Substituted oxazolidinones, their production method, therapeutic agents containing it and their application

Description of the invention

The invention relates to the field of blood coagulation.

The present invention relates to novel oxazolidinone derivatives, a method for their preparation, medicaments containing them, their use as active ingredients for the preparation of medicaments and their use for the prevention of ex vivo blood clotting.

Blood clotting is the body's defense mechanism by which defects in the vessel wall can be 'sealed' quickly and reliably. In this way, blood loss can be prevented or minimized. Stopping bleeding after vessel damage occurs essentially through the coagulation system, which triggers the enzymatic cascade of complex plasma protein reactions. A plurality of blood clotting factors are involved, each of which, after activation, each transforms the next inactive pre-stage into active form. At the end of the cascade, the conversion of soluble fibrinogen to insoluble fibrin occurs so that a blood clot is formed. Traditionally, a distinction is made in blood clotting between the endogenous and extrinsic systems which meet in a final common reaction pathway. Factor Xa, which is formed from the proenzyme of factor X, plays a key role here because it binds both clotting pathways. The activated Xa serine protease cleaves prothrombin to thrombin. The obtained thrombin, in turn, cleaves fibrinogen to fibrin, which is a fibrous-jelly-like clotting substance. Moreover, thrombin is a potent trigger of thrombocyte aggregation and also contributes significantly to hemostasis.

Maintaining normal hemostasis - between bleeding and thrombosis - is subject to a complex regulatory mechanism. Uncontrolled activation of the coagulation system or defective inhibition of the activation processes can result in the formation of local thrombi or emboli in the vessels (arteries, veins, lymph vessels) or in the heart cavities. This can lead to serious conditions such as heart attack, angina pectoris (including unstable angina), re-closure and restenosis after angioplasty or bypass surgery, stroke, transient ischemic attacks, peripheral arterial obstruction, pulmonary embolism, or deep thrombophlebitis; these diseases are also collectively referred to as thromboembolic disorders. In addition, systemic hypercoagulability in coagulopathy from the consumption of coagulation factors may lead to disseminated intravascular thrombus.

These thromboembolic conditions are the most common cause of morbidity and mortality in most industrialized countries (Pschyrembel, Klinisches Worterbuch, 257th edition, 1994, Walter de Gruyter, pp. 199 et seq., Entry "Blutgerinnung"; Rompp Lexikon Chemie, version 1.5, 1998, publishing house Georg Thieme Stuttgart, entry "Blutgerinnung"; Lubert Stryer, Biochemie, Spektrum der Wissenschaft Verlagsgesellschaft mbH Heidelberg, 1990, pp. 259 et seq.).

The anticoagulants known in the art, i.e. substances for inhibiting or preventing blood clotting, have various, sometimes aggravating, disadvantages. An effective method of treatment or prevention in the case of thromboembolic diseases is therefore very difficult and unsatisfactory in practice.

In the treatment and prophylaxis of thromboembolic diseases, heparin is used, which is administered parenterally or subcutaneously. Due to favorable pharmacokinetic properties, low molecular weight heparin is used more and more today; however, the following known disadvantages that occur during treatment with heparin cannot be omitted here as well. Thus, heparin is orally inactive and has, by comparison, only a small half-life. Since heparin simultaneously inhibits many factors of the blood clotting cascade, the effect is non-selective. In addition, there is a high risk of bleeding, in particular, there may be bleeding in the brain and bleeding in the gastrointestinal tract, and may result in thrombocytopenia, drug-induced alopecia or osteoporosis (Pschyrembel, Klinisches Worterbuch, 257th edition, 1994, Walter de Grayter, pp. 610, password "Heparin"; Rompp Lexikon Chemie, version 1.5, 1998, publishing house Georg Thieme Stuttgart, entry "Heparin").

The second class of anticoagulants is vitamin K antagonists. These include, for example, 1,3-indanedione, but above all, compounds such as Warfarin, Phenprocoumon, Dicumarol and other coumarin derivatives which non-selectively inhibit the liver synthesis of various products of certain vitamin K-dependent coagulation factors. However, the action due to this mechanism is very slow (latency to onset of action is 36-48 hours). Although the compounds can be administered orally, due to the high risk of bleeding

Due to the fact that the patient has a narrow therapeutic index, time-consuming individual positioning and monitoring of the patient is necessary. In addition, further side effects such as gastrointestinal disturbances, hair loss and skin necrosis are described (Pschyrembel, Klinisches Worterbuch, 257th edition, 1994, Walter de Gruyter, pp. 292 et seq., Entry "Cumarivate"; Ullmann'sinder Encyclopedia of Industrial Chemistry, 5. edition, publishing house VCH Verlagsgesellschaft, Weinheim, 1985 - 1996, entry "Vitamin K").

Recently, a new type of therapy has been described for the treatment and prevention of thromboembolic diseases. A new type of therapy aims to inhibit factor Xa (e.g. WO-A-99/37304; WO-A-99/06371; J. Hauptmann, J. Stiirzebecher, Thrombosis Research 1999, 93, 203; F. Al-Obeidi, JA Ostrem, Factor Xa inhibitors by classical and combinatorial chemistry, DDT 1998, 3, 223; F. Al-Obeidi, JA 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; B.-Y. Zhu, RM Scarborough, Curr. Opin. Gard. Pulm. Rhenium. Inv. Drugs 1999, 1 (1), 63). It has been shown that various compounds, both peptide and non-peptide, are active in animal tests as inhibitors of factor Xa.

The object of the invention is therefore to provide new substances for the control of diseases which exhibit a wide range of therapeutic effects.

Such compounds should in particular be suitable for a more effective prophylaxis and / or treatment of thromboembolic disorders and should - at least in part - suffer from the above-described disadvantages of the prior art, the term "thromboembolic disorders" in the context of the present application being particularly understood. stressful diseases such as heart attack, angina pectoris (including unstable angina), re-closure and restenosis after angioplasty or aorticardial bypass, stroke, transient cerebral ischemic attacks, peripheral arterial occlusion disorders, pulmonary embolism, or deep thrombophlebitis.

It is a further object of the invention to provide novel anticoagulants which inhibit blood coagulation factor Xa with increased selectivity and overcome - at least in part - the problems of prior art therapeutic methods for thromboembolic diseases.

