Non-imidazole histamine H3 ligands: Part V. synthesis and preliminary pharmacological investigation of 1-[2-thiazol-4-yl- and 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazine derivatives

Article abstract of DOI:10.1007/s00044-012-0372-8

Series of 1-[2-thiazol-4-yl-(2-aminoethyl)]- and 1-[2-thiazol-5-yl-(2- aminoethyl)]-4-n-propylpiperazine derivatives have been prepared and in vitro tested as H₃-receptor antagonists (the electrically evoked contraction of the guinea-pig jejunu

Full text of DOI:10.1007/s00044-012-0372-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:3640–3652
DOI 10.1007/s00044-012-0372-8
ORIGINAL RESEARCH
Non-imidazole histamine H3 ligands: part V. synthesis
and preliminary pharmacological investigation of 1-[2-thiazol-4-
yl- and 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazine
derivatives
•
Roman Guryn Marek Staszewski
•
´
Krzysztof Walczynski
Received: 4 January 2012 / Accepted: 15 November 2012 / Published online: 29 November 2012
Ó The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract Series of 1-[2-thiazol-4-yl-(2-aminoethyl)]- and
1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazine deriv-
atives have been prepared and in vitro tested as H3-receptor
antagonists (the electrically evoked contraction of the guinea-
pig jejunum). It appeared that by comparison of homologous
pairs, the 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpipera-
zines (3a,b and 4a–d) have much higher potency than their
analogous 1-[2-thiazol-4-yl-(2-aminoethyl)]-4-n-propylpiper-
azines (2a–k). Based on the obtained results, we observed the
5-position of 2-methyl-2-R-aminoethyl substituents in the
thiazole ring is favourable for histamine H3 receptor antag-
onist activity, whereas its presence in position 4 leads, almost
in each case, to strong decrease of activity.
The histamine H3 receptor, which was discovered in 1983
by Arrang and co-workers (Arrang et al., 1983), mainly
located in the CNS, is a presynaptic autoreceptor that does
not only modulate the production and the release of hista-
mine from histaminergic neurons (Arrang et al., 1987) but
also regulates the release of other neurotransmitters like
acetylocholine (Clapham and Kilpatrick, 1992; Yokatoni
et al., 2000), dopamine (Schlicker et al., 1993), norepi-
nephrine (Schlicker et al., 1990), serotonin (Schlicker
et al., 1988) and glutamate (Brown and Reymann, 1996) in
both the CNS and peripheral nervous system. Enhancement
of neurotransmitter release by histamine H3 receptor
antagonist shows a clinical approach to the treatment of
several CNS disorders (Esbenshade et al., 2006; Cemkov
et al., 2009), including attention deficit hyperactivity dis-
order (Quades, 1987), sleep disorders (Monti, 1993), epi-
lepsy (Vahora et al., 2001) and schizophrenia (Velligan and
Miller, 1999). Pharmacological data also suggest a potential
role for H3 antagonists in the control of feeding, appetite,
and support the role of H3 receptor in obesity (Hancock,
2003; Hancock et al., 2004).
Keywords Histamine H3-receptor Á H3-antagonists Á
1-[2-thiazol-4-yl-(2-aminoethyl)]- and 1-[2-thiazol-5-yl-
(2-aminoethyl)]-4-n-propylpiperazine derivatives
Introduction
Histamine plays a variety of physiological roles in the
central nervous system (CNS) and peripheral tissues
through the four known G protein-coupled receptors, H1,
H2, H3 and H4 (Hough, 2001). H1 and H2 receptor antago-
nists are well-known therapeutic agents and are in use for
the treatment of allergic disease (Leurs et al., 2002) and
peptic ulcer (Brimblecombe et al., 1978), respectively. The
newly discovered H4 receptor seems to have a role in reg-
ulating inflammatory responses (Thurmond et al., 2004).
Early generation of H3 receptor ligands were based on
structures containing the imidazole moiety, many of which
have found utility as pharmacological tools (Stark et al.,
1996; Van der Goot and Timmerman, 2000). However,
antagonist carrying on the imidazole heterocycle is the
potential issue for drug–drug interactions through inhibition
of hepatic cytochrome P450 enzymes and poor CNS pene-
tration (Lin and Lu, 1998; Zhang et al., 2005). For these
reasons, and after the successful cloning of the human
histamine H3 receptor by Lovenberg (Lovenberg et al.,
1999), efforts have been directed towards the discovery of
H3 antagonists without an imidazole moiety as these com-
pounds may offer improvements in binding affinity, CNS
penetration, and reduced potential for cytochrome P450
´
R. Guryn Á M. Staszewski Á K. Walczynski (&)
Department of Synthesis and Technology of Drugs, Medical
´
University, Muszynskiego Street 1, 90-145 Łodz, Poland
e-mail: krzysztof.walczynski@umed.lodz.pl
´ ´
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Med Chem Res (2013) 22:3640–3652
3641
enzymes inhibition (Cowart et al., 2004). A number of non-
imidazole antagonists have since been reported (Ganellin
et al., 1998; Celanire et al., 2005). Representative exam-
ples of non-imidazole H3 antagonists included among oth-
ers were JNJ-5207852 (hH3RKi = 0.6 nM) (Apodaca et al.,
2003), UCL 2190 (rH3RKi = 4 nM) (Meier et al., 2001)
and ABT-239 (hH3RKi = 0.45 nM) (Cowart et al., 2002)
(Chart 1).
Previously, our laboratory has described several non-imid-
azole piperazine-based histamine H3 antagonists, consisting of
1-(2-thiazolobenzo)-, 1-(2-thiazolopyridine)- and 1-[2-thiazol-
5-yl-(2-aminoethyl)] moieties with moderate to pronounced
´
affinity for the receptor (Walczynski et al., 1999, 2005;
Frymarkiewicz and Walczynski, 2009). The SAR of 1-[(2-
thiazolobenzo)-4-n-propyl]piperazines and 1-[(2-thiazolopyri-
dine)-4-n-propyl]piperazines series, showed no significant
O
N
N
O
JNJ-5207852
O
N
O
UCL2190
CH3
N
N
H3C
N
S
ABT-239
CN
N
N
C3H7
1
The target molecules of this study
CH3
R
CH3
N
N
N
n
R1
R1
N
S
N
N
S
S
for n=2, 4
N
N
N
N
N
N
C3H7
C3H7
C3H7
2a-k
3a,b
4a-d
where R=CH3 and R1=H
or R=CH3 and R1=CH3; C3H7
where R1=COR2
or R=CH3 and R1=(CH2)n-C6H5 for n=1-5
or R=CH3 and R1=COR2
and
R2=C6H5;4-CH3C6H4;
4-Cl-C6H4; 4-O2NC6H4
where R2=CH3; C6H5;4-CH3C6H4;
4-Cl-C6H4; 4-O2NC6H4
Chart 1 Representative non-imidazole H3-histamine receptor antagonists and the target molecules of this study
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Med Chem Res (2013) 22:3640–3652
Scheme 1 Synthesis of 1-[2-
thiazol-4-yl-(2-aminoethyl)]-4-
n-propylpiperazines 2a–k
O
OC2H5
O
O
S
N
S
LiBH4
DME
Cl
+
C3H7
N
N
OC2H5
N
N
NH2
5
6
7
C3H7
OSO2CH3
OH
NHCH3
Br
N
N
S
N
S
N
S
n
CH3SO2Cl
pyridine
CH3NH2
N
N
CH3CN
N
N
N
8
9
10
C3H7
C3H7
C3H7
H
N
RCOCl NaHCO3/
DME
CH3OH
R
CH3
R1
N
R
O
H3C
N
CH3
N
CH3
n
N
S
N
N
S
N
S
N
N
N
N
2a-d
2e-g
N
2h-k
C3H7
C3H7
C3H7
for R1=C6H5;4-CH3C6H4;
4-ClC6H4; 4-NO2C6H4
for n=3,4,5
for R=CH3; C3H7; (CH2)
where n=1, 2
n
´
difference in H3 activities (Walczynski et al., 1999, 2005).
