108605-62-5 Usage
Description
A77 1726, also known as Teriflunomide, is an immunosuppressant drug marketed by Sanofi for the treatment of multiple sclerosis (MS) and rheumatoid arthritis. It is the active metabolite of Leflunomide and acts as an inhibitor of the mitochondrial enzyme dihydroorotate dehydrogenase, inhibiting pyrimidine formation and resulting in reduced B and T cell proliferation. A77 1726 is a white solid.
Uses
Used in Pharmaceutical Industry:
A77 1726 is used as a disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis.
A77 1726 is used as an immunosuppressant for the treatment of multiple sclerosis (MS), reducing the frequency of relapses and slowing the progression of the disease.
A77 1726 is used as an inhibitor of the mitochondrial enzyme dihydroorotate dehydrogenase, leading to reduced B and T cell proliferation, which helps in managing the immune response in both rheumatoid arthritis and multiple sclerosis.
Clinical Use
Immunomodulating agent:
Treatment of relapsing remitting multiple sclerosis
Synthesis
Numerous syntheses of teriflunomide have been developed to date, most relying on the use of 4-
trifluoromethyl aniline (167). The current optimized method for scale-up synthesis of teriflunomide,
developed by Keshav and coworkers, begins with reaction of commercial 4-trifluoromethyl aniline 167
and ethylacetoacetate (168) in refluxing xylenes, providing acetoamidate 169 in 51% yield . The resulting acetoamidate 169 was then treated with H2O2, KBr, and concentrated HCl at room
temperature, providing bromide 170 in 67% yield. Bromide 170 was reacted with NaCN in DMSO,
generating teriflunomide (XXVI) in 85% yield.
Drug interactions
Potentially hazardous interactions with other drugs
Lipid-lowering agents: effect significantly reduced by
colestyramine - avoid; concentration of rosuvastatin
increased - consider reducing rosuvastatin dose.
Live vaccines: risk of generalised infections - avoid.
Metabolism
Teriflunomide is the active metabolite of leflunomide.
It is moderately metabolised and teriflunomide is
the only component detected in plasma. The main
biotransformation pathway is hydrolysis with oxidation
being a minor pathway. Secondary pathways involve
oxidation, N-acetylation and sulfate conjugation.
Teriflunomide is excreted in the gastrointestinal tract
mainly through the bile as unchanged drug and most
likely by direct secretion.
References
1) Manna et al. (1999), Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression; J. Immunol., 162 2095
2) Davis et al. (1996), immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase; Biochemistry, 35 1270
3) Seah et al. (2008), Oxidative bioactivation and toxicity of leflunomide in immortalized human hepatocytes and kinetics of the non-enzymatic conversion to its major metabolite, A77 1726; Drug Metab. Lett., 2 153
Check Digit Verification of cas no
The CAS Registry Mumber 108605-62-5 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,0,8,6,0 and 5 respectively; the second part has 2 digits, 6 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 108605-62:
(8*1)+(7*0)+(6*8)+(5*6)+(4*0)+(3*5)+(2*6)+(1*2)=115
115 % 10 = 5
So 108605-62-5 is a valid CAS Registry Number.
InChI:InChI=1/C12H9F3N2O2/c1-7(18)10(6-16)11(19)17-9-4-2-8(3-5-9)12(13,14)15/h2-5,17,19H,1H3/b11-10-
108605-62-5Relevant articles and documents
Leflunomide analogues as potential antiinflammatory agents.
Huang, Wen-Hsin,Yang, Chiao-Li,Lee, An-Rong,Chiu, Hui-Fen
, p. 313 - 314 (2003)
A series of leflunomide (1a) analogues were examined for antiinflammatory activity using the carrageenan-induced paw edema assay. Some of the compounds were significantly more potent than leflunomide, particularly those with electron-donating or negative inductive groups situated in the phenyl rings. In contrast, all the nonsubstituted compounds or with further chain-extension in the 4-position of the rings led to a decrease in activity. The LD(50) values of the most active compounds (1d, g-j) in male ICR mice were significantly greater than those of either 1a or its active metabolite 2 and therefore merit further study.
In vitro monitoring of ring opening of leflunomide: A surface enhanced Raman scattering and DFT based approach
Sharma, Poornima,Gangopadhyay, Debraj,Singh, Pushkar,Mishra,Deckert, Volker,Popp, Jürgen,Singh, Ranjan K.
, p. 127 - 132 (2014)
The in vitro mechanism of ring opening of leflunomide resulting in the formation of a metabolite A771726 has been studied by time series surface enhanced Raman spectra using NaOH buffer at pH ~10. The decomposition of leflunomide into A771726 through NO bond cleavage was identified by the Raman signature of CN bond of A771726. The experimental results have been correlated with theory by transition state calculations of the reaction using different basic catalysts; OH-, formate and formate + water and water alone. The reaction barrier energy is found to be lowest with OH-as a catalyst.
Simple preparation method of teriflunomide
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Paragraph 0063; 0069-0071; 0072; 0076-0077; 0078; 0082; ..., (2021/07/08)
The invention provides a simple preparation method of teriflunomide, and belongs to the field of medicinal chemistry. The preparation method comprises the following steps of: (1) mixing 5-methylisoxazole-4-formic acid and a condensing agent in a solvent under an alkaline condition, and carrying out condensation reaction to obtain an active ester system; (2) mixing the active ester system and 4-trifluoromethylaniline in a solvent, and carrying out condensation reaction to obtain an intermediate leflunomide; and (3) carrying out alkali treatment and acid treatment on the obtained intermediate leflunomide to obtain teriflunomide. According to the method, the 5-methylisoxazole-4-formic acid reacts with the 4-trifluoromethylaniline in the form of active ester, so that the reaction activity of the 5-methylisoxazole-4-formic acid and the 4-trifluoromethylaniline is improved, the reaction condition is mild, the obtained intermediate leflunomide does not need to be purified, and the yield of teriflunomide is improved.
Preparation method of teriflunomide
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Paragraph 0051-0077, (2020/04/02)
The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of teriflunomide. The preparation method includes: (1) mixing cyanoacetic acid, a condensingagent, an aprotic solvent and an alkaline reagent, and c