AU2004202422B2 - Substituted oxazolidinones and their use in the field of blood coagulation - Google Patents

Description

Our Ref: 12259411 P/00/011 Regulation 3:2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): Bayer Aktiengesellschaft Patente und Lizenzen 51368 Leverkusen Germany Address for Service: Invention Title: DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street Sydney, New South Wales, Australia, 2000 Substituted oxazolidinones and their use in the field of blood coagulation The following statement is a full description of this invention, including the best method of performing it known to me:- 5951 WO 01/47919 PCT/EP00/12492 -1- SUBSTITUTED OXAZOLIDINES AND THEIR USE IN THE FIELD OF BLOOD COAGULATION The present invention relates to the field of blood coagulation. In particular, the present invention relates to novel oxazolidinone derivatives, to processes for their preparation and to their use as active compounds in medicaments.

Blood coagulation is a protective mechanism of the organism which helps to "seal" defects in the wall of the blood vessels quickly and reliably. Thus, loss of blood can be avoided or kept to a minimum. Haemostasis after injury of the blood vessels is effected mainly by the coagulation system in which an enzymatic cascade of complex reactions of plasma proteins is triggered. Numerous blood coagulation factors are involved in this process, each of which factors converts, on activation, the respectively next inactive precursor into its active form. At the end of the cascade comes the conversion of soluble fibrinogen into insoluble fibrin, resulting in the formation of a blood clot. In blood coagulation, traditionally the intrinsic and the extrinsic system, which end in a joint reaction path, are distinguished. Here factor Xa, which is formed from the proenzyme factor X, plays a key role, since it connects the two coagulation paths. The activated serine protease Xa cleaves prothrombin to thrombin. The resulting thrombin, in turn, cleaves fibrinogen to fibrin, a fibrous/gelatinous coagulant. In addition, thrombin is a potent effector of platelet aggregation which likewise contributes significantly to haemostasis.

Maintenance of normal haemostasis between bleeding and thrombosis is subject to a complex regulatory mechanism. Uncontrolled activation of the coagulant system or defective inhibition of the activation processes may cause formation of local thrombi or embolisms in vessels (arteries, veins, lymph vessels) or in heart cavities. This may lead to serious disorders, such as myocardial infarct, angina pectoris (including unstable angina), reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transitory ischaemic attacks, peripheral arterial occlusive disorders, pulmonary embolisms or deep venous thromboses; hereinbelow, these disorders are collectively also referred to as thromboembolic disorders. In addition, in the case of consumption coagulopathy, hypercoagulability may systemically result in disseminated intravascular coagulation.

These thromboembolic disorders are the most frequent cause of morbidity and mortality in most industrialized countries (Pschyrembel, Klinisches Worterbuch [clinical dictionary], 2 5 7 th edition, 1994, Walter de Gruyter Verlag, page 199 ff., entry "Blutgerinnung" [blood coagulation]; Rimpp Lexikon Chemie, Version 1998, Georg Thieme Verlag Stuttgart, entry "Blutgerinnung"; Lubert Stryer, Biochemie [biochemistry], Spektrum der Wissenschaft Verlagsgesellschaft mbH Heidelberg, 1990, page 259 ff.).

The anticoagulants, i.e. substances for inhibiting or preventing blood coagulation, which are known from the prior art have various, often grave disadvantages.

Accordingly, in practice, an efficient treatment method or prophylaxis of thromboembolic disorders is very difficult and unsatisfactory.

In the therapy and prophylaxis of thromboembolic disorders, use is firstly made of heparin, which is administered parenterally or subcutaneously. Owing to more favourable pharmacokinetic properties, preference is nowadays more and more given to low-molecular-weight heparin; however, even with low-molecular-weight heparin, it is not possible to avoid the known disadvantages described below, which are involved in heparin therapy. Thus, heparin is ineffective when administered orally and has a relatively short half-life. Since heparin inhibits a plurality of factors of the blood coagulation cascade at the same time, the action is nonselective. Moreover, there is a high risk of bleeding; in particular, brain haemorrhages and gastrointestinal bleeding may occur, which may result in thrombopenia, drug-induced alopecia or osteoporosis (Pschyrembel, Klinisches Worterbuch, 257 th edition, 1994, Walter de Gruyter Verlag, page 610, entry "Heparin"; Rompp Lexikon Chemie, Version 1998, Georg Thieme Verlag Stuttgart, entry "Heparin").

A second class of anticoagulants are the vitamin K antagonists. These include, for example, 1,3-indanediones, and especially compounds such as warfarin, phenprocoumon, dicumarol and other coumarin derivatives which inhibit the synthesis of various products of certain vitamin K-dependent coagulation factors in the liver in a non-selective manner. Owing to the mechanism of action, however, the onset of the action is very slow (latency to the onset of action 36 to 48 hours). It is possible to administer the compounds orally; however, owing to the high risk of bleeding and the narrow therapeutic index, a time-consuming individual adjustment and monitoring of the patient are required. Moreover, other adverse effects, such as -3gastrointestinal disturbances, hair loss and skin necroses, have been described (Pschyrembel, Klinisches Worterbuch, 2 5 7 th edition, 1994, Walter de Gruyter Verlag, page 292 ff., entry "coumarin derivatives"; Ullmann's Encyclopedia of Industrial Chemistry, 5 h edition, VCH Verlagsgesellschaft, Weinheim, 1985- 1996, entry "vitamin Recently, a novel therapeutic approach for the treatment and prophylaxis of thromboembolic disorders has been described. This novel therapeutic approach aims to inhibit factor Xa (cf. WO-A-99/37304; WO-A-99/06371; J. Hauptmann, J. Sttirzebecher, Thrombosis Research 1999, 93, 203; F. Al-Obeidi, J. A. Ostrem, Factor Xa inhibitors by classical and combinatorial chemistry, DDT 1998, 3, 223; F. Al-Obeidi, J. A. Ostrem, Factor Xa inhibitors, Exp. Opin. Ther. Patents 1999, 9, 931; B. Kaiser, Thrombin and factor Xa inhibitors, Drugs of the Future 1998, 23, 423; A. Uzan, Antithrombotic agents, Emerging Drugs 1998, 3, 189; Zhu, R. M. Scarborough, Curr. Opin. Card. Pulm. Ren. Inv. Drugs 1999, 1 63). It has been shown that, in animal models, various both peptidic and nonpeptidic compounds are effective as factor Xa inhibitors.

Accordingly, it is an object of the present invention to provide novel substances for controlling disorders, which substances have a wide therapeutic spectrum.

In particular, they should be suitable for a more efficient prophylaxis and/or treatment of thromboembolic disorders, avoiding at least to some extent the -disadvantages-of-the-prioar t describedabove, where the-term-"thromboembolic disorders" in the context of the present invention is to be understood as meaning, in particular, serious disorders, such as myocardial infarct, angina pectoris (including unstable angina), reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transitory ischaemic attacks, peripheral arterial occlusive disorders, pulmonary embolisms or deep venous thromboses.

It is another object of the present invention to provide novel anticoagulants which inhibit the blood coagulation factor Xa with increased selectivity, avoiding at least to some extent- the problems of the therapeutic methods for thromboembolic disorders known from the prior art.

P WPI)OCS\CRNJX ISPCC\I22594I doc-2210''2K)7 3a- A first aspect of the invention provides a compound of the general formula (I) 0 in which: R represents thiophene (thienyl) which is mono- or polysubstituted by a radical from the group consisting of halogen; (Ci-Cs)-alkyl or trifluoromethyl, R represents one of the groups below:

A-,

D-M-A-,

where: the radical represents phenyl; the radical represents a saturated or partially unsaturated, ono- or bicyclic 4to 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 represents -CH 2

-SO

2 or represents a covalent bond; where the groups and defined above may each optionally be mono- or polysubstituted by a radical from the group consisting of halogen; trifluoromethyl; oxo; cyano; nitro; carbamoyl; pyridyl; (Ci-C,)-alkanoyl; (Ci-C 4 )-hydroxyalkylcarbonyl; -COOR 27 -CONR 28R2; -S0 2

NR

28

R

29

-OR

30 -NR30R 31 (Ci-C 6 alkyl and (C 3

-C

7 )-cycloalkyl, P \WPD0CSCRNVJXJSpcc%12259411 doc-2211O/2007 3b Z where (CI-C 6 -alkyl for its part may optionally be substituted by a radical from the group consisting of cyano; -OR 27

-NR

28 R 2 and -C(NR 27

R

28 )=NR 29 where: 27 2 29) R R 2 and R 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 )-alkanloyl, carbamoyl, tri fl uorom ethyl, phenyl or pyridyl, and/or R 27and R 21or R 27and R 29together with the nitrogen atom to which they are attached form a saturated or partially unsaturated 5- to 7-membered heterocycle having up to three, identical or different hieteroatoms from the group consisting of N, 0 and S, and R 30 and R 3 1are identical or different and independently of one another each represents hydrogen, (C 1

-C

4 )-alkyl, (C 3 -C+)cycloalkyl, (C I -C 4 hydroxyalkyl or -C0R 33 where R 3 represents (C 1 -C()-alkoxy, (C 1

-C

4 )-alkoxy-(Ci -C 4 )-alkyl, (C -C 4 alkoxycarbonyl-(CI -C 4 )-alkyl, (C 1

-C

4 )-aminoalkyl, (C 1 I -C 4 alkoxycarbonyl, (C 1

-C

4 )-alkanoyl-(C 1

-C

4 )-alkylI, (C 3

-C

7 )-cycloalkyl, (C 2

C

6 -alkenyl, (C 1 -C8)-alkyl, which may optionally be substituted by phenyl or acetyl, (C6,-C 1 4 )-aryl, (C 5

-C

1 o)-heteroaryl, tri fluoromethyl, tetrahydrofuranyl or butyrolactone, R R Re', R' and R 8 each represents hydrogen and their pharmaceutically acceptable salts, hydrates, hydrates of salts and prodrugs, P\WPDOCS\CRN'JXJ'SpCI 12294 11 dm-22IIO2007

O

0 -3c- Z except for compounds of the general formula in which

ID

R' represents 2-thiophene which is substituted in the 5-position by a radical from the group consisting of chlorine, bromine, methyl and trifluoromethyl, 2 1 R 2 represents D-A-: where: the radical represents phenylene; the radical represents a saturated 5- or 6-membered heterocycle, which is attached to 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 0; where the group 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.

A second aspect of the invention provides a process for preparing a substituted oxazolidinone according to the first aspect where either according to a process alternative

[A]

compounds of the general fonnula (II) P \WPDOCS'CRN JXJSpa%122 S94I I do.22/102007 3d

O

R 2R R3 R 6 R

R

7

(II)

HN 8

\R

8 in which the radicals R 2 R, R4, R 5

R

6

R

7 and R are each as defined in the first aspect are reacted with carboxylic acids of the general formula ([II) HO R

T

(III),

in which the radical R' is as defined in the first aspect, or else with the corresponding carbonyl halides, 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) P:\WPDOCS\CRN'JXJ'Sprc 1225I)41 I doc-22/10'2007 3e-

O

N 0 R3

R

4

-R

7 R -N R in which the radicals R R 3 R R, R R 7 and R 8 are each as defined in the first aspect or else according to a process alternative compounds of the general formula (IV)

R

3

R

6

R

7 0

R

5 R R

(IV),

in which the radicals R R 4

R

5

R

7 and R 8 are each as defined in the first aspect.

are converted, using a suitable selective oxidizing agent in an inert solvent, into the corresponding epoxide of the general formula (V) P \WPIX)C'CWRN'JXASjpckI 2259.f I d-22/IO 2(X]7 3f-

R

3

R

6

R

7 0

R

s 5 R R in which the radicals R 3

R

4

R

5

R

7 and R 8 are each as defined in the first aspect and, by reaction in an inert solvent, if appropriate in the presence of a catalyst, with an amine of the general formula (VI) R2-NH2 (VI), in which the radical R 2 is as defined in the first aspect the compounds of the general formula (VII)

(VII),

in which the radicals R 2 R R 4 R R 6

R

7 and R 8 are each as defined in the first aspect are initially prepared and, P \WPDOCS'CRNJXJSpCc\I2259-t I doc-22/10/2007 3gsubsequently, 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 (1) N 0 3 0 in which the radicals R R 2 R R 4 R R 7 and R 8 are each as defined in the first aspect where both for process alternative and for process alternative 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 and for process alternative 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 P\WPIDOCS\CRN\JXJ\Spc\122S941 I dc-221I102007 Q- 3h

O

Z where both for process alternative and for process alternative in the case IN where the compound prepared in this manner has a BOC amino protective group in 0 the molecule, removal of this BOC amino protective group by customary methods Cmay follow

(N

Sand/or

(N

Swhere both for process alternative and for process alternative 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 and for process alternative 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.

A third aspect of the invention provides a medicament comprising at least one compound of the general formula according to the first aspect and one or more pharmacologically acceptable auxiliaries or excipients.

A fourth aspect of the invention provides the use of a compound of the general formula (1) according to the first aspect, in the manufacture of a medicament or pharmaceutical composition for the prophylaxis and/or treatment of thromboembolic disorders.

A fifth aspect of the invention provides the use of a compound according to the first aspect, in the manufacture of a medicament or pharmaceutical composition for the prophylaxis and/or treatment of disorders which are influenced positively by inhibition of factor Xa.

P WPIDOCS'CRN\JXiASpM\I225941 I d- 22/IO2007 -3i 0 A sixth aspect of the invention provides the use of a compound according to the first I0 aspect, in the manufacture of a pharmaceutical composition for the treatment of disseminated intravascular coagulation (DIC).

A seventh aspect of the invention provides the use of a compound according to the first 0aspect in the manufacture of a pharmaceutical composition for the prophylaxis and/or treatment of disorders such as atherosclerosis; arthritis; Alzheimer's disease or cancer.

An eighth aspect of the invention provides the use of a compound according to the first aspect, in the manufacture of a pharmaceutical composition for the inhibition of factor Xa.

A ninth aspect of the invention provides a method for the prevention of the coagulation of blood in vitro, the method comprising adding to said blood at least one compound according to the first aspect.

A tenth aspect of the invention provides the use of a compound according to the first aspect for preventing the coagulation of blood ex vivo.

An eleventh aspect of the invention provides the use of a compound according to the first aspect for preventing coagulation ex vivo for biological samples which contain factor Xa.

A twelth aspect of the invention provides a method for the treatment of disorders which are influenced positively by inhibition of factor Xa in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound according to the first aspect.

A thirteenth aspect of the invention provides a method for the treatment of thromboembolic disorders in a subject, the method comprising administering to the subject a phanraceutical composition comprising a compound according to the first aspect.

P\WPL)OCS'CRN1XJ\Spcc\2259411 doc.22/10/2007 O(3 O- 3j

O

Z A fourteenth aspect of the invention provides a method for the treatment of disseminated I intravascular coagulation (DIC) in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound according to the first aspect.

A fifteenth aspect of the invention provides a method for the treatment of a disorder Sselected from atherosclerosis; arthritis; Alzheimer's disease or cancer in a subject, the

(N

Smethod comprising administering to the subject a pharmaceutical composition comprising 0 a compound according to the first aspect.

Herein disclosed are substituted oxazoldinones of the general formula (1) 0 2 R,

N

.R ,R 6 RL_-yN 0 in which.represents optionally benzo-fused thiophene. (thienyl) wvhich may optionally be mono- or polysubstitu ted; 10'1

R

represents any organic radical;, Rz;, R' and R 8 are identical or different and each represents hydrogen or represents (CI-C 6 )-alkyl I and I e'p rict ly.Icucjpiabic -s hydfaics a1nd piut~I except for compounds of the general formula in which the radical R' is an unsubstituted 2-thiophene. radical and the radical R 2is simultaneously a mono- or 3 4 58 polysubstituted phenyl radical and the radicals R R, R' and R are each simultaneously hydrogen.

Preference is given here to compounds of the general formula in which R I represents optionally benzo-fused thiophene (thienyl) which may optionally be mono- or polysubstiruted by a radical from the gr-oup consisting of halogen; cyano; nitro; amnino- amninomrhdw;

(C

1

-C

8 )-alkyI which for- its part n y optionally he mono- or polvsubrtiuted by halogen; 7 )-cycloalkyJ: (C,-C8)-alkoxy; imidazolinyl; -C(=NH)NH 2 carbamoyl; and mono- and di-

(C

1 -C4)-alkyl-aminocarbonyl, R 2 represents one of the groups below:

A-,

A-M-,

D-M-A-,

B-M-A-,

B-,

B-M-B-,

D-M-B-,

where: the radical represents (C 6

-C

14 )-aryl, preferably (C 6 -Clo)-aryl, in particular phenyl or naphthyl, very particularly preferably phenyl; the radical 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 0; the radical represents a saturated or partially unsaturated, monoor bicyclic, optionally benzo-fused 4- to 9-membered heterocycle which contains up to three heteroatoms and/or hetero chain members -_____-from-the-group-consistii-of-S'-SO, SOf' NyNOjN- oxide)-and 0; the radical represents -NHl-, -CH 2

-CH

2

CH

2

-NH-CU

2

-CH

2 -NII-, -OCH 2

-CH

2 -CONEI-, -NHCO-, -COO-, -OOC-,

-SO

2 or represents a covalent bond; where the groups and 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 )-al kanoyl; (C 3

-C

7 )-cyc loalkanoyl; (C 6

-C

1 4 )-arylcarbonyl; (C 5

-C

1

O)-

heteroaryl carbon yl; (C 1

-C

6 )-al kanoyloxymethyloxy;

(C

1 -Cil)-hydroxyalkylcarbonyl; -C00R 27 -S0 2 R 27 -C(N1R 27

R

28 )=NR 29 -C0NR 28 R 29 -S0 2

NR

28

R

29 -OR 30 -NR 30

R

31

(C]-C

6 )-alkyl and (C 3 -C7)-cycloalkyl, where (CI-C 6 )-alkyl and (C 3 -C+)Cycloalkyl for their part may optionally be substituted by a radical from the group consisting of cyano; -OR 2; -NR2 R 2; -CO(NH),(NR2 R 2) and ~-C(NR2 R 2)=N29, where: V is either 0or I and R 27, R 2'and R 29are 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 27and R 2 1 or R 27 and R 29together 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, 0 and S, and R 30 adR 3 1 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,

-CII

2 C(NR 27 R 2

)=NR

29 or -C0R 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 amninoalkyl, (C 1

-C

4 )-alkox ycarbonyl, (I -C4)-alkanoyl-

(C

1

-C

4 )-alkyl, (C 3

-C

7 )-cycl oalkyl, (C 1

-C

6 )-alkenyl, (CI-C8)-alkyl, which may optionally be substituted by -7phenyl or acetyl, (C 6

-C

1 4 )-aryl, (Cs-Clo)-heteroaryl, trifluoromethyl, tetrahydrofuranyl or butyrolactone,

R

3

R

4 R, R R 7 and R 8 are identical or different and each represents hydrogen or represents (Ci-C 6 )-alkyl and their pharmaceutically acceptable salts, hydrates and prodrugs, except for compounds of the general formula in which the radical R' 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.

Preference is also given here to compounds of the general formula in which R' represents thiophene (thienyl), in particular 2-thiophene, which may optionally be mono- or polysubstituted by halogen, preferably chlorine or bromine, by amino, aminomethyl or (Ci-Cs)-alkyl, preferably methyl, where the (Ci-Cs)-alkyl radical for its part may optionally be mono- or polysubstituted by halogen, preferably fluorine,

R

2 represents-one fthegroups-below:-

A-,

A-M-,

D-M-A-,

B-M-A-,

B-,

B-M-,

B-M-B-,

D-M-B-,

where: the radical represents (C 6

-C

14 )-aryl, preferably (C 6 -Cio)-aryl, in particular phenyl or naphthyl, very particularly preferably phenyl; the radical 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 0; the radical represents a saturated or partially unsaturated 4- to 7membered 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 0; the radical represents -CH 2

-CH

2

CH

2

-NH-CH

2

CH

2

-OCH

2 -CH20-, -CONH-, -NHCO-, -COO-, -OOC-, -Sor represents a covalent bond; where the groups and 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; (CI-C 6 )-alkanoyl; (C 3

-C

7 )-cycloalkanoyl;

(C

6 -C 14)arylcarbonyl;

(C

5 -Clo)-heteroarylcarbonyl;

(CI-C

6 alkanoyloxymethyloxy;

-COOR

27 -S0 2 R27; _C(NR 2 7

R

28

)=NR

29

-CONR

2 8

R

2 9 -S0 2

NR

2 8

R

29

-OR

3 0

-NR

3 0

R

31

(C-C

6 )-alkyl and (C 3 C7)-cycloalkyl, where (Ci-C 6 )-alkyl and (C3-C 7 )-cycloalkyl for their part may optionally be substituted by a radical from the group consisting of cyano; -OR27; -NR28R 29

-CO(NH)(NR

2 7 R 2 8 and -C(NR27R)=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, (Ci-C 4 )-alkyl or (C 3

-C

7 cycloalkyl, and/or

R

2 7 and R 28 or R 27 and R 2 9 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

3 0 and R 3 1 are identical or different and independently of one another each represents hydrogen, (Ci-C 4 )-alkyl, (C3-C 7 )-cycloalkyl, (CI-C4)-alkylsulphonyl, (Ci-C4)-hydroxyalkyl,

(CI-C

4 aminoalkyl, di-(C 1

-C

4 )-alkylamino-(Ci-C 4 )-alkyl, (Ci-C 4 alkanoyl, (C 6 -Ci4)-arylcarbonyl,

(C

5 -Clo)-heteroarylcarbonyl, (Ci-C4)-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 (Ci-C 6 )-alkyl and their pharmaceutically acceptable salts, hydrates and prodrugs, except for compounds of the general formula in which the radical R' 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---- Particular preference is given here to compounds of the general formula in which R' represents thiophene (thienyl), in particular 2-thiophene, which may optionally be mono- or polysubstituted by halogen, preferably chlorine or bromine, or by (Ci-Cs)-alkyl, preferably methyl, where the (Ci-Cs)-alkyl radical for its part may optionally be mono- or polysubstituted by halogen, preferably fluorine, 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 represents phenyl or naphthyl, in particular phenyl; the radical 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 0; the radical represents a saturated or partially unsaturated 5- or 6membered 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 0; the radical represents

-NH-CH

2

-CH

2

-OCH

2

-CH

2 -CONH-, -NHCO- or represents a covalent bond; where the groups and defined above may in each case optionally be mono- or polysubstituted by a radical from the group consisting of halogen; trifluoromethyl; oxo; cyano; pyridyl; (Ci-C 3 alkanoyl; (C 6 -Clo)-arylcarbonyl; (Cs-C 6 )-heteroarylcarbonyl;

(CI-C

3 alkanoyloxymethyloxy; -C(NR2R28)=NR 29 -CONR8R29; -S0 2

NR

28

R

29 -OH; -NR 3 0

R

31

(C-C

4 )-alkyl; and cyclopropyl, cyclopentyl or cyclohexyl, where (Ci-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 2 7 R8) and -C(NR 2 7

R

28

)=NR

2 9 where: 11 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, (Ci-C 4 )-alkyl or else cyclopropyl, cyclopentyl or cyclohexyl and/or

R

27 and R 28 or R 2 7 and R 29 together with the nitrogen atom to which they are attached may form a saturated or partially unsaturated 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, (Ci-C 4 )-alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (Ci-C 4 )-alkylsulphonyl, (Ci-C 4 hydroxyalkyl, (Ci-C 4 )-aminoalkyl, di-(C 1

-C

4 )-alkylamino- (Ci-C 4 )-alkyl, (Ci-C 3 )-alkanoyl or phenylcarbonyl,

R

3

R

4

R

5

R

6 R and R 8 are identical or different and each represents hydrogen or represents (Ci-C 6 )-alkyl and-theirpharmaceutically acceptable salts, hydrates and prodrugs, except for compounds of the general formula in which the radical R' 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.

