Melphalan USP (Alkeran) is used to treat multiple myeloma; plasmacytic myeloma; cancer of breast and ovary.
antineoplastic, alkylating agent
ChEBI: A phenylalanine derivative comprising L-phenylalanine having [bis(2-chloroethyl)amino group at the 4-position on the phenyl ring.
Melphalan (Alkeran) is an amino acid derivative of mechlorethamine that possesses the same general spectrum of antitumor activity as do the other nitrogen mustards. However, the bioavailability of the oral preparation is quite variable (25–90%) from one patient to another.
The major indications for melphalan are in the palliative therapy of multiple myeloma and cancers of the breast or ovary. Because it does not produce alopecia, melphalan is occasionally substituted for cyclophosphamide in the CMF regimen for breast cancer.
Melphalan produces less nausea and vomiting than does cyclophosphamide; however, its bone marrow suppression tends to be more prolonged and affects both white cells and platelets. Peak suppression of blood counts occurs 14 to 21 days after a 5-day course of drug therapy; recovery is generally complete within 3 to 5 weeks.
Diethyl sodium phthalimidomalonate (Barger and Weichselbaum, Organic Syntheses, 1943, Coll. Vol. II, 384) (6.52 g) was dissolved in boiling methyl ethyl ketone (80 ml) and a solution of p-nitrobenzyl chloride (3.44 g; 1.0 mol) in the same solvent (20 ml) was added, Sodium iodide (ca 0.5 g) dissolved in hot methyl ethyl ketone (10 ml) was introduced, and produced an immediate precipitation. The mixture was refluxed for 1.5 hours, cooled, filtered, evaporated under vacuum and the residual gum crystallized from ethanol. The di-ethyl-p-nitrobenzyl-phthalimidomalonate formed colorless prisms (88%), MP 103° to 105°C, sharpening to 104° to 105°C on recrystallizing from ethanol.
Diethyl-p-nitrobenzyl-phthalimidomalonate (70 g) and sodium carbonate (70 g) in water (700 ml) were refluxed overnight with mechanical stirring (to avoid bumping). The clear brown solution was acidified with hydrochloric acid and refluxing and stirring were continued for a further 40 minutes. The mixture was cooled and the colorless precipitate (31 g) collected. A second crop (18.5 g) was obtained on evaporation of the mother liquors. Crystallization from aqueous ethanol gave the compound N-carboxybenzoyl-p-nitro-DL-phenylalanine as small needles, MP 198° to 200°C.
The N-carboxybenzoyl compound (2.7 g) was refluxed for 30 minutes with acetic anhydride (10 ml), the mixture taken to dryness (vacuum) and the residue heated with water. The cooled gummy product became granular on rubbing and crystallized from methyl ethyl ketone-petrol or aqueous ethanol in almost colorless needles, MP 184° to 186°C, of p-nitro-N-phthaloyl-DLphenylalanine.
A solution of p-nitro-N-phthaloyl-DL-phenylalanine (1.0 g) in methanol (25 ml) and a solution of cinchonidine (0.865 g) in methanol (30 ml) were mixed. Crystallization soon set in. The mixture was left overnight, and the colorless needles (0.97 g), MP 209° to 210°C, collected. After two recrystallizations from methanol the cinchonidine salt of the D-acid had MP 211°C.
Evaporation of the mother liquors from the original cinchonidine experiment gave a gum which crystallized readily from aqueous ethanol in almost colorless needles (0.73 g), MP 191° to 192.5°C. Two recrystallizations from aqueous ethanol gave the cinchonidine salt of the L-acid, MP 192.5° to 194°C. To the salt (2.9 g) in warm ethanol (50 ml) was added water (50 ml) and a slight excess (ca 10 ml) of N aqueous sodium hydroxide. The mixture was diluted with water, cooled, filtered from the precipitated base and the filtrate acidified with hydrochloric acid. Refluxing with 2 N ethanolic hydrogen chloride yielded p-nitro-N-phthaloyl-L-phenylalanine ethyl ester, according to US Patent 3,032,585.
