|Company Name:||Wuhan Vanzpharm Inc. Gold|
|Pirfenidone Chemical Properties|
|Hazard Codes ||Xn|
|Risk Statements ||22|
|Safety Statements ||36|
|WGK Germany ||3|
|Pirfenidone Usage And Synthesis|
|Overview||Pirfenidone (PFD) is a novel kind of pyridine ketones which has a broad-spectrum anti-fibrotic effect, being able to prevent and reverse the formation of fibrosis and scar. It entered into market in Shionogi, Japan in 2008 and has been approved by the US food and Drug Administration. It is the first drug which has gone through phase III clinical trials (including repeating, randomized, and placebo-control) which has demonstrates its effectiveness in treating idiopathic pulmonary fibrosis (IPF); moreover, the drug has relative good efficacy in treating some fibrotic diseases such as renal interstitial fibrosis and liver fibrosis. Furthermore, it is also widely applied in the phase II clinical study in kidney disease (focal segmental glomerulosclerosis), hypertrophic cardiomyopathy, adult type I neurofibromatosis, youth I type of neurofibromatosis and plexiform neurofibromas, diabetes together with kidney disease.|
The above information is edited by the Chemicalbook of Dai Xiongfeng.
|Preparation||(1) The synthesis of the 5-methyl -2 (1H) - pyridone③ |
Add 1500 g (13.87 mol) of 2-amino-5-methylpyridine②, 35 L of 5% sulfuric acid to the reaction kettle and stir at room temperature for 15 min. Cool to 0 ~ 5 °C after all the solid being totally dissolved. Slowly add 1665 g of sodium nitrite (24.1 mol) into 5 L of water, stir for maintaining temperature at 3h; after the completion of the reaction, heat and reflux until no more gas is generated; use sodium carbonate to adjust pH to neutral, evaporate to dryness under reduced pressure; add 25 L of methanol to the kettle, add 30 g of activated charcoal for heating and reflux for 20min, filter, evaporate the filtrate evaporated to dryness under reduced pressure with the residue being recrystallized by ethanol to obtain pale yellow crystals③.
(2)The Synthesis of pirfenidone ①
Successively add 1000 g (9.16 mol) of 5-methyl-2 (1H)-pyridone, 2245 g (11.01 mol) of iodobenzene, 1391 g (10.08 mol) of potassium carbonate, 32.1 g (0.32 mol) of cuprous chloride and 3.5 L of dimethylsulfoxide into the 10L 3-neck flask, and stir slowly to raise the temperature to 180 °C and maintain the reaction for about 5 h. After the completion of the reaction, cool to room temperature, filter the reaction solution, wash the filter cake with 1 L of dimethyl sulfoxide; combine the filtrate and evaporate to dryness under reduced pressure; add 3 L of 20% acetic acid aqueous solution, and heat to 65 °C; stir for 30 min; stand static for layer separation; further extract the lower oil with 20% aqueous acetic acid (1L X 3) and then combine the aqueous phases. Add solid sodium hydroxide to the aqueous phase to adjust the pH to 13, cool to room temperature, separate out the precipitate; filter; wash the filter cake with water; after drying the filter cake, add 3.2L of ethyl acetate for heating reflux for about 15 min; filter it in hot condition, cool for separate the crystals; allow it to stand overnight; filter; have the filter cake dried under reduced pressure for 5h to obtain the pirfenidone①.
Figure 1 The synthetic route of Pirfenidone (PFD)
This method is a modification of the method 1, which applies the diazotization of 2-amino--5- methylpyridine, hydrolyze to obtain 5-methyl-2 (1H)-pyridone, which have reaction together with bromobenzene in 1: 1.2 (molar ratio); Using DMF as the solvent, CuBr as the catalyst, add 5% of the 1,10-phenanthrolin as the ligand, have reaction at 90°C for 2 hours to obtain the pirfenidone.
Figure 2: The Synthetic route of pirfenidone
|Pharmacological effects||PFD is a potent inhibitor of a cytokine by regulating or inhibiting certain factors, thus inhibiting the biological activities of fibroblast cells and reducing the cell proliferation and the synthesis of collagen matrix. Meanwhile, PFD can also inhibit the secretion of inflammatory mediators, reduce lipid peroxidation, and exert its anti-inflammatory and antioxidant effects. |
1. Inhibition of collagen synthesis
Fibroblast growth factor (bFGF), transforming growth factor -β (transforming growth factor-β, TGF-β), connective tissue growth factor (connective tissue growth factor, CTGF) and tissue inhibitor of metalloproteinase 1 (TIMP - 1) are growth factors that related with fibrotic diseases. They can promote fibroblast proliferation and growth, increase the synthesis of collagen matrix and prevent the degradation of extracellular matrix (ECM). They are expressed to different extent during the formation of organ fibrosis. PFD can effectively reduce the expression of the proteins such as bFGF, TGF - β, CTGF and TIMP - 1 in the fibroblast cells of lung and kidney and be correlated with the reduction of collagen synthesis and matrix.