Particular preference is given here to compounds of the general formula in which 12- R' represents 2-thiophene which may optionally be substituted in the 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 represents phenyl or naphthyl, in particular phenyl; the radical 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 0; the radical represents a saturated or partially unsaturated 5- or 6membered 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 andtor hetero chain members from the-group-consisting-of S- SO, SO 2 and 0; the radical represents

-NH-CH

2

-CH

2

-NH-,

-OCH

2

-CH

2 -CONH-, -NHCO- or represents a covalent bond; where the groups and defined above may in each case optionally be mono- or polysubstituted by a radical from the group consisting of halogen; trifluoromethyl; oxo; cyano; pyridyl; (Ci-C 3 alkanoyl; (C6-Clo)-arylcarbonyl;

(C

5

-C

6 )-heteroarylcarbonyl; (CI-C 3 alkanoyloxymethyloxy;

-CONR

28 R29; -SO 2

NR

28 R29; -OH; -NR3R 3 1 (Ci-C 4 )-alkyl; and cyclopropyl, cyclopentyl or cyclohexyl, 13where (Ci-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, (Ci-C 4 )-alkyl or else cyclopropyl, cyclopentyl or cyclohexyl and/or

R

27 and R 28 or R 2 7 and R 29 together with the nitrogen atom to which they are attached may form a saturated or partially unsaturated 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, (Ci-C 4 )-alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (CI-C 4 )-alkylsulphonyl, (Ci-C 4 hydroxyalkyl, I(C-C4-amrinalkyl, di-(Ci-C 4 )-alkylamino- (Ci-C4)-alkyl, (Ci-C 3 )-alkanoyl or phenylcarbonyl,

R

3

R

4 RS, R 6 R and R 8 are identical or different and each represents hydrogen or represents (Ci-C 4 )-alkyl and their pharmaceutically acceptable salts, hydrates and prodrugs, except for compounds of the general formula in which the radical R' 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.

-14- Very particular preference is given here to compounds of the general formula in which R' 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 represents phenylene; the radical represents a saturated 5- or 6-membered heterocycle, which is attached to 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 0; where the group 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 R 4

R

5

R

6

R

7 and R 8 each represent hydrogen and their pharmaceutically acceptable salts, hydrates and prodrugs.

Very particular preference is also given here to the compound having the following formula 0$ 0

HN

and to its pharmaceutically acceptable salts, hydrates and prodrugs.

In the compounds of the general formula above, the radical R' may in particular represent optionally benzo-fused thiophene (thienyl) which may optionally be mono- or polysubstituted by a radical from the group consisting of halogen; cyano; nitro; (Ci-Cs)-alkyl, which for its part may optionally be mono- or polysubstituted by halogen; (C 3

-C

7 )-cycloalkyl; (Ci-Cs)-alkoxy; imidazolinyl; -C(=NH)NH 2 carbamoyl; and mono- and di- (C -C 4 )-alkylaminocarbonyl.

In the compounds of the general formula the radical R may preferably represent thiophene (thienyl), in particular 2-thiophene, which may optionally be mono- or polysubstituted by halogen, preferably chlorine or bromine, or by (CI-Cs)-alkyl, preferably methyl, where the (Ci-Cs)-alkyl radical, preferably the methyl radical, may for its part optionally be mono- or polysubstituted by halogen, preferably fluorine.

In the compounds of the general formula the radicals R R 4 R R R 7 and R 8 may be identical or different and may represent, in particualr, hydrogen or (Ci-C 6 )-alkyl, preferably hydrogen or (Ci-C4)-alkyl, very particularly preferably hydrogen.

The radical R 2 i.e. the organic radical, can in particular be selected from the substituent groups listed below: In the compounds of the general formula the radical -16- R' may, in particular, represent a group of the following formula:

Y-X'-(CH

2 )p-X-(CO)n-(CH 2 )o-(CR 9 Ri)m-(CH 2 )o2where: m is an integer from 0 to 6, preferably from 1 to 3, n is either 0 or 1, p is an integer from 0 to 3, preferably either 0 or 1, oj is an integer 0 or 1, 02 is an integer 0 or 1,

R

9 and R' 1 are identical or different and each represents hydrogen; (CI-C 4 alkyl, preferably methyl; (Ci-C 4 )-alkoxy, preferably methoxy; (C 3

-C

7 cycloalkyl; hydroxyl or fluorine, X and X' are identical or different and each represents O; N-R" or a covalent bond, where R" represents H; (Ci-C 4 )-alkyl, preferably methyl, or (C 3

-C

7 cycloalkyl, Y represents a 3- to 7-membered saturated or partially unsaturated cyclic hydrocarbon radical which optionally contains 1 to 3 identical or different heteroatoms and/or hetero chain members from the group consisting of N, O, S, SO and SO 2 where: this radical Y may optionally be substituted by a 5- or 6-membered aromatic or a 3- to 7-membered saturated or partially unsaturated -17cyclic hydrocarbon radical which optionally contains up to 3 identical or different heteroatoms from the group consisting of N, O and S and where this radical may for its part optionally be substituted by a radical from the group consisting of cyano; hydroxyl; halogen; (Ci-C 4 )-alkyl; -C(=NR' 2

)NRI

3

R'

3 and -NR' 4

R

5 where:

R

12 represents hydrogen, (Ci-C 4 )-alkyl or (C 3

-C

7 )-cycloalkyl;

R'

3 and R' 3 are identical or different and independently of one another each represents hydrogen, (Ci-C 4 )-alkyl or (C 3

-C

7 cycloalkyl and/or

R'

3 and R 13 together with the N atom to which they are attached form a 5- to 7-membered heterocycle which may optionally contain up to 2 further heteroatoms from the group consisting of N, O and S;

R'

4 and R 15 are identical or different and independently of one another each represents hydrogen, (Ci-C 4 )-alkyl, (C 3

-C

7 )-cycloalkyl or (Ci-C 5 )-alkanoyl; and/or this radical Y may furthermore optionally be substituted by a radical from the group consisting of oxo; cyano; thiono; halogen; -OR1 6

=NR

16

-NR'

6

R'

7

-C(=NR'

8

)NR'

9

R'

9 and

(C

1 -C4)-alkyl, in which (Ci-C 4 )-alkyl for its part may optionally be substituted by a radical from the group consisting of hydroxyl; cyano; -NR' 6

R'

7 and -C(=NRi)NR' 9

R

9 18where:

R

16 and R 17 are identical or different and independently of one another each represents hydrogen, (CI-C 4 )-alkyl,

(C

3

-C

7 )-cycloalkyl or (Ci-C 3 )-alkanoyl;

R'

8 represents hydrogen, (Ci-C 4 )-alkyl or (C 3

-C

7 cycloalkyl;

R

1 9 and R' 9 are identical or different and independently of one another each represents hydrogen, (Ci-C 4 )-alkyl or (C 3

C

7 )-cycloalkyl and/or

R

1 9 and R 1 9 together with the N atom to which they are attached form a 5- to 7-membered heterocycle which may optionally contain up to 2 further heteroatoms from the group consisting of N, O and S.

Particular preference is given to compounds of the general formula in which the radical

R

2 represents a group of the following formula:

Y-X'-(CH

2 )p-X-(CO)n-(CH 2 )ol-(CR 9 R ')m-(CH 2 2 where m is an integer from 0 to 3, n is an integer 0 or 1, p is an integer 0 or 1, ol is an integer 0 or 1, 19- 02 is an integer 0 or 1,

R

9 and R' 0 are identical or different and each represents hydrogen; methyl; methoxy; hydroxyl or fluorine, X and X' are identical or different and each represents O; N-R" or a covalent bond, where R" represents H or methyl, Y represents a 5- to 7-membered saturated cyclic hydrocarbon radical which optionally contains 1 or 2 identical or different heteroatoms and/or hetero chain members from the group consisting of N, O, S, SO and SO 2 in particular cyclohexyl, piperazinyl, morpholinyl, thiomorpholinyl, diazepinyl, pyrrolidinyl and piperidinyl, where: this radical Y may optionally be substituted by a 5- or 6-membered aromatic or a 5- to 7-membered saturated or partially unsaturated cyclic hydrocarbon radical which optionally contains up to 2 identical or different heteroatoms from the group consisting of N, O and S and where th-isradiral-frit-g-part-may be substituted by a radical from the group consisting of cyano; hydroxyl; fluorine; chlorine; (Ci-C 4 )-alkyl; -C(=NR2)NRI3R13'; and -NR 4

R'

5 where:

R

12 represents hydrogen, methyl, ethyl, cyclopropyl, cyclopentyl or cyclohexyl;

R

1 3 and R 1 3 are identical or different and independently of one another each represents hydrogen, methyl, ethyl, cyclopropyl, cyclopentyl or cyclohexyl and/or

R

1 3 and R 13 together with the N atom to which they are attached form a 5- to 7-membered heterocycle which may optionally contain up to 2 further heteroatoms from the group consisting of N, O and S, in particular piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl;

R

1 4 and R 15 are identical or different and independently of one another each represents hydrogen, methyl, ethyl, cyclopropyl, cyclopentyl or cyclohexyl or else acetyl; and/or this radical Y may furthermore optionally be substituted by a radical from the group consisting of oxo; cyano; thiono; fluorine; chlorine; -OH; -OCH 3

=NR

1 6 -NH2; -N(CH 3 2

-C(=NR'

8

)NR'

9

R'

9 and methyl, in which methyl for its part may optionally be substituted by a radical from the group consisting of hydroxyl; cyano; -NR6R 1 7 and -C(=NR' 8

)NR'

9

R

9 where:

R

1 6 and R 17 are identical or different and independently of one another each represents hydrogen, methyl, (C 3

-C

7 cycloalkyl or acetyl;

R

18 reprsents hydrogen, methyl or (C 3

-C

7 )-cycloalkyl; R1 9 and R 1 9 are identical or different and independently of one another each represents hydrogen, methyl or (C 3

-C

7 cycloalkyl and/or -21-

R'

9 and R' 9 together with the N atom to which they are attached form a 5- to 7-membered heterocycle which may optionally contain up to 2 further heteroatoms from the group consisting of N, O and S, in particular piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.

Likewise, in the compounds of the general formula the radical

R

2 may represent a group of the formula below: Z-(CO)t-(CR 2 0

R

2 1)swhere: s is an integer from 1 to 6, t is either 0 or 1,

R

20 and R 2 1 are identical or different and each represents hydrogen, (C 1

-C

4 alkyl, (Ci-C 4 )-alkoxy, (C3-C 7 )-cycloalkyl, hydroxyl or fluorine, Z represents a radical which is selected from the group consisting of -cyano;-C(-NR2R2 )=NR24; -CO(NH),NR 2 2

R

23 and -NR25R 26 where: u is either 0 or 1, preferably 0, and

R

22

R

23 and R 24 are identical or different and independently of one another each represents hydrogen, (Ci-C 4 )-alkyl or (C 3

-C

7 cycloalkyl, preferably hydrogen or methyl, and/or

R

22 and R 23 together with the N atom to which they are attached form a 5- to 7-membered heterocycle which may optionally contain -22up to 2 further heteroatoms and/or hetero chain members from the group consisting of N, O, S, SO and SO 2

R

2 5 and R 26 are identical or different and independently of one another each represents hydrogen, (Ci-C 4 )-alkyl or (C 3

-C

7 )-cycloalkyl, preferably hydrogen, methyl or ethyl, where (Ci-C 4 )-alkyl and (C3-C7)-cycloalkyl for their part may optionally be substituted by hydroxyl or (Ci-C 6 )-alkoxy.

Furthermore, in the compounds of the general formula the radical

R

2 may represent one of the following groups:

A-,

A-M-,

D-M-A-,

B-M-A-,

B-,

B-M-,

B-M-B-,

D-M-B-,

where: the radical represents (C6-C 1 4 )-aryl, preferably (C 6 -Cio)-aryl, in particular phenyl or naphthyl, very particularly preferably phenyl; the radical 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 0; the radical represents a saturated or partially unsaturated 4- to 7membered 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 represents

-CH

2

-CH

2

CH

2

-NH-CH

2

-CH

2

-OCH

2

-CH

2 -CONH-, -NHCO-, -COO-, -OOC-, or represents a covalent bond; 23 where the groups and 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

1 o)-heteroarylcarbonyl; (C 1 C6)-alkanoyloxymethyloxy; -COOR 27; -SOR 2; -C(NR2 R 8)=NR29 -C0NR 8

R

29

-SO

2 N RR; -OR 30

-NR

3 R, (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 28R29

-CO(NII),(NR

27 R 2 1) and -C(NR 27 R 2

)=NR

29 where: v is either 0or l and R 2, R 28and R 29are 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 17and R" or R 27and R 29together with the nitrogen atom to which they are -atachd-orma--atratd-or-partaliyunsaturated- 5- to 7-membered heterocycle having up to three, preferably up to two, identical or different heteroatoms from the group consisting of N, 0 and S, and R 30and R 31are 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

-C

1 4-arylcarbonyl,

(C

5 -C io)-heteroarylcarbonyl, (C 1

-C

4 )-al kylami nocarbonyl or

-CH

2

C(NR

27

R

28 )=NR 29 Preference is also given to compounds of the general formula in which the radical -24- R' 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 represents phenyl or naphthyl, in particular phenyl; the radical 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 represents a saturated or partially unsaturated 5- or 6membered 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 0; the radical represents

-NH-CH

2

-CH

2

-OCH

2

-CH

2 -CONH-, -NHCO- or represents a covalent bond; where thegoups-- 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-C 3 )-alkanoyl; (C 6 -Clo)-arylcarbonyl; (C5-C6)-heteroarylcarbonyl; (CI -C 3 )-alkanoyloxymethyloxy;

-C(NR

2 7

R

28

)=NR

29

-CONR

2 8

R

29 -S0 2

NR

28

R

2 9 -OH; -NR30R 3 1; (C 1

-C

4 alkyl; and cyclopropyl, cyclopentyl or cyclohexyl, where (Ci-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 -NR28R29; -CO(NH)v(NR 2 7

R

2 8 and -C(NR27 R 28)=NR 29 where: v is either 0 or 1, preferably 0, and

R

27

R

28 and R 2 9 are identical or different and independently of one another each represents hydrogen, (Ci-C 4 )-alkyl or else cyclopropyl, cyclopentyl or cyclohexyl and/or

R

27 and R 28 or R 27 and R 2 9 together with the nitrogen atom to which they are attached may form a saturated or partially unsaturated 5- to 7membered heterocycle having up to two identical or different heteroatoms from the group consisting of N, O and S, and

R

3 0 and R 31 are identical or different and independently of one another each represents hydrogen, (Ci-C 4 )-alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (CI-C4)-alkylsulphonyl, (Ci-C 4 )-hydroxyalkyl, (CI-C 4 aminoalkyl, di-(Ci-C4)-alkylamino-(Ci-C 4 )-alkyl, (CI-C 3 )-alkanoyl or phenylcarbonyl.

Likewise, in the compounds of the general formula the radical

R

2 may represent a group of the following formula: R32 W where

R

32 represents hydrogen or (Ci-C 4 )-alkyl, preferably hydrogen or methyl, and W represents S, NH or O, preferably S.

Moreover, in the compounds of the general formula the radical may be a group of the formula below -26-

H

3 C N S Finally, in the compounds of the general formula the radical

R

2 may be a group of the formula below 100 To date, oxazolidinones have essentially only been described as antibiotics, and in individual cases also as MAO inhibitors and fibrinogen antagonists (review: Riedl, Endermann, Exp. Opin. Ther. Patents 1999, 9 625), where a small aminomethyl] group (preferably 5-[acetylaminomethyl]) appears to be essential for the antibacterial activity.

Substituted aryl- and heteroarylphenyloxazolidinones in which a mono- or polysubstituted phenyl radical may be attached to the N atom of the oxazolidinone ring and which may have an unsubstituted N-methyl-2-thiophenecarboxamide radical in the 5-position of the oxazolidinone ring, and their use as antibacterial substances, are known from U.S. Patents US-A-5 929 248, US-A-5 801 246, US-A-5 756 732, 654 435, US-A-5 654 428 and US-A-5 565 571.

In addition, benzamidine-containing oxazolidinones are known as synthetic intermediates in the synthesis of factor Xa inhibitors and/or fibrinogen antagonists (WO-A-99/31092, EP-A-623615).

Depending on the substitution pattern, the compounds of the general formula (I) according to the invention may exist in stereoisomeric forms which are either like image and mirror image (enantiomers) or not like image and mirror image -27- (diastereomers). The invention relates both to the enantiomers or diastereomers and to their respective mixtures. The racemic forms, like the diastereomers, can be separated in a known manner into the stereoisomerically uniform components.

Furthermore, certain compounds of the general formula can be present in tautomeric forms. This is known to the person skilled in the art, and such compounds are likewise within the scope of the invention.

Physiologically acceptable, i.e. pharmaceutically compatible, salts can be salts of the compounds according to the invention with inorganic or organic acids. Preference is given to salts with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or to salts with organic carboxylic or sulphonic acids, such as, for example, acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.

Other pharmaceutically compatible salts which may be mentioned are salts with customary bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts, derived from ammonia or organic amines, such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine or methylpiperidine.

According to the invention, "hydrates" are forms of the compounds of the general formula above which form a molecule compound (solvate) in the solid or liquid state by hydration with water. In the hydrates, the water molecules are attached through secondary valencies by intermolecular forces, in particular hydrogen bridges. Solid hydrates contain water as so-called crystal water in stoichiometric ratios, where the water molecules do not have to be equivalent with respect to their binding state.

Examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates.

Equally suitable are the hydrates of salts of the compounds according to the invention.

According to the invention, "prodrugs" are forms of the compounds of the general formula above which for their part can be biologically active or inactive, but which -28can be converted into the corresponding biologically active form (for example metabolically, solvolytically or in another way).

Halogen represents fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.

(Ci-C8)-Alkyl represents a straight-chain or branched alkyl radical having 1 to 8 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. The corresponding alkyl groups with fewer carbon atoms, such as, for example, (Ci-C 6 )-alkyl and (Ci-C 4 )-alkyl, are derived analogously from this definition. In general, preference is given to (Ci-C 4 )-alkyl.

The meaning of the corresponding component of other more complex substituents, such as, for example, alkylsulphonyl, hydroxyalkyl, hydroxyalkylcarbonyl, alkoxyalkyl, alkoxycarbonyl-alkyl, alkanoylalkyl, aminoalky or alkylaminoalkyl is likewise derived from this definition.

(C

3

-C

7 )-Cycloalkyl represents a cyclic alkyl radical having 3 to 7 carbon atoms.

Examples which may be mentioned are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The corresponding cycloalkyl groups having fewer carbon atoms, such as, for example, (C 3

-C

5 )-cycloalkyl, are derived analogously from this definition. Preference is given to cyclopropyl, cyclopentyl and cyclohexyl.

The meaning of the corresponding component of other more complex substituents, such as, for example, cycloalkanoyl, is likewise derived from this definition.

In the context of the invention, (C 2

-C

6 )-alkenyl represents a straight-chain or branched alkenyl radical having 2 to 6 carbon atoms. Preference is given to a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms. Examples which may be mentioned are: vinyl, allyl, isopropenyl and n-but-2-en-l-yl.

(j-Cs)-Alkoxy represents a straight-chain or branched alkoxy radical having 1 to 8 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy, n-heptoxy and n-octoxy. The corresponding alkoxy groups having fewer carbon atoms, such as, for -29example, (Ci-C 6 )-alkoxy and (Ci-C 4 )-Alkoxy, are derived analogously from this definition. In general, preference is given to (Ci-C 4 )-alkoxy.

The meaning of the corresponding component of other more complex substituents, such as, for example alkoxy-alkyl, alkoxvcarbonyl-alkyl and alkoxvcarbonyl, is likewise derived from this definition.

Mono- or di-(C-C4)-alkvlaminocarbonvl represents an amino group which is attached via a carbonyl group and which has a straight-chain or branched or two identical or different straight-chain or branched alkyl substitutents having in each case 1 to 4 carbon atoms. Examples which may be mentioned are: methylamino, ethylamino, n-propylamino, isopropylamino, t-butylamino, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino and N-t-butyl-N-methylamino.

Ci-C6)-Alkanovl represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms which carries a doubly attached oxygen atom in the 1-position and is attached via the 1-position. Examples which may be mentioned are: formyl, acetyl, propionyl, n-butyryl, i-butyryl, pivaloyl, n-hexanoyl. The corresponding alkanoyl groups with fewer carbon atoms, such as, for example, (Ci-C 5 )-alkanoyl, (Ci-C 4 )-alkanoyl and (Ci-C 3 )-alkanoyl, are derived analogously from this definition.

In general, preference is given to (CI-C 3 )-alkanoyl.

The meaning of the corresponding component of other more complex substituents, such as, for example, cycloalkanoyl and alkanoylalkyl, is likewise derived from this definition.

(C

3

-C

7 )-Cvcloalkanoyl represents a cycloalkyl radical having 3 to 7 carbon atoms as defined above which is attached via a carbonyl group.

(C1-C6)-Alkanoyloxvmethyloxy represents a straight-chain or branched alkanoyloxymethyloxy radical having 1 to 6 carbon atoms. Examples which may be mentioned are: acetoxymethyloxy, propionoxymethyloxy, n-butyroxymethyloxy, i-butyroxymethyloxy, pivaloyloxymethyloxy, n-hexanoyloxymethyloxy. The corresponding alkanoyloxymethyloxy groups having fewer carbon atoms, such as, for example, (Ci-C3)-alkanoyloxymethyloxy, are derived analogously from this definition. In general, preference is given to (Ci-C3)-alkanoyloxymethyloxy.

(C

6

-C

1 4 )-Aryl represents an aromatic radical having 6 to 14 carbon atoms. Examples which may be mentioned are: phenyl, naphthyl, phenanthrenyl and anthracenyl. The corresponding aryl groups with fewer carbon atoms, such as, for example, (C 6 -Clo)-aryl are derived analogously from this definition. In general, preference is given to

(C

6 -Clo)-aryl.

The meaning of the corresponding component of other more complex substituents, such as, for example, arylcarbonyl, is likewise derived from this definition.

or a 5- to 10-membered aromatic heterocycle having up to 3 heteroatoms and/or hetero chain members from the group consisting of S, O, N and NO (N-oxide) represents a mono- or bicyclic heteroaromatic which is attached via a carbon ring atom of the heteroaromatic or, if appropriate, via a nitrogen ring atom of the heteroaromatic. Examples which may be mentioned are: pyridyl, pyridyl N-oxide, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl or isoxazolyl, indolinyl, indolyl, benzo[b]thienyl, benzo[b]furyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl. The corresponding heterocycles having a smaller ring size, such as, for example, 5- or 6-membered aromatic heterocycles, are derived analogously from this definition. In general, preference is given to 5- or 6-membered aromatic heterocycles, such as, for example, -pyridylpyridyl N-oxide, pyrimidyl,-pyridazinyl-furyl-and-thienyl The meaning of the corresponding component of other more complex substituents, such as, for example, (C5-Cl)-heteroarylcarbonyl, is likewise derived from this definition.

A 3- to 9-membered saturated or partially unsaturated, mono- or bicyclic, optionally benzo-fused heterocycle having up to 3 heteroatoms and/or hetero chain members from the group consisting of S. SO, SO, N, NO (N-oxide) and 0 represents a heterocycle which may contain one or more double bonds, which may be mono- or bicyclic, to which a benzene ring may be fused to two adjacent carbon ring atoms and which is attached via a carbon ring atom or a nitrogen ring atom. Examples which may be mentioned are: tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2- -31 dihydropyndinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl N-oxide, O thiomorpholinyl, azepinyl, 1,4-diazepinyl and cyclohexyl. Preference is given to Z piperidinyl, morpholinyl and pylTrolidinyl.

\O

The corresponding cycles having a smaller nng size, such as, for example, 5- to 7membered cycles, are denved analogously from this definition.

