レフルノミド

N-[4-(トリフルオロメチル)フェニル]-5-メチルイソオキサゾール-4-カルボアミド · 5-メチル-N-[4-(トリフルオロメチル)フェニル]-4-イソオキサゾールカルボアミド · イソオキサゾールレフノミド · レフルノミド · アラバ · N-(4-トリフルオロメチルフェニル)-5-メチルイソオキサゾール-4-カルボアミド · 5-メチル-N-[4-(トリフルオロメチル)フェニル]イソオキサゾール-4-カルボキサミド · レフルノミド (JAN)

https://huagongshe.com/ja/chemical/3899

識別子と物理属性

CAS No.	75706-12-6
分子式	C12H9F3N2O2
平均分子量	270.21 g/mol
単同位体質量	270.06161219 g/mol
SMILES	Cc1oncc1C(=O)Nc1ccc(C(F)(F)F)cc1
InChIKey	VHOGYURTWQBHIL-UHFFFAOYSA-N
PubChem CID	3899
ChEMBL	CHEMBL960
ChEBI	CHEBI:6402
EC No.	616-254-6
DTXSID	DTXSID9023201
現地名	レフルノミド

化学・物理的性質

XLogP	2.5
極性表面積	55.1
水素結合供与体数	1
水素結合受容体数	6
回転可能結合数	2
重原子数	19
形式電荷	0
複雑度	327
医薬品	Pharmaceuticals -> Antineoplastic and immunomodulating agents -> ImmunosuppressantsPharmaceuticals -> Listed in ZINC15
LogP（分配係数）	log Kow = 2.43 /Estimated/2.83.9
Color/Form	Crystals from toluene
溶解度	In water, 153 mg/L at 25 °C /Estimated/8.44e-02 g/L水にほとんど溶けず、メタノールに溶けやすく、塩化メチレンにやや溶けにくい。
Human Drugs	Breast FeedingLactationMilk, HumanAntirheumatic AgentsImmunosuppressive AgentsFDA approved drugs -> Active ingredientEMA approved medicines: Human medicine
融点	165-166 °C166.5 °C165 - 166 °C
蒸気圧	1.25X10-6 mm Hg at 25 °C /Estimated/
ヘンリー定数	Henry's Law constant = 1.23X10-10 atm-cu m/mol at 25 °C /Estimated/
Physical Description	Solid
Other Experimental Properties	Hydroxyl radical reaction rate constant = 7.33X10-12 cu cm/molc-sec at 25 °C /Estimated/
沸点	289.3±40.0 °C(Predicted)
密度	1.392±0.06 g/cm3(Predicted)
貯蔵条件	2-8°C
pKa（酸解離定数）	10.8(at 25℃)
外観・状態	Solid
色	白い
Merck	14,5432
ヘンリー定数	8.0×104 mol/(m3Pa) at 25℃, HSDB (2015)
安定性	購入日から2年間安定です。この DMSO またはエタノール溶液は、-20°C で 1 か月間保存できます。
主な用途	医薬品医薬品低分子化合物
InChI	1S/C12H9F3N2O2/c1-7-10(6-16-19-7)11(18)17-9-4-2-8(3-5-9)12(13,14)15/h2-6H,1H3,(H,17,18)
InChIKey	VHOGYURTWQBHIL-UHFFFAOYSA-N
SMILES	Cc1oncc1C(=O)Nc2ccc(cc2)C(F)(F)F
CAS データベース	75706-12-6(CAS DataBase Reference)

化学的特性

Off White Crystalline Solid

安全性と法規制

GHS 分類	DangerH301 (99.3%): Toxic if swallowed [Danger Acute toxicity, oral]P261, P264, P264+P265, P270, P271, P280, P301+P316, P302+P352, P304+P340, P305+P351+P338, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 134 reports by companies from 11 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.
FDA 要件	The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl leflunomide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
Hazard Classes and Categories	Acute Tox. 3 (99.3%)
保管条件	Commercially available leflunomide tablets should be stored at a controlled room temperature of 25 °C, but may be exposed to temperatures ranging from 15-30 °C. The tablets should be protected from light.
処分方法	SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air qualitypotential migration in soil or watereffects on animal, aquatic, and plant lifeand conformance with environmental and public health regulations.
相互作用	Concurrent use with rifampin may increase the plasma concentration of leflunomidecaution is recommended.Concurrent use with these medications /hepatotoxic medications or methotrexate/ may increase the risk of side effects and medication-induced hepatic toxicityin a small study evaluating the concurrent use of leflunomide (100 mg/day followed by 10 to 20 mg/day) and methotrexate (10 to 25 mg/week with folate), an increased risk of hepatotoxicity was reporteddosage adjustment may be needed.In vivo drug interaction studies have demonstrated a lack of a significant drug interaction between leflunomide and tri-phasic oral contraceptives, and cimetidine.M1 was shown to cause increases ranging from 13-50% in the free fraction of diclofenac, ibuprofen and tolbutamide at concentrations in the clinical range. In vitro studies of drug metabolism indicate that M1 inhibits CYP 450 2C9, which is responsible for the metabolism of many NSAIDs. M1 has been shown to inhibit the formation of 4'-hydroxydiclofenac from diclofenac in vitro.

用途

説明

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.

使用

By virtue of its immunosuppressant effects, leflunomide has found use in organ transplantation and treatment of rheumatoid arthritis and other autoimmune diseases.

一般的な説明

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.