Chemical Properties
White Solid
Originator
Hexastat,Roger Bellon,France,1979
Uses
As experimental insect chemosterilant.
Uses
An antitumor agent which also acts as a chemosterilant for male houseflies and other insects. Antineoplastic.
Production Methods
Commercial manufacture of altretamine follows a simple, high yield alkylation sequence built around melamine as the core heterocycle. Producers first generate an excess of dimethyl sulphate or methyl chloride under controlled alkaline conditions, then carry out exhaustive N methylation of melamine’s three exocyclic amino groups to form the fully substituted hexamethylated triaminotriazine. The reaction is typically run in polar solvents with a base to neutralise the liberated acid, followed by purification through crystallisation to remove partially methylated by products.
Indications
Although both DNA and RNA synthesis are inhibited
in cells exposed to hexamethylmelamine (Hexalen), the
molecular mechanisms of these effects are not known.
Definition
A hexamethyl-2,4,6-
triamine derivative of 1,3,5-triazine.
Manufacturing Process
50 g of hexamethylolmelamine-hexamethyl ether in 950 cc methanol are
hydrogenated, at 90°C to 100°C, in the presence of 2 g Raney nickel with 100
atmospheres excess pressure of hydrogen in a steel autoclave holding 2 L
until the absorption of hydrogen is terminated. After the catalyst has been
filtered off with suction, the methanol is distilled off. As a result, 23.1 g (86%
of the theoretical) of crude hexamethylmelamine are formed having a melting
point of 158°C to 162°C. After recrystallization from methanol, the pure
product is obtained having a melting point of 168°C.
brand name
Hexalen (Millot Laboratories,
France).
Therapeutic Function
Antitumor
General Description
Colorless crystalline solid. Insoluble in water.
General Description
Altretamine is available in 50-mg capsules for oraladministration as a second-line treatment for ovarian cancer.The mechanism of action has not been firmly established, althoughthe spectrum of activity is similar to that for otheralkylating agents; however, cross-resistance is not seen.Cytotoxicity has been correlated with metabolism to give thecarbinolamines, which may form imines capable of crosslinking,or decompose to give formaldehyde, which may reactwith nucleophiles on DNA or proteins. The agent is well absorbedupon oral administration, well distributed, and highly(90%) plasma protein bound. The agent is extensively metabolizedin the liver by CYP to give demethylated metabolites via the previously mentioned carbinolamines. Elimination occursprimarily in the urine as mostly demethylated metaboliteswith a terminal elimination half-life of 4 to 10 hours.Myleosuppression and nausea/vomiting are dose-limitingtoxicities. Other adverse effects include lethargy, agitation,hallucinations, skin rash, and elevations in transaminase levels,flulike symptoms, abdominal cramps, and diarrhea.
Air & Water Reactions
Insoluble in water.
Reactivity Profile
Altretamine neutralizes acids in exothermic reactions to form salts plus water. 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.
Mechanism of action
Hexamethylmelamine is readily absorbed after oral
administration, with peak plasma levels achieved after 1
hour.The drug is readily metabolized to form a number
of demethylated metabolites. Urinary elimination is the
primary route of drug excretion.
Clinical Use
Hexamethylmelamine is useful for the treatment of
ovarian adenocarcinoma and is frequently combined
with cyclophosphamide, cisplatin, and doxorubicin in
the treatment of this tumor. It also has some activity
against small cell lung cancer.
Side effects
Nausea and vomiting are the major toxicities associated
with hexamethylmelamine administration. Myelosuppression
and a peripheral neuropathy also may
occur.
Metabolism
This unique structure is believed to damage tumor cells through the production of the weakly alkylating species formaldehyde, a product of CYP450-mediated N-demethylation. Administered orally, altretamine is extensively metabolized on first pass, producing primarily mono- and didemethylated metabolites. Additional demethylation reactions occur in tumor cells, releasing formaldehyde in situ before the drug is excreted in the urine.
Pesticide Type
Insecticide
