Non-imidazole histamine H3 ligands. Part III. New 4-n-propylpiperazines as non-imidazole histamine H3-antagonists

Article abstract of DOI:10.1016/j.ejmech.2004.09.010

In search for a new lead of non-imidazole histamine H₃-receptor antagonists, a series of 1[(2-thiazolopyridine)-4-n-propyl]piperazines, the analogous 1-[(2-oxazolopyridine)-4-npropyl]piperazines, 1-[(2-benzothiazole)-4- n-propyl]piperazine and 1-[(2-benzooxazole)4-n-propyl]piperazine were 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 thiazolo derivatives have slightly higher activity than their oxazolo analogues. The most potent compound of these series is the 1-(2-thiazolo[4,5-c]pyridine)-4-n-propylpiperazine (3c) with pA₂ = 7.25 (its oxazole analogue (4g) showed pA₂ = 6.9). The structure-activity relationships for compounds with various positions of the nitrogen in the benzene ring for the thiazoles compared with oxazoles are discussed.

Full text of DOI:10.1016/j.ejmech.2004.09.010

European Journal of Medicinal Chemistry 40 (2005) 15–23
www.elsevier.com/locate/ejmech
Original article
Non-imidazole histamine H3 ligands. Part III. New 4-n-propylpiperazines
as non-imidazole histamine H3-antagonists
Krzysztof Walczyn´ski a,*, Obbe P. Zuiderveld b, Henk Timmerman b
a Department of Synthesis and Technology of Drugs, Medical University Muszyn´skiego, Muszyn´skiego Street 1, 90-145 Łódz´, Poland
b Leiden/Amsterdam Centre for Drug Research, Division of Medicinal Chemistry, Vrije Universiteit, De Boelelaan 1083,
1081 HV Amsterdam, The Netherlands
Received 5 April 2004; received in revised form 1 September 2004; accepted 6 September 2004
Available online 15 December 2004
Abstract
In search for a new lead of non-imidazole histamine H3-receptor antagonists, a series of 1[(2-thiazolopyridine)-4-n-propyl]piperazines, the
analogous 1-[(2-oxazolopyridine)-4-npropyl]piperazines, 1-[(2-benzothiazole)-4-n-propyl]piperazine and 1-[(2-benzooxazole)4-n-propyl]-
piperazine were 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 thiazolo derivatives have slightly higher activity than their oxazolo analogues. The most
potent compound of these series is the 1-(2-thiazolo[4,5-c]pyridine)-4-n-propylpiperazine (3c) with pA2 = 7.25 (its oxazole analogue (4g)
showed pA2 = 6.9). The structure–activity relationships for compounds with various positions of the nitrogen in the benzene ring for the
thiazoles compared with oxazoles are discussed.
© 2004 Elsevier SAS. All rights reserved.
Keywords: Histamine H3-receptor; H3-antagonists; 1-[(2-Thiazolopyridine)-4-n-propyl]piperazines; 1[(2-Oxazolopyridine)-4-n-propyl]piperazines; 1-[(2-
Benzothiazole)-4-n-propyl]piperazine; 1-[(2-Benzooxazole)-4-n-propyl]piperazine
1. Introduction
target for the design of new therapeutics. However, hista-
mine H3-receptors antagonists have not been introduced into
therapy yet, but potential therapeutic applications have been
proposed, e.g. memory and learning deficits [10–12], epi-
lepsy [13,14], Alzheimer’s disease [15,16], and attention-
deficit hyperactivity disorder [17].
Histamine H3-receptors have been shown to be inhibitory
presynaptic autoreceptors, which modulate the synthesis [1]
and release [2] of histamine at histaminergic neurons in the
central nervous system (CNS). The H3-receptors also occur
as heteroreceptors on nonhistaminergic, as serotoninergic [3],
cholinergic [4], noradrenergic [5] and dopaminergic [6] neu-
rons. After several efforts made by various laboratories to
clone the H3-receptor, Lovenberg et al. [7] cloned and iden-
tified the human histamine H3-receptor. When Drutel et al.
[8] identified the cDNAs of three functional rat H3-receptor
isoforms (H3A, H3B, and H3C) and one non-functional trun-
cated H3-receptor (H3T), it became clear that a new chapter
in the understanding of the role of the third histamine recep-
tor subtype has been opened [9].
Since the discovery of thioperamide (Ki = 4.3 nM) [18]
(Chart 1), the prototype of H3-antagonist, many potent ligands
carrying an imidazole moiety have been described [19–24]
among others, potent and selective antagonists with high in
vitro and in vivo activity FUB 470 [25] and ciproxifan [26]
(Chart 1). The most representative compound of this group is
GT 2331 (Ki = 0.12 nM) [27] (Chart 1); the first histamine
H3-antagonist to be taken into human clinical trials. Because
of the presence of the imidazole nucleus in most active
ligands, these compounds may show poor blood–brain bar-
rier (BBB) penetration [28], but not always. In this light, for
potential therapeutic use, the design of histamine H3-receptor
ligands devoid of an imidazole ring is desirable. Early attempts
to replace the imidazole moiety in existing H3-receptor ligands
with other nitrogen containing heterocycles have met with
Actually it has become evident that the H3-receptor is the
part of a general regulatory system, which may serve as the
* Corresponding author. Tel.: +48 42 677 9196.
E-mail address: kwalczynski@pharm.am.lodz.pl (K. Walczyn´ski).