Herein disclosed is a process for preparing the compounds of the general formula (I) according to the invention where either, according to one process alternative a 0 compounds of the general formula (I) 0

R

RR

6 4 R (II),

HN

\R

mn \vhich the radicals R 2, R 4

R

6 and R 7 are each as defined above, are reacted with carboxvlic acids of the general formula (E) HO R' (III), 0 I nO the radical R' is as defined above.

-32or 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) 0

RR

RR

4 R 7 RL-N R in which the radicals R 2

R

3

R

4

R

5

R

6

R

7 and R 8 are each as defined above, or else according to a process alternative compounds of the general formula (IV)

R

3

R

6

R

7 0

R

4

(IV),

in which the radicals R 3

R

4

R

5

R

6

R

7 and R 8 are each as defined above, are converted, using a suitable selective oxidizing agent in an inert solvent, into the corresponding epoxide of the general formula (V) -33in which the radicals R 3

R

4

R

5

R

6

R

7 and R 8 are each as defined above, 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 above, the compounds of the general formula (VII) (vn), in which the radicals R 2

R

3

R

4

R

5

R

6

R

7 and R 8 are each as defined above, 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) -34- R-N R (I) in which the radicals R 2

R

3

R

4 RS, R 6

R

7 and R 8 are each as defined above, where both for process alternative and for process alternative 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 and for process alternative 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 and for process alternative 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 and for process alternative 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 and for process alternative 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.

The processes according to the invention can be illustrated in an exemplary manner by the equations below:

[A]

F O C F O 0\ HOBT EDCI O (iso-Pr)2,EtN C

S

NH

2 0

HN

0 F 0 C F 0 ^0 S P )-O 36- 0 H ls/ C1

MCPBA

/Cl II '.NH 2 0 N C

CDI

HC D1 HNo The oxidation step described above, which is optional, can be illustrated in an exemplary manner by the equation below: F 0 Ss ci

S

HN

0 F 0 NMO/0s0 4 I o"\s~J

CI

HNT

NalO 4

O

Suitable solvents for the processes described above are organic solvents which are inert under the reaction conditions. These include halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethylene or trichloroethylene, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons, such as benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide, dimethyl sulphoxide, acetonitrile, pyridine, hexamethylphosphoric triamide or water.

It is also possible to use solvent mixtures of the solvents mentioned above.

-37- Suitable activating or coupling agents for the processes described above are the reagents which are customarily used for this purpose, for example N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide HCI, N,N'-dicyclohexylcarbodiimide, 1-hydroxy-1H-benzotriazole

H

2 0 and the like.

Suitable bases are the customary inorganic or organic bases. These preferably include alkali metal hydroxides, such as, for example, sodium hydroxide or potassium hydroxide, or alkali metal carbonates, such as sodium carbonate or potassium carbonate, or sodium methoxide or potassium methoxide or sodium ethoxide or potassium ethoxide or potassium-tert-butoxide, or amides, such as sodium amide, lithium bis-(trimethylsilyl)amide or lithium diisopropylamide, or amines, such as triethylamine, diisopropylethylamine, diisopropylamine, 4-N,N-dimethylaminopyridine or pyridine.

The base can be employed here in an amount of from 1 to 5 mol, preferably from 1 to 2 mol, based on 1 mol of the compounds of the general formula (II).

The reactions are generally carried out in a temperature range of from -78 0 C to reflux temperature, preferably in the range from 0°C to reflux temperature.

The reactions can be carried out at atmospheric, elevated or reduced pressure (for example in the range from 0.5 to 5 bar). In general, the reactions are carried out at atmospheric pressure.

Suitable selective oxidizing agents, both for the preparation of the epoxides and for the optional oxidation to give the sulphone, sulphoxide or N-oxide, are m-chloroperbenzoic acid (MCPBA), sodium metaperiodate, N-methylmorpholine N-oxide (NMO), monoperoxyphthalic acid or osmium tetroxide.

With respect to the preparation of the epoxides, the preparation conditions which are customary for this purpose are employed.

With respect to more detailed process conditions for the optional oxidation to give the sulphone, sulphoxide or N-oxide, reference is made to the following literature: M. R. Barbachyn et al., J. Med. Chem. 1996, 39, 680 and WO-A-97/10223.

-38- Furthermore, reference is made to Examples 14 to 16 given in the experimental part.

The optional amidation is carried out under customary conditions. For more details, reference is made to Examples 31 to 35 and 140 to 147.

The compounds of the general formulae (RIl), (IV) and (VI) are known per se to the person skilled in the art or can be prepared by customary methods. For oxazolidinones, in particular the 5-(aminomethyl)-2-oxooxazolidines required, cf.

WO-A-98/01446; WO-A-93/23384; WO-A-97/03072; J. A. Tucker et al., J. Med.

Chem. 1998, 41, 3727; S. J. Brickner et al., J. Med. Chem. 1996, 39, 673; W. A. Gregory et al., J. Med. Chem. 1989, 32, 1673.

The compounds of the general formula according to the invention have an unforeseeable useful pharmacological activity spectrum and are therefore particularly suitable for the prophylaxis and/or treatment of disorders.

The compounds of the general formula according to the ivnention including the compounds which are excluded by disclaimer from the chemical product protection act in particular as anticoagulants and can therefore preferably be employed in medicaments for the prophylaxis and/or therapy of thromboembolic disorders. For the purpose of the present invention, "thromboembolic disorders" include, in particular, serious disorders such as myocardial infarct, angina pectoris (including unstable angina), reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transitory ischaemic attacks, peripheral arterial occlusion disorders, pulmonary embolisms or deep venous thromboses.

Furthermore, the compounds of the general formula according to the invention including the compounds which are excluded by disclaimer from the chemical product protection are also suitable for treating disseminated intravascular coagulation (DIC).

Finally, the compounds of the general formula according to the invention including the compounds which are excluded by disclaimer from the chemical product protection are also suitable for the prophylaxis and/or treatment of atherosclerosis and arthritis, and additionally also for the prophylaxis and/or treatment of Alzheimer's disease and cancer.

-39- The compounds of the general formula according to the invention including the compounds excluded by disclaimer from the chemical product protection- act in particular as selective inhibitors of the blood coagulation factor Xa and do not inhibit, or only inhibit at considerably higher concentrations, other serine proteases as well, such as thrombin, plasmin or trypsin.

In the context of the present invention, inhibitors of the blood coagulation factor Xa in which the IC 5 0 values for the factor Xa inhibition are lower by a factor of 100, preferably by a factor of 500, in particular by a factor of 1000, than the IC 50 values for the inhibition of other serine proteases, in particular thrombin, plasmin and trypsin, are referred to as being ,,selective", where with a view to the test methods for selectivity, reference is made to the test methods of Examples A-I) a.l) and a.2) described below.

The compounds of the general formula according to the invention including the compounds which are excluded by disclaimer from the chemical product protection can furthermore be used for preventing coagulation ex vivo, for example for banked blood or biological samples which contain factor Xa.

The present invention thus provides oxazolidinones of the formula effecting in particular an unexpected, strong and selective inhibition of factor Xa, and this also applies to the compounds excluded by disclaimer from the chemical product protection.

The present invention further provides medicaments and pharmaceutical compositions comprising at least one compound of the general formula according to the invention together with one or more pharmacologically acceptable auxiliaries or excipients, which medicaments and pharmaceutical compositions can be used for the indications mentioned above.

Furthermore, the present invention relates to a method for the prophylaxis and/or treatment of disorders of the human or animal body, in particular of the abovementioned disorders, using the compounds of the general formula according to the invention including the compounds excluded by disclaimer from the chemical product protection.

Furthermore, the present invention also includes a method for preventing blood coagulation in vitro, in particular in banked blood or biological samples which contain factor Xa, which method is characterized in that compounds of the general formula including the compounds excluded by disclaimer from the chemical product protection are added.

All customary administration forms are suitable for administration of the compounds according to the invention. Administration is preferably carried out orally, lingually, sublingually, buccally, rectally or parenterally bypassing the intestinal tract, that is intravenously, intraarterially, intracardially, intracutaneously, subcutaneously, transdermally, intraperitoneally or intramuscularly). Particularly suitable are oral and intravenous administration. Very particular preference is given to oral administration, this being a further advantage with respect to the prior-art therapy of thromboembolic disorders.

The novel active compounds of the general formula can be converted in a known manner into the customary formulations, such as tablets, sugar-coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert nontoxic pharmaceutically suitable excipients or solvents. Here, the therapeutically active compound should in each case be present in a concentration of from about 0.1 to 95% by weight, preferably from 0.5 to 90% by weight, in particular from 1 to by weight, of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.

In spite of this, if appropriate, it may be necessary to depart from the amounts mentioned, namely depending on the body weight or on the type of administration route, on the individual response to the medicament, on the manner of its formulation and the time or interval at which administration takes place. Thus, in some cases it may be adequate to manage with less than the abovementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. In the case of the administration of relatively large amounts, it may be advisable to divide these into several individual administrations over the course of the day.

The formulations are prepared, for example, by extending the active compounds with solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, it -41being possible, for example if the diluent used is water, optionally to use organic solvents as auxiliary solvents.

In general it has proved advantageous in the case of intravenous administration to administer amounts from approximately 0.001 to 10 mg/kg, preferably approximately 0.01 to 10 mg/kg, in particular approximately 0.1 to 8 mg/kg, of body weight to achieve effective results.

In general, it has proved advantageous in the case of oral administration to administer amounts from approximately 0.01 to 50 mg/kg, preferably approximately 0.1 to mg/kg, in particular approximately 0.5 to 8 mg/kg, of body weight to achieve effective results.

In spite of this, if appropriate, it may be necessary in the case of intravenous or oral administration to depart from the amounts mentioned, namely depending on the body weight or on the type of administration route, on the individual response to the medicament, on the manner of its formulation and the time or interval at which administration takes place. Thus, in some cases it may be adequate to manage with less than the abovementioned mininum amount, while in other cases the upper limit mentioned must be exceeded. In the case of the administration of relatively large amounts, it may be advisable to divide these over the course of the day, namely into several individual doses or as a continuous infusion.

Compared to the conventional preparations for treating thromboembolic disorders, the compounds of the general formula according to the invention including the compounds excluded by disclaimer from the chemical product protection- are distinguished in particular by the fact that a greater therapeutic range is achieved by the selective inhibition of factor Xa. For the patient, this means a lower risk of bleeding, and for the treating physician, this means that the patient is easier to adjust.

Moreover owing to the mechanism the onset of action is more rapid. Above all, however, the compounds according to the invention permit an oral administration form, which is a further advantage of the therapy with the compounds according to the invention.

The present invention is illustrated by the examples below; however, these examples are not meant to restrict the invention in any way.

-42- Examples A Evaluation of the physiological activity 1. General test methods The particularly advantageous biological properties of the compounds according to the invention can be determined by the following methods.

a) Test description (in vitro) a.1) Determination of the factor Xa inhibition The enzymatic activity of human factor Xa (FXa) was measured using the conversion of a chromogenic substrate specific for FXa. Factor Xa cleaves p-nitroaniline from the chromogenic substrate. The determinations were carried out in microtitre plates as follows.

The test substances, in various concentrations, were dissolved in DMSO and incubated at 25 0 C with human FXa (0.5 nmol/l dissolved in 50 mmol/l of tris buffer [C,C,C-tris(hydroxymethyl)-aminomethane], 150 mmol/1 of NaCI, 0.1% BSA (bovine serum albumin), pH 8.3) for 10 minutes. Pure DMSO was used as control.

The chromogenic substrate (150 Cjmol/l of Pefachrome® FXa from Pentapharm) was -then adaed Aftfer wnimcubtion time of 20 minutes at 25 0 C, the extinction at 405 nm was determined. The extinctions of the test mixtures containing test substance were compared with the control mixtures without test substance, and the IC 50 values were calculated from these data.

a.2) Determination of the selectivity To assess selective FXa inhibition, the test substances were examined for their inhibition of other human serine proteases such as thrombin, trypsin and plasmin. To determine the enzymatic activity of thrombin (75 mU/ml), trypsin (500 mU/ml) and plasmin (3.2 nmol/l), these enzymes were dissolved in tris buffer (100 mmol/1, 20 mmol/l CaCI 2 pH 8.0) and incubated with test substance or solvent for minutes. The enzymatic reaction was then started by adding the corresponding -43specific chromogenic substrates (Chromozym Thrombin® from Boehringer Mannheim, Chromozym Trypsin® from Boehringer Mannheim, Chromozym Plasmin® from Boehringer Mannheim) and the extinction at 405 nm was determined after 20 minutes. All determinations were carried out at 37°C. The extinctions of the test mixtures containing test substance were compared with the control samples without test substance, and the IC 50 values were calculated from these data.

a.3) Determination of the anticoagulant action The anticoagulant action of the test substances was determined in vitro in human plasma. To this end, human blood was drawn off in a mixing ratio of sodium citrate/blood of 1/9 using a 0.11 molar sodium citrate solution as receiver.

Immediately after the blood had been drawn off, it was mixed thoroughly and centrifuged at about 2000 g for 10 minutes. The supernatant was pipetted off. The prothrombin time (PT, synonyms: thromboplastin time, quick test) was determined in the presence of varying concentrations of test substance or the corresponding solvent using a commercial test kit (Neoplastin® from Boehringer Mannheim). The test compounds were incubated with the plasma at 37 0 C for 10 minutes. Coagulation was then started by addition of thromboplastin, and the time when coagulation occurred was determined. The concentration of test substance which effected a doubling of the prothrombin time was determined.

b) Determination of the antithrombotic activity (in vivo) b.1) Arteriovenous shunt model (rat) Fasting male rats (strain: HSD CPB:WU) having a weight of 200-250 g were anaesthetized using a Rompun/Ketavet solution (12 mg/kg/ 50 mg/kg). Thrombus formation was initiated in an arteriovenous shunt in accordance with the method described by Christopher N. Berry et al., Br. J. Pharmacol. (1994), 113, 1209-1214.

To this end, the left jugular vein and the right carotid artery were exposed. The two vessels were connected by an extracorporeal shunt using a polyethylene tube (PE of a length of 10 cm. In the middle, this polyethylene tube was attached to a further polyethylene tube (PE 160) of a length of 3 cm which contained a roughened nylon thread which had been arranged to form a loop, to form a thrombogenic surface. The extracorporeal circulation was maintained for 15 minutes. The shunt was then -44removed and the nylon thread with the thrombus was weighed immediately. The weight of the nylon thread on its own had been determined before the experiment was started. Before the extracorporeal circulation was set up, the test substances were administered to the animals while awake either intravenously via the tail vein or orally using a pharyngeal tube.

The results are shown in Table 1: Table 1: Antithrombotic activity in the arteriovenous shunt model (rat) after oral or intravenous administration Example

ED

50 [mg/kg] p.o. ED 50 [mg/kg] i.v.

1 17 6 44 3 3 114 3 115 3 123 3 162 3 b.2) Arterial thrombosis model (rat) Male fasting rats (strain: HSD CPB: WU) were anaesthetized as described above. On average, the rats had a weight of about 200 g. The left carotid artery was exposed (about 2 cm). The formation of an arterial thrombus was induced by mechanical injury to the blood vessel in accordance with the method described by K. Meng et al., Naunyn-Schmiedeberg's Arch. Pharmacol. (1977), 301, 115-119. To this end, the exposed carotid artery was clamped from the blood flow, cooled to -12°C in a metal trough for 2 minutes and, to standardize the size of the thrombi, simultaneously compressed using a weight of 200 g. The blood flow was then additionally reduced by a clip which was placed around the carotid artery distally from the injured section of the vessel. The proximal clamp was removed, and the wound was closed and reopened after 4 hours to remove the injured section of the vessel. The section of the vessel was opened longitudinally and the thrombus was removed from the injured section of the vessel. The moist weight of the thrombi was determined immediately.

The test substances were administered to the animals while awake at the beginning of the experiment, either intravenously via the tail vein or orally using a pharyngeal tube.

-46b.3) Venous thrombosis model (rat) Male fasting rats (strain: HSD CPB: WU) were anaesthetized as described above. On average, the rats had a weight of about 200 g. The left jugular vein was exposed (about 2 cm). The formation of a venous thrombus was induced by mechanical injury to the blood vessel in accordance with the method described by K. Meng et al., Naunyn-Schmiedeberg's Arch. Pharmacol. (1977), 301, 115-119. To this end, the jugular vein was clamped from the blood flow, cooled to -12 0 C in a metal trough for 2 minutes and, to standardize the size of the thrombi, simultaneously compressed using a weight of 200 g. The blood flow was re-opened and the wound was closed.

After 4 hours, the wound was re-opened to remove the thrombi from the injured sections of the vessel. The moist weight of the thrombi was determined immediately.

The test substances were administered to the animals while awake at the beginning of the experiment, either intravenously via the tail vein or orally using a pharyngeal tube.

-47- B Preparation Examples Starting materials The preparation of 3-morpholinone is described in US 5 349 045.

The preparation of N-(2,3-epoxypropyl)phthalimide is described in Chern et al.

Tetrahedron Lett. 1998,39,8483.

The substituted anilines can be obtained by reacting, for example, 4-fluoronitrobenzene, 2,4-difluoronitrobenzene or 4-chloronitrobenzene with the appropriate amines or amides in the presence of a base. This can also be carried out using Pd catalysts, such as Pd(OAc)2/DPPF/NaOt-Bu (Tetrahedron Lett. 1999,40,2035) or copper (Renger, Synthesis 1985,856; Aebischer et al., Heterocycles 1998,48,2225).

Likewise, it is possible to initially convert halogenated aromatics without nitro group into the corresponding amides, followed by nitration in the 4-position (US3279880).

I. 4 4 -Morpholin-3-onyl)nitrobenzene

NO

2 H

NO

2

NO

2

N

O NMP, NaH F NTO

O

2 mol (202 g) of morpholin-3-one Pfeil, U. Harder, Angew. Chem. 79, 1967, 188) are dissolved in 2 1 of N-methylpyrrolidone (NMP). Over a period of 2 h, 88 g (2.2 mol) of sodium hydride (60% in paraffin) are then added a little at a time. After the evolution of hydrogen has ceased, 282 g (2 mol) of 4-fluoronitrobenzene are added dropwise with cooling at room temperature, over a period of 1 h, and the reaction mixture is then stirred overnight. At 12 mbar and 76 0 C, 1.7 1 of the liquid volume are then distilled off, the residue is poured into 2 1 of water and this mixture is extracted twice with in each case 11 of ethyl acetate. After washing of the combined organic phases with water, the mixture is dried over sodium sulphate and the solvent is distilled off under reduced pressure. Purification is carried out by silica gel chromatography using hexane/ethyl acetate and subsequent crystallization -48 from ethyl acetate. This gives 78 g of product as a colourless to brownish solid, in a yield of 17.6% of theory.

'H-NMR (300 Miz, 3.86 (in, 2 H, CH 2

CH

2 4.08 (in, 2 H, CH 2

CH

2 4.49 2 H, CH 2 CO), 7.61 2 H, 'J=8.95 Hz, CHCH), 8.28 2 H, 'J=8.95 Hz,

CHCH)

MS 222 (74, 193 (100), 164 150 136 117 106 90 76 63 50 The following compounds were synthesized analogously: 3 -fluoro- 4 4 -morpholin-3-onyl)nitrobenzene 4 -(N-piperidonyl)nitrobenzene 3 -fluoro- 4 -(N-piperidonyl)nitrobenzene 4-(N-pyrroli don yl )ni trobenzene 3 -fluoro- 4 -(N-pyrrolidonyl)nitrobenzene 11. 4 4 -Morpholin-3-onyl)aniline NO 2

NH

2

H

2 Pd/C 0 0 In an autoclave, 63 g (0.275 mol) of 4 4 -morpholin-3-onyi)nitrobenzene are dissolved in 200 ml of tetrahydrofuran, admixed with 3.1 g of Pd/C (5%ig) and hydrogenated at 70 0 C and a hydrogen pressure of 50 bar for 8 h. The catalyst is filtered off, the solvent is then distilled off under reduced pressure and the product is purified by crystallization from ethyl acetate. 20 g of product are obtained as a colourless to bluish solid, in a yield of 37.6% of theory.

Purification can also be carried out by silica gel chromatography using hexane/ethyl acetate.

'H-NMR (300 MHz, CDCI 3 3.67 (mn, 2 H, CH 2

CI-

2 3.99 (in, 2 H, CH 2

CH

2 4.27 2 H, CH 2 CO), 6.68 2 H, '.J=8.71 Hz, CHCH), 7.03 2 H, 'J=8.71 Hz,

CHCH)

-49- MS 192 (100, 163 133 119 106 92 67 (27), 52 28 (22) The following compounds were synthesized analogously: 3-fluoro-4-(4-morpholin-3-onyl)aniline 4-(N-piperidonyl)aniline 3-fluoro-4-(N-piperidonyl)aniline 4-(N-pyrrolidonyl)aniline 3-fluoro-4-(N-pyrrolidonyl)aniline General method for preparing 4-substituted anilines by reacting l-fluoro-4nitrobenzenes and l-chloro-4-nitrobenzenes with primary or secondary amines, followed by reduction X RN,R H R R'NR"

H

-O ,O NH 2 X= F, CI Equimolar amounts of the fluoronitrobenzene or chloronitrobenzene and the amine are dissolved in dimethyl sulphoxide or acetonitrile (0.1 M to 1 M solution), and the mixture is stirred at 100 0 C overnight. After cooling to RT, the reaction mixture is diluted with ether and washed with water. The organic phase is dried over MgSO 4 filtered and concentrated. If a precipitate forms in the reaction mixture, the precipitate is filtered off and washed with ether or acetonitrile. If the mother liquor also contains product, it is worked up as described using ether and water. The crude products can be purified by silica gel chromatography (dichloromethane/cyclohexane and dichloromethane/ethanol mixtures).

For the subsequent reduction, the nitro compound is dissolved in methanol, ethanol or ethanol/dichloromethane mixtures (0.01 M to 0.5 M solution) admixed with palladium on carbon and stirred under an atmospheric hydrogen pressure overnight. The mixture is then filtered and concentrated. The crude product can be purified by silica gel chromatography (dichloromethane/ethanol mixtures) or preparative reversed-phase HPLC (acetonitrile/water mixtures).

Alternatively, the reducing agent used can also be iron powder. To this end, the nitro compound is dissolved in acetic acid (0.1 M to 0.5 M solution) and, at 90'C, six equivalents of iron powder and water (0.3 to 0.5 times the volume of the acetic acid) are added a little at a time over a period of 10-15 min. After a further 30 min at the mixture is filtered and the filtrate is concentrated. The residue is worked up by extraction with ethyl acetate and 2N aqueous sodium hydroxide solution. The organic phase is dried over magnesium sulphate, filtered and concentrated. The crude product can be purified by silica gel chromatography (dichloromethane/ethanol mixtures) or preparative reversed-phase 1-PLC (acetonitrilelwater mixtures).

The following starting materials were prepared in an analogous manner: 111-1. tert-butvl-l-(4-aminophenyl)-L-prolinate MS (ESI): m/z 304 (M+H+MeCN, 100), 263 HPLC (method rt 2.79 min.

111-2. l-( 4 -aminophenyl)-3-piperidinecarboxamide MS (ESI): m/z 220 100); HPLC (method rt 0.59 min.

111-3. 4 -aminophenvl)-4pieridincarboxamide MS (ESI): m/z 220 100); HPLC (method r 0.57 min.

111-4. l-( 4 -aminophenyl)-4-piperidinone MS (ESI): mlz 191 100); HPLC (method 11 0.64 min.

111-5. l-( 4 -aminophenyl)-L-Prolinamide MS (ESI): m./z 206 100); HPLC (method rt 0.72 min.

111-6. 4 -aminophenyl)-3.piperidiny]LmethanoI MS (ESI): m/z 207 100); HLPLC (method rt 0.60 min.

