Histamine H1 receptor ligands - Part II. Synthesis and in vitro pharmacology of 2-[2-(phenylamino)thiazol-4-yl]ethanamine and 2-(2-benzhydrylthiazol-4-yl)ethanamine derivatives

Article abstract of DOI:10.1016/S0014-827X(00)00087-2

New 2-[2-(phenylamino)thiazol-4-yl]ethanamine and 2-(2-benzhydrylthiazol-4-yl)ethanamine derivatives were prepared and tested in vitro as H₁ receptor antagonists. The compounds with 2-phenylamino substitution with meta-halide substituents at the phenyl ring, showed weak H₁-antagonistic activity (pA₂: 4.62-5.04) and this activity was completely lost in the case of meta-methyl substituent (pA₂ : 4). When the phenylamino group was replaced by benzhydryl groups of classic antihistamines, the resulting compounds exhibited slightly improved H₁-antagonistic activity (at the meta-position pA₂: 6.38-6.15; at the para-position pA₂: 6.04-5.87).

Full text of DOI:10.1016/S0014-827X(00)00087-2

www.elsevier.nl/locate/farmac
Il Farmaco 55 (2000) 569–574
Histamine H1 receptor ligands
Part II. Synthesis and in vitro pharmacology of
2-[2-(phenylamino)thiazol-4-yl]ethanamine and
2-(2-benzhydrylthiazol-4-yl)ethanamine derivatives
Krzysztof Walczyn´ski a,*, Roman Guryn a, Obbe P. Zuiderveld b, Ming-Qiang Zhang b,1,
Henk Timmerman b
a Department of Synthesis and Technology of Drugs, Medical Academy, Muszyn´skiego Street 1, 90-145 L*o´dz, Poland
b Leiden/Amsterdam Center for Drug Research, Di6ision of Medicinal Chemistry, Vrije Uni6ersiteit, De Boelelaan 1083,
1081 HV Amsterdam, The Netherlands
Received 17 June 1999; accepted 1 July 2000
Abstract
New 2-[2-(phenylamino)thiazol-4-yl]ethanamine and 2-(2-benzhydrylthiazol-4-yl)ethanamine derivatives were prepared and
tested in vitro as H1 receptor antagonists. The compounds with 2-phenylamino substitution with meta-halide substituents at the
phenyl ring, showed weak H1-antagonistic activity (pA2: 4.62–5.04) and this activity was completely lost in the case of
meta-methyl substituent (pA2B4). When the phenylamino group was replaced by benzhydryl groups of classic antihistamines, the
resulting compounds exhibited slightly improved H1-antagonistic activity (at the meta-position pA2: 6.38–6.15; at the para-posi-
tion pA2: 6.04–5.87). © 2000 Elsevier Science S.A. All rights reserved.
Keywords: Histamine H1-receptor; H1-antagonists; 2-[2-(Phenylamino)thiazol-4-yl]ethanamines; 2-(2-Benzhydrylthiazol-4-yl)ethanamines
1. Introduction
[3]. Generally, in attempting to identify histamine H1-
receptor antagonists with potentially greater clinical
efficacy than earlier compounds, two approaches have
been adopted. In one approach, attempts have been
made to identify compounds combining H1-receptor
antagonism with additional and potentially beneficial
properties [4–6]. The second approach has been made
to antihistamines, which do not easily penetrate the
CNS, in the hope of limiting side effects such as seda-
tion and most recently arrhythmia.
It is more than 60 years since the discovery of the
first histamine H1-receptor antagonists. Many different
structural classes of compounds are now known to
show high antagonist potency at this receptor. The
therapeutic potential for antihistaminic drugs has in-
creased due to the discovery of several new antihis-
taminic compounds, which are non-sedating. Some of
these new compounds (cetirizine [1], loratadine [2], etc.)
are widely and successfully used against histamine-me-
diated allergic responses (rhinitis, urticaria). It has been
demonstrated that some modern H1-antagonists, i.e.
cetirizine and loratadine, have a remarkable specificity
for H1-receptors, whereas most classical H1-antagonists
are less selective and interact with many other receptors
(i.e. adrenergic, serotonergic and cholinergic receptors)
These subjects have been extensively reviewed, in-
cluding some detailed accounts of structure–activity
relationships [7–11].
