Claims for Patent: 7,157,456

Summary for Patent: 7,157,456

Title:	Substituted oxazolidinones and their use in the field of blood coagulation
Abstract:	The invention relates to the field of blood coagulation. Novel oxazolidinone derivatives of the general formula (I) ##STR00001## processes for their preparation and their use as medicinally active compounds for the prophylaxis and/or treatment of disorders are described.
Inventor(s):	Straub; Alexander (Wuppertal, DE), Lampe; Thomas (Wuppertal, DE), Pohlmann; Jens (Wuppertal, DE), Rohrig; Susanne (Essen, DE), Perzborn; Elisabeth (Wuppertal, DE), Schlemmer; Karl-Heinz (Wuppertal, DE), Pernerstorfer; Joseph (Wuppertal, DE)
Assignee:	Bayer HealthCare AG (Leverkusen, DE)
Application Number:	10/181,051
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,157,456
Patent Claims:	1. A compound of the formula (I) ##STR00174## characterized in that R.sup.1 represents an optionally benzo-fused thiophene group which may optionally be mono- or polysubstituted by a radical selected from the group consisting of halogen; cyano; nitro; amino; aminomethyl; (C.sub.1 C.sub.8)-alkyl which for its part may optionally be mono- or polysubstituted by halogen; (C.sub.3 C.sub.7)-cycloalkyl; (C.sub.1 C.sub.8)-alkoxy; imidazolinyl; --C(.dbd.NH)NH.sub.2; carbamoyl; and mono- and di-(C.sub.1 C.sub.4)-alkyl-aminocarbonyl, R.sup.2 represents D-M-A-, where ##STR00175## the radical "A" represents optionally substituted the radical "D" represents ##STR00176## and the radical "M" represents a covalent bond; where the group "A" defined above may optionally be mono- or polysubstituted by a radical selected from the group consisting of halogen; trifluoromethyl; cyano; nitro; carbamoyl; (C.sub.1 C.sub.6)-alkanoyl; --OR.sup.30; --NR.sup.30R.sup.31, and (C.sub.1 C.sub.6)-alkyl, where R.sup.30 and R.sup.31 are identical or different and independently of one another each represents hydrogen, (C.sub.1 C.sub.4)-alkyl, or C(O)R.sup.33, where R.sup.33 represents (C.sub.1 C.sub.4)-aminoalkyl, or (C.sub.1 C.sub.8)-alkyl, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are identical or different and each represents hydrogen or represents (C.sub.1 C.sub.6)-alkyl or a pharmaceutically acceptable salt or hydrate thereof except for compounds of the formula (I) in which the radical R.sup.1 is an unsubstituted 2-thiophene radical and the radical R.sup.2 is simultaneously a mono- or polysubstituted phenyl radical and the radicals R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each simultaneously hydrogen. 2. The compound of the formula (I) according to claim 1, characterized in that R.sup.1 represents thiophene which may optionally be mono- or polysubstituted by halogen, amino, aminomethyl or (C.sub.1 C.sub.8)-alkyl, where the (C.sub.1 C.sub.8)-alkyl radical for its part may optionally be mono- or polysubstituted by halogen, R.sup.2 represents D-M-A-, where the radical "A" represents optionally substituted ##STR00177## the radical "D" represents ##STR00178## and the radical "M" represents a covalent bond; where the group "A" defined above may optionally be mono- or polysubstituted by a radical selected from the group consisting of halogen; trifluoromethyl; cyano; nitro; carbamoyl; (C.sub.1 C.sub.6)-alkanoyl; --OR.sup.30; --NR.sup.30R.sup.31, and (C.sub.1 C.sub.6)-alkyl, where R.sup.30 and R.sup.31 are identical or different and independently of one another each represents hydrogen, (C.sub.1 C.sub.4)-alkyl, (C.sub.1 C.sub.4)-alkanoyl, or (C.sub.1 C.sub.4)-alkylaminocarbonyl, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are identical or different and each represents hydrogen or represents (C.sub.1 C.sub.6)-alkyl or a pharmaceutically acceptable salt or hydrate thereof except for compounds of the formula (I) in which the radical R.sup.1 is an unsubstituted 2-thiophene radical and the radical R.sup.2 is simultaneously a mono- or polysubstituted phenyl radical and the radicals R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each simultaneously hydrogen. 3. The compound of the formula (I) according to claim 1, characterized in that R.sup.1 represents thiophene which may optionally be mono- or polysubstituted by halogen or by (C.sub.1 C.sub.8)-alkyl, where the (C.sub.1 C.sub.8)-alkyl radical for its part may optionally be mono- or polysubstituted by halogen, R.sup.2 represents D-M-A-, where: the radical "A" represents optionally substituted ##STR00179## the radical "D" represents ##STR00180## and the radical "M" represents a covalent bond; where the group "A" defined above may optionally be mono- or polysubstituted by a radical selected from the group consisting of halogen; trifluoromethyl; cyano; (C.sub.1 C.sub.3)-alkanoyl; --OH; --NR.sup.30R.sup.31; and (C.sub.1 C.sub.4)-alkyl; where R.sup.30 and R.sup.31 are identical or different and independently of one another each represents hydrogen, (C.sub.1 C.sub.4)-alkyl or (C.sub.1 C.sub.3)-alkanoyl, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are identical or different and each represents hydrogen or represents (C.sub.1 C.sub.6)-alkyl or a pharmaceutically acceptable salt or hydrate thereof except for compounds of the formula (I) in which the radical R.sup.1 is an unsubstituted 2-thiophene radical and the radical R.sup.2 is simultaneously a mono- or polysubstituted phenyl radical and the radicals R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each simultaneously hydrogen. 