0223-5234/$ - see front matter © 2004 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2004.09.010

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K. Walczyn´ski et al. / European Journal of Medicinal Chemistry 40 (2005) 15–23
4-(phenoxymethyl)benzyles [39] moieties. Compound (2) (Ki
= 0.086 nM) [38] (Chart 1) is one of the most potent non-
imidazole histamine H3-receptor antagonists, reported so far,
possessing also a strong inhibitory activity on the main his-
tamine metabolising enzyme, histamine N-methyltransferase.
Previously we reported the synthesis and biological evalu-
ation of 1-[(2-benzothiazole)-4substituted]piperazine deriva-
tives as non-imidazole histamine H3-receptor antagonists
[40,41]. It was shown that the most potent compounds under
in vitro screening conditions were the n-propyl-, iso-propyl-
and allylbenzothiazole derivatives. These results suggested
that for optimal size in the alkyl homologues series, the sub-
stituent should consist of three carbon atoms independently
on a presence or an absence of a double bond.
In the continuation of our earlier work, in search for the
new lead of non-imidazole histamine H3-receptor antagonist,
we have studied the influence on H3-receptor antagonistic
activity; of the introduction of an additional nitrogen at vari-
ous positions in the benzene ring and replacement of the sul-
phur atom by oxygen in the thiazole ring, keeping 1-n-
propylpiperazine moiety present. Therefore, the series of
1-[(2thiazolopyridine)-4-n-propyl]piperazines (3) (Chart 1)
and the analogous 1-[(2-oxazolopyridine)-4-n-propyl]
piperazines (4) (Chart 1) were synthesised and their activi-
ties were pharmacologically determined.
2. Chemistry
The general synthetic procedure used in this study is illus-
trated in Scheme 1. The series of 1-[(2-thiazolopyridine)-4-
n-propyl]piperazines (3a–d) (Table 1) and the analo-
gous 1-[(2oxazolopyridine)-4-n-propyl]piperazines (4e–h)
(Table 1) were prepared from the appropriate 2-(methyl-
thio)thiazolo- (3a1–d1) or 2-(methylthio)oxazolepyridines
(4e1–h1) by nucleophilic substitution of the methylthio group
by 1-n-propylpiperazine (5).
The crude products were purified with column chromatog-
raphy. All free bases were treated with methanolic HBr and
the corresponding hydrobromides were precipitated with dry
diethyl ether.
The appropriate 2-(methylthio)thiazolo- (3a1–d1) and
2-(methylthio)oxazolopyridines (4e1–h1) were synthesised
according to known methods [42–45] as shown in Schemes 2,
3, respectively. The 2-(methylthio)thiazolopyridines (3a1–
d1) were obtained by subsequent treatment of sodium salts
Chart 1. Structures of some known histamine H3-receptor antagonists and
the target molecules of this study.
limited success [29–31]. One of the first successful replace-
ments of the imidazole ring of a known compound was
reported by Ganellin et al. [32] UCL1972 (Ki = 39 nM; ED50
= 1.1 mg/kg) (Chart 1). Based on the structure of the hista-
mine H3-receptors, weak active sabeluzole (antagonist), and
dimaprit as potential leads led to the discovery of the active
benzothiazole (1) (pA2 = 7.67; pKi = 8.2) [33], and JB 98064
(pKB = 8.38; pKi = 8.7) [34] (Chart 1), respectively. Only
very recently several groups have described series of potent
non-imidazole based histamine H3-antagonists. Thus these
groups have used such nuclei as pyrrolidine [35] and
piperidine linked with substituted: fluorenes [36],
2-phenylimidazopyridines [37], aminoquinolines [38] and
of (a2, b3, c2, d3) with methyl iodide in C
2H5OH.
The thiazolopyridine-2-thiones (a2, c2) were obtained
according to Procedure A (Scheme 2). Thus, 2-chloro-3-
Scheme 1. Synthesis of 1-[(2-thiazolopyridine)-4-n-propyl]piperazines (3a–d) and the analogous 1-[(2-oxazolopyridine)-4-n-propyl]piperazines (4e–h).

K. Walczyn´ski et al. / European Journal of Medicinal Chemistry 40 (2005) 15–23
17
Table 1
Histamine H3-receptor antagonistic activity of compounds (3a–d), (4e–h), (9) and (10) as tested on the in vitro test system on the guinea-pig jejunum
Compound
m
R
pA2 (S.E.M.) H3 N (caviae)
Compound
m
R
pA2 (S.E.M.) H3 N (caviae)
9
2
7.17 (0.06)
7.08 (0.03)
6.98 (0.02)
7.25 (0.07)
5.98 (0.07)
11 (5)
21 (4)
18 (2)
20 (4)
18 (2)
10
2
6.95 (0.04)
6.63 (0.13)
6.64 (0.03)
6.90 (0.07)
5.42 (0.05)
22 (4)
15 (4)
30 (3)
20 (4)
43 (3)
3a
3b
3c
3d
2
3
2
2
4e
4f
2
2
2
2
4g
4h
S.E.M. – Standard error of the mean. N – Number of different animal preparations. Caviae – Number of animals.
nitropyridine (a1) or 4-chloro-3-nitropyridine (c1) was con-
verted to the corresponding thiazolopyridine-2-thiones (a2)
[42], (c2) [43]) by treatment with H2S in a water solution of
sodium hydroxide in the presence of sodium sulphide and
carbon disulphide. The thiazolopyridine-2-thiones (b3) [44]
and (d3) [45] (Procedure B; Scheme 2) were obtained as
follows: firstly the treatment of doubly lithiated 4-(b1) [44]
or 2(pivaloyloamino)pyridine (d1) [45]—synthesised by the
reaction of 4- or 2-aminopyridine with pivaloyl chloride in
dry dichloromethane in the presence of triethylamine—with
tetraisopropylothiuram disulphide (TITD) [44] led to (b2) or
(d2). Subsequent hydrolysis of (b2) or (d2) in 20% ethanolic
sodium hydroxide solution gave the 2-mercaptothiazo-
lopyridines (b3) [44] or (d3) [45]).
