RS-34821, SU-101, HWA-486, Arava,75706-12-6,
Aventis Pharma (Originator), Lepetit , Kyorin (Licensee), Sugen (Licensee)
Antiarthritic Drugs, Brain Cancer Therapy, Disease-Modifying Drugs, IMMUNOMODULATING AGENTS, Immunosuppressants, Oncolytic Drugs, Ovarian Cancer Therapy, Prostate Cancer Therapy, Psoriatic Arthritis, Treatment of , Rheumatoid Arthritis, Treatment of, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Treatment of Transplant Rejection, Dihydroorotate Dehydrogenase Inhibitors, Inhibitors of Signal Transduction Pathways, PDGFR Inhibitors
Inhibits dihydroorotate dehydrogenase, the fourth enzyme in the pyrimidine biosynthetic pathway; antagonizes growth-factor mediated smooth muscle cell proliferation in vitro.
- HSDB 7289
- HWA 486
- Leflunomida [INN-Spanish]
- Leflunomidum [INN-Latin]
- SU 101 (pharmaceutical)
Leflunomide (brand names: Arabloc, Arava, Lunava, Repso) is an immunosuppressive disease-modifying antirheumatic drug (DMARD), used in active moderate to severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibitor.
Bottle of Leflunomide (Arava) and tablet
Rheumatoid arthritis and psoriatic arthritis are the only indications that have received regulatory approval. Clinical studies regarding the following diseases have been conducted:
Its principle dose-limiting side effects are liver damage, lung disease and immunosuppression. The most common side effects (occurring in >1% of those treated with it) are, in approximately descending order of frequency: diarrhoea, respiratory tract infections, hair loss, high blood pressure, rash, nausea, bronchitis, headache, abdominal pain, abnormal liver function tests, back pain, indigestion, urinary tract infection, dizziness, infection, joint disorder, itchiness, weight loss, loss of appetite, cough, gastroenteritis, pharyngitis, stomatitis, tenosynovitis, vomiting, weakness, allergic reaction, chest pain, dry skin, eczema,paraesthesia, pneumonia, rhinitis, synovitis, cholelithiasis and shortness of breath. Whereas uncommon side effects (occurring in 0.1-1% of those treated with the drug) include: constipation, oral thrush, stomatitis, taste disturbance, thrombocytopenia and hives. Rarely (in 0.1% of those treated with it) it can cause: anaphylaxis, angiooedema, anaemia, agranulocytosis, eosinophilia,leucopenia, pancytopenia, vasculitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, cutaneous lupus erythematosus, severe infection, interstitial lung disease, cirrhosis and liver failure.
- Pregnancy, women of childbearing potential (unless contraception used)
- Liver disease, hepatitis B/Cseropositive
- Active serious infections
Other immunomodulatory treatments should be avoided due to the potential for additive immunosuppressant effects, or in the case of immunostimulants like echinacea or astragalus, reduced therapeutic effects. Likewise live vaccines (like haemophilus influenzae type b vaccine and yellow fever vaccines) should be avoided due to the potential for severe infection due to the immunosuppressive nature of the treatment.
The concomitant use of methotrexate, in particular, may lead to severe or even fatal liver- or hepatotoxicity. Seventy-five percent of all cases of severe liver damage reported until early 2001 were seen under combined drug therapy leflunomide plus methotrexate.However, some studies have shown that the combination of methotrexate and leflunomide in patients with rheumatoid arthritis gave better results than either drug alone.
Mechanism of action
Leflunomide is an immunomodulatory drug that achieves its effects by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase(an enzyme involved in de novo pyrimidine synthesis) (abbreviation DHODH), which plays a key role in the de novo (from scratch) synthesis of the uridine monophosphate (rUMP), which is required for the synthesis of DNA and RNA, hence leflunomide inhibits the reproduction of rapidly dividing cells, especially lymphocytes. The inhibition of human DHODH by teriflunomide, the active metabolite of leflunomide, occurs at levels (approximately 600 nM) that are achieved during treatment of rheumatoid arthritis (RA). Teriflunomide also inhibits several tyrosine kinases. Teriflunomide prevents the expansion of activated and autoimmune lymphocytes by interfering with their cell cycle progression while nonlymphoid cells are able to use another pathway to make their ribonucleotides by use of salvage pyrimidine pathway, which makes them less dependent on de novo synthesis. Teriflunomide also has antiviral effects against numerous viruses including CMV, HSV1 and the BK virus, which it achieves by inhibiting viral replication by interfering with nucleocapsid tegumentation and hence virion assembly.