51 111-7. [1 -(4-aminophenyl)-2-piperidinyllmethanoI MIS (ESD): mn/z 207 100); HPLC (method rt 0.59 min.

111-8. ethyl 1 -(4-aminophenyl)-2-piperidinecarboxvlate MIS (ESI): m/z 249 35), 175 (100); HPLC (method rt 2.43 min.

111-9. [1 -(4-aminophenyl)-2-pyvrrolidinvllmethanoI MS (ESI): mn/z 193 HPLC (method rt 0.79 min.

111-10. 4-(2-methylhexahydro-5H-pyrrolo[3,4-dlisoxazol-5-yl)phenylamine starting from 2-methyl hex Aydro-2H-pyrrolo[3,4-d] isox azole (Ziegler, Carl et al.; J. Heterocyci. Chem.; 25; 2; 1988; 7 19-723) MIS (ESI): m/z 220 50), 171 (100); FIPLC (method rt 0.54 min.

111-I1. 4-(0 -pyrrol idin vl)-3- (trifluoromethylban iline MIS (ESI): m/z 231 100); HPLC (method rt 3.40 min.

111-12. 3-chloro-4-(1-DyrrolidinyI)aniline MIS (ESI): m/z 197 100); HPLC (method rt 0.78 min.

I1.-13. 5-amino-2-(4-morpholinyl)benzamide MIS (ESI): m/z 222 100); HPLC (method rt 0.77 min.

111-14. 3-methoxy-4-(4-morpholinyl)aniline MIS (ESI): m/z 209 100); HPLC (method rt 0.67 min.

111-15. 1 -I5-amino-2-(4-morpholinyl)phenyllethanone -52- MS (ESI): m/z 221 100); HPLC (method rt 0.77 min.

General method for preparing 4-substituted anilines by reacting 1-fluoro-4nitrobenzenes with amides, followed by reduction

R.'

F R" R"'N O R" 0

O

R R R R R R' O O O "O NH2 The amide is dissolved in DMF and admixed with 1.5 equivalents of potassium tertbutoxide. The mixture is stirred at RT for 1 h, and 1.2 equivalents of the 1-fluoro-4nitrobenzene are then added a little at a time. The reaction mixture is stirred at RT overnight, diluted with ether or ethyl acetate and washed with sat. aqu. sodium bicarbonate solution. The organic phase is dried over magnesium sulphate, filtered and concentrated. The crude product can be purified by silica gel chromatography (dichloromethane/ethanol mixtures).

For the subsequent reduction, the nitro compound is dissolved in ethanol (0.01 M to M solution), admixed with palladium on carbon and stirred under atmospheric hydrogen pressure overnight. The mixture is then filtered and S-concentrated._-The cudepduct__can be purified by silica gel chromatography (dichloromethane/ethanol mixtures) or preparative reversed-phase HPLC (acetonitrile/water mixtures).

Alternatively, the reducing agent used can also be iron powder. To this end, the nitro compound is dissolved in acetic acid (0.1 M to 0.5 M solution) and, at 90 0 C, six equivalents of iron powder and water (0.3 to 0.5 times the volume of the acetic acid) are added a little at a time over a period of 10-15 min. After a further 30 min at the mixture is filtered and the filtrate is concentrated. The residue is worked up by extraction with ethyl acetate and 2N aqueous sodium hydroxide solution. The organic phase is dried over magnesium sulphate, filtered and concentrated. The crude product can be purified by silica gel chromatography (dichloromethane/ethanol mixtures) or preparative reversed-phase HPLC (acetonitrile/water mixtures).

53 The following starting materials were prepared in an analogous manner: IV- 1. 1 4 -amino-2-(trifluoromethyl)phenyll.2.pvrrolidinone MS (ESI): m/z 245 100); HPLC (method rt 2.98 min IV-2. 4 4 -amino- 2 -(trifluoromethyl)phenvll.3.morpholinone MS (ESI): m/z ()=261 100); HPLC (method rt 2.54 min.

IV-3. 4 4( 4 amino- 2 -chlorop~henyl).3-morpholinone MS (ESI): m/z ()=227 100); HPLC (method rt 1.96 min.

IV-4. 4 4 -amino-2-methylphenyl)-3-morpholinone MS (ESI): m/z 207 100); HPLC (method 11 0.71 min.

5 -amino- 2 3 -oxo-4-morpholinyl)benzonitrile MS (ESI): m/z 218 100); HPLC (method rt 1.85 min.

IV-6. l-( 4 -amino-2-chlorophenyl)-2-pyrrolidinone MS (ESI): m/z 211 100); I-IPLC (method rt 2.27 min.

IV-7. 4 4 -amino-2,6-dimethylpheny)-3-morphohinone starting from 2 -fluoro-1,3-dimethyl-5-nitrobenzene (Bartoli et aL, J. Org. Chem.

1975, 40, 872): MIS (ESI): m/z 221 100); HIPLC (method rt 0.77 min.

IV-8. 4 4( 2 4 -d ianlinophenyj)-3-morpholi none starting from 1 -fluoro-2,4-dinitrobenzene: MS (ESI): m/z 208 100); HIPLC (method ml 0.60 min.

54 IV-9. 4-(4-amino-2-chlorop~henyvl)-2-methyl-3-morpholinone starting from 2-methyl-3-morpholinone (Pfeil, Harder, Angew. Chem. 1967, 79, 188): MIS (ESI): m/z 241 100); HPLC (method rt 2.27 min.

IV-1O. 4-(4-amino-2-chlorophenyl)-6-methyl-3-morpholinone starting from 6-methyl-3-mborpholinone (EP 350 002): MS (ESI): m/z 241 100); HPLC (method r 2.43 min.

55 Synthesis Example The Examples 1 to 13, 17 to 19 and 36 to 57 below refer to process variant Example 1 Preparation of 5-cbloro-N-{ [(5S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-1,3oxazolidin-5-yllmethyll-2-thiophenecarboxan-ide F 0 2K 0 N-b

N

HNS

0 (5S)-5-(Aminomethyl)-3-(3-fl uoro-4..morphol inophenyl)- I,3-ox azoli din-2-one (preparation see S. J. Brickner et al, J. Med. Chem. 1996, 39, 673) (0.45 g, 1.52 mmol), 5-chlorothiophene-2-carboxylic acid (0.25 g, 1.52 mmol) and 1-hydroxy-1I-benzotriazole hydrate (HOBT) (0.3 g, 1.3 equivalents) are dissolved in 9.9 ml of DMIF. 0.31 g (1.98 mmol, 1.3 equivalents) of N'-(3-dimethylaminopropyl)- N-ethylcarbodiimide (EDCI) are added, and 0.39 g (0.53 ml, 3.05 mmol, 2 equivalents) of diisopropylethylamnine (DLEA) are added dropwise at room emperature-The-mixture-s- stirred at room temperature overnight. 2 g of silica gel are added, and the mixture is evaporated to dryness under reduced pressure. The residue is chromatographed on silica gel using a toluene/ethyl acetate gradient. This gives 0.412 g (61.5% of theory) of the target compound of melting point 197 0

C.

Rf (SIO 2 toluene/ethyl acetate 1:1) 0.29 (starting material 0.0); MIS (DCI) 440.2 Cl pattern; 'H-NMR (d 6 -DMSO, 300 MI-z) 2.95 (in, 4H), 3.6 2H), 3.72 (in, 4H), 3.8 (dd, IN), 4.12 IH), 4.75-4.85 (in, 1H), 7.05 111), 7.15-7.2 (in, 3H), 7.45 (dd, IH), 7.68 1H), 8.95 IH).

56- Example 2 [(5S)-3-(4-morpholinophenyl)-2-oxo- 1,3-oxazolidin-5-yllmethyl 1-2thiophenecarboxamide is obtained analogously from benzyl 4-morpholinophenylcarbamate via the (aminomethyl)-3-(3-fl uoro-4-morpholinophenyl 1,3-oxazolidin-2-one intermediate (see Example 1).

198'C;

IC

50 value 43 nM; Rf (SiO 2 toluene/ethyl acetate 1: 1) 0.24.

Example3 5-Chloro-N-({(5S)-3- [3-fluoro-4-(1 ,4-thiazinan-4.yl)phenyl-2-oxo-1,3-oxazoli- }methyl)-2-thiophenecarboxamide is obtained analogously from (5S)-5-(amilnomethyl)-3-[3-fluoro-4-( 1,4-thiazinan-4yl)phenyl]-1,3-oxazoildin-2-one (preparation see M. R. Barbachyn et aL, J. Med.

Chem. 1996, 39, 680).

193'C; Yield: 82%; Rf (SiO 2 toluene/ethyl acetate 1: 1) 0.47 (starting material 0.0).

57 Example4 5

S)-

3 3 -fluoro-4-(1,4-thiazinan-4-yI)phenyl]..2.oxo1,3lmethyl)-2-tbiophenecarboxamide

SFN

is obtained analogously from 5-bromothiophene-2-carboxylic acid.

200"C.

Example N-(f [3-Fluoro-4-(1 ,4-thiazinan-4-yl)phenyi]-2-oxo 1 yl lmethyl)-5-methyl-2-thiophenecarboxamide F 0 S N Nk

CH

3 is obtained analogously from 5-methylthiophene-2-carboxylic acid.

167C.

58 Example6 [(5S)-3-(6-methylthieno[2,3-blpyridin..2.y)2oxo. 1,3-oxazolidin-5yI]methyl 1-2-thiophenecarboxamide is obtained analogously from (5S)-5-(ami nomethyl)-3 -(6-methylthi eno pyri din-.

2-yi)- 1,3-oxazolidin-2-one (preparation see EP-A-7 85 200).

247'C.

Example 7 5-Chloro-N-1 5 S)-3-(3-methyl-2-oxo-2,3-dihydro- 1 ,3-benzothiazol-6-yI)-2-oxo_ 1,3-oxazolid in- 5 -yllmethyl}-2-thiophenecarboxamide 0 0N S 0

NH

is obtained analogously from 6-[(5S)-5-(aminomethyl)-2-oxo- 1,3-oxazolidin-3-yl]-3methyl-i ,3-benzothi azol -2(3H)-one (preparation see EP-A-738 726).

217'C.

59- Example 8 5-Chloro-N-[((5S)-3-{3-fluoro-4-[4-(4-pyridinyl)piperazinolphenyl}..2.oxol,3oxazolidin-5-yl)methyl]-2-thiophenecarboxan-jde is obtained analogously from (5S)-5-(aminomethyl)-3-{ 3-fluoro-4-[4-(4pyridinyI)piperazino]phenyl-1,3-oxazolidin2one (preparation analogously to J. A.

Tucker et J. Med. Chem. 1998, 41, 3727).

MS (ESI) 516 (M+L1),CI pattern.

Example9 (5S)- 3 3 -fluoro-4-(4-methylpiperazino)penyl-2.oxo-.1 ,3-oxazolidin-5-yllmethyl)-2-thiophenecarboxamide is obtained analogously from methylpiperazino)phenyl]-1 ,3-oxazolidin-2-oi (5S)-5-(aminomethyl)-3-[3-fluoro-4-(4- Example 3 -fluoro-4-(4-tert-butoxycarbonylpiperazin-1-yl)phenylII2.

oxo- l, 3 -oxazolidin-5-yllmethyl)-2-thiophenecarboxamide 0 O

I

is obtained analogously from (5S)-5-(aminomethyl)-3-[3-fluoro-4-(4-tert-butoxycarbonylpi perazin- l-yl )phenyl] -1 ,3-oxazolidin-2-one (preparation see WO-A-93/23384, which has already been cited).

184'C; Rf (SiO 2 toluene/ethyl acetate 1: 1) 0.42.

Example 11 5-Chioro-N-({ (5S)- 3 -[3-fluoro-4-(piperazin- 1-yl)phenyl]-2-oxo- 1,3-oxazolidin-5yl lmethyl)-2-thiophenecarboxamide is obtained by reacting Example. 12 with trifluoroacetic acid in methylene chloride.

IC

50 value 140 nM; 61 'H-NMR [d 6 -DMSO]: 3.01-3.25 (in, 8H), 3.5-3.65 (mn, 2H), 3.7-3.9 (in, IH), 4.05-4.2 (in, 1H), 4.75-4.9 (in, IH), 7.05-7.25 (in, 3H), 7.5 (dd, 1H), 7.7 1H), 8.4 (broad s, IH), 9.0 1H).

Example 12 5-Chloro-N-[((SS)-3-(2,4'-bprdnl5y x-,-xzldi--lmtyl2 thiophenecarboxamidde

N

0 NA0 0 is obtained analogously from (5S)-5-aminoinethyl-3-(2,4 '-bipyridinyl-5-yl)-2-oxo- I ,3-oxazolidin-2-one (preparation see EP-A-789 026).

Rf (SiO0 2 ethyl acetate/ethanol 1:2) 0.6; MS (ESI) 515 Cl pattern.

Example 13 [(5S)-2-oxo-3-(4-piperid inophenyl)-1 ,3-oxazolidin-5-yllmethyl thiophenecarboxamide 62 is -obtained from 5-(hydroxymethyl)-3-(4-piperidinophenyl)- 1,3-oxazolidin-2-one (preparation see DE 2708236) after mesylation, reaction with potassium phthalimide, hydrazinolysis and reaction with 5-chlorothiophene-2-carboxylic acid.

Rf (SiO 2 ethyl acetate/toluene 1: 1) 0.3 1; m.p. 205'C.

Example 17 (5S)-2-oxo-3-[4-(2-oxo- 1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5yllmethyl)-2-thiophenecarboxamide 00 0 Analogously to the known synthesis scheme (see S.J. Brickner et al., J. Med. Chem.

1996, 39, 673), l-(4-aminophenyl)pyrroldin-2-one (preparation see Reppe et al., Justus Liebigs Ann. Chem.; 596; 1955; 209) gives, after reaction with benzyloxycarbonyl chloride, followed by reaction with R-glycidyl butyrate, mesylation, reaction with potassium phthalimide, hydrazinolysis in methanol and reaction with 5-chlorothiophene-2-carboxylic acid, finally 5-chloro-N-( {(5S)-2-oxo- 3 I -pyrroli1din yl)phenyl 1 ,3-oxazoli din-5 -yl methyl)-2-thi ophenecarboxamide. The 5-chloro-N-( (5S)-2-oxo-3-[4-(2-oxo- 1-pyrrolidinyl)phenyl]- 1,3-oxazolidin-5-yl Imethyl)-2-thiophenecarboxamide obtained in this manner has an IC 50 value of 4 nM (test method for the IC 5 o value according to Example A- La. I described above) "determination of the inhibition of factor Xa").

229'C; Rf value (SiO 2 to]luene/ethyl acetate 1: 1) 0.05 (starting material: 0.0); MS (ESI): 442.0 M+Na, Cl pattern), 420.0 M+H, Cl pattern), 302.3 215(52%), 145 (100%); 'Hi-NMIR (c1-DMSO, 300 MHz): 2.05 2.45 3.6 3.77-3.85 4.15(t,1H), 4.75-4.85 7.2 (d,1Hl), 7.5 7.65 7.69 (d,1IH), 8.96 (t,1IH).

-63- The individual steps of the synthesis of Example 17 described above with the respective precursors are as follows: At -20 0 C, 4 g (22.7 mmol) of 1-( 4 -aminophenyl)pyrrolidin-2-one and 3.6 ml (28.4 mmol) of N,N-dimethylaniline in 107 ml of tetrahydrofuran are admixed slowly with 4.27 g (25.03 mmol) of benzyl chloroformate. The mixture is stirred at for 30 minutes and then allowed to warm to room temperature. 0.5 1 of ethyl acetate are added, and the organic phase is washed with 0.5 1 of saturated NaCI solution. The organic phase is separated off and dried with MgSO 4 and the solvent is evaporated under reduced pressure. The residue is triturated with diethyl ether and filtered off with suction. This gives 5.2 g (73.8% of theory) of benzyl 4-(2-oxo-1pyrrolidinyl)phenylcarbamate as light-beige crystals of melting point 174 0

C.

At -10 0 C and under argon, 1.47 g (16.66 mmol) of isoamyl alcohol in 200 ml of tetrahydrofuran are admixed dropwise with 7.27ml of a 2.5 M solution of n-butyllithium (BuLi) in hexane, a further 8 ml of BuLi solution being required for the added indicator N-benzylidenebenzylamine to change colour. The mixture is stirred at -10 0 C for 10 minutes and cooled to -78°C, and a solution of 4.7 g (15.14 mmol) of benzyl 4 2 -oxo-l-pyrrolidinyl)phenylcarbamate is added slowly.

Another 4 ml of n-BuLi solution are then added until the colour of the indicator changes to pink. The mixture is stirred at -78°C for 10 minutes, 2.62 g (18.17 mmol) of R-glycidyl butyrate are added and the mixture is stirred at -78 0 C for another minutes.

Overnight, the mixture is allowed to warm to room temperature, 200 ml of water are added and the THF fraction is evaporated under reduced pressure. The aqueous residue is extracted with ethyl acetate and the organic phase is dried with MgSO 4 and evaporated under reduced pressure. The residue is triturated with 500 ml of diethyl ether and the precipitated crystals are filtered off with suction under reduced pressure.

This gives 3.76 g (90% of theory) of (5R)-5-(hydroxymethyl)-3-[4-(2-oxo-l-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one of melting point 148 0 C, with an Rf value (SiO 2 toluene/ethyl acetate 1:1) of 0.04 (starting material 0.3).

-64- At- 0°C, 3.6 g (13.03 mmol) of (5R)-5-(hydroxymethyl)-3-[4-(2-oxo-1pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one and 2.9 g (28.67 mmol) of triethylamine are initially charged with stirring in 160 ml of dichloromethane. 1.79 g (15.64 mmol) of methanesulphonyl chloride are added with stirring, and the mixture is stirred at 0°C for 1.5 hours and then at room temperature for 3 h.

The reaction mixture is washed with water and the aqueous phase is reextracted with methylene chloride. The combined organic extracts are dried with MgSO 4 and concentrated. The residue (1.67 g) is then dissolved in 70 ml of acetonitrile, admixed with 2.62 g (14.16 mmol) of potassium phthalimide and stirred in a closed vessel at 180 0 C in a microwave oven for 45 minutes.

The mixture is filtered off from insoluble residues, the filtrate is evaporated under reduced pressure and the residue (1.9 g) is dissolved in methanol and admixed with 0.47 g (9.37 mmol) of hydrazine hydrate. The mixture is boiled for 2 hours, cooled, admixed with saturated sodium bicarbonate solution and extracted six times with a total of 2 1 of methylene chloride. The combined organic extracts of the crude (aminomethyl)-3-[4-(2-oxo-l-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one are dried with MgSO 4 and concentrated under reduced pressure.

The end product, 5-chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-l-pyrrolidinyl)phenyl]-1,3- }methyl)-2-thiophenecarboxamide, is prepared by dissolving 0.32 g (1.16 mmol) of the (5S)-5-(aminomethyl)-3-[4-(2-oxo-l-pyrrolidinyl)phenyl]-1,3oxazolidin-2-one prepared above, 5-chlorothiophene-2-carboxylic acid (0.19 g; 1.16 mmol) and 1-hydroxy-IH-benzotriazole hydrate (HOBT) (0.23 g, 1.51 mmol) in 7.6ml of DMF. 0.29 g (1.51 mmol) of N'-(3-dimethylaminopropyl)-Nethylcarbodiimide (EDCI) are added, and 0.3 g (0.4 ml; 2.32 mmol, 2 equivalents) of diisopropylethylamine (DIEA) are added dropwise at room temperature. The mixture is stirred at room temperature overnight.

The mixture is evaporated to dryness under reduced pressure and the residue is dissolved in 3 ml of DMSO and chromatographed on an RP-MPLC using an TFA gradient. From the appropriate fractions, the acetonitrile fraction is evaporated and the precipitated compound is filtered off with suction. This gives 0.19 g (39% of theory) of the target compound.

65 The following compounds were prepared in an analogous manner: Example 18 5-Chloro-N-({ (5S)- 2 -oxo- 3 -[4-(-pyrrolidinyl)phenyl]-1,3oxazolidin-5 yl lmethyi)-2-thiophenecarboxamide Analogously to Example 17, 4 -pyrrolidin-lI-yl-ani line (Reppe et al, Justus Liebigs Ann. Chem.; 596; 1955; 151) gives the compound 5-chloro-N-({(5S)-2-oxo-3-[4-(1pyrrolidinyl)phenyl]-1I,3-oxazolidin-5-yl }methyl)-2-thiophenecarboxamide.

IC

5 o=40 nM; 216*C; Rf value (SiO 2 toluene/ethyl acetate 1:1) 0.31 [starting material: 0.01.

Example 19 (5S)- 2 -oxo-3-[4-(diethylamino)pheiyl].1,3-oxazolidin-5yI )methyl)-2-thiophenecarboxamide Analogously, N,N-diethylphenyl-1,4-diamine (US-A-2 811 555; 1955) gives the compound 5-chloro-N-(f (5 S)- 2 -ox o-3 ethyl ami'no)phenyl I -1,3-oxazolidin-5yl) methyl)-2-thiophenecarboxamide.

IC

50 =270 nM; 181'C; Rf value (SiO 2 toluene/ethyl acetate 1:1) 0.25 [starting material: 0.01.

Example 36 5

S)-

3 2 -methyl-4-(4-morpholinyl)phenyl].2oxo-.1,3-oxazolidin-5yl lmethyl)-2-thiophenecarboxamide starting from 2 -methyl-4-(4-rnorphol inyl)ani line (J.E.LuValle et al. J.Am.Chem.Soc.

1948, 70, 2223): MS (ESI): m/z 436 100), CI pattern; HPLC (method rt 3.77 (98).

IC

50 1.26 piM 66 Example 37 [(5S)-3-(3-chloro-4-morpholinophenyl).2oxo.1 yllmethyll-2-thiophenecarboxanuide starting from 3 -chloro-4-(4-morpholinyl)ani line (H.R.Snyder et al. J.Phanin.Sci.

1977, 66, 1204): MIS (ESI): m/z 456 100), C1 2 pattern; 1-PLC (method rt (100).

IC

50 33 nM Example 38 5-Chloro-N-({(5S)-3- 4 4 -morpholinylsulphonyl)phenyl]-2-oxo-1 ,3-oxazolidin- 5-yl)methyl)-2-tbiopbenecarboxamide.

starting from 4 4 -morpholinylsulphonyl)ani line (Adams et al. J.Am. Chem. Soc.

1939, 61, 2342): MIS (ESI): mlz 486 100), Cl pattern; I-IPLC (method rt (100).

IC

50 2 AM Example 39 -azetidinylsulphonyl)phenyl]-2-oxo- 1,3-oxazolidin-5- -ylfmethy)-2-hiophenearboxan-destarting from 1 -azeti dinylsulphonyl)ani line: MIS (DCI, N11 3 m/z 473 ([M+NH 4 100), Cl pattern; HPLC (method rt 4. 10 (100).

IC

50 0.84 M Example 5-Chloro-N-[((5S)-3-{4- [(dimethylamino)sulphonyllphenyl }-2-oxo- 1,3oxazolidin- 5 -yl)methyl]-2-thiophenecarboxamide starting from 4 -amino-NN-dimethylbenzenesulphonamide (I.K.Khanna et al.

J.Med.Chem. 1997, 40, 1619): MS (ESI): m/z 444 100), Cl pattern; -67- HPLC (method rt 4.22 (100).

IC

50 90 nM General method for the acylation of 5-(aminomethyl)-3-[4-(2-oxo-l-pyrrolidinyl)phenyl]-l,3-oxazolidin-2-one with carbonyl chlorides.