The 2-(methylthio)oxazolopyridines [46] (4e1–h1;
Scheme 3) were obtained by subsequent treatment of (e2–
h2) with methyl iodide in DMF in the presence of K2CO3.
The 2-thiooxazolopyridines [46] (f2–h2) were obtained by
cyclisation reaction of the appropriate aminohydroxypy-
ridines (f1–h1) with potassium ethyl xanthate in refluxing
ethanol. The 2-thiooxazolo[5,4-b]pyridine (e2) [46]
(Scheme 3) was obtained by treatment of 3-amino-
hydroxypyridine (e1) with thiophosgene in THF under N2.
2-Amino-3-hydroxypyridine (h1) is commercially avail-
able, while 3-amino-4-hydroxypyridine (g1) [47] and
3-amino-2-hydroxypyridine (e1) [48] are easily obtained via
hydrogenation of the corresponding nitro derivatives. The syn-
thesis of 4-amino-3-hydroxypyridine (f1) [46] is schemati-
cally shown in Scheme 4. To the 4(pivaloyloamino)pyridine
(b1), after ortho lithiation with n-BuLi, was introduced the
hydroxyl group, using the reactive electrophile trimethyl
borate (B(OCH3)3), what resulted in 3-hydroxy-4-
(pivaloyloamino)pyridine (6). Cleavage of the pivaloyl group
with 10% HCl led to the desired pyridinol (f1) in good yield.
The 1-[(2-benzothiazole)-4-n-propyl]piperazine (9) [41]
and 1-[(2-benzooxazole)-4-npropyl]piperazine (10) were pre-
pared using well established pathways (Scheme 5), from
2-chlorobenzothiazole (7) or 2-chlorobenzooxazole (8)
through nucleophilic substitution of the chlorine atom by 1-n-
propylpiperazine (5). The crude products were purified with
column chromatography. Free bases were treated with metha-
nolic HBr and the corresponding hydrobromides were pre-
cipitated with dry diethyl ether.
The TITD [44] was prepared by the reaction of diisopro-
pylamine with carbon disulphide in aqueous sodium hydrox-
ide solution in the presence of potassium ferricyanide.
3. Pharmacology
All target compounds were tested for H3-antagonistic
effects in vitro, following standard methods, using the elec-
trically contracting guinea-pig jejunum [49]. The potency is
expressed by its pA2 value, calculated according to Arunlak-
shana and Schild [50] regression analysis, in all cases at least
three concentrations were used.
4. Results and discussion
The presented series of 1-[(2-thiazolopyridine)-4-n-pro-
pyl]piperazines (3), 1-[(2-thiazolobenzo)-4-n-propyl]pipe-

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K. Walczyn´ski et al. / European Journal of Medicinal Chemistry 40 (2005) 15–23
Scheme 2. The synthesis of 2-methylthiothiazolopyridines (3a1–d1).
Scheme 3. The synthesis of 2-methylthiooxazolopyridines (4e1–h1).
razine (9) and their analogous 1-[(2-oxazolopyridine)-4-n-
propyl]piperazines (4), 1-[(2-oxazolobenzo)-4-n-propyl]-
piperazine (10) possess moderate to pronounced H3-receptor
antagonist activity (Table 1).
It appeared that by comparison of homologous pairs, the
1-[(2-thiazolopyridine)-4-n-propyl]piperazines (3) have
slightly higher activity than their corresponding 1-[(2-
oxazolopyridine)-4-n-propyl]piperazine analogues (4). The
Scheme 4. The synthesis of 4-amino-3-hydroxypyridine (f1).

K. Walczyn´ski et al. / European Journal of Medicinal Chemistry 40 (2005) 15–23
19
Scheme 5
.
The synthesis of 1-[(2-thiazolobenzo)-4-n-propyl]piperazine (9) and 1-[(2oxazolbenzo)-4-n-propyl]piperazine (10).
same can be observed for compounds (9) and (10). Benzothia-
zole derivative (9; pA2 = 7.17) has slightly higher activity
than its benzooxazole analogue (10; pA2 = 6.95).
exchangeable by D2O) number of protons, and approximate
coupling constant in Hertz. Elemental analyses (C, H, N) for
all compounds were measured on Heraeus EA 415-0 and are
within 0.4% of the theoretical values. TLC was performed
on silica gel PF254 plates (Merck), using the following elut-
In the case of thiazole series (3a–d; 9), the introduction of
additional nitrogen at various positions in the benzene ring,
lead to compound (3c; pA2 = 7.25), containing nitrogen in
5-position in benzene ring with slightly higher affinity and to
compound (3a; pA2 = 7.08), containing nitrogen in 7-position
in benzene ring with slightly lower affinity compared to the
benzene derivative (9). Compounds (3b) containing nitrogen
in 6- and, particularly (3d) containing nitrogen in 4-position
in benzene ring, have a somewhat lower activity.
