 7Harom);
6.95–6.87 (m, 3Harom); 3.96–3.92 (t, 2H, O–CH2; J =
6.55 Hz); 2.66–2.29 (m, 21H: 8Hpip, CH2–N–, –CH3, CH2–
Ph); 1.88–1.72 (m, 4H, CH2–CH2–CH2); 1.52–1.33 (m,
12H, CH2–CH2–CH2); Rf = 0.17.
1a. C23H41N3O (M = 375.61); yield 56.50 %; sticky
1
oil; H NMR (d in ppm; CDCl3); 7.32–7.24 (m, 2Harom);
6.96–6.81 (m, 3Harom); 3.97–3.91 (t, 2H, O–CH2;
J = 6.55 Hz); 2.49–2.30 (m, 14H: 8Hpip, CH2–N); 2.27 (s,
6H, CH3) 1.82–1.73 (m, 2H, CH2–CH2–CH2); 1.56–1.32
(m, 12H, CH2–CH2–CH2); TLC (dichloromethane–metha-
nol–concentrated ammonium hydroxide 89:10:1) Rf =
0.46.
Elemental analysis for trihydrochloric acid salt C31
H49N3O 3HCl (M = 589.14); decomposition tempera-
turetrihydrochloric acid salt = 232.6–234.2 °C.
C
H
N
Calculated
Found
63.20
62.85
8.90
9.22
7.13
7.08
Elemental analysis for trihydrochloric acid salt C23
H41N3O 3HCl (M = 484.99); decomposition tempera-
turetrihydrochloric acid salt = 256.5–258.5 °C.
1h. C33H53N3O (M = 507.81); yield 50.0 %; sticky oil;
1H NMR (d in ppm; CDCl3); 7.30–7.14 (m, 7Harom);
6.95–6.86 (m, 3Harom); 3.96–3.92 (t, 2H, O–CH2; J =
6.45 Hz); 2.63–2.21 (m, 18H: 8Hpip, CH2–N–, CH2–Ph);
2.20 (s, 3H, CH3); 1.82–1.72 (m, 2H, CH2–CH2–CH2);
1.68–1.61 (m, 2H, CH2–CH2–CH2); 1.49–1.30 (m, 16H,
CH2–CH2–CH2); Rf = 0.26.
C
H
N
Calculated
Found
56.96
56.72
9.14
9.42
8.66
8.66
General method for the preparation of 1-(7-
phenoxyheptyl)-4-[4-(N-methyl-N-
phenylalkylamino)butyl]piperazines 1f–h
Elemental analysis for trihydrochloric acid salt C33
H53N3O 3HCl (M = 617.19); decomposition tempera-
turetrihydrochloric acid salt = 238.5–240 °C.
To a suspension of 1-(7-phenoxyheptyl)-4-[4-(N-methyl-
amino)butyl]piperazine (11; Scheme 2) (0.003 mol) and
potassium carbonate (0.012 mol) in 30 mL of acetonitrile
was added the corresponding phenylalkyl halide
(0.0033 mol). The mixture was stirred for 24 h at room
temperature, and filtered. The solvent was evaporated to
give the respective crude product which was purified by
column chromatography. In each case, the mixture of
C
H
N
Calculated
Found
64.22
63.85
9.14
9.44
6.81
7.18
General method for the preparation of 1-(7-
phenoxyheptyl)-4-[4-(N-methylamino)butyl]piperazine
N-amides 1j, k
dichloromethane–methanol–concentrated
ammonium
hydroxide 189:10:1 was used as eluent. The title products
were obtained as a sticky oils. Free bases were treated with
methanolic hydrochloric acid. The obtained solids were
recrystallized twice from ethanol.
To a solution of 1-(7-phenoxyheptyl)-4-[4-(N-methyl-
amino)butyl]piperazine (11; Scheme 2) (0.005 mol) in
20.0 mL of anhydrous dichloromethane was added triflu-
oroacetic anhydride (0.005 mol) or benzoyl chloride
(0.005 mol), respectively, and triethylamine (0.01 mol).
