645-05-6

Usage

Uses

Used in Anticancer Applications:
Altretamine is used as an antitumor agent for the treatment of ovarian cancer. It is considered a second-line treatment option and has shown cytotoxicity through its metabolism to carbinolamines.
Used in Antimalarial Applications:
Altretamine is also used as an antimalarial agent, indicating its potential to combat malaria-causing parasites.
Used as an Insect Chemosterilant:
Altretamine serves as an experimental chemosterilant for male houseflies and other insects, which could be useful in controlling insect populations.
Used in Pharmaceutical Industry:
Altretamine is used in the pharmaceutical industry for the development of oral administration treatments, specifically in the form of 50-mg capsules for the treatment of ovarian cancer.

Originator

Hexastat,Roger Bellon,France,1979

Indications

Although both DNA and RNA synthesis are inhibited in cells exposed to hexamethylmelamine (Hexalen), the molecular mechanisms of these effects are not known.

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.

Therapeutic Function

Antitumor

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.

Hazard

Toxic.

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.

InChI:InChI=1/C9H24N6/c1-10(2)13-7-14(11(3)4)9-15(8-13)12(5)6/h7-9H2,1-6H3

Upstream product

• 108-77-0 1,3,5-trichloro-2,4,6-triazine 
• 506-59-2 N,N-dimethylammonium chloride 
• 124-40-3 dimethyl amine 
• 1467-79-4 NCNMe₂ 
• 123-39-7 N-Methylformamide 
• 103-83-3 N,N'-dimethylbenzylamine 
• 3140-74-7 2-chloro-4,6-bis(dimethylamino)-1,3,5-triazine 
• 51-80-9 bis-(dimethylamino)methane 

Downstream Products

• 124-40-3 dimethyl amine 
• 108-80-5 isocyanuric acid 

Relevant academic research and scientific papers

N-Methylmelamines: Synthesis, Characterization, and Physical Properties

N-Methylmelamines have recently gained importance as valuable compounds for manufacturing modified melamine formaldehyde resins and other polymer building blocks. A great advantage of these polymers is the reduction of the carcinogenic formaldehyde. Selecting the polymerization processes (e.g., substance polymerization, polymerization in solution) and controlling the polymerization reaction and properties of these novel materials requires knowledge of the properties of the individual melamine derivatives used as new building blocks. All possible permutations of N-methylmelamines were prepared, and reaction progress was monitored by GC/MS. 2,4,6-Tris(dimethylamino)-1,3,5-triazine was prepared to complete the series; this is, however, also a possible byproduct in various synthesis routes. The reaction conditions were optimized to obtain high yields of each derivative with the highest possible purity. The substances were characterized by NMR and IR spectroscopy, mass spectrometry, elemental analysis, and single-crystal X-ray diffraction. In addition, physical properties, such as solubility, melting points, and pKb values, were determined. The number of amino-, methylamino-, and dimethylamino groups has a significant effect on these properties. In summary, we found that by increasing the number of amino- and methylamino groups, solubility and pKb increase. With increasing number of amino groups, the compounds tend to form hydrogen bonds, and thus, the melting point shifts to higher temperature ranges where they start to decompose.

Dialkylcyanamides are more reactive substrates toward metal-mediated nucleophilic addition than alkylcyanides

The dialkylcyanamide complexes Q[PtCl3(NCNR2)] (Q = Ph3PCH2Ph, R2 = Me21, Et 22, C5H103, C4H8O 4; Q = NMe4, R2 = Me25; Q = NEt4, R 2 = Me26) were synthesized either by dissolving Q 2[Pt2(μ-Cl)2Cl4] in neat NCNR2 (1-4) or by substitution of a NCNR2 ligand with Cl- in [PtCl2(NCNR2)2] by its treatment with QCl (5, 6). Nucleophilic addition of dibenzylhydroxylamine, HON(CH2Ph)2, to 1-6 results in the formation of the complexes Q[PtCl3{NHC(NR2)ON(CH2Ph) 2}] (Q = Ph3PCH2Ph, R2 = Me 2, 7; Et2, 8; C5H10, 9; C 4H8O, 10; Q = Me4N, R2 = Me 211; Q = Et4N, R2 = Me2, 12) that further convert at room temperature in the solid state (1-24 h) or in a solution (0.5-2 h) to the imine complexes Q[PtCl3{N(CH2Ph)C(H)Ph}] (Q = Ph3PCH2Ph, 13; Me4N, 14; Et4N, 15) and the corresponding dialkylureas H2NC(O)NR2. The competitive reactivity study of the nucleophilic addition of HON(CH 2Ph)2 to (Ph3PCH2Ph)[PtCl 3(NCR′)] (R′ = Ph, NR2, CH2Ph) indicated that the reactivity of the coordinated NCNR2 is comparable to NCPh, while NCCH2Ph appeared to be much less reactive than the former two ligands. Compounds 1-6 and 13 were fully characterized by elemental analyses (C, H, N), high resolution ESI-MS, IR, and 1H and 13C{1H} NMR spectroscopy. The structure of 1 was additionally verified by a single-crystal X-ray diffraction.