The invention therefore relates to substituted oxazolidinones of the general formula I

<img file="PL201121B1_D0001.tif" />

wherein ₁

R¹ is a thiophene (thienyl) group which is substituted one or more times with a substituent selected from the group consisting of halogen, (C1-C8) -alkyl or trifluoromethyl,

R² stands for one of the following groups:

AND-,

DMA-, where the symbol "A" stands for a phenyl group, the symbol "D" stands for tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl N-oxide, thiomorpholinyl group, azepinyl or 1,4-diazepinyl, the symbol "M" represents the group -CH2-, -SO2- or a covalent bond, where

The groups "A" and "D" as defined above may be optionally substituted one or more times by a substituent selected from the group consisting of halogen, trifluoromethyl, oxo, cyano, nitro, carbamoyl, pyridyl, (C1-C6) -alkanoyl, (C1-C4) -hydroxyalkylcarbonyl, -COOR²⁷, -CONR²⁸R²⁹, -SO2NR²⁸R²⁹, -OR³⁰; -NR³⁰R³¹, the group (C1-C₆) -alkyl and (C₃-C₇) -cycloalkyl, the (C1-C6) -alkyl group in turn may be optionally substituted by a substituent selected from cyano, -OR²⁷, -NR²⁸R²⁹ and -C (NO²⁷R²⁸) = NO²⁹where

28 29

R²⁷, R²⁸ and r²⁹ are the same or different and are independently of each other hydrogen, (C1-C4) -alkyl, (C3-C7) -cycloalkyl, (C1-C4) -alkanoyl, carbamoyl, trifluoromethyl, phenyl or pyridyl groups, and / or

28 27 29

R²⁷ and r²⁸ or R.²⁷ and r²⁹ together with the nitrogen atom to which they are bound, they form a tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl N-oxide, thiomorpholinyl, azepinyl or 1,4- group diazepinyl,

R³⁰ and r³¹ are the same or different and are independently of each other hydrogen, (C1-C4) -alkyl, (C3-C7) -cycloalkyl, (C1-C4) -hydroxyalkyl or -COR groups³³where

R³³ is (C1-C6) -alkoxy, (C1-C4) -alkoxy- (C1-C4) -alkyl, (C1-C4) -alkoxycarbonyl- (C1-C4) -alkyl, (C1-C4) -aminoalkyl, (C1-C4) -alkoxycarbonyl, (C1-C4) -alkanoyl (C1-C4) -alkyl, (C3-C7) -cycloalkyl, (C2-C6) -alkenyl, (C1-C8) -alkyl group which can be optionally substituted with a phenyl or acetyl group, (C6-C14) -aryl, pyridyl, pyridyl N-oxide, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl or isoxazolyl, indolizinyl, indolyl, benzo [b] thienyl, benzo [b] furyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl, trifluoromethyl, and tetrahydrofuron

R³, R⁴, R⁵, R⁶, R⁷ and r⁸ represent hydrogen atoms, but to the exclusion of compounds of general formula I in which

R¹ represents a 2-thiophene group that is substituted at the 5-position by a substituent selected from the group consisting of chlorine, bromine, methyl or trifluoromethyl,

R² stands for the DA- group, where the symbol "A" stands for a phenylene group, the symbol "D" stands for a pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl group, which through a nitrogen atom is linked to "A", which has a group in the immediate vicinity of the binding nitrogen atom carbonyl and in which the ring carbon member may be replaced by a heteroatom from the series S, N and O, wherein the group "A" as defined above in the meta position with respect to the oxazolidinone bond may be optionally substituted with one or two substituents selected from the group consisting of fluoro, chloro, nitro, amino, trifluoromethyl, methyl or cyano, and R³, R⁴, R⁵, R⁶, R⁷ and r⁸ are hydrogen atoms.

Compounds of the general formula I in which

R¹ is a thiophene (thienyl) group which is one or more substituted by halogen, (C1-C8) -alkyl or trifluoromethyl,

R² stands for one of the following groups:

AND-,

DMA-, where the symbol "A" stands for a phenyl group, the symbol "D" stands for tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl N-oxide, thiomorpholinyl group, azepinyl or 1,4-diazepinyl, the symbol "M" represents the group -CH2- or a covalent bond,

The groups "A" and "D" as defined above may be optionally substituted one or more times by a substituent selected from the group consisting of halogen, trifluoromethyl, oxo, cyano, nitro, carbamoyl, pyridyl, (C1- C6) -alkanoyl group -COOR²⁷, -CON-R²⁸R²⁹, -SO2NR²⁸R²⁹, -OR³⁰; -NR³⁰R³¹, the group (C1-C₆) -alkyl and (C₃-C₇) -cycloalkyl, the (C1-C6) -alkyl group in turn may be optionally substituted by a substituent selected from cyano, -OR²⁷, -NR²⁸R²⁹ and -C (NO²⁷R²⁸) = NO²⁹where

28 29

R²⁷, R²⁸ and r²⁹ are the same or different and are independently of each other hydrogen atoms, (C1-C4) -alkyl, (C3-C7) -cycloalkyl groups, and / or

R²⁷ and r²⁸ or R.²⁷ and r²⁹ together with the nitrogen atom to which they are bound, they form a tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl N-oxide, thiomorpholinyl, azepinyl or 1,4- group diazepinyl and

R³⁰ and r³¹ are the same or different and are independently hydrogen, (C1-C4) -alkyl, (C3-C7) -cycloalkyl, (C1-C4) -hydroxyalkyl, (C1-C4) -alkanoyl, (C6-C14) groups -arylcarbonyl or pyridylcarbonyl, pyridylcarbonyl N-oxide, pyrimidylcarbonyl, pyridazinylcarbonyl, pyrazinylcarbonyl, thienylcarbonyl, furylcarbonyl, pyrrolylcarbonyl, pyrazolylcarbonyl, imidazolyliazolycarbonyl, indidazolylcarbonylcarbonyl, isoxylcarbonylcarbonyl benzo [b] thienylcarbonyl, benzo [b] furylcarbonyl, indazolylcarbonyl, quinolylcarbonyl, isoquinolylcarbonyl, naphthyridinylcarbonyl or quinazolinylcarbonyl, and R³, R⁴, R⁵, R⁶, R⁷ and r⁸ represent hydrogen atoms, but to the exclusion of compounds of general formula I in which

R¹ represents a 2-thiophene group that is substituted at the 5-position by a substituent selected from the group consisting of chlorine, bromine, methyl or trifluoromethyl,

R² stands for the DA- group, where the symbol "A" stands for a phenylene group, the symbol "D" stands for a pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl group, which through a nitrogen atom is linked to "A", which has a group in the immediate vicinity of the binding nitrogen atom carbonyl and in which the ring carbon member may be replaced by a heteroatom from the series S, N and O, wherein the group "A" as defined above in the meta position with respect to the bond with the oxazolidinone may be optionally substituted one or two times with a substituent selected from the group consisting of fluoro, chloro, nitro, amino, trifluoromethyl, methyl or cyano, and R³, R⁴, R⁵, R⁶, R⁷ and r⁸ are hydrogen atoms.