Previously we reported the synthesis and biological
evaluation of 2-(2-phenylthiazol-4-yl)ethanamines and
2-(2-benzylthiazol-4-yl)ethanamines as histamine H1-re-
ceptor ligands [12]. The compounds with 2-phenyl sub-
stitution showed H1-agonistic activity. When the phenyl
group was replaced by a benzyl group, the resulting
compounds all exhibited weak H1-antagonistic activity.
These results prompted us to investigate a series of
* Corresponding author. Tel.: +48-42-78 3628; fax: +48-42-78
4796.
1 Present address: Department of Medicinal Chemistry, Organon
Laboratories Ltd., Newhouse, Lanarkshire ML1 5SH Scotland, UK.
0014-827X/00/$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(00)00087-2

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K. Walczyn´ski et al. / Il Farmaco 55 (2000) 569–574
2-[2-(phenylamino)thiazol-4-yl]ethanamines and 2-(2-
benzhydrylthiazol-4-yl)ethanamines, with the aim of ex-
plaining the influence of breaking the conjugation
between phenyl and thiazole ring-systems on activity of
2-substituted-thiazoles. Since many classic H1-antago-
nists carry the characteristic benzhydryl group which
constitutes, together with the tertiary amine, the phar-
macophore of histamine H1-antagonists, we also inves-
tigated the influence of substituents in the second
phenyl ring on antagonistic activity in comparison with
a series of 2-(2-benzylthiazol-4-yl)ethanamines.
tuted-phenylacetonitriles were purchased from commer-
cial sources.
The appropriate phenylthioureas (1a–e) were ob-
tained according to Frank and Smith [13] by the action
of benzoyl isothiocyanate on 3-substituted aniline and
alkaline hydrolysis of obtained 1-benzoyl-2-(3-
substituted-phenyl)thiourea.
The appropriate a,a-diphenylacetonitriles (4a–g)
were directly obtained according to Robb and Schultz
[14] by the reaction of the crude a-bromo-a-phenylace-
tonitrile (obtained by the reaction of the 3- or 4-substi-
tuted-benzylnitrile with bromine) with benzene in the
presence of anhydrous aluminum trichloride.
The appropriate benzhydrylthioamides (5a–g) were
prepared according to Fairfull et al. [15] by the reaction
of the nitrile with hydrogen sulfide in pyridine in the
presence of triethylamine.
2. Chemistry
All 2-substituted-thiazol-4-ylethanamine derivatives
were prepared using well established pathways (Scheme
1). The 3-substituted-anilines, and the 3- and 4-substi-
Scheme 1. Synthesis of 2-[2-(phenylamino)thiazol-4-yl] ethanamines (3a–e) and 2-(2-benzhydrylthiazol-4-yl)ethanamines (7a–g).

K. Walczyn´ski et al. / Il Farmaco 55 (2000) 569–574
571
2-[2-(Phenylamino)thiazol-4-yl]ethyl-4-phthalimides
(2a–e) and 2-(2-benzhydrylthiazol-4-yl)ethyl-4-phthal-
imides (6a–g) were obtained by reaction of the corre-
sponding thioamide with 1-bromo-4-phthalimido-
butanone-2 [16] in n-propanol in the presence of con-
centrated hydrochloric acid. All phthalimide derivatives
were purified by column chromatography.
2-[2-(Phenylamino)thiazol-4-yl]ethanamines
(3a–e)
Scheme 2. Synthesis of N,N-dimethyl-2-(2-benzhydrylthiazol-4-
yl)ethanamine (8).
and 2-(2-benzhydrylthiazol-4-yl)ethanamines (7a–g)
were obtained after hydrazinolysis of the corresponding
phthalimides, followed by purification by column
chromatography.
