Description
Cisapride is a gastroprokinetic useful in the treatment of reflux esophagitis, constipation,
and a variety of gastro-intestinal motility disorders. Its novel mechanism of action is
thought to involve the enhancement of acetylcholine release in the mysenteric plexus of
the gut. It is reportedly devoid of CNS and cardiac side-effects.
Chemical Properties
White Solid
Originator
Janssen (Belgium)
Uses
A Serotonin 5-HT4 receptro agonist. Used as a Gastroprokinetic
Uses
Cisapride Monohydrate is a cardioactive drug that causes prolongation of cardiac repolarization in human; selective serotonin 5-HT4 receptor agonist.
Uses
isoflavone used as a cholagogue and cathartic
Uses
Peristaltic stimulant;5-HT antagonist
Definition
ChEBI: The amide resulting from formal condensation of 4-amino-5-chloro-2-methoxybenzoic acid with cis-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-amine. It has been used (as its monohydrate or as its tartrate) for the treatment of gastro-oeso
hageal reflux disease and for non-ulcer dyspepsia, but its propensity to cause cardiac arrhythmias resulted in its complete withdrawal from many countries, including the U.K., and restrictions on its use elsewhere.
Manufacturing Process
A mixture of 1-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinone (140
mg), benzylamine (61 mg), Pd 10% on charcoal (100 mg) and a 0.02%
solution of thiophene in THF was reacted under hydrogen gas for 3 hours at
50°C. The catalyst was filtered off and fresh palladium 10% on charcoal (100
mg) was added. Debenzylation of the formed intermediate took place under
hydrogen atmosphere for 18 hours at 50°C. The reaction mixture was filtered
and evaporated under a stream of nitrogen to yield 1-[3-(4-fluorophenoxy)-
propyl]-3-methoxy-4-piperidinamine having a cis/trans ratio of about 93/7.
1-[3-(4-Fluorophenoxy)-propyl]-3-methoxy-4-piperidinamine (50 g) was
dissolved in methyl isobutylketone (250 ml) and a nitric acid solution (65%,
12.8 ml) was carefully added so that the temperature of the solution did not
exceed 45°C. The reaction mixture was stirred at a temperature of 30°C and
seeded. When crystallisation started, the reaction mixture was cooled to 0°C
and stirred for another 2 hours. The product was filtered off, washed with a
small amount of toluene and dried, yielding 1-[3-(4-fluorophenoxy)-propyl]-3-
methoxy-4-piperidinamine nitrate (m.p. 60°C).
1-[3-(4-Fluorophenoxy)-propyl]-3-methoxy-4-piperidinamine nitrate was
dissolved in water (95 ml). The reaction mixture was stirred and toluene (95
ml) was added. A NaOH solution (50%, 10.3 ml) was slowly added and the
temperature of the reaction mixture was raised to 75°C. After 30 min, the
aqueous layer was discarded and the organic layer was evaporated, yielding
1-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinamine having a
cis/trans ratio equal to or higher than 98/2.
To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (20.2 g) in methyl
isobutylketone (250 ml) and triethyl amine (15.3 ml) was slowly dropped
ethyl chloroformate (9.6 ml). The reaction mixture was stirred for 30 min at
room temperature. To the formed mixed anhydride was then added 1-[3-(4-
fluorophenoxy)-propyl]-3-methoxy-4-piperidinamine (28.2 g) and the reaction
mixture was stirred for 2 hours at room temperature. Subsequently, the
reaction mixture was washed with water (80 ml) and a NaOH solution (6.5%
w/v, 50 ml). The organic layer was warmed to 65°C and methanol (50 ml)
and water (8.5 ml) were added. The solution was cooled slowly and stirred for
2 days during which crystallisation occurred, yielding benzamide, 4-amino-5-
chloro-N-(1-(3-(4-fluorophenoxy)propyl)-3-methoxy-4-piperidinyl)-2-methoxy-
, monohydrate, cis- (Cisapride) having a cis/trans ratio higher than 99/1.
Brand name
Propulsid (Janssen);Calmax;Cisapid;Cismotil;Digenol;Prepulsid.
Therapeutic Function
Gastrointestinal drug
Biological Activity
5-HT 4 receptor agonist and gastrokinetic agent. Stimulates intestinal acetylcholine release, possibly via 5-HT 4 receptor-dependent and -independent mechanisms, leading to increased intestinal motility.
Clinical Use
Cisapride has been successfully used to treat
gastroparesis and mild gastroesophageal reflux disease.
Side effects
The most frequent side effect has been diarrhea. A few
patients had seizure activity that was reversible after
medication was discontinued. Cisapride was pulled
from the U. S. market after deaths from drug-associated
cardiac arrhythmias, including ventricular tachycardia,
ventricular fibrillation, torsades de pointes, and QT prolongation.
Veterinary Drugs and Treatments
Proposed uses for cisapride in small animals includes esophageal
reflux and treatment
of primary gastric stasis disorders. Cisapride
has been found to be useful in the treatment of constipation and
megacolon in cats.
Metabolic pathway
Cisapride 14C labeled at the carbonyl carbon and 3H
labeled at the fluorophenyl moiety or at the piperidine
ring is investigated using some animals. N-
Dealkylation at the nitrogen of the piperidine ring,
resulting in the main urinary metabolite norcisapride,
and aromatic hydroxylation of the fluorinated phenyl
ring are the major metabolic pathways in dogs and
humans. Norcisapride excretion accounts for 14% of
the dose in dogs and 41-45% in humans. Minor
metabolic pathways are O-dearylation of the 4-
fluorophenyl group and oxidation on the piperidine ring
(rat, rabbits and dogs: Lavrijsen et al. (1986)15).
