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ChemicalBook--->CAS DataBase List--->75706-12-6

75706-12-6

75706-12-6 Structure

75706-12-6 Structure
IdentificationMore
[Name]

Leflunomide
[CAS]

75706-12-6
[Synonyms]

5-METHYLISOXAZOLE-4-(4-TRIFLUOROMETHYLCARBOXANILIDE)
5-METHYL-N-[4-(TRIFLUOROMETHYL)PHENYL]-4-ISOXAZOLECARBOXAMIDE
ALPHA,ALPHA,ALPHA-TRIFLUORO-5-METHYL-4-ISOXAZOLECARBOXY-P-TOLUIDIDE
HWA 486
LEFLUNOMIDE
N-(4-TRIFLUOROMETHYLPHENYL)-5-METHYLISOXAZOL-4-CARBOXAMIDE
5-methylisoxazole-4-carboxylicacid(4-trifluoromethyl)anilide
5-methyl-n-(4-(trifluoromethyl)phenyl)-4-isoxazolecarboxamid
LeflunamideAnti-Rheumatic
Leflunamide
α,α,α-Trifluoro-5-methyl-4-isoxazolecarboxy-p-toluidide
4-Isoxazolecarboxamide, 5-methyl-N-[4-(trifluoromethyl)phenyl]-
LEFLUNOMIDE(SUBJECTTOPATENTFREE)
LEFLUNOMIDE/5-METHYL-N-[4-(TRIFLUOROMETHYL)PHENYL]-4-ISOXAZOLE CARBOXAMIDE
5-METHYL-N-(4-(TRIFLUOROMETHYL)PHENYL)ISOXAZOLE-4-CARBOXAMIDE
5-Methylisoxazole-4-[4-trifluoromethylcarboxanilide]q
Arava
Isoxazol lefunomide
RS-34821
[EINECS(EC#)]

616-254-6
[Molecular Formula]

C12H9F3N2O2
[MDL Number]

MFCD00867593
[Molecular Weight]

270.21
[MOL File]

75706-12-6.mol
Chemical PropertiesBack Directory
[Appearance]

Off White Crystalline Solid
[Melting point ]

166.5 °C
[Boiling point ]

289.3±40.0 °C(Predicted)
[density ]

1.392±0.06 g/cm3(Predicted)
[storage temp. ]

2-8°C
[solubility ]

Practically insoluble in water, freely soluble in methanol, sparingly soluble in methylene chloride.
[form ]

neat
[pka]

10.8(at 25℃)
[color ]

White
[Usage]

An immunosuppressive. Inhibits T and B cell proliferation. Activity is attributed mainly to its metabolite, a malononitrile derivative, which is beleived to inhibit dihydroorotate dehydrogenase as well as several protein tyrosine kinases. Therape
[Merck ]

14,5432
[Stability:]

Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20° for up to 1 month.
[InChIKey]

VHOGYURTWQBHIL-UHFFFAOYSA-N
[CAS DataBase Reference]

75706-12-6(CAS DataBase Reference)
Safety DataBack Directory
[Hazard Codes ]

Xn,Xi
[Risk Statements ]

R22:Harmful if swallowed.
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:Wear suitable protective clothing .
[RIDADR ]

UN 2811 6.1/PG 3
[WGK Germany ]

3
[RTECS ]

NY2354200
[HazardClass ]

6.1
[PackingGroup ]

III
[HS Code ]

2934990002
[Hazardous Substances Data]

75706-12-6(Hazardous Substances Data)
Raw materials And Preparation ProductsBack Directory
[Raw materials]

Acetic acid-->Thionyl chloride-->Sodium chloride-->Hydroxylamine hydrochloride-->Sodium acetate-->Glycine-->4-Aminobenzotrifluoride-->Sodium hydroxide-->Triethyl orthoformate-->Acetic anhydride-->Acetyl ketene
Material Safety Data Sheet(MSDS)Back Directory
[msds information]

Leflunomide(75706-12-6).msds
Hazard InformationBack Directory
[Description]