Particularly preferred are compounds of the general formula I in which

R¹ is a thiophene (thienyl) group which is one or more substituted by halogen, (C1-C8) -alkyl or trifluoromethyl,

R² stands for one of the following groups:

AND-,

DMA-, where the symbol "A" represents a phenyl group, the symbol "D" represents a tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl N-oxide or thiomorpholinyl group, the symbol "M" denotes a covalent bond, the groups "A" and "D" as defined above may be optionally substituted one or more times by a substituent selected from the group consisting of a halogen atom, trifluoromethyl, oxo, cyano, pyridyl, (C.₁-C₃) -alkanoyl, -CONR²⁸R²⁹, -SO₂NO²⁸R²⁹, -OH, -NR³⁰R³¹, a (C1-C4) -alkyl group and a cyclopropyl, cyclopentyl or cyclohexyl group,

Wherein the (C1-C4) -alkyl group in turn may be optionally substituted by a substituent selected from the group consisting of cyano, -OH, -OCH₃, -NR²⁸R²⁹ and -C (NO²⁷R²⁸) = NO²⁹where

28 29

R²⁷, R²⁸ and r²⁹ are the same or different and are independently of each other hydrogen atoms, (C1-C4) -alkyl groups or cyclopropyl, cyclopentyl or cyclohexyl groups, and / or

28 27 29

R²⁷ and r²⁸ or R.²⁷ and r²⁹ together with the nitrogen atom to which they are bound, they form a tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl N-oxide, thiomorpholinyl, azepinyl or 1,4- group diazepinyl and

R³⁰ and r³¹ are the same or different and are independently of each other hydrogen atoms, (C1-C4) -alkyl groups, cyclopropyl, cyclopentyl, cyclohexyl, (C1-C4) -hydroxyalkyl, (C1-C3) -alkanoyl or phenylcarbonyl groups, and R³, R⁴, R⁵, R⁶, R⁷ and r⁸ represent hydrogen atoms, but to the exclusion of compounds of general formula I in which

R¹ represents a 2-thiophene group that is substituted at the 5-position by a substituent selected from the group consisting of chlorine, bromine, methyl or trifluoromethyl,

R² stands for the DA- group, where the symbol "A" stands for a phenylene group, the symbol "D" stands for a pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl group, which through a nitrogen atom is linked to "A", which has a group in the immediate vicinity of the binding nitrogen atom carbonyl and in which the ring carbon member may be replaced by a heteroatom from the series S, N and O, wherein the group "A" as defined above in the meta position with respect to the bond with the oxazolidinone may be optionally substituted one or two times with a substituent selected from the group consisting of fluoro, chloro, nitro, amino, trifluoromethyl, methyl or cyano, and R³, R⁴, R⁵, R⁶, R⁷ and r⁸ are hydrogen atoms.

Furthermore, compounds of the general formula I in which

R¹ represents a 2-thiophene group that is substituted at the 5-position by a substituent selected from the group consisting of chlorine, bromine, methyl or trifluoromethyl,

R² stands for one of the following groups:

AND-,

DMA-, where the symbol "A" stands for a phenyl group, the symbol "D" stands for tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, morpholinyl, morpholinyl N-oxide or thiomorpholinyl group, the symbol " M "represents a covalent bond, the groups" A "and" D "as defined above may in each case be optionally substituted one or more times by a substituent selected from the group consisting of halogen, trifluoromethyl, oxo, cyano, pyridyl, (C.₁-C₃) -alkanoyl, the group -CONR²⁸R²⁹, -SO₂NO²⁸R²⁹, -OH, -NR³⁰R³¹, a (C1-C4) -alkyl group and a cyclopropyl, cyclopentyl or cyclohexyl group, the (C1-C4) -alkyl group in turn being optionally substituted by a substituent selected from cyano, -OH, -OCH₃, -NR²⁸R²⁹ and -C (NO²⁷R²⁸) = NO²⁹where

28 29

R²⁷, R²⁸ and r²⁹ are the same or different and are independently of each other hydrogen atoms, (C1-C4) -alkyl groups or cyclopropyl, cyclopentyl or cyclohexyl groups, and / or

28 27 29

R²⁷ and r²⁸ or R.²⁷ and r²⁹ together with the nitrogen atom to which they are bound, they form a tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl N-oxide, thiomorpholinyl or azepinyl group 1,4-diazepinyl and

R³⁰ and r³¹ are the same or different and are independently of each other hydrogen atoms, (C1-C4) -alkyl groups, cyclopropyl, cyclopentyl, cyclohexyl, (C1-C4) -hydroxyalkyl, (C1-C3) -alkanoyl or phenylcarbonyl groups, and R³, R⁴, R⁵, R⁶, R⁷ and r⁸ represent hydrogen atoms, but to the exclusion of compounds of general formula I in which

R¹ represents a 2-thiophene group that is substituted at the 5-position by a substituent selected from the group consisting of chlorine, bromine, methyl or trifluoromethyl,

R² stands for the DA- group, where the symbol "A" stands for a phenylene group, the symbol "D" stands for a pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl group, which through a nitrogen atom is linked to "A", which has a group in the immediate vicinity of the binding nitrogen atom carbonyl and in which the ring carbon member may be replaced by a heteroatom from the series S, N and O, wherein the group "A" as defined above in the meta position with respect to the bond with the oxazolidinone may be optionally substituted one or two times with a substituent selected from the group consisting of fluoro, chloro, nitro, amino, trifluoromethyl, methyl or cyano, and R³, R⁴, R⁵, R⁶, R⁷ and r⁸ are hydrogen atoms.

Preferably in compounds of general formula I

R¹ it may represent a thiophene (thienyl) group, especially 2-thiophene, which may be optionally one or more substituted by halogen, preferably chlorine or bromine, or a (C1-C8) alkyl group, preferably methyl, the (C1-C8 group being The) alkyl, preferably methyl, in turn may optionally be one or more substituted with halogen, preferably fluorine.

