Leflunomide
Immunosuppressants Chemical Properties Uses Production method Precautions- Product Name
- Leflunomide
- CAS No.
- 75706-12-6
- Chemical Name
- Leflunomide
- Synonyms
- Leflunamide;LeflunoMida;Arava;Leflunomide for peak identification CRS;5-METHYL-N-(4-(TRIFLUOROMETHYL)PHENYL)ISOXAZOLE-4-CARBOXAMIDE;efL;SU101;HWA 486;unomide;RS-34821
- CBNumber
- CB1367708
- Molecular Formula
- C12H9F3N2O2
- Formula Weight
- 270.21
- MOL File
- 75706-12-6.mol
Leflunomide Property
- 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.
- pka
- 10.8(at 25℃)
- color
- White
- 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
- Hazard Codes
- Xn,Xi
- Risk Statements
- 22-36/37/38
- Safety Statements
- 26-36
- 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)
Hazard and Precautionary Statements (GHS)
- Symbol(GHS)
-
- Signal word
- Danger
- Hazard statements
-
H301Toxic if swalloed
H315Causes skin irritation
H319Causes serious eye irritation
H335May cause respiratory irritation
- Precautionary statements
-
P261Avoid breathing dust/fume/gas/mist/vapours/spray.
P264Wash hands thoroughly after handling.
P264Wash skin thouroughly after handling.
P270Do not eat, drink or smoke when using this product.
P301+P310IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P302+P352IF ON SKIN: wash with plenty of soap and water.
P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.
N-Bromosuccinimide Price
- Product number
- L5025
- Product name
- Leflunomide
- Purity
- Immunosuppressant
- Packaging
- 25mg
- Price
- $66.6
- Updated
- 2024/03/01
- Product number
- 1356960
- Product name
- Leflunomide
- Purity
- United States Pharmacopeia (USP) Reference Standard
- Packaging
- 200mg
- Price
- $489
- Updated
- 2024/03/01
- Product number
- L0250
- Product name
- Leflunomide
- Purity
- >98.0%(HPLC)(N)
- Packaging
- 1g
- Price
- $130
- Updated
- 2024/03/01
- Product number
- L0250
- Product name
- Leflunomide
- Purity
- >98.0%(HPLC)(N)
- Packaging
- 200mg
- Price
- $43
- Updated
- 2024/03/01
- Product number
- J65917
- Product name
- Leflunomide
- Packaging
- 100mg
- Price
- $143.65
- Updated
- 2024/03/01
Leflunomide Chemical Properties,Usage,Production
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.
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.
Chemical Properties
Off White Crystalline Solid
Originator
Hoechst MarionRoussel (Germany)
Uses
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. Therapeutical
Uses
vasodilator
Uses
By virtue of its immunosuppressant effects, leflunomide has found use in organ transplantation and treatment of rheumatoid arthritis and other autoimmune diseases.
Uses
anti-Altzheimer therapeutic
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.
Precautions
Leflunomide is teratogenic in animal models; it is absolutelycontraindicated in pregnancy, in women whomay become pregnant, and in breast-feeding women.Because of its long half-life, the M1 metabolite ofleflunomide may remain in the body for up to 2 years;therefore, a drug elimination procedure using cholestyramineshould be used before any attempt at pregnancy.This drug is not recommended for use in children.Caution should be used when administering thisdrug to individuals with renal or hepatic disease, heavyalcohol use, or immunosuppression.
The long half-life of leflunomide must be taken intoaccount to prevent drug interactions. Hepatotoxicity ispossible if leflunomide is given in conjunction with a hepatotoxicagent such as methotrexate or certain NSAIDs.Leflunomide inhibits CYP2C9, the enzyme responsiblefor the metabolism of numerous drugs. Rifampin inducesthe P450 enzyme responsible for converting leflunomide to its M1 metabolite.Cholestyramine enhances the clearanceof leflunomide and its M1 metabolite.
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
Leflunomide Preparation Products And Raw materials
Raw materials
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View Lastest Price from Leflunomide manufacturers
- Product
- Leflunomide 75706-12-6
- Price
- US $35.00-1.20/kg
- Min. Order
- 1kg
- Purity
- 99%
- Supply Ability
- g-kg-tons, free sample is available
- Release date
- 2024-04-17
- Product
- Leflunomide 75706-12-6
- Price
- US $0.00/KG
- Min. Order
- 100g
- Purity
- 98%+
- Supply Ability
- 100kg
- Release date
- 2020-10-12
- Product
- Leflunomide 75706-12-6
- Price
- US $1.00-1.00/KG
- Min. Order
- 1g
- Purity
- 99%
- Supply Ability
- 50tons
- Release date
- 2020-04-29