Histamine H1 receptor ligands. Part I. Novel thiazol-4-ylethanamine derivatives: Synthesis and in vitro pharmacology

Article abstract of DOI:10.1016/S0014-827X(99)00060-9

A series of 2-substituted thiazol-4-ylethanamines have been synthesized and tested for their histaminergic H₁-receptor activities. The compounds with 2-phenyl substitution, regardless of the different physicochemical properties of the meta-substituents at the phenyl ring, showed weak H₁-agonistic activity with pD₂ values ranging from 4.35 to 5.36. When the phenyl group was replaced by a benzyl group, the resulting compounds all exhibited weak H₁-antagonistic activity (pA₂: 4.14-4.82). Copyright (C) 1999 Elsevier Science S.A.

Full text of DOI:10.1016/S0014-827X(99)00060-9

www.elsevier.nl/locate/farmac
Il Farmaco 54 (1999) 533–541
Histamine H1 receptor ligands
Part I. Novel thiazol-4-ylethanamine derivatives: synthesis and
in vitro pharmacology
K. Walczyn´ski a,*, H. Timmerman b, O.P. Zuiderveld b, M.Q. Zhang b, R. Glinka a
a
*
Department of Synthesis and Technology of Drugs, Medical Academy, Muszyn´skiego Street 1, 90-145 Lo´dz´, Poland
b Leiden/Amsterdam Center for Drug Research, Di6ision of Medicinal Chemistry, Vrije Uni6ersiteit, De Boelelaan 1083,
1081 HV Amsterdam, The Netherlands
Received 16 September 1998; accepted 24 May 1999
Abstract
A series of 2-substituted thiazol-4-ylethanamines have been synthesized and tested for their histaminergic H1-receptor activities.
The compounds with 2-phenyl substitution, regardless of the different physicochemical properties of the meta-substituents at the
phenyl ring, showed weak H1-agonistic activity with pD2 values ranging from 4.35 to 5.36. When the phenyl group was replaced
by a benzyl group, the resulting compounds all exhibited weak H1-antagonistic activity (pA2: 4.14–4.82). © 1999 Elsevier Science
S.A. All rights reserved.
Keywords: Histamine H1-receptor; H1-receptor agonist; H1-receptor antagonists; 2-(2-Phenylthiazol-4-yl)ethanamines; 2-(2-Benzylthiazol-4-
yl)ethanamines
and a substitution, especially phenyl, at the C2 position
is beneficial [9–13]. At present, the best known H1-re-
ceptor agonists are substituted 2-phenylhistamines 1
(Fig. 1) [12,13]. Most compounds of this series possess
full intrinsic activity and their potency ranges from 0.5
to 128% relative to histamine. The substitution at the
phenyl ring is preferably attached to the meta position
and there is no clear structure–activity relationship
trend (electronic, steric, etc.) as far as these substituents
are concerned [12]. Replacement of the imidazole moi-
ety by other aromatic heterocycles usually results in
1. Introduction
Whereas a vast number of potent and selective his-
tamine H1-receptor antagonists have long been avail-
able either as effective therapeutic agents for allergic
diseases or as chemical tools for pharmacological inves-
tigation [1], the search for histamine H1-receptor ago-
nists has been less successful. Recently it became
apparent that histamine is not only a mediator of
allergic reactions but also a neurotransmitter. His-
tamine acts, via the activation of H1-receptors, as an
endogenous anticonvulsant in the central nervous sys-
tem and also plays an important role in seizure [2]. This
means selective histamine H1-receptor agonists are not
only useful pharmacological tools but also potential
therapeutic agents.
To date, most H1-receptor agonists (full or partial)
are histamine derivatives, i.e. they have an imidazol-
4(5)-ylethanamine moiety in common [2–8]. The amino
group in the ethylamine side chain is preferably primary
* Corresponding author. Tel.: +48-42-678 3628; fax: +48-42-678
4796.
Fig. 1. Structures of some known histamine H1-receptor agonists and
the target molecules of this study.
0014-827X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(99)00060-9

534
K. Walczyn´ski et al. / Il Farmaco 54 (1999) 533–541
decreased activity [14–17] but some of these hetero-
cyclic analogues, e.g. 2-(thiazol-2-yl)ethanamine (2),
still possess full intrinsic activity. This implies that the
Np–Nt tautomeric system of imidazole may not be
necessary for the activation of H1-receptors [1]. In the
present study we have synthesized a series of novel
thiazol-4-ylethanamines (3 and 4) in which a meta-sub-
stituted phenyl or benzyl is attached to position 2 of the
thiazole nucleus. All these compounds were tested for
their H1-receptor activity by a functional assay in
guinea-pig ileum. The synthesis and structure–activity
relationships of these thiazole derivatives are the sub-
jects of this report.
Scheme 2. Synthesis of 2-(thiazol-4-yl)ethanamine (8).
quent hydrazinolysis, except for 5e which was treated
with 5 N HCl under reflux, basification with sodium
hydroxide and extraction with chloroform led to the
pure amines, after separation by column chromatogra-
phy. All free bases were treated with methanolic HBr
and hydrobromides were precipitated with dry diethyl
ether. Likewise, 2-(thiazol-4-yl)ethanamine (8) was ob-
tained from the hydrazinolysis of the corresponding
phthalimide 7 which was prepared by the condensation
of thioformamide and 1-bromo-4-phtalimidobutanone-
2 [20] (Scheme 2).
2. Chemistry
All 2-substituted thiazol-4-ylethanamine derivatives
were prepared using the general method as shown in
Scheme 1. The benzo- and phenylacetonitriles as start-
ing materials were purchased from commercial sources.