Then, as described in US Patent 3,032,584, ethyl N-phthaloyl pnitrophenylalaninate (9.0 g) was hydrogenated in a mixture of ethyl acetate (120 g) and methanol (80 g) with a palladium-calcium carbonate (1% Pd) catalyst (1.4 g). When gas uptake was complete, the filtrate from the hydrogenation mixture was evaporated under reduced pressure. The residual gum was taken up in ether, the solution filtered, and a slight excess of a dry ethereal hydrogen chloride solution added slowly with stirring. The gummy precipitate became granular on rubbing and the ether-washed product was crystallized from ethyl acetate-acetone [1st crop, 2.8 g, MP 188° to 192°C (decomp.); 2nd crop, 3.9 g, MP 189° to 192°C (decomp.)] . Part of the first batch was recrystallized from ethyl acetate and gave very slightly tinted needles, MP 188° to 190°C (decomp.) of ethyl N-phthaloyl paminophenylalaninate hydrochloride.
The free base was obtained from the hydrochloride by adding a slight excess of dilute ammonium hydroxide to the aqueous solution, and crystallizing the product from aqueous methanol. A further recrystallization with charcoal treatment gave almost colorless needles, MP 110° to 112°C of ethyl Nphthaloyl p-aminophenylalaninate.
Ethyl N-phthaloyl p-aminophenylalaninate (3.15 g) (unrecrystallized) was suspended in water (50 g) and glacial acetic acid (30 g) added. To the clear solution, ethylene oxide (8.0 g) was added, the mixture allowed to stand for 17 hours, and then poured into water (350 g). The solution was neutralized with sodium hydrogen carbonate and the liberated gum extracted with ether. The ethereal solution was dried (magnesium sulfate) and evaporated. The residual gum (3.95 g) was dissolved in benzene (50 g) and the solution dried azeotropically by distilling off some of the solvent. Freshly distilled phosphorus oxychloride (8 g) was added and the mixture heated under reflux for 30 minutes.
The solvent was evaporated off under reduced pressure, and the residual gum refluxed with concentrated hydrochloric acid (50 g) for 6 hours. The solution was allowed to cool overnight. It was filtered from the phthalic acid crystals, and freeze-dried, and to the pink residue was added acetone (160 g) and ethyl acetate (50 g). The mixture was left in the cold room overnight and the clear pink supernatant liquid poured off. The pink gummy hydrochloride remaining in the flask was dissolved in water (20 g), saturated sodium acetate solution added until precipitation was complete, and the product collected and dried in a desiccator. The crude p-bis-(2-chloroethyl)-aminophenylalanine (3.6 g) was crystallized from methanol giving colorless needles, MP 172° to 174°C (decomp.) of p-bis-(2-chloroethyl)-aminophenylalanine.
Melphalan is available in 2-mg tablets and 50-mg vials fororal and IV administration, respectively in the treatment ofmultiple myeloma, breast and ovarian cancer, and in highdosetherapy when bone marrow transplant is being utilized.The mechanisms of resistance are the same as those seen formechlorethamine. The agent is poorly absorbed when givenby the oral route. Melphalan is highly plasma protein bound(80%–90%) and inactivated in the blood by water to givethe hydroxy metabolites. Elimination occurs primarily in thefeces with an elimination half-life of 38 to 108 minutes. Thecommonly seen adverse effects are myelosuppression, nausea,and vomiting. Nausea is normally mild with normal doses butbecomes severe when high doses are used during bone marrowtransplant. Less commonly seen adverse effects are hypersensitivityreactions, skin rash, and alopecia. Secondarycancers are also of concern with the use of the agent.
White to buff-colored powder. Odorless or with a faint odor. An antineoplastic medicine.
Air & Water Reactions
Insoluble in water.
Melphalan is a nitrogen mustard. May be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen may be generated in combination with strong reducing agents, such as hydrides.