4. The compound of the formula (I) according to claim 1, characterized in that R.sup.1 represents 2-thiophene which may optionally be substituted in the 5-position by a radical selected from the group consisting of chlorine, bromine, methyl and trifluoromethyl, R.sup.2 represents D-M-A-, where: the radical "A" represents optionally substituted ##STR00181## the radical "D" represents ##STR00182## and the radical "M" represents a covalent bond; where the group "A" defined above may optionally be mono- or polysubstituted by a radical selected from the group consisting of halogen; trifluoromethyl; cyano; (C.sub.1 C.sub.3)-alkanoyl; --OH; --NR.sup.30R.sup.31; and (C.sub.1 C.sub.4)-alkyl; where R.sup.30 and R.sup.31 are identical or different and independently of one another each represents hydrogen, (C.sub.1 C.sub.4)-alkyl or (C.sub.1 C.sub.3)-alkanoyl, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are identical or different and each represents hydrogen or represents (C.sub.1 C.sub.4)-alkyl or a pharmaceutically acceptable salt or hydrate thereof except for compounds of the formula (I) in which the radical R.sup.1 is an unsubstituted 2-thiophene radical and the radical R.sup.2 is simultaneously a mono- or polysubstituted phenyl radical and the radicals R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each simultaneously hydrogen. 5. The compound of the formula (I) according to claim 1, characterized in that R.sup.1 represents 2-thiophene which is substituted in the 5-position by a radical selected from the group consisting of chlorine, bromine, methyl and trifluoromethyl, R.sup.2 represents D-A-, where: the radical "A" represents ##STR00183## the radical "D" represents ##STR00184## where the group "A" defined above may optionally be mono- or disubstituted in the meta position with respect to the point of attachment to the oxazolidinone, by a radical selected from the group consisting of fluorine, chlorine, nitro, amino, trifluoromethyl, methyl and cyano, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 each represent hydrogen or a pharmaceutically acceptable salt or hydrate thereof. 6. The compound having the following formula ##STR00185## or a pharmaceutically acceptable salt or hydrate thereof. 7. Process for preparing the substituted oxazolidinone of claim 1, where either according to a process alternative (A) a compound of the formula (II) ##STR00186## in which the radicals R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each as defined in claim 1 is reacted with carboxylic acid of the formula (III) ##STR00187## in which the radical R.sup.1 is as defined in claim 1, or else with a corresponding carbonyl halide, or else with a corresponding symmetric or mixed carboxylic anhydride of the carboxylic acid of the formula (III) defined above in an inert solvent, if appropriate in the presence of an activating or coupling agent and/or a base, to give a compound of the formula (I) ##STR00188## in which the radicals R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each as defined in claim 1, or else according to a process alternative (B) a compound of the formula (IV) ##STR00189## in which the radicals R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each as defined in claim 1, is converted, using a suitable selective oxidizing agent in an inert solvent, into the corresponding epoxide of the formula (V) ##STR00190## in which the radicals R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each as defined in claim 1, and, by reaction in an inert solvent, if appropriate in the presence of a catalyst, with an amine of the formula (VI) R.sup.2--NH.sub.2 (VI), in which the radical R.sup.2 is as defined in claim 1, a compound of the formula (VII) ##STR00191## in which the radicals it R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each as defined in claim 1, is initially prepared and, subsequently, in an inert solvent in the presence of phosgene or a phosgene equivalent, cyclized to give a compound of the formula (I) ##STR00192## in which the radicals it R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each as defined in claim 1, where--both for process alternative (A) and for process alternative (B)--in the case where R.sup.2 contains a 3- to 7-membered saturated or partially unsaturated cyclic hydrocarbon radical having one or more identical or different heteroatoms from the group consisting of N and S, an oxidation with a selective oxidizing agent to afford the corresponding sulphone, sulphoxide or N-oxide may follow and/or where--both for process alternative (A) and for process