Triethylenetetramine

Triethylenetetramine (TETA and trien), also known as trientine (INN) when used medically, is an organic compound with the formula [CH2NHCH2CH2NH2]2. The pure freebase is a colorless oily liquid, but, like many amines, older samples assume a yellowish color due to impurities resulting from air-oxidation. It is soluble in polar solvents. The branched isomer tris(2-aminoethyl)amine and piperazine derivatives may also be present in commercial samples of TETA.[1] The hydrochloride salts are used medically as a treatment for copper toxicity.

Triethylenetetramine
Names
Preferred IUPAC name
N1,N1′-(Ethane-1,2-diyl)di(ethane-1,2-diamine)
Other names
  • N,N'-Bis(2-aminoethyl)ethane-1,2-diamine
  • TETA
  • trien
  • trientine (INN)
  • trientine dihydrochloride
  • MK-0681
Identifiers
CAS Number
3D model (JSmol)
Beilstein Reference
 605448
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.003.591
EC Number
  • 203-950-6
Gmelin Reference
 27008
KEGG
MeSH Trientine
PubChem CID
RTECS number
  • YE6650000
UNII
UN number 2259
InChI
  • InChI=1S/C6H18N4/c7-1-3-9-5-6-10-4-2-8/h9-10H,1-8H2 Y
    Key: VILCJCGEZXAXTO-UHFFFAOYSA-N Y
SMILES
  • NCCNCCNCCN
Properties
Chemical formula
 C6H18N4
Molar mass 146.238 g·mol−1
Appearance Colorless liquid
Odor Fishy, ammoniacal
Density 982 mg mL−1
Melting point −34.6 °C; −30.4 °F; 238.5 K
Boiling point 266.6 °C; 511.8 °F; 539.7 K
Solubility in water
 Miscible
log P 1.985
Vapor pressure <1 Pa (at 20 °C)
Refractive index (nD)
 1.496
Thermochemistry
Heat capacity (C)
 376 J K−1 mol−1 (at 60 °C)
Hazards
GHS labelling:
Pictograms
Signal word
 Danger
Hazard statements
 H312, H314, H317, H412
Precautionary statements
 P273, P280, P305+P351+P338, P310
Flash point 129 °C (264 °F; 402 K)
Lethal dose or concentration (LD, LC):
  • 550 mg kg−1 (dermal, rabbit)
  • 2.5 g kg−1 (oral, rat)
Related compounds
Related amines
  • Ethylenediamine
  • Diethylenetriamine
  • Cyclam
Related compounds
  • Ethylenediaminetetraacetic acid
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Y verify (what is YN ?)
Infobox references

Uses

The reactivity and uses of TETA are similar to those for the related polyamines ethylenediamine and diethylenetriamine. It is primarily used as a crosslinker ("hardener") in epoxy curing.[2][3]

Medical uses
Trientine
Clinical data
Trade namesSyprine, Cuprior, Cufence, others
AHFS/Drugs.comMonograph
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
IUPAC name
  • (2-aminoethyl)({2-[(2-aminoethyl)amino]ethyl})amine
DrugBank
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.003.591

The hydrochloride salt of TETA, referred to as trientine hydrochloride, is a chelating agent that is used to bind and remove copper in the body to treat Wilson's disease, particularly in those who are intolerant to penicillamine.[9] Some recommend trientine as first-line treatment, but experience with penicillamine is more extensive.[13]

Trientine hydrochloride (brand name Syprine) was approved for medical use in the United States in November 1985.[9]

Trientine tetrahydrochloride (brand name Cuprior) was approved for medical use in the European Union in September 2017.[11] It is indicated for the treatment of Wilson's disease in adults, adolescents and children five years of age or older who are intolerant to D-penicillamine therapy.[11]

Trientine dihydrochloride (brand name Cufence) was approved for medical use in the European Union in July 2019.[12] It is indicated for the treatment of Wilson's disease in adults, adolescents and children five years of age or older who are intolerant to D-penicillamine therapy.[12]