The appropriate meta-substituted thiobenzamides and
thiophenylacetamides were directly obtained according
to Fairful et al. [18] by the reaction of the nitrile with
hydrogen sulfide in pyridine in the presence of triethyl-
amine. 3-Nitrothiobenzamide (5j) was obtained accord-
ing to Scheibye et al. [19] by the reaction of
3-nitrobenzamide and Lawesson’s reagent in hexa-
methylphosphoamide (HMPA). All 4-[(2-phthalimido)-
ethyl]thiazole derivatives were obtained by reaction of
the appropriate thioamide and 1-bromo-4-phtalimi-
dobutanone-2 [20] in n-propanol in the presence of
concentrated hydrochloric acid. All phthalimide deriva-
tives were purified by column chromatography. Subse-
3. Pharmacology
All compounds were tested for H1 agonistic or antag-
onistic effects in vitro using standard methods, applying
the guinea-pig ileum [24,25]. Male guinea pigs weighing
300–400 g were sacrificed by a blow on the head. The
ileum was excised and placed in phosphate buffer at
room temperature (r.t.) (pH 7.4) containing (mM)
NaCl (136.9); KCl (2.68); NaHPO4 (7.19). After flush-
Scheme 1. Synthesis of 2-phenyl- and 2-benzyl-thiazol-4-ylethanamines (3a–j and 4a–f).

K. Walczyn´ski et al. / Il Farmaco 54 (1999) 533–541
535
ing 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); and glucose (5.5) at 37°C
under a constant load of 0.5 g. After a 30 min equilibra-
tion period with washings every 10 min, a sub-maximal
priming dose of histamine (1 mM) was given and washed
out (standard washing procedure: 3 changes of buffer
during 30 min). After washing out, a concentration
response curve (CRC) of histamine was constructed
followed by the CRCs of the compounds 8 and 3a–j.
Each curve was followed by a standard washing proce-
dure. pD2 values were calculated by standard methods.
The antagonistic activity of given compounds was mea-
sured by recording a CRC for histamine in the presence
of the testing compounds 4a–f which were added 5 min
before histamine. This procedure was repeated with
higher concentrations of the compounds. The antago-
nism was of a competitive nature causing a parallel shift
of the CRC. The pA2 values were calculated according
to Arunlakshana and Schild [25]. In appropriate cases,
the nature of the H1-agonistic effect was checked by
determining, using a standard method, the competitive
antagonism by the H1 antagonist temelastine (3 nM).
4. Results and discussion
2-(Thiazol-4-yl)ethanamine (8) and its 2-phenyl- and
2-benzyl-substituted derivatives (3a–3j and 4a–4f) were
tested for histamine H1-receptor activity in vitro on
isolated guinea-pig ileum as described in Section 6.
2-(Thiazol-4-yl)ethanamine (8) showed weak H1-receptor
agonistic activity with a pD2 value of 4.70 (intrinsic
activity=1). Since this compound, like 2-(thiazol-2-
yl)ethanamine (2), lacks the tautomerism that is present
in histamine, the agonistic activity shown by this com-
pound is consistent with the notion that the Nt–H
tautomer of histamine monocation is the active form of
histamine at H1-receptors [5,6]. As in the case of meta-
substituted-2-(phenyl)histamine series [2], all derivatives
of the present series with a phenyl group substituted at
C2 position of the thiazole ring (3a–j) showed H1-recep-
tor agonistic activity. The potencies of these compounds
(3a–j) are remarkably lower than those of their 2-phenyl-
histamine counterparts with pD2 values ranging from
Table 1
Structures, formulas and results of the pharmacological screening on the isolated guinea-pig ileum for 2-[2-phenyl-4-thiazolyl]ethanamines (3) and
for 2-(thiazol-4-yl)ethanamine (8)
Comp.
R
pD29SEM (n)*
Max. contrac-
Max. contraction b
9SEM (n) in the presence
of 3 nM temelastine
Max. contraction c
9SEM (n) in the presence
of atropine 10 nM
tion a9SEM (n)
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
F
Cl
Br
NO2
CF3
CH3
OH
OCH3
NH2
4.8090.03 (10)
4.9090.08 (6)
5.1590.05 (6)
5.1990.04 (6)
5.0390.07 (10)
5.3690.06 (6)
4.8790.06 (6)
4.8090.08 (10)
4.3590.04 (6)
4.3590.04 (6)
4.7090.09 (8)
6.7390.16 (11)
56.894.45 (10)
71.795.78 (6)
47.494.73 (6)
39.093.19 (6)
42.097.30 (10)
67.596.58 (6)
45.997.99 (6)
62.395.36 (10)
59.494.80 (6)
68.193.23 (6)
97.293.43 (8)
100 (11)
59.590.83 (2)
33.491.46 (2)
22.5911.45 (2)
0.090.0 (2)
18.899.11 (4)
0.090.0 (2)
0.090.0 (2)
89.098.24 (4)
3.193.1 (2)
75.496.69 (2)
52.490.63 (2)
100 (4)
76.894.78 (3)
n.d d
75.594.74 (3)
99.4914.98 (2)
94.095.77
n.d d
94.497.81 (2)
75.596.27 (3)
89.5910.5 (2)
88.999.97 (3)
n.d d
3j
8
histamine
100
a Maximum height of contraction caused by the compound relative to histamine as 100%.
b Maximum height of contraction caused by the compound of the 2e CRC relative to its own reference (as 100%) in the presence of temelastine.
c Maximum height of contraction caused by the compound of the 2e CRC relative to its own reference (as 100%) in the presence of atropine.
d n.d., not determined.

536
K. Walczyn´ski et al. / Il Farmaco 54 (1999) 533–541
Fig. 2. Agonistic activity exerted by thiazole derivatives 3a and 8 in comparison with histamine. Open symbols represent the dose–response curves
of the agonists and closed symbols represent the dose–response curves after incubation with 3 nM temelastine, 0.5 h prior to the agonist challenge.
