XAMOTEROL HEMIFUMARATE

Originator

Sepan,Yamanouchi

The Uses of XAMOTEROL HEMIFUMARATE

Stimulant (cardiac).

The Uses of XAMOTEROL HEMIFUMARATE

Xamoterol is an authentic β1-adrenoceptor (β1-AR) agonist that has been shown to mimic the autoantibody effect on rat atria β1-AR apoptosis.

Background

Xamoterol is a β1-adrenoceptor partial agonist that has shown to improve systolic and diastolic function in studies with heart failure patients. It modulates the sympathetic control of the heart but has no agonist action on β2-adrenoceptors.

Definition

ChEBI: Xamoterol is a member of morpholines.

Manufacturing Process

A suspension of 1-p-benzyloxyphenoxy-2,3-epoxypropane (11.5 g) in isopropanol (6 ml) is added to a stirred mixture of 4-(N-beta- aminoethylcarbamoyl) morpholine hydrogen sulphate (12.7 g), potassium hydroxide (7.0 g) and isopropanol (10 ml) and the mixture is stirred at 45°C for 1 hour and then evaporated to dryness under reduced pressure. The residual oil is stirred with water, the mixture is filtered and the solid residue is dissolved in acetone. A 30% solution of hydrogen chloride in propanol is added until the pH of the mixture is less than 2, and the mixture is filtered. The solid residue is crystallised from water and there is thus obtained 1-p- benzyloxyphenoxy-3-(beta-morpholinocarbonamidoethyl)amino-2-propanol hydrochloride (4.9 g).
A solution of the above compound in a mixture of ethanol (20 ml) and acetic acid (20 ml) is shaken with a 30% palladium-on-charcoal catalyst (0.1 g) in an atmosphere of hydrogen at laboratory temperature and pressure until 250 ml of hydrogen is absorbed. The mixture is filtered, the filtrate is evaporated to dryness under reduced pressure and to the residue is added a hot solution of fumaric acid (1.25 g) in ethanol (15 ml). The mixture is kept at 5°C for 12 hours and is then filtered, and the solid residue is washed with hot ethanol and then dried. There is thus obtained 1-p-hydroxyphenoxy-3-beta- (morpholinocarbonamido)ethyl-amino-2-propanol hydrogen fumarate, m.p. 168-169°C (with decomposition).
The 4-(N-beta-aminoethylcarbamoyl)morpholine hydrogen sulphate used as starting material may be obtained as follows:
Morpholine (4.35 g) and phenyl chloroformate (6.35 g) are separately and simultaneously added dropwise during 20 min to a stirred mixture of toluene (10 ml), water (5 ml) and sodium hydroxide (2 g) which is maintained at 0°C. The mixture is stirred for a further 2 hours whilst the temperature is allowed to rise to 20°C. The toluene solution is separated, the aqueous solution is extracted twice with toluene and the combined toluene solutions are washed with water, dried and evaporated to dryness under reduced pressure. The residue is crystallised from petroleum ether (boiling point 60-80°C) and there is thus obtained N-phenoxycarbonylmorpholine, melting point 46.5-47.5°C.
A mixture of the above compound (11 g) and ethylenediamine (27.8 g) is stirred at laboratory temperature for 3 days and the excess of ethylene diamine is removed by evaporation under reduced pressure. The residue is dissolved in methanol, the solution is cooled to 5°C and concentrated sulfuric acid is added until the pH of the solution is 2. A filter-aid (Celite, 10 g) is added and the mixture is stirred for 1 hour and then filtered. The filtrate is evaporated to dryness under reduced pressure and the residue is stirred with ethyl acetate. The mixture is filtered and there is thus obtained as solid residue 4-(N-beta-aminoethylcarbamoyl)morpholine hydrogen sulphate, melting point 168-169°C.

Therapeutic Function

Beta-adrenergic blocker, Cardiac stimulant

Metabolism

Not Available