These results prompted us to replace the benzo ring by
2-methyl-2-alkylaminoethyl amide, 2-methyl-2-alkylamino-
ethyl and 2-methyl-2-phenylalkylaminoethyl chains at position
5 of 1-(2-thiazol-5-yl)-4-n-propylpiperazine moiety. The high-
est affinity for these series has been seen in the compound with
the N-methyl-N-phenylpropylamino substituent 1 (Chart 1;
pA2 = 8.27; electric field stimulation assay on guinea-pig
jejunum) and with slightly lower potencies for compounds
carrying on N-methyl-N-benzylamino and N,N-dimethylamino
substituents with pA2 = 7.75 and 7.78, respectively (Fry-
markiewicz and Walczynski, 2009).
of the thiazole ring. Therefore, the series of 1-[2-thiazol-
4-yl-(2-aminoethyl)]-4-n-propylpiperazines 2a–k (Chart 1),
bearing the substituents showing the highest affinity in
previously described 1-[2-thiazol-5-yl-(2-aminoethyl)]-
4-n-propylpiperazines (Frymarkiewicz and Walczynski, 2009),
was prepared and pharmacologically evaluated (electric
field stimulation assay on guinea-pig jejunum). In addi-
tion, with the aim of the complement 1-[2-thiazol-5-yl-(2-
aminoethyl)]-4-n-propylpiperazines series, 1-[2-thiazol-5-y
l-(2-methyl-2-phenylethyl)]- 3a, 1-[2-thiazol-5-yl-(2-methy
l-2-phenylbutylaminoethyl)]-4-n-propylpiperazine 3b and
1-[2-thiazol-5-yl-(2-methyl-2-phenylcarbonylaminoethyl)]-4-n-
propylpiperazine amides 4a–d (Chart 1) were synthesized.
In this study, we report on synthesis and preliminary
pharmacological investigation of new 1-[2-thiazol-5-yl-
In continuation of our earlier work, we studied the
influence, on H3-receptor antagonistic activity, of the intro-
duction of 2-CH3-2-R-aminoethyl-substitution at position 4
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Med Chem Res (2013) 22:3640–3652
3643
Scheme 2 Synthesis of 1-[2-
thiazol-5-yl-(2-methyl-2-
phenylalkylaminoethyl)]-4-n-
propyl- piperazines 3a, b and
1-[2-thiazol-5-yl-(2-methyl-2-
phenylcarbonylaminoethyl)]-4-
n-propyl- piperazine
CH3
CH3
N
H
N
n
Br
n
N
S
N
S
CH3CN
N
N
amides 4a–d
for n=2, 4
N
N
C3H7
C3H7
11
3a,b
CH3
CH3
R
N
N
H
O
N
S
RCOCl/K2CO3
DME
N
S
N
N
N
N
C3H7
C3H7
11
4a-d
for R=C6H5;4-CH3C6H4; 4-ClC6H4; 4-NO2C6H4
(2-aminoethyl)]-4-n-propylpiperazine derivatives 2 and 1-[2-
thiazol-5-yl-(2-methyl-2-phenylethyl-, 1-[2-thiazol-5-yl-
(2-methyl-2-phenylbutylaminoethyl)]-4-n-propylpiperazines
3 and 1-[2-thiazol-5-yl-(2-methyl-2-phenylcarbonylami-
noethyl)]-4-n-propylpiperazine amides 4.
methy-2-alkylaminoethyl)]-4-n-propylpiperazines 2a,b and
1-[2-thiazol-4-yl-(2-methy-2-phenylalkylaminoethyl)]-4-n-
propylpiperazines 2c,d were prepared from 1-[2-thiazol-
4-yl-(2-mesyloxyethyl)]-4-n-propylpiperazine
9 through
nucleophilic substitution of the mesyloxy group by an
appropriate secondary amine in methanol. Compounds 2e–g,
1-[2-thiazol-4-yl-(2-methyl-2-phenylalkylaminoethyl)]-4-
n-propylpiperazine, were obtained from 1-[2-thiazol-4-y
l-(2-methylaminoethyl)]-4-n-propylpiperazine 10 by alkyl-
ation with the corresponding primary phenyloalkyl halides in
acetonitrile followed by purification with column chroma-
tography. [2-Thiazol-4-yl-(2-metyl-2-phenylcarbonylami-
noethyl)]-4-n-propylpiperazine amides 2h–k were obtained
by standard methods. Compound 10 was acetylated with an
appropriate acid chloride in the presence of NaHCO3 in
DME, followed by purification with column chromato-
graphy.
Chemistry
The general synthetic procedure used in this study is illus-
trated in Schemes 1 and 2. 1-[2-Thiazol-4-yl-(2-methyla-
minoethyl)]-4-n-propylpiperazine 10 (Scheme 1) was
prepared from compound 5 by four-step synthesis including
cyclization reaction of 1-(4-n-propyl)piperazine thioamide 5
with ethyl 4-chloroacetoacetate 6 to 1-[2-thiazol-4-yl-(2-
methoxycarbonylethyl)]-4-n-propylpiperazine 7, reduction
with LiAlH4 in dry ethyl ether to 1-[2-thiazol-4-yl-(2-
hydroxyethyl)]-4-n-propylpiperazine 8, mesylation with
methanesulfonyl chloride in dry pyridine to 1-[2-thiazol-4-
yl-(2-mesyloxyethyl)]-4-n-propylpiperazine 9 and finally
through nucleophilic displacement of the mesyloxy group by
methylamine in methanol to 1-[2-thiazol-4-yl-(2-methyla-
minoethyl)]-4-n-propylpiperazine 10. 1-[2-Thiazol-4-yl-(2-
Compounds 3a, b, 1-[2-thiazol-5-yl-(2-methyl-2-pheny-
lalkylaminoethyl)]-4-n-propylpiperazine (Scheme 2), were
synthesized from compound 11 by alkylation with the corre-
sponding primary phenylalkyl halides in acetonitrile followed
by purification with column chromatography. Amides 4a–d
were obtained by acetylation of 1-[2-thiazol-5-yl-(2-meth-
ylaminoethyl)]-4-n-propylpiperazine 11 (Scheme 2) with an
123

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Med Chem Res (2013) 22:3640–3652
Table 1 H3 antagonistic activity of 1-[2-thiazol-4-yl-(2-aminoethyl)]-4-n-propylpiperazines 2a–k and their homologous series 1-[2-thiazol-5-yl-
(2-aminoethyl)]-4-n-propylpiperazines 3a,b and 4a–d as tested on the in vitro test system on the guinea-pig jejunum
R
CH3
N
CH3
N
R
N
S
N
S
n HBr
m HBr
N
N
N
N
C3H7
2a-k
C3H7
3a,b and 4a-d
R
Cpd.
