Vinorelbine

Bezeichnung:Vinorelbine

CAS-Nr71486-22-1

Englisch Name:Vinorelbine

CBNumberCB3469220

SummenformelC45H54N4O8

Molgewicht778.93

MOL-Datei71486-22-1.mol

Vinorelbine physikalisch-chemischer Eigenschaften

alpha	D20 +52.4° (c = 0.3 in CHCl3)
Dichte	1.36±0.1 g/cm3(Predicted)
storage temp.	Store at 4°C, protect from light
Löslichkeit	>25.9mg/mL in DMSO
Aggregatzustand	Powder
pka	11.36±0.60(Predicted)

Sicherheit

HS Code	2939799090
Giftige Stoffe Daten	71486-22-1(Hazardous Substances Data)
Toxizität	LD50 in mice (mg/m2): 72 i.v.; 78 orally (Mathé, Reizenstein)

Gefahreninformationscode (GHS)

Vinorelbine Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
Vinorelbine is a semisynthetic vinca alkaloid differing from vinblastine in the catharantine moiety of the molecule. It is claimed to have a broad spectrum of action both in vifro and in vivo; clinically it has been found effective in the treatment of non-small cell lung cancer, advanced breast cancer, ovarian cancer and Hodgkins disease.
Originator
CNRS (France)
Verwenden
antimigraine, 5HT[1B/1D] agonist
Verwenden
Vinorelbine base is an antineoplastic agent with anti-mitotic properties.
Definition
ChEBI: A vinca alkaloid with a norvinblastine skeleton.
Manufacturing Process
(+/-)-5-Ethyl-1,2,3,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester and (+)-tartaric acid were dissolved in hot 95% ethanol. The resulting solution was allowed to slowly cool to room temperature and refrigerated overnight. The crystals were filtered, washed with cold ethanol, and recrystallized from 95% ethanol, cooling as before to give the (+)-tartrate salt of (+)-5-ethyl- 1,2,3,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester.
The salt of (+)-5-ethyl-1,2,3,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester was dissolved in on ice, and 3 N sodium hydroxide was slowly added until the pH reached 11-12. The solution was extracted with chloroform, dried (Na 2 SO 4 ) and evaporated in vacuum to give (+)-5-ethyl-1,2,3,6-tetrahydro- pyridine-3-carboxylic acid ethyl ester as a mobile oil.
Reduction of (+)-5-ethyl-1,2,3,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester with LiAlH 4 in THF, using the usual protocols associated with this reagent gave the (+)-5-ethyl-1,2,3,6-tetrahydro-pyridine-3-ol. This material was used directly in the next step.
To a solution of the (+)-5-ethyl-1,2,3,6-tetrahydro-pyridine-3-ol in ethanol and triethylamine water, cooled equiv.) was added allyl bromide and the mixture heated at reflux for 12 h. The mixture was evaporated in vacuo and the residue dissolved in chloroform and washed with 5% aqueous K 2 CO 3 . The chloroform layer was dried (MgSO 4 ) and evaporated in vacuo to give the (+)- 1-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridin-3-ol.
The (+)-1-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridin-3-ol was converted into its methanesulfonate ester in the standard manner by treatment with methanesulfonic acid.
To a solution of the (+)-1-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridin-3-methanesulfonate in acetone was added lithium bromide (6.9 g, 0.08 mol) and the suspension heated at reflux. The acetone was evaporated in vacuo, and the residue partitioned between chloroform and cold aqueous 5% K 2 CO 3 solution. The chloroform layer was dried (MgSO 4 ), filtered, and evaporated in vacuo to give a brown oil. Fractional distillation gave the (+)-1-allyl-5-ethyl- 1,2,3,6-tetrahydro-pyridin-3-bromide.
To a solution of N-phenylsulfonyl indole (5.14 g, 20 mmol) in dry THF (100 ml) under argon, and cooled to -65°C., was added t-butyl lithium (13 ml, 22 mmol, 1.7 M in pentane). The solution was allowed to warm to 0°C and stirred for 1 h. The above solution was added via canula to a stirred solution of dimethyloxalate (9.5 g, 80 mmol) in THF (250 ml) at 0°C. After 4 h at 0°C the mixture was quenched with saturated aqueous NH 4 Cl and extracted with ethyl acetate (3 times 100 ml). The dried (MgSO 4 ) extract was evaporated in vacuum, and the residue purified by chromatography over silica gel eluting with hexane/ethyl acetate (b 10:1) to give the N-phenylsulfonyl-2-methoxalyl indole (2.3 g, 34%). Melting point 111°-112°C (from ethyl acetate).
To the (+)-1-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridin-3-bromide in a flame dried flask under argon was added Mg powder and dry THF. The mixture was heated at reflux and two drops of 1,2-dibromoethane added to initiate Grignard reagent formation. After 3 h the turbid suspension was cooled to room temperature and added to a solution of the N-phenylsulfonyl-2- methoxalyl indole in THF, at 0°C under argon. After 30 min the solution was quenched with saturated aqueous NH 4 Cl solution, and diluted with ethyl acetate. The dried (MgSO 4 ) extract was evaporated in vacuo to give the (+)- methyl 2-[2-(N-phenylsulfonyl)indolyl]-2-hydroxy-3-[3-(N-allyl 5-ethyl- 1,2,3,6-tetrahydro-peridine)]propionate consisting of a mixture of diastereomers at C-2 (1:1). For the purpose of characterization, one of the diastereomers was purified by chromatography over silica gel eluting with hexane/ethyl acetate/10% aqueous NH 4 OH/MeOH (15:3:1) to give the (+)- methyl 2-[2-(N-phenylsulfonyl)indolyl]-2-hydroxy-3-[3-(N-allyl-5-ethyl- 1,2,3,6-tetrahydro-pyridine)]propionate.
To a solution
Trademarks
Navelbine (Pierre).
Therapeutic Function
Antineoplastic
Pharmakokinetik
This semisynthetic alkaloid is unique in having oral bioavailability, but it currently is available only for IV injection. The initial phase elimination half-life is on par with that observed for vincristine and vinblastine, and the terminal phase half-life is between 28 and 44 hours.
Clinical Use
Vinorelbine is particularly useful in the treatment of advanced non–small cell lung cancer and can be administered alone or in combination with cisplatin. It is thought to interfere with mitosis in dividing cells through a relatively specific action on mitotic microtubules.
Nebenwirkungen
Although dose-limiting granulocytopenia is the major adverse effect, potentially fatal interstitial pulmonary changes have been noted, and patients with symptoms of respiratory distress should be promptly evaluated. As with all vinca alkaloids, elimination is primarily hepatobiliary, and dosage reduction should be considered in patients with liver dysfunction.
Arzneimittelwechselwirkung
Potentially hazardous interactions with other drugs
Antibacterials: increased risk of neutropenia with clarithromycin; possible increased risk of ventricular arrhythmias with delamanid.
Antifungals: metabolism possibly inhibited by itraconazole, increased risk of neurotoxicity.
Antimalarials: avoid with piperaquine with artenimol.
Antipsychotics: avoid concomitant use with clozapine (increased risk of agranulocytosis).
Stoffwechsel
Metabolism of vinorelbine appears to be hepatic. All metabolites of vinorelbine are formed by the CYP3A4 isoform of cytochromes P450, except 4-O-deacetylvinorelbine which is likely to be formed by carboxylesterases.
4-O-deacetylvinorelbine is the only active metabolite and the main one observed in blood. Excretion is mainly by the biliary route (18.5
% appears in the urine).

Vinorelbine Upstream-Materialien And Downstream Produkte

Vinorelbine Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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