Data are presented as means 9SEM.
activity at H1-receptors, acted as weak antagonists
(Table 2). Although a significant decrease in H1-agonis-
tic activity has also been observed among meta-substi-
4.35 to 5.36 (Table 1) and they all behave as partial
agonists (intrinsic activity from 0.39 to 0.71). No defin-
ite structure–activity relationships can be drawn from
the present series but it appears that higher potencies
are found in compounds substituted by an electron-
withdrawing group (Table 1).
tuted-2-(benzyl)histamines
compared
with
their
2-phenyl analogues, such a clear-cut transformation
from agonist to antagonists by the simple replacement
of a phenyl with a benzyl group is quite unique among
H1-receptor ligands. Since it has been suggested that the
phenyl group of 2-phenylhistamines may bind to the
same receptor site as the so-called ‘cis ring’ of H1-an-
tagonists [23], it is not unreasonable to speculate that
the agonistic 2-phenylthiazoles (3a–j) and the antago-
The contractions caused by 3a–j and 8 were antago-
nized by temelastine, a highly selective H1-receptor
antagonist [21]. For example, a rightward shift of the
dose–response curves of 8 was observed after the treat-
ment of the ileum with 3 nM temelastine (Fig. 2). It is
not possible to calculate pA2 values for temelastine,
except for the full agonist 8, for which temelastine pA2
was found to be 9.33, not different from the value
found using histamine as agonist (pA2=9.63 in our
hands). We observed with our other compounds (3a–j)
a rapid depression of the maximum contractions of the
organ upon applying high concentrations (\0.1 mM).
The cause of this decrease in contraction is unclear. For
compounds 3a, 3b, 3h and 3j something other than the
H1 receptor seems to play a role in the contraction as
well, because we observe only a partial antagonism by
temelastine. Recently, several 2-substituted histamine
derivatives have been found to stimulate G-proteins
directly [22]. It remains to be determined whether such
a mechanism also exists for the thiazole derivatives in
the present study.
Table 2
Structures, formulas and results of the pharmacological screening on
the isolated guinea-pig ileum for 2-[2-benzyl-4-thiazolyl]ethanamines
(4)
Comp.
R
pA29SEM (n)
4a
4b
4c
4d
4e
4f
H
F
Cl
Br
CH3
OCH3
4.1690.08 (15)
4.5390.12 (5)
4.8290.12 (3)
4.6590.11 (3)
4.6390.2 (4)
4.1490.38 (4)
9.6390.07 (11)
The results for compounds 8 and 3a–j are summa-
rized in Table 1. We have checked whether the com-
pounds might activate muscarinic receptors, by
applying atropine. Clearly, none of the compounds
tested seems to activate a muscarinic receptor system.
The benzyl derivatives (4a–f), which lost their intrinsic
Temelastine

K. Walczyn´ski et al. / Il Farmaco 54 (1999) 533–541
537
nistic 2-benzylthiazoles (4a–f) bind to the receptor in a
similar pattern, but the conjugation between the thia-
zole and phenyl rings is important for the activation of
the receptor. At higher concentrations (\100 mM), all
2-benzylthiazoles (4a–f) caused total suppression of the
concentration–response curves for histamine.
solubility), and triethylamine (0.03 mol) is added. Dry
hydrogen sulfide is passed through the solution in a steady
stream for 2–4 h for compounds 5a–d, 5f–j and 12–16
h for compounds 5k–p at r.t. The mixture is then poured
into water, and the thioamide collected by filtration. All
thioamides were used in further reactions without extra
purification; optimized spectral data were not obtained.
5a:C7H7NS(137);m.p.:115–116°C, [m.p.:115–116°C]
[18]. Yield: 94.0%; 1H NMR (DMSO): 8.15–8.25 (m, 5H,
arom.); 9.75 (s*, 2H, NH2CꢀS).
5. Conclusions
5b: C7H6FNS (155); m.p.: 110–111.5°C. Yield: 78.0%;
1H NMR (DMSO): 8.0–8.2 (m, 1H, arom.); 8.4–8.75 (m,
2H, arom.); 9.1 (s, 1H, arom.); 10.2 (s*, 2H, NH2CꢀS).
5c: C7H6ClNS (171.5); m.p.: 121–122°C. Yield: 77.0%;
1H NMR (DMSO): 7.6–7.75 (m, 1H, arom.); 7.9–7.8 (m,
2H, arom.); 8.1 (s, 1H, arom.); 10.15 (s*, 2H, NH2CꢀS).
5d: C7H6BrNS (215.9); m.p.: 126–127°C. Yield: 76.5%;
1H NMR (DMSO): 7.1–7.3 (m, 1H, arom.); 7.5–7.7 (m,
2H, arom.); 7.9 (s, 1H, arom.); 10.0 (s*, 2H, NH2CꢀS).
5f: C8H6F3NS (205); m.p.: 68–69°C. Yield: 97.5%; 1H
NMR(DMSO):8.1–8.3(m, 1H, arom.);8.6–8.85(m, 2H,
arom.); 9.35 (s, 1H, arom.); 10.4 (s*, 2H, NH2CꢀS).
5g: C8H9NS (151); m.p.: 88–90.5°C. Yield: 85.6%; 1H
NMR (DMSO): 2.35 (s, CH3); 7.4–7.75 (m, 4H, arom.);
9.6 (s*, 2H, NH2CꢀS).