n
pA2 (sem) H3
N (caviae)
Cpd.
m
pA2 (sem) H3
N (caviae)
CH3–
2a
2b
2c
2d
2e
2f
3
3
3
3
3
3
3
2
2
2
2
6.76 (014)
6.92 (0.10)
7.12 (0.18)
6.81 (0.15)
6.61 (0.11)
6.72 (0.11)
6.69 (0.05)
5.65 (0.00)
5.80 (0.10)
6.23 (0.11)
6.03 (0.02)
9 (3)
9 (3)
9 (3)
9 (3)
9 (3)
9 (3)
9 (3)
6 (2)
9 (3)
9 (3)
9 (3)
*
3
3
3
3
3
3
3
2
2
2
2
7.78 (0.03)
7.53 (0.05)
7.76 (0.06)
7.61 (0.06)
8.27 (0.05)
7.80 (0.03)
7.25 (0.04)
7.45 (0.01)
7.61 (0.16)
7.73 (0.11)
7.76 (0.02)
21 (6)
18 (5)
18 (5)
9 (3)
C3H7–
*
Ph–CH2–
*
Ph–(CH2)2–
Ph–(CH2)3–
Ph–(CH2)4–
Ph–(CH2)5–
Ph–CO–
3a
*
20 (6)
9 (3)
3b
*
2g
2h
2i
11 (5)
9 (3)
4a
4b
4c
4d
p-CH3–Ph–CO–
p-Cl–Ph–CO–
p-NO2–Ph–CO–
9 (3)
2j
9 (3)
2k
9 (3)
Thioperamide—pA2 H3 = 8.43, (sem) (0.07); N (caviae)—18 (6)
H3 antagonistic activity of all compounds marked with asterisk was described in previous paper (Frymarkiewicz and Walczynski, 2009)
sem standard error of the mean, N number of different animal preparation; cavie number of animals; m and n number of HBr
appropriate acid chloride with the presence of K2CO3 in DME,
followed by purification with column chromatography.
All free bases were dissolved in small amount of n-pro-
panol and treated with methanolic HBr. The hydrobromides
crystallized as white solid.
Results and discussion
The compounds were in vitro tested as H3 receptor antagonists—
the electrically evoked contraction of the guinea-pig jejunum.
The presented series of 1-[2-thiazol-4-yl-(2-amino-
ethyl)]-4-n-propylpiperazines (2a–k) and their analogous
1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazine
(3a,b and 4a–d) derivatives possess weak to pronounced
H3-receptor antagonist potency (Table 1).
The 1-(4-n-propyl)piperazine thioamide (5) was directly
obtained by the reaction of the 1-n-propylpiperazine
dihydrobromide with potassium thiocyanate in aqueous
solution (Frymarkiewicz and Walczynski, 2009).
The 5-phenylpentyl bromide was obtained according to
Collins (Collins and Davis, 1961). The 5-phenyl-1-penta-
nol was converted into the bromide by treatment with 50 %
aqueous hydrobromic acid and concentrated sulphuric acid.
The ethyl 4-chloroacetoacetate, 1-n-propylpiperazine
dihydrobromide, benzyl bromide, 1-bromo-3-phenylpropane,
1-bromo-4-phenylbutane 5-phenyl-1-pentanol, dimethylamine
solution in methanol, N-methylpropylamine, N-benzylmeth-
ylamine, N-methyl-2-phenethylamine, benzoyl chloride,
p-toluoyl chloride, 4-chlorobenzoyl chloride and 4-nitrobenzoyl
chloride were all purchased from commercial sources.
The introduction of 2-methyl-2-R-aminoethyl-substituents
at position 4 of the thiazole ring led to the derivatives 2a, b,
d–k having, independent of the sort of substituent, weak
activity, except for derivative 2c showing moderate affinity
with pA2 = 7.12.
It appeared that by comparison of homologous pairs,the
1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazines (3a,b
and 4a–d) have much higher potency than their analogous 1-[2-
thiazol-4-yl-(2-aminoethyl)]-4-n-propylpiperazines (2a–k). The
differences are observed inside of each series. In the case
of 1-[2-thiazol-4-yl-(2-aminoethyl)]-4-n-propylpiperazines,
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Med Chem Res (2013) 22:3640–3652
3645
elongation of alkyl chain from one to three methylene
groups results in an increase of potency for 2a pA2 = 6.76
and 2b pA2 = 6.96, this is in opposition to the 1-[2-thiazol-
5-yl-(2-aminoethyl)]-4-n-propylpiperazine derivatives where
the 1-[2-thiazol-5-yl-(2-N,N-dimethylaminoethyl)]-4-n-propyl-
piperazine shows slightly higher potency than its N-methyl-
N-propyl analogue (pA2 = 7.78; pA2 = 7.53, respectively).
In the 2-methyl-2-phenylalkyl derivatives of 1-[2-thiazol-
4-yl-(2-aminoethyl)]-4-n-propylpiperazine (2c–g), there is
no significant difference in affinity. Elongation of alkyl
chain from one to five methylene groups does not influence
antagonistic activity (pA2 ranging from 6.81 for compound
2d to 6.69 for compound 2g). In the analogues series, there is
no significant difference in affinity among the methyl and
ethyl derivatives (pA2 = 7.76 and 7.61 for compound 3a). A
further elongation in the alkyl chain length to 3 methylene
groups results in an increase of antagonistic activity,
reaching the maximum for 1-[2-thiazol-5-yl-(2-methyl-
2-phenylpropylaminoethyl)]-4-n-propylpiperazine (pA2 =
8.27); activity decreases on further lengthening up to 5
methylene groups (pA2 = 7.80 for compound 3b and 7.25
for 1-[2-thiazol-5-yl-(2-phenylpentylmethylaminoethyl)]-
4-n-propylpiperazine). Replacement of hydrogen by p-benzoyl
substituent at the end of N-methyl group leads to the com-
pounds 2h–k (pA2 from 5.65 to 6.23) and their analogues
4a–d (pA2 from 7.45 to 7.76). By comparison of homologous
pairs, the 1-[2-thiazol-5-yl-(2-methyl-2-phenylcarbonylami-
noethyl)]-4-n-propylpiperazineamides 4a–d have much higher
potency than their analogous 1-[2-thiazol-4-yl-(2-methyl-2-
phenylcarbonylaminoethyl)]-4-n-propylpiperazine amides
2h–k. In both series, a slightly higher activity is observed for
compounds carrying on electron-withdrawing substituent at
para-position in the benzene ring.
uncorrected. For all compounds, 1H NMR spectra were
recorded on a Varian Mercury 300 MHz spectrometer.