Also in the compounds of general formula I the substituent R² preferably it may be one of the following groups:

R being

R³² is a hydrogen atom or a (C1-C4) alkyl group, preferably a hydrogen atom or a methyl group, and

W is S, NH or O, preferably S.

₂

Moreover, in compounds of general formula I, the substituent R² may be a group of formula

HjCT N fc ₂

Finally, in compounds of general formula I, R² may be a group of formula

So far, oxazolidinones have essentially only been described as antibiotics, in particular also as MAO inhibitors and fibrinogen antagons (reviewed: Riedl, B., Endermann, R., Exp. Opin. Ther.

PL 201 121 B1

Patents 1999, 9 (5), 625), a small 5- [acyl-aminomethyl] group (preferably 5- [acetyl-aminomethyl]) appears to be essential for the antibacterial effect.

Substituted aryl and heteroarylphenyl oxazolidinones, where the N atom of the oxazolidinone ring is bonded with a monosubstituted or multisubstituted phenyl group and which may have an unsubstituted N-methyl-2-thiophenecarboxamide group at the 5-position of the oxazolidinone ring, and their use as antibacterial substances are known from United States patents Nos. US-A-5929248, US-A-5801246, US-A-5756732, US-A-5654435, US-A-5654428 and US-A-5565571.

Furthermore, benzamidine-containing oxazolidinones are known as synthetic intermediates for the preparation of factor Xa inhibitors or fibrinogen antagonists (WO-A-99/31092, EP-A-623615).

The compounds according to the invention of general formula I, depending on the substitution pattern, may exist in stereoisomeric forms which either behave as image and mirror image (enantiomers) or which do not behave as image and mirror image (diastereomers). The invention relates to both the enantiomers or diastereomers and to the mixtures in question. Racemic forms and diastereomers can be separated into stereoisomerically homogeneous components in a known manner.

Furthermore, certain compounds of the general formula I may exist in tautomeric forms. This is known to those skilled in the art and such compounds are also included in the invention.

Physiologically non-objectionable, ie, pharmaceutically acceptable salts, may be the salts of the compounds of the invention with inorganic or organic acids. Salts with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids, such as, for example, acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid are preferred. , malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.

Also suitable as pharmaceutically acceptable salts are salts with known bases, such as alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. 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.

Halogen means fluorine, chlorine, bromine and iodine. Chlorine or fluorine is preferred.

The (C1-C8) alkyl group means a straight or branched alkyl group with 1-8 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl and n-hexyl. Alkyl groups having a lower number of carbon atoms, e.g. (C1-C6) alkyl and (C1-C4) alkyl groups, are analogously derived from this definition. Generally a (C1-C4) alkyl group is considered to be preferable.

The meaning of the corresponding compound substituent components is also derived from this definition, such as, for example, alkylsulfonyl, hydroxyalkyl, hydroxyalkylcarbonyl, alkoxyalkyl, alkoxycarbonylalkyl, alkanoylalkyl, aminoalkyl or alkylaminoalkyl.

The (C3-C7) cycloalkyl group represents a cyclic alkyl group of 3-7 carbon atoms. By way of example, mention may be made of a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group. The corresponding cycloalkyl groups having a lower number of carbon atoms are analogously derived from this definition, such as, for example, a (C3-C5) cycloalkyl group. Cyclopropyl, cyclopentyl and cyclohexyl groups are preferred.

The meaning of the corresponding substituent substituents, such as, for example, cycloalkanoyl, is derived from this definition.

In the context of the invention, a (C2-C6) alkenyl group denotes a straight or branched alkenyl group having 2 to 6 carbon atoms. A straight or branched alkenyl group with 2-4 carbon atoms is preferred. Examples of such groups are vinyl, allyl, isopropenyl and n-but-2-en-1-yl.

The (C1-C8) -alkoxy group means a straight or branched alkoxy group having 1-8 carbon atoms. Examples that may be mentioned are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, n-hexoxy, n-heptoxy and n-octoxy. The corresponding alkoxy groups are also derived from this definition

With fewer carbon atoms such as, for example, (C1-C6) alkoxy and (C1-C4) alkoxy. Generally a (C1-C4) alkoxy group is considered to be preferable.

The meanings of the corresponding compound substituent components, such as, for example, alkoxy-alkyl, alkoxycarbonyl-alkyl and alkoxycarbonyl, also come from this definition.

A mono- or di- (C1-C4) -alkylaminocarbonyl group is an amino group which is bonded via a carbonyl group and which has one straight or branched or two identical or different straight or branched alkyl substituents having 1-4 carbon atoms each. Examples include methylamino, ethylamino, n-propylamino, isopropylamino, t-butylamino, N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl -Nn-propylamine and Nt-butyl-N-methylamine.

The (C1-C6) -alkanoyl group denotes a straight or branched alkyl group with 1-6 carbon atoms which in the 1-position contains a doubly bonded oxygen atom and is linked via the 1-position. Examples are formyl, acetyl, propionyl, n- butyryl, isobutyryl, pivaloyl, n-hexanoyl. Alkanoyl groups having a lower number of carbon atoms are analogously derived from this definition, such as, for example, (C1-C5) -alkanoyl, (C1-C4) -alkanoyl and (C1-C3) -alkanoyl groups. Generally a (C1-C3) alkanoyl group is assumed to be preferable.

The meanings of the corresponding compound substituent components, such as, for example, the cycloalkanoyl and alkanoylalkyl groups also derive from this definition.

The (C3-C7) cycloalkanoyl group is the above-defined cycloalkyl group of 3-7 carbon atoms which is bonded via a carbonyl group.

The (C1-C6) -alkanoyloxymethyloxy group means a straight or branched alkanoyloxymethyloxy group with 1-6 carbon atoms. Examples are acetoxymethyloxy, propionoxymethyloxy, n-butyroxymethyloxy, isobutyroxymethyloxy, pivaloyloxymethyloxy, n-hexanoyloxymethyloxy. Correspondingly, corresponding alkanoyloxymethyloxy groups with fewer carbon atoms are derived from this definition, such as, for example, a (C1-C3) alkanoyloxymethyloxy group. In general, a (C1-C3) alkanoyloxymethyloxy group is preferred.

A (C6-C14) -aryl group represents an aromatic group of 6-14 carbon atoms. By way of example, mention may be made of the phenyl, naphthyl, phenanthrenyl and anthracenyl groups. Aryl groups with fewer carbon atoms, such as, for example, a (C6-C10) aryl group, are analogously derived from this definition. Generally a (C6-C10) aryl group is assumed to be preferable.

