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) processes for their preparation and their use as medicinally active compounds for the prophylaxis and/or treatment of disorders are described.

1 . Compounds of the general formula (I) 
       
         
           
           
               
               
           
         
         in which: 
         R 1  represents optionally benzo-fused thiophene (thienyl) which may optionally be mono- or polysubstituted; 
         R 2  represents any organic radical; 
         R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are identical or different and
 each represents hydrogen or represents (C 1 -C 6 )-alkyl 
 
         and their pharmaceutically acceptable salts, hydrates and prodrugs, 
         except for compounds of the general formula (I) in which the radical R 1  is an unsubstituted 2-thiophene radical and the radical R 2  is simultaneously a mono- or polysubstituted phenyl radical and the radicals R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are each simultaneously hydrogen. 
       
     
     
         2 . Compounds of the general formula (I) according to  claim 1 , characterized in that
 R 1  represents optionally benzo-fused thiophene (thienyl) which may optionally be mono- or polysubstituted by a radical from the group consisting of halogen; cyano; nitro; amino; aminomethyl; (C 1 -C 8 )-alkyl which for its part may optionally be mono- or polysubstituted by halogen; (C 3 -C 7 )-cycloalkyl; (C 1 -C 8 )-alkoxy; imidazolinyl; —C(═NH)NH 2 ; carbamoyl; and mono- and di-(C 1 -C 4 )-alkyl-aminocarbonyl,   R 2  represents one of the groups below:
 A-, 
 A-M-, 
 D-M-A-, 
 B-M-A-, 
 B—, 
 B-M-, 
 B-M-B—, 
 D-M-B—,
 where: 
 the radical “A” represents (C 6 -C 14 )-aryl, preferably (C 6 -C 10 )-aryl, in particular phenyl or naphthyl, very particularly preferably phenyl; 
 the radical “B” represents a 5- or 6-membered aromatic heterocycle which contains up to 3 heteroatoms and/or hetero chain members, in particular up to 2 heteroatoms and/or hetero chain members, from the group consisting of S, N, NO (N-oxide) and O; 
 the radical “D” represents a saturated or partially unsaturated, mono- or bicyclic, optionally benzo-fused 4- to 9-membered heterocycle which contains up to three heteroatoms and/or hetero chain members from the group consisting of S, SO, SO 2 , N, NO (N-oxide) and O; 
 the radical “M” represents —NH—, —CH 2 —, —CH 2 CH 2 —, —O—, —NH—CH 2 —, —CH 2 —NH—, —OCH 2 —, —CH 2 O—, —CONH—, —NHCO—, —COO—, —OOC—, —S—, —SO 2 — or represents a covalent bond; 
 where 
 the groups “A”, “B” and “D” defined above may each optionally be mono- or polysubstituted by a radical from the group consisting of halogen; trifluoromethyl; oxo; cyano; nitro; carbamoyl; pyridyl; (C 1 -C 6 )-alkanoyl; (C 3 -C 7 )-cycloalkanoyl; (C 6 -C 14 )-arylcarbonyl; (C 5 -C 10 )-heteroarylcarbonyl; (C 1 -C 6 )-alkanoyloxymethyloxy; (C 1 -C 4 )-hydroxy-alkylcarbonyl; —COOR 27 ; —SO 2 R 27 ; —C(NR 27 R 28 )═NR 29 ; —CONR 28 R 29 ; —SO 2 NR 28 R 29 ; —OR 30 ; —NR 30 R 31 , (C 1 -C 6 )-alkyl and (C 3 -C 7 )-cycloalkyl,
 where (C 1 -C 6 )-alkyl and (C 3 -C 7 )-cycloalkyl for their part may optionally be substituted by a radical from the group consisting of cyano; —OR 27 ; —NR 28 R 29 ; —CO(NH) v (NR 27 R 28 ) and —C(NR 27 R 28 )═NR 29 , 
 
 where: 
 v is either 0 or 1 and 
 R 27 , R 28  and R 29  are identical or different and independently of one another each represents hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 1 -C 4 )-alkanoyl, carbamoyl, trifluoromethyl, phenyl or pyridyl,
 and/or 
 