Exchange of sulphur by oxygen in thiazole ring results in
a series of compounds (4e–4h) with a slightly lower activity
compared to the benzo derivative (10). In this series, similar
results were observed, as in the thiazole one; the most potent
compound is 1-[(2oxazolo[4,5-c]pyridine)-4-n-propy]lpipera-
zine (4g; pA2 = 6.9), containing nitrogen in 5-position in ben-
zene ring and again the lowest activity has been showed by
1-[(2oxazolo[4,5-b]pyridine)-4-n-propyl]piperazine (4h; pA2
= 5.42), compound containing nitrogen in 4-position in ben-
zene ring. Because the lowest activities of both series are pre-
sented by compound (4h) and its thiazole analogue (3d), we
concluded that the 4-position of nitrogen in benzene ring is
unfavourable for blocking histamine H3-receptors.
Clearly, thiazoles (3a–d; 9) display a higher activity than
their oxazole (4e–4h; 10) analogues. We observe, that the 5-
or possibly 7-position of nitrogen in the benzene ring (3c) or
(3a) is favourable for histamine H3-receptor antagonist activ-
ity, whereas its presence in position-4 (3d, 4h) leads to a strong
decrease of activity. These results show that the 5- or possi-
bly also 7-position for nitrogen in the benzene ring for thia-
zole series leads to moderate pronounced histamine H3-
receptor affinity.
ing
mixtures:
(a)
methylene
chloride/
methanol: 19:1; (b) methylene chloride/methanol: 9:1;
(c) methylene chloride/ethyl acetate: 9:1. Flash column
chromatography was carried out using silica gel 30–60 µm
(J.T. Baker B.V.), employing the same eluent as was indi-
cated by TLC.
The 2-chloro-3-nitropyridine, 4-chloro-3-nitropyridine,
4-aminopyridine, 2-aminopyridine, 2-amino-3-hydroxypyri-
dine, 3-nitro-4-hydroxypyridine, 3-nitro-2-hydroxypyridine,
pivaloyl chloride, potassium ethyl xanthate, 1-n-propyl-
piperazine, 2-chlorobenzothiazole, 2-chlorobenzooxazole
were all purchased from commercial sources.
5.1. Chemistry
5.1.1. General method for the preparation
of thiazolo[5,4-b]- [42] and thiazolo[4,5-c]pyridine-2-
thiones [43]—(a2) and (c2)
A solution of sodium hydroxide (6 g, 0.45 mol) in 32 ml
of water was saturated with hydrogen sulphide. To this hot
solution 2-chloro-3-nitropyridine (a1) or 4-chloro-
3niropyridine (c1) (8 g, 0.05 mol) was added and the reaction
mixture was heated under reflux for 5 min. To the boiling
solution sodium sulphide nonahydrate (24 g, 0.1 mol) was
added portion wise and hydrogen sulphide was bubbled into
the boiling reaction mixture for 2.5 h. Thereafter, the reac-
tion mixture was treated with aqueous sodium hydroxide
(2.8 g, 0.07 mol in 12 ml of water), saturated with hydrogen
sulphide, and finally, after cooling to room temperature, car-
bon disulphide (17 g, 22 ml, 0.23 mol) was added. The reac-
tion mixture was stirred at 45 °C for 3 h and then 5 h at 110 °C,
cooled and neutralised with acetic acid. The separated prod-
uct was filtered, dissolved in aqueous ammonia, charcoaled
and filtered. The filtrate was acidified with acetic acid, the
product was filtered off and washed with small amount of
cold ethanol.
Based on the obtained results, the 1-(2-thiazolo[4,5-
c]pyridine)-4-n-propylpiperazine (3c) was chosen as a new
lead for non-imidazole histamine H3-receptor antagonists.
5. Experimental protocols
General methods. All melting points (m.p.) were mea-
sured in open capillaries on an electrothermal apparatus and
are uncorrected. For all compounds H NMR spectra were
recorded on aVarian Mercury 300 MHz spectrometer. Chemi-
cal shifts are expressed in ppm downfield from internal TMS
as reference. 1H NMR data are reported in order: multiplicity
(br, broad; s, singlet; d, doublet; t, triplet; m, multiplet; *,
a2. C6H4N2S2 (167.98);Yield 52% (Ref. [42] 97%); m.p. >
290 °C (Ref. [42] >290 °C); 1H NMR (d in ppm; DMSO-d6):
14.3 (br*, 1H, NH); 8.45–8.35 (dd, 1H(6); J = 4.8, 1.6 Hz);
8.2–8.15 (dd, 1H(4); J = 8, 1.6 Hz); 7.45–7.35 (dd, 1H(5); J
= 8, 4.8 Hz). TLC(a) Rf = 0.34.
1
c2. C6H4N2S2 (167.98);Yield 46% (Ref. [44] 66%); m.p. >
300 °C (Ref. [42] >300 °C); 1H NMR (d in ppm; DMSO-d6):

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K. Walczyn´ski et al. / European Journal of Medicinal Chemistry 40 (2005) 15–23
14.25 (br*, 1H, NH); 8.8–8.7 (d, 1H(4); J = 0.8 Hz); 8.55–8.5
(d, 1H(6); J = 6 Hz); 7.35–7.3 (dd, 1H(7); J = 6, 0.8 Hz). TLC(b)
Rf = 0.08.
d3. C6H4N2S2 (167.98);Yield 75% (Ref. [45] 85%); m.p.