Leflunomide is an orally-available disease-modifying antirheumatic drug and was launched as Arava in the US for the treatment of rheumatoid arthritis (RA) ; it is the first and only drug to be indicated to slow down structural joint damage of RA, so addressing an unmet medical need.
Leflunomide is prepared in 3 steps from the appropriate acetoacetic anilide using a nitrile oxide- enamine cycloaddition reaction to assemble the isoxazole ring. Leflunomide is a prodrug, being extensively metabolized in vivo into the corresponding 2-cyano-3-hydroxy-2-butenamide resulting from fragmentation of the isoxazole ring. This cyanoenol is actually the active metabolite and several experiments in animals have demonstrated that after oral administration, substantial and sustained levels of this metabolite were delivered to the systemic circulation.
In vitro, Leflunomide’s active metabolite inhibits dihydroorotate dehydrogenase, an enzyme involved in the biosynthesis of pyrimidine nucleotides, probably accounting for its immunosuppressive effect in vivo. Other mechanisms of action such as inhibition of tyrosine kinase and inhibition of responsiveness to interleukin-2 have been proposed. In diverse models of autoimmune or allergic diseases, Leflunornide showed efficacy both prophylactically and therapeutically.
[Originator]

Hoechst MarionRoussel (Germany)
[Definition]

ChEBI: A monocarboxylic acid amide obtained by formal condensation of the carboxy group of 5-methyl-1,2-oxazole-4-carboxylic acid with the anilino group of 4-(trifluoromethyl)aniline. The prodrug of teriflunomide.
[Indications]

Leflunomide (Arava) is an isoxazole derivative approved for the treatment of rheumatoid arthritis in 1998. Limited data suggest that it is comparable in efficacy to sulfasalazine and produces fewer adverse effects. It has a faster onset of action (4 weeks) than other DMARDs.
[Manufacturing Process]

In US Patent No. 4,284,786 is described two methods of preparation of 5- methylisoxazole-4-carboxylic-(4-trifluoromethyl)-anilide.
The method 1
A mixture of 0.55 mole of diketene (46.3 g) and 30 ml of acetonitrile is added dropwise, at 75°C, to a solution of 0.5 mole of 4-trifluoromethylaniline (30.6 g) in 150 ml of acetonitrile. The mixture is heated to boiling under reflux for 2.5 hours. When it has cooled to room temperature, the crystals which are precipitated are filtered off, washed with cold ethanol and dried. This gives 79.1 g (64.5% of theory) of crystalline acetoacetic acid-4- trifluoromethylanilide, melting point (after recrystallization from ethanol) 155°C.
The acetonitrile phase is evaporated to dryness under reduced pressure. The crystalline residue (42.1 g) is recrystallized from 80 ml of ethanol. This gives a further 24.1 g (19.7% of theory) of crystals. Melting point (after recrystallization from ethanol) 155°C. Total yield: 84.2% of theory.
0.75 mole of acetoacetic acid 4-trifluoromethylanilide (183.9 g) is boiled under reflux for 1.5 hours with 0.83 mole of orthoformic acid triethyl ester (123 g) and 2.25 mole of acetic anhydride (229.7 g). After the mixture has cooled to room temperature, the crystals which have precipitated are filtered off and washed first with a small amount of acetic anhydride and then with petroleum ether. This gives 116.1 g (51.4% of theory) of crystalline 2- ethoxymethyleneacetoacetic acid 4-trifluoromethylanilide, melting point (after recrystallization from toluene) 124-125°C.
The combined filtrates are concentrated under reduced pressure. The crystals of the crystal paste which thereupon remains are filtered off, washed first with a small amount of acetic anhydride and then with petroleum ether and dried. A further 56.1 g (24.8% of theory) of crystals are thus obtained. Melting point (after recrystallization from toluene) 124-125°C. Total yield: 76.2% of theory.
A solution 0.1 mole of 2-ethoxymethyleneacetoacetic acid 4- trifluoromethylanilide (30.1 g) in 60 ml of ethanol is added dropwise at 5- 10°C to the mixture of 0.11 mole of hydroxylamine hydrochloride (7.65 g) in 50 ml of water and 0.11 mole of sodium hydroxide (4.4 g) in 10 ml of water. The mixture is heated under reflux for 15 min. The crystals which are precipitated after cooling are filtered off, washed with water and dried. 19.6 g (72.6% of theory) of crystalline 5-methylisoxazole-4-carboxylic acid 4- trifluoromethyl-anilide are thus obtained, melting point (after recrystallization from toluene) 166.5°C.A solution 0.1 mole of 2-ethoxymethyleneacetoacetic acid 4- trifluoromethylanilide (30.1 g) in 60 ml of ethanol is added dropwise at 5- 10°C to the mixture of 0.11 mole of hydroxylamine hydrochloride (7.65 g) in 50 ml of water and 0.11 mole of sodium hydroxide (4.4 g) in 10 ml of water. The mixture is heated under reflux for 15 min. The crystals which are precipitated after cooling are filtered off, washed with water and dried. 19.6 g (72.6% of theory) of crystalline 5-methylisoxazole-4-carboxylic acid 4- trifluoromethyl-anilide are thus obtained, melting point (after recrystallization from toluene) 166.5°C.
The method 2
0.1 mole of 5-methylisoxazole-4-carboxylic acid chloride (14.6 g) and 20 ml of a 5 N potassium hydroxide solution are added dropwise to 0.1 mole of trifluoromethylaniline (16.1 g), suspended in 150 ml of water, in such a way that the pH of the reaction mixture does not rise above 5. The mixture is subsequently shaken with 150 ml of methylene chloride. The methylene chloride phase is washed with water and, after drying with sodium sulfate is, evaporated to dryness under reduced pressure. This gives 24.4 g (90.2% of theory) of a crystalline 5-methylisoxazole-4-carboxylic acid 4-trifluoromethylanilide, melting point (after recrystallization from toluene) 166.5°C.
[Brand name]