 R 27  and R 28  or R 27  and R 29  together with the nitrogen atom to which they are attached form a saturated or partially unsaturated 5- to 7-membered heterocycle having up to three, preferably up to two, identical or different heteroatoms from the group consisting of N, O and S, and 
 R 30  and R 31  are identical or different and independently of one another each represents hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 1 -C 4 )-alkylsulphonyl, (C 1 -C 4 )-hydroxyalkyl, (C 1 -C 4 )-aminoalkyl, di-(C 1 -C 4 )-alkylamino-(C 1 -C 4 )-alkyl, —CH 2 C(NR 27 R 28 )═NR 29  or —COR 33 ,
 where 
 R 33  represents (C 1 -C 6 )-alkoxy, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxycarbonyl-(C 1 -C 4 )-alkyl, (C 1 -C 4 )-aminoalkyl, (C 1 -C 4 )-alkoxycarbonyl, (C 1 -C 4 )-alkanoyl-(C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 1 -C 6 )-alkenyl, (C 1 -C 8 )-alkyl, which may optionally be substituted by phenyl or acetyl, (C 6 -C 14 )-aryl, (C 5 -C 10 )-heteroaryl, trifluoromethyl, tetrahydrofuranyl or butyrolactone, 
 
 
   R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are identical or different and
 each represents hydrogen or represents (C 1 -C 6 )-alkyl 
   and their pharmaceutically acceptable salts, hydrates and prodrugs,   except for compounds of the general formula (I) in which the radical R 1  is an unsubstituted 2-thiophene radical and the radical R 2  is simultaneously a mono- or polysubstituted phenyl radical and the radicals R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are each simultaneously hydrogen.   
     
     
         3 . Compounds of the general formula (I) according to  claim 1 , characterized in that
 R 1  represents thiophene (thienyl), in particular 2-thiophene, which may optionally be mono- or polysubstituted by halogen, preferably chlorine or bromine, by amino, aminomethyl or (C 1 -C 8 )-alkyl, preferably methyl, where the (C 1 -C 8 )-alkyl radical for its part may optionally be mono- or polysubstituted by halogen, preferably fluorine,   R 2  represents one of the groups below:
 A-, 
 A-M-, 
 D-M-A-, 
 B-M-A-, 
 B—, 
 B-M-, 
 B-M-B—, 
 D-M-B—,
 where: 
 the radical “A” represents (C 6 -C 14 )-aryl, preferably (C 6 -C 10 )-aryl, in particular phenyl or naphthyl, very particularly preferably phenyl; 
 the radical “B” represents a 5- or 6-membered aromatic heterocycle which contains up to 3 heteroatoms and/or hetero chain members, in particular up to 2 heteroatoms and/or hetero chain members, from the group consisting of S, N, NO (N-oxide) and O; 
 the radical “D” represents a saturated or partially unsaturated 4- to 7-membered heterocycle which contains up to three heteroatoms and/or hetero chain members from the group consisting of S, SO, SO 2 , N, NO (N-oxide) and O; 
 the radical “M” represents —NH—, —CH 2 —, —CH 2 CH 2 —, —O—, —NH—CH 2 —, —CH 2 —NH—, —OCH 2 —, —CH 2 O—, —CONH—, —NHCO—, —COO—, —OOC—, —S— or represents a covalent bond; 
 where 
 the groups “A”, “B” and “D” defined above may in each case optionally be mono- or polysubstituted by a radical from the group consisting of halogen; trifluoromethyl; oxo; cyano; nitro; carbamoyl; pyridyl; (C 1 -C 6 )-alkanoyl; (C 3 -C 7 )-cycloalkanoyl; (C 6 -C 14 )-arylcarbonyl; (C 5 -C 10 )-heteroaryl-carbonyl; (C 1 -C 6 )-alkanoyloxymethyloxy; —COOR 27 ; —SO 2 R 27 ; —C(NR 27 R 28 )═NR 29 ; —CONR 28 R 29 ; —SO 2 NR 28 R 29 ; —OR 30 ; —NR 30 R 31 , (C 1 -C 6 )-alkyl and (C 3 -C 7 )-cycloalkyl,
 where (C 1 -C 6 )-alkyl and (C 3 -C 7 )-cycloalkyl for their part may optionally be substituted by a radical from the group consisting of cyano; —OR 27 ; —NR 28 R 29 ; —CO(NH) v (NR 27 R 28 ) and —C(NR 27 R 28 )═NR 29 , 
 
 where: 
 v is either 0 or 1 and 
 R 27 , R 28  and R 29  are identical or different and independently of one another each represents hydrogen, (C 1 -C 4 )-alkyl or (C 3 -C 7 )-cycloalkyl,
 and/or 
 