N NH 2 CI R O3 0O) 0 Under argon and at room temperature, an about 0.1 molar solution of (aminomethyl)-3-[4-(2-oxo-l-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one (from Example 45) (1.0 eq.) and absolute pyridine (about 6 eq.) in absolute dichloromethane is added dropwise to the appropriate acid chloride (2.5 The mixture is stirred at room temperature for about 4 h, and about 5.5 eq of PStrisamine (Argonaut Technologies) are then added. The suspension is stirred gently for 2 h, diluted with dichloromethane/DMF and then filtered (the resin is washed with dichloromethane/DMF) and the filtrate is concentrated. If appropriate, the product that is obtained is purified by preparative RP-HPLC.

The following compounds were prepared in an analogous manner: Example 41 N-({2-oxo-3-[4-(2-oxo- -pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2thiophene-carboxamide LC-MS (method m/z 386 100); LC-MS: rt 3.04 (100).

IC

5 0 1.3 AM 68 General method for preparing acyl derivatives starting from 5-(aminomethyl)-3- [4-(2-oxo-l1-pyrrolidinyl)phenyl-1,3-oxazolidin.2one and carboxylic acids N

NH

2 HO

R

Q0 0 The appropriate carboxylic acid (about 2 eq.) and a mixture of absolute dichloromethane/DMF (about 9:1) are added to 2.9 eq. of resin-bonded carbodiimide (PS-carbodiimide, Argonaut Technologies). The mixture is shaken gently at room temperature for about 15 min, 5-(aminomethyl)-3-[4-(2-oxo-l1-pyrrolidinyl)phenyl]- 1,3-oxazolidin-2-one (from Example 45) (1.0 eq.) is then added and the mixture is shaken overnight, after which the resin is filtered off (and washed with dichloromethane), and the filtrate is concentrated. If appropriate, the resulting product is purified by preparative RP-1-PLC.

The following compounds were prepared in an analogous manner: Example 42 2-oxo-3- [4-(2-oxo-l1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5.

yl }methyl)-2-thiophenecarboxamide LC-MS: m/z 400 100); LC-MS (method rt 3.23 (100).

IC

50 0.16 ItM Example 43 5-Bromo-N-({2-oxo-3- [4-(2-oxo-l1-pyrrolid inyl)phenyl]- 1,3-oxazolidin-5yl }methyl)-2-thiophenecarboxamide LC-MS m/z 466 100); LC-MS (method rt 3.48 (78).

-69-

IC

50 0.0 14 AM Example 4 5 -Chloro-N({( 5 S)-2-oxo-3-[4-(3-oxo-4..morpholiny)phenyl].1,3..oxazoidin.5yI )methyl)-2-tbiophenecarboxamide 0 0 NO N230 S c CI a) 2-((2R)-2-Hydroxy-3-{ 4 3 -oxo- 4 -morphoiinyi)phenyllamino~propyl). 11-isoindole-1,3(2H)i-dione: A suspension of 2 2

S)-

2 -oxi ranyl methyl -IH-i soi ndol e- 1 ,3 (21)-di one Gutcait et al. Tetrahedron Asym. 1996, 7, 1641) (5.68 g, 27.9 mmol) and 4-(4-aminophenyl)- 3-morpholinone (5.37 g, 27.9 mmol) in ethanol/water 140 ml) is refluxed for 14-h (the precipitate dissolves, after some time again formation of a precipitate). The precipitate (desired product) is filtered off, washed three times with diethyl ether and dried. The combined mother liquors are concentrated under reduced pressure and, after addition of a second portion of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole- 1,3(2H)-dione (2.84 g, 14.0 mmol), suspended in ethanol/water 70 ml) and refluxed for 13 h (the precipitate dissolves, after some time again formation of a precipitate). The precipitate (desired product) is filtered off, washed three times with diethyl ether and dried. Total yield: 10.14 g, 92% of theory.

MS (ESI): m/z 418 84), 396 93); HPLC (method rt 3.34 (100).

b) 2 2 -Oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione: Under argon and at room temperature, N,N'-carbonyldiimidazole (2.94 g, 18.1 mmol) and dimethylaminopyridine (a catalytic amount) are added to a suspension of the amino alcohol (3.58 g, 9.05 mmol) in tetrahydrofuran (90ml). The reaction suspension is stirred at 60 0 C for 12 h (the precipitate dissolves, after some time again formation of a precipitate), admixed with a second portion of N,N'carbonyldiimidazole (2.94 g, 18.1 mmol) and stirred at 60 0 C for another 12 h. The precipitate (desired product) is filtered off, washed with tetrahydrofuran and dried.

The filtrate is concentrated under reduced pressure and further product is purified by flash chromatography (dichloromethane/methanol mixtures). Total yield: 3.32 g, 87% of theory.

MS (ESI): m/z 422 100); HPLC (method rt 3.37 (100).

c) 5-Chloro-N-({(5S)- 2 -oxo-3-[4-(3-oxo-4-morpholinyl)phenyl].l,3-oxazolidin-5yl}methyl)-2-thiophenecarboxamide: At room temperature, methylamine (40% strength in water, 10.2 ml, 0.142 mol) is added dropwise to a suspension of the oxazolidinone (4.45 g, 10.6 mmol) in ethanol (102 ml). The reaction mixture is refluxed for 1 h and concentrated under reduced pressure. The crude product is used without further purification for the next reaction.

-71- Under argon and at 0 0 C, 5-chlorothiophene-2-carbonyl chloride (2.29 g, 12.7 mmol) is added dropwise to a solution of the amine in pyridine (90 ml). Ice-cooling is removed and the reaction mixture is stirred at room temperature for I h and admixed with water. Dichioromethane is added and the phases are separated, and the aqueous phase is then extracted with dichloromethane. The combined organic phases are dried (sodium sulphate), filtered and concentrated under reduced pressure. The desired product is purified by flash chromatography (dichioromethane/methanol mixtures).

Total yield: 3.92 g, 86% of theory.

M.p: 232-233 0 c; 'H NMR (DMSO-d', 200 MHz): 9.05-8.90 J 5.8 Hz, 1H), 7.70 J 4.1 Hz, 1H), 7.56 J 9.0 Hz, 211), 7.41 J 9.0 Hz, 2H), 7.20 J 4.1 Hz, 111), 4.93-4.75 (in, 1H1), 4.27-4.12 (in, 311), 4.02-3.9 1 (mn, 2H), 3.9 1-3.79 (dd, J 6.1 Hz, 9.2 Hz, 111), 3.76-3.66 (in, 2H), 3.66-3.54 (in, 2H); MS (ESD: m/z 436 100, Cl pattern); HPLC (method rt 3.60 (100); [cX2 'D -380 (c 0.2985, DMSO); ee: 99%.

IC

50 0.7 nM The following compounds were prepared in an analogous manner: Example (5S)-2-oxo-3- 4 3 -oxo- 4 -morpbolinyl)phenyl]-1,3-oxazolidins..

yllmethyl)-2-thiophenecarboxamide MS (ESI): mn/z 831 100), 416 66); HPLC (method rt 3.65 (100).

IC

50 4.2 nM Example 46 (5S)-2-oxo-3- [4-(3-oxo-4-morpholinyl)phenyl]-1 yl~methyl)-2-thiopbenecarboxamide MIS (ESI): m/~z 480 100, Br pattern); HPLC (method rt 3.87 (100).

IC

50 0.3 nM 72 Example 47 3 3 -isopropyl-2-oxo-2,3-dihydro-1,3-benzoxazoI.6-yI).2-oxo.

1 ,3-oxazolidin-5-yllmethyl 1-2-thiophenecarboxamide o ci

CI

0

S

CIH

200 mg (0.61 mmol) of 6 -[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl-3-isopropyl-1,3-benzoxazol-2(3H)-one hydrochloride (EP 738726) are suspended in 5 ml of tetrahydrofuran and admixed with 0.26 ml (1.83 mmol) of triethylamine and 132 mg (0.73 mmol) of 5-chlorothiophene-2-carbonyl chloride. The reaction mixture is stirred at room temperature overnight and then concentrated. The product is isolated by column chromatography (silica gel, methylene chloride/ethanol 50/1 to 20/1). This gives 115 mg (43% of theory) of the desired compound.

MIS (ESI): m/z 436 100); HPLC (method rt 3.78 min.

The following compounds were prepared in an analogous manner: 73 -74 ;tructure M.P. 0 C1 IC 50

[AM]

4.

1221 0.13 rom 5-amino-2-pyrrolidinobnzonitrile (Grell, Humaus, Griss, Sauter, R.; Rupprecht, E. et al.; 41; 5219) 5556 0.04 0 from 3-(4-amidno-phenyl)oxazolidin-2-one (Artico, M. et al.; Farmaco Ed.Sci. 1969, 24; 179) 56 qNI 0CW 18 0.004 0 57 o226 0.58 00 58 28-230 Examples 20 to 30 and 58 to 139 below refer to process variant and Examples and 21 describe the preparation of precursors.

Example Preparation of N-allyl-5-chloro-2-thiophenecarboxamide 0 o NH2 Cl- CI CI H \C Y I An ice-cooled solution of 2.63 ml (35 mmol) of allylamine in 14.2 ml of absolute pyridine and 14.2 ml of absolute THF is admixed dropwise with 2-carbonyl chloride (7.61 g, 42 mmol). Ice-cooling is removed and the mixture is stirred at room temperature for 3 h and then concentrated under reduced pressure.

The residue is admixed with water and the solid is filtered off. The crude product is purified by flash chromatography over silica gel (dichloromethane).

Yield: 7.20 g (99% of theory); MS (DCI, NH4): m/z 219 (M+NH 4 100), 202 32); HPLC (method rt 3.96 min (98.9).

Example 21 Preparation of 5 -chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide 0 0 S

CI

H 0 H An ice-cooled solution of 2.0 g (9.92 mmol) of N-allyl-5-chloro-2thiophenecarboxamide in 10 ml of dichloromethane is admixed with metachloroperbenzoic acid (3.83 g, about 60% strength). The mixture is stirred overnight, during which it is allowed to warm to room temperature, and is then washed with 10% sodium hydrogen sulphate solution (three times). The organic phase is washed with saturated sodium bicarbonate solution (twice) and with saturated sodium -76chloride solution, dried over magnesium sulphate and concentrated. The product is purified by silica gel chromatography (cyclohexane/ethyl acetate 1:1).

Yield: 837 mg (39% of theory); MS (DCI, NH 4 m/z =253 (M+NH 4 100), 218 HPLC (method rt 3.69 min (about General method for preparing substituted N-(3-amino-2-hydroxypropyl)-5chloro-2-thiophenecarboxamide derivatives starting from 5-chloro-N-(2oxiranylmethyl)-2-thiophenecarboxamide R-N H C R N CI H OHH At room temperature or at temperatures up to 80 0 C, 5-chloro-N-(2-oxiranylmethyl)- 2-thiophenecarboxamide (1.0 eq.) is added a little at a time to a solution of the primary amine or aniline derivative (1.5 to 2.5 eq.) in 1,4-dioxane, 1,4-dioxane/water mixtures or ethanol, ethanol/water mixtures (about 0.3 to 1.0 mol/). The mixture is stirred for 2 to 6 hours and then concentrated. From the reaction mixture, the product can be isolated by silica gel chromatography (cyclohexane/ethyl acetate mixtures, dichloromethane/methanol mixtures or dichloromethane/methanol/triethylamine mixtures).

The following compounds were prepared in an analogous manner: Example 22

N-[

3 -(Benzylamino)-2-hydroxypropyl]-5-chloro-2-thiophenecarboxamide MS (ESI): m/z 325 100); HPLC (method rt 3.87 min (97.9).

Example 23 3 3 -cyanoanilino)-2-hydroxypropyl]-2-thiophenecarboxamide MS (ESI): m/z 336 100); HPLC (method rt 4.04 min (100).

77 Example 2 3 4 -cyanoanilino)-2-hydroxypropyi]-2-thiophenecarboxamide MS (ESI): m/z 336 100); HPLC (method rt(% 4.12 min (100).

Example 5-Chloro-N-{3-[4-(cyanomethyl)anilino]-2-hydroxypropyl..2 thiophenecarboxamide MS (ESI): m/z 350 100); HPLC (met hod rt(% 3.60 min (95.4).

Example 26 5-Chloro-N-{3-[3-(cyanomethyl)anilino]-2-hydroxypropy}..2thiophenecarboxamide MS (ESI): m/z 350 100); HPLC (method rt 3.76 min (94.2).

Example 58 tert-Butyl 4 3 -{[(5-chloro-2-thienyl)carbonyl]amino).2-hydroxypropyl)amino]benzylcarbamate starting from teri-butyl 4-aminobenzylcarbamate (Bioorg. Med. Chem. Lett.; 1997; 192 1-1926): MS (ES-pos): m/z ()=440 100), (ES-neg): m/z 438 100); HPLC (method rt 4.08 (100).

Example 59 tert-Butyl 4 3 -{[(5-chloro-2-thienyl)carbonyI]amino}-2-hydroxypropyI)aminophenyl-carbamate starting from N-zert-butyloxycarbonyl- 1,4-phenylenediamine: MS (ESI): m/z 426 (Mi-H, 45), 370 (100); -78- HPLC (method 11(%t 4.06 (100).

Example 6 tert-Butyl 2-hyd roxy-3-{ [4-(2-oxo- l-pyrrolidinyl)phenyIlamino~propyl-carbamate starting from 1-( 4 -armnophenyl)-2-pyrrol idi none (Justus Liebigs Ann. Chem.; 1955; 596; 204): MS (DCI, Nil 3 m/z ()=350 100); HPLC (method rt(% 3.57 (97).

Example 61 5-Chloro-N-(3-{ 3 -fluoro- 4 3 -oxo-4-morpholinyl)phenyl~amino..2.hydroxypropyl)-2-thiophenecarboxamide 800 mg (3.8 mmol) of 4 4 -ami no- 2 -fl uorophen yl)-3 morphol inone and 700 mg (3.22 mmol) of 5 -chlIoro-N-( 2 -ox iran yl meth yl-2-th 1ophenec arbox amde in 15 ml of ethanol and 1 ml of water are heated under reflux for 6 hours. The mixture is concentrated under reduced pressure and treated with ethyl acetate, precipitated crystals are filtered off with suction and the mother liquor is chromatographed giving 276 mg (17% of theory) of the target compound.

-R -eh laeat) -25 Example 62 nilino- 2 -hydroxypropyi)-5-chloro-2.thiophenecarboxamide starting from aniline: MIS (DCI, NI-I 3 mlz ()=311 100), Cl pattern; HPLC (method rt(% 3.79 (100).

Example 63 5-Chloro-N-(2-hyd roxy-3-{ 4 3 -oxo- 4 -morphoinyl)phenyllamino~propyl)-2 thiophenecarboxamide -79 starting from 4-(4-aminophenyl)-3-morpholinone: MS (ESI): mlz 410 50), Cl pattern; HPLC (method rt (100).

Example 64 N-[3-({4-IIAcetyl(cyclopropyl)aminophenyl)amino)-2-hydroxypropyl]-5-cbloro 2-thiophenecarboxamide starting from N-(4-aminophenyl)-N-cyclopropylacetamide: MS (ESI): m/z ()=408 100), Cl pattern; HPLC (method rt (100).

Example N-13-(4-[Acetyl(methyl)ainolpenyllamino)-2-hydroxypropyl]-5-chloro-2thiophenecarboxamide starting from N-(4-aminophenyl)-N-methyl acetamide: MS (ESI): m/z 382 100); HPLC (method rt 3.31 min.

Example 66 5-Chloro-N-(2-hydroxy-3-{[4-(1H-1,2,3-triazol- 1-yl)phenyllaminolpropyl)-2thiophenecarboxamide starting from 4-(1H-1,2,3-triazol-1-yl)aniline (Bouchet et aL; J.Chem.Soc.Perkin Trans.2; 1974; 449): MS (ESI): m/z 378 100); HPLC (method rt 3.55 min.

Example 67 tert-butyl I(5-choro-2-thienyl)carbonyllamino}-2-hydroxypropyl)amninolphenyl}-L-prolinate MS (ESD: m/z 480 100); HPLC (method rt 3.40 min.

80 Example 68 5 -Chloro- 2 -thienyl)carbonyllamino}..2.hydroxypropyl)amino]phe.

nyl)-4-piperidinecarboxamide MS (ESD: m/z 437 100); HPLC (method 11 2.39 min.

Example 69 1 [(5-Cbloro- 2 -thienyl)carbonyl]amino)-2hydroxypropyl).amino]phe.

nyl}-3-piperidinecarboxamide MS (ESI): m/z =437 100); HPLC (method rt 2.43 min.

Example 5-Chloro-N-(2-hydroxy-3-{ [4-(4-oxo- I-piperidinyl)phenyl]amino)propyl)-2thiophenecarboxamide MS (ESI): m/z 408 100); HPLC (method rt 2.43 min.

Exampie 71 4 4 4(- 3 2 -tienyl)carbonyl]amino}..2.hydroxypropyj)amino]phenyl}-L-prolinamide MS (ESI): m/z 423 100); HPLC (method ml 2.51 min.

Example 72 5-Chloro-N-[2-hyd roxy-3-({4- [3-(hydroxymethyl)-l1-piperidinyilphenyl}amino)propyl]-2-thiophenecarboxamide MS (ESI): mlz 424 100); I-PLC (method ml 2.43 min.

81 Example 73 2 -hydroxy-3-({4-[2-(hydroxymethyl).l-piperidinyllphenyl..

amino)propyl]-2-thiophenecarboxamide MIS (ESI): m/z 424 100); HPLC (method rt 2.49 min.

Example 74 Ethyl 1-14-[(3-f [(S-chloro- 2 -thienyl)carbonyllamidno)-2-hydroxypropyl).

amino]phenyl}-2-piperidinecarboxylate MIS (ESI): m/z 466 100); 1-PLC (method rt 3.02 min.

Example 5-Chloro-N-[2-bydroxy-3-({ 4-[2-(hydroxymethyl)- 1-pyrrolidinyllphenyl Jamino)propyl]-2-thiophenecarboxamide MS (ESI): m/z 410 100); HPLC (method rt 2.48 min.

Example 76 5-hoo-{-hydroxy-3-{ 4 2 -methylhexahydro-5H-pyrrolo[3,4.dlisoxazol-5yl)phenyllaminolpropyl)-2-thiophenecarboxamide MIS (ESI): m/z 437 100).

HPLC (method ml 1.74 min.

Example 77 5-Chloro-N-(2-bydroxy-3-f 4 -(l-pyrrolidinyl)-3-(trifluoromethyl)phenyl].

aminolpropyl)-2-thiophenecarboxamide MIS (ESI): m/z 448 100); HPLC (method rt 3.30 min.

82 Example 78 5-Chloro-N-(2-hydroxy-3-{ [4-(2-oxo-1 -pyrrolidinyl)-3-(trifluoromethy)pheinylJamino) propyl)-2-thioph enecarboxamide MS (ESI): m/z 462 100); HPLC (method rt 3.50 minl.

Example 79 5-Chloro-N-(3-{13-chloro-4-(3-oxo-4-morpholinyl)phenylj amino}-2-hydroxypropyl)-2-thiophenecarboxamide MS (ESI): mlz 444 100); HPLC (method rt 3.26 min.

Example loro-N-(2-hydroxy-3-{ [4-(3-oxo-4-morpholinyl)-3-(triflu oromethyl)p hen yl amino) propyl)-2-thiophenecarboxaniide MS (ESI): m/z 478 100); HPLC (method rt =3.37 min.

Example 81 5-Chloro-N-(2-hydroxy-3-{ [3-methyl-4-(3-oxo-4-morph olinyl)ph enyl] amnino)propyl)-2-thiophenecarboxamide MS (ESI): rnlz 424 100); HPLC (method rt 2.86 min.

Example 82 5-Chloro-N-(3-{13-cyan o-4-(3-oxo-4-morpholinyl)ph enyll amino)}-2-hydroxyprop3y1)-2-thiophenecarboxamide MS (ESI): m/z 43 5 100); HPLC (method rt 3. 10 min.

83 Example 83 5-Chloro-N-(3-{ [3-chloro-4-(1 -pyrrolidinyl)phenyllamino)-2-hydroxypropy1)-2thiophenecarboxamide MS (ESI): m/z M% 414 100); HPLC (method rt 2.49 min.

Example 8 5-Chloro-N-(3-{ [3-cbloro-4-(2-oxo-l1-pyrrolidinyl)phenyllamino}-2-hydroxypropyl)-2-thiophenecarboxamidde MS (ESI): m/z =428 100); HPLC (method ii 3.39 min.

Example 5-Chioro-N-(3-f 3 ,5-dimethyl-4-(3-oxo-4-morpholinyI)phenyllamino..2hyd roxypropyl)-2-thiophenecarboxamide MS (ESI): m/z 438 100); 1-WLC (method rt 2.84 min.

Example 86 tIiiuuu buynyl)- 4 4 -zuorpholiny~hnlaip o-2-hydroxypropyl)- 5-chioro-2-thiophenecarboxamide MS (ESI): m/z 439 100); HPLC (method rt 2.32 min.

Example 87 5-Chloro-N-(2-hyd roxy-3-{ 3 -methoxy-4-(4-morpholinyl)phenyllamino~propyl).

2-thiophenecarboxamide MS (ESI): mlz 426 100); HPLC (method rt 2.32 min.

84- Example 88 3 -Acetyl- 4 4 -morpholinyl)phenyllaminol.2.ydroxypropy)-5.chloro.2thiophenecarboxamide MIS (ESD: m/z 438 100); HPLC (method rt 2.46 min.

Example 89 [3-A mino- 4 3 -oxo-4-morpholinyi)phenyllamino}..2.hydroxypropyI)-5chioro-2-thiopbenecarboxamide MS (ESI): m/z 425 100); HPLC (method ii 2.45 min.

Example 5-Chloro-N.(3-{ 3 -chloro- 4 2 -methyl-3-oxo-4morpholinyl)phenyl]amino}-2hyd roxypropyl)-2-thiophenecarboxamide MIS (ESI): m/z 458 100); HPLC (method rt 3.44 min.

Example 91 ik~ ph~y~hnyjmn) hydroxypropyl)-2-thiophenecarboxamide MIS (ESI): m/z 458 100); HPLC (method it 3.48 min.

Example 91a Chioro-N-[ 2 -hyd roxy-3- (14-[(3-oxo-4.morpholinyl)methyllphenyI jamino)propyl]-2-thiophenecarboxamide starting from 4 4 -ami no-benzyl)-3 -morphol inone (Surrey et al.; J. Amer. Chem.

Soc.; 77; 1955; 633): MIS (ESI): m/z 424 100); 85 HPLC (method rt 2.66 min.

General method for preparing 3-substituted 5-chloro-N-[(2-oxo-1,3-oxazolidin- 5-yl)methyl]-2-tbiophenecarboxamide derivatives starting from substituted

N-(

3 -amino- 2 -hydroxypropyl).5-chloro..2.thiophenecarboxanjde derivatives 0 N, S 0 0 S CI H H H

HS

R

At room temperature, carbodiimidazole (1.2 to 1.8 eq.) or a similar phosgene equivalent are added to a solution of the substituted N-(3-amino-2-hydroxypropyl)-5chloro-2-thiophenecarboxamide derivative (1.0 eq.) in absolute THE (about 0.1 mol/l). At room temperature or, if appropriate, at elevated temperature (up to 0 the mixture is stirred for 2 to 18 h and then concentrated under reduced pressure. The product can be purified by silica gel chromatography (dichloromethane/methanol mixtures or cyclohexane/ethyl acetate mixtures).

The following compounds were prepared in an analogous manner: Example 27 N-[(3-Benzyl-2-oxo- 1,3-oxazolidin-S-yI)metbyl]-5-chloro-2.

thiophenecarboxamide MIS (DCI, NH 4 m/z ()=372 (M+Na, 100), 351 HIPLC (method rt min (100).

Example 28 hloro-N-{ 3 3 -cyanophenyl)-2-oxo- 1,3-oxazolidin-5-yl]methy1-2thiophenecarboxamide MIS (DCI, NH1 4 m/z ()=362 42), 145 (100); HPLC (method rt(% 4.13 min (100).