The formation of I and III type collagen fibers is also closely related to the synthesis of collagen matrix. At the same time of reducing TGF-β expression, PFD can also reduce the generation α I collagen. PFD also inhibit the expression of pulmonary fibrosis I collagen. In addition, PFD also has inhibitory effect on the expression of type III collagen mRNA and can reduce the synthesis of collagen type III.
2. The anti-inflammatory effects
PFD can inhibit to the inflammatory mediators to varying degrees for exerting their anti-inflammatory effects. When the inflammatory cytokines is overexpressed inside the lung, the inflammation reaction is exacerbated, thus making alveolar wall being thickening, reducing the function of pulmonary alveoli, and ultimately causing fibrosis. PFD primarily take anti-inflammatory effects by inhibiting the expression of inflammatory mediators, reducing vascular permeability, and reducing the agglomeration of neutropenia and inflammatory cells, thus further preventing or slowing down the fibrosis of organs and tissues.
3. Anti-oxidation effect
PFD mainly exert their antioxidant effects by scavenging free radicals and inhibiting lipid peroxidation and oxidative stress mitigation.
|Pharmacokinetics||After the rat intravenous injection 400 mg• kg-1 of this product, the product is cleared from the plasma according to two-compartment model with a plasma clearance rate being 0.10mL • min-1 • g-1 and the apparent volume of distribution being 0.6 mL • g-1, and the half-life being 8.6min. After intravenous injection, pirfenidone is rapidly distributed in the body fluids with the drug concentration in the tissues reaching peak within 5 min with the concentration among liver, kidneys, lungs and other parts rich in blood containing relative high levels; the concentration in lower fat tissue is relative low; rat: oral administration of pirfenidone: 250 ~ 300 mg • kg-1 • d-1 yields a bioavailability of being 25.7%. The 24 h average plasma concentration is (1.9 ± 0.1) μg • mL-1after 14 day of drug administration; 97 % of the metabolites are excreted from the kidney with 24 h excretion accounting for 97% of the total.
|Clinical application||1. Idiopathic pulmonary fibrosis degeneration |
Idiopathic pulmonary fibrosis (IPF) is an unexplained, poor prognosis and high-mortality chronic inflammatory interstitial lung disease. At the same time, PFD is an anti-inflammatory, anti-fibrotic agent which can be used for the treatment of IPF.
2. Liver Fibrosis
3. Renal fibrosis disease
4. Multiple Sclerosis
Multiple sclerosis (MS) is a central nervous system-related and the immune-related inflammation and demyelinating diseases. Immune factors relating to it are activation of stellate cells, glial cell, and endothelial cell and the increase of lymphocytes, while PDF have effects of inhibiting the cell activation.
5. Myocardial fibrosis
Cardiovascular diseases such as hypertension, cardiomyopathy, and atrial fibrillation can all lead to myocardial fibrosis, thereby resulting in the disease progression or development. Using PDF for treatment of cardiomyopathy caused by Duchenne muscular dystrophy can inhibit myocardial fibrosis, improve the cardiac function. PFD can reduce the incidence of atrial fibrillation and myocardial remodeling through inhibiting fibrosis.
6. Neoplastic diseases: neurofibroma, leiomyoma, and malignant gliomas.
7. Prevention of fibrosis after the organ transplant.
8. Rheumatoid arthritis.
|Adverse reactions||Common adverse reactions include light sensitivity, fatigue, rash, and nausea; other adverse reactions also include upper gastrointestinal discomfort, bloating, anorexia, diarrhea, and skin itching.
|Chemical Properties||Off-White Solid|
|Usage||Pirfenidone has demonstrated activity in multiple fibrotic conditions, including those of the lung, kidney and liver|
|Biological Activity||Antifibrotic agent, effective in models of pulmonary and lung fibrosis. Inhibits collagen production and fibroblast proliferation. Regulates cytokine levels following oral administration in vivo . Potent scavenger of free radicals and inhibitor of lipid peroxidation.|
|Pirfenidone Preparation Products And Raw materials|