 R 27  and R 28  or R 27  and R 29  together with the nitrogen atom to which they are attached form a saturated or partially unsaturated 5- to 7-membered heterocycle having up to three, preferably up to two, identical or different heteroatoms from the group consisting of N, O and S, and 
 R 30  and R 31  are identical or different and independently of one another each represents hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 1 -C 4 )-alkylsulphonyl, (C 1 -C 4 )-hydroxyalkyl, (C 1 -C 4 )-aminoalkyl, di-(C 1 -C 4 )-alkylamino-(C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkanoyl, (C 6 —O 14 )-arylcarbonyl, (C 5 -C 10 )-heteroarylcarbonyl, (C 1 -C 4 )-alkylaminocarbonyl or —CH 2 C(NR 27 R 28 )═NR 29 , 
 
   R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are identical or different and
 each represents hydrogen or represents (C 1 -C 6 )-alkyl 
   and their pharmaceutically acceptable salts, hydrates and prodrugs,   except for compounds of the general formula (I) in which the radical R 1  is an unsubstituted 2-thiophene radical and the radical R 2  is simultaneously a mono- or polysubstituted phenyl radical and the radicals R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are each simultaneously hydrogen.   
     
     
         4 . Compounds of the general formula (I) according to  claim 1 , characterized in that
 R 1  represents thiophene (thienyl), in particular 2-thiophene, which may optionally be mono- or polysubstituted by halogen, preferably chlorine or bromine, or by (C 1 -C 8 )-alkyl, preferably methyl, where the (C 1 -C 8 )-alkyl radical for its part may optionally be mono- or polysubstituted by halogen, preferably fluorine,   R 2  represents one of the groups below:
 A-, 
 A-M-, 
 D-M-A-, 
 B-M-A-, 
 B—, 
 B-M-, 
 B-M-B—, 
 D-M-B—,
 where: 
 the radical “A” represents phenyl or naphthyl, in particular phenyl; 
 the radical “B” represents a 5- or 6-membered aromatic heterocycle which contains up to 2 heteroatoms from the group consisting of S, N, NO (N-oxide) and O; 
 the radical “D” represents a saturated or partially unsaturated 5- or 6-membered heterocycle which contains up to two heteroatoms and/or hetero chain members from the group consisting of S, SO, SO 2 , N, NO (N-oxide) and O; 
 the radical “M” represents —NH—, —O—, —NH—CH 2 —, —CH 2 —NH—, —OCH 2 —, —CH 2 O—, —CONH—, —NHCO— or represents a covalent bond; 
 where 
 the groups “A”, “B” and “D” defined above may in each case optionally be mono- or polysubstituted by a radical from the group consisting of halogen; trifluoromethyl; oxo; cyano; pyridyl; (C 1 -C 3 )-alkanoyl; (C 6 -C 10 )-arylcarbonyl; (C 5 -C 6 )-heteroarylcarbonyl; (C 1 -C 3 )-alkanoyloxymethyloxy; —C(NR 27 R 28 )═NR 29 ; —CONR 28 R 29 ; —SO 2 NR 28 R 29 ; —O H; —NR 30 R 31 ; (C 1 -C 4 )-alkyl; and cyclopropyl, cyclopentyl or cyclohexyl,
 where (C 1 -C 4 )-alkyl and cyclopropyl, cyclopentyl or cyclohexyl for their part may optionally be substituted by a radical from the group consisting of cyano; —OH; —OCH 3 ; —NR 28 R 29 ; —CO(NH) v (NR 27 R 28 ) and —C(NR 27 R 28 )═NR 29 , 
 
 where: 
 v is either 0 or 1, preferably 0, and 
 R 27 , R 28  and R 29  are identical or different and independently of one another each represents hydrogen, (C 1 -C 4 )-alkyl or else cyclopropyl, cyclopentyl or cyclohexyl and/or 
 R 27  and R 28  or R 27  and R 29  together with the nitrogen atom to which they are attached may form a saturated or partially unsaturated 5- to 7-membered heterocycle having up to two identical or different heteroatoms from the group consisting of N, O and S, and 
 R 30  and R 31  are identical or different and independently of one another each represents hydrogen, (C 1 -C 4 )-alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (C 1 -C 4 )-alkylsulphonyl, (C 1 -C 4 )-hydroxyalkyl, (C 1 -C 4 )-aminoalkyl, di-(C 1 -C 4 )-alkylamino-(C 1 -C 4 )-alkyl, (C 1 -C 3 )-alkanoyl or phenylcarbonyl, 
 
   R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are identical or different and
 each represents hydrogen or represents (C 1 -C 6 )-alkyl 
   and their pharmaceutically acceptable salts, hydrates and prodrugs,   except for compounds of the general formula (I) in which the radical R 1  is an unsubstituted 2-thiophene radical and the radical R 2  is simultaneously a mono- or polysubstituted phenyl radical and the radicals R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are each simultaneously hydrogen.   
     
