148-82-3 Usage
Uses
1. Used in Oncology:
Melphalan is used as an antineoplastic alkylating agent for the treatment of multiple myeloma, plasmacytic myeloma, and cancers of the breast and ovary. It works by attaching an alkyl group to guanine bases in DNA, leading to DNA interstrand and intrastrand crosslinks, cytotoxicity, and apoptosis.
2. Used in High-Dose Therapy:
Melphalan is also used in high-dose therapy when bone marrow transplant is being utilized. It is administered in combination with other chemotherapy drugs to enhance chemo-sensitivity and efficacy in resistant cases.
3. Used as a Glucocorticoid:
Although not explicitly mentioned in the provided materials, Melphalan is sometimes used in conjunction with glucocorticoids to manage certain conditions.
Adverse Effects:
Common adverse effects of Melphalan include myelosuppression, nausea, and vomiting. Nausea is usually mild with normal doses but becomes severe when high doses are used during bone marrow transplant. Less common adverse effects include hypersensitivity reactions, skin rash, and alopecia. Secondary cancers are also a concern with the use of the agent.
Brand Name:
Alkeran (GlaxoSmithKline) is the brand name under which Melphalan is marketed.
Originator
Alkeran,Burroughs-Wellcome,US,1964
Indications
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.
Manufacturing Process
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.
Therapeutic Function
Cancer chemotherapy
Air & Water Reactions
Insoluble in water.
Reactivity Profile
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.
Hazard
Strong irritant to eyes and mucous membranes. Confirmed carcinogen.
Fire Hazard
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.
Clinical Use
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.
Side effects
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.
Safety Profile
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.
Synthesis
Melphalan, L-3-[p-[bis-(2-chloroethyl)amino]phenyl]alanine (30.2.1.13), 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 (30.2.1.8). Reacting this with an ethanol
in the presence of hydrogen chloride gives the hydrochloride of 4-nitro-L-phenylalanine ethyl
ester (30.2.1.9), the amino group of which is protected by changing it to phthalamide by a
reaction with succinic anhydride to give 30.2.1.10. The nitro group in this molecule is
reduced to an amino group using palladium on calcium carbonate as a catalyst. The resulting aromatic amine (30.2.1.11) is then reacted with ethylene oxide, which forms a bis-(2-
hydroxyethyl)-amino derivative (30.2.1.12). 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).
Potential Exposure
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).
Carcinogenicity
Melphalan is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.
Environmental Fate
The release to the environment of melphalan may result
through various waste streams. It is practically insoluble in
water, insoluble in chloroform and ether, slightly soluble in
methanol, and soluble in ethanol, propylene glycol, 2% carboxymethyl
cellulose, and alkaline and dilute acid solutions. It
hydrolyzes in aqueous solution.
If released into water, melphalan is expected to adsorb to
suspended solids and sediment in the water based on the
estimated Koc, using a structure estimation method based on
molecular connectivity indices, of 355. Volatilization from
water surfaces is not expected to be an important fate process
based on this compound’s estimated Henry’s law constant,
developed using a fragment constant estimation method, of
4.2×10-13 atmm3 mol-1 and its estimated vapor pressure,
according to a model of gas/particle partitioning of semivolatile
organic compounds in the atmosphere of 3×10-10mmHg at
25 C. Hydrolysis in water and in moist soil will be an important
fate process according to melphalan’s experimental neutral
aqueous hydrolysis rate constant at 25℃ of 0.15 h-1 which
corresponds to a half-life of 4.6 h at pH 7. In line with soil
compartment, insufficient data are available to determine the
rate or importance of biodegradation of melphalan in water.
If released to soil, it is expected to have moderate mobility
based on its estimated Koc. Volatilization from moist soil
surfaces is not expected to be an important fate process based
on its estimated Henry’s law constant, or from dry soil surfaces,
based on its estimated vapor pressure. Contrarily, hydrolysis in
moist soil may be an important fate process according to its
experimental neutral aqueous hydrolysis rate constant and its
half-life. There are no available data to determine the rate or
importance of biodegradation of melphalan in soil.
If released to air, the value of its vapor pressure indicates
that it will exist solely in the particulate phase in the atmosphere.