N,N-Dimethyl-2-(2-benzhydrylthiazol-4-yl)ethana-
mine (8) was prepared by reaction of the 2-(2-ben-
zhydrylthiazol-4-yl)ethanamine (7a) with formaldehyde
in formic acid (Scheme 2). The crude product was
purified by column chromatography.
Table 1
Structures and results of the pharmacological screening on the iso-
lated
ethanamines
guinea-pig
ileum
for
2-[2-(phenylamino)thiazol-4-yl]
3. Pharmacology
The histaminergic H1 antagonism of the compounds
was established on isolated guinea pig ileum by conven-
tional methods; the pA2 values were compared with the
potency of temelastine (Tables 1 and 2) [17].
Comp.
R
pA29sem(n)
3a
3b
3c
3d
H
F
Cl
Br
CH3
4.4490.08(9)
4.6290.14(9)
4.6190.19(6)
5.0490.07(6)
B4(9)
4. Results and discussion
3e
2-[2-(Phenylamino)thiazol-4-yl]ethanamines (3a–e),
2-(2-benzhydrylthiazol-4-yl)ethanamines (7a–g) and
N,N-dimethyl-2-(2-benzhydrylthiazol-4-yl)ethanamine
(8) were tested for histamine H1-receptor activity in
vitro on isolated guinea pig ileum as described in the
Section 5.
The data reported in Table 1 show that the pheny-
lamine group attached at position 2 in 4-thiazo-
lethanamine yields weak H1-antagonists (3a–d); in the
case of the 3-methyl analogue 3e the H1-activity was
completely lost.
Temelastine
9.6390.07(11)
Table 2
Structures and results of the pharmacological screening on the iso-
lated guinea-pig ileum for 2-(2-benzhydrylthiazol-4-yl)ethanamines
All 2-(2-benzhydrylthiazol-4-yl)ethanamines and
N,N-dimethyl-2-(2-benzhydrylthiazol-4-yl)ethanamine
(7a–g and 8) showed weak H1-antagonistic activity
(Table 2). The antagonistic activities of the present
series with the benzhydryl group substituted at position
C2 of the thiazole ring 7a–g are comparable with the
activities of the corresponding 2-(benzhydryl)histamines
[18]. No definite structure–activity relationships can be
drawn from the present series as the influence of a
substituent in the benzhydryl group is only seen for
meta substituents; the activity of 7b–d is slightly higher
than that of the unsubstituted compound 7a, whereas in
the classical diphenhydramines type of compounds only
para substitution increases the H1 activity. We conclude
therefore that the benzhydryl groups play a different
role in both classes.
Comp.
3-R1
4-R1
R2,R3
pA29sem(n)
7a
7b
7c
7d
7e
7f
7g
8
H
F
H
H
H
H
F
Cl
Br
H
H,H
H,H
H,H
H,H
H,H
H,H
H,H
CH3,CH3
5.8890.11(7)
6.1590.15(7)
6.3890.15(6)
6.1690.16(5)
5.9990.18(7)
6.0490.13(6)
5.8790.12(6)
5.9890.14(6)
9.6390.07(11)
Cl
Br
H
H
H
H
Temelastine

572
K. Walczyn´ski et al. / Il Farmaco 55 (2000) 569–574
The same conclusion can be reached by comparing
duced pressure. The solid was then recrystallized from
isopropyl alcohol. 4a. C14H11N (193); b.p.: 122–125°C/
1–2 mmHg. M.p.: 74–75°C [16]. M.p.: 71–73°C. Yield:
76%. 4b. C14H10FN (211). 1H NMR (CDCl3–TMS) (l):
5.1 (s, 1H, CH); 7.40 (m, 9H, arom.). B.p.: 143–147°C/
0.3 mmHg. Sticky oil. Yield: 71%. 4c. C14H10ClN
(227.5). B.p.: 163–166°C/0.1 mmHg. M.p.: 50.5–
52.5°C. Yield: 67%. 4d. C14H10BrN (271.9). B.p.: 160–
164°C/0.2 mmHg. M.p.: 76–78°C. Yield: 63%. 4e.
