Triethylenetetramine

Triethylenetetramine

Skeletal formula of triethylenetetramine
Ball and stick model of triethylenetetramine
Spacefill model of triethylenetetramine
Names
Preferred IUPAC name N^1,N^1′-(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	112-24-3^Y hydrochloride: 38260-01-4
3D model (JSmol)	Interactive image
Beilstein Reference	605448
ChEBI	CHEBI:39501^Y hydrochloride: CHEBI:9706
ChEMBL	ChEMBL609^Y hydrochloride: ChEMBL3989777
ChemSpider	21106175^Y hydrochloride: 64521
DrugBank	DB06824
ECHA InfoCard	100.003.591
EC Number	203-950-6
Gmelin Reference	27008
KEGG	C07166^Y
MeSH	Trientine
PubChem CID	5565 hydrochloride: 71433
RTECS number	YE6650000
UNII	SJ76Y07H5F^Y hydrochloride: HC3NX54582
UN number	2259
CompTox Dashboard (EPA)	DTXSID9023702
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):
LD50 (median dose)	550 mg kg^−1 (dermal, rabbit) 2.5 g kg^−1 (oral, rat)
Pharmacology
Legal status	CA: ℞-only[1][2]
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

Triethylenetetramine (TETA and trien), also known as trientine (INN) when used medically, is an organic compound with the formula [CH₂NHCH₂CH₂NH₂]₂. The pure free base 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.[3] The hydrochloride salts are used medically as a treatment for copper toxicity.

Uses

Epoxy 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.[4][5] TETA, like other aliphatic amines, react quicker and at lower temperatures than aromatic amines due to less negative steric effects since the linear nature of the molecule provides it the ability to rotate and twist.

Medical uses

Trientine

Clinical data
Trade names	Syprine, Cuprior, Cufence, others
AHFS/Drugs.com	Monograph
License data	US DailyMed: Trientine
Pregnancy category	AU: D[6][7]
Routes of administration	By mouth
ATC code	A16AX12 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[6][7] CA: ℞-only[8] UK: POM (Prescription only)[9][10] US: ℞-only[11][12][13] EU: Rx-only[14][15]
Identifiers
IUPAC name (2-aminoethyl)({2-[(2-aminoethyl)amino]ethyl})amine
DrugBank	DB06824 DBSALT001269
PDB ligand	104 (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID9023702
ECHA InfoCard	100.003.591

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.[11] Some recommend trientine as first-line treatment, but experience with penicillamine is more extensive.[16]

Trientine hydrochloride (brand name Syprine) was approved for medical use in the United States in November 1985.[11]

Trientine tetrahydrochloride (brand name Cuprior) was approved for medical use in the European Union in September 2017.[14] 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.[14]

Trientine dihydrochloride (brand name Cufence) was approved for medical use in the European Union in July 2019.[15] 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.[15]

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).[15]

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.[17] The New York Times said that this "egregious" price increase caused public outrage.[17] 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.[17] 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.[17]

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.[4][18]

Coordination chemistry

TETA is a tetradentate ligand in coordination chemistry, where it is referred to as trien.[19] Octahedral complexes of the type M(trien)L₂ can adopt several diastereomeric structures.[20]

References

1. "Health product highlights 2021: Annexes of products approved in 2021". Health Canada. 3 August 2022. Retrieved 25 March 2024.
2. "Regulatory Decision Summary for Waymade-Trientine". Health Canada. 20 April 2021. Retrieved 25 March 2024.
3. "Ethyleneamines" (PDF). Huntsman. 2007. Archived from the original (PDF) on 2019-03-06. Retrieved 2016-07-10.
4. 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.
5. "Triethylenetetramine". webbook.nist.gov. Retrieved 2022-07-20.
6. "Trientine Waymade". Therapeutic Goods Administration (TGA). 25 January 2021. Retrieved 8 September 2021.
7. "AusPAR: Trientine dihydrochloride". Therapeutic Goods Administration (TGA). 3 May 2021. Retrieved 8 September 2021.
8. "Summary Basis of Decision (SBD) for Mar-Trientine". Health Canada. 23 October 2014. Retrieved 29 May 2022.
9. "Cuprior 150 mg film-coated tablets - Summary of Product Characteristics (SmPC)". (emc). Retrieved 21 September 2020.
10. "Trientine dihydrochloride Tillomed 250 mg capsules, hard - Summary of Product Characteristics (SmPC)". (emc). Retrieved 21 September 2020.
11. "Syprine- trientine hydrochloride capsule". DailyMed. 22 December 2016. Retrieved 21 September 2020.
12. "Trientine hydrochloride capsule". DailyMed. 28 February 2020. Retrieved 21 September 2020.
13. "Cuvrior- trientine tetrahydrochloride tablet, film coated". DailyMed. 20 May 2022. Retrieved 21 January 2023.
14. "Cuprior EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 21 September 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
15. "Cufence EPAR". European Medicines Agency (EMA). 24 May 2019. Retrieved 21 September 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
16. 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.^[dead link‍]
17. Thomas K (23 February 2018). "Patients Eagerly Awaited a Generic Drug. Then They Saw the Price". The New York Times. Retrieved 21 September 2020.
18. 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.
19. von Zelewsky A (1995). Stereochemistry of Coordination Compounds. Chichester: John Wiley. ISBN 047195599X.
20. 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.