Melphalan will be removed from the atmosphere by
wet or dry deposition. On other hand, vapor-phase melphalan
will be degraded in the atmosphere by reaction with photochemically
produced hydroxyl radicals with an estimated halflife
of about 1.7 h.
An estimated bioconcentration factor value of 0.24, from an
experimental log Kow of -0.52, suggests that the potential for
bioconcentration in aquatic organisms is very low.
Metabolism
Spontaneous hydrolysis degradation rather than
enzymatic metabolism. Percentage of dose excreted in
the urine as active or toxic moiety ranges from 11-93%;
20-50% excreted in the faeces within 6 days
Shipping
UN2811 Toxic solids, organic, n.o.s., Hazard
Class: 6.1; Labels: 6.1-Poisonous materials, Technical
Name Required. UN3249 Medicine, solid, toxic, n.o.s.,
Hazard Class: 6.1; Labels: 6.1-Poisonous materials
Purification Methods
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.]
Toxicity evaluation
Melphalan is a bifunctional alkylating agent of the nitrogen
mustard type that binds to cellular macromolecules and it is cell
cycle phase-nonspecific. This drug has the capacity to interfere
with normal mitosis and cell division in rapidly proliferating
tissues. Activity occurs as a result of formation of an unstable
ethylenimmonium ion, which alkylates or binds with many
intracellular molecular structures including nucleic acids. Its
cytotoxic action is primarily due to cross-linking of strands of
DNA and RNA, as well as inhibition of protein synthesis.
Waste Disposal
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
Check Digit Verification of cas no
The CAS Registry Mumber 148-82-3 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 1,4 and 8 respectively; the second part has 2 digits, 8 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 148-82:
(5*1)+(4*4)+(3*8)+(2*8)+(1*2)=63
63 % 10 = 3
So 148-82-3 is a valid CAS Registry Number.
InChI:InChI=1/C9H11NO2.C5H11Cl2N/c10-8(9(11)12)6-7-4-2-1-3-5-7;1-8(4-2-6)5-3-7/h1-5,8H,6,10H2,(H,11,12);2-5H2,1H3/t8-;/m0./s1
148-82-3Relevant articles and documents
Aminopeptidase expression in multiple myeloma associates with disease progression and sensitivity to melflufen
Miettinen, Juho J.,Kumari, Romika,Traustadottir, Gunnhildur Asta,Huppunen, Maiju-Emilia,Sergeev, Philipp,Majumder, Muntasir M.,Schepsky, Alexander,Gudjonsson, Thorarinn,Lievonen, Juha,Bazou, Despina,Dowling, Paul,O‘gorman, Peter,Slipicevic, Ana,Anttila, Pekka,Silvennoinen, Raija,Nupponen, Nina N.,Lehmann, Fredrik,Heckman, Caroline A.
, (2021)
Multiple myeloma (MM) is characterized by extensive immunoglobulin production leading to an excessive load on protein homeostasis in tumor cells. Aminopeptidases contribute to proteolysis by catalyzing the hydrolysis of amino acids from proteins or peptides and function downstream of the ubiquitin–proteasome pathway. Notably, aminopeptidases can be utilized in the delivery of antibody and peptide-conjugated drugs, such as melflufen, currently in clinical trials. We analyzed the expression of 39 aminopeptidase genes in MM samples from 122 patients treated at Finnish cancer centers and 892 patients from the CoMMpass database. Based on ranked abundance, LAP3, ERAP2, METAP2, TTP2, and DPP7 were highly expressed in MM. ERAP2, XPNPEP1, DPP3, RNPEP, and CTSV were differentially expressed between relapsed/refractory and newly diagnosed MM samples (p a substrate for aminopeptidases LAP3, LTA4H, RNPEP, and ANPEP. The sensitivity of MM cell lines to melflufen was reduced by aminopeptidase inhibitors. These results indicate critical roles of aminopeptidases in disease progression and the activity of melflufen in MM.
An Improved Process for the Synthesis of Melphalan and the Hydrochloride Salt
-
Paragraph 0042, (2016/02/18)
The present invention relates to an improved process for the preparation of Melphalan, more specifically the invention relates to an efficient process for the preparation of substantially pure Melphalan hydrochloride (I).
