624-49-7 Usage
Uses
Used in Pharmaceutical Industry:
Dimethyl fumarate is used as an immunomodulator for the treatment of relapsing forms of multiple sclerosis (MS). It increases anti-inflammatory cytokines, decreases proinflammatory cytokines, and activates the Nrf2 pathway to protect neuronal cells.
Used in Chemical Industry:
Dimethyl fumarate is used in cycloaddition reactions involving ylides, benzenes, and amino acids.
Used in Food Industry:
Dimethyl fumarate is added to food grains for preservation.
Used in Tobacco Industry:
Dimethyl fumarate is used in the tobacco industry for preservation.
Used in Leather Industry:
Dimethyl fumarate is used in the leather industry for preservation.
Used in Clothing Industry:
Dimethyl fumarate is used in the clothing industry for preservation.
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
https://www.drugbank.ca/drugs/DB08908
Mrowietz, Ulrich; Altmeyer, Peter; Bieber, Thomas; et al.[2007]. "Treatment of psoriasis with fumaric acid esters[Fumaderm?]". JDDG. 5[8]: 716–7.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204063s020lbl.pdf
https://chemicalwatch.com/1719/eu-agrees-to-ban-dimethyl-fumarate-dmf-in-consumer-products
Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372[9648]:1502–17.?
Nylander A, Hafler DA. Multiple sclerosis. J Clin Invest. 2012;122(4]:1180–8.?
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.?
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.?
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.?
National Multiple Sclerosis Society. What is MS? 2015. http:// www.nationalmssociety.org. Accessed 3 Dec 2015.
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.
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.
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
Ferguson B, Matyszak MK, Esiri MM, et al. Axonal damage in acute multiple sclerosis lesions. Brain 1997;120:393-9
Silber E, Sharief MK. Axonal degeneration in the pathogenesis of multiple sclerosis. J Neurol Sci 1999;170:11-18
Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338:278-85
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
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
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
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
https://www.rxlist.com/tecfidera-drug.htm#side_effects_interactions
https://www.webmd.com/drugs/2/drug-163864/dimethyl-fumarate-oral/details
https://www.drugs.com/sfx/dimethyl-fumarate-side-effects.html
Originator
Biogen Idec (United States)
Synthesis Reference(s)
Synthetic Communications, 21, p. 223, 1991 DOI: 10.1080/00397919108020815The Journal of Organic Chemistry, 55, p. 329, 1990 DOI: 10.1021/jo00288a056
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
Clinical Use
Treatment of relapsing-remitting multiple sclerosisTreatment of moderate to severe plaque psoriasis
Drug interactions
Potentially hazardous interactions with other drugsAminophylline and theophylline: enhanced effect of
aminophylline and theophylline.Anaesthetics: enhanced hypotensive effect. Anti-arrhythmics: increased risk of bradycardia, AV
block and myocardial depression with amiodarone;
increased risk of bradycardia and myocardial
depression with dronedarone.Antibacterials: metabolism increased by rifampicin;
metabolism possibly inhibited by clarithromycin,
erythromycin and telithromycin.Antidepressants: enhanced hypotensive effect with
MAOIs; concentration of imipramine and possibly
other trycyclics increasedAntiepileptics: effect probably reduced by
barbiturates, fosphenytoin, phenytoin, and
primidone; enhanced effect of carbamazepine;
increased levels of fosphenytoin and phenytoin.Antifungals: negative inotropic effect possibly
increased with itraconazole.Antihypertensives: enhanced hypotensive effect;
increased risk of first dose hypotensive effect of postsynaptic alpha-blockersAntipsychotics: concentration of lurasidone
increased.Antivirals: concentration increased by atazanavir and
ritonavir - reduce dose of diltiazem with atazanavir;
concentration reduced by efavirenz; use telaprevir
with caution.Avanafil: possibly increases avanafil concentration.Beta-blockers: risk of bradycardia and AV block if
co-prescribed with beta-blockers.Cardiac glycosides: increased digoxin concentration.Ciclosporin: increased ciclosporin concentrations.Cilostazol: increased cilostazol concentration -
avoid.Colchicine: possibly increased risk of colchicine
toxicity - suspend or reduce colchicine, avoid
concomitant use in renal or hepatic failure.Cytotoxics: concentration of bosutinib, ibrutinib and
olaparib possibly increased - avoid or reduce dose;
possibly increased risk of bradycardia with crizotinib.Fingolimod: increased risk of bradycardia.Ivabradine: concentration of ivabradine increased -
avoid.Lipid lowering drugs: concentration of lomitapide
possibly increased - avoid.Sirolimus: sirolimus concentration increased.