Arava (Sanofi Aventis).
[Therapeutic Function]

Immunosuppressive, Antiarthritic
[Biological Functions]

Leflunomide is inactive, but teriflunomide inhibits pyrimidine de novo synthesis at low therapeutic doses by inhibiting dihydroorotate dehydrogenase (the rate-determining enzyme for the synthesis of UMP), decreasing DNA and RNA synthesis, and arresting the cell proliferation cycle and production of antibodies. The reduction of dihydroorotate to orotate occurs concurrently with the reduction of its cofactor, ubiquinone (coenzyme Q). The inhibition of dihydroorotate dehydrogenase by teriflunomide demonstrates noncompetitive and uncompetitive kinetics. Administration of leflunomide in patients with rheumatoid arthritis results in progressive removal of B cells and down-regulation of the immune process. Teriflunomide not only inhibits B-cell proliferation but also T-cell proliferation, blocking the synthesis of immunosuppressive cytokines. At high therapeutic doses, leflunomide inhibits protein tyrosine kinases.
[General Description]

Leflunomide (Arava), an isoxazole prodrug, is an orally activeDMARD marketed in 1998 for the treatment of RA. Itis well absorbed and extensively metabolized in vivo to itsactive metabolite, 2-cyano-3-hydroxy-2-buteneamide (teriflunomide),resulting from a reductive ring opening of theisoxazole ring. Unlike MTX, teriflunomideblocks T-cell proliferation by inhibiting dihydroorotate dehydrogenase,the rate-limiting enzyme in the de novobiosynthesis of pyrimidine that is believed to be responsiblefor the immunosuppressive properties of leflunomide.For this reason, it is not surprising that leflunomide has avery comparable therapeutic efficacy to the first-lineDMARD, MTX as shown in several extended open clinicaltrials. However, even though leflunomide is well toleratedlike MTX, several cases of toxic neuropathy have beenobserved during its use, thus careful monitoring of the patient’sneurological status during treatment is mandatory.Like MTX, leflunomide is contraindicated in pregnancy orin women considering pregnancy.
[Biological Activity]

Immunosuppressant agent. In vitro the active metabolite A77 1726 (RS-61980) inhibits dihydroorotate dehydrogenase (K i = 2.7 μ M) and de novo pyrimidine synthesis in T-cells; blocks lymphocyte cell cycle progression and proliferation. A77 1726 also inhibits anti-CD3/CD28-induced cytokine production in PBMC cells (IC 50 = 21-27 μ g/ml). In vivo reduces inflammation in several animal models of autoimmune disease, arthritis, asthma and graft rejection.
[Biochem/physiol Actions]

Immunosuppressive; inhibits T and B cell proliferation. Activity is attributed mainly to its metabolite, a malononitrile derivative, which is believed to inhibit dihydroorotate dehydrogenase (in the de novo pyrimidine synthesis pathway) as well as several protein tyrosine kinases.
[Pharmacokinetics]