The meanings of the corresponding component of other complex substituents, such as, for example, arylcarbonyl, are also derived from this definition.

The invention also relates to a process for the preparation of the compounds of the general formula I according to the invention.

[A] compounds of general formula II

<img file="PL201121B1_D0002.tif" />

wherein R², R³, R⁴, R⁵, R⁶, R⁷ and r⁸ are as defined above, are reacted with carboxylic acids of general formula III ^ho\/^r1 C.¹¹)’

T where R.¹ is as defined above, either with the corresponding carboxylic acid halides, preferably with carboxylic acid chlorides, or with the corresponding symmetrical or mixed carboxylic acid anhydrides of the above-defined carboxylic acids of general formula III,

In inert solvents, optionally in the presence of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide.HCl, N, N'-dicyclohexylcarbodiimide or 1-hydroxy-1H-benzotriazole.H2O and / or in the presence of a base such as such as alkali metal hydroxides, such as, for example, sodium or potassium hydroxide, or alkali metal carbonates, such as sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethoxide, or potassium t-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 to give compounds of general formula I

<img file="PL201121B1_D0003.tif" />

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and r⁸ are as defined above or according to another variant [B] the compounds of general formula IV

<img file="PL201121B1_D0004.tif" />

wherein R¹, R³, R⁴, R⁵, R⁶, R⁷ and r⁸ are as defined above, when using m-chloroperbenzoic acid (MCPBA), sodium metaperiodate, N-methylmorpholine N-oxide (NMO), monoperoxy phthalic acid or osmium tetroxide, in an inert solvent is converted into the corresponding epoxide compound of general formula V

<img file="PL201121B1_D0005.tif" />

wherein R¹, R³, R⁴, R⁵, R⁶, R⁷ and r⁸ are as defined above, and by reaction in an inert solvent, optionally in the presence of a catalyst, with an amine of the general formula VI

R² - NH2 (VI) where R² is as defined above, first the compounds of general formula VII are obtained

<img file="PL201121B1_D0006.tif" />

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and r⁸ are as defined above, and then cyclized in an inert solvent in the presence of phosgene or phosgene equivalents, such as e.g. carbonyldiimidazole (CDI) to compounds of general formula I

PL 201 121 B1

<img file="PL201121B1_D0007.tif" />

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and r⁸ have the meaning given above, with both variant [A] and variant [B] - in the case where R² denotes a pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepinyl or 1,4-diazepinyl group, oxidation can then be carried out using m-chloroperbenzoic acid (MADCPodate), sodium methoxide N-methylmorpholine N-oxide (NMO), monoperphthalic acid or osmium tetroxide, yielding the corresponding sulfone, sulfoxide or N-oxide and / or for both variant [A] and variant [B] - in the case of when there is a cyano group in the compounds thus obtained, then the amidination of this cyano group can be carried out by known methods and / or for both variant [A] and variant [B] in the case when the BOC amino-protecting group is present in the compounds thus obtained, then the BOC amino-protecting group using known methods and / or both for variant [A] and variant [B] in the case when the compounds obtained in this way contain an aniline or benzylamino group, such amino group can then be reacted with various reagents such as carboxylic acids, carboxylic acid anhydrides, carboxylic acid chlorides, isocyanates, sulfonic acid chlorides or alkyl halides to give corresponding derivatives and / or for both variant [A] and variant [B ] if there is a phenyl ring in the compounds thus obtained, it can then be reacted with chlorosulfonic acid and then reacted with amines to give the corresponding sulfonamides.

The methods according to the invention can be illustrated by the following schemes:

<img file="PL201121B1_D0008.tif" />

PL 201 121 B1

[B]

<img file="PL201121B1_D0009.tif" />

The above-described, possibly following oxidation step can be exemplified by the following scheme:

<img file="PL201121B1_D0010.tif" />

Suitable solvents for the processes described above are organic solvents which are inert under the reaction conditions. Hydrogen halides such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichlorethane, tetrachloroethane, 1,2-dichloroethylene or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol or glycol ethylene glycol are mentioned here. diethylene, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or t-butanol, hydrocarbons such as benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine, hexamethylphosphoric triamide, or water.

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

The activating or coupling agents used in the above-described processes are N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide.HCl, N, N'-dicyclohexylcarbodiimide or 1-hydroxy-1H-benzotriazole.H2O as indicated above.

Suitable bases are known inorganic or organic bases. Preferred are alkali metal hydroxides, such as, for example, sodium or potassium hydroxide, or alkali metal carbonates, such as sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethoxide, or potassium t-butoxide, or amides such as 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 used in an amount of 1-5 moles, preferably 1-2 moles, based on 1 mole of the compounds of general formula II.

The reaction can generally be carried out at a temperature from -78 ° C to reflux, preferably from 0 ° C to reflux.

The reaction can be carried out at normal, elevated or reduced pressure (e.g. in the range 0.5-5 x 10⁵ Bye).

In general, the process is carried out under normal pressure.

PL 201 121 B1

Suitable oxidizing agents for the preparation of epoxy compounds as well as for the optionally carried out oxidation to a sulfone, sulfoxide or N-oxide are, as indicated above, m-chloroperbenzoic acid (MCPBA), sodium metaperiodate, N-methylmorpholine N-oxide (NMO) , monoperoxy phthalic acid or osmium tetroxide.

Conditions conventionally employed in such reactions are used to prepare epoxy compounds.

With respect to more detailed data on the reaction conditions for the optionally performed oxidation to a sulfone, sulfoxide or N-oxide, reference can be made to the following literature: MR Barbachyn et al., J. Med. Chem. 1996, 39, 680 and WO-A-97/10223.

In addition, reference is made to examples 14 to 16 given in the experimental section.

The optionally used amidination is carried out under conventional conditions. For details, reference is made to Examples 31-35 and 140-147.

Compounds of general formulas II, III, IV and VI are known to the person skilled in the art and can be prepared in a known manner. For oxazolidinones, especially the 5- (aminomethyl) -2-oxo-oxazolidinones used see WO-A-98/01446, WO-A-93/23384, WO-A-97/03072, JATucker et al., J. Med. Chem. 1998, 41, 3727; SJ Brickner et al., J. Med. Chem. 1996, 39, 673; WA Gregory et al., J. Med. Chem. 1989, 32, 1673.

The compounds of the general formula I according to the invention have an unpredictable, valuable pharmacological range and are therefore suitable for use in the prevention and / or treatment of diseases.