     
         5 . Compounds of the general formula (I) according to  claim 1 , characterized in that
 R 1  represents 2-thiophene which may optionally be substituted in the 5-position by a radical from the group consisting of chlorine, bromine, methyl or trifluoromethyl,   R 2  represents one of the groups below:
 A-, 
 A-M-, 
 D-M-A-, 
 B-M-A-, 
 B—, 
 B-M-, 
 B-M-B—, 
 D-M-B—,
 where: 
 the radical “A” represents phenyl or naphthyl, in particular phenyl; 
 the radical “B” represents a 5- or 6-membered aromatic heterocycle which contains up to 2 heteroatoms from the group consisting of S, N, NO (N-oxide) and O; 
 the radical “D” represents a saturated or partially unsaturated 5- or 6-membered heterocycle which contains a nitrogen atom and optionally a further heteroatom and/or hetero chain member from the group consisting of S, SO, SO 2  and 0; or contains up to two heteroatoms and/or hetero chain members from the group consisting of S, SO, SO 2  and O; 
 the radical “M” represents —NH—, —O—, —NH—CH 2 —, —CH 2 —NH—, —OCH 2 —, —CH 2 O—, —CONH—, —NHCO— or represents a covalent bond; 
 where 
 the groups “A”, “B” and “D” defined above may in each case optionally be mono- or polysubstituted by a radical from the group consisting of halogen; trifluoromethyl; oxo; cyano; pyridyl; (C 1 -C 3 )-alkanoyl; (C 6 -C 10 )-arylcarbonyl; (C 5 -C 6 )-heteroarylcarbonyl; (C 1 -C 3 )-alkanoyloxymethyloxy; —CONR 28 R 29 ; —SO 2 NR 28 R 29 ; —OH; —NR 30 R 31 ; (C 1 -C 4 )-alkyl; and cyclopropyl, cyclopentyl or cyclohexyl,
 where (C 1 -C 4 )-alkyl and cyclopropyl, cyclopentyl or cyclohexyl for their part may optionally be substituted by a radical from the group consisting of cyano; —OH; —OCH 3 ; —NR 28 R 29 ; —CO(NH) v (NR 27 R 28 ) and —C(NR 27 R 28 )═NR 29 , 
 
 where: 
 v is either 0 or 1, preferably 0, and 
 R 27 , R 28  and R 29  are identical or different and independently of one another each represents hydrogen, (C 1 -C 4 )-alkyl or else cyclopropyl, cyclopentyl or cyclohexyl 
 and/or 
 R 27  and R 28  or R 27  and R 29  together with the nitrogen atom to which they are attached may form a saturated or partially unsaturated 5- to 7-membered heterocycle having up to two identical or different heteroatoms from the group consisting of N, O and S, and 
 R 30  and R 31  are identical or different and independently of one another each represents hydrogen, (C 1 -C 4 )-alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (C 1 -C 4 )-alkylsulphonyl, (C 1 -C 4 )-hydroxyalkyl, (C 1 -C 4 )-aminoalkyl, di-(C 1 -C 4 )-alkylamino-(C 1 -C 4 )-alkyl, (C 1 -C 3 )-alkanoyl or phenylcarbonyl, 
 
   R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are identical or different and
 each represents hydrogen or represents (C 1 -C 4 )-alkyl 
   and their pharmaceutically acceptable salts, hydrates and prodrugs,   except for compounds of the general formula (I) in which the radical R 1  is an unsubstituted 2-thiophene radical and the radical R 2  is simultaneously a mono- or polysubstituted phenyl radical and the radicals R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are each simultaneously hydrogen.   
     
     
         6 . Compounds of the general formula (I) according to  claim 1 , characterized in that
 R 1  represents 2-thiophene which is substituted in the 5-position by a radical from the group consisting of chlorine, bromine, methyl and trifluoromethyl,   R 2  represents D-A-:
 where: 
 the radical “A” represents phenylene; 
 the radical “D” represents a saturated 5- or 6-membered heterocycle, which is attached to “A” via a nitrogen atom, 
 which has a carbonyl group directly adjacent to the linking nitrogen atom and 
 in which one carbon ring member may be replaced by a heteroatom from the group consisting of S, N and O; 
 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 from the group consisting of fluorine, chlorine, nitro, amino, trifluoromethyl, methyl and cyano, 
   R 3 , R 4 , R 5 , R 6 , R 7  and R 8  each represent hydrogen   and their pharmaceutically acceptable salts, hydrates and prodrugs.   
     
