Leflunomide

Bezeichnung:Leflunomide

CAS-Nr75706-12-6

Englisch Name:Leflunomide

CBNumberCB1367708

SummenformelC12H9F3N2O2

Molgewicht270.21

MOL-Datei75706-12-6.mol

Leflunomide physikalisch-chemischer Eigenschaften

Schmelzpunkt	166.5 °C
Siedepunkt	289.3±40.0 °C(Predicted)
Dichte	1.392±0.06 g/cm3(Predicted)
storage temp.	2-8°C
Löslichkeit	Practically insoluble in water, freely soluble in methanol, sparingly soluble in methylene chloride.
Aggregatzustand	Solid
pka	10.8(at 25℃)
Farbe	White
Merck	14,5432
Stabilität	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 Datenbank	75706-12-6(CAS DataBase Reference)

Sicherheit

Kennzeichnung gefährlicher	Xn,Xi
R-Sätze:	22-36/37/38
S-Sätze:	26-36
RIDADR	UN 2811 6.1/PG 3
WGK Germany	3
RTECS-Nr.	NY2354200
HazardClass	6.1
PackingGroup	III
HS Code	2934990002
Giftige Stoffe Daten	75706-12-6(Hazardous Substances Data)

Gefahreninformationscode (GHS)

Leflunomide Chemische Eigenschaften,Einsatz,Produktion Methoden

R-Sätze Betriebsanweisung:
R22:Gesundheitsschädlich beim Verschlucken.
R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.
S-Sätze Betriebsanweisung:
S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
S36:DE: Bei der Arbeit geeignete Schutzkleidung tragen.
Beschreibung
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.
Chemische Eigenschaften
Off White Crystalline Solid
Originator
Hoechst MarionRoussel (Germany)
Verwenden
vasodilator
Verwenden
By virtue of its immunosuppressant effects, leflunomide has found use in organ transplantation and treatment of rheumatoid arthritis and other autoimmune diseases.
Verwenden
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
Verwenden
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.
Trademarks
Arava (Sanofi Aventis).
Therapeutic Function
Immunosuppressive, Antiarthritic
Biologische Funktion
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.
Allgemeine Beschreibung
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.
Biologische Aktivität
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.
Pharmakokinetik
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.
Pharmakologie
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.
Nebenwirkungen
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.
Vorsichtsmaßnahmen
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.
Einzelnachweise
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

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