>300 °C (Ref. [45] >300 °C); 1H NMR (d in ppm; DMSO-
d6): 14.35 (br*, 1H, NH); 8.4–8.3 (dd, 1H(5); J = 5.0, 1.6 Hz);
8.1–8.2 (dd, 1H(7); J = 7.9, 5 Hz); 7.3–7.2 (dd, 1H(6); J = 5.0,
1.6 Hz); TLC(a) Rf = 0.41.
5.1.2. General method for the preparation
of thiazolo[5,4-c]- [44] and thiazolo[4,5-b]pyridine-2-
thiones [45]—(b3) and (d3)
5.1.3. General method for the preparation
of 2-thiooxazolopyridines [46]—(f2–h2)
5.1.2.1. Pivaloylaminopyridines—(b1) and (d1). To a solu-
tion of 4-aminopyridine or 2-aminopyridine (19.2 g, 0.2 mol)
and triethylamine (37 ml, 0.27 mol) in dichloromethane
(100 ml) at 0 °C was cautiously added a solution of pivaloyl-
(trimethylacetyl) chloride (28.8 ml, 0.23 mol) in dichlo-
romethane (30 ml). The mixture was stirred in an ice bath for
1 h and then allowed to warm to room temperature and stirred
overnight. Cold water (50 ml) was added and the organic layer
was washed with saturated NaHCO3 water solution (2 ×
100 ml). After drying (MgSO4) and evaporation of the sol-
vent, the crude brown product of 4-(pivaloylamino)pyridine
(b1) was recrystallised from dichloromethane/hexane and
2-(pivaloylamino)pyridine (d1) from ethyl acetate/hexane to
give the pure product as colourless crystals, 28.5 g (85.0%)
with m.p. 133–135 °C (Ref. [44] 133–135 °C) and 30 g
(90.0%) with m.p. 71–73 °C (Ref. [45] 72–73 °C), respec-
tively.
To a solution of the corresponding aminohydroxypy-
ridines (f1–h1) (11 g, 0.1 mol) in ethanol (225 ml) was added
potassium ethyl xanthate (32 g, 0.2 mol) in one portion. This
heterogeneous mixture was then heated to reflux with stir-
ring under an atmosphere of N2 for 18 h, cooled to room tem-
perature, and concentrated in vacuo. The residue was dis-
solved with water and acidified to pH 5 with acetic acid. The
resulting precipitate was filtered, washed with water (3 ×
50 ml) and dried under reduced pressure to give 2-thiooxa-
zolopyridines (f2–h2) as yellow–brown solids.
f2. C6H4N2SO (M = 148.98);Yield 79% (Ref. [46] 83%);
m.p. >290 °C; 1H NMR (d in ppm; DMSO-d6): 8.65 (s, 1H(7));
8.35–8.3 (d, 1H(5); J = 6.1 Hz); 7.4–7.35 (d, 1H(4), J = 6.1);
TLC(b) Rf = 0.26.
g2. C6H4N2SO (M = 148.98);Yield 50% (Ref. [46] 52%);
m.p. >290 °C; 1H NMR (d in ppm; DMSO-d6): 8.55 (s, 1H(4));
8.35–8.3 (d, 1H(6); J = 5.9 Hz); 7.5–7.45 (d, 1H(7); J = 5.9);
TLC(b) Rf = 0.11.
5.1.2.2. 3-(N,N-Disopropyldithiocarbamato)-4- and 3-(N,N-
disopropyldithiocarbamato)2-pivaloylamino)pyridines—
(b2) and (d2). To a solution of 4- (b1) or 2-(piva-
loylamino)pyridine (d1) (13.3 g, 0.075 mol) in dry THF
(120 ml) at –78 °C, n-butyllithium (63 ml, 2.5 M in hexane,
0.157 mol) was added. The mixture was then allowed to warm
rapidly to 0 °C and stirred at this temperature for 2.5 h. The
reaction mixture was cooled to –78 °C and solution of TITD
(26.35 g, 0.075 mol) in THF (100 ml) was slowly added. The
mixture was then allowed to warm up and when it had just
become clear, water (120 ml) and ether (120 ml) were added.
The organic layer was separated, washed with water (2 ×
150 ml), dried (Na2SO4) and evaporated. The crude products
(b2) and (d2) were recrystallised from ethyl acetate, 17.6 g
(73.2%) with m.p. 118–119 °C (Ref. [44] 118–119 °C) and
16.6 g (69.0%) with m.p. 129.5–131 °C (Ref. [45] 130–
131 °C), respectively.
h2. C6H4N2SO (M = 148.98);Yield 66% (Ref. [46] 73%);
m.p. >290 °C; 1H NMR (d in ppm; CD3OD): 8.25–8.2 (dd,
1H(5); J = 5.2, 1.2 Hz); 7.7–7.6 (dd, 1H(7); J = 8.1, 1.2 Hz);
7.2–7.25 (dd, 1H(6); J = 8.1, 5.2 Hz); TLC(a) Rf = 0.11.
5.1.3.1. The synthesis of 2-thiooxazolo[5,4-b]pyridine [46]
—(e2). To a solution of 3-amino-2-hydroxypyridine (e1)
(7.86 g, 0.0714 mol) in anhydrous THF (220 ml) with stir-
ring under N2, was added thiophosgene (6.5 ml, 0.0875 mol).
