Apixaban CAS 503612-47-3
Introduction：Basic information about Apixaban CAS 503612-47-3, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Apixaban Basic informationIndications and Usage Mechanisms of Action Clinical Research Drug Interactions Warnings and Precautions
| Product Name: | Apixaban |
| Synonyms: | Apixaban;Apixaban, BMS 562247-01;1H-Pyrazolo[3,4-c]pyridine-3-carboxamide, 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-;1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;BMS562247;BMS 562247-01;1-(4-Methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid aMide;1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxaMide |
| CAS: | 503612-47-3 |
| MF: | C25H25N5O4 |
| MW: | 459.5 |
| EINECS: | 639-684-6 |
| Product Categories: | Inhibitors;Inhibitor;API;503612-47-3 |
| Mol File: | 503612-47-3.mol |
Apixaban Chemical Properties
| Melting point | 235-238°C |
| Boiling point | 770.5±60.0 °C(Predicted) |
| density | 1.42 |
| storage temp. | Refrigerator |
| solubility | DMSO (Slightly, Heated), Methanol (Slightly) |
| form | Solid |
| pka | 15.01±0.20(Predicted) |
| color | White to Off-White |
| InChI | 1S/C25H25N5O4/c1-34-19-11-9-18(10-12-19)30-23-20(22(27-30)24(26)32)13-15-29(25(23)33)17-7-5-16(6-8-17)28-14-3-2-4-21(28)31/h5-12H,2-4,13-15H2,1H3,(H2,26,32) |
| InChIKey | QNZCBYKSOIHPEH-UHFFFAOYSA-N |
| SMILES | C1(=O)N(C2=CC=C(N3CCCCC3=O)C=C2)CCC2C(C(N)=O)=NN(C3=CC=C(OC)C=C3)C1=2 |
Safety Information
| WGK Germany | WGK 3 |
| Storage Class | 11 - Combustible Solids |
| Hazardous Substances Data | 503612-47-3(Hazardous Substances Data) |
| Indications and Usage | Apixaban is a new form of oral anticoagulant drug developed by Bristol Myers Squibb and Pfizer. It is a new form of oral Xa factor inhibitor, and its commercial name is Eliquis. Apixaban is used to treat adult patients undergoing elective hip or knee replacement surgery to prevent venous thromboembolism (VTE) |
| Mechanisms of Action | Apixaban(503612-47-3) is an oral selective activated Xa factor inhibitor and can prevent thrombin generation and thrombosis. |
| Clinical Research | Apixaban(503612-47-3) is the third new oral anticoagulant to go on sale, following dabigatran and rivaroxaban, and it has already been approved in Europe for preventing venous thromboembolism in patients undergoing elective hip or knee replacement surgery. Out of these three oral anticoagulants approved in Europe, compared to the current standard preventative treatment against venous thromboembolism, enoxaparin, rivaroxaban excelled in the record experiment, and apixaban excelled in the advance experiment. Rivaroxaban’s curative effects were slightly superior, but it caused more severe bleeding than apixaban. Researchers attributed these differences to medication time, as rivaroxaban was taken 6-8 hours after surgery in the record experiment, while apixaban was used 18 hours after surgery in the advance experiment. These drugs have better curative effect when used closer to time of surgery, but also have an increased bleeding risk. Clinical research showed that compared to a daily subdermal injection of 40mg enoxaparin, 2 oral 2.5mg dosages of apixaban had better preventative effects against venous thromboembolism following hip or knee replacement surgery and did not increase bleeding risk. |
| Drug Interactions | 1.A double inhibitor of strong CYP3A4 and P-gp increases apixaban’s blood levels: decrease Eliquis dosage to 2.5mg or avoid simultaneous usage. 2.A inductor of strong CYP3A4 and P-gp can decrease apixaban’s blood levels: avoid simultaneous usage. |
| Warnings and Precautions |
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| Description | Eliquis (apixaban), a direct inhibitor of factor Xa (FXa), was approved by the European Commission on May 18, 2011 for prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery. Apixaban (357.5 mg) also prevents thrombus formation without inducing adverse bleeding events in a porcine model of aortic heterotopic valve replacement. Formulations containing apixaban have been used to prevent blood clot formation in patients with atrial fibrillation. |
| Originator | Bristol Myers Squibb Company (United States) |
| History | Apixaban is an oral anticoagulant jointly developed by Bristol-Myers Squibb (BMY) and Pfizer (PFE) for the prevention of stroke and systemic embolism in patients with atrial fibrillation. It is marketed under the brand name Eliquis. The drug was approved for use by the European Medicines Agency in 2011 and by the U.S. Food and Drug Administration in 2012. |
| Uses | Apixaban is a highly selective, reversible inhibitor of Factor Xa with Ki of 0.08 nM and 0.17 nM in human and rabbit, respectively. |
| Definition | ChEBI: A pyrazolopyridine that is 7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide substituted at position 1 by a 4-methoxyphenyl group and at position 6 by a 4-(2-oxopiperidin-1-yl)phenyl group. It is used for theprevention and treatment of thromboembolic diseases. |
| Brand name | Eliquis |
| Pharmacokinetics | The maximum plasma concentration (Cmax) of apixaban occurs 3–4 h after oral administration. The absorption of apixaban appears to occur primarily in the small intestine and decreases progressively throughout the gastrointestinal tract. Compared with oral administration, the bioavailability of 2.5 mg of apixaban solution was approximately 60% and 84% lower when released in the distal small bowel and ascending colon, respectively. For oral doses up to 10 mg, the absolute bioavailability of apixaban is~50%, resulting from the incomplete absorption and first-pass metabolism in the gut and liver[1]. |