Metabolism
Diltiazem is almost completely absorbed from the
gastrointestinal tract after oral doses, but undergoes
extensive first-pass hepatic metabolism resulting in a
bioavailability of about 40%. It is extensively metabolised
in the liver, mainly by the cytochrome P450 isoenzyme
CYP3A4; one of the metabolites, desacetyldiltiazem,
has been reported to have 25-50% of the activity of the
parent compound.About 2-4% of a dose is excreted in urine as unchanged
diltiazem with the remainder excreted as metabolites in
bile and urine.
Check Digit Verification of cas no
The CAS Registry Mumber 624-49-7 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 6,2 and 4 respectively; the second part has 2 digits, 4 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 624-49:
(5*6)+(4*2)+(3*4)+(2*4)+(1*9)=67
67 % 10 = 7
So 624-49-7 is a valid CAS Registry Number.
624-49-7Relevant articles and documents
Dimethyl fumarate is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases
Andersen, Jacob Lauwring,Nielsen, Christine Juul F?lled,Gotfred-Rasmussen, Helle,Nissen, Poul,Gesser, Borbala,Rasmussen, Mads Kirchheiner,Iversen, Lars,Funder, Erik Daa,Gothelf, Kurt Vesterager,Toth, Rachel,Arthur, J. Simon C.
, (2018)
Dimethyl fumarate (DMF)?has been applied for decades in the treatment of psoriasis and now also multiple sclerosis. However, the mechanism of action has remained obscure and involves high dose over long time of this small, reactive compound implicating many potential targets. Based on a 1.9 ? resolution crystal structure of the C-terminal kinase domain of the mouse p90 Ribosomal S6 Kinase 2 (RSK2) inhibited by DMF?we describe a central binding site in RSKs and the closely related Mitogen and Stress-activated Kinases (MSKs). DMF reacts covalently as a Michael acceptor to a conserved cysteine residue in the αF-helix of RSK/MSKs. Binding of DMF prevents the activation loop of the kinase from engaging substrate, and stabilizes an auto-inhibitory αL-helix, thus pointing to an effective, allosteric mechanism of kinase inhibition. The biochemical and cell biological characteristics of DMF inhibition of RSK/MSKs are consistent with the clinical protocols of DMF treatment.
REACTIONS OF BENZYLCHLOROBIS(TRIPHENYLPHOSPHINE)PALLADIUM(II) WITH DIMETHYL ACETYLENEDICARBOXYLATE
Hiraki, Katsuma,Itoh, Toshihiro,Eguchi, Katsuya,Onishi, Masayoshi
, p. C16 - C20 (1983)
Benzylchlorobis(triphenylphosphine)palladium(II) reacted with dimethyl acetylenedicarboxylate to give Cl(PPh3)>2> (II) and PdCl(PPh3)> (III).Complexes II and III reacted with Tl(acac) to afford
Protic, imidazolium ionic liquids as media for (Z)- to (E)-alkene isomerization
Janus, Ewa,Lozynski, Marek,Pernak, Juliusz
, p. 210 - 211 (2006)
The quantitative isomerization of (Z)- to (E-alkene in protic, imidazolium ionic liquids is demonstrated. The isomerization parameters were determined. The mechanism on the addition of the protic imidazolium species to carbon-carbon double bond is presented. Copyright
Aminal-catalyzed isomerization of and addition to dimethyl maleate
Cook,Voges, Andrea B,Kammrath, Aster E
, p. 7349 - 7352 (2001)
The amine moiety of aminals adds to dimethyl maleate via azomethine ylid intermediates. The products of this reaction, in turn, cause dimethyl maleate to isomerize to dimethyl fumarate.
Unusual formation of tetrahydropyridazine-3,4,5,6-tetracarboxylic and pyrroletetracarboxylic esters upon decomposition of methyl diazoacetate in the presence of pyridine
Tomilov,Platonov,Averkiev,Shulishov,Nefedov
, p. 187 - 191 (2003)
Thermal, photolytic, and thermocatalytic decomposition of methyl diazoacetate (MDA) in the presence of Rh2(OAc)4 or Cu(acac)2 in refluxing pyridine afforded isomeric trans, cis- and cis, trans-3,4,5,6-tetra(methoxycarbonyl)-1,4,5,6-tetrahydropyridazines (～1 : 1) in a total yield of 30-70%. Decomposition of MDA in refluxing o-xylene in the presence of Rh2(OAc)4 and pyridine (20 mol.%) gave rise to 2,3,4,5-tetra(methoxycarbonyl)pyrrole in a yield of up to 40%. In these transformations of MDA, neither dimethyl fumarate (or dimethyl maleate) nor the corresponding 2-pyrazolines were generated as intermediates.