C14H10FN (211). B.p.: 140–146°C/0.3 mmHg. M.p.:
the activity of the present benzhydryl compounds with
these of the corresponding benzyl analogues, the latter
showing a somewhat lighter antagonistic activity,
whereas in the classic compounds the benzene analogs
have almost completely lost the H1 blocking properties.
5. Experimental
1
5.1. Chemistry
43–44°C. Yield: 65%. 4f. C14H10ClN (227.5). H NMR
(CDCl3–TMS) (l): 5.15 (s, 1H, CH); 7.4 (m, 9H,
arom.). B.p.: 154–157°C/0.3 mmHg. M.p.: 74–75°C.
Yield: 79%. 4g. C14H10BrN (271.9). B.p.: 166–168°C/
0.1 mmHg. M.p.: 80.5–81°C. Yield: 70%.
All melting points (m.p.) were taken in open capil-
laries on an electrothermal apparatus and are uncor-
rected. For all compounds 1H NMR spectra were
recorded on a Varian EM 360 (60 MHz) spectrometer.
Chemical shifts are expressed in parts per million
5.3. General method for the preparation of
thioureas — 1a–e
1
downfield from the internal standard TMS. H NMR
data are reported in the order: multiplicity (s, singlet; d,
doublet; t, triplet; m, multiplet; *, exchangeable by
D2O); number of protons; and approximate coupling
constant in hertz. 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 (Merck). Column
chromatography was carried out using silica gel 30–60
mm (J.T. Baker), employing the same eluent as was
indicated by TLC.
Benzoyl chloride (0.1 mol) was added dropwise to a
solution of ammonium thiocyanate (0.11 mol) in 50 ml
of dry acetone. After the addition was complete, the
mixture was refluxed for 5 min. A solution of the
appropriate aniline (0.1 mol) in 25 ml of dry acetone
was then added at such a rate that the solution refluxed
gently. The mixture was poured into 750 ml of water,
and the resulting precipitate was separated by filtration.
The crystals were treated for 5 min with a boiling
solution of 15 g of sodium hydroxide in 135 ml of
water. The solution was acidified with concentrated
hydrochloric acid and then made slightly basic with
ammonium hydroxide. The solid was collected, washed
with water, and recrystallized from toluene. 1a.
C7H8N2S (152). M.p.: 152.5–153°C [12]. M.p.:: 152–
154°C. Yield: 75%. 1b. C7H7FN2S (170). M.p.: 115–
117.5°C. Yield: 70%. 1c. C7H7ClN2S (186.5). M.p.:
139–140.5°C. Yield: 71%. 1d. C7H7BrN2S (230.9).
5.2. General method for the preparation of
h,h-diphenylacetonitriles — 4a–g
An appropriate phenylacetonitrile solution (0.35 mol)
in benzene was placed in a flask equipped with a
dropping funnel and an efficient stirrer, and heated to
110°C. Bromine (0.39 mol) was added over a period of
1 h (during the addition and for 15 min thereafter the
temperature of the liquid was maintained at 105–
110°C). The resulting benzene solution of the corre-
sponding a-bromo-a-phenylacetonitrile was added in
small portions to the boiling mixture, containing pow-
dered anhydrous aluminum trichloride (0.35 mol) in
130.0 ml of dry benzene, over a period of 2 h. After the
addition was complete, the reaction mixture was
refluxed for an additional 1 h period. The flask was
then cooled, and the mixture was poured into a stirred
mixture of 350 g of crushed ice and 35 ml of concen-
trated hydrochloric acid. The benzene layer was sepa-
rated. The aqueous layer was extracted with 200 ml of
ether in two equal portions. The ether and benzene
solutions were combined and washed successively with
water, saturated sodium bicarbonate solution and wa-
ter. The organic layer was dried over 50 g of anhydrous
sodium sulfate. The drying agent was separated from
the solution, and the solvents were removed by heating
on a steam bath. The residue was distilled under re-
1
M.p.: 154–155°C. Yield: 73%. 1e. C8H10N2S (166). H
NMR (DMSO-d6) (l): 2.3 (s, 3H, CH3); 6.8–7.2 (m,
4H, arom.); 7.35 (s*, 2H, NH2); 9.9 (s*, 1H, NH). M.p.:
100–102.5°C. Yield: 65%.