The umpolung of substituent effect in nucleophilic aromatic substitution. A new approach to the synthesis of N,N-disubstituted melamines (triazine triskelions) under mild reaction conditions

By the umpolung of substituent effect 1,3,5-triazines substituted with three dialkylamino groups were prepared under mild reaction conditions by treatment of cyanuric chloride with tertiary amines. Quaternary N-triazinylammonium salts were identified as reactive intermediates activating the triazine ring and strongly promoting the persubstitution of all chlorine atoms. The final degradation of intermediate N-triazinylammonium chlorides proceeded at room temperature or in boiling dichloromethane spontaneously within irreversible evolution of appropriate chloroalkane.

Atom efficient cyclotrimerization of dimethylcyanamide catalyzed by aluminium amide: A combined experimental and theoretical investigation

A novel method for the cyclotrimerization of dimethylcyanamide to form hexamethylmelamine has been developed using an aluminium amide catalyst; detailed DFT modelling of the catalytic cycle supports a triple insertion, nucleophilic ring closure, deinsertion mechanism. The Royal Society of Chemistry.

Synthesis and cytotoxic activity of trisubstituted-1,3,5-triazines

1,3,5-Triazine derivatives were screened for phototoxicity as well as the cytotoxic activities against leukemia and adenocarcinoma derived cell lines in comparison to the normal human keratinocytes. A simple and environmentally friendly procedure has been developed for the synthesis of 1,3,5-triazine derivatives under microwave irradiation in the presence of a HY zeolite. The catalyst can be recovered and reused. Thus, the procedure provides a simple and green synthetic methodology under environmentally friendly conditions. Structure-activity relationships between the chemical structures and antimycobacterial and photosynthesis-inhibiting activity of the evaluated compounds are also discussed.

A novel series of potent cytotoxic agents targeting G2/M phase of the cell cycle and demonstrating cell killing by apoptosis in human breast cancer cells

Breast cancer, a leading cause of mortality in women, warrants the development and biological evaluation of new anticancer agents. A novel series of thiopyridine triazine derivatives was synthesized and investigated in the human breast cancer cell line, MDA-MB-468. SM40, the most potent derivative, induced a G2/M arrest and apoptosis with a possible involvement of p53. The cytotoxicity of SM40 was also examined against the NCI 60 cell line panel and its potency was rationalized using molecular modeling. Results suggest that SM40 is a promising cytotoxic agent.

Reactions of bis(silyl-substituted) methyllithium with α-hydrogen- free nitriles into 1,3,5-triazines

Bis(silyl-substituted) methyllithium has been found to catalyze a conversion of α-hydrogen-free nitriles directly to yield 2,4,6-trisubsituted s-triazines. The generally high yields and relatively mild reaction conditions of this procedure suggest an alternative to other aromatic nitrile cyclotrimerization reactions. Silicotropic rearrangements from C to N or N to N and an unusual elimination of LiCR2R (R=SiMe3, R=SiMe2NMe2) were observed.

A practical and easy synthesis of 2,4,6-trisubstituted-s-triazines

Triflic anhydride was found to be efficient for the cyclotrimerization of dialkylcyanamides under mild conditions. The same reaction can be applied to aryl nitriles and thiocyanates.

Addition reactions of bis(trimethylsilyl)methyl- and 1-azzallyl-lithium with cyanoamines into triazines or β-diketiminatolithium compounds

Reactions of bis(trimethylsily)methyl lithium reagent Li[CHR2] (R = SiMe3) and 1-azaallyllithium, [LiN(R)C(But) CHR]2 with cyanoamines R′CN (R' = Me2N, 1-piperidyl or o, p-pyridyl) yielded β-diketiminatolithiums (1, 2, 5, 7, 8) or symmetrically and mixed substituted triazines (3, 4, 6, 9, 10), respectively. The mechanistic pathways involve silicotropic rearrangements from C to N or N to N and an unusual elimination of Li[CHR2]. The complexes 1, 6, 7, and 10 had been characterized by X-Ray diffraction.

Reaction of disubstituted cyanamides with formamides under high pressure

High pressure-assisted co-cyclization of disubstituted cyanamides with formamide or monosubstituted formamides gave 2-amino- or 2-monosubstituted amino-4,6-bis(disubstituted amino)-1,3,5-triazines in one pot.