Chemical shifts are expressed in ppm downfield from
1
internal TMS as reference. H NMR data are reported in
order: multiplicity (br, broad; s, singlet; d, doublet; t,
triplet; m, multiplet; * exchangeable by D2O) number of
protons, and approximate coupling constant in Hertz. 13C
NMR spectra were recorded on Bruker Avance III
600 MHz spectrometer. Elemental analysis (C, H, N) for
all compounds were measured on Perkin Elmer Series II
CHNS/O Analyzer 2400 and are within 0.4 % of the
theoretical values. TLC was performed on silica gel 60 F254
plates (Merck). Flash column chromatography was carried
˚
out using silica gel 60 A 50 lm (J. T. Baker B. V.),
employing the same eluent as was indicated by TLC.
Chemistry
The synthesis of 1-[2-thiazol-4-yl-(2-
methoxycarbonylethyl)]-4-n-propylpiperazine (7)
The 1-(4-n-propyl)piperazine thioamide (5) (0.032 mol)
was added to a solution of ethyl 4-chloroacetoacetate (6)
(0.032 mol) in 70 mL of n-propanol. The reaction mixture
was heated at 90 °C for 6 h. After cooling, the solvent was
removed in vacuo. The hydrochloride product was obtained
as brown solid. The free base was obtained as follows: the
hydrochloride of the 1-[2-thiazol-4-yl-(2-methoxycarbon-
ylethyl)]-4-n-propylpiperazine (7) was mixed with satu-
rated aqueous sodium bicarbonate solution for 1 h at room
temperature and then water layer was extracted with
dichloromethane (2 9 30 mL). The organic extracts were
washed with water (3 9 30 mL), dried (Na2SO4), filtered
and evaporated to give compound 7 as a sticky oil: The free
base was dissolved in small amount of n-propanol and
treated with methanolic HBr. The dihydrobromide crys-
tallized as white solid.
7. C14H23N3O2S (M = 297); yield 82.6 %; sticky oil; 1H
NMR (CDCl3) d: 0.89–0.95 (t, 3H, CH2CH3 J = 7.5 Hz);
1.25–1.29(t, 3H, CH3CH2O–) 1.48–1.60 (m, 2H, –CH2CH2
CH3); 2.33–2.38 (m, 2H, –CH3CH2 CH2–); 2.52–2.56 (m,
4H CH2CH2N); 3.46–3.50 (m, 4H, –CH2CH2N); 3.60 (s,
2H, CH2CO–) 4.14–4.22(q, 2H CH2O, J = 7.2 Hz) 6,39 (s,
1H, Hthiazole); TLC (methylene chloride:methanol 19:1)
Rf = 0.21
Summarizing, 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-pro-
pylpiperazines display a higher activity than their 1-[2-thia-
zol-4-yl-(2-aminoethyl)]-4-n-propylpiperazine analogues. We
observe that the position 5 of 2-methyl-2-R-aminoethyl-sub-
stituents in the thiazole ring is favourable for histamine H3
receptor antagonist activity, whereas its presence in position 4
leads, almost in each case, to strong decrease of activity.
The highest potency for both homologous series is seen in
the compound with the 2-methyl-2-phenylpropylaminoethyl
substituent (pA2 = 8.27) and with slightly lower potencies for
compounds carrying on 2,2-dimethylaminoethyl, 2-methyl-2-
(4-chlorophenyl)carbonylaminoethyl and 2-methyl-2-(4-nitro-
phenyl)-carbonylaminoethyl substituents (pA2 = 7.78; pA2 =
7.73 and pA2 = 7.76, respectively).
Elemental analysis for dihydrobromide C14H25Br2N3O2 S (459.26)
C
H
N
Experimental protocols
Calculated
Found
36.61 %
36.25 %
5.49 %
5.38 %
9.15 %
9.18 %
General Methods. All melting points (mp) were measured
in open capillaries on an electrothermal apparatus and are
mpdihydrobromide 220–222 °C
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Med Chem Res (2013) 22:3640–3652
CH3SO3CH2, J = 6.6 Hz) 6,29 (s, 1H, Hthiazole); TLC
(methylen chloride:methanol 10:1) Rf = 0.44.
The synthesis of 1-[2-thiazol-4-yl-(2-hydroxyethyl)]-
4-n-propylpiperazine (8)
The synthesis of 1-[2-thiazol-4-yl-(2-methylaminoethyl)]-4-
To a solution of the 1-[2-thiazol-4-yl-(2-methoxycarbon-
ylethyl)]-4-n-propylpiperazine (7) (0.032 mol) in 110 mL
of DME at 55 °C, LiBH4 (0.055 mol) was added. The
mixture was stirred at 70 °C for 24 h. The solvent was
evaporated and remaining material was dissolved in 60 mL
of methanol and was heated at 70 °C for 24 h. The solvent
was evaporated and the residue was purified by column
chromatography on silica gel. The title products were
obtained as sticky oil. The free base was dissolved in small
amount of n-propanol and treated with methanolic HBr.
The dihydrobromide crystallized as white solid.
8. C12H21N3OS (M = 256); yield 75.0 %.; 1H NMR
(CDCl3) d: 0.89–0.95 (t, 3H, CH2CH3 J = 7.5 Hz);
1.51–1.60 (m, 2H, –CH2CH2 CH3); 2.33–2.38 (m, 2H,
–CH3CH2 CH2–); 2.52–2.56 (m, 4H CH2CH2N); 2.75–2.78
(t, 2H, CH2-thiazole J = 5.7 Hz); 3.45–3.49 (m, 4H,
–CH2CH2N); 3.84–3.87 (t, 2H CH2OH, J = 5.7 Hz) 4.01
(s* br, H, OH–) 6.20 (s, 1H, Hthiazole); TLC (methylen
chloride:methanol 10:1) Rf = 0.27.
n-propylpiperazine (10)
The crude 1-[2-thiazol-4-yl-(2-mesyloxyethyl)]-4-n-pro-
pylpiperazine 9 (0.008 mol) was dissolved in 30 mL of
40 % solution methylamine in methanol. The mixture was
stirred at room temperature for 24 h. Then, organic solvent
was evaporated, and residue was dissolved in DME
(40 mL), alkalized with solid NaHCO3 (0.001 mol) and
stirred for 1 h. The mixture was filtered and DME was
evaporated to give compound 2 as a yellowish sticky oil.
The free base was dissolved in small amount of n-propanol
and treated with methanolic HBr. The treehydrobromide
crystallized as white solid.
