5-methyl-N-[4-(trifluoromethyl)phenyl]-1,2-oxazole-4-carboxamide

• ChemBase编号: 968
• 分子式: C12H9F3N2O2
• 平均质量: 270.2072696
• 单一同位素质量: 270.0616122
• SMILES: FC(F)(F)c1ccc(NC(=O)c2c(onc2)C)cc1
• Canonical SMILES: O=C(c1cnoc1C)Nc1ccc(cc1)C(F)(F)F
• InChI: 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

名称和登记号

名称

• IUPAC标准名: 5-methyl-N-[4-(trifluoromethyl)phenyl]-1,2-oxazole-4-carboxamide
• IUPAC传统名: leflunomide; 5-methyl-N-[4-(trifluoromethyl)phenyl]-1,2-oxazole-4-carboxamide
• 商标名: Arava
• 别名: Leflunomidum [INN-Latin]; Lefunomide [INN-Spanish]; leflunomide; Leflunomide; 5-Methylisoxazole-4-[4-trifluoromethylcarboxanilide]; Leflunomida; 5-Methyl-N-[4-(trifluoromethyl)phenyl]-4-isoxazolecarboxamide; Leflunomidum; 5-methyl-N-[4-(trifluoromethyl)phenyl]-1,2-oxazole-4-carboxamide; 5-Methylisoxazole-4-(4-trifluoromethyl)carboxanilide; Leflunomide; Arava

登记号

• CAS号: 75706-12-6
• MDL号: MFCD00867593
• PubChem SID: 24278516; 46506013; 160964431
• PubChem CID: 3899

理论计算性质

JChem

• Acid pKa: 10.412348
• 质子受体: 2
• 质子供体: 1
• LogD (pH = 5.5): 2.5070803
• LogD (pH = 7.4): 2.506685
• Log P: 2.5070858
• 摩尔折射率: 64.1569 cm^3
• 极化性: 21.993195 Å^3
• 极化表面积: 55.13 Å^2
• 可自由旋转的化学键: 3
• 里宾斯基五规则: true

ALOGPS 2.1

• Log P: 2.52
• LOG S: -3.51
• 溶解度: 8.44e-02 g/l

分子性质

理化性质

• 溶解度: 21 mg/L (poorly soluble); Dichloromethane; DMSO; Ether; Ethyl Acetate; Methanol
• 外观: Off White Solid
• 熔点: 153-156°C
• 疏水性(logP): 2.324; 2.8

安全信息

• 保存条件: -20°C; -20°C Freezer
• RTECS编号: NY2354200
• 欧盟危险性物质标志: 有害性(Harmful) (Xn)
• 联合国危险货物编号: 2811
• 德国WGK号: 3
• 联合国危险货物等级: 6.1
• 联合国危险货物包装类别(PG): 3
• 危险公开号: 22-36/37/38
• 安全公开号: 26
• GHS危险品标识: GHS06
• GHS警示词: Danger
• GHS危险声明: H301-H315-H319-H335
• GHS警示性声明: P261-P301 + P310-P305 + P351 + P338
• 个人保护装置: dust mask type N95 (US), Eyeshields, Faceshields, Gloves
• RID/ADR: UN 2811 6.1/PG 3
• 保存温度: 2-8°C

药理学性质

• 相关基因信息: human ... DHODH(1723)