| Clinical Use | Apixaban is an oral anticoagulant with highly selective inhibitionof factor Xa. It was approved by the European MedicinesAgency (EMA) for the treatment of venous thromboembolic eventsand first marketed in Germany under the brand name Eliquis inJune 2011. Apixaban was co-developed by Bristol-Myers Squibband Pfizer and represents the first approved drug for this indicationsince warfarin over 50 years ago. |
| Side effects | Possible side effects of Apixaban are: bleeding gums, nosebleeds, heavy vaginal bleeding, red, pink, or brown urine; red or black, tarry stools; coughing or spitting up blood or a substance that looks like coffee grounds; swelling or joint pain, headache, rash, chest pain or tightness in the chest, swelling of the face or tongue, trouble breathing, wheezing. Feeling dizzy or fainting.Apixaban prevents your blood from clotting properly, so if you get a cut or injury, it may take longer than usual for the bleeding to stop. This medication may also cause you to bruise or bleed more easily. |
| Synthesis | Although several convenientpreparations of apixaban (BMS-562247) have been reported, the most likely process-scale route is described in the scheme. Thestarting material 4-iodoaniline (14) was acylated with 5-bromovalerylchloride (15) and triethylamine followed by cyclization underbasic conditions to give lactam 16 in 49% yield. Intermediate 16was then reacted with phosphorus pentachloride to provide thea,a-dichlorinated lactam 17 in 87% yield.30 This dichloride was reactedwith excess morpholine to affect an alkylation¨Celiminationsequence to afford enaminolactam 18 in 86% yield. N-Arylationof this iodide with valerolactam 19 using a copper (I) catalyst resultedin a 77% yield of the desired p-bispiperidone 20. Interestingly,sequential exposure of 20 to a nitrile imine generated fromthe treatment of ethyl 2-chloro-2-(2,4-methoxyphenyl)-hydrazono)acetate 21 with base resulted in a [3+2] dipolarcycloadditonreaction. Upon acidification with 4 N HCl, pyrazole 22 was furnishedin 67% over two steps. Conversion of the ester within 22to the corresponding amide was achieved via a mixture of formamideand sodium methoxide to give apixaban (III) in 71% yield. It isimportant to note that intermediate 21 was prepared from commerciallyavailable 4-methoxyaniline (23) by sequential diazotizationand condensation with ethyl 2-chloroacetoacetate (24). |
| in vitro | apixabanhas exhibited a high degree of potency, selectivity, and efficacy on factor xa with ki of 0.08 nm and 0.17 nm for human factor xa and rabbit factor xa, respectively [1]. apixaban prolonged the clotting times of normal human plasma with the concentrations (ec2x) of 3.6, 0.37, 7.4 and 0.4 μm, which are required respectively to double the prothrombin time (pt), modified prothrombin time (mpt), activated partial thromboplastin time (aptt) and heptest. besides, apixaban showed the highest potency in human and rabbit plasma, but less potency in rat and dog plasma in both the pt and aptt assays [3]. |
| in vivo | apixaban exihibited the excellent pharmacokinetics with very low clearance (cl: 0.02 l kg-1h-1), and low volume of distribution (vdss: 0.2 l/kg) in the dog. besides, apixaban also showed a moderate half-life with t1/2 of 5.8 hours and good oral bioavailability (f: 58%) [1]. in the arteriovenous-shunt thrombosis (avst), venous thrombosis (vt) and electrically mediated carotid arterial thrombosis (ecat) rabbit models, apixaban produced antithrombotic effects with ec50 of 270 nm, 110 nm and 70 nm in a dose-dependent manner[3]. apixaban significantly inhibited factor xa activity with an ic50 of 0.22 μm in rabbit ex vivo[4]. in chimpanzee, apixaban also showed small volume of distribution (vdss: 0.17 l kg-1), low systemic clearance (cl: 0.018 l kg-1h-1), and good oral bioavailability (f: 59%) [5]. |
| Drug interactions | Potentially hazardous interactions with other drugs Analgesics: increased risk of haemorrhage with IV diclofenac and ketorolac - avoid. Antibacterials: avoid with clarithromycin and telithromycin; concentration possibly reduced by rifampicin - avoid if treating DVT/PE. Anticoagulants: increased risk of haemorrhage with other anticoagulants - avoid. Antidepressants: concentration possibly reduced by St John’s wort - avoid if treating DVT/PE. Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin, phenobarbital, phenytoin and primidone - avoid if treating DVT/PE with carbamazepine. Antifungals: concentration increased by ketoconazole - avoid; avoid with itraconazole, posaconazole and voriconazole. Antivirals: avoid with atazanavir, boceprevir, darunavir, fosamprenavir, indinavir, lopinavir, ritonavir, saquinavir, telaprevir and tipranavir. Cobicistat: avoid concomitant use. |
| Metabolism | Apixaban is metabolised in the liver mainly via the P450 cytochromes CYP3A4 and CYP3A5. Apixaban has multiple routes of elimination. Of the administered apixaban dose in humans, approximately 25% was recovered as metabolites, with the majority recovered in faeces. Renal excretion of apixaban accounts for approximately 27% of total clearance. There are also additional contributions from biliary and direct intestinal excretion. |
| References | https://en.wikipedia.org/wiki/Apixaban https://www.drugbank.ca/drugs/DB06605 [1] Wonkyung Byon. “Apixaban: A Clinical Pharmacokinetic and Pharmacodynamic Review.” Clinical Pharmacokinetics 58 10 (2019): 1265–1279. |
Apixaban Preparation Products And Raw materials