2. C13H24N4S (M = 268); yield 68.9 %; 1H NMR
(CDCl3) d: 0.90–0.95 (t, 3H, CH2CH3 J = 7.5 Hz);
1.50–1.60 (m, 2H, –CH2 CH3); 2.01 (s* br, 1H, NH);
2.32–2.37 (m, 2H, –CH3CH2 CH2–); 2.45 (s, 3H –CH3);
2.52–2.56; (m, 4H CH2CH2N); 2.73–2.77 (t, 2H, CH2-thi-
azole, J = 6.6 Hz); 2.86–2.91 (t, 2H, CH2N J = 6.6 Hz)
3.45–3.48 (m, 4H, CH2CH2N); 6.19 (s, 1H, Hthiazole); TLC
(chloroform metanol concentrated ammonium hydroxide
60:10:1) Rf = 0.10.
Elemental analysis for dihydrobromide C12H21N3OSx2HBr (M =
417,22)
C
H
N
Calculated
Found
34.54 %
34.30 %
5.56 %
5.52 %
10.07 %
10.07 %
Elemental analysis for treehydrobromide C13H27N4 Br3S (511,20)
C
H
N
mpdihydrobromide 244–246 °C
Calculated
Found
30.54 %
30.61 %
5.32 %
5.23 %
10.96 %
10.97 %
mptreehydrobromide 226–228 °C
The synthesis of 1-[2-thiazol-4-yl-(2-mesyloxyethyl)]-4-n-
propylpiperazine (9)
General method for the preparation of 1-[2-thiazol
-4-yl-(2-alkylmethylaminoethyl)] (2a,b) and 1-[2-
thiazol-4-yl-(2-phenylalkylmethylaminoethyl)] 4-n
-propylpiperazines (2c,d)
To a cooled solution of the 1-[2-thiazol-4-yl-(2-hydroxy-
ethyl)]-4-n-propylpiperazine (8) (0.009 mol) in 10 mL of
dry pyridine, while stirring, methanesulfonyl chloride
(0.009 mol) was added dropwise. The mixture was stirred
at room temperature for 0.5 h. Then, reaction mixture was
poured out in ice-cold water (40 mL) and extracted with
ethyl ether (3 9 50 mL). The combined organic extracts
were dried (Na2SO4), filtered and evaporated to give
compound 9 as a sticky yellow oil. The crude com-
pound 9 was used in the next step without further
purification.
To a solution of 1-[2-thiazol-4-yl-(2-mesyloxyethyl)]-4-n-
propylpiperazine (9) (0.002 mol) in 5.0 mL of methanol,
the corresponding amine (0.004 mol) was added (in case of
the compound 2a—33 % solution dimethylamine in meth-
anol was used). The mixture was stirred at 50 °C for
6–10 h. (monitored by TLC). After the completion of
reaction, the solvent was evaporated and the residue was
alkalized with saturated aqueous NaHCO3 solution (15 mL)
and stirred for 0.5 h. Then, the mixture was extracted with
ethyl ether (3 9 30 mL). The combined organic extracts
were dried (Na2SO4), filtered and evaporated. The residue
was purified by column chromatography on silica gel. The
1
9. C13H23N3O3S2 (M = 333); yield 58.1 %; H NMR
(CDCl3) d: 0.90–0.95 (t, 3H, CH2CH3 J = 7.4 Hz);
1.48–1.60 (m, 2H, –CH2CH2 CH3); 2.33–2.38 (m, 2H,
–CH3CH2 CH2–); 2.52–2.56 (m, 4H CH2CH2N); 2.92 (s,
3H, CH3SO3) 2.96–3.02 (t, 2H, CH2-thiazole J = 6.6 Hz);
3.45–3.48 (m, 4H, –CH2CH2N); 4.49–4.52 (t, 2H
123

Med Chem Res (2013) 22:3640–3652
3647
title products were obtained as sticky oil. The free base was
dissolved in small amount of n-propanol and treated with
methanolic HBr. The hydrobromide crystallized as white
solid to give compounds 2a–d.
(s, 1H, Hthiazole); 7.11–7.26 (m,5H,–Harom); TLC (chlorek
metylenu:metanol 10:1) Rf = 0.23.
IR (for treehydrobromide; KBr) cm-1: 3435, 3071,
2963, 2918, 2702, 2653, 2579, 2459, 1615, 1429, 1287,
1185, 1097, 1056, 969, 751, 699.
2a. C14H26N4S (M = 282); yield 64.0 %.; 1H NMR
(CDCl3) d: 0.89–0.94 (t, 3H, –CH2CH3 J = 7.2 Hz);
1.47–1.57 (m, 2H, –CH2CH2CH3); 2.74 (s, 3H, –NCH3);
2.31–2.36 (m, 2H, –CH3CH2CH2–); 2.51–2.54 (m, 4H
CH2CH2N); 2.58–2.64 (m, 2H, CH2N)); 2.72–2.75 (m, 2H
CH2-thiazole) 3.45–3.48 (m, 4H, –CH2CH2N 6.29 (s, 1H,
Hthiazole); TLC (chloroform:methanol:concentrated ammo-
nium hydroxide 40:10:1) Rf = 0.19. mpthreehydrobromide
242–244 °C.
Elemental analysis for treehydrobromide C20H33Br3N4S (601.31)
C
H
N
Calculated
Found
39.95 %
39.57 %
5.53 %
5.47 %
9.32 %
9.19 %
mpthreehydrobromide 232–234 °C
IR (for dihydrobromide; KBr) cm-1: 3446, 3052, 2962,
2914, 2660, 2587, 2520, 2467, 1613, 1592, 1470, 1432,
1287, 1168, 1133, 997, 969, 813, 662.
2d. C21H32N4S (M = 373); yield 16.9 %; 1H NMR
(CDCl3) d: 0.89–0.94 (t 3H, –CH2CH3 J = 7.3 Hz);
1.47–1.59 (m, 2H, –CH2CH2 CH3); 2.32–2.34 (m, 2H,
–CH3CH2 CH2–); 2.36 (s, 3H, –NCH3); 2.52–2.59 (m, 4H
CH2CH2N); 2.64–2.70 (m, 2H –NCH2CH2-thiazole);
2.70–2.85 (m, 6H, –CH2–thiazole –CH2CH2Ph,); 3.45–3.54
(m, 4H, –CH2CH2N); 6.16 (s, 1H, Hthiazole); 7.18–7.30 (m,
5H, Harom); (TLC (chloroform:metanol:amoniak 60:10:1)
Rf = 0.55.
Elemental analysis for dihydrobromide C14H29Br3N3S (525,22)
C
H
N
Calculated
Found
33.01 %
32.70 %
5.57 %
5.67 %
10.67 %
10.62 %
mpthreehydrobromide 242–244 °C
IR (for treehydrobromide; KBr) cm-1: 3430, 3071,
2962, 2928, 2702, 2653, 2577, 2458, 1613, 1594, 1456,
1411, 1357, 1289, 1181, 1098, 1055, 968, 807, 751, 698.