86 Example 29 5-Chloro-N-(13-[4-(cyanomethyl)phenyl-2-oxo-.I,3-oxazolidin-5-yllmethyl)-2thiophenecarboxamide MS (ESI): m/z 376 100); HPLC (method A1 4.12 min Example S-Chloro-N-({3-[3-(cyanomethyl)phenyl].2-oxo. I,3-oxazolidin-5-yllmethyl)-2thiophenecarboxamide MIS (ESI): m/z 376 100); HPLC (method rt 4.17 min Example 92 tert-Butyl [(S-chloro-2-thienyl)carbonylaminolmethyl)2ox-1 ,3-oxazolidin-3-yIlbenzyicarbamate starting from Example 58: MIS (ESI): m/z 488 (M+Na, 23), 349 (100); HPLC (method r1(%t 4.51 (98.5).

Example 93 terf-Butyl 4- [(5-chloro-2-thienyl)carbonyl]aminolmethyl)2 0 xo-1,3-oxazolidin-3-yllphenyicarbamate starting from Example 59: MIS (ESI): m/z 493 (M+Na, 70), 452 10), 395 (100); HPLC (method rt 4.41 (100).

Example 94 terl-Butyl 2-oxo-3-[4-(2-oxo-1 -pyrrolidinyl)phenyl]- 1,3-oxazolidin-5-yl }methylcarbamate starting from Example MIS (DCI, NH- 3 m/z 393 (M+NH 4 100); 87 HPLC (method ii(%t 3.97 (100).

Example 5-Chloro-N({ 3 3 -fluoro-4-(3-oxo-4-morpholinyl)pheny]2oxo.1,3.oxazolidin- )methyl)-2-thiophenecarboxamide F$ro 1/ 260 mg (0.608 mmol) of 5-chloro-N-(3- {[3-fl uoro- 4 3 -oxo-4-morpholinyl)phenyl].

amino) 2 -hydroxypropyl)-2-thiophenecarbox amide (from Example 61), 197 mg (1.22 mmol) of carbonylimidazole and 7 mg of dimethylaminopyridine in 20 ml of dioxane are boiled under reflux for 5 hours. 20 ml of acetonitrile are then added, and the mixture is stirred in a closed vessel in a microwave oven at 180'C for 30 minutes.

The solution is concentrated using a rotary evaporator and chromatographed on an RP-HPLC column. This gives 53 mg (19% of theory) of the target compound.

NMR (300 MHz, de-DMSO): 8= 3.6-3.7 3.85 (dd,1H), 3.95 4.2 4.21 4.85 4.18 (s,214), 7.19 (d,IH,thiophene), 7.35 (dd,1H), 7.45 7.55 (dd,1H), 7.67 (d,1H,thiophene), 8.95 (t,1H,CONH).

Example 96 5-Chloro-N-[(2-oxo-3-phenyl-1,3-oxazolidin.5yl)methyI..2 thiophenecarboxamide starting from Example 62: MIS (ESI): m/z 359 71), 337 100), Cl pattern; 1-PLC (method rt(% 4.39 (100).

IC

50 2 jItM 88 Example 97 5-Chioro-N({2-oxo-3-[4-(3-oxo-4-morpbolinyl)phenyl.1,3.oxazolidin5yl metbyl)-2-thiophenecarboxamide starting from Example 63: MS (ESI): m/z 458 66), 436 100), CI pattern; HPLC (method rt(% 3.89 (100).

IC

50 1.4 nM Example 98 3 4 -[Acetyi(cyclopropyl)amino]phenyl )-2-oxo- 1,3-oxazolidin-5-yl)methyl]- 5-cbloro-2-thiopbenecarboxamide starting from Example 64: MS (ESI): m/z 456 55), 434 100), Cl pattern; IJPLC (method rt (100).

IC

50 50 nM Example 99 3 4 [Acety(methyl)aminolphenyly-2-oxo.1,3-oxazolidin5.y)methyl].5 chloro-2-thiophenecarboxamide MIS (ESI): m/z 408 30), 449 (M+H+MeCN, 100); HPLC (method rt 3.66 min.

Example 100 2-oxo-3- H-i ,2,3-triazol-1I-yi)plienyll- 1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide MIS (ESI): m/z 404 45), 445 (M+H+MeCN, 100); ITIPLC (method rt 3.77 min.

Example 101 Tert-butyl 1 [(S-chioro-2-thienyl)carbonyllamino~methyl)-2oxo-1,3oxazolidin-3-yllphenyl )-L-proiinate 89- MS (ESD): m/z 450 (M+H-56, 25), 506 100); HPLC (method rt 5.13 min.

Example 102 [(5-Chloro-2-thienyl)carbonyl]amino~metby)2-oxo1,3-oxazolidin-3yl]phenyl}-4-piperidinecarboxamide MS (ESI): m/z 463 100); HPLC (method rt 2.51 min.

Example 103 [(5-Chloro-2-thienyl)carbony]amino)metyl)-2-oxo..1,3..oxazolidin-3yIlphenyl}-3-piperidinecarboxamide MS (ESI): m/z 463 100); HPLC (method rt 2.67 min.

Example 104 5-Chloro-N-({2-oxo-3- 4 -(4-oxo-l1-piperidinyl)phenyl]- 1,3-oxazolidin-5yl )methyl)-2-thiophenecarboxamide MS (ESI): m/z ()=434 40), 452 (M+H+H 2 0, 100), 475 (M+H+MeCN, UPLC (method ml 3.44 min.

Example 105 I [(5-Chloro-2-thieny)carbonyllamino)methyl)-2oxo. 1,3-oxazolidin-3yIlphenyl)-L-prolinamide MS (ESI): mlz 449 (M+FI, 100); HPLC (method rt 3.54 min.

Example 106 5-Chloro-N-[(3-{4-[3-(hydroxymethyl)- 1-piperidinyllphenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide MS (ESI): m/z 450 100); HPLC (method rt 2.53 min.

Example 107 5-Cbloro-N-[(3-{4-[2-(bydroxymethyl)- 1-piperidinyllphenyl)-2-oxo-1 ,3-oxazoliethyl]-2-thiophenecarboxamide MS (ESI): ni/z 450 100); HPLC (method 11 2.32 mmn.

Example 108 Ethyl 1 [(5-chloro-2-thienyl)carbonyl]amino)metbyl)-2-oxo-1 ,3-oxazolidin-3-yl]phenyl}-2-piperidinecarboxylate MS (ESI): m/z 492 100); HPLC (method rt 4.35 min.

Example 109 -Chtoro-N--(3.-44-2(h-ydroxymethyl)- 1-pyrrolidinyllpbenyl)-2-oxo- 1,3-oxazolidin-5-yl)methyl]-2-thiopbenecarboxamide MS (ESI): m/z 436 100); HPLC (method rt1= 2.98 min.

Example 110 5-Chloro-N-({2-oxo-3-[4-(1 -pyrrolidinyl)-3-(trifluoromethyl)phenyl]- 1,3-oxazolilmethyl)-2-thiopbenecarboxamide MS (ESI): m/z 474 100); HPLC (method rt 4.63 min.

-91- Example 111 5-Chloro-N-({3-[4-(2-methylhexahydro-5H-pyrroo[3,4.disoxazo..5y)pheny1..

2 -oxo-l, 3 -oxazolidin-5-yllmethyl)-2-thiophenecarboxamide MS (ESI): m/z 463 100); HPLC (method it 2.56 min.

Example 112 5-Chloro-N-({ 2 -oxo- 3 -[4-(2-oxo--pyrrolidinyl)3(trifluoromethyl)phenyl]-l,3.

}methyl)-2-thiopbenecarboxamide MS (ESI): m/z 488 100); HPLC (method rt =3.64 min.

Example 113 5-Chloro-N-({3-[3-chloro-4-(3-oxo-4-morpholinyl)phenyl].2oxo.1 ,3-oxazolidin- 5-yllmethyl)-2-thiophenecarboxamide MS (ESI): m/z 470 100); HPLC (method rt 3.41 min.

Exampie 114 5 .Chlor-N- 2 -oxo 3 oxo-4-morpholinyl).3(trfluoromethyl)phenyl].1,3.

oxazolidin-5-yl lmethyl)-2-thiophenecarboxamide MS (ESI): m/z 504 100); HPLC (method rt 3.55 min.

Example 115 5-Chloro-N-({3- 3 -methyi- 4 -(3-oxo-4-morpholinyl)phenyl-2-oxo-.1 ,3-oxazolidin- 5-yllmethyl)-2-thiophenecarboxamide MS (ESI): m/z 450 100); HPLC (method rt 3.23 min.

92 Example 116 5-Chloro-N-({3-[3-cyano-4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin- }methyl)-2-thiophenecarboxamide MS (ESI): m/z 461 100); HPLC (method rt 3.27 min.

Example 117 5-Chloro-N-({3-[3-chloro-4-(1-pyrrolidinyl)phenyl-2-oxo- 1,3-oxazolidin-5yI~methyl)-2-thiophenecarboxamide MS (ESI): mn/z 440 100); HIPLC (method rt 3.72 min.

Example 118 5-Chloro-N-({3- [3-chloro-4-(2-oxo-l1-pyrrolidinyl)phenyl]-2-oxo-1 ,3-oxazolidin- 5-yl~methyl)-2-thiophenecarboxamide MS (ESI): m/z 454 100); HPLC (method rt 3.49 min.

Example 119 5ChoroIN-kt3 5-dijehl4(- nopilni~h -mx zolidin-5-yl }methyi)-2-thiophenecarboxamide MS (ESI): m/z 464 100); HPLC (method rt 3.39 min.

Example 120 mlnocarbonyl)-4-(4-morphoiinyl)phenyl]-2-oxo- 1,3-oxazolidin-5yI~methyl)-5-chloro-2-tbiophenecarboxamide MS (ESI): m/z 465 100); HPLC (method rt 3.07 min.

-93 Example 121 5-Chloro-N-({3-[3-methoxy-4-(4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5yl)methyl)-2-thiophenecarboxamide MS (ESI): m/z 452 100); HIPLC (method rt 2.86 min.

Example 122 [3-Acetyl-4-(4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl)methyl)-5chloro-2-thiophenecarboxamide MS (ESI): m/z %)=464 100); HPLC (method rt 3.52 min.

Example 123 [3-A mino-4-(3-oxo-4-morpholinyl)phenyl]-2-oxo- 1,3-oxazolidin-5-yl)methyl)-5-chloro-2-thiophenecarboxamide MS (ESI): mlz 451 100); HPLC (method f1 3.16 min.

Example 124 5-Chloro-N-(13- [3-chloro-4-(2-methyl-3-oxo-4-morpholiny)phenylJ-2-o-xo-1 ,3oxazolidin-5-yI }methyl)-2-thiopbenecarboxamidde MS (ESI): m/z 484 100); HPLC (method 11 3.59 min.

Example 125 5-Chloro-N-((3-13-chloro-4-(2-methyl-5-oxo-4-morpholinyl)phenyl]-2-oxo-1,3- )methyl)-2-thiophenecarboxamide MS (ESI): m/z 484 100); HPLC (method rt 3.63 mmn.

-94 Example 125a 5-Chloro-N-[(2-oxo-3-{4-[(3-oxo-4-morpbolinyl)methyl]phenyl}- 1,3-oxazolidin- 5-yl)metbyl]-2-thiophenecarboxamide MS (ESD): m/z 450 100); HPLC (method rt1= 3.25 min.

Via epoxide opening with an amine and subsequent cyclization to give the corresponding oxazolidinone, it was also possible to prepare the following compounds: Example No. Structure p. 0 C] IC 50

[AM]

126 N 029Z 0.013 F F F 0 r0

F

F 0 127 O'N k 0 Br 159 0.0007 00 0 N ONNVYK(Br D.001 0 130 NNN 206 0.0033 0 0 130a r-\F 0 194 0 0 131 0195

,''SC

0 0 132 206 .12 j 0 95 Example No. Structure M.P. IC 50

[AM]

13 0 F 0 13 0 C O27 0.482 0 from 1 -(4-amino-phenyl)piperidin-3-oI (Tong, L.K.J. et al.; J.Amer.Chem.Soc 1960; 82, 1988). 135 i1r 002 1.1

F

136 CN NY239 1.2 Fj 0 D.044 138 0- 5 0.42 N-0-0 0 139i.. 217 1.7 0 -96- Examples 14 to 16 below are working examples for the optional oxidation step.

Example 14 5-Chloro-N-({(5S)-3-[3-fluoro-4-(1-oxo-1 [lambda] 4 ,4-thiazinan-4-yI)phenyl]-2oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide F 0 O=S N N

S

HN

At 0°C, 5-chloro-N-({(5S)-3-[3-fluoro-4-(1,4-thiazinan-4-yl)phenyl]-2-oxo-1,3oxazolidin-5-yl)methyl)-2-thiophenecarboxamide (0.1 g, 0.22 mmol) from Example 3 in methanol (0.77 ml) is added to a solution of sodium periodate (0.05 g, 0.23 mmol) in water (0.54 ml), and the mixture is stirred at 0°C for 3 h. 1 ml of DMF is then added, and the mixture is stirred at RT for 8 h. After addition of a further 50 mg of sodium periodate, the mixture is once more stirred at RT overnight. The mixture is then admixed with 50 ml of water, and the insoluble product is filtered off with suction. Washing with water and drying gives 60 mg (58% of theory) of crystals.

257 0

C;

Rf (silica gel, toluene/ethyl acetate 1:1) 0.54 (starting material 0.46);

IC

50 value 1.1 pM; MS (DCI) 489 (M+NH4), Cl pattern.

97 Example Preparation of 5-chloro-N-({(S5S)-3- -dioxo-l1[lambda] 6 ,4-thiazinan-4-yi)-3fluorophenyl]-2-oxo-1 3 -oxazolidin-5-yllmethyl)-2..thiophenecarboxamide F0

CI

S

HN

0 (5S)-3-[3-fluoro-4-( 1, 4 -thiazinan-4-yl)phenyl]-2-oxo-1I,3-oxazolidin- 5-yl~methyl)-2-thiophenecarboxamide from Example 3 (0.1 g, 0.22 mmol) in 3.32 ml of a mixture of 1 part of water and 3 parts of acetone is admixed with 80 mg (0.66 mmol) of N-methylmorpholine N-oxide (NMO) and 0.1 ml of a 2.5% strength solution of osmium tetroxide in 2 -methyl-2-propanol. The mixture Is stirred at room temperature overnight, and another 40 mg of NMO are added. The mixture is stirred for a further night and then poured into 50 ml of water and extracted three times with ethyl acetate. The organic phase gives, after drying and concentrating, 23 mg and the aqueous phase, after removal of the insoluble solid by filtration with suction, 19 mg (in total 39% of theory) of the target compound.

238 0

C<

Rf (toluene/ethyl acetate 1: 1) 0. 14 (starting material 0.46);

IC

50 value 210 nM; MS (DCI): 505 (M+NI-L4), Cl pattern.

Example 16 5-Chloro-N-{ 3 3 -fluoro-4-morpholinophenyl)-2-oxo-.1 ,3-oxazolidin-Syllmethyl)-2-thiophenecarboxamide N-oxide is obtained by treating 5-chloro-N- {[(5S)-3-(3-flIuoro-4-morpholinophenyl)-2-oxol, 3 -oxazolidin-5-yllmethyl)-2-thiophenecarboxamide from Example 1 with the magnesium salt of monoperoxyphthalic acid.

MS (ESI): 456 21%, Cl pattern), 439 (100%).

-98- The Examples 31 to 35 and 140 to 147 below refer to the optional amidination step.

General method for preparing amidines and amidine derivatives starting from cyanomethylphenyl-substituted 5-chloro-N-[(2-oxo-1,3-oxazolidin-5-yl)methyl]- 2-thiophenecarboxamide derivatives The cyanomethylphenyl-substituted 5-chloro-N-[(2-oxo-1,3-oxazolidin-5-yl)methyl]- 2-thiophenecarboxamide derivative in question (1.0 eq.) is, together with triethylamine (8.0 stirred at RT in a saturated solution of hydrogen sulphide in pyridine (about 0.05 0.1 mol/1) for one to two days. The reaction mixture is diluted with ethyl acetate (EtOAc) and washed with 2 N hydrochloric acid. The organic phase is dried with MgSO 4 filtered and concentrated under reduced pressure.

The crude product is dissolved in acetone (0.01-0.1 mol/1) and admixed with methyl iodide (40 The reaction mixture is stirred at room temperature (RT) for 2 to 5 h and then concentrated under reduced pressure.

The residue is dissolved in methanol (0.01-0.1 mol/1) and, to prepare the unsubstituted amidines, admixed with ammonium acetate (3 eq.) and ammonium chloride (2 To prepare the substituted amidine derivatives, primary or secondary amines (1.5 eq.) and acetic acid (2 eq.) are added to the methanolic solution. After h, the solvent is removed under reduced pressure and the residue is purified by chromatography over an RP8 silica gel column (water/acetonitrile 9/1-1/1 0.1% trifluoroacetic acid).

The following compounds were prepared in an analogous manner: Example 31: N-({3-[4-(2-Amino-2-iminoethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5chloro-2-thiophenecarboxamide MS (ESI): m/z 393 100); HPLC (method rt 2.63 min 99- Example 32: 5-Chloro-N-({3-13-(4,5-dihydro-1H-imidazol-2-ylmethyl)phenylj-2-oxo.1,3.

oxazolidin-5-yllmethyl)-2-thiophenecarboxamide MS m/z 419 100); HPLC (method rt 2.61 min Example 33: 5-Chloro-N-II(3-{3-[2-imino-2-(4-morpholinyl)ethyljpenyl)-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide MS (ESI): m/z 463 100); HPLC (method 11 2.70 min Example 34: 5-Chloro-N-[(3-3-12-imino-2-(1 -pyrrolidinyl)ethyl]phenyl}-2-oxo-l1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide MS (ESI): m/z 447 100); HPLC (method 11 2.82 min Example mino-2-iminoethyl)phenyl]-2-oxo- 1,3-oxazolidin-5-yl~methyl)-5chloro-2-thiophenecarboxamide MS (ESI): m/z 393 100); HPLC (method rt 2.60 min Example 140 3-[4-(4,5-dihyd ro-l1H-imidazol-2-ylmethyl)phenyl]-2-oxo- 1,3-oxa- }methyl)-2-thiophenecarboxam-ide MS (ESI): mlz 419 100); HPLC (method rt 2.65 min -100- Example 141 -Chloro-N-[(3-{4-[2-imino-2-(4-morpbolinyl)ethyllphenyl}..2.oxol ,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxantide MS (ESD): m/z 463 100); HPLC (method rt 2.65 min Example 142 S-Cbloro-N-[(3-{4-[2-imino-2-(1.piperidinyl)ethyllphenyl).2oxo.1,3..oxazolidin.

5-yl)methyl]-2-thiophenecarboxamide MS (ESI): m/z =461 100); HPLC (method rt 2.83 min Example 143 5-Chloro-N-[(3-{4-[2-imino-2-(1 -pyrrolidinyl)ethyllphenyl-2-oxo-1 ,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide MS (ESI): m/z 447 100); HPLC (method rt 2.76 min Exampile 144 -Chlo oN--( 3 4 4 42IifctL^kk'y~upntylanino)-2--1ninethylpieny}l-2.oxo.1 ,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide MS (ESI): m/z 461 100); HPLC (method rt 2.89 mmd Example 145 3 4 2 -imino- 2 2 2 2 -trifluoroethyl)aminoethyllphenyl).2oxo- 1 ,3-oxazolidin-5-yilmethyi 2 -thiophenecarboxamide MS (ESI): m/z 475 100); HPLC (method rt= 2.79 min -101- Example 146 N-({3-[4-(2-Anilino-2-iminoethyl)phenyl]-2-oxo- 1,3-oxazolidin-5-yl}methyl)-5chloro-2-thiophenecarboxamide MS (ESI): m/z 469 100); HPLC (method rt 2.83 min Example 147 5-Chloro-N-[( 3 4 -[2-imino-2-(2-pyridinylamino)ethyl]phenyl}-2-oxo-l,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide MS (ESI): m/z 470 100); HPLC (method rt 2.84 min Examples 148 to 151 below refer to the removal of BOC amino protective groups: General method for removing Boc protective groups (tert-butyloxycarbonyl): R-N O R-NH,

H

Aqueous trifluoroacetic acid (TFA, about 90%) is added dropwise to an ice-cooled solution of a tert-butyloxycarbonyl-(Boc) protected compound in chloroform or dichloromethane (about 0.1 to 0.3 mol/1). After about 15 min, ice-cooling is removed and the mixture is stirred at room temperature for approximately 2-3 h, and the solution is then concentrated and dried under high vacuum. The residue is taken up in dichloromethane or dichloromethane/methanol and washed with saturated sodium bicarbonate or IN sodium hydroxide solution. The organic phase is washed with saturated sodium chloride solution, dried over a little magnesium sulphate and concentrated. If appropriate, purification is carried out by crystallization from ether or ether/dichloromethane mixtures.

The following compounds were prepared in an analogous manner from the corresponding Boc-protected precursors: 102 Example 148 N-({3-[4-(Aminomethyl)phenyl]-2-oxo- 1,3-oxazolidin-5-yllmethyl)-5-chloro-2thiophene-carboxamide starting from Example 92: MIS (ESI): m/z 349 (M-NH 2 25), 305 (100); HPLC (method rt 3.68 (98).

IC

50 2.2 IAM Example 149 [3-(4-Aminophenyl)-2-oxo-1 ,3-oxazolidin-5-yllmethyl )-5-chloro-2thiophenecarboxamide starting from Example 93: MS (ESI): m/z 352 HPLC (method rt (100).

IC

50 2 ILM An alternative enantiomerically pure synthesis of this compound is shown in the scheme below (cf. also Delalande DE 2836305,1979; Chem.Abstr. 186926): 1. Bubl 0 0 2. R-glycidyl butyratt 0 L- Y

OH

0 0 3. NH 4

CI/H

2 0 1 phthalimide, DEAD/PPh 3 0

NH

2

NH

2

.H

2 0 in ethanol N

H

O CI 5-chloro-2-thiophenecarboxylic 0S

C

acid, EDC/HOBT 0 Zn/HCI, H 2 N- i N H N

C

YS

0 103 Example 150 5-Chloro-N-({3-[4-(glycylamino)pheny]-2-oxo-1,3-oxazolidin..5.yl)methyl)-2thiophenecarboxamide starting from Example 152: MS (ES-pos): m/z 408 (100); I-PLC (method rt 3.56 (97).

IC

50 2 AiM Example 151 5-(Aminometbyl)-3-[4-(2-oxo-l1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one starting from Example MS (ESI): m/z 276 100); HPLC (method rt(% 2.99 (100).

IC

50 2 AiM The Examples 152 to 166 below refer to the amino group derivatization of aniline- or benzylamine-substituted oxazolidinones using various reagents: Example 152 5-Chloro-N-({3-[4-(N-tert-butyloxycarbonyl.glycylamino)phenyl..2oxo.1,3.

}methyl)-2-thiophenecarboxamide 0 HI

N.

0A<J N> H

H

0

H

At 0 0 C, 754 mg (2.1 mmol) of 3 4 -aminophenyl)-2-oxo-1,3-oxazolidin-5yl]methyl}-5-chloro-2-thiophenecarboxamide (from Example 149) are added to a solution of 751 mg (4.3 mmol) of Boc-glycine, 870 mg (6.4 mmol) of HOBT (1-hydroxy-1H-benzotriazole x H 2 1790 mg (4.7 mmol) of HBTU [0-(benzotri azol-1I-yI)-N,N,N '-tetramethyl uroniurn hex afi uorophosphate] and 1.41 ml (12.9 mmol) of N-methylmorpholine in 15 ml of DMF/CH 2 Cl 2 The -104mixture is stirred at room temperature overnight and then diluted with water. The precipitated solid is filtered off and dried. Yield: 894 mg (79.7% of theory); MIS (DCI, NH 3 m/z 526 (M+NH 4 100); HPLC (method rt 4.17 (97).

