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Questions And Answer

• Synthesis

  Reddy et. al. reported a total synthesis of zafirlukast 15 by coupling bromide 24,  derived from commercially available 3-methoxy-4-methylbenzoic acid 23 with 1-methyl-5- nitroindole 25. Bromination of 23 with DBDMH in the presence AIBN in CHCl3, afforded  bromomethylbenzoic acid derivative 24 in 81% yield. Alkylation of indole 25 with  bromide 24 in dioxane mediated by ZnBr2 at 60-65 °C furnished indole 26 in 62% yield.  Acid 26 was coupled with o-toluene sulfonamide 22 using DCC in the presence of DMAP  as a catalyst to give sulfonamide 27 in 63% yield. Catalytic hydrogenation of 27 using  Raney Ni in MeOH smoothly afforded amine, which upon acylation with cyclopentyl  chloroformate 20 yielded the target molecule 15 in 89% yield.;

• Anti-leukotriene antiasthmatic drugs

  Zafirlukast is a highly selective and long-acting oral lys-LTs antagonist. Leukotrienes play an important role in the pathogenesis of asthma. These substances are peptides, being capable of selectively binding to LTC4, LTD4 and LTE4 receptor for antagonism of its effect, reducing the symptoms of asthma and improving lung function. This product is both a preventive agent of inflammation caused by asthma (being antagonistic to leukotriene proinflammatory activity) and a relief drug for bronchial asthma (be antagonistic to leukotriene induced bronchial smooth muscle contraction). The use of this product does not change the smooth muscle response to β2 receptors and has good efficacy in the treatment of bronchoconstriction caused by antigen, aspirin, exercise and cold air, being able to reduce the dosage of hormone and β2 receptor agonist. ;

• Mechanism of Action

  Zafirlukast is potent oral polypeptide trinaphthalene receptor antagonist of the slow response substances of supersensitive reactions such as LTC4, LTD4 and LTE4. It belongs to competitive inhibitor and has high selectivity, which can effectively prevent trinaphthalene-induced increased vascular permeability, tracheal edema and eosinophil infiltration.
  Five-day doses of the drug reduce cellular and non-cellular inflammatory substances in the trachea due to antigen stimulation. In the bronchoalveolar lavage fluid of 48h after antigen challenge, the drug can inhibit the increase of eosinophils, lymphocytes and tissue cells, as well as reduce the peroxide produced by alveolar macrophage stimulation. It can inhibit antigen-induced airway hyperresponsiveness and platelet-activating factor-induced bronchospasm.
  Long-term use of this drug can reduce the airway sensitivity to methacholine.
  Asthma patients has a 10 times higher sensitivity to leukotriene D4 than the average person with a single oral dose of the drug increasing the tolerance of asthma patients to inhaled LTD4 by 100 times with significant protective effect within 12 and 24h t. It can inhibit bronchospasm caused by various kinds of stimuli (such as sulfur dioxide, exercise and cold air), reducing early and late inflammatory reactions caused by various causes such as pollen, cat hair, ragweed and mixed antigens. For some patients, the drug can completely prevent the movement and allergens caused by asthma attacks. The drug can be used to maintain first-line treatment of asthma patients who are on demand for beta-agonist therapy but are not adequately controlled. For patients with clinical symptoms, the drug can relieve symptoms (reduce the symptoms of diurnal asthma), improve lung function, reduce the amount of β-agonists and the incidence of asthma exacerbations.
  Clinical study finds that medication within 2h, before the plasma concentration of the drug has reached the peak; it can already have a significant first-dose effect on basal bronchial tension. The symptoms of asthma can be initially alleviated within 1 week, mostly occurring in the first few days. Oral administration has a Tmax of 3h with twice daily (30 ~ 80mg, bid), we can see the plasma accumulation of Zafirlukast change from undetectable level to 2.9 times of the first dose with an average of 1.45 and median 1.27. The PBP was 99% and the t1/2 was 10h. Zafirlukast has a pharmacokinetic in healthy people compared with asthma youth and adults. When administered by body weight, there is no gender difference in the drug's metabolism. As with food, most patients (75%) have reduced bioavailability. Metabolism is complete, mainly excretion (89%) and urine (10%) excretion. ;

• Pharmacokinetics

  This product is highly selective with only acting on leukotriene receptors. It does not affect prostaglandins, thromboxanes, cholinergic and histamine receptors. Oral absorption is good with plasma concentration reaching peak at about 3 hours. Medication within 2 hour has 10% undergoing urinary excretion and 89% undergoing stool excretion and half-life of about 10 hours. Pharmacokinetics in the normal population and kidney damage patients has no significant difference. The bioavailability of most patients can decrease by 40% if co-administrated with food. ;