5.4. General method for the preparation of
benzhydrylthioamides — 5a–g
The appropriate nitrile (0.1 mol) was dissolved in at
least an equal weight of dry pyridine and triethylamine
(0.1 mol) was added. Dry hydrogen sulfide was passed
through the solution in a steady stream for 12 h at
room temperature (r.t.). The mixture was poured into a
stirred solution of 1500 ml of water and 100 ml of
concentrated hydrochloric acid, and the thioamide col-
lected by filtration. All thioamides were crystallized
from ethanol. TLC (9:1 chloroform–ethyl acetate). 5a.
C14H13N2S (241). M.p.: 146–148°C. Yield: 95%. TLC
(Rf=0.57). 5b. C14H12FN2S (259). M.p.: 119–120.5°C.

K. Walczyn´ski et al. / Il Farmaco 55 (2000) 569–574
573
Yield: 56%. TLC (Rf=0.51). 5c. C14H12ClN2S (275.5).
5.6. General methods for the preparation of the
thiazoles 3a–e and 7a–g
M.p.: 120–121°C. Yield: 91%. TLC (Rf=0.53). 5d.
C14H12BrN2S (319.9). 1H NMR (CDCl3–TMS) (l):
5.65 (s, 1H, CH); 6.95 (s*, 2H, NH2); 7.3 (m, 9H,
arom.). M.p.: 113–115°C. Yield: 58%. TLC (Rf=0.58).
5e. C14H12FN2S (259). M.p.: 127–129°C. Yield: 68%.
TLC (Rf=0.50). 5f. C14H12ClN2S (275.5). M.p.: 167–
168°C. Yield: 58%. TLC (Rf=0.50). 5g. C14H12BrN2S
(319.9). M.p.: 173–174°C. Yield: 84%. TLC (Rf=0.49).
The appropriate 2-[2-(phenylamino)thiazol-4-yl]ethyl-
4-phthalimide or 2-(2-benzhydryl-thiazol-4-yl)ethyl-4-
phthalimide (0.0025 mol) was added to a solution of
hydrazine in methanol (50.0 ml, 1.0 M), and the reac-
tion 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 vacuum provided
a white sticky semi-solid, which was purified by column
5.5. General method for the preparation of
phthalimides — 2a–e and 6a–g
chromatography
(eluent:
88:20:2
chloroform–
methanol–concentrated ammonium hydroxide). The ti-
tle products were obtained as a sticky oils. 3a.
C11H13N3S (219). Yield: 34%. TLC (Rf=0.30).
C11H13N3S·2C4H4O4 (451). M.p.: 146–147.5°C. 3b.
C11H12FN3S (237). Yield: 32%. 1H NMR (CDCl3–
TMS) (l): 2.7 (t, J=6 Hz, 2H, CH2); 3.1 (t, J=6 Hz,
2H, CH2); 4.1 (s*, 2H, NH2); 6.3 (s, 1H, Hthiazole); 6.8
(m, 1H, arom.); 7.2 (m, 3H, arom.); 7.45 (s*, 1H, NH).
TLC (Rf=0.61). C11H12FN3S·2C4H4O4 (469). M.p.:
153–154.5°C. 3c. C11H12ClN3S (253.5). Yield: 31%.
TLC (Rf=0.18). C11H12ClN3S·2C4H4O4 (485.5). M.p.:
151–153°C. 3d. C11H12BrN3S (297.9). Yield: 28%. TLC
(Rf=0.24). C11H12BrN3S·2C4H4O4 (530). M.p.: 162–
163°C. 3e. C12H15N3S (233). Yield: 67%. TLC (Rf=
0.43) C12H15N3S·2C4H4O4 (465). M.p.: 146–147°C.
All free bases were treated with methanolic maleic
acid and maleic acid salts were precipitated with dry
diethyl ether. 7a. C18H18N2S (294). Yield: 72%. TLC
(Rf=0.14). C18H18N2S·2HBr (455.8). M.p.: 209–211°C.
1-Bromo-4-phthalimido-2-butanone (0.01 mol) and
the appropriate thiourea or thioamide (0.02 mol) were
mixed with n-propanol (50.0 ml) and concentrated hy-
drochloric acid (5.0 ml), and the reaction mixture was
heated to reflux for 2 h. After cooling, the precipitate
was filtered off and washed with n-propanol and ether.
After air drying, the product was obtained as yellowish
hydrochloride.
The free base, in each case, was obtained as follows:
the salt of an appropriate phthalimide was treated 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 product. All phthalimide derivatives were
purified by column chromatography on silica gel (elu-
ent: 9:1 chloroform–ethyl acetate) for 2-[2-(pheny-
lamino)thiazol-4-yl]ethyl-4-phthalimides
and
95:5
dichloromethane–ethyl acetate for 2-(2-benzhydrylthia-
zol-4-yl)ethyl-4-phthalimides). 2a. C19H15N3O2S (349).
M.p.: 162–165°C. Yield: 62%. TLC (Rf=0.39). 2b.
C19H14FN3O2S (367). M.p.: 142.5–144.5°C. Yield:
1
7b. C18H17FN2S (312). Yield: 43%. H NMR (CDCl3–
TMS) (l): 1.75 (s*, 2H, NH2); 3.0 (m, 4H, 2CH2); 5.8
(s, 1H, CH); 6.9 (s, 1H, Hthiazole); 7.3 (m, 9H, arom.).
TLC (Rf=0.22). C18H17FN2S·HBr (393.3). M.p.: 192–
193°C. 7c. C18H17ClN2S (328.5). Yield: 52%. TLC
(Rf=0.26). C18H17ClN2S·HBr (409.78). M.p.: 198–
200°C. 7d. C18H17BrN2S (372.9). Yield: 73%. TLC
(Rf=0.22). C18H17BrN2S·HBr (454.2). M.p.: 144–
146°C. 7e. C18H17FN2S (312). Yield: 72%. TLC (Rf=
0.27). C18H17FN2S·HBr (393.3). M.p.: 179–181°C. 7f.
C18H17ClN2S (328.5). Yield: 83%. TLC (Rf=0.22).
C18H17ClN2S·2HBr (490.7). M.p.: 204–206°C. 7g
C18H17BrN2S (372.9). Yield: 85%. TLC (Rf=0.22).
C18H17BrN2S·HBr (454.2). M.p.: 188–189°C.
1
44.5%. TLC (Rf=0.36). 2c. C19H14ClN3O2S (383.5). H
NMR (CDCl3–TMS) (l): 3.0 (t, J=7 Hz, 2H, CH2);
4.05 (t, J=7 Hz, 2H, CH2); 6.35 (s, Hthiazole); 7.05 (m,
1H, arom.); 7.4 (m, 3H, arom); 7.7 (m, 4H, arom.); 7.9
(s*, 1H, NH). M.p.: 148–150°C. Yield: 36.5%. TLC
(Rf=0.12). 2d. C19H14BrN3O2S (427.9). M.p.: 167–
168°C. Yield: 31%. TLC (Rf=0.66). 2e. C20H17N3O2S
(363). M.p.: 126.5–128.5°C. Yield: 74.0%. TLC (Rf=
0.10). 6a. C26H20N2O2S (424). M.p.: 110–111°C. Yield:
67%. TLC (Rf=0.46). 6b. C26H19FN2O2S (442). Sticky
oil. Yield: 86%. TLC (Rf=0.46). 6c. C26H19ClN2O2S
(458.5). Sticky oil. Yield: 70%. TLC (Rf=0.47). 6d.
All free bases were treated with methanolic HBr and
hydrobromides were precipitated with dry diethyl ether.
1
C26H19BrN2O2S (502.9). H NMR (CDCl3–TMS) (l):
3.05 (t, J=7 Hz, 2H, CH2); 4.1 (t, J=7 Hz, 2H, CH2);
5.75 (s, 1H, CH); 6.9 (s, 1H, Hthiazole 7.5 (m, 9H,
arom.); 8.0 (m, 4H, arom.). Sticky oil. Yield: 60%. TLC
(Rf=0.40). 6e. C26H19FN2O2S (442). Sticky oil. Yield:
65%. TLC (Rf=0.47). 6f. C26H19ClN2O2S (458.5).
Sticky oil. Yield: 59%. TLC (Rf=0.51). 6g.
C26H19BrN2O2S (502.9). Sticky oil. Yield: 60%. TLC
(Rf=0.47).
5.7. N,N-Dimethyl-2-(2-benzhydrylthiazol-4-yl)-
ethanamine (8)
2-(2-Benzhydrylthiazol-4-yl)ethanamine (1.40 g, 0.005
mol) was dissolved in 100% formic acid (11.5 g) and
36% formaldehyde (0.9 g) was added. The mixture was
heated for 10 h at 100–105°C. After cooling the mix

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ture was alkalinized with sodium hydroxide to pH 12
and extracted with diethyl ether (3×50.0 ml). The
crude product, was purified by column chromatography
on silica gel (eluent: 90:10:1 chloroform–methanol–
concentrated ammonium hydroxide). 8. C20H22N2S
1
(322). Yield: 47%. H NMR (CDCl3–TMS) (l): 2.3 (s,
6H, 2CH3); 2.75 (t, J=6 Hz, 2H, CH2); 2.95 (t, J=6
Hz, 2H, CH2); 5.9 (s, 1H, CH); 6.6 (s, 1H, Hthiazole); 7.4
(m, 10H, arom.). TLC (Rf=0.24). C20H22N2S·2HBr
(484.3). M.p.: 244–246°C.
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[8] A.M. Ter Laak, M.J. van Drooge, H. Timmerman, G.M. Donne
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5.8. Pharmacology
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 r.t. (pH 7.4) containing
NaCl (136.9 mM); KCl (2.68 mM); NaHPO4 (7.19
mM). After flushing the intraluminal contents, seg-
ments about 2 cm were cut and mounted for isotonic
contractions in water jacked 20 ml organ baths filled
with oxygenated (95:5 O2–CO2, v/v) Krebs buffer con-
taining NaCl (117.5 mM); KCl (5.6 mM); MgSO4 (1.18
mM); CaCl2 (2.5 mM); NaH2PO4 (1.28 mM); NaHCO3
(25 mM); glucose (5.5 mM) at 37°C under a constant
load of 0.5 g. After a 30 min equilibration period with
washing every 10 min, a submaximal priming dose of
histamine (1 mM) was given and washed out (standard
washing procedure: 3 changes of buffer during 30 min).
After washing, the antagonistic activity of the com-
pound was measured by recording a concentration re-
sponse curve (CRC) for histamine in the presence of the
testing compounds (3a–e, 7a–h and 8) which were
added 5 min before histamine. This procedure was
repeated with higher concentration of the compounds.
The antagonism was of a competitive nature causing a
parallel shift in the CRC. The pA2 values and slopes
were determined according to Arunlakshana and Schild
[17].
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49–85.
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