     
         7 . Compound according to  claim 1  having the following formula 
       
         
           
           
               
               
           
         
       
       and its pharmaceutically acceptable salts, hydrates and prodrugs. 
     
     
         8 . Process for preparing substituted oxazolidinones according to  claim 1 ,
 where   either according to a process alternative   [A] compounds of the general formula (II)   
       
         
           
           
               
               
           
         
         
           in which 
           the radicals R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are each as defined in  claim 1  are reacted with carboxylic acids of the general formula (III) 
         
       
       
         
           
           
               
               
           
         
         
           in which 
           the radical R 1  is as defined in  claim 1 , 
         
         or else with the corresponding carbonyl halides, preferably carbonyl chlorides, or else with the corresponding symmetric or mixed carboxylic anhydrides of the carboxylic acids of the general formula (III) defined above in inert solvents, if appropriate in the presence of an activating or coupling agent and/or a base, to give compounds of the general formula (I) 
       
       
         
           
           
               
               
           
         
         
           in which 
           the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are each as defined in  claim 1 , or else according to a process alternative 
         
         [B] compounds of the general formula (IV) 
       
       
         
           
           
               
               
           
         
         
           in which 
           the radicals R 1 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are each as defined in  claim 1 , 
         
         are converted, using a suitable selective oxidizing agent in an inert solvent, into the corresponding epoxide of the general formula (V) 
       
       
         
           
           
               
               
           
         
         
           in which 
           the radicals R 1 , R 3 , R 4 , R 5 , R 6 , R 7  and R 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 general formula (VI)
   R 2 —NH 2   (VI),
 
 in which 
 the radical R 2  is as defined in  claim 1 , 
 
         the compounds of the general formula (VII) 
       
       
         
           
           
               
               
           
         
         
           in which 
           the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are each as defined in  claim 1 , 
         
         are initially prepared and, 
         subsequently, in an inert solvent in the presence of phosgene or phosgene equivalents, such as, for example, carbonyldiimidazole (CDI), cyclized to give the compounds of the general formula (I) 
       
       
         
           
           
               
               
           
         
         
           in which 
           the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are each as defined in  claim 1 , 
         
         where—both for process alternative [A] and for process alternative [B]—in the case where R 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 various reagents such as carboxylic acids, carboxylic anhydrides, carbonyl chlorides, isocyanates, sulphonyl chlorides or alkyl halides to give the corresponding derivatives 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 amines to give the corresponding sulphonamides may follow. 
       
     
     
         9 . Medicaments, comprising at least one compound of the general formula (I) according to  claim 1  and one or more pharmacologically acceptable auxiliaries or excipients. 
     
     
         10 . Use of compounds of the general formula (I) 
       
         
           
           
               
               
           
         
         in which: 
         R 1  represents optionally benzo-fused thiophene (thienyl) which may optionally be mono- or polysubstituted; 
         R 2  represents any organic radical; 
         R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are identical or different and
 each represents hydrogen or represents (C 1 -C 6 )-alkyl 
 
         and their pharmaceutically acceptable salts, hydrates and prodrugs, 
         for preparing medicaments or pharmaceutical compositions for the prophylaxis and/or treatment of thromboembolic disorders, in particular myocardial infarct, angina pectoris (including unstable angina), reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transitory ischaemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thromboses. 
       
     
     
         11 . Use of compounds of the general formula (I) according to  claim 10  for preparing medicaments or pharmaceutical compositions for the prophylaxis and/or treatment of disorders which are influenced positively by inhibition of factor Xa. 
     
     
         12 . Use of compounds of the general formula (I) according to  claim 10  for preparing medicaments or pharmaceutical compositions for the treatment of disseminated intravascular coagulation (DIC). 
     
     
         13 . Use of compounds of the general formula (I) according to  claim 10  for preparing medicaments or pharmaceutical compositions for the prophylaxis and/or treatment of disorders such as atherosclerosis; arthritis; Alzheimer's disease or cancer. 
     
     
         14 . Use of compounds of the general formula (I) according to  claim 10  for preparing medicaments or pharmaceutical compositions for the inhibition of factor Xa. 
     
     
         15 . Method for preventing the coagulation of blood in vitro, in particular in the case of banked blood or biological samples containing factor Xa, characterized in that compounds of the general formula (I) according to  claim 10  are added.