Dimethyl fumarate

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Not to be confused with Dimethylformamide.
Dimethyl fumarate
Dimethyl fumarate
Names
IUPAC name
Dimethyl (E)-butenedioate
Other names
trans-1,2-Ethylenedicarboxylic acid dimethyl ester
(E)-2-Butenedioic acid dimethyl ester
Identifiers
624-49-7 YesY
ChEBI CHEBI:76004 N
ChemSpider 553171 YesY
EC Number 210-849-0
7045
Jmol 3D model Interactive image
UNII FO2303MNI2 YesY
  • InChI=1S/C6H8O4/c1-9-5(7)3-4-6(8)10-2/h3-4H,1-2H3/b4-3+ YesY
    Key: LDCRTTXIJACKKU-ONEGZZNKSA-N YesY
  • InChI=1/C6H8O4/c1-9-5(7)3-4-6(8)10-2/h3-4H,1-2H3/b4-3+
    Key: LDCRTTXIJACKKU-ONEGZZNKBJ
  • O=C(OC)\C=C\C(=O)OC
Properties
C6H8O4
Molar mass 144.127 g/mol
Appearance White crystalline solid
Density 1.37 g/cm3, solid
Melting point 102 to 105 °C (216 to 221 °F; 375 to 378 K)[1]
Boiling point 192 to 193 °C (378 to 379 °F; 465 to 466 K)[1]
Pharmacology
ATC code N07XX09
Vapor pressure {{{value}}}
Related compounds
Related diesters
 Diethyl fumarate, dimethyl maleate, dimethyl malonate, dimethyl adipate
Related compounds
 Fumaric acid
Methyl acrylate
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references

Dimethyl fumarate (DMF) is the methyl ester of fumaric acid. DMF was initially recognized as a very effective hypoxic cell radiosensitizer.[2] Later, DMF combined with three other fumaric acid esters (FAE) was licensed in Germany as oral therapy for psoriasis (trade name Fumaderm).[3] Other diseases, such as necrobiosis lipoidica, granuloma annulare, and sarcoidosis were also found to respond to treatment with DMF in case reports or small patient series.[4] Phase III clinical trials found that DMF (BG-12) successfully reduced relapse rate and increased time to progression of disability in multiple sclerosis (trade name Tecfidera).[5][6] DMF is thought to have immunomodulatory properties without significant immunosuppression.[7]

In a non-medical use, DMF was applied as a biocide in furniture or shoes to prevent growths of mold during storage or transport in a humid climate. However, due to incidences of allergic reactions after skin contact the European Union banned DMF in consumer products since 1998, and since January 2009 the import of products containing DMF was also banned.[8]

Medical use

Tecfidera was shown to have a significant effect on relapse rate and time to progression in phase III clinical trials of multiple sclerosis.[5][6]

Tecfidera was recommended for approval in the European Union as a peroral treatment for MS by EMA on March 21, 2013.[9]

Side effects

One serious side effect that has been described is progressive multifocal leukoencephalopathy.[10]

Reactions

Dimethyl fumarate is an ester and an α,β-unsaturated electrophilic compound which can quickly undergo Michael additions with nucleophiles. Dimethyl fumarate is also an effective diene acceptor in the thermal Diels-Alder reaction, where the reactivity of its vinylenic bond is enhanced by the two electron-withdrawing ester groups. Due to the geometry of the starting ester, the Diels-Alder product will have a trans configuration. With this reaction, compounds with bicyclo skeletons can be synthesized, e.g. a diester with a norbornene (bicyclo[2.2.1]heptene) skeleton from dimethyl fumarate and cyclopentadiene.

Mechanism of action

The precise mechanism of action of dimethyl fumarate is unknown. The compound (and its metabolite, monomethyl fumarate) activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway and has been identified as a nicotinic acid receptor agonist in vitro.[11] Dimethyl fumarate is a lipophilic, highly mobile molecule in human tissue. As a α,β-unsaturated electrophilic compound, dimethyl fumarate is rapidly attacked by the detoxifying agent glutathione (GSH) in a Michael addition reaction.[12][13][14] Dimethyl fumarate is highly reactive: when administered orally, it does not survive long enough to be absorbed into blood without being attacked by GSH. However, part of it is hydrolyzed by esterases to produce monomethylfumarate, which is more resistant.[15]

History

The American company Biogen Idec developed DMF as a capsule containing microtablets for the treatment of multiple sclerosis, under the code name BG-12; it was approved, under the trade name Tecfidera, for the treatment of adults with relapsing forms of MS on March 27, 2013.[16][17]

Consumer products

Dimethyl fumarate has been found to be an allergic sensitizer at very low concentrations, producing eczema that is difficult to treat. Concentrations as low as 1 ppm may produce allergic reactions.[18] There are only a handful of equally potent sensitizers.[19]

The sensitizing risk was brought to public attention by the "poison chair" incident, where Chinese manufacturer Linkwise produced two-seater sofas with dimethyl fumarate sachets inside to inhibit mould while they were in storage or transport.[20][21] In Finland where the chairs were sold from 2006–2007, sixty users were given serious rashes.[19] The cause was identified as dimethyl fumarate-induced allergic reaction by Tapio Rantanen from Finland, and his original article became the cover story in the July issue of the British Journal of Dermatology.[18] In the United Kingdom, sofas sold by Argos, Land of Leather and Walmsley Furnishing containing the chemical caused over a hundred injuries.[19][21] Argos withdrew the sofas from stores and contacted buyers to collect those that had been sold — with Land of Leather withdrawing the sofas without notifying buyers and Walmsley saying they had removed the sachets from sofas they sold after the danger came to light.[21] Complaints have been made that dates on the sofas were altered and sofas containing the sachets sold.[21] Land of Leather and Walmsley are facing a ₤10 million class action suit over their reaction to the incident, joining the manufacturer in denying the sofas are connected to their customers injuries.[21][22][23] The danger came to public attention when the BBC Watchdog program alerted consumers to the sofas.[21][22][24]

In the European Union the use of dimethyl fumarate for consumer products has been forbidden since 1998, and since January 2009 the import of products containing dimethyl fumarate is also forbidden.[8]

The EU Commission Decision 2009/251 of 17 March 2009 requiring Member States to ensure that products containing the biocide dimethylfumarate are not placed or made available on the market has definitely forbidden any marketing of products containing dimethyl fumarate into the European Union.[25] The ban on dimethyl fumarate as laid down in Decision 2009/251 establishes a maximum concentration of dimethyl fumarate in products of 0.1 ppm. Products containing more than 0.1 ppm dimethyl fumarate shall be withdrawn from the market and recalled by consumers as of 1 May 2009.

References

  1. ↑ 1.0 1.1 Acros MSDS[verification needed]
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ 5.0 5.1 Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ 6.0 6.1 Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ 8.0 8.1 Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ 18.0 18.1 Lua error in package.lua at line 80: module 'strict' not found.
  19. ↑ 19.0 19.1 19.2 Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ 21.0 21.1 21.2 21.3 21.4 21.5 Lua error in package.lua at line 80: module 'strict' not found.
  22. ↑ 22.0 22.1 BBC - Consumer - TV and radio - itchy sofas[dead link]
  23. ↑ BBC: Judge rejects 'toxic sofa' claims in burns injury cases, 18 March 2010
  24. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  25. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

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