Generation and cycloaddition of polymer-supported azomethine ylide via a 1,2-silatropic shift of α-silylimines: Traceless synthesis of pyrrolidine derivatives
Komatsu, Mitsuo,Okada, Hirofumi,Akaki, Tatsuo,Oderaotoshi, Yoji,Minakata, Satoshi
, p. 3505 - 3508 (2002)
(matrix presented) The 1,3-bipolar cycloaddition of polymer-supported azomethine ylides to dipolarophiles gave pyrrolidine derivatives in good yields. The azomethine ylides were generated from resin-bound α-silylimines via a 1,2-silatropic shift. The features of this method are not only a traceless synthesis but also a uniaue solid-phase route to pyrrolidines with extensive diversity.
Zwitterion-Catalyzed Isomerization of Maleic to Fumaric Acid Diesters
Lam, Ying-Pong,Lam, Zachary,Yeung, Ying-Yeung
, p. 1183 - 1190 (2021/01/09)
Fumaric acid diesters are important building blocks for organic synthesis. A class of zwitterionic organocatalysts based on an amide anion/iminium cation charge pair were found to be effective in catalyzing the isomerization of maleic acid diesters to give fumaric acid diesters. Comparison of the performance of different zwitterionic organocatalysts toward the reaction revealed that nonclassical hydrogen bonding was involved in the stabilization of the Michael adduct intermediate.
A donor-acceptor complex enables the synthesis of: E -olefins from alcohols, amines and carboxylic acids
Chen, Kun-Quan,Shen, Jie,Wang, Zhi-Xiang,Chen, Xiang-Yu
, p. 6684 - 6690 (2021/05/31)
Olefins are prevalent substrates and functionalities. The synthesis of olefins from readily available starting materials such as alcohols, amines and carboxylic acids is of great significance to address the sustainability concerns in organic synthesis. Metallaphotoredox-catalyzed defunctionalizations were reported to achieve such transformations under mild conditions. However, all these valuable strategies require a transition metal catalyst, a ligand or an expensive photocatalyst, with the challenges of controlling the region- and stereoselectivities remaining. Herein, we present a fundamentally distinct strategy enabled by electron donor-acceptor (EDA) complexes, for the selective synthesis of olefins from these simple and easily available starting materials. The conversions took place via photoactivation of the EDA complexes of the activated substrates with alkali salts, followed by hydrogen atom elimination from in situ generated alkyl radicals. This method is operationally simple and straightforward and free of photocatalysts and transition-metals, and shows high regio- and stereoselectivities.
Small-Molecule Investigation of Diels-Alder Complexes for Thermoreversible Crosslinking in Polymeric Applications
Rowlett, Jarrett R.,Deglmann, Peter,Sprafke, Johannes,Roy, Nabarun,Mülhaupt, Rolf,Bruchmann, Bernd
, p. 8933 - 8944 (2021/07/20)
Combinations of dienes and dienophiles were examined in order to elicit possible combinations for thermoreversible crosslinking units. Comparison of experimental results and quantum calculations indicated that reaction kinetics and activation energy were much better prediction factors than change in enthalpy for the prediction of successful cycloaddition. Further testing on diene-dienophile pairs that underwent successful cycloaddition determined the feasibility of thermoreversibility/retro-reaction of each of the Diels-Alder compounds. Heating and testing of the compounds in the presence of a trapping agent allowed for experimental determination of reverse kinetics and activation energy for the retro-reaction. The experimental values were in good agreement with quantum calculations. The combination of chemical calculations with experimental results provided a strong insight into the structure-property relationships and how quantum calculations can be used to examine the feasibility of the thermoreversibility of new Diels-Alder complexes in potential polymer systems or to fine-tune thermoreversible Diels-Alder systems already in use.
Dimethyl Fumarate: Heterogeneous Catalysis for the Development of an Innovative Flow Synthesis
Dedè, Fabiana,Piccolo, Oreste,Vigo, Daniele
, p. 292 - 299 (2021/02/20)
The present work describes the development of an improved synthesis of the active pharmaceutical ingredient (API) dimethyl fumarate. The use of continuous flow technology and the newly developed methylation conditions solve some of the issues of previous commercial production strategies, e.g., reaching complete conversion and avoiding the formation of toxic impurities. The optimization was carried out using the design of experiment approach and afforded a very efficient, sustainable process, suitable for the industrial application.
Xn:Harmful;