The mixture was stirred at room temperature for 1 h. Then,
water (10.0 mL) was added (in the case of reaction with
trifluoroacetic anhydride, K2CO3 was added to the mixture
to pH=12) and the aqueous layer was extracted with
dichloromethane (2 9 15.0 mL). The combined organic
extracts were washed with water (3 9 10 mL), dried
(Na2SO4), filtered, and evaporated to give 1j as a sticky oil,
1f. C29H45N3O (M = 451.71); yield 37.50 %; sticky oil;
1H NMR (d in ppm; CDCl3); 7.31–7.22 (m, 7Harom);
6.95–6.87 (m, 3Harom); 3.96–3.92 (t, 2H, O–CH2; J =
6.45 Hz); 3.48 (s, 2H, CH2–Ph); 2.52–2.35 (m, 14H: 8Hpip
,
CH2–N); 2.18 (s, 3H, CH3); 1.80–1.73 (m, 4H, CH2–CH2–
CH2); 1.52–1.35 (m, 10H, CH2–CH2–CH2); Rf = 0.41.
Elemental analysis for trihydrochloric acid salt
C29H45N3O 3HCl (M = 561.09); decomposition tempera-
turetrihydrochloric acid salt = 235.9–237 °C.
123

Med Chem Res (2013) 22:1287–1304
1301
or 1k as a white solid which was crystallized twice from
ethyl acetate. The crude 1j was purified by column
chromatography.
6H, –CH2–CH2–CH2–); TLC (dichloromethane–methanol–
concentrated ammonium hydroxide 189:10:1) Rf = 0.15.
15b. C8H13NO4 (M = 187.20); yield 90.5 %; mp =
78.4–79.2 °C; [mp 62–64 °C (Banik and Becker, 2001)],
1H NMR (d in ppm; CDCl3); 11.12 (s, 1H, *, OH);
3.60–3.50 (m, 6H, –CH2–O–CH2–, CH2–COOH);
3.42–3.32 [m, 2H, CH2–C(O)–]; 2.60–2.50 (m, 4H, –CH2–
N–CH2–); TLC (dichloromethane–methanol–concentrated
ammonium hydroxide 189:10:1) Rf = 0.3.
1j. C24H38F3N3O2 (M = 457.58); yield 52.7 %; sticky
1
oil; H NMR (d in ppm; CDCl3); 7.30–7.25 (m, 2Harom);
6.95–6.87 (m, 3Harom); 3.96–3.92 (t, 2H, O–CH2; J =
6.45 Hz); 3.47–3.38 [m, 2H, (O)C–N–CH2]; 3.11–3.01 (ds,
3H, N–CH3); 2.50–2.34 (m, 12H, –CH2–piperazine, 8Hpip);
1.82–1.27 (m, 14H, CH2–CH2–CH2–); TLC (dichloro-
methane–methanol–concentrated ammonium hydroxide
189:10:1) Rf = 0.58.
Synthesis of 1-(7-phenoxyheptyl)-4-[4-[(piperidin-1-yl)-
1,4-dioxo]butyl]piperazine 16a and 1-(7-phenoxyheptyl)-4-
[4-[(morpholin-4-yl)-1,4-dioxo]butyl]piperazine 16b
Elemental analysis for dihydrochloric acid salt
C24H38F3N3O2 2HCl (M = 530.51); mpdihydrochloric acid salt
244.5–246.2 °C with decomposition.
=
To
a solution of 1-(7-phenoxheptyl)piperazine (5f)
(0.001 mol) in 10 mL of anhydrous dichloromethane with
3 ml of pyridine, was added the compound 14a or 14b
(0.0015 mol), respectively. After 1 h of stirring, DCC
(0.002 mol) was added. The mixture was stirred at room
temperature for 20 h. The suspension was filtered. The
filter cake was washed with dichloromethane (2 9 50 mL).
The solvent was evaporated to give the respective crude
product which was purified by column chromatography.
Both title products were obtained as white solids.