It has an oral bioavailability of 80%, protein binding of >99%, metabolism sites of the GI mucosa and liver, volume of distribution (Vd) of 0.13 L/kg, elimination half-life of 14-18 days and excretion routes of faeces (48%) and urine (43%).
5-Substd. 4-isoxazolecarboxamides with platelet antiaggregating and other activities
Leflunomide can be obtained by several related ways: 1) The reaction of diketene (I) with 4-(trifluoromethyl)-aniline (II) in hot acetonitrile gives N-[4-(trifluoro-methyl) phenyl]acetoacetamide (III) , which by reaction with triethyl orthoformate (IV) in refluxing acetic anhydride yields the corresponding ethoxymethylene derivative (V). Finally, this compound is cyclized with hydroxylamine in refluxing ethanol/water. 2) The reaction of ethyl acetoacetate (VI) with triethyl orthoformate (IV) as before gives the corresponding ethoxymethylene derivative (VII), which by cyclization with hydroxylamine as before affords 5-methylisoxazole-4-carboxylic acid ethyl ester (VIII). The hydrolysis of (VIII) under acidic conditions yields the free acid (IX), which is converted into the acid chloride (X) by standard methods. Finally, this compound is condensed with 4-(trifluoro-methyl)aniline (II) by means of triethylamine in acetonitrile. 3) The formation of leflunomide from acid (IX) or its derivatives such as ethyl (VIII) or other esters can also be performed through other standard procedures of amide formation. 4) The N-[4-(trifluoromethyl)phenyl]acetoacetamide (III) can also be obtained by reaction of 4-(trifluoro-methyl) aniline (II) with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (XI) in refluxing xylene.
Leflunomide is a pyrimidine synthase inhibitor of the DMARD-type (disease-modifying anti-rheumatic drug) marketed by Sanofi-Aventis. Unlike NSAIDs, which only deal with symptoms of rheumatoid arthritis, DMARDs target the cause of it. DMARDs are not necessarily structurally or mechanistically related. The effect of leflunomide is possibly due to its regulation of the immune system via affecting lymphocytes. Its synthesis  is relatively straightforward starting with a Knoevenagel condensation of ethyl acetoacetate (39) and triethyl orthoformate in the presence of acetic anhydride. The resulting ethyl ethoxymethylene acetoacetate (448) is next condensed with hydroxylamine hydrate in methanol to yield ethyl 5-methylisoxazole-4-carboxylate (449). The ethyl ester is hydrolysed under acidic conditions and the carboxylic acid activated with thionyl chloride in DMF for amide formation with 4-trifluoromethylaniline (450) (Scheme 86).
Synthesis of leflunomide.
Ramakrishnam, A.; Gobind, K.; Neeraj, K.; Dnyaneshwar, S. An Improved Process for Preparation of Leflunomides. WO Patent 2007/086076, Aug 2, 2007.
US patent 5,494,911 discloses process for preparation of Teriflunomide in Example- 4 as shown in given below scheme-I.
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by SANOFI AVENTIS US
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|Conditions : Concentration – 1 mg / 100 ml
|Solvent designation schedule
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UV and IR Spectra. H.-W. Dibbern, RM Muller, E. Wirbitzki, 2002 ECV
NIST / EPA / NIH Mass Spectral Library 2008
Handbook of Organic Compounds. NIR, IR, Raman, and UV-Vis Spectra Featuring Polymers and Surfactants, Jr., Jerry Workman.Academic Press, 2000.
Handbook of ultraviolet and visible absorption spectra of organic compounds, K. Hirayama. Plenum Press Data Division, 1967.
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