产品相关信息

• 纯度: 95%
• 成盐信息: Free Base
• Empirical Formula (Hill Notation): C12H9F3N2O2

详细说明

DrugBank - DB01097

• Drug Groups: approved; investigational
• Description: Leflunomide is a pyrimidine synthesis inhibitor belonging to the DMARD (disease-modifying antirheumatic drug) class of drugs, which are chemically and pharmacologically very heterogeneous. Leflunomide was approved by FDA and in many other countries (e.g., Canada, Europe) in 1999.
• Indication: For the management of the signs and symptoms of active rheumatoid arthritis (RA) to improve physical function and to slow the progression of structural damage associated with the disease. Has also been used for the prevention of acute and chronic rejection in recipients of solid organ trasnplants and is designated by the FDA as an orphan drug for this use.
• Pharmacology: Leflunomide is a pyrimidine synthesis inhibitor indicated in adults for the treatment of active rheumatoid arthritis (RA). RA is an auto-immune disease characterized by high T-cell activity. T cells have two pathways to synthesize pyrimidines: the salvage pathways and the de novo synthesis. At rest, T lymphocytes meet their metabolic requirements by the salvage pathway. Activated lymphocytes need to expand their pyrimidine pool 7- to 8-fold, while the purine pool is expanded only 2- to 3-fold. To meet the need for more pyrimidines, activated T cells use the de novo pathway for pyrimidine synthesis. Therefore, activated T cells, which are dependent on de novo pyrimidine synthesis, will be more affected by leflunomide's inhibition of dihydroorotate dehydrogenase than other cell types that use the salvage pathway of pyrimidine synthesis.
• Toxicity: LD₅₀=100-250 mg/kg (acute oral toxicity)
• Affected Organisms: Humans and other mammals
• Biotransformation: Primarily hepatic. Leflunomide is converted to its active form following oral intake.
• Absorption: Well absorbed, peak plasma concentrations appear 6-12 hours after dosing
• Half Life: 2 weeks
• Protein Binding: >99.3%
• Elimination: The active metabolite is eliminated by further metabolism and subsequent renal excretion as well as by direct biliary excretion. In a 28 day study of drug elimination (n=3) using a single dose of radiolabeled compound, approximately 43% of the total radioactivity was eliminated in the urine and 48% was eliminated in the feces. It is not known whether leflunomide is excreted in human milk.; Many drugs are excreted in human milk, and there is a potential for serious adverse reactions in nursing infants from leflunomide.
• Distribution: * 0.13 L/kg
• References: Goldenberg MM: Leflunomide, a novel immunomodulator for the treatment of active rheumatoid arthritis. Clin Ther. 1999 Nov;21(11):1837-52; discussion 1821. [Pubmed] ; Li EK, Tam LS, Tomlinson B: Leflunomide in the treatment of rheumatoid arthritis. Clin Ther. 2004 Apr;26(4):447-59. [Pubmed] ; Sanders S, Harisdangkul V: Leflunomide for the treatment of rheumatoid arthritis and autoimmunity. Am J Med Sci. 2002 Apr;323(4):190-3. [Pubmed] ; Breedveld FC, Dayer JM: Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2000 Nov;59(11):841-9. \ [Pubmed] ; Reitzik M, Lownie JF: Familial polyostotic fibrous dysplasia. Oral Surg Oral Med Oral Pathol. 1975 Dec;40(6):769-74. [Pubmed] ; Herrmann ML, Schleyerbach R, Kirschbaum BJ: Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases. Immunopharmacology. 2000 May;47(2-3):273-89. [Pubmed] ; Schattenkirchner M: The use of leflunomide in the treatment of rheumatoid arthritis: an experimental and clinical review. Immunopharmacology. 2000 May;47(2-3):291-8. [Pubmed] ; Fox RI: Mechanism of action of leflunomide in rheumatoid arthritis. J Rheumatol Suppl. 1998 Jul;53:20-6. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

Selleck Chemicals - S1247

Research Area: Anaplastic astrocytoma
Biological Activity:
Leflunomide is a pyrimidine synthesis inhibitor belonging to the DMARD (disease-modifying antirheumatic drug) class of drugs. Leflunomide is used to relieve symptoms caused by rheumatoid arthritis, such as inflammation, swelling, stiffness, and joint pain. This medicine works by stopping the body from producing too many of the immune cells that are responsible for the swelling and inflammation. [1]

Sigma Aldrich - L5025

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.
Application
By virtue of its immunosuppressant effects, leflunomide has found use in organ transplantation1 and treatment of rheumatoid arthritis2 and other autoimmune diseases.

Toronto Research Chemicals - L322750

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

参考文献

• Goldenberg MM: Leflunomide, a novel immunomodulator for the treatment of active rheumatoid arthritis. Clin Ther. 1999 Nov;21(11):1837-52; discussion 1821. Pubmed
• Li EK, Tam LS, Tomlinson B: Leflunomide in the treatment of rheumatoid arthritis. Clin Ther. 2004 Apr;26(4):447-59. Pubmed
• Sanders S, Harisdangkul V: Leflunomide for the treatment of rheumatoid arthritis and autoimmunity. Am J Med Sci. 2002 Apr;323(4):190-3. Pubmed
• Breedveld FC, Dayer JM: Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2000 Nov;59(11):841-9. Pubmed\
• Reitzik M, Lownie JF: Familial polyostotic fibrous dysplasia. Oral Surg Oral Med Oral Pathol. 1975 Dec;40(6):769-74. Pubmed
• Herrmann ML, Schleyerbach R, Kirschbaum BJ: Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases. Immunopharmacology. 2000 May;47(2-3):273-89. Pubmed
• Schattenkirchner M: The use of leflunomide in the treatment of rheumatoid arthritis: an experimental and clinical review. Immunopharmacology. 2000 May;47(2-3):291-8. Pubmed
• Fox RI: Mechanism of action of leflunomide in rheumatoid arthritis. J Rheumatol Suppl. 1998 Jul;53:20-6. Pubmed
• www.mayoclinic.com/health/drug-information/DR60155
• Vrenken, T., et al.: J. Hepatol., 49, 799 (2008)
• Mazzucco, G., et al.: Clin. Nephrol., 70, 163 (2008)
• Davies, M., et al.: J. Med. Chem., 52, 2683 (2008)