C
H
N
Calculated
Found
54.34
54.50
7.60
7.82
7.92
7.85
1k. C29H43N3O2 (M = 465.68); yield 82.0 %; mp
1
94.4–96.0 °C; H NMR (d in ppm; CDCl3); 7.81–7.48 [m,
5Harom, C(O)Ph]; 7.31–7.26 (m, 2Harom); 6.96–6.88 (m,
3Harom); 3.98–3.93 (t, 2H, O–CH2; J = 6.54 Hz); 3.51–
3.49 (m, 2H, CH3–N–CH2–); 2.64–2.41 (m, 12H: 8Hpip
,
16a. C26H41N3O3 (M = 443.63); yield 67.0 %; mp =
1
CH2–piperazine); 2.24 (s, 3H, N–CH3); 1.81–1.36 (m, 14H,
CH2–CH2–CH2); TLC (dichloromethane–methanol–con-
centrated ammonium hydroxide 189:10:1) Rf = 0.8.
Elemental analysis for dihydrochloric acid salt C29
57.0–59.3 °C; H NMR (d in ppm; CDCl3); 7.31–7.25 (m,
2Harom); 6.96–6.88 (m, 3Harom); 3.98–3.93 (t, 2H, O–CH2;
J = 6.55 Hz); 3.65–3.62 [m, 2H, CH2–C(O)–]; 3.57–3.53
(m, 4Hpiperazine); 3.48–3.45 [m, 2H, CH2–C(O)–];
2.68–2.66 (m, 4Hpiperidine); 2.45–2.32 [m, 6H, –CH2–N–
(CH2)2–]; 1.81–1.26 (m, 16H, CH2–CH2–CH2); TLC
(dichloromethane–methanol–concentrated ammonium hydrox-
ide 89:10:1) Rf = 0.81.
H43N3O2 2HCl (M = 538.61); mpdihydrochloric
237.0–238.5 °C with decomposition.
=
acid salt
C
H
N
16b. C25H39N3O4 (M = 445.61); yield 0.58.33 %;
mp = 92.4–93.3 °C; 1H NMR (d in ppm; CDCl3);
7.30–7.25 (m, 2Harom); 6.95–6.88 (m, 3Harom); 3.97–3.93
(t, 2H, O–CH2; J = 6.55 Hz); 3.69–3.54 [m, 12H, CH2–
C(O)–, 4Hpiperazine, 4Hmorpholine]; 2.69–2.64 (m, 4Hmorpholine);
2.45–2.31 (m, 6H, 4Hpiperazine, –CH2–N), 1.80–1.25 (m, 10H,
CH2–CH2–CH2); TLC (dichloromethane–methanol–concen-
trated ammonium hydroxide 189:10:1) Rf = 0.3.
Calculated
Found
64.67
64.36
8.61
8.51
7.80
7.82
Synthesis of 4-(piperidin-1-yl)-4-oxobutyric acid 15a
and 4-(morpholin-4-yl)-4-oxobutyric acid 15b
To a solution of succinic anhydride (13; Scheme 3)
(0.08 mol) in 10.0 mL of anhydrous dichloromethane was
added piperidine 14a or morpholine 14b (0.08 mol),
respectively. The mixture was stirred at room temperature
for 2 h. The solvent was evaporated to give the respective
product (15a or 15b) as a white solid which was crystal-
lized twice from ethyl acetate.
Synthesis of 1-(7-phenoxyheptyl)-4-[4-(piperidn-
1-yl)butyl]piperazine 1l and 1-(7-phenoxyheptyl)-4-
[4-(morpholin-4-yl)butyl]piperazine 1m
To a solution of the appropriate compound (16a or
b) (Scheme 3) (0.0004 mol) in 20.0 mL of anhydrous
diethyl ether was added LiAlH4 (0.0025 mol). The mixture
was stirred at room temperature for 2.5 h. Then, the next
portion of LiAlH4 (0.0025 mol) was added. The mixture
was stirred at room temperature for 20 h and quenched by
dropwise addition of 10 % aqueous NaOH solution
15a. C9H15NO3 (M = 185.22); yield 92.0 %; mp =
93.6–94.8 °C; [mp 71–72 °C (Banik and Becker, 2001)],
1H NMR (d in ppm; CDCl3); 7.27 (br, 1H, *, OH);
3.58–3.55 (m, 2H, CH2–COOH); 3.44–3.41 [m, 2H, CH2–
C(O)–]; 2.73–2.64 (m, 4H, –CH2–N–CH2–); 1.69–1.55 (m,
123

1302
Med Chem Res (2013) 22:1287–1304
(0.5 mL), after 10 min the next portion of 10 % aqueous
NaOH solution (0.5 mL) and water (0.5 mL). The sus-
pension was stirred for 30 min, and filtered. The filter cake
was washed with ether (2 9 10 mL). The combined
organic extracts were washed with water (3 9 10.0 mL),
dried (Na2SO4), and filtered. The solvent was evaporated
and the respective title product was obtained as a sticky oil.