2b. C16H30N4S (M = 310); yield 68.0 %.; 1H NMR
(CDCl3) d: 0.87–0.95 (m 6H, –CH2CH3); 1.47–1.60 (m,
4H, –CH2CH2 CH3); 2.32 (s, 3H, –NCH3); 2.34–2.43 (m,
4H, –CH3CH2 CH2–); 2.52–2.55 (m, 4H CH2CH2N); 2.76
(s, 4H –NCH2CH2thiazole); 3.45–3.48 (m, 4H, –CH2CH2N);
6.29 (s, 1H, Hthiazole); TLC (chloroform:methanol:concen-
trated ammonium hydroxide 40:10:1) Rf = 0.25.
Elemental analysis for treehydrobromide C21H35Br3N4S (615.32)
C
H
N
Calculated
Found
40.72 %
40.57 %
5.70 %
5.37 %
9.05 %
9.02 %
IR (for treehydrobromide; KBr) cm-1: 3428, 3073,
2963, 2923, 2708, 2655, 2581, 2527, 2469, 1611, 1591,
1459, 1426,1356, 1289, 1239, 1181, 1133, 1099, 1055,
1028, 967, 898, 808, 760, 721, 638, 548.
mpthreehydrobromide 216–218 °C
General method for the preparation of 1-[2-thiazol-4
-yl-(2-phenylalkylmethylaminoethyl)] 4-n-
propylpiperazines (2e–g) and 1-[2-thiazol
-5-yl-(2-phenylalkylmethylaminoethyl)] 4-n-
propylpiperazines (3a,b)
Elemental analysis for treehydrobromide C16H33Br3N4S (553.27)
C
H
N
Calculated
Found
34.73 %
34.71 %
6.01 %
6.07 %
10.13 %
10.13 %
mpthreehydrobromide 242–244 °C
To a solution of 1-[2-thiazol-4-yl-(2-methylaminoethyl)]-
4-n-propylpiperazine (10) (0.002 mol) or 1-[2-thiazol-5-yl-
(2-methylaminoethyl)]-4-n-propylpiperazine (11) (0.002 mol)
with the presence of K2CO3 (0.003 mol) in 5.0 mL of ace-
tonitrile, the corresponding phenylalkyl bromide (0.002 mol)
was added. The mixture was stirred at room temperature for
6–10 h (monitored by TLC). Then, inorganic salt was filtered
off and solvent was evaporated. The residue was purified by
column chromatography on silica gel. The title products were
2c. C20H30N4S (M = 359); yield 41.0 %; 1H NMR
(CDCl3) d: 0.81–0.86 (t 3H, –CH2CH3 J = 7.4 Hz);
1.38–1.51 (m, 2H, –CH2CH2 CH3); 2.16 (s, 3H, –NCH3);
2.22–2.28 (m, 4H, –CH3CH2 CH2–); 2.36–2.45 (m, 4H
CH2CH2N); 2.63–2.76 (m, 4H –NCH2CH2-thiazole);
3.35–3.44 (m, 4H, –CH2CH2N) 3.46 (s, 2H, CH2Ph) 6.29
123

3648
Med Chem Res (2013) 22:3640–3652
obtained as sticky oil. The free base was dissolved in small
amount of n-propanol and treated with methanolic HBr. The
hydrobromide crystallized as white solid to give compounds
2e–g and 3a,b, respectively.
NCH3); 2.41–2.52 (m, 6H, CH2CH2N CH2CH2Ph
2.56–2.61 (t, 2H –CH2Ph 2,76 (s, 4H, thiazole CH2CH2N);
3.39–3.46 (m, 4H, –CH2CH2N) 6.17 (s, 1H, Hthiazole);
7.12–7.28 (m,5H,–Harom); TLC (chloroform:metanol:amo-
niak 60:10:1) Rf = 0.51.
IR (for threehydrobromide; KBr) cm-1: 3427, 3305,
3077, 2937, 2876, 2653, 2580, 2458, 1616, 1597, 1434,
1286, 1185, 1096, 967, 807, 756, 701, 528.
2e. C22H34N4S (M = 387); yield 39.8 %; 1H NMR
(CDCl3) d: 0.91–0.96 (t 3H, –CH2CH3 J = 7.3 Hz);
1.49–1.62 (m, 2H, –CH2CH2 CH3); 1.76–1.86 (m, 2H,
–CH2CH2 CH2); 2.29 (s, 3H, –NCH3); 2.33–2.38 (m, 2H,
–CH3CH2 CH2–); 2.43–2.48 (t, 2H, –NCH2CH2 CH2,
J = 7.5 Hz); 2.51–2.63 (m, 6H, –CH2CH2N, CH2Ph,);
2.71(s, 4H, –CH2-thiazole CH2CH2N); 3.42–3.45 (m, 4H,
–CH2CH2N); 6.34 (s, 1H, Hthiazole); 7.12–7.28 (m,5H,–Harom);
TLC (chloroform:metanol:amoniak 60:10:1) Rf = 0.46.
IR (for threehydrobromide; KBr) cm-1: 3428, 3075,
2962, 2922, 2649, 2577, 2519, 2458, 2363, 1620, 1453, 1430,
1403, 1286, 1240, 1185, 1134, 1033, 967, 808, 753, 700.
Elemental analysis for threehydrobromide C24H41Br3N4S (M =
657.40)
C
H
N
Calculated
Found
43.84 %
43.75 %
6.29 %
6.32 %
8.52 %
8.55 %
mpthreehydrobromide 214–216 °C
Elemental analysis for threehydrobromide C22H37Br3N4S (629.7)
1
C
H
N
3a. C21H32N4S (M = 372.56); yield 48.0 %; H NMR
(CDCl3) d: 0.90–0.92 (t 3H. –CH2CH3 J = 7.2 Hz); 1.50–
1.56 (m, 2H, –CH2CH3); 2.32–2.34 (m, 2H CH3CH2CH2N);
2.35 (s, 3H CH3N); 2.52–2.53 (m, 4H –CH2CH2N);
2.62–2.67 (m, 4H CH2Ph CH2N) 2.77–2.82 (m, 2H –CH2N
–CH2-tiazol); 3.43–3.45 (m 4H –CH2CH2N); 6.87 (s 1H
Hthiazole); 7.16–7.28 (m 5H Harom.); TLC (chloroform:meth-
anol 9:1) Rf = 0.23.
Calculated
Found
41.98 %
41.93 %
5.93 %
5.96 %
8.90 %
8.88 %
mpthreehydrobromide 220–222 °C
2f. C23H36N4S (M = 401); yield 40.5 %; 1H NMR
(CDCl3) d: 0.90–0.94 (t 3H, –CH2CH3 J = 7.3 Hz);
1.47–1.67 (m, 6H, –CH2CH2 CH3, CH2CH2N; CH2 CH2Ph);
2.27 (s, 3H, –NCH3); 2.32–2.44 (m, 4H, –CH3CH2 CH2,
NCH2CH2 CH2–); 2.41–2.49 (m, 4H CH2CH2N); 2.59–2.64
(t, 2H, CH2Ph J = 7.2 Hz); 2.72 (s, 4H, –thiazole
CH2CH2N); 3.42–3.48 (m, 4H, –CH2CH2N); 6.16 (s, 1H,
Hthiazole); 7.16–7.29 (m,5H,–Harom); TLC (chloroform:met-
anol:amoniak 60:10:1) Rf = 0.49.