alternative (B)--in the case where the compound prepared in this manner has a cyano group in the molecule, an amidination of this cyano group by customary methods may follow and/or where--both for process alternative (A) and for process alternative (B)--in the case where the compound prepared in this manner has a BOC amino protective group in the molecule, removal of this BOC amino protective group by customary methods may follow and/or where--both for process alternative (A) and for process alternative (B)--in the case where the compound prepared in this manner has an aniline or benzylamine radical in the molecule, a reaction of this amino group with a carboxylic acid, carboxylic anhydride, carbonyl chloride, isocyanate, sulphonyl chloride or alkyl halide to give the corresponding derivative may follow and/or where--both for process alternative (A) and for process alternative (B)--in the case where the compound prepared in this manner has a phenyl ring in the molecule, a reaction with chlorosulphonic acid and subsequent reaction with an amine to give the corresponding sulphonamide may follow. 8. A pharmaceutical composition comprising at least one compound of the formula (I) according to claim 1 and one or more pharmacologically acceptable auxiliaries or excipients. 9. A method for treatment of atherosclerosis comprising administering an effective amount of a compound of claim 1 to a patient in need thereof. 10. The compound of claim 2 or 3 wherein R.sup.1 represents an optionally substituted 2-thiophene group, and wherein said halogen substituent is chlorine or bromine, and said (.sub.1 C.sub.8)-alkyl substituent is methyl, where the methyl radical for its part optionally may be mono- or polysubstituted by fluorine. 11. The process of claim 7 wherein in process alternative "A", the corresponding carbonyl halide of carboxylic acid (III) is a carbonyl chloride. 12. The process of claim 7 wherein in process alternative "B", the phosgene equivalent employed in the cyclization of compound (VII) is carbonyldimidazole (CDI). 13. A method for treatment of a thromboembolic disorder comprising administering to a patient in need thereof an effective amount of a compound of claim 1, wherein the thromboembolic disorder is myocardial infarct, pulmonary embolism or deep venous thrombosis. 14. The compound of claim 6 that is purified and isolated. 15. A racemic mixture of a compound having the following formula ##STR00193## and its enantiomer, or a pharmaceutically acceptable salt or hydrate thereof. 16. A compound having the following formula: ##STR00194## 17. A pharmaceutical composition comprising the compound of claim 6 and one or more pharmacologically acceptable auxiliaries or excipients. 18. A pharmaceutical composition comprising the compound of claim 14 and one or more pharmacologically acceptable auxiliaries or excipients. 19. A pharmaceutical composition comprising the compound of claim 16 and one or more pharmacologically acceptable auxiliaries or excipients. 20. The process of claim 7 wherein the substituted oxazolidinone that is prepared is ##STR00195## or a pharmaceutically acceptable salt or hydrate thereof. 21. A process for the preparation of the compound of claim 6 comprising reacting a compound of the following formula ##STR00196## with 5-chlorothiophene-2-carbonyl chloride in an inert solvent to prepare the compound of claim 6. 22. The process of claim 21 wherein the inert solvent comprises pyridine. 23. A method for the treatment of atherosclerosis comprising administering an effective amount of the composition of claim 17 to a patient in need thereof. 24. A method for the treatment of myocardial infarct, pulmonary embolism or deep venous thrombosis comprising administering an effective amount of the composition of claim 17 to a patient in need thereof. 25. A method for the treatment of atherosclerosis comprising administering an effective amount of the composition of claim 18 to a patient in need thereof. 26. A method for the treatment of myocardial infarct, pulmonary embolism or deep venous thrombosis comprising administering an effective amount of the composition of claim 18 to a patient in need thereof. 27. A composition comprising a compound having formula (a): ##STR00197## or a pharmaceutically acceptable salt or hydrate thereof, wherein the composition is substantially free of the enantiomer of the compound of formula (a) and substantially free of the salts and hydrates of the enantiomer of the compound of formula (a). 28. A pharmaceutical composition comprising the composition of claim 27 and one or more pharmacologically acceptable auxiliaries or excipients. 29. A method for the treatment of atherosclerosis comprising administering an effective amount of the composition of claim 28 to a patient in need thereof. 30. A method for the treatment of myocardial infarct, pulmonary embolism or deep venous thrombosis comprising administering an effective amount of the composition of claim 28 to a patient in need thereof.