In each case, the mixture of dichloromethane–methanol–
concentrated ammonium hydroxide 89:10:1 was used as
eluent. The free base was treated with methanolic HCl and
the obtained solid was recrystallized twice from dry
ethanol.
(1 9 10-6 mol/L)]. Whole jejunum segments (2 cm) were
prepared 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. Con-
tractions 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 max-
imally between 15 and 20 V and continuously at a fre-
quency of 0.1 Hz and a duration of 0.5 ms, with
rectangular-wave electrical pulses, delivered by a Grass
Stimulator S-88 (Grass Instruments Co., Quincy, USA).
After 30 min of stimulation, 5 min before adding (R)-a-
methylhistamine, pyrilamine (1 9 10-5 mol/L concentra-
tion 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 adding the tested compounds, the pyrilamine
(1 9 10-5 mol/L concentration in organ bath) was added,
and after 20 min cumulative concentration–response
curves (half-log increments) of (R)-a-methylhistamine, H3-
agonist, were recorded until no further change in response
was found. Statistical analysis was carried out with the
Students’ t test. In all test p \ 0.05 was considered to be
statistically significant. The potency of an antagonist is
expressed by its pA2 value, calculated from the Arunl-
akshana and Schild (1959) regression analysis where at
least three concentrations were used. The pA2 values were
compared with the potency of thioperamide.
1l. C26H41N3O (M = 415.67); yield 86.72 %; sticky oil;
1H NMR (d in ppm; CDCl3); 7.30–7.24 (m, 2Harom);
6.95–6.87 (m, 3Harom); 3.96–3.92 (t, 2H, O–CH2; J =
6.55 Hz); 2.64–2.27 (m, 14H, N–CH2, Hpiperazine);
1.99–1.25 (m, 24H, CH2–CH2–CH2–, Hpiperidine); TLC
Rf = 0.3
Elemental analysis for trihydrochloric acid salt C26
H41N3O 3HCl (M = 455.13); decomposition tempera-
turetrihydrochloric acid salt = 262.0–263.0 °C.
C
H
N
Calculated
Found
59.48
59.40
9.21
9.48
8.00
7.96
1m. C25H39N3O2 (M = 417.64); yield 61.5 %; sticky
1
oil; H NMR (d in ppm; CDCl3); 7.30–7.25 (m, 2Harom);
6.95–6.88 (m, 3Harom); 3.97–3.92 (t, 2H, O–CH2; J =
6.55 Hz); 3.74–3.70 (4Hmorpholine); 2.70–2.34 (m, 18H, N–
CH2, Hpiperazine, 4Hmorpholine); 1.80–1.36 (m, 14H, CH2–
CH2–CH2–) ppm; TLC Rf = 0.5.
H1 antagonistic activity for the products
9b, 1b, 1f, and 1l
Elemental analysis for trihydrochloric acid salt C25
H39N3O2 3HCl (M = 457.10); decomposition tempera-
turetrihydrochloric acid salt = 277.0–278.0 °C.
Selected final products were tested for H1 antagonistic
effects in vitro, following standard methods, using the
guinea pig ileum (Arunlakshana and Schild, 1959).
C
H
N
Male guinea pigs weighing 300–400 g were euthanized
by a blow on the head. The ileum was excised and placed
in phosphate buffer at room temperature (pH 7.4) con-
taining (mM) 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 10-6 mol/L) at 37 °C under a constant load of 0.5 g.