Qualitative structure–activity relationships (H1 ago-
nism) as seen for 2-(meta-substituted)phenylhistamines
are also found for the thiazolyl analogues, in which the
Nt has been exchanged for a sulfur atom. In the analogues
benzyl derivatives however, the thiazole compounds
behave as H1 antagonists whereas the histamine deriva-
tives are still (weak) agonists. Although the potency of
the compounds synthesized is not very high, the agonistic
activity exerted by 2-(thiazol-4-yl)ethanamine 8 and its
2-phenyl derivatives 3a-j support the concept that the
tautomerism of imidazole in histamine is not essential for
the activation of H1-receptors. The transformation of the
agonistic 2-phenylthiazoles 3a–j to the antagonistic 2-
benzylthiazoles 4a–f indicates that the conjugation be-
tween the two aromatic rings (benzene and thiazole) may
be important for the activation of H1-receptors. As the
imidazole analogues show higher activities than the
corresponding thiazoles, we suggest that the sulfur atom
does not interact with a receptor site. Further studies are
necessary to clarify this latter observation.
5h: C7H7NOS (153); m.p.: 137–138.5°C. Yield: 40.0%;
1H NMR (DMSO): 8.0–8.2 (m, 4H, arom.); 9.65 (s*, 2H,
NH2CꢀS); 9.9 (s*, HO).
5i: C8H9NOS (167); m.p.: 98–99.5°C. Yield: 90.0%; 1H
NMR (DMSO): 3.85 (s, OCH3); 7.45–7.85 (m, 4H,
arom.); 9.75 (s*, 2H, NH2CꢀS).
5j: C7H8N2S (152); m.p.: 133.5–135°C. Yield: 72.0%;
1H NMR (DMSO): 3.35 (s,* 2H, NH2); 7.55–7.8 (m, 4H,
arom.); 9.8 (s*, 2H, NH2CꢀS).
6. Experimental protocols
1
5k: C8H9NS (151); m.p.: 98–99°C. Yield: 56.0%; H
6.1. Chemistry
NMR (DMSO): 3.4 (s, CH2ꢁbenzyl); 7.6–7.9 (m, 5H,
arom.); 9.8 (s*, 2H, NH2CꢀS).
General methods. All melting points (m.p.) were taken
in open capillaries on an Electrothermal apparatus and
are uncorrected. For all compounds H NMR spectra
were recorded on a Varian EM 360 (60 MHz) spectrom-
eter. Chemical shifts are expressed in ppm downfield from
internal TMS as reference. H NMR data are reported
in order of multiplicity (s, singlet; d, doublet; t, triplet;
m, multiplet; *, exchangeable by D2O), number of
protons, and approximate coupling constant in Hz.
Elemental analysis (C, H, N) for all compounds were
measured on Heraeus EA 415-0 and are within 90.4%
of the theoretical values. TLC was performed on Silica
Gel PF254 plates (E. Merck). Column chromatography
was carried out using Silica Gel 30–60 mm (J.T. Baker).
1
5l: C8H8FNS (169); m.p.: 75–76°C. Yield: 43.5%; H
NMR (DMSO): 4.35 (s, CH2ꢁbenzyl); 7.8–8.1 (m, 4H,
arom.); 10.3 (s*, 2H, NH2CꢀS).
1
5m: C8H8ClNS (185.5); m.p.: 107.5–108.5°C. Yield:
47.0%; 1H NMR (DMSO): 4.25 (s, CH2ꢁbenzyl); 7.4–7.7
(m, 4H, arom.); 10.15 (s*, 2H, NH2CꢀS).
1
1
5n: C8H8BrNS (229.9); m.p.: 126–127°C. Yield: H
NMR (DMSO): 51.4%; 4.15 (s, CH2ꢁbenzyl); 7.25–7.6
(m, 4H, arom.); 10.05 (s*, 2H, NH2CꢀS).
1
5o: C9H11NS (165); m.p.: 78–79°C. Yield: 35.6%; H
NMR (DMSO): 2.4 (s, CH3); 4.1 (s, CH2ꢁbenzyl); 7.6–7.9
(m, 4H, arom.); 9.75 (s*, 2H, NH2CꢀS).
5p: C9H11NOS (181); m.p.: 83–84°C. Yield: 39.7%; 1H
NMR (DMSO): 4.3 (s, CH2ꢁbenzyl); 4.65 (s, OCH3)
7.4–7.7 (m, 4H, arom.); 9.95 (s*, 2H, NH2CꢀS).
6.2. General method for compounds 5a–d, and 5f–p
— preparation of thioamides
6.3. Preparation of 3-nitrothiobenzamide (5e)
The appropriate nitrile (0.03 mol) is dissolved in at least
an equal weight of pyridine (more if the nitrile is of low
3-Nitrobenzamide (0.01 mol) with Lawesson’s reagent
(0.005 mol) in 10.0 ml of HMPA was heated 4.0 h at 80°C.

538
K. Walczyn´ski et al. / Il Farmaco 54 (1999) 533–541
The reaction mixture was allowed to cool to r.t. and
7.0 Hz, CH2); 4.0–4.25 (t, J=7.0 Hz, CH2); 7.05 (s,
H-thiazole); 7.25–8.0 (m, 8H, arom.); TLC ((9:1 chlo-
roform–ethyl acetate, Rf=0.70).
was then poured into water. The suspension was ex-
tracted with ether. The combined ether phases were
dried (MgSO4) and the ether was distilled off. The
residue was purified by column chromatography on
Silica Gel, employing the same eluent as indicated by
TLC.
6e: C19H13N3O4S (379); m.p.: 199–200°C. Yield:
1
49.7%; H NMR (CDCl3+TMS) (l): 3.1–3.25 (t, J=
7.0 Hz, CH2); 3.95–4.1 (t, J=7.0 Hz, CH2); 7.05 (s,
H-thiazole); 7.25–8.1 (m, 8H, arom.); TLC (19:1 chlo-
roform–ethyl acetate, Rf=0.37).