Leflunomide is a pro-drug that is rapidly and almost completely metabolized (half-life, <60 minutes) following oral administration to teriflunomide, the pharmacologically active α-cyanoenol metabolite. The C3-H of the isoxazole ring is essential for the ring opening to its active metabolite. The reaction is similar to CYP1A2-catalyzed dehydration of aldoximes. The exact mechanism of action of leflunomide in the management of rheumatoid arthritis has not been fully elucidated but appears to principally involve inhibition of B-lymphocyte (B-cell) proliferation, reducing antibody formation. Activated lymphocytes must proliferate and synthesize large quantities of cytokines, requiring increased de novo synthesis of uridine monophosphate (UMP) and other pyrimidine nucleotides for its cell life cycle. Therefore, any substance that reduces the intracellular concentration of pyrimidine nucleotides will affect the growth of these activated cells.
[Pharmacology]

Leflunomide is a prodrug that is converted to an active malonitrilamide metabolite, A77 1726 (M1). M1 inhibits T-cell proliferation by blocking de novo pyrimidine synthesis and inhibiting the tyrosine kinases that are associated with certain cytokine and growth factor receptors.
[Clinical Use]

Leflunomide is a DMARD with anti-inflammatory and immunosuppressive activity used for the management of rheumatoid arthritis. It retards structural damage associated with arthritis in adults who have moderate to severe active rheumatoid arthritis. Leflunomide also is being investigated for use in patients with solid tumors and organ transplant recipients.
[Side effects]

Diarrhea occurs in approximately one-third of patients taking this drug; indigestion, nausea, and vomiting occur in about 10%. Other common adverse effects include weight changes, headache, skin rashes, pruritus, and reversible alopecia and hepatic enzyme elevation.Although leflunomide acts as an immunosuppressive, it does not appear to cause significant bone marrow depression.
[Veterinary Drugs and Treatments]

Leflunomide is an immunomodulating drug that may be useful in dogs for treating a variety of immune-related conditions such as IMHA, systemic and cutaneous reactive histiocytosis, granulomatous meningoencephalitis, etc; it can be used as part of transplant rejection protocols in dogs.
Leflunomide has been used with methotrexate to treat rheumatoid arthritis in cats.
[Drug interactions]

Potentially hazardous interactions with other drugs Hepatotoxic or haemotoxic drugs: increased risk of toxicity. Cytotoxics: risk of toxicity with methotrexate. Lipid-lowering agents: effect significantly reduced by colestyramine - avoid. Live vaccines: avoid concomitant use.
[Metabolism]

After oral doses leflunomide undergoes rapid first-pass metabolism in the liver and gut wall to teriflunomide (A-771726), which is responsible for the majority of the in vivo activity. Teriflunomide is mostly eliminated as unchanged drug in the bile and as metabolites in the urine. It is thought to undergo enterohepatic recycling and has an elimination half-life of about 18-19 days after repeated oral doses.
[storage]

Store at -20°C
[References]

1) Teschner et al. (2010), Leflunomide: a drug with a potential beyond rheumatology; Immunotherapy, 2 637 2) Davis et al. (1996), The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase; Biochemistry, 35 1270 3) Latchoumycandane et al. (2007), Mitochondrial protection by the JNK inhibitor leflunomide rescues mice from acetaminophen-induced liver injury; Hepatology, 45 412
Questions And AnswerBack Directory
[Immunosuppressants]

Leflunomide is a kind of isoxazole immunosuppressive drugs with anti-proliferative activity , modern pharmacology classifies  this product  as antipyretic, analgesic and anti-inflammatory drugs . This product can be rapidly converted to the active metabolites  and play a role by the liver and intestinal cytoplasm and microsomes , its; main mechanism is  during DNA synthesis, inhibiting a key enzyme-DHODH (DHODH) activity, so that the nucleotides within the B lymphocyte  are depleted , it terminates the biosynthesis of DNA and RNA, the cells can not enter s phase, and ultimately can not proliferate, resulting in anti-rheumatic effects, it is suitable for the treatment of adults with active rheumatoid arthritis, ankylosing spondylitis, it can slow bone destruction, alleviate the symptoms and signs. In addition, leflunomide can also inhibit the tyrosine kinase activity, thereby inhibiting proliferation of T cell, B cell  and non-immune cells, but it can also, by biosynthesis inhibition of cyclooxygenase-2 (COX2) , inhibit prostaglandin synthesis and exert anti-inflammatory effects and inhibit mast cells and basophils histamine release. When  this product is used in organ transplant patients,the  dose adjustment is difficult, it is mainly used to treat rheumatoid arthritis and other autoimmune diseases.
After oral administration of the product, it is rapidly transformed to the active metabolite  in the intestinal wall and liver  , F is 80%,it  does not affect the  absorption of the meal. Tmax is 6~12 h, if the first dose is administered as a loading dose of 100mg, it can reach steady-state plasma concentrations in 3 days, otherwise it needs numbers of months to reach steady-state plasma concentrations. Active metabolite PPB is 99.3%, which is mainly  distributed in the liver, kidney and skin, less in brain tissue. After further metabolization of the active metabolite,  43% of the marker is excreted in the urine of, 48% is excreted by the fecal , T1/2 is about 2 weeks, enterohepatic circulation leads to a longer half-life of the active metabolite  which is the main factor. High-fat diet does not have a big effect on the plasma concentrations of drugs. Activated charcoal or cholestyramine inhibits absorption of the drug.
  • The main side effects of leflunomide include  anorexia, vomiting, abdominal pain, diarrhea, gastritis and gastroenteritis, skin rashes, hair loss and reversible transaminase elevation.
  • The drug may cause liver toxicity and is contraindicated in patients with preexisting liver disease. The ALT should be monitored monthly initially and periodically thereafter. Leflunomide may cause bone marrow toxicity; a complete blood cell count with platelets is recommended monthly for 6 months and then every 6 to 8 weeks thereafter. It is teratogenic and should be avoided during pregnancy.
[Chemical Properties]