The compounds of the invention of the general formula I - including the compounds excluded in the discussion of product protection - especially act as anticoagulants and can therefore be used in medicaments for the prevention and / or treatment of thromboembolic disorders. "Thromboembolic disorders" within the meaning of the invention include particularly severe conditions such as myocardial infarction, angina pectoris (including unstable angina), re-closure and restenosis following angioplasty or bypass surgery, stroke, transient ischemic attacks, associated with peripheral arterial obstruction, pulmonary embolism, or deep thrombophlebitis.

Furthermore, the compounds of the present invention of general formula I - including those which are excluded from the discussion of product protection - are suitable for the treatment of disseminated intravascular thrombus (DIC).

Furthermore, the compounds of the invention of general formula I - including those excluded for the purpose of product protection - are suitable for the prevention and / or treatment of arteriosclerosis and arthritis, as well as for the prevention and / or treatment of Alzheimer's disease and cancer.

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

"Selective" in the context of the invention are those inhibitors of blood coagulation factor Xa in which the IC50 values ​​for factor Xa inhibition, compared to the IC50 values ​​for the inhibition of other serine proteases, in particular thrombin, plasmin and trypsin, are 100 times, preferably 500 times. times, in particular 1000 times lower, with reference to the test methods for selectivity tests referring to the test methods described in Examples A-1) a.1) and a.2).

The compounds of the invention of general formula I - including those excluded for the purpose of product protection - can also be used to prevent clotting ex vivo, e.g. in the case of preserving blood or biological samples containing factor Xa.

The invention therefore relates to the oxazolidinones of the formula I, which in particular exhibit an unexpected, strong and selective inhibition of factor Xa, the same also being true of compounds excluded in the discussion of product protection.

The invention further relates to medicaments containing at least one compound of general formula I and one or more pharmacologically acceptable excipients or carriers.

These agents can be used for the prevention and / or treatment of diseases, in particular for the above-mentioned diseases of the human or animal body - including compounds excluded in the discussion of product protection.

PL 201 121 B1

The invention further relates to the use of compounds of general formula I

<img file="PL201121B1_D0011.tif" />

in which all symbols have the above meaning, for the preparation of medicaments or pharmaceutical compositions for the prevention and / or treatment of diseases such as hardening of the arteries, arthritis, Alzheimer's disease or cancer, or of thromboembolic diseases, especially such as heart attack, angina (including unstable angina), re-closure and restenosis after angioplasty or aorticardial bypass, stroke transient ischemic attacks, peripheral arterial occlusive disease, pulmonary embolism, or deep thrombophlebitis.

It is particularly advantageous to use the compounds of general formula I above for the preparation of medicaments or pharmaceutical compositions for the prevention and / or treatment of conditions positively influenced by the inhibition of factor Xa and for the manufacture of medicaments or pharmaceutical compositions for the treatment of disseminated intravascular thrombi ( DIC).

A further subject of the invention is the use of compounds of general formula I for the prevention of ex vivo blood clotting.

The invention further relates to the use of the compounds of general formula I for the prevention of ex vivo blood clotting in biological samples containing factor Xa.

For the administration of the compounds according to the invention, all known administration forms are contemplated. Oral, intra-lingual, sublingual, buccal, rectal or parenteral administration (i.e. bypassing the intestinal tract, i.e. intravenous, intraarterial, intracardiac, intradermal, subcutaneous, transdermal, intraperitoneal or intramuscular) is preferably used. Oral and intravenous administration is particularly preferred. Oral administration is especially preferred, which is an additional advantage over the prior art therapy of thromboembolic diseases.

The new active substances of the general formula I can be converted into known preparations, such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable carriers or solvents.

The therapeutically active compound should in each case be present in a concentration of about 0.1-95% by weight, preferably 0.5-90% by weight, especially 1-85% by weight of the total mixture, i.e. in an amount sufficient to achieve the dosage range indicated.

Nevertheless, it may possibly be desirable to deviate from the above-mentioned amounts, namely depending on body weight or on the type of administration route, on individual drug behavior, on the type of preparation and on the point or time interval over which administration occurs. Thus, in some cases it may be sufficient to use less than the above-mentioned minimum amounts, while in other cases the upper limit mentioned should be exceeded. When larger amounts are administered, several single doses per day may be recommended.

The formulations are prepared, for example, by mixing the active ingredients with solvents and / or carriers, optionally with the use of emulsifiers and / or dispersants, whereby, for example, when water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.

In general, when administered intravenously, it has proven advantageous to administer about 0.001-10 mg / kg, preferably about 0.01-10 mg / kg, especially about 0.1-8 mg / kg body weight, in order to obtain effective results.

PL 201 121 B1

In general, when administered orally, it has proven advantageous to administer about 0.01-50 mg / kg, preferably about 0.1-10 mg / kg, especially about 0.5-8 mg / kg body weight, in order to obtain effective results.

Nevertheless, it may possibly be desirable to deviate from the above-mentioned amounts when administering intravenously or orally, namely depending on the body weight or on the type of administration route, on individual behavior towards the drug, on the type of preparation and on the point or time interval over which the administration. Thus, in some cases it may be sufficient to use less than the above-mentioned minimum amounts, while in other cases the upper limit mentioned should be exceeded. When larger amounts are administered, it may be advisable to split such a dose over the course of the day, namely by administration of several single doses or as long-term infusions.

The compounds according to the invention of the general formula I - including the compounds excluded in the discussion of product protection - are distinguished, compared with known formulations for the treatment of thromboembolic diseases, in particular in that a greater therapeutic range is achieved by selective inhibition of factor Xa. For the patient this means a lower risk of bleeding and for the treating physician a better patient positioning. In addition, there is a faster - conditioned by the mechanism - to start action. Above all, however, the compounds according to the invention can be administered orally, which is a further advantage of the therapy with the compounds according to the invention.

The invention is explained in more detail in the following examples, which, however, in no way limit the invention.

A. Assessment of physiological action

1. General testing methods

The particularly advantageous biological properties of the compounds according to the invention can be ascertained by the following methods.

a) Overview of the test (in vitro)

a.1) Factor Xa inhibition measurement

The enzymatic activity of human factor Xa (FXa) is measured by the reaction of an FXa-specific chromogenic substrate, where factor Xa cleaves p-nitroaniline from the chromogenic substrate. The determinations are performed in the microtiter plates as follows.