IR (for threehydrobromide; KBr) cm-1: 3507, 3451,
3052, 2959, 2915, 2695, 2583, 2526, 1578, 1430, 1409,
1309, 1291, 1243, 1188, 1161, 1093, 1033, 964, 810, 756,
728, 703, 623, 544, 510.
Elemental analysis for threehydrobromide C21H35Br3N4S (M = 615.34)
C
H
N
IR (for threehydrobromide; KBr) cm-1: 3523, 3422,
3067, 2965, 2938, 2705, 2655, 2582, 2529, 2469, 1613,
1592, 1457, 1413, 1357, 1289, 1182, 1097, 1029, 969, 809,
748, 705, 669, 550.
Calculated
Found
40.99 %
40.92 %
5.73 %
5.51 %
9.11 %
9.16 %
mpthreehydrobromide 204–206 °C
Elemental analysis for threehydrobromide C23H39Br3N4S (643.7)
1
3b. C23H36N4S (M = 400.62) yield 61.0 %; H NMR
(CDCl3) d: 0.91–0.93 (t, 3H. –CH2CH3 J = 7.2 Hz); 1.49–
1.56 (m, 4H –CH2CH2CH2N); 1.62–1.67 (m, 2H CH2CH3);
2.23 (s, 3H CH3N); 2.32–2.34 (m, 2H CH3CH2CH2N);
2.38–2.40 (t, 2H J = 7.2 Hz CH2N); 2.50–2.55 (m, 6H
–CH2CH2N –CH2Ph); 2.61–2.63 (t, 2H J = 7.2 Hz CH2N);
2.77–2.79(t, 2H J = 7.2 Hz CH2-tiazol); 3.42–3.43 (m, 4H
–CH2CH2N); 6.87 (s, 1H Hthiazole); 7.15–7.26 (m 5H Harom.);
TLC (chloroform: methanol 9:1) Rf = 0.14.
C
H
N
Calculated
Found
42.93 %
42.73 %
6.11 %
6.27 %
8.71 %
8.67 %
mpthreehydrobromide 217–219 °C
2g. C24H38N4S (M = 415); yield 66.8 %; 1H NMR
(CDCl3) d: 0.88–0.93 (t 3H, –CH2CH3 J = 7.3 Hz);
1.27–1.37 (m, 2H, (CH2)2CH2(CH2)2); 1.45–1.65 (m, 6H,
–CH2CH2 CH3, CH2CH2N); 2.30–2.35 (m, CH3CH2CH2–
IR (for threehydrobromide; KBr) cm-1: 3471, 3399,
3052, 2938, 2639, 2597, 2473, 1627, 1498, 1434, 1291,
1193, 1027, 964, 846, 752, 722, 597.
123

Med Chem Res (2013) 22:3640–3652
3649
Elemental analysis for threehydrobromide C23H39Br3N4S (M = 643.39)
2i. C21H30N4OS (M = 386); yield 71.9 %; (d in ppm;
CDCl3, 600 MHz); 171.53; 161.18; 159.80; 139.83;
133.26; 128.69; 126.73; 121.78; 60.08; 52.05; 46.07;
44.05; 33.09; 28.34; 21.50; 20.46; 13.29;.TLC (dichloro-
methane: methanol: 10:1) Rf = 0.28.
C
H
N
Calculated
Found
42.93 %
42.87 %
6.11 %
6.14 %
8.71 %
8.78 %
IR (for dihydrobromide; KBr) cm-1: 3431, 3102, 3000,
2926, 2768, 2569, 2514, 2462, 1597, 1478, 1455, 1406,
1362, 1291, 1276, 1184, 1122, 1075, 998, 967, 834, 786,
715, 640, 565, 476.
mpthreehydrobromide 260–262 °C
MS m/z (relative intensity) 386 (M?, 12), 288 (43), 152
General method for the preparation of 1-[2-thiazol-4-
yl-(2-methyl-2-phenylcarbonylaminoethyl)]-4-n-
propylpiperazine amides 2h–k and 1-[2-thiazol-5-yl-
(2-methyl-2-phenylcarbonylaminoethyl)]-4-n-
propylpiperazine amides 4a–d
(13), 139 (22), 126 (15), 119 (100) 111 (14), 98 (20), 91 (30).
Elemental analysis for dihydrobromide C21H30Br2N4OS (M = 547.8)
C
H
N
To a solution of 1-[2-thiazol-4-yl-(2-methylaminoethyl)]-
4-n-propylpiperazine (2) or 1-[2-thiazol-5-yl-(2-methylami-
noethyl)]-4-n-propylpiperazine (11) (0.001 mol) in 10 mL
of DME, the corresponding acid chloride (0.001 mol) was
added. After 15 min, NaHCO3 (0.001 mol) was added and
the mixture was stirred at room temperature for 24 h. The
solvent was evaporated and the residue was suspended with
H2O (30 mL) and extracted with chloroform (3 9 30 mL).
The combined organic extracts were dried (Na2SO4), fil-
tered and evaporated. The residue was purified by column
chromatography on silica gel. The title products were
obtained as sticky oil. The free base was dissolved in small
amount of n-propanol and treated with methanolic HBr. The
hydrobromide crystallized as white solid to give compounds
Calculated
Found
46.00 %
45.91 %
5.88 %
5.94 %
10.22 %
10.16 %
mpdihydrobromide 210–212 °C
2j. C20H27ClN4OS (M = 407); yield 49,5 %; (d in ppm;
CDCl3, 600 MHz); 171.86; 161.34; 159.80; 136.81;
132.00; 129.73; 127.53; 121.78; 59.73; 51.27; 46.95;
43.56; 31.33; 27.54; 20.46; 13.29; TLC (dichloromethane:
methanol: 10:1) Rf = 0.38.
IR (for dihydrobromide; KBr) cm-1: 3101, 3072, 2967,
2928, 2759, 2706, 2574, 2463, 1617, 1596, 1441, 1408,
1291, 1215, 1186, 1122, 1093, 1073, 1014, 965, 915, 845,
786, 757, 691, 670, 639, 553, 474.
1
2h–k and 4a–d, respectively. Because H NMR data for
compounds 2h–k and 4a–d have been illegible. 13C NMR
data are presented for these derivatives.
MS m/z (relative intensity) 406 (M?, 10), 308 (37), 152
(15), 141 (23), 139 (100), 126 (19), 111 (18), 98 (25).
2h. C20H28N4OS (M = 372); yield 82.9 %; (d in ppm;
CDCl3, 600 MHz); 171.67; 161.18; 159.80; 137.06;
129.94; 128.00; 127.15; 122.37; 59.28; 52.05; 45.42;
43.59; 33.16; 27.08; 20.46; 13.29;. TLC (dichloromethane:
methanol: 10:1) Rf = 0,36.
Elemental analysis for dihydrobromide C20H29Br2ClN4OS (M =
568.81)
C
H
N
IR (for dihydrobromide; KBr) cm-1: 3399, 3104, 3077,
2974, 2919, 2793, 2919, 2793, 2703, 2664, 2576, 2465,
1599, 1501, 1439, 1406, 1275, 1218, 1187, 1122, 1072,
1029, 998, 967, 841, 798, 723, 637, 566, 463.