This homogeneous mixture was stirred at room temperature
for 1 h, adjusted to pH 5 with 10 N NaOH, and evaporated in
vacuo. The residue was diluted with water, and the precipi-
tate was filtered, washed with H2O (3 × 25 ml), and dried
under vacuum to give (e2) as an orange–yellow solid.
e2. C6H4N2SO (M = 148.98);Yield 63% (Ref. [46] 70%);
1
m.p. >290 °C; H NMR (d in ppm; CDCl3): 7.45–7.4 (dd,
1H(6); J = 6.5, 1.9 Hz); 7.35–7.3 (dd, 1H(4); J = 7.2, 1.9 Hz);
6.35–6.3 (dd, 1H(5); J = 7.2, 6.5 Hz); TLC(a) Rf = 0.52.
5.1.2.3. Thiazolo[5,4-c]- [44] and thiazolo[4,5-b]pyridine-
2-thiones [45]—(b3) and (d3). A suspension of 3-(N,N-
disopropyldithiocarbamato)-4- (b2) or 2-(pivaloylamino)-
pyridine (d2) (10 g, 0.0282 mol) in 20% ethanolic sodium
hydroxide (200 ml) was refluxed for 4 h. The mixture was
cooled and acidified with acetic acid to give a colourless solid
which was filtered and washed with water. Drying gave solid
(b3) and (d3).
5.1.4. General method for the preparation of 2-
(methylthio)thiazolopyridines—(3a1–3d1)
The corresponding thione (a2), (c2), (b3) or (d3) (1.68 g,
0.01 mol) was dissolved in ethanolic sodium ethylate (pre-
pared from 0.23 g sodium (0.01 mol) in 50 ml of absolute
ethanol) and the solution was evaporated to dryness. The resi-
due was dissolved in 1,2-dimethoxyethan (75 ml) and methyl
iodide (1.76 g, 0.01 mol) was added. The reaction mixture
was heated under reflux for 10 min, the solvent was evapo-
rated, water (25 ml) was added and the separated product was
filtered off. In each case, the crude product was purified by
b3. C6H4N2S2 (167.98); Yield 46% (Ref. [44] 66%);
1
m.p. >290 °C (Ref. [44] >275 °C); H NMR (d in ppm;
DMSO-d6): 14.25 (br*, 1H, NH); 8.8 (s, 1H(7)); 8.55–8.5 (d,
1H(5); J = 6 Hz); 7.35–8.3 (dd, 1H(4); J = 6 Hz); TLC(b)
Rf = 0.18.

K. Walczyn´ski et al. / European Journal of Medicinal Chemistry 40 (2005) 15–23
21
column chromatography. All compounds were crystallised
from n-hexane.
5.1.6. General method for the preparation of 1-[(2-thiazol-
opyridine)-4-npropyl]piperazines—(3a–d)
The appropriate methylthio derivative (3a1–d1) (0.87 g,
0.005 mol) was treated with few drops of ethanol and 1-n-
propylpiperazine (5) (1.28 g, 0.01 mol) and the reaction mix-
ture was heated at 60 °C for 45–120 min.After cooling, water
(25 ml) and dichloromethane (25 ml) were added and organic
layer was separated, dried (Na2SO4) and evaporated to give
the crude product which was purified by column chromatog-
raphy.
3a1. C7H7N2S2 (M = 182.98);Yield 65% (Ref. [42] 70%);
m.p. 87–88 °C (Ref. [42] 88.5 °C); H NMR (d in ppm;
1
CDCl3): 8.3–8.25 (dd, 1H(6); J = 4.8, 1.6 Hz); 8.0–7.9 (dd,
1H(4); J = 8.0, 1.6 Hz); 7.25–7.15 (dd, 1H(5); J = 8.0, 4.8 Hz);
2.75 (s, 3H); TLC(c) Rf = 0.33.
3b1. C7H7N2S2 (M = 182.98);Yield 48%; m.p. 84–86 °C;
1H NMR (d in ppm; CDCl3): 9.05–9 (d, 1H(7); J = 0.8); 8.65–
8.6 (d, 1H(5); J = 5.5 Hz); 7.65–7.6 (dd, 1H(4); J = 5.5, 0.8 Hz);
2.8 (s, 3H); TLC(c) Rf = 0.12.
3c1. C7H7N2S2 (M = 182.98);Yield 40% (Ref. [43] 41%);
m.p. 83–85 °C (Ref. [43] 85 °C); 1H NMR (d in ppm; CDCl3):
9.2–9.1 (d, 1H(4); J = 0.8 Hz); 8.5–8.4 (d, 1H(6); J = 5 Hz);
8.28.1 (dd, 1H(7); J = 5.0, 0.8 Hz); 2.8 (s, 3H); TLC(c) Rf
= 0.09.
3d1. C7H7N2S2 (M = 182.98);Yield 56%; m.p. 74–76 °C;
1H NMR (d in ppm; CDCl3): 8.65–8.6 (dd, 1H(5); J = 4.8,
1.6 Hz); 8.15–8.1 (dd, 1H(7); J = 7.9, 1.6 Hz); 7.25–7.2 (dd,
1H(6); J = 7.9, 4.8 Hz); 2.85 (s, 3H); TLC(c) Rf = 0.26.
3a. C13H18N4S (M = 294.00); Yield 63%; m.p. 93–95 °C
1
(for free base) and 277–276 °C (for dihydrobromide); H
NMR (d in ppm; CDCl3): 8.3–8.25 (dd, 1H(6); J = 4.8, 1.6 Hz);
8.0–7.9 (dd, 1H(4); J = 8.0, 1.6 Hz); 7.15–7.25 (dd, 1H(5)
;
J = 8.0, 4.8 Hz); 3.80–3.70 (m, 4H“piperazine”); 2.70–2.60 (m,
4H“piperazine”); 2.45–2.30 (t, 2H, J = 7.5 Hz); 1.60–1.45 (m,
2H); 1.00–0.85 (t, 3H; J = 7.3 Hz); TLC(b) Rf = 0.39.
