リバーロキサバン

用途

リバーロキサバン（Rivaroxaban）は経口抗凝固薬の一つである。最初に開発された直接第Xa因子阻害薬（英語版）である。商品名イグザレルト。消化管からの吸収率が高く、投与4時間後に第Xa因子の阻害効果が最大となり、効果は8?12時間持続する。 リバーロキサバンは血中の遊離第Xa因子およびプロトロンビナーゼ（英語版）複合体に結合した第Xa因子を共に阻害するよう最適化されたオキサゾリジノン（英語版）誘導体である。直接第Xa因子阻害選択性が高く、生物学的利用能も高いので、速やかに効果が発現する。第Xa因子の阻害は凝固系の内因性経路および外因性経路を両方阻害して、トロンビン生成および血栓形成を共に抑制する。リバーロキサバンはトロンビン（活性化第II因子）を阻害せず、また血小板に対して作用しないことが示されている。

効能

抗血栓薬, 第Xa因子阻害薬

商品名

イグザレルト (バイエル薬品); イグザレルト (バイエル薬品)

説明

Rivaroxaban is an orally active, direct inhibitor of Factor Xa (Ki = 0.4 nM), which is a crucial component of the intrinsic and extrinsic pathways of the blood coagulation cascade. It demonstrates >10,000-fold greater selectivity for Factor Xa compared to other related serine proteases (thrombin, trypsin, plasmin, FVIIa, FIXa, FXIa, urokinase, and activated protein C). In various animal arterial and venous thrombosis models, rivaroxaban is reported to inhibit thrombin formation without prolonging bleeding time and has been approved for clinical use as an anticoagulant in the prevention of stroke and the treatment of venous thromboembolisms.

化学的特性

White Solid.
Rivaroxaban has limited pH-independent solubility in aqueous medium (5–7 mg/L; pH 1–9), but is, for instance, slightly soluble in polyethylene glycol 400 (2,431 mg/L). Using a validated Caco-2 cell assay, the apparent permeability values of the rivaroxaban molecule at concentrations of 1–100 μM were approximately 8 × 10?6 cm/s. With a log P value (octanol/water partition) coefficient of 1.5, rivaroxaban exhibits moderate lipophilicity, reflected in its low-to-moderate affinity to peripheral tissues[1].
IUPAC: 5-chloro-N-[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl]thiophene-2-carboxamide

使用

Rivaroxaban is a novel antithrombotic agent. It is a novel, oral, selective direct inhibitor of factor Xa developed by Bayer Healthcare. It has been approved by the EMEA and FDA for the prevention ofvenous thromboembolism in adult patients after total hip replacement or total kneereplacement surgery.

定義

ChEBI: Rivaroxaban is a monocarboxylic acid amide obtained by formal condensation of the carboxy group of 5-chlorothiophene-2-carboxylic acid with the amino group of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one. An anticoagulant used for prophylaxis of venous thromboembolism in patients with knee or hip replacement surgery. It has a role as an anticoagulant and an EC 3.4.21.6 (coagulation factor Xa) inhibitor. It is a member of thiophenes, an organochlorine compound, an oxazolidinone, a member of morpholines, a lactam, an aromatic amide and a monocarboxylic acid amide.

副作用

Regarding safety, there was no statistical difference in the incidence of major postoperative bleeding between any of the rivaroxaban dose groups and enoxaparin although there did appear to be a dose dependency in the rivaroxaban set. In addition to bleeding and subsequent posthemorrhagic anemia, presenting as weakness, paleness, asthenia, dizziness, headache, or unexplained swelling, other common adverse events included nausea, increased GGT, and an increase in transglutaminase. Owing to its mechanism of action, there is a bleeding risk, so the drug is contraindicated in patients with clinically active bleeding. Rivaroxaban is also contraindicated in pregnant and breast-feeding women and in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk.

合成

To date, several methods have been reported for the synthesis of rivaroxaban. Most of them share the use of 5-S-hydroxymethyl or 5-S-aminomethyl oxazolidinones (2and 3 respectively) as key intermediates. Condensation of 3-morpholinone with 4-fluoronitrobenzene followed by catalytic hydrogenation provides N-(p-aminophenyl)morpholinone for subsequent reaction with (S)-2-(phthalimidomethyl)oxirane. With establishment of the aminoalcohol adduct, cyclization with 1,1′-carbonyldiimidazole generates the central oxazolidinone. Deprotection and acylation with 5-chlorothiophene-2-carbonyl chloride affords rivaroxaban.
An Improved Synthesis of Rivaroxaban