71486-22-1

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.

CNRS (France)

antimigraine, 5HT[1B/1D] agonist

ChEBI: A vinca alkaloid with a norvinblastine skeleton.

(+/-)-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 of the (+)-methyl 2-[2-(N-phenylsulfonyl)indolyl]-2-hydroxy-3- [3-(N-allyl-5-ethyl-1,2,3,6-tetrahydropyridine)]propionate (a mixture of diastereomers at C-2) in dry dimethoxyethane at -50°C under argon was added sodium naphthalenide (1 M in THF). The mixture was quenched with trifluoroacetic acid, and extracted with ethyl acetate (3 times 10 ml). The extract was washed with saturated aqueous NaHCO 3 solution, dried (MgSO 4 ) and evaporated in vacuo to give the (+)-methyl 2-(2-indolyl)-2-hydroxy-3-[3- (N-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridine )]propionate. The mixture of diastereomers was not separated but chromotagraphed over silica gel eluting with hexane/ethyl acetate/10% aqueous NH 4 OH/MeOH (5:1:1) to remove more polar impurities.
A solution of the (+)-methyl 2-(2-indolyl)-2-hydroxy-3-[3-(N-allyl-5-ethyl- 1,2,3,6-tetrahydro-pyridine)]propionate (mixture of diastereomers), and vindoline in 1% HCl/MeOH was heated at reflux for 2 h. The solution was evaporated in vacuo and the residue dissolved in chloroform and washed with saturated aqueous NaHCO 3 solution. The chloroform layer was dried over MgSO 4 , filtered, and evaporated to give a foam consisting of a mixture of S-and R-diastereomers. The diastereomeric mixture was separated by preparative HPLC eluting with hexane/CH 2 Cl 2 /MeOH/10% aqueous NH 4 OH to give S-(+)-4-acethoxy-9-[2-(1-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridin-3-yl)-1- (1H-indol-2-yl)-1-methoxycarbonyl-ethyl]-3a-ethyl-5-hydroxy-8-methoxy-6- methyl-3a,4,5,5a,6,11,12,12b-octahydro-1H-6,12a-diaza-indeno[7,1- ca]fluorene-5-carboxylic acid methyl ester.
The S-(+)-4-acethoxy-9-[2-(1-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridin-3yl)-1- (1H-indol-2-yl)-1-methoxycarbonyl-ethyl]-3a-ethyl-5-hydroxy-8-methoxy-6- methyl-3a,4,5,5a,6,11,12,12b-octahydro-1H-6,12a-diaza-indeno[7,1- ca]fluorene-5-carboxylic acid methyl ester in 1,2-dichloroethane, containing proton sponge at 25°C, was treated with 1-chloroethyl chloroformate (0.056 ml, 0.512 mmol, 2.0 equiv.) and the resulting solution stirred for 3 h. The mixture was evaporated in vacuo, and the residue dissolved in methanol and heated at reflux for 3 h. The methanol was evaporated and the residue dissolved in chloroform and purified by chromatography over silica gel eluting with CHCl 3 , MeOH, 10% aqueous NH 4 OH (20:1) to give S-(+)-4-acethoxy-9- [2-(5-ethyl-1,2,3,6-tetrahydro-pyridin-3yl)-1-(1H-indol-2-yl)-1- methoxycarbonyl-ethyl]-3a-ethyl-5-hydroxy-8-methoxy-6-methyl- 3a,4,5,5a,6,11,12,12b-octahydro-1H-6,12a-diaza-indeno[7,1-ca]fluorene-5- carboxylic acid methyl ester.
To a solution of the S-(+)-4-acethoxy-9-[2-(5-ethyl-1,2,3,6-tetrahydro- pyridin-3yl)-1-(1H-indol-2-yl)-1-methoxycarbonyl-ethyl]-3a-ethyl-5-hydroxy- 8-methoxy-6-methyl-3a,4,5,5a,6,11,12,12b-octahydro-1H-6,12a-diaza- indeno[7,1-ca]fluorene-5-carboxylic acid methyl ester in dioxane and glacial acetic acid was added 37% aqueous formaldehyde and the mixture stirred at 35°C for 24 h. The solution was evaporated in vacuo and the residue suspended in chloroform and washed with cold aqueous 5% K 2 CO 3 solution. The chloroform layer was dried (MgSO 4 ), filtered, and evaporated. The residue was chromatographed eluting with EtOAc/MeOH, 10% NH 4 OH to give the product navelbine.

Navelbine (Pierre).

Antineoplastic

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.

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.

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.

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).

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).

Store at 4°C, protect from light