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624-49-7

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Identification

Name
Dimethyl fumarate
CAS
624-49-7
Synonyms
BIS-METHYL ESTER
DIMETHYL FUMARATE
(E)-2-Butenedioic acid dimethyl ester
FUMARIC ACID DIMETHYL ESTER
TIMTEC-BB SBB008222
(E)-CH3OC(O)CH=CHC(O)OCH3
2-Butenedioic acid, dimethyl ester, (E)-
2-Butenedioicacid(E)-,dimethylester
Allomaleic acid dimethyl ester
allomaleicaciddimethylester
Boletic acid dimethyl ester
boleticaciddimethylester
Dimethyl (2E)-2-butenedioate
Dimethyl trans-ethylenedicarboxylate
Dimethylester kyseliny fumarove
dimethylester,(e)-2-butenedioicaci
dimethylesterkyselinyfumarove
dimethylfumalate
dimethyltrans-butenedioate
Ethylene, 1,2-bis(methoxycarbonyl)-, trans-
EINECS(EC#)
210-849-0
Molecular Formula
C6H8O4
MDL Number
MFCD00064438
Molecular Weight
144.13
MOL File
624-49-7.mol

Chemical Properties

Appearance
fine white crystalline powder
Melting point 
102-106 °C(lit.)

mp 
102-106 °C(lit.)

Boiling point 
192-193 °C(lit.)

bp 
192-193 °C(lit.)

density 
1,37 g/cm3
refractive index 
1.4062 (estimate)
Fp 
192-193°C
storage temp. 
Store at RT.
solubility 
1.6g/l
form 
Liquid
color 
Clear colorless to faintly yellow
Stability:
Stable. Incompatible with acids, bases, oxidizing agents, reducing agents.
PH
4.0-6.0 (10g/l, H2O, 20℃)suspension
Water Solubility 
Soluble in water (1.6 mg/ml at 20°C), methanol (30-36 mg/ml), ethanol (10 mg/ml at 25°C), DMSO (29 mg/ml at 25°C), and DMF (~12 mg/ml).
Merck 
14,4287
BRN 
774590
Contact allergens
Dimethylfumarate, a strong irritant, is used as an industrial wide spectrum biocide in Asia and mainly in China, for textiles, leather, seeds, food, and cosmetic ingredients. It provoked a worldwide epidemic of severe contact dermatitis, initially from Chinese sofas sold in Finland, Great Britain, and France. It also induced severe burning and contact allergy due to shoes, and to contaminated clothing as well. This chemical, presents as is (white powder) or as tablets contained in little bags disposed in/or around the materials to protect, progressively evaporates and contaminates the environment. It is forbidden in the European Union since 2008
CAS DataBase Reference
624-49-7(CAS DataBase Reference)
NIST Chemistry Reference
2-Butenedioic acid (E)-, dimethyl ester(624-49-7)
EPA Substance Registry System
624-49-7(EPA Substance)

Hazard Information

Chemical Properties
fine white crystalline powder
Uses
immunomodulator
Uses
trans-1,2-Ethylenedicarboxylic Acid is used in cycloaddition reactions involving ylides, benzenes and amino acids.
Definition
ChEBI: An enoate ester resulting from the formal condensation of both carboxy groups of fumaric acid with methanol. Used for treatment of adults with relapsing forms of multiple sclerosis.

Safety Data

Hazard Codes 
Xn
Risk Statements 
R21:Harmful in contact with skin.
R38:Irritating to the skin.
R41:Risk of serious damage to eyes.
R43:May cause sensitization by skin contact.
R36/37/38:Irritating to eyes, respiratory system and skin .
Safety Statements 
S26:In case of contact with eyes, rinse immediately with plenty of water and seek medical advice .
S36/37/39:Wear suitable protective clothing, gloves and eye/face protection .
RIDADR 
UN 3077 9 / PGIII
WGK Germany 
1

RTECS 
EM6125000

TSCA 
Yes
HS Code 
29171990

Raw materials And Preparation Products

Material Safety Data Sheet(MSDS)