PROCESS FOR THE PURIFICATION OF MELPHALAN
-
, (2014/12/12)
A method for the purification and preparation of melphalan that allows to obtain melphalan with purity higher than 99.5% is described.
PROCESS FOR THE PREPARATION OF MELPHALAN HYDROCHLORIDE
-
, (2012/05/20)
The present invention provides a simple and efficient method for synthesis of 4-[bis (2-chloroethyl)-amino]-L-phenylalanine hydrochloride. The process involves the treatment of 4-[bis(2-chloroethyl)-amino]-L-phenylalanine free base with hydrochloric acid in water followed by isolation of 4-[bis(2-chloroethyl)-amino]-phenylalanine hydrochloride of desired purity.
THERAPEUTIC FOR HEPATIC CANCER
-
, (2011/02/18)
A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.
SPECIFIC BINDING PROTEINS AND USES THEREOF
-
, (2011/04/19)
The present invention relates to specific binding members, particularly antibodies and fragments thereof, which bind to amplified epidermal growth factor receptor (EGFR) and to the de2-7 EGFR truncation of the EGFR. In particular, the epitope recognized by the specific binding members, particularly antibodies and fragments thereof, is enhanced or evident upon aberrant post-translational modification. These specific binding members are useful in the diagnosis and treatment of cancer. The binding members of the present invention may also be used in therapy in combination with chemotherapeutics or anti-cancer agents and/or with other antibodies or fragments thereof.
Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same
-
, (2010/05/13)
Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.
Pharmaceutical formulations
-
, (2008/06/13)
The present invention relates to a new two-component pharmaceutical formulation of melphalan in which the two components comprise (a) freeze-dried mephalan hydrochloride and (b) a solvent-diluent comprising a citrate, propylene glycol and ethanol. Substantially pure melphalan, substantially pure melphalan hydrochloride and methods for preparing them are also described.
High molecular weight prodrug derivatives of antiinflammatory drugs
-
, (2008/06/13)
Compounds of the formula 1, PS - O - A - (CH2)n- B - D (1), wherein PS-O represents an alkoxide residue of any of the free hydroxy groups of a polysaccharide (PS-OH) compound with molecular weight (Mw) of from 40,000 to 5,000,000 selected from dextran, carboxymethyl dextran, diethylaminoethyl dextran, starch, hydroxyet-hyl starch, alginates, glycogen, pullullan, agarose, cellulose, chitosan, chitin and carrageenan,A is a carbonyl group or absent,n is zero or a positive integer from 1 to 14,B is oxygen, a carbonyl group, NR wherein R is hydrogen or lower alkyl, or B is absent, and, D is (i) a group of the formula:, R1 - CO - (11), wherein R1-CO- represents the acyl residue of a carboxylic acid drug (R1-COOH) used in the treatment of inflammatory disorders; or (ii) a group of the formula:, R2 - O - (12), wherein R2-O- refers to the C-21 alkoxide residue of a known antiinflammatory steroid (R2-OH) or an alkoxide residue of any other drug or medicament containing a hydroxy functional group used in the treatment of inflammatory disorders; with the proviso that when A is absent, n is 0, and B is absent, then R1-CO- is different from the acyl residue of acetylsalicylic acid;, and non-toxic pharmaceutically acceptable acid addition salts thereof;, and non-toxic pharmaceutically acceptable cation salts thereof. Such compounds are biolabile prodrugs providing controlled release and prolonged duration of action of the parent active antiinflamma-tory agents locally at the administration site after intra-articular, intra-muscular, subcutaneous or extra-dural application while at the same time being highly stable in aqueous solution in the pH range 3--5. After oral administration of such prodrugs the parent drug is liberated selectively in the terminal ileum and the colon over an extended period of time.
Process for producing N-phthaloyl-p-nitro-L-phenylalanine
-
, (2008/06/13)
N-Phthaloyl-p-nitro-L-phenylalanine, an intermed-iate in the production of melphalan, or an ester thereof is prepared by reacting p-nitro-L-phenylalanine or an ester thereof with an N-substituted phthalimide.