After a 30 min equilibration period with washings every
10 min, a sub maximal priming dose of histamine (1 mM)
was given and washed out (standard washing procedure:
three changes of buffer during 30 min). After washing out,
Calculated
Found
56.98
57.20
8.80
9.04
7.97
7.90
Pharmacology
All final products were tested for H3 antagonistic effects in
vitro on the guinea pig jejunum (Vollinga et al., 1992)
using standard methods.
Male guinea pigs weighing 300–400 g were sacrificed
by a blow on the head. A portion of the small intestine,
20–50 cm proximal to the ileocecal 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
123

Med Chem Res (2013) 22:1287–1304
1303
´
Kiec-Kononowicz K, Ligneau X, Stark H, Schwartz JC, Schunack W
(1995) Azines and diazines as potential histamine H3-receptor
antagonists. Arch Pharm Med Chem 328:445–450
the antagonistic activity of given compounds was measured
by recording a concentration response curve (CRC) for his-
tamine in the presence of the tested compounds (9b, 1b, 1f,
and 1l) which was added 5 min before histamine. This pro-
cedure was repeated with higher concentrations of the com-
pounds. Theantagonismwasofa competitive naturecausinga
parallel shift of the CRC. The pA2-values were calculated
according to Arunlakshana and Schild (1959). The pA2 values
were compared with the potency of pyrilamine.
Labella FS, Queen G, Glavin G, Durant G, Stein D, Brandes IJ (1992)
H3 receptor antagonist, thioperamide, inhibits adrenal steroido-
genesis and histamine binding to adrenocortical microsomes and
binds to cytochrome P450. Br J Pharmacol 107:161–164
Lehman MR, Thompson CD, Marvel CS (1933) Quaternary ammo-
nium salts from halogenated alkyl dimethylamines. III. omega-
bromo-heptyl-, -octyl-, -nonyl- and -decyl-dimethylamines.
J Am Chem Soc 55:1977–1981
Leurs R, Tulup MT, Menge WM, Adolfs MJ, Zuiderveld OP,
Timmerman H (1995) Evaluation of receptor selectivity of the
H3 receptor antagonists, iodophenpropit and thioperamide: an
interaction with the 5-HT3 receptor revealed. Br J Pharmacol
116:2315–2321
References
Leurs R, Blandina P, Tedford C, Timmerman H (1998) Therapeutic
potential of histamine H3 receptor agonists and antagonists.
Trends Pharmacol Sci 19:177–183
Leurs R, Bakker RA, Timmerman H, de Esch IJ (2005) The histamine
H3 receptor: from gene cloning to H3 receptor drugs. Nat Rev
Drug Discov 4:107–120
Ligneau X, Lin J, Vanni-Mercier G, Jouvet M, Muir JL, Ganellin CR,
Stark H, Elz S, Schunack W, Schwartz JC (1998) Neurochemical
and behavioral effects of ciproxifan, a potent histamine H3-
receptor antagonist. J Pharmacol Exp Therap 287:658–666
Ligneau X, Morriset S, Tradivel-Lacombe J, Gbabou F, Ganellin CR,
Stark H, Schunack W, Schwartz JC, Arrang JM (2000) Distinct
pharmacology of rat and human histamine H3 receptors: role of
two amino acids in the third transmembrane domain. Br J
Pharmacol 131:1247–1250
Alves-Rodrigues A, Leurs R, Wu TS, Prel GD, Foged C, Timmerman
H (1996) [3H]-thioperamide as a radioligand for the histamine H
H3 receptor in rat cerebral cortex. Br J Pharmacol 118:
2045–2052
Apodaca R, Dvorac CA, Xiao W, Barbier AJ, Boggs JD, Wilso SJ,
Lovenberg TW, Carruthers NI (2003) A new class of diamine-
based human histamine H3 receptor antagonists: 4-(aminoalk-
oxy)benzylamines. J Med Chem 46:3938–3944
Arrang JM, Garbarg M, Schwartz JC (1983) Auto-inhibition of brain
histamine release mediated by a novel class (H3) of histamine
receptor. Nature 302:832–837
Arrang JM, Garbarg M, Schwartz JC (1985) Autoregulation of
histamine release in brain by presynaptic H3-receptors. Neuro-
science 15:553–562
Littmann ER, Marvel CS (1930) Cyclic quaternary ammonium salts
from halogenated aliphatic tertiary amines. J Am Chem Soc
52:287–294
Arrang JM, Garbarg M, Schwartz JC (1987) Autoinhibition of
histamine synthesis mediated by presynaptic H3-receptors.
Neuroscience 23:149–157
Liu C, Ma X, Jiang X, Wilson SJ, Hofistra CI, Blevit J, Pyati J, Li XB,
Chai WY, Carruthers N, Lovenberg TW (2001) Cloning and
pharmacological characterization of a fourth histamine receptor
(H4) expressed in bone marrow. Mol Pharmacol 59:420–426
Lovenberg TW, Roland BL, Wilson SJ, Jiang X, Pyati J, Huvar A,
Jackson MR, Erlander MG (1999) Accelerated communication:
cloning and functional expression of the human histamine H3
receptor. Mol Pharmacol 55:1101–1107
Lovenberg TW, Pyti J, Chang H, Wilson SJ, Erlander MG (2000)
Cloning of rat histamine H3 receptor reveals distinct species
pharmacological profiles. J Pharmacol Exp Therap 293:771–778
Meier G, Apelt J, Reichert U, Grassman S, Ligneau X, Elz S,
Leurguin F, Ganellin CR, Schwartz JC, Schunack W, Stark H
(2001) Influence of imidazole replacement in different structural
classes of histamine H3-receptor antagonists. Eur J Pharm Sci
13:249–259
Arunlakshana O, Schild HO (1959) Some quantitative uses of drug
antagonists. Br J Pharmacol 14:48–58
Banik BK, Becker FF (2001) Polycyclic aromatic compounds as
anticancer agents: structure–activity relationships of chrysene
and pyrene derivatives. Bioorg Med Chem 9:593–605
Berlin M, Boyce CW, de Lera Ruiz M (2011) Histamine H3 receptor
as a drug discovery target. J Med Chem 54:26–53
Capuano B, Crosby IT, Lloyd EJ, Podloucka A, Taylor DA (2008)
Synthesis and preliminary pharmacological evaluation of
4’-Arylalkyl analogues of Clozapine. IV. The effects of the
aromatic and isosteric replacement. Aust J Chem 61:930–940
Clapham J, Kilpatrick GJ (1992) Histamine H3-receptors modulate
the release of [3H]-acetylcholine from slices of rat entorhinal
cortex: evidence for the possible existence of H3-receptor
subtypes. J Pharmacol 107:919–923
Collins RF, Davis M (1961) The chemotherapy of schistosomiasis.
Part IV. Some ethers of 4-amino-2-methoxyphenol. J Chem Soc
(May):1863–1879
Cowart M, Faghih R, Curtis MP, Gfesser GA, Bennani YL, Black LA,
Pan L, Marsh KC, Sullivan JP, Esbenshade TA, Fox GB,
Hancock AA (2005) 4-(2-[2-(2(R)-Methylpyrrolidin-1-yl)ethyl]
benzofuran-5-yl)benzonitrile and related 2-aminoethylbenzofu-
ran H3 receptor antagonists potently enhance cognition and
attention. J Med Chem 48:38–55
`
Miko T, Ligneau X, Pertz HH, Arrang JM, Ganellin CR, Schwartz JC,
Schunack W, Stark H (2003) Novel nonimidazole histamine h3
receptor antagonists: 1-(4-(phenoxymethyl)benzyl)piperidines
and related compounds. J Med Chem 46:1523–1530
`
Miko T, Ligneau X, Pertz HH, Arrang JM, Ganellin CR, Schwartz JC,
Schunack W, Stark H (2004) Structural variations of 1-(4-
(phenoxymethyl)benzyl)piperidines as nonimidazole histamine
H3 receptor antagonists. Bioorg Med Chem 12:2727–2736
¨
Schlicker E, Betz R, Gothert M (1988) Histamine H3 receptor-
´
Frymarkiewicz A, Walczynski K (2009) Non-imidazole histamine H3
mediated inhibition of serotonin release in the rat brain cortex.