Questions And Answer

Overview
Dimethyl fumarate[DMF] is the methyl ester of fumaric acid[1, 2]. DMF, marketed in Germany under the trade name of Fumaderm, is used for oral therapy of psoriasis in combination with other drugs[2]. Later it has been used to treat adults with relapsing multiple sclerosis[a chronic inflammatory, demyelinating and neurodegenerative disease of the CNS resulting in neurological disability] since 2013(trade name Tecfidera)[3]. DMF is thought to have immunomodulatory properties without significant immunosuppression. In preclinical studies, dimethyl fumarate exhibited anti-inflammatory and cytoprotective properties that are generally thought to be mediated via activation of the nuclear factor [erythroid-derived 2]-like 2 transcriptional pathway, which is involved in the cellular response to oxidative stress.
In a non-medical use, DMF has been used 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 has banned DMF in consumer products since 1998, and since January 2009 the import of products containing DMF has also been banned[4].
Indication
Dimethyl fumarate[DMF] is mainly indicated for the treatment of the relapsing-remitting Multiple sclerosis(MS), which is a chronic inflammatory, demyelinating and neurodegenerative disease of the CNS, resulting in neurological disability[5, 6]. The disease typically begins in young adults(average age of onset &29 years) and affects twice as many women as men[7, 8]. Initially, most(80–85 %) individuals with MS have a relapsing-remitting[RRMS] disease course with defined clinical exacerbations of neurological symptoms, followed by complete or incomplete remission[7, 8]. Around 50 % of patients develop a secondary progressive MS within 10–15 years of RRMS onset and &89 % of patients develop secondary progressive MS after 25 years[9]. Globally, the estimated median incidence of MS is 2.5 per 100,000 persons and it has a median estimated prevalence of 30 per 100,000 persons[8].
The pathogenic process of the relapsing-remitting multiple sclerosis involves the migration of auto-reactive T cells across the blood–brain-barrier into the central nervous system where they damage myelin, oligodendrocyte and nerve fibers and lead to further immune cell recruitment[10]. This inflammatory process causes lesions[predominantly in the cerebellum, brain stem, spinal cord, optic nerves and white matter of brain ventricles] that result in the symptoms typical of MS, including weak/stiff muscles, limb numbness/tingling, balance problems, visual disturbances and cognitive dysfunction[11]. The lesional inflammatory environment also contributes to MS pathogenesis through the generation of proinflammatory cytokines and oxygen and nitrogen free radicals, establishing a cycle of inflammation and oxidative stress[12].
Mode of action
In MS, neuronal tissue damage is thought to be caused by aberrant activation and subsequent infiltration of immune cells into the CNS12. Infiltrating cells propagate inflammatory processes within the CNS13, ultimately leading to oligodendrocyte damage that results in demyelination and subsequent axonal transection and neurodegeneration[13, 14]. In addition to pathogenic adaptive autoimmunity processes, the release of free radicals[oxygen and nitrogen] by infiltrating monocytes leads to mounting oxidative stress[15-17]. As cells of the CNS are highly sensitive to excessive oxidative stress, this further promotes neurodegenerative processes.
Dimethyl fumarate has demonstrated beneficial effects in preclinical models of neuro-inflammation, neuro-degeneration, and toxic oxidative stress but its precise mechanism of action remains unclear[18, 19]. As a second-generation fumarate ester, dimethyl fumarate appears to exert its effects predominantly through activation of the nuclear factor[erythroid-derived 2]-like 2[Nrf2] antioxidant response pathway[19], which modulates the expression of biomolecules involved in the phase 2 detoxification pathway, and is an important cellular defense mechanism involved in the response to oxidative and xenobiotic stress, and immune homeostasis. The activation of the Nrf2 pathway has a clear role in maintaining immune homeostasis and also appears to have a role in promoting modulation of functional immune responses[20].