The test substances are dissolved in DMSO at various concentrations and incubated with human FXa for 10 minutes (0.5 nmol / liter dissolved in 50 mmol / liter Tris buffer [C, C, C-tris- (hydroxymethyl) -aminomethane], 150 mmol / liter NaCl, 0.1% BSA (Bovine Serum Albumin, pH = 8.3) at 25 ° C. Pure DMSO was used as a control. The chromogenic substrate (150 gmol / liter Pefachrome® FXa from Pentapharm) is then added. After 20 minutes of incubation at 25 ° C, the extinction at 405 nm is determined. The extinction of the test samples with the test substance is compared with the control samples without test substance and the IC50 values ​​are calculated from this.

a.2) Determination of selectivity

To determine the selective inhibition of FXa, test substances are tested for inhibition of other human serine proteases such as thrombin, trypsin, plasmin.

To determine the enzymatic activity of thrombin (76 mU / ml), trypsin (500 mU / ml) and plasmin (3.2 nmol / liter), these enzymes are dissolved in Tris buffer (100 mmol / liter, 20 mmol / liter CaCl2, pH = 8.0) and incubated with the test substance or solvent for 10 minutes. The enzymatic reaction is then started by adding a suitable specific chromogenic substrate (Chromozym Thrombin® from Boehringer Mannheim, Chromozym Trypsin® from Boehringer Mannheim, Chromozym Plasmin® from Boehringer Mannheim) and the enzymatic reaction is started and the extinction is determined after 20 minutes at 405 nm. All determinations are carried out at 37 ° C. The extinction of the test samples with the test substance is compared with the control samples without test substance and the IC50 values ​​are calculated from this.

a.3) Determination of the anticoagulant activity

The anticoagulant activity of test substances is determined in vitro in human plasma. For this, human blood is collected using a 0.11 molar sodium citrate solution in a 1/9 sodium citrate / blood mixture. The blood is mixed well immediately after collection and centrifuged for 10 minutes at about 2000 g. The supernatant is removed by pipette. The prothrombin time (PT, synonym: thromboplastin time, Quick test) is determined in the presence of different concentrations of the test substance or an appropriate solvent with a commercial test kit

PL 201 121 B1 (Neoplastin® from Boehringer Mannheim). Test compounds are incubated with plasma for 10 minutes at 37 ° C. Coagulation is then induced by the addition of thromboplastin and the time point for the onset of clotting is determined. The concentration of the test substance is determined which doubles the prothrombin time.

b) Determination of anticoagulant activity (in vivo) b.1) Arteriovenous fistula model (rat)

Male fasted rats (strain: HSD CPB: WU) weighing 200-250 g are anesthetized with the Rompun / Ketavet solution (12 mg / kg / 50 mg / kg). Thrombosis is induced in a venous fistula based on the method described by Christopher N. Berry et al., Br. J. Pharmacol. (1994), 113, 1209-1214. For this purpose, the left jugular vein and the right carotid artery are dissected. An extracorporeal fistula is placed between the two vessels using a 10 cm long polyethylene (PE 60) hose. This polyethylene hose is connected in the center to a further 3 cm long polyethylene hose (PE 160) which contains a roughened and looped nylon thread to obtain a thrombogenic surface. The extracorporeal circulation lasts for 15 minutes. The fistula is then removed and the nylon thread with the thrombus is immediately weighed. The weight of the nylon thread itself is determined before starting the experiment. The test substances are administered to the sleepy animals, prior to the introduction of extracorporeal circulation, either intravenously via the tail vein or orally via an esophageal tube.

The results are summarized in Table 1.

Table 1

Anticoagulant activity in a venous-arterial fistula model (rat) after oral or intravenous administration

<td>Example</td><td>ED50 [mg / kg] orally</td><td>ED50 [mg / kg] intravenously</td>

<td> 1</td><td></td><td> 10</td>

<td> 17</td><td></td><td> 6</td>

<td> 44</td><td> 3</td><td></td>

<td> 95</td><td></td><td> 3</td>

<td> 114</td><td></td><td> 3</td>

<td> 115</td><td></td><td> 3</td>

<td> 123</td><td> 3</td><td></td>

<td> 162</td><td></td><td> 3</td>

b.2) Arterial thrombosis model (rat)

Male fasted rats (strain: HSD CPB: WU) are anesthetized as described above. The average weight of the rats is approximately 200 g. The left carotid artery (approximately 2 cm) is dissected out. An arterial thrombus is induced by mechanical injury to the vessel according to the method described by K. Meng et al., Naunyn-Schmiedeberg's Arch. Pharmacol. (1977), 301, 115-119. Then, the dissected carotid artery is clamped, inhibiting the blood flow, cooled in a metal trough to -12 ° C for 2 minutes, and in order to standardize the size of the thrombus, it is simultaneously compressed with a weight of 200 g. Then, the blood flow is additionally reduced by means of a clamp placed on the carotid artery. distal to the injured section of the vessel. The proximal clamp is removed, the wound is closed and reopened after 4 hours to remove the injured section of vessel. This section of the vessel opens longitudinally and the thrombus is removed from the injured section of the vessel. The wet weight of the thrombi is determined immediately. The test substances are administered intravenously to the sleepy animals at the beginning of the experiment, either via the tail vein or orally via an esophageal tube.

b.3) Venous thrombus model (rat)

Male fasted rats (strain: HSD CPB: WU) are anesthetized as described above. The average weight of the rats is approximately 200 g. The left jugular vein (approximately 2 cm) is dissected. Venous thrombus formation is induced by mechanical injury to the vessel according to the method described by K. Meng et al., Naunyn-Schmiedeberg's Arch. Pharmacol. (1977), 301, 115-119. Then, the prepared jugular vein is clamped, inhibiting the blood flow, cooled in a metal trough to -12 ° C for 2 minutes and at the same time to standardize the size of the thrombus.

The pressure is compressed with a weight of 200 g. The blood flow reopens and the wound closes. After 4 hours, the wound is reopened to remove the thrombus from the injured section of the vessel. The wet weight of the thrombi is determined immediately. At the beginning of the experiment, the test substances are administered intravenously to the dormant animals via the tail vein or orally via an esophageal tube.

B. Manufacturing Examples

Starting compounds

A method for producing 3-morpholinone is described in US 5349045.

The preparation of N- (2,3-epoxypropyl) -phthalimide is described in J.-W. Chern et al., Tetrahedron Lett. 1998, 39, 8483.