Naunyn-Schmideberg’s Arch Pharmacol 337:588–590
ligands, part IV: SAR of 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-
propylpiperazine derivatives. Eur J Med Chem 44:1674–1681
Glase SA, Robertson DW, Wise LD (2002) Attention deficit hyper-
activity disorder: Pathophysiology and design of new treatments.
Annu Rep Med Chem 37:11–20
¨
Schlicker E, Fink K, Hinterthaner M, Gothert M (1989) Inhibition of
noradrenaline release in the rat brain cortex via presynaptic H3
receptors. Naunyn-Schmideberg’s Arch Pharmacol 340:633–638
123

1304
Med Chem Res (2013) 22:1287–1304
´
¨
Schlicker E, Malinowska M, Kathmann M, Gothert M (1994)
Modulation of neurotransmitter release histamine H3 heterore-
ceptors. Fundam Clin Pharmacol 8:128–137
Walczynski K, Guryn R, Zuiderveld OP, Timmerman H (1999b) Non-
imidazole histamine H3 ligands, part 2: new 2-substituted
benzothiazoles as histamine H3 antagonists. Arch Pharm Pharm
Med Chem 332:389–398
Stark H, Sipll W, Ligneau X, Arrang JM, Ganellin CR, Schwartz JC,
Schunack W (2001) Different antagonist binding properties of
human and rat histamine H3 receptors. Bioorg Med Chem Lett
11:951–954
´
Walczynski K, Zuiderveld OP, Timmerman H (2005) Non-imidazole
histamine H3 ligands. Part III. New 4-n-propylpiperazines as
non-imidazole histamine H3-antagonists. Eur J Med 40:15–23
Witkin JM, Nelson DL (2004) Selective histamine H3 receptor
antagonists for treatment of cognitive deficiencies and other
disorders of the central nervous system. Pharmacol Ther 103:
1–20
Wulff BS, Hastrup S, Rimvall K (2002) Characteristics of recombi-
nantly expressed rat and human histamine H3 receptors. Eur J
Pharmacol 453:33–41
Yoshimatsu H, Itateyama E, Kondou S, Tajima D, Himeno K, Hidaka
S, Kurokawa M, Sakata T (1999) Hypothalamic neuronal
histamine as a target of leptin in feeding behavior. Diabetes
48:2286–2291
Zaragoza F, Stephensen H, Peschke B, Rimvall K (2005) 2-(4-
Alkylpiperazin-1-yl)quinolines as a new class of imidazole-free
histamine H3 receptor antagonists. J Med Chem 48:306–311
´
Tkaczynski T (1966) Synthesis of ethylene amines N-hydroxyethyl-
piperazine and N,N-bis-hydroxyethylpiperazine. Acta Pol Pharm
4:355–357
Van der Goot H, Schepers MJ, Sterk GJ, Timmerman H (1992)
Isothiourea analogs of histamine as potent agonists or antago-
nists of the histamine H3-receptor. Eur J Med Chem 27:511–517
Van Es A, Stevens W (1965) Mixed carboxylic acid anhydrides: V.
Synthesis of alkyl formates. Recl Trav Chim Pays-Bas 84:
704–709
Vohora D, Pal SN, Pillai KK (2001) Histamine and selective H3-
receptor ligands: a possible role in the mechanism and manage-
ment of epilepsy. Pharmacol Biochem Behav 68:735–741
Vollinga RC, Zuiderveld OP, Scheerens H, Bast A, Timmerman H
(1992) A simple and rapid in system for the screening of
histamine H3-ligands. Methods Find Exp Clin Pharmacol
105:747–751
´
Walczynski K, Guryn R, Timmerman H, Zuiderveld O (1999a) Non-
imidazole histamine H3 ligands. Part I. Synthesis of 2-(1-
piperazinyl)- and 2-(hexahydro-1H-1,4-diazepin-1-yl)benzothia-
zole derivatives as H3-antagonists with H1 blocking activities. Il
Farmaco 54:684–694
123