• Indications

  Clinically suitable for the prevention and treatment of chronic mild to moderate asthma, especially for patients with aspirin or aspirin asthma, or with upper respiratory tract diseases (such as nasal polyps, allergic rhinitis), but not for the treatment of acute asthma. It is suitable for hormone-resistant asthma or asthmatic patients who refuse use of hormone. In cases of serious asthma, additional administration with this product can maintain control of asthma attacks or to reduce the amount of hormones. ;

• Medicine interactions

  • In combination with aspirin, the plasma concentration of the drug can be increased by about 45%, but not to the corresponding clinical effect.
  • Combination with erythromycin, theophylline and terfenadine can cause the reduction of plasma concentrations (30%, 40% and 54%).
  • Combination with warfarin can extend the maximum prothrombin time by about 35%. Therefore, upon the combination of the above two drugs, the patients should be closely monitored of prothrombin time.
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• Adverse reactions

  It can cause headache, gastrointestinal reactions, elevated aminotransferases, pharyngitis, rhinitis, urticaria, angina edema, rash, blisters and so on. A larger dose of medication can increase the incidence of hepatocellular carcinoma, histiocytic sarcoma and bladder cancer. ;

• Precautions

  1. Patients allergic to this product and children under 12 years of age should be disabled.
  2. Pregnant women, lactating women and liver damage should not use.
  3. Patients of cirrhosis, liver function damage use with caution.
  4. This product does not apply to relieve bronchial spasm during acute exacerbation of asthma, nor should it be used as an alternative to inhaled or oral glucocorticoid therapy.
  5. The product of cytochrome P4502C9 enzyme system has inhibitory effect.
  6. Information on the pharmacological Effects, pharmacokinetics, indications, drug interactions, and adverse Reactions Related to anti-asthma.
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• Synthesis

  5-nitroindole(I, 5.0 g, 30.8 mmol) and methyl-4-(bromomethyl)-3-methoxybenzoate (II, 7.99 g, 30.8 mmol) were dissolved in 30 ml of dioxane, Silver oxide (7.15 g, 30.8 mmol) was added under nitrogen protection and stirring and heated at 60 ° C for 20 h. The solvent was distilled off under reduced pressure and 50 ml of ethyl acetate was added. Filtrate; concentrate of the filtrate, followed by chromatography with eluting by 3: 7 ethyl acetate-hexanes. The resulting yellow oil was crystallized from methylene chloride-hexane to give 4.6 g of Compound (III) in 45% yield, m.p. 153-155 ° C.
  Compound (III) (0.44 g, 1.29 mmol) was added to a suspension of free sodium hydride (0.031 g, 1.29 mmol) in 100 ml of dry tetrahydrofuran under nitrogen atmosphere, and add after iodomethane (0.18 g, 1.29mmo1) after 10 minutes for reaction of 30 min. Pour 30 ml of 1 mol / L hydrochloric acid and extract with ethyl acetate (2 x 50 ml). The extract was washed with saturated brine, dried and concentrated. The residue was separated by chromatography and eluted with hexane-methylene chloride-ethyl acetate 50: 45: 5. The resulting yellow oil was crystallized from a mixture of dichloromethane and hexane to give 0.33 g of compound (IV) Rate of 72%, melting point 144 ~ 146 ℃.
  Compound (IV) (0.56 g, 1.57 mmol) was dissolved in 30 ml of tetrahydrofuran and 0.1 g of 10% palladium-carbon catalyst was added and hydrogenated at 0.345 MPa for 2 h. Filtration and concentration of the filtrate followed by purification by chromatography gave 1 g of ethyl acetate-hexane as eluent to give 0.5 g of compound (V) in a yield of 98%.
  Compound (V) (0.25 g, 0.77 mmol) and N-methylmorpholine (0.77 mmol) were dissolved in 3 mL of dichloromethane; cyclopentyl chloroformate (0.11 g, 0.77 mmol) was added under nitrogen and stirred for 2 h. Pour 1mol / L hydrochloric acid, extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated. The remaining viscous oil was purified by chromatography eluting with 3: 7 ethyl acetate-hexane to give 0.25 g of compound (VI) in 74% yield.
  Compound (VI) is hydrolyzed with lithium hydroxide at room temperature to give compound (VII). (VII) and o-methylbenzenesulfonamide, in the presence of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride and 4-(dimethylamino) pyridine, are condensed in methylene chloride, to give zafirlukast; yield 69%, mp 138-140 ° C. ;

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