5e: C7H6N2O2S (182); m.p.: 126–127.5°C. Yield:
1
6f: C20H13F3N2O2S (402); m.p.: 144–145.5°C. Yield:
43.9%; H NMR (DMSO): 8.15–8.25 (m, 1H, arom.);
1
39.2%; H NMR (CDCl3+TMS) (l): 3.1–3.3 (t, J=
8.6–8.9 (m, 2H, arom.); 9.25 (s, 1H, arom.); 10.35 (s*,
2H, NH2CꢀS); TLC (9:1 chloroform–ethyl acetate,
Rf=0.34).
7.0 Hz, CH2); 4.0–4.2 (t, J=7.0 Hz, CH2); 7.05 (s,
H-thiazole); 7.25–8.1 (m, 8H, arom.); TLC (9:1 chloro-
form–ethyl acetate, Rf=0.57).
6g: C20H16N2O2S (348); m.p.: 165–166.5°C. Yield:
62.0%; H NMR (CDCl3+TMS) (l): 2.25 (s, CH3);
3.25–3.5 (t, J=7.0 Hz, CH2); 4.05–4.25 (t, J=7.0 Hz,
CH2); 6.85 (s, H-thiazole); 7.0–7.15 (m, 2H, arom.);
7.35–7.7 (m, 6H, arom.); TLC (9:1 chloroform–ethyl
acetate, Rf=0.39).
6.4. General method for compounds 6a–p and 7
— preparation of 4-[(2-phthalimido)ethyl]thiazoles
1
1-Bromo-4-phthalimido-2-butanone (0.01 mol) and
an appropriate meta-substituted-thiobenzamide or
meta-substituted-thiobenzylamide or thiourea (0.02
mol), were mixed with n-propanol (50.0 ml) and con-
centrated hydrochloric acid (5.0 ml) and the reaction
mixture was heated to reflux for 2.0 h. After cooling,
the precipitate was filtered and washed with n-propanol
and ether. The hydrochloride product was obtained as
a brown solid. The free base, in each case, was obtained
as follows: the hydrochloride of an appropriate phthal-
imide was mixed with saturated aqueous potassium
carbonate solution overnight at r.t. The solid was
filtered, washed with water, ether and air-dried to leave
a white or light-brown solid. All phthalimide deriva-
tives were purified by column chromatography on Silica
Gel, employing the same eluent as was indicated by
TLC.
6h: C19H14N2O3S (350); m.p.: 113–114°C. Yield:
1
33.6%; H NMR (DMSO) (l): 3.1–3.25 (t, J=7.0 Hz,
CH2); 4.0–4.2 (t, J=7.0 Hz, CH2); 6.95 (s, H-thiazole);
7.3–7.7 (m, 4H, arom.); 7.95–8.1 (m, 4H, arom.); 9.9
(s*, HO) TLC (9:1 chloroform–ethyl acetate, Rf=
0.51).
6i: C20H16N2O3S (364); m.p.: 106.5–108°C. Yield:
1
67.3%; H NMR (CDCl3+TMS) (l): 3.1–3.25 (t, J=
7.0 Hz, CH2); 3.8 (s, OCH3); 4.0–4.15 (t, J=7.0 Hz,
CH2); 7.0 (s, H-thiazole); 7.2–7.4 (m, 4H, arom.); 7.5–
7.9 (m, 4H, arom.); TLC (9:1 chloroform–ethyl acetate,
Rf=0.41).
6j: C19H15N3O2S (349); m.p.: 118–119°C. Yield:
1
42.8%; H NMR (CDCl3+TMS) (l): 2.9–3.05 (t, J=
7.0 Hz, CH2); 3.3 (s*, NH2); 3.75–3.95 (t, J=7.0 Hz,
CH2); 6.75 (s, H-thiazole); 6.9–7.1 (m, 4H, arom.);
7.45–7.75 (m, 4H, arom.); TLC (9:1 chloroform–ethyl
acetate, Rf=0.47).
7: C13H10N2O2S (258); m.p.: 107.5–108.5°C, [m.p.:
101–102°C] [15]. Yield: 78.5%; 1H NMR (CDCl3+
TMS) (l): 3.1–3.4 (t, J=7.0 Hz, CH2); 3.9–4.25 (t,
J=7.0 Hz, CH2); 6.85 (s, 1H(‘5’)-thiazole); 7.3–7.8 (m,
4H, arom.); 8.55 (s, 1H(‘2’)-thiazole); TLC (9:1 chloro-
form–ethyl acetate, Rf=0.30).
6k: C20H16N2O2S (348); m.p.: 151.5–152.5°C. Yield:
1
56.0%; H NMR (CDCl3+TMS) (l): 3.0–3.25 (t, J=
7.0 Hz, CH2); 3.95–4.15 (t, J=7.0 Hz, CH2); 3.25 (s,
CH2ꢁbenzyl); 6.9 (s, H-thiazole); 7.2–7.3 (m, 5H,
arom.); 7.75–7.95 (m, 4H, arom.); TLC (9:1 chloro-
form–ethyl acetate, Rf=0.41).
6l: C20H15FN2O2S (366); m.p.: 142–143°C. Yield:
57.4%; 1H NMR (CDCl3+TMS) (l): 3.05–3.25 (t,
J=7.0 Hz, CH2); 4.0–4.2 (t, J=7.0 Hz, CH2); 4.25 (s,
CH2ꢁbenzyl); 6.9 (s, H-thiazole); 7.05–7.35 (m, 4H,
arom.); 7.75–7.95 (m, 4H, arom.); TLC (9:1 chloro-
form–ethyl acetate, Rf=0.37).