Adverse reactions
Some severe adverse reactions associated with iodomethane may include anaphylaxis and angioedema, progressive multifocal leukoencephalopathy, lymphopenia, liver injury and flushing[21]. Common side effects may include flushing/warmth, itching, redness, and burning feeling of the skin. Taking this drug with food may reduce flushing. Some other side effects may also include stomach/abdominal pain, heartburn, indigestion, diarrhea, nausea, and vomiting may also occur. These effects usually improve or go away as your body adjusts to the medication. If any of these effects persist or worsen, tell your doctor or pharmacist promptly[22, 23].
Warning and Risk
Patients who are allergic to dimethyl fumarate should be disabled.
To make sure dimethyl fumarate is safe for administration, the patients should tell your doctor if he/she have: an active infection; or low white blood cell[WBC] counts.
It is not known whether dimethyl fumarate will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using dimethyl fumarate.
If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of dimethyl fumarate on the baby. It is not known whether dimethyl fumarate passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby[23].
References
  1. https://www.drugbank.ca/drugs/DB08908
  2. Mrowietz, Ulrich; Altmeyer, Peter; Bieber, Thomas; et al.[2007]. "Treatment of psoriasis with fumaric acid esters[Fumaderm®]". JDDG. 5[8]: 716–7.
  3. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204063s020lbl.pdf
  4. https://chemicalwatch.com/1719/eu-agrees-to-ban-dimethyl-fumarate-dmf-in-consumer-products
  5. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372[9648]:1502–17. 
  6. Nylander A, Hafler DA. Multiple sclerosis. J Clin Invest. 2012;122(4]:1180–8. 
  7. Menge T, Weber MS, Hemmer B, et al. Disease-modifying agents for multiple sclerosis: recent advances and future pros- pects. Drugs. 2008;68(17]:2445–68. 
  8. World Health Organization. Atlas: multiple sclerosis resources in the world; 2008. http://www.who.int/mental_health/neurology/ Atlas_MS_WEB.pdf. Accessed 14 Feb 2014. 
  9. Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain. 1989;112(Pt 1]:133–46. 
  10. National Multiple Sclerosis Society. What is MS? 2015. http:// www.nationalmssociety.org. Accessed 3 Dec 2015.
  11. National Institute of Neurological Disorders and Stroke. Multiple sclerosis: hope through research. 2015. http://www.ninds.nih.gov/ disorders/multiple_sclerosis/detail_multiple_sclerosis.htm. Accessed 3 Dec 2015.
  12. Ortiz GG, Pacheco-Moises FP, Bitzer-Quintero OK, et al. Immunology and oxidative stress in multiple sclerosis: clinical and basic approach. Clin Dev Immunol. 2013;2013:708659.
  13. De Stefano N, Narayanan S, Matthews PM, et al. In vivo evidence for axonal dysfunction remote from focal cerebral demyelination of the type seen in multiple sclerosis. Brain 1999;122:1933-9
  14. Ferguson B, Matyszak MK, Esiri MM, et al. Axonal damage in acute multiple sclerosis lesions. Brain 1997;120:393-9
  15. Silber E, Sharief MK. Axonal degeneration in the pathogenesis of multiple sclerosis. J Neurol Sci 1999;170:11-18
  16. Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338:278-85
  17. Witherick J, Wilkins A, Scolding N, et al. Mechanisms of oxidative damage in multiple sclerosis and a cell therapy approach to treatment. Autoimmune Dis 2011;164608
  18. Linker RA, Lee DH, Ryan S, et al. Fumaric acid esters exert Neuroprotective effects in neuro-inflammation via activation of the Nrf2 antioxidant pathway. Brain 2011;134:678-92
  19. Scannevin RH, Chollate S, Jung MY, et al. Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the Nrf2 pathway. J Pharmacol Exp Ther 2012;341:274-84
  20. Nguyen T, Sherratt PJ, Pickett CB. Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol 2003;43:233-60
  21. https://www.rxlist.com/tecfidera-drug.htm#side_effects_interactions
  22. https://www.webmd.com/drugs/2/drug-163864/dimethyl-fumarate-oral/details
  23. https://www.drugs.com/sfx/dimethyl-fumarate-side-effects.html

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