Example 153 N-[(3-14-[(Acetylamino)methylphenyl..2oxo.1 ,3-oxazolidin-5-yI)methyl]-5chloro-2-thiophenecarboxan-jde 00 At0Camxtr f 0m (.82mo) fN({-4(aiomty-peyl--x Afrd *aithe e p odutfYe 30 mg (87%mo of heory),noehy~peyl--oo MIS (ESI): mlz 408 18), 305 HPLC (method rt (97).

IC

50 0.6 ItM Example 154 minocarbonyl)amino]methyllphenyl)-2-oxo. metbyl}-5-chloro-2-tbiopbenecarboxamide 0 N H1 H a N \N HN rN, 0 105 At- room temperature, 0.19 ml (0.82 mmol) of trimethylsilylisocyanate are added dropwise to a mixture of 30 mg (0.082 mmol) of N-({3-[4-(aminomethyl)phenyl]-2oxo-1I,3-oxazolidin-5-yl )methyl)-5-chloro-2-thiophene-carboxamide (from Example 148) in 1.0 ml of dichioromethane. The mixture is stirred overnight and, after addition of ether, the product is then obtained by filtration. Yield: 21.1 mg (52% of theory), MIS (ESI): m/z 409 305 (72); HPLC (method r1 3.67 (83).

IC

50 1.3 AM General method for acylating 3 4 -aminopbenyl)-2-oxo-1,3-oxazolidin.5yllmethyl)-5-cbloro-2-thiophenecarboxamide with carbonyl chlorides: 0 0 'J

S

H

Under argon, an approximately 0. 1 molar solution of N- I 3 -(4-aminophenyl)-2-oxo- 1 ,3-oxazoldin-5-yl]methyl -5-chloro-2-thiophenecarboxamide (from Example 149) eq.) in absolute dichloromethane/pyridine (19:1) is added dropwise to the itr~pae acid chloride (2.5 The mixture is-stirred overnight and then admixed with about 5 eq. of PS trisamine (Argonaut Technologies) and 2 ml of absolute dichloromethane. The mixture is stirred gently for I h and then filtered off, and the filtrate is concentrated. If appropriate, the products are purified by preparative RP-

HPLC.

The following compounds were prepared in an analogous manner: Example 155 N-({3-[4-(Acetylamino)phenyl]-2-oxo-.1 ,3-oxazolidin-5-yl }methyl)-5-chloro-2thiophene-carboxamide LC-MS: m/z 394 100); -106- LC-MS (method rt 3.25 (100).

IC

50 1.2 AM Example 156 5-Chloro-N-[(2-oxo-3-{4-[(2-thienylcarbonyl)aminophenyl..1,3.oxazolidin.5yl)methyl]-2-thiophenecarboxamide LC-MS: m/z 462 (Mi-H, 100); LC-MS (method rt(% 3.87 (100).

IC

50 1.3 1 iM Example 157 S-Chioro-N-[(3-{4-[(methoxyacetyl)amino]phenyl..2oxo 1 methyl]-2-thiophenecarboxamide LC-MS: m/z 424 100); LC-MS (method rt(% 3.39 (100).

IC

50 0.73 pAM Example 158 Chloro-2- th ienyl)ca rbonyi ]amino) methyl)..2.oxo- 1,3-oxazolidin-3yl]pbenyl}- 3 ,5-dimetbyl-4-isoxazolecarboxami de 'LC-MS: m/z 475 100).

IC

50 0.46 A~M2 Example 159 3 4 -{[(3-chloropropyl)sulphonyl]amino~pheny)-2-oxo-1,3oxazolidin-5-yllmethyl)-2-thiophenecarboxamide 0 S-Nj 0 11H

ZCI

-107- An ice-cooled solution of 26.4 mg (0.15 mmol) of 3-chloro-l-propanesulphonyl chloride and 0.03 ml (0.2 mmol) of triethylamine in 3.5 ml of absolute dichloromethane is admixed with 35 mg (0.1 mmol) of N-{[3-(4-aminophenyl)-2-oxo-1,3oxazolidin-5-yl]-methyl}-5-chloro-2-thiophene-carboxamide (from Example 149).

After 30 min, ice-cooling is removed and the mixture is stirred at room temperature overnight, and 150 mg (about 5.5 eq.) of PS-trisamine (Argonaut Technologies) and ml of dichloromethane are then added. The suspension is stirred gently for 2 h and filtered (the resin is washed with dichloromethane/methanol), and the filtrate is concentrated. The product is purified by preparative RP-HPLC. Yield: 19.6 mg of theory), LC-MS: m/z 492 100); LC-MS (method rt 3.82 (91).

IC

5 0 1.7 iM Example 160 5-Chloro-N-({3-[4-(1,1-dioxido-2-isothiazolidinyl)phenyl]-2-oxo-1,3-oxazolidin- 5-yl}methyl)-2-thiophenecarboxamide 0 0

O

A mixture of 13.5 mg (0.027 mmol) of 5-chloro-N-{[3-(4-{[(3-chloropropyl)sulphonyl]amino}phenyl)-2-oxo- 1,3-oxazolidin-5-yl]methyl }-2-thiophene-carboxamide (from Example 159) and 7.6 mg (0.055 mmol) of potassium carbonate in 0.2 ml of DMF is heated at 100 0 C for 2 h. After cooling, the mixture is diluted with dichloromethane and washed with water. The organic phase is dried and concentrated. The residue is purified by preparative thin-layer chromatography (silica gel, dichloromethane/methanol, 95:5). Yield: 1.8 mg (14.4% of theory), MS (ESI): m/z 456 15), 412 (100); LC-MS (method rt 3.81

IC

5 0 0.14 AM 108 Example 161 5-Chloro-N-[((5S)-3-{4-[(5-chloropentanoyl)aminolphenyl).2-oxo1,3.oxazoli.

din-5-yl)methyl]-2-thiophenecarboxamide

CI-C

0 0fs g (1.29 mmol) of N- {[(5S)-3-(4-aminophenyl)-2-oxo- 1,3-oxazolidin-5yl] methyl)I-5-chloro-2-thiophenecarboxamide (from Example 149) is dissolved in 27 ml of tetrahydrofuran and admixed with 0.2 g (1.29 mmol) of chloride and 0.395 ml (2.83 mmol) of triethylamine. The mixture is concentrated under reduced pressure and chromatographed over silica gel using a toluene/ethyl acetate=1:1 ethyl acetate gradient. This gives 315 mg (52% of theory) of a solid.

211VC.

Example 162 (SS)-2-oxo-3-[4-(2-oxo-1 -piperidinyl)phenyl]-1 methyl)-2-thiophenecarboxamide KiN Under inert conditions, 5 ml of DMSO are admixed with 30 mg of Nail (60% in paraffin oil), and the mixture is heated at 75'C for 30 min, until the evolution of gas has ceased. A solution of 290 mg (0.617 mmol) of 5-chloro-N-[((5S)-3-{4-[(5chloropentanoyl)amino]phenyl )-2-oxo-1I, 3 -oxazolidin-5-yl)methyl]-2-thiophenecarboxamide (from Example 161) in 5 ml of methylene chloride is then added dropwise, and the mixture is stirred at room temperature overnight. The reaction Is terminated and the mixture is poured into 100 ml of water and extracted with ethyl 109 acetate. The evaporated organic phase is chromatog'raphed on an RP-8 column and the product is eluted with acetonitrile/water. This gives 20 mg of theory) of the target compound.

205'C; NMR (300 MHz, d 6 -DMSO): 6 1.85 2.35 3.58 3.85 4.2 4.82 7.18 (d,1H,thiophene), 7.26 7.5 2.68 IH,thiophene), 9.0 1H,CONH).

IC

50 2.8 nM Example 163 S-Chloro-N-[((5S)-3-{4-[(3-bromopropionyl)aminophenyl..2oxo.1 ,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide 0S B r 0f4oo"S is obtained in an analogous manner from Example 149.

Example 1164 5-Chloro-N-({ (5S)- 2 -oxo-3-[4-(2-oxo-l1-azetidinyl)phenyll- 1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide is obtained in an analogous manner by cyclization of the open-chain bromopropionyl compound from Example 163 using NaHIDMSO.

MIS (ESI): m/z 406 100), CI pattern.

IC

50 380 nM -110 Example 165 tert-Butyl [(S-chioro-2-thienyl)carbony llaminolmethyl)-2-oxo- 1,3-oxazolidin-3-yl]phenyl}-3,5-dioxo- 1-piperazinecarboxylate 00 A solution of 199 mg (0.85 mmol) of Boc-i minodi acetic acid, 300 mg (2.2 mmol) of HOBT, 0.66 ml (6 mmol) of N-methylmorpholine and 647 mg (1.7 mmol) of HBTU is admixed with 300 mg (0.85 mmol) of [3-(4-aminophenyl)-2-oxo-1,3oxazolidin-5-ylI-methyl)-5-chloro-2-thiophene-carboxamide in 6 ml of a mixture of DMF and dichloromethane The mixture is stirred overnight, diluted with dichloromethane and then washed with water, saturated ammonium chloride solution, saturated sodium bicarbonate solution, water and saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and concentrated. The crude product is purified by silica gel chromatography (dichioromethane/methanol 98:2). Yield: 134mig (29% of theory); MS (ESI): mlz 571 (M+Na, 82), 493 (100); HPLC (method rt 4.39

IC

50 2 I.tM Example 166 mino-2-oxo-l1-pyrrolidinyl]phenyl)-2-oxo- 1,3-oxazolidin- 5-yl)methyl]-5-chloro-2-thiophenecarboxamide trifluoroacetate 0BOCNH

COOH

0

HOBT

,i s1 C1 EOC, DIEA or0 S 'H -111- CI Me 3 SI,

K

2 CO 3

'CH

3 BOCNH O O C TFA 0

H

2 N

O

0 N2-(tert-Butoxycarbonyl)-N1 [(5-chloro-2-thienyl)carbonyl]amino) methyl)-2-oxo-1, 3 -oxazolidin-3-yl]phenyl)-D-methionineamide 429 mg (1.72 mmol) of N-BOC-D-methionine, 605 mg (1.72 mmol) of N-1 (4-aminophenyl)-2-oxo- 1 ,3-oxazolidin-5-yl]methyl )-5-chloro-2-thiophenecarboxamide, and 527 mg (3.44 mmol) of HOBT hydrate are dissolved in 35 ml of DMIF and admixed with 660 mg (3.441 mmol) of EDCI hydrochloride and then dropwise with 689 mg (5.334 mmol) of N-ethyl-diisopropylamine. The mixture is stirred at room temperature for two days. The resulting suspension is filtered off with suction and the residue is washed with DMF. The combined filtrates are admixed with a little silica gel, concentrated under reduced pressure and chromatographed over silica gel using a toluene TIOEA7 gradient. This gives 170 mg (17% of theory) of the target compound of melting point 183 0

C.

Rf (SiO 2 toluene/ethyl acetate=1:1):0.2.

H-NMR (300 MHz, d 6 -DMSO): (s,IH,BOC), 1.88-1.95 2.08 (s,3H,SMe), 2.4-2.5 (m,2H, partially obscurbed by DMSO), 3.6 3.8 (m,1H), 4.15 4.8 7.2 (IH, thiophene), 7.42 part of an AB system, 2H), 7.6 part of an AB system, 21H1), 7.7 1H, thiophene), 8.95 (t,1H, CH 2 NHCO), 9.93 (bs, 1H,NH).

-112tert-Butyl 5 -chloro-2-thienyl)carbonyIlamino~methyl).2oxo-l, 3 -oxazolidin- 3 -yIlphenyI}.2-oxo3pyrrolidinylcarbamate 170 mg (0.292 mmol) of N2-(tert-butoxycarbonyl)-N {[(5-chloro-2thi enyl)carbonyl ]amino)} methyl)-2-oxo- 1,3-oxazolidin-3-yI]phenyl I -D-methionineamide are dissolved in 2 ml of DMSO and admixed with 178.5 mg (0.875 mmol) of trimethylsuiphonium iodide and 60.4 mg (0.437 mmol) of potassium carbonate, and the mixture is stirred at 80'C for 3.5 hours. The mixture is then concentrated under high vacuum and the residue is washed with ethanol. 99 mg of the target compound remain.

'H-NMR (300 MHz, d 6 -DMSO): 6 =1.4 (s,IH,BOC), 1.88-2.05 2.3-2.4 3.7-3.8 (m,3H4), 3.8-3.9 4.1-4.25 4.25-4.45 4.75- 4.95 7.15 (IH, thiophene), 7.25 7.52 part of an AB system, 2H), 7.65 part of an AB system, 2H), 7.65 1H, thiophene), 9.0 (broad s,1H).

N-[((5S)-3-{4-[(3R)-3-Amino-2-oxo-l1-pyrrolidinyllpbenyl)-2-oxo- 1,3-oxazolidin- 5-yI)methyll-5-chloro-2-thiophenecarboxamide trifluoroacetate 97 mg (0.181 mmol) of tert-butyl (3R)-1I- j4-[5S)-5-({[(5-chloro-2thienyl)carbonyllamino I methyl)-2-oxo- 1 ,3-oxazolidin-3-yl]phenyl 2 -oxo-3-pyrrolidinylcarbamate are suspended in 4 ml of methylene chloride, 1.5 ml of trifluoroacetic acid are added and the mixture is stirred at room temperature for 1 hour. The mixture is then concentrated under reduced pressure and the residue is purified on an RP- -4-LC--(-aeetenitrile/waterl0;1.-% TFA gradient). Evaporation of the appropriate fraction gives 29 mg (37% of theory) of the target compound of melting point 241'C (decomp.).

Rf (SiO 2 ,EtOH/TEA=l7:1) 0.19.

'H-NMR (300 MHz, d 6 -DMSO).- 6 =1.92-2.2 2.4-2.55 (m,1H, partially obscured by DMSO peak), 3.55-3.65 3.75-3.95 (m,314), 4.1-4.3 (m,214), 4.75-4.9 7.2 (IH, thiophene), 7.58 part of an AB system, 2H), 7.7 part of an AB system, 2H), 7.68 1H, thiophene), 8.4 (broad s,3H, NI-3), 8.9 I H,NHCO).

-113- The Examples 167 to 170 below refer to the introduction of sulphonamide groups in phenyl-substituted oxazolidinones: General method for preparing substituted sulphonamides starting from 5-chloro-N-[( 2 -oxo-3-phenyl-1,3-oxazolidin-5-yl)methyl]-2thiophenecarboxamide Under argon and at 5 0 C, 5-chloro-N-[(2-oxo-3-phenyl-l,3-oxazolidin-5-yl)methyl]-2thiophenecarboxamide (from Example 96) is added to chlorosulphonic acid (12 eq.).

The reaction mixture is stirred at room temperature for 2 h and then poured into icewater. The resulting precipitate is filtered off, washed with water and dried.

Under argon and at room temperature, the precipitate is then dissolved in tetrahydrofuran (0.1 mol/1) and admixed with the appropriate amine (3 eq.), triethylamine (1.1 eq.) and dimethylaminopyridine (0.1 The reaction mixture is stirred for 1-2 h and then concentrated under reduced pressure. The desired product is purified by flash chromatography (dichloromethane/methanol mixtures).

The following compounds were prepared in an analogous manner: Example 167 5-Chloro-N-({2-oxo-3-[4-(1-pyrrolidinylsulphonyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide MS (ESI): m/z 492 ([M+Na] 100), 470 68), Cl pattern; -114 HPLC (method rt(% 4.34 (100).

1C 50 0.5 ,iM Example 168 5-Chloro-N-[(3-{4-[(4-methyl-1-piperazinyl)sulphonyllphenyl)-2oxo. 1,3-oxazolidin-5-yl)methyll-2-thiophenecarboxamide MS (ESI): m/z ()=499 100), Cl pattern; HPLC (method rt 3.3 (100).

Example 169 S-Chloro-N-({2-oxo-3-[4-(1-piperidinylsulphony)phenyl]-1,3.oxazolidin.5.yl} methyl)-2-thiophenecarboxamide MS (ESI): m/z 484 100), Cl pattern; HPLC (method '1 4.4 (100).

Example 170 5-Chloro-N-[(3-{4- [(4-hyd roxy-lI-piperidinyl)sulpbonyllphenyl }-2-oxo-1,3-oxazolidin-5-yI)methyl]-2-thiophenecarboxamide MS (ESI): mlz 500 100), CI pattern; HPLC (method rt 3.9 (100).

Example 171 2-oxo-3-[4-(1-pyrrolidinyl)phenyl].1 ,3-oxazoiidin-5-yl lmethyl)-2thiophenecarboxamide

H

3 C c H 3 115- 780 mg (1.54 mmol) of tert-butyl [(5-chloro-2-thienyl)carbonyl]amino)methyl)- 2 -oxo-1,3-oxazolidin-3-yl]phenyl}prolinate are dissolved in 6 ml of dichloromethane and 9 ml of trifluoroacetic acid, and the mixture is stirred at for two days. The reaction mixture is then concentrated and stirred with ether and 2N aqueous sodium hydroxide solution. The aqueous phase is concentrated and stirred with ether and 2N hydrochloric acid. The organic phase of this extraction is dried over MgSO 4 filtered and concentrated. The crude product is chromatographed over silica gel (CH 2

CI

2 /EtOH/conc. aqu. NH 3 sol. 100/1/0.1 to 20/1/0.1).

This gives 280 mg (40% of theory) of the product.

MS (ESI): m/z 406 100); HPLC (method rt 3.81 min.

HPLC parameter and LC-MS parameter for the HPLC and LC-MS data given in the examples above (the unit of the retention time (rt) is minutes): Column: Kromasil C18, L-R temperature: 30°C, flow rate 0.75 ml min 1 eluent: A 0.01 M HCIO 4 B CH 3 CN, gradient: 0.5 min 98%A 4.5 min min Column: Kromasil C18 60*2, L-R temperature: 30 0 C, flow rate 0.75 ml min 1 eluent: A 0.01 M H 3

PO

4 B CH 3 CN, gradient: 0.5 min 90%A 4.5 min min Column: Kromasil C18 60*2, L-R temperature: 30 0 C, flow rate 0.75 ml min"', eluent: A 0.005 M HC10 4 B CH 3 CN, gradient: 0.5 min 98%A 4.5 min min Column: Symmetry C18 2.1x150 mm, column oven: 50 0 C, flow rate 0.6 ml min eluent: A 0.6 g 30% strength HCI/ 1 of water, B CH 3 CN, gradient: 0.0 min 90%A 4.0 min 10%A min -116- MHZ-2Q, Instrument Micromass Quattro LCZ Column Symmetry C18, 50 mm x 2.1 mm, 3.5 pm, temperature: 40'C, flow rate ml min-', eluent A CH 3 CN 0.1% formic acid, eluent B water 0.1% formic acid, gradient: 0.0 min 10% A 4 min 90% A 6 min 90% A MHZ-2P, Instrument Micromass Platform LCZ Column Symmetry C18, 50 mm x 2.1 mm, 3.5 pm, temperature: 40 0 C, flow rate ml min' 1 eluent A CH 3 CN 0.1% formic acid, eluent B water 0.1% formic acid, gradient: 0.0 min 10% A 4 min 90% A 6 min 90% A MHZ-7Q, Instrument Micromass Quattro LCZ Column Symmetry C18, 50 mm x 2.1 mm, 3.5 pm, temperature: 40°C, flow rate ml min" eluent A CH 3 CN 0.1% formic acid, eluent B water 0.1% formic acid, gradient: 0.0 min 5% A 1 min 5% A 5 min 90% A 6 min 90% A General method for preparing oxazolidinones of the general formula B by solidphase-supported synthesis Reactions with different resin-bonded products were carried out in a set of separated reaction vessels.

5-(Bromomethyl)-3-(4-fluoro-3-nitrophenyl)-1,3-oxazolidin-2-one A (prepared from epibromohydrin and 4-fluoro-3-nitrophenyl isocyanate using LiBr/Bu 3 PO in xylene analogously to US 4128654, Ex.2) (1.20 g, 3.75 mmol) and ethyldiisopropylamine (DIEA, 1.91 ml, 4.13 mmol) were dissolved in DMSO (70 ml), admixed with a secondary amine (1.1 eq., amine component 1) and reacted at 55 0 C for 5 h. TentaGel SAM resin (5.00 g, 0.25 mmol/g) was added to this solution, and the mixture was reacted at 75 0 C for 48 h. The resin was filtered, washed repeatedly with methanol (MeOH), dimethylformamide (DMF), MeOH, dichloromethane (DCM) and diethyl ether and dried. The resin (5.00 g) was suspended in dichloromethane (80 ml), admixed with DIEA (10 eq.) and 5-chlorothiophene-2-carbonyl chloride [prepared by reacting 5-chlorothiophene-2-carboxylic acid (5 eq.) and 1-chloro-l-dimethylamino- 2-methylpropene (5 eq.) in DCM (20 ml) at room temperature for 15 minutes] and the mixture was reacted at room temperature for 5 h. The resulting resin was filtered, washed repeatedly with MeOH, DCM and diethyl ether and dried. The resin was then -117suspended in DMF/water (v/v 9:2, 80 ml), admixed with SnC1 2 *2H 2 0 (5 eq.) and reacted at room temperture for 18 h. The resin was washed repeatedly with MeOH, DMF, water, MeOH, DCM and diethyl ether and dried. This resin was suspended in DCM, admixed with DIEA (10 eq.) and, at 0°C, with an acid chloride (5 eq. of acid derivative and the mixture was reacted at room temperature overnight. Prior to the reaction, carboxylic acids were converted into the corresponding acid chlorides by reaction with l-dimethylamino-l-chloro-2-methylpropene (1 eq., based on the carboxylic acid) in DCM at room temperature for 15 min. The resin was washed repeatedly with DMF, water, DMF, MeOH, DCM and diethyl ether and dried. If the acid derivative 1 used was an Fmoc-protected amino acid, the Fmoc protective group was removed in the last reaction step by reaction with piperidine/DMF 1/4) at room temperature for 15 minutes, and the resin was washed with DMF, MeOH, DCM and diethyl ether and dried. The products were then removed from the solid phase using trifluoroacetic acid (TFA)/DCM the resin was filtered off and the reaction solutions were concentrated. The crude products were filtered over silica gel (DCM/MeOH, 9:1) and evaporated, giving a set of products B.

02 0 R R2 ON N 0R 0 F N O H N NkO L_6 N12 Br R Br

A

TentaGelSAM NH 2 R O TentaGelSAM Cl S C 02Cl 0 0 R 02 vy\, .q

TGSAM

118- SnCI 2 Eq

\M

TFA/DCM,

1/1 Compounds which were prepared by solid-phase-supported synthesis: Example 172 N-({3-[3-Amino-4-(1-pyrrolidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5chloro-2-thiophenecarboxamide-- Analogously to the general procedure for preparing the derivatives B, 5 g (1.25mmol) of TentaGel SAM resin were reacted with pyrrolidine as amine derivative 1. The aniline obtained after reduction with SnCI 2 *2H 2 0 was, without any further acylation step, removed from the solid phase and concentrated. The crude product was partitioned between ethyl acetate and NaHCO 3 solution and the organic phase was salted out using NaCI, decanted and evaporated to dryness. This crude -119product was purified by vacuum flash chromatography over silica gel (dichioromethane/ethyl acetate, 3:1 1:2).

'H-NMR (300 MHz, CDCl 3 1.95 2.08, br, 4 H; 3.15-3.3 0, br, 4 H; 3.65-3.8 1, m, 2 H; 3.89, ddd, I1H; 4.05, dd, 1 H; 4.8 1, dddd, 1 H; 6.46, dd, I H; 6.72, dd, 1 H; 6.90, dd, 1 H; 6.99, dd, 1 H; 7.03, dd, 1 H; 7.29, d, 1 H.