Calculated
Found
42.22 %
42.33 %
5.14 %
5.01 %
9.85 %
9.98 %
mpdihydrobromide 221–223 °C
MS m/z (relative intensity) 372 (M?, 17), 274 (66), 261
(13), 152 (17), 139 (41), 126 (24), 111 (17), 105 (100), 77 (33).
2k. C20H27N5O3S (M = 417); yield 75,5 % (d in ppm;
CDCl3, 600 MHz); 171.98; 161.57; 159.87 148.38; 143.12;
127.64; 123.71; 121.87; 55.24; 45.42; 43.81; 33.25; 27.89;
20.53; 13.32; TLC (dichloromethane: methanol: 10:1)
Rf = 0.43.
IR (for dihydrobromide; KBr) cm-1: 3430, 3102, 1620,
1597, 1522, 1439, 1410, 1352, 1290, 1179, 1073, 1031,
965, 869, 851, 747, 723, 639, 558, 457.
Elemental analysis for dihydrobromide C20H30Br2N4OS (M = 534.37)
C
H
N
Calculated
Found
44.91 %
45.00 %
5.28 %
5.47 %
10.48 %
10.58 %
mpdihydrobromide 227–228 °C
123

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Med Chem Res (2013) 22:3640–3652
MS m/z (relative intensity) 417 (M?, 22), 319 (100), 208
26.25; 20.52; 13.30; TLC (dichloromethane: methanol:
concentrated ammonium hydroxide 89:10:1) Rf = 0.74
IR (for dihydrobromide; KBr) cm-1: 3522, 3422, 3034,
2988; 2938, 2896, 2656, 2569, 2458, 1622, 1430, 1399,
1339, 1291, 1257, 1174, 1089, 1039, 968, 832, 793, 758,
728, 682, 600, 552, 480.
(21), 152 (32), 139 (75), 126 (26), 120 (26), 111(31),
104(31), 98 (64).
Elemental analysis for dihydrobromide C20H29Br2N5O3S (M = 579.37)
C
H
N
MS m/z (relative intensity) 406 (M?, 18), 288 (27), 308
(28), 237 (34), 224 (100), 152 (64), 141 (21), 139 (92), 112
(31), 111 (43), 98 (45).
Calculated
Found
41.46 %
41.45 %
5.05 %
5.07 %
12.09 %
12.05 %
mpdihydrobromide 195–197 °C
Elemental analysis for dihydrobromide C20H29Br2ClN4OS (M = 568.81)
Calculated
Found
42.22 %
42.41 %
5.14 %
5.22 %
9.85 %
9.61 %
4a. C15H29Br3N4OS (M = 372); yield 80,1 %; (d in
ppm; CDCl3, 600 MHz); 172.87; 159.28; 138.48; 131.10;
130.04; 128.00; 126.46; 120.54; 56.47; 51.26; 45.44;
39.64; 32.76; 26.28; 20.49; 13.29;.TLC (dichlorometh-
ane:methanol: 19:1) Rf = 0.32.
IR (for dihydrobromide monohydrate; KBr) cm-1: 3509,
3436, 3046, 2971, 2923, 2681, 2586, 2522, 2464, 2084,
1629, 1607, 1575, 1443, 1402, 1360, 1294, 1221, 1098,
1075, 1023, 969, 794, 743, 714, 631, 546.
mpdihydrobromide 206–208 °C
4d. C20H27N5O3S (M = 417) yield 83.0 %; (13C d in
ppm; CDCl3, 600 MHz); 172.98; 159.67; 148.27; 140.43;
138.48; 126.87; 123.71; 120.51; 56.42; 51.56; 45.48;
39.81; 32.76; 26.22; 20.51; 13.32; TLC (dichloromethane:
methanol: 10:1) Rf = 0.43.
IR (for dihydrobromide monohydrate; KBr) cm-1: 3451,
3039, 2968, 2934, 2903, 2784, 2696, 2601, 2515, 2457,
1625, 1599, 1524, 1445, 1429, 1404, 1353, 1290, 1260,
1176, 1095, 1033, 1009, 968, 870, 742, 725.
MS m/z (relative intensity) 372 (M?, 24), 274 (40), 237
(60), 224 (100), 152 (21), 139 (30), 112 (20), 105 (64), 98
(34), 77 (34).
MS m/z (relative intensity) 417 (M?, 26), 319 (55), 237
(20), 224 (100), 152 (27), 150 (39) 141 (21), 139 (34),120
(25), 112 (29), 111 (68), 98 (88).
Elemental analysis for dihydrobromide monohydrate C20H30Br2N4OS
H2O (M = 552.39)
C
H
N
Calculated
Found
43.48 %
43.73 %
5.84 %
5.74 %
10.14 %
10.20 %
Elemental analysis for dihydrobromide monohydrate C20H29Br2
N5O3S H2O (M = 597.39)
mpdihydrobromide 224–226 °C
Calculated
Found
40.20 %
40.46 %
5.23 %
5.03 %
11.72 %
11.77 %
4b. C21H30N4OS (M = 387) yield 79,2 %; (d in ppm;
CDCl3, 600 MHz); 172.67; 159.80; 140.06; 138.48; 128.32;
125.97; 120.45; 56.39; 51.34; 45.42; 39.75; 32.84; 26.16;
21.50; 20.46; 13.29; TLC (dichloromethane: methanol:
concentrated ammonium hydroxide 89:10:1) Rf = 0.51.
IR (for dihydrobromide; KBr) cm-1: 3430, 3079, 2967,
2920, 2637, 2564, 2452, 1611, 1479, 1437,1400, 1285, 1270,
1199, 1068, 1039, 968, 925, 873, 839, 757, 726, 583, 508.
MS m/z (relative intensity) 386 (M?, 20), 288 (27), 237
(80), 224 (95), 152 (25), 139 (28), 119 (100)112 (31), 111
(45), 98 (39), 91 (36).
mpdihydrobromide 195–197 °C
Pharmacology
All compounds were tested for H3 antagonistic effects
in vitro on the guinea-pig jejunum using standard methods
(Vollinga et al., 1992).
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 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
Elemental analysis for dihydrobromide C20H30Br2N4OS (M = 534.37)
Calculated
Found
45.99 %
45.92 %
5.88 %
5.91 %
10.22 %
10.16 %
mpdihydrobromide 196–198 °C
4c. C20H27ClN4OS (M = 407) yield 78,3 %; (d in ppm;
CDCl3, 600 MHz); 172.87; 159.28; 138.53; 136.18 129.26;
128.96; 127.53; 120.00; 56.39; 51.23; 45.57; 39.61; 32.82;
123

Med Chem Res (2013) 22:3640–3652
3651
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Open Access This article is distributed under the terms of the
Creative Commons Attribution License which permits any use, dis-
tribution, and reproduction in any medium, provided the original
author(s) and the source are credited.
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