White crystalline powder, melting at 166.5 ℃.
[Uses]

(1) It is hydrogenated acid dehydrogenase inhibitor with immunosuppressive and anti-inflammatory effects for the treatment of adults with active rheumatoid arthritis.
(2) Nonsteroidal anti-inflammatory drug.
[Production method]

Ethyl acetoacetate, triethyl orthoformate and acetic anhydride are refluxed together to the complete reaction of raw materials, about 5h. Distillate and collect  140 150 ℃/1.87kPa fraction, the compound ( I) is obtained, in 85% yield.
Compound (I) is dissolved in ethanol,the mixture of hydroxylamine hydrochloride, sodium acetate and water is added dropwise at 10-15 ℃ and 1h, After dropping,react for about 8h.Concentrated hydrochloric acid and glacial acetic acid are added ,then reflux  for 5h. Concentrate under reduced pressure to 1/2 volume, cool to 10 ℃, filtration, recrystallize ethanol-water  ,compound (Ⅱ) is obtained, it is white crystalline powder, melting point 145-146.5 ℃, in 80% yield.
Compound (II) is dissolved in toluene and thionyl chloride is added dropwise at 50-55℃, reflux for 3h. After concentration, distillation, collect  78-79 ℃/1.87kPa fraction, the compound (III) is obtained, in 75% yield.
Trifluoromethyl aniline and triethylamine are dissolved  in dichloromethane, at 0-5 ℃ solution ,the compound (Ⅲ) is added. Then at 25--30 ℃ reaction lasts 3h. Water is added, the organic layer is separated, wash with water, wash with brine, and dry. Concentrate under reduced pressure to 1/3 volume, petroleum ether is added, cool, filter, and recrystallize from ethyl acetate to give white crystals powder of leflunomide , m.p. 166~167 ℃, in yield 81%.
[Precautions]

1, people who are leflunomide and its metabolites allergy, pregnant women or women who may become pregnant and lactating women are disabled.
2, patients with severe liver damage and hepatitis B or hepatitis C serology markers positive should use with caution. ALT and white cells should be checked regularly during medication.
3, patients with immune deficiency, uncontrolled infection, active gastrointestinal disease, renal insufficiency, bone marrow dysplasia should use with caution.
4. For males who prepare fertility, treatment interruption should be considered, at the same time   cholestyramine should be taken .
5, during treatment of this product, the effect and safety of the immunization live vaccine have  no clinical data, the immunization vaccine should not be used during medication.
6, for children using the product,the safety and efficacy have not been studied, so patients younger than 18 years of age are not recommended to the FDA.
7, if the overdose or toxicity occurs, cholestyramine or activated charcoal  can be administered orally to promote excretion of leflunomide.
8, the active metabolite of the product can cause diclofenac, ibuprofen, tolbutamide plasma concentration increasing from 13% to 50%, while the combination of rifampicin can increase blood concentrations of the active metabolite increasing by about 40% . In addition, the product may increase the liver toxicity of methotrexate.
Spectrum DetailBack Directory
[Spectrum Detail]

Leflunomide(75706-12-6)MS
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