Mangafodipir trisodium

Originator

Teslascan ,Nycomed Amersham Health Inc.

Uses

sclerosing agent

Uses

Mangafodipir Trisodium is a contrast agent delivered intravenously to enhance contrast in magnetic resonance imaging (MRI) of the liver. It protects against hepatic ischemia-reperfusion injury in mice and decreases hematotoxicity and enhanced cytotoxicity of anticancer agents.

Manufacturing Process

Sodium N,N'-bis(pyridoxal-5-phosphate)ethylenediimine
A 265.2 g (1 mole) of pyridoxal-5-phosphate was slurried in 1 L of methanol, and 400 mL of 5 M NaOH was added. When the solution was homogeneous, 34.2 mL of 1,2-diaminoethane was added rapidly with vigorous stirring. The imine product sodium N,N'-bis(pyridoxal-5-phosphate)ethylenediimine or sodium 5-(N-(3-hydroxy-2-methyl-5-phosphonomethyl-4-pyridyl) methylideneaminoethyleneiminomethyl)-2-hydroxy-3-methyl-5- pyridylmethylphosphate was stirred for 1 hr, 400 mL of diethyl ether was added, and the slurry was filtered. The filtrate was washed with 600 mL of ethanol and dried at 60°C in vacuo. A 290 g of the bis-imine with a melting point of 215-220°C (decomp.) was isolated (90% yield, based on the tetrasodium salt).
N,N'-bis(Pyridoxal-5-phosphate)ethylenediamine
To the diimine obtained was added 1.5 L of deionized water and 1.5 L of methanol. The yellow solution formed was stirred while sparging with nitrogen. Then 13 g of 5% Pt on carbon was added, and the apparatus was purged with hydrogen. The reaction was allowed to proceed for 5 hr with continuous addition of hydrogen. HPLC analysis showed complete reduction to the amine. The reaction mixture was sparged with nitrogen for 15 min and then filtered through Celite. The filtrate was concentrated in vacuo at 60°C to about 500 mL. The solution, containing N,N'-bis(pyridoxal-5-phosphate) ethylenediamine or 5-(N-(3-hydroxy-2-methyl-5-phosphonomethyl-4- pyridyl)methylaminoethyleneaminomethyl)-2-hydroxy-3-methyl-5- pyridylmethylphosphoric acid salt was used directly for the next step. If desired the diamine can be isolated as off-white crystals by the addition of 200 ml of 97% formic acid and allowing the product to crystallize at room temperature overnight. The diamine is isolated by filtration and washed with 150 mL of cold deionized water.
N,N'-Bis-(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid synthesis
The diamine obtained was dissolved in a 100 g (2.5 mole) of NaOH, and 130 g (0.9 mole) of bromoacetic acid was dissolved in 180 mL of deionized water. Each solution was charged to an addition funnel. NaOH solution was added to the diamine solution to bring the pH to 11. The temperature was raised to 42°C, and bromoacetic acid and NaOH solution were added concurrently to maintain the pH at 11. The progress of the reaction was checked by HPLC. A 675 g of cation exchange resin (AMBERLITE IRC-50) was added, and the mixture was placed in a refrigerator for 14 hr. The pH had dropped to 6.5. The resin was removed by filtration, and the filtrate treated with 260 g of cation exchange resin (DOWEX 50W-X8). The pH dropped to about 4. The resin was removed by filtration, and the solution was concentrated in vacuo at 60°C to a viscous oil. The oil was dried in vacuo for 48 hr to yield a resinous solid containing N,N'-bis-(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid or N,N'-bis(3-hydroxy-2-methyl-5-phosphonomethyl-4-pyridylmethyl) ethylenediamine-N,N'-diacetic acid (DPDP). The resinous solid obtained was dissolved in 600 mL of 88% formic acid, then 1.5 L of methanol and 2.2 L of ethanol was added, and the mixture was cooled to 0°C for 2 hr. The solvent mixture was decanted from the resulting gum. The gum was dissolved in 800 mL of deionized water which was then concentrated in vacuo to about 600- 650 mL. Seed crystals were added, and the solution was allowed to stand overnight. The product was isolated by filtration, washed with 400 mL of cold water, 250 mL of ethanol, and then dried in vacuo to yield 65 g of DPDP in 85-90% purity by HPLC.
The 65 g of product was then dissolved in 75 mL of 88% formic acid containing 5 mL of deionized water with heating to 60°C. Cold water was added to a total volume of 1 L, and the solution was allowed to stand at 25°C for 16 hr to crystallize. The product was isolated by filtration, washed with 200 mL cold water, and dried in vacuo at 60°C to yield 55 g of DPDP in 93- 95% purity by HPLC. A second recrystallization, using the same procedure yields 50 g of DPDP in 96-98% purity by HPLC, melting point 174-180°C (decomp.).
Sodium salt of Mn(DPDP)
A 4.16 g (6.25 mmole) portion of DPDP was dissolved in 15 mL of rigorously degassed water by the addition of 1.0 g (25 mmoles) of NaOH. A 1.25 g (6.25 mmole) quantity of manganese dichloride tetrahydrate was added, and the solution immediately turned yellow. After stirring for 30 min, 0.25 g (6.25 mmole) of solid NaOH was added to bring the pH up to 6.5. Then degassed water was added to bring the volume of the solution to 25 mL. The clear yellow solution was sterilized by being filtered through a 0.2 micron filter to yield the sodium salt of a manganese chelate complex of N,N'-bis-(pyridoxal5-phosphate)ethylenediamine-N,N'-diacetic acid or N,N'-bis(3-hydroxy-2- methyl-5-phosphonomethyl-4-pyridylmethyl)ethylenediamine-N,N'-diacetic acid.

brand name

Teslascan (GE Healthcare).

Therapeutic Function

Diagnostic aid

General Description

Mangafodipirtrisodium is a clear bright to dark yellow chelate of paramagneticmanganese for intravenous administration.Manganese is distributed to the liver and pancreas and shortensthe T1-weighted relaxation time. It is indicated to detectmetastatic lesions of the liver, focal pancreatic lesions, andhepatocellular carcinoma.

Raw materials

Preparation Products