Example 173 N-[(3-{3-(B-Alanylamino)-4-[(3-hydroxypropyl)aminoj phenyl}-2-oxo-1 ,3-oxazolidin-5-yI)methylj-5-chloro-2-thiophenecarboxamide H 2

N

0 H0N 0 H C I H N

S

0 Analogously to the general procedure for preparing the derivatives B, 5 g (1.25 mrniol) of TentaGel SAM resin were reacted with azetidine as amine derivative 1 and Fmoc-13-alanine as acid derivative 1. The crude product obtained after the removal was stirred in methanol at room temperature for 48 h and evaporated to dryness. This crude product was purified by reversed phase HPLC using a water/TFAlacetonitri le gradient.

'H-NMR (400 MHz, CD 3 OD): 2.31, tt, 2 H; 3.36, t, 2 H; 3.54, t, 2 H; 3.62, t, 2 H; 3.72, dd, 1 H; 3.79, dd, 1 H; 4.01, dd, 1 H; 4.29, dd, 2 H; 4.43, t, 2 H; 4.85-4.95, mn, 1 H; 7.01, d, 1 H; 4.48 -7.55, in, 2 H; 7.61, d, 1 H; 7.84, d, 1 H.

Example 174 min o-1I -pyrrolid inyl)-3-n itrop hen l-2-oxo- 1,3-o xazolid in-5-yI} methyl)-5-chloro-2-thioph enecarboxamide -120- HN N Analogously to the general procedure for preparing the derivatives B, 130 mg (32.5 umol) of TentaGel SAM resin were reacted with tert-butyl 3pyrrolidinylcarbamate as amine derivative 1. The nitrobenzene derivative obtained after the acylation with 5-chlorothiophenecarboxylic acid was removed from the solid phase and concentrated. This crude product was purified by reversed phase HPLC using a water/TFA/acetonitrile gradient.

'H-NMR (400 MHz, CD30H): 2.07-2.17, m, 1 H; 2.39-2.49, m, I H; 3.21-3.40, m, 2 H; 3.45, dd, 1 H; 3.50-3.60, m, 1 H; 3.67, dd, 1 H; 3.76, dd, 1 H; 3.88-4.00, m, 2 H; 4.14 4.21, t, 1 H; 4.85 4.95, m, 1 H; 7.01, d, 1 H; 7.11, d, 1 H; 7.52, d, 1 H; 7.66, dd, 1 H; 7.93, d, 1 H.

Example 175 N-({3-[3-Amino-4-(1-piperidinyl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)-5chloro-2-thiophenecarboxamide

H

2 N 0 ci CN N H H C

N-P

Analogously to the general procedure for preparing the derivatives B, 130 mg (32.5 gmol) of TentaGel SAM resin were reacted with piperidine as amine derivative 1. The aniline obtained after the reduction was, without any further acylation step, removed from the solid phase and concentrated. This crude product was purified by reversed phase HPLC using a water/TFA/acetonitrile gradient.

'H-NMR (400 MHz, CD30H): 1.65-1.75, m, 2 H; 1.84-1.95, m, 4 H; 3.20-3.28, m, 4 H; 3.68, dd, 1 H; 3.73, dd, 1H; 3.90, dd, 1 H; 4.17, dd, 1 H; 4.80-4.90, m, 1 H; 7.00, d, 1 H; 7.05, dd, 1 H; 7.30-7.38, m, 2H; 7.50, d, 1 H.

-121- Example 176 N-({3-[3-(Acetylamino)-4-(1-pyrrolidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophenecarboxamide Analogously to the general procedure for preparing the derivatives B, 130 mg (32.5 ilmol) of TentaGel SAM resin were reacted pyrrolidine as amine derivative 1 and acetyl chloride as acid derivative 1. The crude product was partitioned between ethyl acetate NaHCO 3 solution and the organic phase was salted out using NaC1, decanted and evaporated to dryness. This crude product was purified by vacuum flash chromatography over silica gel (dichloromethane/ethyl acetate, 1:1-0:1).

'H-NMR (400 MHz, CD 3 0H): 1.93 2.03, br, 4 H; 2.16, s, 3 H; 3.20-3.30, br, 4 H; 3.70, d, 2 H; 3.86, dd, 1H; 4.10, dd, 1 H; 4.14, dd, 1 H; 4.80-4.90, m, 1 H; 7.00, d, 1 H; 7.07, d, 1 H; 7.31, dd, 1 H; 7.51, d, 1 H; 7.60, d, 1 H.

The following compounds were prepared analogously to the general procedure.

Example Structure Ret. HPLC time 177 2.62 79.7 0

N

C17 N N

N

0 178 O N 'f 0 0 N 2.49 33.7 C0 N 122 Example Structure Ret. HPLC time 179 J 0 .63 46.7 180 J3.37 44.8 s~

N'Q

181 N N02.16 83 'N-N 0 0 C1 182 N2.31 93.3 N) N /N

NN

0 N

NCI\

0N 6- 0 C1 123xample tructure Ret. HPLC time 185 0\ .72 75.2 0 ci N 0 188 0 3.9 56.

0 190 0 .61 63.9 S N N sg

ON

NN

N-N

00 'r o"" N N r;TN 124 ExamplejStructure 'Ret. HPLC time 10/J1 191 2. 5 2 70.1 0 0 CI N N C N N Na 0

N

0 192? 3.52 46.6 N N j S

N

193 0 0 2.87 50.1

N

0N N Ci 194 00 0 3.25 71.1 Nj~

N

-No 195 2.66 67 N 0\ 0

N

N

125 126- 127 Example Structure Ret. HPLC time 07 0.8 63.6 000 0 ~0 C I 'N\S N N 0 209 02.56 67.9 s N N N-c5-N N~j 0N 2100 0 0 0 3.67 78.4 C1 211 2.54 69.8 s N 0 N NN 0 212 0.f0 0 3.84 59.2 0 N Y

NN

CIs 128 Example Structure Ret. HPLC time 13 0 o0 2.41 67.8

NN

N

214 0 ro 0 j 2.41 75.4 ci N NL

N

215 0N 0 0 4.01 81.3 CI N z- 216 0 0 0 O 3.46 49.5 N

N

217 4.4 60.2 Q 0 Ci1 218 3.79 70.9 N

N

0 -129xample tructure Ret. HPLC time 19 0 .57 51.5 0 0 220 0 0 2.68 100 N N

NN

N N ci0

N

22 0 0 0 .76 69.3 24 oI .45 17.4 N NQ

N

-130- -131- Example Structure Ret. HPLC time 31 O 0 .39 64.2

N

32 0 N 0 .85 4.9 N Q 33 0 0 04 4.17 141 sC N 234 .21 61).8 0 0 0 2.75 100 N N ci-e\ \4a2

N

2360 00J 3.94 s N'>L 0 0 0 132 Example Structure Ret. HPLC time 237 Q0.65 75.8 C Ke 238 4 .4 75.3 0 0- 0 23 0.24 62.2 EN /0 F 0 0 I 240 0 0 y 0. 76 75.1 N N 0 241 0 oO Y .17 72.5 N \N r ~I NN N N o 0 133xample tructure Ret. HPLC _time 243 04.12 51.6 CI-- \S

N

0 44 .71 6.2 0 0 0 S N'-jZ 0 .86 62 N 0 N N s.

0

I

246 5.23 58.3 0 00 2 4 7 0 1 72

NN

N

N

2470 417 2.

134 Examnple Structure Ret. HPLC time 248 3.35 59.6 0

CI,)

249 0 "N 2.41 60.3 r.31 5.2N

N

s N~>J 004 3.1 6 252 0 0 2.9f9.

0 NN-J

N

-135- Example Structure Ret. HPLC time 253 0 0 2 .81 67 .4 N 't o

N

254 'O N .19 75.4 seCI N All products of the solid-phase-supported synthesis were characterized by LC-MS.

As standard, the following separation system was used: HP 1100 with UV detector (208 400 nm), oven temperature 40°C, Waters-Symmetry C18 column (50 mm x 2.1 mm, 3.5 pm), mobile phase A: 99.9% acetonitrile/0.1% formic acid, mobile phase B: 99.9% water/ 0.1% formic acid; gradient: Time flow rate 0.00 10.0 90.0 0.50 4.00 90.0 10.0 0.50 6.00 90.0 10.0 0.50 6. 10 10.0 90.0 1.00 7.50 10.0 90.0 0.50 The substances were detected using a Micromass Quattro LCZ MS, ionization: ESI positive/negative.

In the structures listed above which comprise the radical(s)

N

what is mennt ic in Parh rs H NH

N

N or -0, 1 UI 1 I UI IlC or -n lunction.

P \WPDOCS'CRNX'JJSpcc\122594| 1 doc-22/10/2007 Q- 135a- 0 Throughout this specification and the claims which follow, unless the context Irequires otherwise, the word "comprise", or variations such as "comprises" or O "comprising", will be understood to imply the inclusion of a stated integer or group of integers or steps but not the exclusion of any other integer or group of integers or Csteps.

C

The articles and "an" are used herein to refer to one or to more than one to Sat least one) of the grammatical object of the article. By way of example, "an C 10 element" means one element or more than one element.

Persons skilled in the art will appreciate that numerous variations and modifications will become apparent. All such variations and modifications which become apparent to persons skilled in the art, should be considered to fall within the spirit and scope that the invention broadly appearing before described.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgement or any form of suggestion that the prior art forms part of the common general knowledge in Australia.

Claims (8)

1. A compound of the general formula (I) RN- R-N R0 R C< I o in which: R' represents thiophene (thienyl) which is mono- or polysubstituted by a radical from the group consisting of halogen; (Ci-C 8 )-alkyl or trifluoromethyl, R 2 represents one of the groups below: A-, D-M-A-, where: the radical represents phenyl; the radical represents a saturated or partially unsaturated, mono- or bicyclic 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 0; the radical represents -CH 2 -SO 2 or represents a covalent bond; where the groups and defined above may each optionally be mono- or polysubstituted by a radical from the group consisting of halogen; trifluoromethyl; oxo; cyano; nitro; carbamoyl; pyridyl; P MP0S\CRN\JXJ\.Spcc\I25MI I cla-Amdo.22/JIft2(07 -137- 0 (C 1 -C 6 )-alkanoyl; (C 1 -C 4 )-hydroxy-alkylcarbonyl; -C00R 7 -CONR 28R 29; -S 2 NR 2R 2; -NR 3R", (C,-C,)-alkyl and (C 3 -C-,)-cycloalkyl, where (C I-C 6 )-alkyl for its part may optionally be substituted by a radical from the group consisting of cyano; -OR 27 ]28 29 27 28 29 -NR 'R 9and -C(NR 2 R )=NR where: 27 28 29 R R and R 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, tri flu orom ethyl, phenyl or pyridyl, and/or R 27and R 28or R 27 and R 29 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated to 7-membered heterocycle having up to three, identical or different heteroatoms from the group consisting o~f N, 0 and S, and R 30 and R 3 are identical or different and independently of one another each represents hydrogen, (C 1 -C 4 )-alkyl, (C 3 cycloalkyl, (C I-C 4 )-hydroxyalkyl or -C0R 3 3 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 -C 4 )-alkyl, (C 1 -C 4 )-aminoalkyl, (C 1 -C4)-alkoxycarbonyl, (C 1 -C 4 )-alkanoyl-(C 1 -C 4 )-alkyl, PA\WPDOCSCRN\)XRP 6122i94I I cdn- d--22J11V-2O7 -138- 0 Z (C 3 -C 7 )-cycloalkyl, (C 2 -C 6 )-alkenyl, (C 1 -Cs)-alkyl, which INO may optionally be substituted by phenyl or acetyl, (C 6 -CI 4 aryl, (Cs-Clo)-heteroaryl, trifluoromethyl, tetrahydrofuranyl Cor butyrolactone, R 3 R 4 R 5 R 6 R 7 and R 8 each represents hydrogen 0and their pharmaceutically acceptable salts, hydrates, hydrates of salts and prodrugs, except for compounds of the general formula in which R' 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 represents phenylene; the radical represents a saturated 5- or 6-membered heterocycle, which is attached to 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 0; where the group 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, P \WPDOCS\CRN\JXJ\Spcc\ 1259411 claim doc-22/10-2007 O O -139- R 4 R 6 R 7 and R 8 each represent hydrogen. O

2. A compound of the general formula according to Claim 1, wherein R represents thiophene (thienyl) which is mono- or polysubstituted by halogen, by (Ci-C 8 )-alkyl or by trifluoromethyl, R 2 represents one of the groups below: SA-, D-M-A-, where: the radical represents phenyl; the radical 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 0; the radical represents -CH 2 or represents a covalent bond; where the groups and 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 -C 6 )-alkanoyl; -COOR27; -CONR R29; -SO 2 NR2 8 R29; -OR 30 -NR 3 0 R 31 (CI-C 6 )-alkyl and (C 3 -C 7 )-cycloalkyl, where (Ci-C 6 )-alkyl for its part may optionally be substituted by a radical from the group consisting of cyano; -OR 27 -NR2 R 29 and -C(NR 2 7 R 28 )=NR 29 where: R 27 R 28 and R 29 are identical or different and independently P\WPDOCS\CRNUXJSpc\2259411 I lums doc-2 I12007 Q- -140- 0 Z of one another each represents hydrogen, (CI-C 4 \0 alkyl or (C 3 -C 7 )-cycloalkyl, and/or C1 5 R 27 and R 28 or R 27 and R 29 together with the nitrogen atom to which C, they are attached form a saturated or partially unsaturated CNI 5- to 7-membered heterocycle having up to three, identical Sor different heteroatoms from the group consisting of N, O CNI and S, and R 30 and R 3 1 are identical or different and independently of one another each represents hydrogen, (Ci-C 4 )-alkyl, (C 3 -C 7 cycloalkyl, (Ci-C 4 )-hydroxyalkyl, (Ci-C)-alkanoyl, (C 6 -C- 1 4 )-arylcarbonyl or (Cs-Clo)-heteroarylcarbonyl, R 3 R 4 R 5 R 6 R and R 8 each represents hydrogen and their pharmaceutically acceptable salts, hydrates, hydrates of salts and prodrugs, except for compounds of the general formula in which R' 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 represents phenylene; the radical represents a saturated 5- or 6-membered heterocycle, which is attached to via a nitrogen atom, which has a carbonyl group directly adjacent to the linking nitrogen atom and P:\WPDOCS\CRKUXR~p X1225UI I d.-ndA.?2/IO.O7 where the group defined above may optionally be mono- or N disubstituted in the meta position with respect to the point of attachment to the oxazolidinone, by radical from the group consisting of fluorine, chlorine, nitro, amino, trifluoromethyl, methyl and cyano, R 3 R 4 R, R 8 each represent hydrogen.

3. A compound of the general formula as defined in claim I or 2 where R 27 and R 28 or R 2 7 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 two identical or different heteroatoms from the group consisting of N, and S.

4. A compound of the general formula according to Claim 1, wherein halogen, by (Ci-Cs)-alkyl or by trifluoromethyl, R2 represents one of the groups below: A-, D-M-A-, where: the radical represents phenyl; the radical 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 0; SO2, N, NO (N-oxide) and O; P \WPDOCS\CRN\IJXJ\Spc\1225941 I clillsdoc.22/1I'2007 Q 142- O Z the radical represents a covalent bond; ID where the groups and defined above may in each case optionally C 5 be mono- or polysubstituted by a radical from the group consisting C of halogen; trifluoromethyl; oxo; cyano; pyridyl; (Ci-C 3 )-alkanoyl; -CONR 2 8 R 29 -S0 2 NR 28 R 29 -OH; -NR 3 oR 3 1 (Ci-C 4 )-alkyl; and cyclopropyl, cyclopentyl or cyclohexyl, where (Ci-C 4 )-alkyl for its part may optionally be substituted by a radical from the group consisting of cyano; -OH; -OCH 3 -NR28R 29 and -C(NR27R28)=NR29, where: R 27 R 2 8 and R 29 are identical or different and independently of one another each represents hydrogen, (Ci-C 4 )-alkyl or else cyclopropyl, cyclopentyl or cyclohexyl and/or R 2 7 and R 2 8 or R 2 7 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 3 1 are identical or different and independently of one another each represents hydrogen, (Ci-C 4 )-alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (CI-C 4 hydroxyalkyl, (Ci-C 3 )-alkanoyl or phenylcarbonyl, R R 4 R 5 R 7 and R 8 each represents hydrogen P \WPDOCS\CRN\JXJ\Spec\22594 I clans dc-22/ IV2007 0 -143- Z and their pharmaceutically acceptable salts, hydrates, hydrates of salts and I\ prodrugs, except for compounds of the general formula in which CN R' represents 2-thiophene which is substituted in the 5-position by a radical C, from the group consisting of chlorine, bromine, methyl and trifluoromethyl, 2 CN R represents D-A-: where: the radical represents phenylene; the radical represents a saturated 5- or 6-membered heterocycle, which is attached to 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 0; where the group 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 R 8 each represent hydrogen. A compound of the general formula according to Claim 1, wherein R' represents 2-thiophene which is substituted in the 5-position by a radical from the group consisting of chlorine, bromine, methyl or trifluoromethyl, P:\WPDX)CS\CRNU \X\Spec122594 I claimsdoc-22/1 O007 -144- SR 2 represents one of the groups below: \D A-, D-M-A-, S 5 where: the radical represents phenyl; CI the radical represents a saturated or partially unsaturated 5- or 6-membered heterocycle which contains a nitrogen atom and CN optionally a further heteroatom and/or hetero chain member from the group consisting of S, SO, SO2 and 0; or contains up to two heteroatoms and/or hetero chain members from the group consisting of S, SO, SO2 and O; the radical represents a covalent bond; where the groups and defined above may in each case optionally be mono- or polysubstituted by a radical from the group consisting of halogen; trifluoromethyl; oxo; cyano; pyridyl; (CI-C,)-alkanoyl; -CONR28R29; -SO 2 NR28R29; -OH; -NRoR31; (Ci-C 4 )-alkyl; and cyclopropyl, cyclopentyl or cyclohexyl, where (Ci-C 4 )-alkyl for its part may optionally be substituted by a radical from the group consisting of cyano; -OH; -OCH 3 -NR 28 R 29 and -C(NR 27 R28)=NR 29 where: R 27 R 28 and R 29 are identical or different and independently of one another each represents hydrogen, (Ci-C 4 )-alkyl or else cyclopropyl, cyclopentyl or cyclohexyl and/or P\WPDOCSWCRN\JXASpM\2259411 dsm s -22II'2D7 -145- 0 Z R 27 and R 28 or R 2 7 and R 29 together with the nitrogen atom to which they are attached may form a saturated or partially unsaturated to 7-membered heterocycle having up to two identical or different heteroatoms from the group consisting of N, O and S, and O R 30 and R 3 1 are identical or different and independently of one another each represents hydrogen, (C -C 4 )-alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (C I-C 4 )-hydroxyalkyl, (Ci-C 3 )-alkanoyl or phenylcarbonyl, R 3 R 4 R 5 R 6 R 7 and R 8 each represents hydrogen and their pharmaceutically acceptable salts, hydrates and prodrugs, except for compounds of the general formula in which R' 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 represents phenylene; the radical represents a saturated 5- or 6-membered heterocycle, which is attached to 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 0; P \WPDOCSCRNVX~pc\l 12259411 cbinido/l 112007 Q- 146- 0 Z where NO the group defined above may optionally be mono- or disubstituted in the meta position with respect to the point of attachment to the Coxazolidinone, by a radical from the group consisting of fluorine, chlorine, S 5 nitro, amino, trifluoromethyl, methyl and cyano, SR 3 R 4 RS, R R, R 8 each represent hydrogen. 6. A process for preparing a substituted oxazolidinone as defined in any one of Claims 1 where either according to a process alternative compounds of the general formula (II) O R 3NR 6 R( 4 R 7 HNR 8 R 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) P:\WPD(OCS\(RNXJSpcck225941 I claims dok-22 10((7

147- O 0 (III), in which the radical R' is as defined in Claim 1, or else with the corresponding carbonyl halides, 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) R 7 R3 R R-LN R 1 in which the radicals R 2 R 3 R 4 R 5 R R 7 and R 8 are each as defined in Claim 1, or else according to a process alternative compounds of the general formula (IV) P:\APDOCS CRN1\XJ\Sp.I22594I11 dcL.,ndr-22M217

148- R 3 R 6 R 7 0 X N R R 5 R (IV), in which the radicals 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) R 3 R 6 R 7 0 R N RR R R in which the radicals R R 4 R S 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) R2-NH 2 (VI), in which the radical R 2 is as defined in Claim 1, the compounds of the general formula (VII) PMPN)CS\CRN\IXJ\cc\1225Q4 I cI do22110r2007

149- 2 N i 7 1N R (VII), 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 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 (1) 0 R R R 4 RR 7 R R 1 (I) 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, where both for process alternative and for process alternative 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 P.\WPDOCSCRNUXJ\Spc\122941 I cls doc-6I 1/2007 c, -150- 0 Z and/or IO where both for process alternative and for process alternative in the case C 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 and for process alternative 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 and for process alternative 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 and for process alternative 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. 7. The process of Claim 6, where according to process alternative the corresponding carbonyl halide is a carbonyl chloride. P \WPDOCSCRNJXAISpm'122594 I djIisn, dm-22/IO01O 7 V -151 0 Z 8. A medicament, comprising at least one compound of the general formula (I) ID according to any one of Claims 1 to 5 and one or more pharmacologically acceptable auxiliaries or excipients. 9. Use of a compound of the general formula as defined in any one of Claims 1 to (N for the manufacture of a medicament or pharmaceutical composition for the Sprophylaxis and/or treatment of thromboembolic disorders. Use according to Claim 9, where the thromboembolic disorder is selected from myocardial infarct, angina pectoris (including unstable angina), reocculsions and restenoses after angioplasty or aorto-coronary bypass, stroke, transitory ischaemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thromboses. 11. Use of a compound as defined in any one of Claims 1 to 5 for the manufacture of a medicament or pharmaceutical composition for the prophylaxis and/or treatment of disorders which are influenced positively by inhibition of factor Xa. 12. Use of a compound as defined in any one of Claims 1 to 5 for the manufacture of a medicament or pharmaceutical composition for the treatment of disseminated intravascular coagulation (DIC). 13. Use of a compound as defined in any one of Claims 1 to 5 for the manufacture of a medicament or pharmaceutical composition for the prophylaxis and/or treatment of a disorder selected from atherosclerosis; arthritis; Alzheimer's disease or cancer. 14. Use ofa compound as defined in any one of Claims 1 to 5 for the manufacture of a medicament or pharmaceutical composition for the inhibition of factor Xa. P:\WPDOCS\CRNUXJ\SpC\1225941 clais doc-6l 1/2007 Q- 152- 0 Z 15. A method for the prevention of the coagulation of blood in vitro, the method I comprising adding to said blood at least one compound as defined in any one of Claims 1 to S 5 16. A method as claimed in Claim 15, where said blood is banked blood or biological samples containing factor Xa. S17. Use of a compound as defined in any one of Claims 1 to 5 for preventing the coagulation of blood ex vivo. 18. Use of a compound as defined in any one of Claims 1 to 5 for preventing coagulation ex vivo for biological samples which contain factor Xa. 19. A method for the treatment of thromboembolic disorders in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound as defined in any one of Claims 1 to A method for the treatment of disorders which are influenced positvely by inhibition of factor Xa in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound as defined in any one of Claims 1 to 21. A method for the treatment of disseminated intravascular coagulation (DIC) in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound as defined in any one of Claims 1 to 22. A method for the treatment of a disorder selected from atheroslerosis; arthritis, Alzheimer's disease or cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound as defined in any one of Claims 1 to 23. A compound of the general formula as defined in any one of Claims 1 to substantially as hereinbefore described, with reference to the Examples.