6a: C19H14N2O2S (334); m.p.: 122.5–123.5°C. Yield:
51.3%; 1H NMR (CDCl3+TMS) (l): 3–3.25 (t, J=7.0
Hz, CH2); 3.95–4.1 (t, J=7.0 Hz, CH2); 6.9 (s, H-thia-
zole); 7.2–7.35 (m, 5H, arom.); 7.75–8.0 (m, 4H,
arom.); TLC (9:1 chloroform–ethyl acetate, Rf=0.53).
6b: C19H13FN2O2S (352); m.p.: 117–118°C. Yield:
1
36.7%; H NMR (CDCl3+TMS) (l): 3.1–3.3 (t, J=
7.0 Hz, CH2); 4.0–4.2 (t, J=7.0 Hz, CH2); 6.1 (s,
H-thiazole); 6.2–7.0 (m, 8H, arom.); TLC (9:1 chloro-
form–ethyl acetate, Rf=0.43).
6m: C20H15ClN2O2S (382.5); m.p.: 86–87°C. Yield:
1
6c: C19H13ClN2O2S (368.5); m.p.: 119–120°C. Yield:
53.6%; H NMR (CDCl3+TMS) (l): 3.0–3.25 (t, J=
1
30.5%; H NMR (CDCl3+TMS) (l): 3.1–3.25 (t, J=
7.0 Hz, CH2); 3.9–4.1 (t, J=7.0 Hz, CH2); 4.2 (s,
CH2ꢁbenzyl); 6.75 (s, H-thiazole); 6.85–7.1 (m, 4H,
arom.); 7.3–7.7 (m, 4H, arom.); TLC (9:1 chloroform–
ethyl acetate, Rf=0.36).
7.0 Hz, CH2); 4.0–4.15 (t, J=7.0 Hz, CH2); 6.75 (s,
H-thiazole); 6.95–7.2 (m, 2H, arom.); 7.3–7.7 (m, 6H,
arom); TLC (9:1 chloroform–ethyl acetate, Rf=0.68).
6d: C19H13BrN2O2S (412.9); m.p.: 126–127°C. Yield:
6n: C20H15BrN2O2S (426.9); sticky oil. Yield: 54.2%;
1
35.5%; H NMR (CDCl3+TMS) (l): 3.1–3.35 (t, J=
1H NMR (CDCl3+TMS) (l): 3.0–3.2 (t, J=7.0 Hz,

K. Walczyn´ski et al. / Il Farmaco 54 (1999) 533–541
539
CH2); 3.85–4.05 (t, J=7.0 Hz, CH2); 4.2 (s,
CH2ꢁbenzyl); 6.8 (s, H-thiazole); 6.9–7.1 (m, 4H,
arom.); 7.2–7.6 (m, 4H, arom.); TLC (9:1 chloroform–
ethyl acetate, Rf=0.46).
240°C. Yield: 34%. Anal. Calc.: C, 34.37; H, 3.38; N,
7.29. Found: C, 34.13; H, 3.24; N, 7.08%.
1
3c: H NMR (CDCl3+TMS) (l): 2.05 (s*, NH2);
2.95–3.15 (t, J=7.0 Hz, CH2); 3.2–3.3 (t, J=7.0 Hz,
CH2); 7.05 (s, H-thiazole); 7.25–8.05 (m, 4H, arom.);
TLC (50:10:1 chloroform–methanol–concentrated am-
monia, Rf=0.36); C11H11ClN2S·2HBr (400.5); m.p.:
224–225°C. Yield: 37%. Anal. Calc.: C, 32.95; H, 3.24;
N, 6.99. Found: C, 32.82; H, 3.13; N, 6.64%.
6o: C21H18N2O2S (362); m.p.: 91–92.5°C. Yield:
1
62.7%; H NMR (CDCl3+TMS) (l): 2.35 (s, CH3);
3.0–3.25 (t, J=7.0 Hz, CH2); 4.0–4.2 (t, J=7.0 Hz,
CH2); 4.25 (s, CH2ꢁbenzyl); 6.9 (s, H-thiazole); 7.0–
7.25 (m, 4H, arom.) 7.85–8.0 (m, 4H, arom.); TLC (9:1
chloroform–ethyl acetate, Rf=0.38).
1
3d: H NMR (CDCl3+TMS) (l): 2.45 (s*, NH2);
1
6p: C21H18N2O3S (378); sticky oil. Yield: 59.5%; H
2.95–3.05 (t, J=7.0 Hz, CH2); 3.1–3.25 (t, J=7.0 Hz,
CH2); 7.05 (s, H-thiazole); 7.3–8.2 (m, 4H, arom.);
TLC (90:10:1 chloroform–methanol–concentrated am-
monia, Rf=0.17); C11H11BrN2S·2HBr (445); m.p.:
230–232°C. Yield: 35%. Anal. Calc.: C, 29.66; H, 2.92;
N, 6.29. Found: C, 29.51; H, 2.88; N, 6.13%.
NMR (CDCl3+TMS) (l): 3.05–3.25 (t, J=7.0 Hz,
CH2); 4.75 (s, OCH3); 4.0–4.15 (t, J=7.0 Hz, CH2);
4.25 (s, CH2ꢁbenzyl); 6.9 (s, H-thiazole); 7.0–7.4 (m,
4H, arom.); 7.75–7.95 (m, 4H, arom.); TLC (9:1 chlo-
roform–ethyl acetate, Rf=0.35).
3f: 1H NMR (CDCl3+TMS) (l): 1.65 (s*, NH2);
2.85–3.0 (t, J=7.0 Hz, CH2); 3.05–3.15 (t, J=7.0 Hz,
CH2); 6.9 s, H-thiazole); 7.25–8.1 (m, 4H, arom.); TLC
100:10:1 chloroform–methanol–concentrated ammo-
nia, Rf=0.33) C12H11F3N2S·2HBr (434); m.p.: 224–
226°C. Yield: 32% Anal. Calc.: C, 33.18; H, 2.99; N,
6.45. Found: C, 32.90; H, 2.82; N, 6.49%.
6.5. General methods for compounds 3a–i, 8, and 4a–f
— preparation of 2-[2-phenyl and 2-benzyl)-
4-thiazolyl]ethanamines
An
appropriate
4-[(2-phthalimido)ethyl]thiazole
(0.0025 mol) was added to a solution of hydrazine in
methanol (50.0 ml, 1.0 M), and the reaction mixture
was heated for 0.5 h until it became homogeneous. The
reaction mixture was then stirred at r.t. for another 2 h.