3b. C13H18N4S (M = 294.00); Yield 48%; m.p. 96–98 °C
(for free base) and >300 °C (for trihydrobromide); 1H NMR
(d in ppm; CDCl3): 8.75 (d, 1H(7); J = 0.6); 8.42–8.38 (d,
1H(5); J = 5.5 Hz); 7.65–7.6 (dd, 1H(4); J = 5.5, 0.6 Hz); 3.74–
3.70 (m, 4H“piperazine”); 2.60–2.40 (m, 4H“piperazine”); 2.37–
2.35 (t, 2H, J = 7.7 Hz); 1.58–1.51 (m, 2H); 0.96–0.91 (t, 3H;
J = 7.3 Hz); TLC(b) Rf = 0.46.
5.1.5. General method for the preparation of 2-
(methylthio)oxazolopyridines—(4e1–4h1)
3c. C13H18N4S (M = 294.00); Yield 40%; m.p. 101–
102 °C (for free base) and 252–253 °C (for dihydrobromide);
To a cooled solution of the corresponding 2-thiooxazo-
lopyridines (e2–h2) (1 g, 0.0066 mol) in anhydrous DMF
(20 ml) with stirring under N2 was added potassium carbon-
ate (1 g, 0.01 mol) followed by iodomethane (0.5 ml,
0.008 mol). The reaction mixture was stirred for 1 h, diluted
with water, and extracted with ethyl acetate (4 × 25 ml). The
combined organic extracts were washed with water (3 ×
25 ml), dried (Na2SO4), filtered, and evaporated to give
2-(methylthio)oxazolopyridines (4e1–4h1) as tan solids. In
each case, the crude product was purified by column chroma-
tography. All compounds were crystallised from isopropyl
ether.
1H NMR (d in ppm; CDCl3): 8.8 (s, 1H(4)); 8.25–8 (d, 1H(6)
;
J = 5.5 Hz); 7.55–7.5 (d, 1H(7); J = 5.5 Hz); 3.74–3.70 (m,
4H“piperazine”); 2.60–2.40 (m, 4H“piperazine”); 2.37–2.35 (t, 2H,
J = 7.7 Hz); 1.58–1.51 (m, 2H); 0.96–0.91 (t, 3H; J = 7.3 Hz);
TLC(b) Rf = 0.44.
3d. C13H18N4S (M = 294.00); Yield 56%; m.p. 86–87 °C
1
(for free base) and 280–282 °C (for dihydrobromide); H
NMR (d in ppm; CDCl3): 8.3–8.25 (dd, 1H(5); J = 5.0, 1.8 Hz);
8.0–7.9 (dd, 1H(7); J = 7.8, 1.8 Hz); 7.15–7.25 (dd, 1H(6)
;
J = 7.8, 5 Hz); 3.80–3.70 (m, 4H“piperazine”); 2.70–2.60 (m,
4H“piperazine”); 2.45–2.30 (t, 2H, J = 7.5 Hz); 1.60–1.45 (m,
2H); 1.00–0.85 (t, 3H; J = 7.3 Hz); TLC(b) Rf = 0.56.
4e1. C7H7N2SO (M = 163.98);Yield 76% (Ref. [46] 93%);
m.p. 80–81 °C (Ref. [46] 81 °C); 1H NMR (d in ppm; CDCl3):
8.2–8.15 (dd, 1H(6); J = 5.0, 1.5 Hz); 7.9–7.8 (dd, 1H(4)
;
5.1.7. General method for the preparation
J = 7.8, 1.5 Hz); 7.3–7.2 (dd, 1H(5); J = 7.8, 5 Hz); 2.75 (s,
3H); TLC(a) Rf = 0.66.
of 1-[(2-oxazolo)-4-n-propyl]piperazines—(4eh)
A mixture of the appropriate 2-(methylthio)oxazolo-
pyridine (4e1–4h1) (1 g, 0.006 mol) and 1-n-propyl-
piperazine (5) (1.54 g, 0.012 mol) was heated to 85 °C for
45 min and cooled to room temperature. The residue was puri-
fied by column chromatography.
4f1. C7H7N2SO (M = 163.98);Yield 73% (Ref. [46] 83%);
m.p. 80–81 °C (Ref. [46] 81 °C); 1H NMR (d in ppm; CDCl3):
8.8 (s, 1H(7)); 8.55–8.5 (d, 1H(5); J = 5.3 Hz); 7.45–7.4 (d,
1H(4), J = 5.3 Hz); 2.75 (s, 3H); TLC(a) Rf = 0.42.
4g1. C7H7N2SO (M = 163.98);Yield 82% (Ref. [46] 83%);
4e. C13H18N4O (278.00); Yield 90%; m.p. 82–83 °C (for
1
1
m.p. 82–83 °C (Ref. [46] 82–83 °C); H NMR (d in ppm;
free base) and 259–260 °C (for dihydrobromide); H NMR
CDCl3): 8.95–8.90 (d, 1H(4); J = 0.9 Hz); 8.5–8.45 (d, 1H(6)
;
(d in ppm; CDCl3): 7.95–7.90 (dd, 1H(6); J = 5.1, 1.6 Hz);
J = 5.5 Hz); 7.45–7.4 (dd, 1H(7); J = 5.5, 0.9 Hz); 2.75 (s,
3H); TLC(a) Rf = 0.37.
