New oxazolidinone derivatives are factor Xa inhibitors useful to treat e.g. acute coronary syndrome, myocardial infarction, angina pectoris, reocclusion, restenosis, stroke, artrial fibrillation, arrhythmia and blood clotting disorder

摘要

#CMT# #/CMT# Oxazolidinone derivatives (I) are new. #CMT# : #/CMT# Oxazolidinone derivatives of formula (I) are new. Z 1>-Z 4>direct bond, O or S; R 2>H or 1-4C alkyl; R 4>-Cl, -F, -Br, -CF 3, -OCF 3, -NO 2or -OCH 3; and n : 0-4. #CMT#[Image]#/CMT# #CMT#ACTIVITY : #/CMT# Hemostatic; Thrombolytic; Cardiant; Vasotropic; Antianginal; Cerebroprotective; Anticoagulant; Antiarrhythmic. #CMT#MECHANISM OF ACTION : #/CMT# Factor Xa inhibitor. Tests details are described but no results given. #CMT#USE : #/CMT# (I) are useful for the treatment or and/or prophylaxis of thromboembolic disease, preferably acute coronary syndrome, myocardial infarction, angina pectoris, reocclusion and restenosis (e.g. after angioplastic or aortocoronary bypass), stroke, transient ischemic attack, peripheral arterial occlusive diseases, pulmonary embolism or deep vein thrombosis, artrial fibrillation, arrhythmia, and blood clotting disorder relating to larger surgical intrusion; for the treatment of thrombocytopenia and disseminated intravascular coagulation; and for the prevention of blood coagulation in-vitro (all claimed), preferably in blood or biological samples, where the surgical intrusion is preferably orthopedic surgery. (I) are useful to treat stenosis and thrombosis. (I) are useful as contrast agent in the intra-operative magnetic resonance imaging (MRI) control, particularly in patients with impaired renal function. (I) are useful to treat acute and chronic diseases. #CMT#ADVANTAGE : #/CMT# (I) eliminate the need to monitor the patient for their clotting status. (I) have a wide therapeutic region. (I) can be administered only once a day. (I) are suitable for clinical and ambulatory use. (I) show little interaction with other medicines and foods. (I) eliminate the need for additional contrast agent and the use of heavy contrast agent (preferably gadolinium halide). (I) has increased selectivity to inhibit blood coagulation factor Xa. #CMT#ORGANIC CHEMISTRY : #/CMT# Preparation: No preparation method is given. #CMT#DEFINITIONS : #/CMT# Preferred Definitions: R 2>H (preferred), methyl or ethyl; R 4>-Cl; Z 1>-Z 4>O or bond, where at least one of Z 1>-Z 4>is O and the other is bond. #CMT#ADMINISTRATION : #/CMT# Administration of (I) is 0.1-1000 (preferably 1-300) mg, orally, parenterally, by infusion or injection. #CMT#SPECIFIC COMPOUNDS : #/CMT# 8 Compounds (I) are specifically claimed e.g. 5-chloro-thiophene-2-carboxylic acid {2-oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-oxazolidin-5-ylmethoxy}-amide of formula (Ia), 5-fluoro-thiophene-2-carboxylic acid {2-oxo-3-[4-(3-oxo-morpholin-4-yl)-phenoxy]-oxazolidin-5-ylmethyl}-amide, 5-fluoro-thiophene-2-carboxylic acid {2-oxo-3-[4-(3-oxo-morpholin-4-yloxy)-phenyl]-oxazolidin-5-ylmethyl}-amide, 5-chloro-thiophene-2-carboxylic acid methyl-{2-oxo-3-[4-(3-oxo-morpholin-4-yl)-phenoxy]-oxazolidin-5-ylmethoxy}-amide and 5-fluoro-thiophene-2-carboxylic acid methyl-{2-oxo-3-[4-(3-oxo-morpholin-4-yl)-phenoxy]-oxazolidin-5-ylmethoxy}-amide. #CMT#[Image]#/CMT# #CMT#EXAMPLE : #/CMT# 2-{(R)-2-Oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-oxazolidin-5-ylmethoxy}-isoindole-1,3-dione was treated with methyl hydrazine in the presence of dichloromethane at -100[deg] C to room temperature for 2.5 hours to give 4-[4-((R)-5-aminooxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one. 4-[4-((R)-5-Aminooxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one was treated with 5-chloro-thiophene-2-carbonyl chloride in pyridine at room temperature for 24 hours to give 5-chloro-N-({(5R)-2-oxo-3-[4-(3-oxo-morpholin-4-y)-phenyl]-1,3-oxazolidin-5-yl}-methoxy)-2-thiophencarboxamide (34%).