Concentration in vacuo provided a white sticky semi-
solid, which was purified by column chromatography
on Silica Gel, employing the same eluent as indicated
by TLC. The title products were obtained as sticky oils.
All free bases were treated with methanolic HBr and
hydrobromides were precipitated with dry diethyl ether.
4-Phthalimido-2-butanone and 1-bromo-4-phthalimido-
2-butanone were obtained according to the US patent
[20].
3g: 1H NMR (CDCl3+TMS) (l): 1.95 (s*, NH2); 2.1
(s, CH3); 2.85–3.0 (t, J=7.0 Hz, CH2); 3.05–3.15 (t,
J=7.0 Hz, CH2); 6.95 (s, H-thiazole); 7.2–7.5 (m, 4H,
arom.); TLC (90:30:2 chloroform–methanol–concen-
trated ammonia, Rf=0.44); C12H14N2S·2HBr (380);
m.p.: 234–236°C. Yield: 53%. Anal. Calc.: C, 37.89; H,
4.21; N, 7.30. Found: C, 37.81; H, 4.53; N, 7.50%.
C12H14N2OS·2HBr (396); m.p. 221–222°C. Yield: 47%.
Anal. Calc.: C, 36.36; H, 4.04; N, 7.07. Found: C,
36.18; H, 3.96; N, 6.89%.
1
3h: H NMR (CDCl3+TMS) (l): 1.85 (s*, NH2);
2.75–2.90 (t, J=7.0 Hz, CH2); 3.0–3.2 (t, J=7.0 Hz,
CH2); 6.95 (s, H-thiazole); 7.25–7.6 (m, 4H, arom.);
8.25 (s*, HO); TLC (90:10:1 chloroform–methanol–
concentrated ammonia, Rf=0.21) C11H12N2OS·2HBr
(382); m.p.: 264–266°C. Yield: 42%. Anal. Calc.: C,
34.55; H, 3.65; N, 7.33. Found: C, 34.38; H, 3.88; N,
7.05%.
8: 1H NMR (CDCl3+TMS) (l): 2.0 (s*, NH2);
2.85–3.0 (t, J=7.0 Hz, CH2); 3.05–3.2 (t, J=7.0 Hz,
CH2); 7.05 (s, 1H(‘5’)-thiazole); 8.8 (s, 1H(‘2’)-thiazole);
TLC (90:30:3 chloroform–methanol–concentrated am-
monia, Rf=0.15). C5H8N2S·HBr (209); m.p.: 160–
161°C, [C5H8N2S·HCl m.p.: 181–183°C] [15]. Yield:
37%. Anal. Calc.: C, 28.71; H, 4.31; N, 13.40 Found: C,
28.48; H, 4.56; N, 13.09%.
3i: 1H NMR (CDCl3+TMS) (l): 1.75 (s*, NH2);
2.90–3.0 (t, J=7.0 Hz, CH2); 3.05–3.15 (t, J=7.0 Hz,
CH2); 3.95 (s, OCH3); 7.05 (s, H-thiazole); 7.4–7.8 (m,
4H, arom.); TLC (50:10:1 chloroform–methanol–con-
centrated ammonia, Rf=0.34).
1
3a: H NMR (CDCl3+TMS) (l): 1.85 (s*, NH2);
2.8–2.95 (t, J=7.0 Hz, CH2); 3.0–3.15 (t, J=7.0 Hz,
CH2); 6.85 (s, H-thiazole); 7.3–7.45 (m, 5H, arom.);
TLC (88:20:2 chloroform–methanol–concentrated am-
monia, Rf=0.43);C11H12N2S·2HBr (366); m.p.: 153–
154°C, [C11H12N2S·2HCl; m.p.: 206–209°C] [26,27].
Yield: 31%. Anal. Calc.: C, 36.06; H, 3.82; N, 7.65.
Found: C, 35.94; H, 3.93; N, 7.51%.
3j: 1H NMR (CDCl3+TMS) (l): 1.80 (s*, NH2);
2.70–2.85 (t, J=7.0 Hz, CH2); 2.9–3.05 (t, J=7.0 Hz,
CH2); 3.30 (s*, NH2, arom.); 6.85 (s, H-thiazole); 7.3–
7.75 (m, 4H, arom.); TLC (100:50:5 chloroform–
methanol–concentrated
ammonia,
Rf=0.21)
1
3b: H NMR (CDCl3+TMS) (l): 1.95 (s*, NH2);
C11H13N3S·3HBr (624); m.p.: 219–221°C. Yield: 33%.
Anal. Calc.: C, 28.57; H, 3.46; N, 6.73. Found: C,
28.53; H, 3.55; N, 6.51%.