The most common side effects include nausea, especially when starting treatment, skin rash, duodenitis (inflammation of the duodenum, the part of the gut leading out of the stomach), and severe colitis (inflammation in the large bowel causing pain and diarrhea).[12]

Society and culture

Controversies

In the United States, Valeant Pharmaceuticals International raised the price of its Syprine brand of TETA from $625 to $21,267 for 100 pills over five years.[14] The New York Times said that this "egregious" price increase caused public outrage.[14] Teva Pharmaceuticals developed a generic, which patients and doctors expected to be cheaper, but when it was introduced in February 2018, Teva's price was $18,375 for 100 pills.[14] Aaron Kesselheim, who studies drug pricing at Harvard Medical School, said that drug companies price the product at what they think the market will bear.[14]

Production

TETA is prepared by heating ethylenediamine or ethanolamine/ammonia mixtures over an oxide catalyst. This process gives a variety of amines, especially ethylene amines which are separated by distillation and sublimation.[2][15]

Coordination chemistry

TETA is a tetradentate ligand in coordination chemistry, where it is referred to as trien.[16] Octahedral complexes of the type M(trien)L2 can adopt several diastereomeric structures.[17]

References
  1. "Ethyleneamines" (PDF). Huntsman. 2007.
  2. Eller K, Henkes E, Rossbacher R, Höke H (2005). "Amines, Aliphatic". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a02_001. ISBN 3527306730.
  3. "Triethylenetetramine". webbook.nist.gov. Retrieved 2022-07-20.
  4. "Trientine Waymade". Therapeutic Goods Administration (TGA). 25 January 2021. Retrieved 8 September 2021.
  5. "AusPAR: Trientine dihydrochloride". Therapeutic Goods Administration (TGA). 3 May 2021. Retrieved 8 September 2021.
  6. "Summary Basis of Decision (SBD) for Mar-Trientine". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  7. "Cuprior 150 mg film-coated tablets - Summary of Product Characteristics (SmPC)". (emc). Retrieved 21 September 2020.
  8. "Trientine dihydrochloride Tillomed 250 mg capsules, hard - Summary of Product Characteristics (SmPC)". (emc). Retrieved 21 September 2020.
  9. "Syprine- trientine hydrochloride capsule". DailyMed. 22 December 2016. Retrieved 21 September 2020.
  10. "Trientine hydrochloride capsule". DailyMed. 28 February 2020. Retrieved 21 September 2020.
  11. "Cuprior EPAR". European Medicines Agency (EMA). Retrieved 21 September 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  12. "Cufence EPAR". European Medicines Agency (EMA). 24 May 2019. Retrieved 21 September 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  13. Roberts EA, Schilsky ML (June 2003). "A practice guideline on Wilson disease" (pdf). Hepatology. 37 (6): 1475–92. doi:10.1053/jhep.2003.50252. PMID 12774027. S2CID 263620.
  14. Thomas K (23 February 2018). "Patients Eagerly Awaited a Generic Drug. Then They Saw the Price". The New York Times. Retrieved 21 September 2020.
  15. Brydson JA (1999). "Epoxide Resins". In Brydson JA (ed.). Plastics Materials (Seventh ed.). Oxford: Butterworth-Heinemann. pp. 744–777. doi:10.1016/B978-075064132-6/50067-X. ISBN 9780750641326.
  16. von Zelewsky A (1995). Stereochemistry of Coordination Compounds. Chichester: John Wiley. ISBN 047195599X.
  17. Utsuno S, Sakai Y, Yoshikawa Y, Yamatera H (1985). "Three Isomers of the Trans -Diammine-[N,N′-bis(2-Aminoethyl)-1,2-Ethanediamine]-Cobalt(III) Complex Cation". Three Isomers of the trans-Diammine-[N,N′-bis(2-Aminoethyl)-1,2-Ethanediamine]-Cobalt(III) Complex Cation. Inorganic Syntheses. Vol. 23. pp. 79–82. doi:10.1002/9780470132548.ch16. ISBN 9780470132548.
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