7.607.50 (dd, 1H(4); J = 7.7, 1.6 Hz); 7.15–7.25 (dd, 1H(5)
;
J = 5.1, 7.7 Hz); 3.80–3.70 (m, 4H“piperazine”); 2.60–2.50 (m,
4H“piperazine”); 2.40–2.30 (t, 2H, J = 7.5 Hz); 1.60–1.50 (m,
2H); 1.00–0.85 (t, 3H; J = 7.3 Hz); TLC(a) Rf = 0.43.
4f. C13H18N4O (278.00); Yield 78%; m.p. 79–80 °C (for
4h1. C7H7N2SO (M = 163.98);Yield 75% (Ref. [46] 91%);
m.p. 62–63 °C (Ref. [46] 63 °C); 1H NMR (d in ppm; CDCl3):
8.5–8.4 (dd, 1H(5); J = 5.0, 1.4 Hz); 7.7–7.6 (dd, 1H(7); J = 8.1,
1.4 Hz); 7.2–7.15 (dd, 1H(6); J = 8.0, 5 Hz); 2.8 (s, 3H); TLC(a)
Rf = 0.51.
1
free base) and 259–262 °C (for dihydrobromide); H NMR
(d in ppm; CDCl3): 8.50 (d, 1H(7); J = 1 Hz); 8.35–8.30 (d,

22
K. Walczyn´ski et al. / European Journal of Medicinal Chemistry 40 (2005) 15–23
1H(5); J = 5.3 Hz); 7.25–7.20 (dd, 1H(4); J = 5.3, 1 Hz); 3.80–
3.75 (m, 4H“piperazine”); 2.60–2.55 (m, 4H“piperazine”); 2.40–
2.35 (t, 2H, J = 7.5 Hz); 1.60–1.50 (m, 2H); 0.96–0.91 (t, 3H;
J = 7.3 Hz); TLC(a) Rf = 0.35.
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 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). 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. Contractions were recorded
isotonically under 1 g tension with Hugo Sachs Hebel-
Messvorsatz (Tl-2)/HFmodem (Hugo Sachs Electronik, Hug-
stetten, Germany) connected to a pen recorder. After equili-
bration for 1 h with washings every 10 min, the muscle
segments were stimulated maximally between 15 and 20 V
and continuously at a frequency 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, cumulative concentration–
response curves (half-log increments) of (R)-a-
methylhistamine, H3-agonist, were recorded until no further
change in response was found. The tested compounds were
added 20 min before generation of concentration–response
curves with (R)-a-methylhistamine as H3-agonist. Statistical
analysis was carried out with the Students’t-test. In all test P
< 0.05 was considered statistically significant. The potency
of an antagonist is expressed by its pA2 value, calculated from
the Arunlakshana and Schild [50] regression analysis where
at least three concentrations were used.
4g. C13H18N4O (278.00); Yield 76%; m.p. 86–87 °C (for
free base) and >300 °C (for dihydrobromide); 1H NMR (d in
ppm; CDCl3): 8.65 (d, 1H(4); J = 1.0); 8.30–8.25 (d, 1H(6)
;
J = 5.5 Hz); 7.25–7.20 (dd, 1H(7); J = 5.5, 1 Hz); 3.80–3.75
(m, 4H“piperazine”); 2.65–2.55 (m, 4H“piperazine”); 2.40–2.35 (t,
2H, J = 7.7 Hz); 1.65–1.55 (m, 2H); 0.96–0.91 (t, 3H;
J = 7.3 Hz); TLC(a) Rf = 0.33.
4h. C13H18N4O (278.00); Yield 90%; m.p. 76–78 °C (for
free base) and >300 °C (for dihydrobromide); 1H NMR (d in
ppm; CDCl3): 8.25–8.00 (dd, 1H(5); J = 5.1, 1.5 Hz); 7.457.40
(dd, 1H(7); J = 8.0, 1.5 Hz); 7.25–7.2 (dd, 1H(6); J = 8.0,
5.1 Hz); 3.80–3.70 (m, 4H“piperazine”); 2.35–2.30 (m, 4H“pip
-
erazine”); 2.20–2.15 (t, 2H, J = 7.7 Hz); 1.50–1.45 (m, 2H);
0.96–0.91 (t, 3H; J = 7.3 Hz); TLC(a) Rf = 0.40.
5.1.8. General method for the preparation
of 1-[(2-thiazolobenzo)-4-n-propyl]piperazine (9)
and 1-[(2-oxazolobenzo)-4-n-propyl]piperazine (10)
To a refluxing mixture of the 1-n-propylpiperazine (5)
(1.28 g, 0.01 mol) and sodium bicarbonate (1.68, 0.02 mol)
in 70 ml of 80% 2-PrOH a solution of 2-chlorobenzothiazole
(7) (0.85 g, 0.005) or 2-chlorobenzooxazole (8) (0.77 g,
0.005 mol) in 4 ml of 2-PrOH was added dropwise. The mix-
ture was refluxed 24 h. The solvent was evaporated under
reduced pressure, and the sticky oil residue was suspended in
100 ml of water. After stirring for 1 h, the mixture was
extracted with CH2Cl2, and the solvent was removed in vacuo.
The products (9) and (10) were purified by column chroma-
tography.
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