2.9–3.0 (t, J=7.0 Hz, CH2); 3.05–3.2 (t, J=7.0 Hz,
CH2); 7.0 (s, H-thiazole); 7.2–7.9 (m, 4H, arom.); TLC
(50:10:1 chloroform–methanol–concentrated ammo-
nia, Rf=0.32); C11H11FN2S·2HBr (384); m.p.: 239–
4a: 1H NMR (CDCl3+TMS) (l): 1.9 (s*, NH2);
2.85–3.00 (t, J=7.0 Hz, CH2); 3.05–3.20 (t, J=7.0

540
K. Walczyn´ski et al. / Il Farmaco 54 (1999) 533–541
Hz, CH2); 4.3 (s, CH2, benzyl); 6.85 (s, H-thiazole);
7.4–7.6 (m, 5H, arom.); TLC (88:20:2 chloroform–
ide to pH 12 and extraction with chloroform (3×
15.0 ml) gave a crude product, which was purified by
column chromatography on Silica Gel, employing the
same eluent as indicated by TLC.
methanol–concentrated
ammonia,
Rf=0.24)
C12H14N2S·2HBr (380); m.p.: 146–147°C, [C12H14N2S·
dipicrate; m.p.: 143.5–144.5°C] [28]. Yield: 78%. Anal.
Calc.: C, 37.89; H, 4.21; N, 7.37. Found: C, 37.64; H,
4.49; N, 7.12%.
1
3e: H NMR (CDCl3+TMS) (l): 2.10 (s*, NH2);
2.75–2.90 (t, J=7.0 Hz, CH2); 2.95–3.10 (t, J=7.0
Hz, CH2); 6.85 (s, H–thiazole); 7.3–8.5 (m, 4H,
arom.); TLC (90:10:1 chloroform–methanol–concen-
trated ammonia, Rf=0.14). C11H11N3O2S·2HBr (411);
m.p.: 250–251°C. Yield: 37%. Anal. Calc.: C, 32.12;
H, 3.16; N, 10.22. Found: C, 31.96; H, 3.21; N,
10.02%.
1
4b: H NMR (CDCl3+TMS) (l): 1.65 (s*, NH2);
2.80–2.95 (t, J=7.0 Hz, CH2); 3.00–3.15 (t, J=7.0
Hz, CH2); 4.3 (s, CH2, benzyl); 6.90 (s, H-thiazole);
7.00–7.50 (m, 4H, arom.); TLC (90:30:2 chloro-
form–methanol–concentrated ammonia, Rf=0.40)
C12H13FN2S·2HBr (398); m.p.: 220–221°C. Yield:
56%. Anal. Calc.: C, 36.18; H, 3.77; N, 7.03. Found:
C, 36.02; H, 3.89; N, 7.13%.
References
1
4c: H NMR (CDCl3+TMS) (l): 1.75 (s*, NH2);
2.80–2.95 (t, J=7.0 Hz, CH2); 3.00–3.15 (t, J=7.0
Hz, CH2); 4.25 (s, CH2, benzyl); 6.85 (s, H-thiazole);
7.15–7.5 (m, 4H, arom.); TLC (90:30:2 chloro-
form–methanol–concentrated ammonia, Rf=0.46)
C12H13ClN2S·2HBr (414.5); m.p.: 213–215°C. Yield:
51%. Anal. Calc.: C, 34.74; H, 3.62; N, 6.76. Found:
C, 34.63; H 3.63; N, 6.72%.
[1] M.Q. Zhang, R. Leurs, H. Timmerman, in: M.E. Wolff (Ed.),
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(1975) 905.
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Soc. 72 (1950) 4526.
1
4d: H NMR (CDCl3+TMS) (l): 1.85 (s*, NH2);
2.8–2.95 (t, J=7.0 Hz, CH2); 3.00–3.15 (t, J=7.0
Hz, CH2); 4.25 (s, CH2, benzyl); 6.85 (s, H-thiazole);
7.15–7.6 (m, 4H, arom.); TLC (90:30:2 chloro-
form–methanol–concentrated ammonia, Rf=0.36)
C12H13BrN2S·2HBr (459); m.p.: 223–225°C. Yield:
48%. Anal. Calc.: C, 31.37; H, 3.27; N, 6.10. Found:
C, 31.17; H, 3.19; N, 6.07%.
1
4e: H NMR (CDCl3+TMS) (l): 1.95 (s*, NH2);
2.30 (s, CH3); 2.80–2.95 (t, J=7.0 Hz, CH2); 3.00–
3.15 (t, J=7.0 Hz, CH2); 4.25 (s, CH2, benzyl); 6.80
(s, H-thiazole); 7.05–7.45 (m, 4H, arom.); TLC
(90:30:2 chloroform–methanol–concentrated ammo-
nia, Rf=0.30) C13H16N2S·2HBr (394); m.p.: 228–
229°C. Yield: 63% Anal. Calc.: C, 39.59; H, 4.57; N,
7.11. Found: C, 39.38; H, 4.76; N, 7.09%.
4f: 1H NMR (CDCl3+TMS) (l): 1.80 (s*, NH2);
2.85–3.00 (t, J=7.0 Hz, CH2); 3.05– 3.15 (t, J=7.0
Hz, CH2); 3.85 (s, OCH3); 4.30 (s, CH2, benzyl); 6.80
(s, H-thiazole); 6.9–7.4 (m, 4H, arom.); TLC (90:30:2
chloroform–methanol–concentrated ammonia, Rf=
0.37). C13H16N2OS·2HBr (410); m.p.: 174–175°C.
Yield: 60%. Anal. Calc.: C, 38.05; H, 4.39; N, 6.83.
Found: C, 37.89; H, 4.42; N, 6.87%.
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Eur. J. Med. Chem. 31 (1996) 397.
6.6. Preparation of 2-[2-(3-nitrophenyl)-4-thiazolyl]-
ethanamine (3e)
Hydrolysis of 6e (0.02 mol) was carried out by
heating with hydrochloric acid (25.0 ml 5 N) under
reflux for 24 h, followed by washing with diethyl
ether (3×20.0 ml), basification with sodium hydrox-

K. Walczyn´ski et al. / Il Farmaco 54 (1999) 533–541
541
[23] A.M. Ter Laak, H. Timmerman, R. Leurs, P.H.J. Nederkoorn,
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.
.