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Chemical name: apixaban;1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxamide; UNII-3Z9Y7UWC1J; Apixaban; Eliquis;
Molecular formula: C25H25N5O4
CAS No.: 503612-47-3
Boiling point: 770.468ºC at 760 mmHg
Refractive index: 1.705
Apixaban is used help prevent strokes or blood clots in people who have atrial fibrillation (a condition in which the heart beats irregularly, increasing the chance of clots forming in the body and possibly causing strokes) that is not caused by heart valve disease. Apixaban is also used to prevent deep vein thrombosis (DVT; a blood clot, usually in the leg) and pulmonary embolism (PE; a blood clot in the lung) in people who are having hip replacement or knee replacement surgery. Apixaban is also used to treat DVT and PE and may be continued to prevent DVT and PE from happening again after the initial treatment is completed. Apixaban is in a class of medications called factor Xa inhibitors. It works by blocking the action of a certain natural substance that helps blood clots to form.
Animal studies have shown an increased risk of maternal bleeding during pregnancy but no increase in fetal malformations or fetal or maternal death. It is unknown if this animal data also translates to humans so apixaban should only be used in pregnancy if the benefits outweigh the risks. It is not know whether apixaban is safe and effective in labor and during birth, though animal studies have shown an increased rate of maternal bleeding. Animal studies in rats show apixaban excreted in milk, though it is not know if this also applies to humans. Nursing mothers should either stop breastfeeding or stop taking apixaban depending on the risk and benefit of each option. Studies to determine safety and effectiveness in pediatric patients have yet to be performed. Studies that involved geriatric patients (at least 75 years old) saw no difference in safety or effectiveness compared to younger patients, though geriatric patients at an especially advanced age may be more susceptible to adverse effects. Dosage adjustments for patients with end stage renal disease(ESRD) are based on estimates of pharmacokinetic principles and not clinical study. Patients with ESRD may experience pharmacodynamics similar to those seen in well controlled studies but it may not lead to the same clinical effects. Dosage adjustments are not necessary in mild hepatic impairment. In moderate hepatic impairment patients may already experience abnormalities in coagulation and so no dose recommendations are possible. Apixaban is not recommended for patients with severe hepatic impairment.
Synthetic route of Apixaban
Route 1: using δ-pentanolactam as raw material, the target compound 1 was obtained by α-position 2: chlorination, condensation-elimination [3 + 2] cyclization-elimination, and Ullmann coupling reaction, which reacted with isobutyl chloroformate to form mixed anhydride.
Route 2: using nitro compound 6 as raw material, the target compound was obtained by reduction-amidation and cyclization-hydrolysis of iron powder to obtain the active amide from the reaction of 2-benzoate-2 with cheap green reagent CDI, and the target compound was obtained by aminolysis. Results: the purity of the obtained apesaban was more than 99.88% by HPLC, and the overall yield was 67.2%. Conclusion: this method overcomes the shortcomings of the methods reported in the literature, such as expensive raw materials, harsh reaction conditions, difficult to monitor the reaction process, low product yield and so on. It has the advantages of easily available raw materials, low production cost, mild reaction conditions, simple operation, high process stability, high purity and yield of apexaban, etc., so it is suitable for industrial production.
List of Intermediates
CAS No.: 473927-63-8 (Z-), CAS No.:27143-07-3 (Z/E-mixture)
CAS No.: 503614-91-3
1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester
CAS No.: 545445-44-1
The future market of Apixaban
BMS applied for patent of Apixaban in 2003, and its international publication number is WO2003/049681.At present, the number of patents for Apixaban has exceeded 100, and the patent in China will expire on September 17, 2022 (CN1578660A).
Although NMPA approved the first imitation of Hansoh Pharma, it is only because Hansoh BE is progressing slightly faster and it does not involve challenging the original research patent.
In April 2017, BMS and Pfizer Pharmaceuticals jointly filed more than a dozen patent infringement lawsuits, including HEC Pharma and Huahai Pharmaceutical.
Apeisaban's patent in China is still very reliable, and it is very difficult to challenge the patent in China. The patent protection of Apexaban will expire on 17th September 2022, under this constraint, if there is no turning point in patent challenge, there will be no domestic generic drug products on the market before this time point, and domestic enterprises that are currently behind schedule will have enough time to complete their BE clinical trials and then wait for the market to open.
In other words, if HEC Pharma and Huahai Pharmaceutical succeed in the US market, they will have plenty of time to be approved for listing at home before their domestic patents expire.
All in all, although Hansoh Pharma was approved for the first time, there is still a long way to go.
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