Strong irritant to eyes and mucous membranes. Confirmed carcinogen.
Flash point data are not available for Melphalan; however Melphalan is probably combustible.
Mechanism of action
Melphalan is orally active, but absorption can be erratic. Absorption is decreased with food, but dosing regimens do not demand an empty stomach. The drug can be formulated for IV administration, but the risk of serious side effects is higher. Melphalan distributes into body water, so toxicity can be pronounced in dehydrated patients or in those with renal dysfunction. Dehydration can be corrected, but dosage adjustments should be considered in patients with renal disease.
This aromatic mustard, used primarily in the treatment of multiple myeloma, is able to stabilize the lone pair of electrons on the mustard nitrogen through resonance with the conjugated phenyl ring, slowing the formation of the reactive aziridinium ion.
Because the lone pair of electrons of melphalan (and other aromatic mustards) is less reactive, there is a greater opportunity for distribution to cancer cells and a decreased incidence of severe side effects. There is a lower incidence of nausea and vomiting compared to mechlorethamine, but patients still experience myelosuppression, which can be severe. This drug also is mutagenic and can induce leukemia.
Confirmed human carcinogen producing leukemia and Hodgkin’s disease. Poison by ingestion, intravenous, and intracerebral routes. Human systemic effects by ingestion: nausea, hypermothty, diarrhea, agranulocytosis, thrombocytopenia. Human reproductive effects by ingestion: menstrual changes. Mutation data reported. A skin irritant. Used as a poison gas. When heated to decomposition it emits toxic fumes of ClandNOx.
Melphalan, L-3-[p-[bis-(2-chloroethyl)amino]phenyl]alanine (18.104.22.168), is a structural analog of chlorambucil in which the butyric acid fragment is replaced with an aminoacid fragment, alanine. This drug is synthesized from L-phenylalanine, the nitration of which with nitric acid gives 4-nitro-L-phenylalanine (22.214.171.124). Reacting this with an ethanol in the presence of hydrogen chloride gives the hydrochloride of 4-nitro-L-phenylalanine ethyl ester (126.96.36.199), the amino group of which is protected by changing it to phthalamide by a reaction with succinic anhydride to give 188.8.131.52. The nitro group in this molecule is reduced to an amino group using palladium on calcium carbonate as a catalyst. The resulting aromatic amine (184.108.40.206) is then reacted with ethylene oxide, which forms a bis-(2- hydroxyethyl)-amino derivative (220.127.116.11). The hydroxy groups in this molecule are replaced with chlorine atoms upon reaction with thionyl chloride, after which treatment with hydrochloric acid removes the phthalamide protection, giving melphalan (30.2.13).
An alkylating agent. Healthcare workers may be exposed. As a drug it is an immunosuppressant, used in the treatment of multiple myeloma and cancer of the ovary. It is also used in investigation of other types of cancer and as an antineoplastic in animals. Human exposure to melphalan occurs principally during its use in cancer treatment. Melphalan is administered orally or intravenously. Adult dosage is 6 mg/day, 5 days per month. Has been used as a military poison gas (a nitrogen mustard, alkaline, crystals).
Melphalan is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.
Purify melphalan by recrystallisation from MeOH, and its solubility is 5% in 95% EtOH containing one drop of 6N HCl. It is soluble in EtOH and propylene glycol but is almost insoluble in H2O. The RS-form has m 180-181o, and the R-form crystallises from MeOH with m 181.5-182o and  D21 -7.5o (c 1.26, 1.0 N HCl). [Bergel & Stock J Chem Soc 2409 1954, Beilstein 14 IV 1689.]
Consult with environmental regulatory agencies for guidance on acceptable disposal practices. Generators of waste containing this contaminant (≥100 kg/mo) must conform to EPA regulations governing storage, transportation, treatment, and waste disposal. It is inappropriate and possibly dangerous to the environment to dispose of expired or waste drugs and pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consideration applicable DEA, EPA, and FDA regulations. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged, and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerat