Histamine H3 Antagonists
397
discarded, the solvent was dried and evaporated to give the crude product
which was purified by column chromatography (Table 5 and 6).
Contractions were recorded isotonically under 1.0 g tension with Hugo Sachs
Hebel-Messvorsatz (Tl-2)/HF-modem (Hugo Sachs Electronik, Hugstetten,
Germany) connected to a pen recorder. After equilibration for one hour 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 incre-
ments) of (R)-α-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)- α-methylhis-
tamine as H3 agonist. Statistical analysis was carried out with the Students’
t-test. In all test p was considered statistically significant. The potency of an
antagonist is expressed by its pA2 value, calculated from the Schild regres-
sion analysis where at least three concentrations were used.
General Method for the Preparation of 2-(N,N′,N′-dimethylalkyl-1,2-ethane-
diamino)benzothiazoles; 2-[4-(1-Methyl- and 1-n-propyl)piperidinyl]benzo-
thiazoles – 6a–c and 12a,b
To the suspension of 2-(N,N′-dimethyl-1,2-diaminoethano)benzothiazole
(6) hydrobromide (0.05 mol) or to the solution of 2-(4-piperidinyl)benzothia-
zole (12) (0.05 mol) in the presence of K2CO3 (0.25 mol) in 100 mL ethylene
glycol dimethyl ether the corresponding alkyl iodide was added. The reaction
mixture was refluxed for 6 hours in the case of compounds 6a–c and heated
at 40 °C for 48 h in the case of compounds 12a,b. The solvent was evapo-
rated, 25 mL of water was added to the residue, and the mixture was extracted
with dichloromethane. The water layer was discarded the solvent was dried,
and evaporated to give the crude product which was purified by column
chromatography (Table 3, 4, 5, and 6).
H3/5HT3 Activity for 4a and 12b Compounds
Upon the addition of some of the new non-imidazole H3 antagonists the
electrically evoked contractions of the guinea-pig jejunum transiently in-
creased. The increase in contractivity upon the addition of 1 M 4a or 12b was
totally abolished in the presence of 1 M of the 5HT3 antagonist ondansetron.
However, the H3 antagonism by the 4a or 12b compounds was not affected
by the presence of ondansteron (10–6).
Preparation of 2-1-(4-Aminopiperidinyl)benzothiazole – 10
The 2-1-(4-carboxylpiperidinyl)benzothiazole amide (9) (0.05 mol) was
dissolved in 150 mL of 5% sodium hydroxide solution and bromine
(0.05 mol) was added dropwise with stirring over a period of half an hour.
(The inside temperature was kept at 35–40 °C.). The mixture was heated for
6 h at 40 °C. After cooling the mixture was extracted with diethyl ether
(3 × 100 mL). The crude product was purified by column chromatography
(Table 5 and 6).
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2-1-(4-Aminopiperidinyl)benzothiazole 10 (0.05 mol) was dissolved in
110 mL of 100% formic acid and 36% formaldehyde (0.035 mol) was added.
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was alkalized with sodium hydroxide to pH 12 and extracted with diethyl
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2.0 (m, 4H); 2.15 (s*, NHCH3); 2.4 (s, 3H, CH3); 2.45–2.6 (m, 1H, (CH2)2
CH-NHCH3"piperidine"); 3.0–3.3 (m, 2H, NCH2"piperidine"); 4.1–4.4 (t 2H,
CH2N"piperidine"); 7.0–7.6 (m, 4H, arom.). TLC (j; Rf = 0.19)
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to the solution of 10 (0.005 mol). The reaction mixture was refluxed for 48 h.
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mixture was extracted with dichloromethane. The aqueous layer was dis-
carded, the solvent was dried and evaporated to give the crude product which
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was heated at 180–190 °C for 6 hours, allowed to cool, poured into water,
and filtered off. The filtrate was treated with 50% potassium hydroxide
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All compounds were tested for H3 antagonistic effects in vitro on the
guinea pig jejunum27using standard methods.
Male guinea pigs weighing 300–400 g were sacrificed by a blow on the
head. A portion of the small intestine, 20–50 cm proximal to the 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.
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Arch. Pharm. Pharm. Med. Chem. 332, 389–398 (1999)