Substituted anilines can be prepared 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 process can also be carried out using Pd catalysts such as Pd (OAc) 2 / DPPF / NaO-t-Bu (Tetrahedron Lett. 1999, 40, 2035) or copper (Renger, Synthesis 1985, 856; Aebischer et al., Heterocycles 1998, 48, 2225). Similarly, haloaromatics without a nitro group can first be converted into the corresponding amides and then nitrated at position 4 (US 3,279,880).

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

<img file="PL201121B1_D0012.tif" />

2 moles (202 g) of morpholin-3-one (E. Pfeil,

U. Harder, Angew. Chem. 79, 1967, 188). 88 g (2.2 mol) of sodium hydride (60% in paraffin) are then added portionwise over the course of 2 hours. After the evolution of hydrogen had ceased, 282 g (2 mol) of 4-fluoronitrobenzene were added dropwise under cooling at room temperature in 1 hour and the reaction mixture was stirred overnight. Then 1.7 liters of liquid volume are distilled off at 12 x 0.1 kPa pressure and at 76 ° C., the residue is poured into 2 liters of water and the mixture is extracted twice with 1 liter of ethyl acetate each time. After the combined organic phases were washed with water, it was dried over sodium sulphate and the solvent was distilled off under reduced pressure. Purification is carried out by chromatography on silica gel with hexane / ethyl acetate (1: 1) and by subsequent recrystallization from ethyl acetate. 78 g of product are obtained as a colorless to brown solid with a yield of 17.6% of theory.

¹H-NMR (300 MHz, CDCl3): 3.86 (m, 2H, CH2CH2), 4.08 (m, 2H, CH2CH2), 4.49 (s, 2H, CH2CO), 7.61 (d, 2H , ³J = 8.95 Hz, CHCH), 8.28 (d, 2H, ³J = 8.95 Hz, CHCH)

MS (rI%) = 222 (74, M.⁺), 193 (100), 164 (28), 150 (21), 136 (61), 117 (22), 106 (24), 90 (37), 76 (38), 63 (32), 50 (25)

The following compounds are prepared in an analogous manner:

3-fluoro-4- (4-morpholin-3-onyl) -nitrobenzene,

4- (N-piperidonyl) -nitrobenzene,

3-fluoro-4- (N-piperidonyl) -nitrobenzene,

4- (N-pyrrolidonyl) -nitrobenzene,

3-fluoro-4- (N-pyrrolidonyl) -nitrobenzene.

II. 4- (4-Morpholin-3-onyl) -aniline

<img file="PL201121B1_D0013.tif" />

PL 201 121 B1

In an autoclave, 63 g (0.275 mol) of 4- (4-morpholin-3-onyl) -nitrobenzene are dissolved in 200 ml of tetrahydrofuran, 3.1 g of Pd / C (5% strength) are added and hydrogenated for 8 hours. in temperature

70 ° C. and under 50 x 10 hydrogen pressure⁵ Bye. After filtering off the catalyst, the solvent is distilled off in vacuo and the product is purified by crystallization from ethyl acetate. The product precipitates in g as a colorless to bluish solid with a yield of 37.6% of theory.

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

¹H-NMR (300 MHz, CDCl3): 3.67 (m, 2H, CH2CH2) 3.99 (m, 2H, CH2CH2), 4.27 (s, 2H, CH2CO), 6.68 (d, 2H, ³J = 8.71Hz, CHCH), 7.03 (d, 2H, ³J = 8.71Hz, CHCH)

MS (rI%) = 192 (100M⁺) 163 (48), 133 (26), 119 (76), 106 (49), 92 (38), 67 (27), 65 (45), 52 (22), 28 (22)

The following compounds are prepared in an analogous manner:

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 1-fluoro-4-nitrobenzenes and 1-chloro-4-nitrobenzenes with primary or secondary amines and subsequent reduction

<img file="PL201121B1_D0014.tif" />

Equimolar amounts of fluoronitrobenzene or chloronitrobenzene and amine are dissolved in dimethyl sulfoxide or acetonitrile (0.1 M to 1 M solution) and stirred overnight at 100 ° C. After cooling to room temperature, the reaction mixture was diluted with ether and washed with water. The organic phase was dried over MgSO4, filtered and concentrated. If a precipitate forms in the reaction mixture, it is filtered off and washed with ether or acetonitrile. If the product is also in the mother liquor, it is worked up as described above with ether and water. The crude products can be purified by chromatography on silica gel (mixtures of dichloromethane / cyclohexane and dichloromethane / ethanol).

For the subsequent reduction, the nitro compound is dissolved in methanol, ethanol or ethanol / dichloromethane mixtures (0.01 M to 0.5 M solution), palladium on carbon (10%) is added and stirred overnight under normal hydrogen pressure. Then it is filtered and concentrated. The crude product can be purified by chromatography on silica gel (dichloromethane / ethanol mixtures) or by preparative reverse phase HPLC (acetonitrile / water mixtures).

Iron powder can also be used as a reducing agent. For this, the nitro compound is dissolved in acetic acid (0.1 M to 0.5 M solution) and 6 equivalents of iron powder and water (0.3-0.5 times the volume of acetic acid) are added in portions at 90 ° C. within 10-15 minutes. After a further 30 minutes at 90 ° C, it is filtered and the filtrate is concentrated. The residue was extracted with ethyl acetate and 2N sodium hydroxide solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product can be purified by chromatography on silica gel (dichloromethane / ethanol mixtures) or by preparative reverse phase HPLC (acetonitrile / water mixtures).

The following starting compounds are prepared in an analogous manner:

III-1. 1- (4-Aminophenyl) -L-proline t-butyl ester MS (ESI): m / z (%) = 304 (M + H + MeCN, 100), 263 (M + H, 20);

HPLC (method 4): rt = 2.79 minutes

III-2. 1- (4-Aminophenyl) -3-piperidinecarboxamide MS (ESI): m / z (%) = 220 (M + H, 100);

HPLC (method 4): rt = 0.59 minutes

PL 201 121 B1

III-3. 1- (4-Aminophenyl) -4-piperidinecarboxamide MS (ESI): m / z (%) = 220 (M + H, 100);

HPLC (method 4): rt = 0.57 minutes

III-4. 1- (4-Aminophenyl) -4-piperidinone MS (ESI): m / z (%) = 191 (M + H, 100);

HPLC (method 4): rt = 0.64 minutes

III-5. 1- (4-Aminophenyl) -L-prolinamide MS (ESI): m / z (%) = 206 (M + H, 100);

HPLC (method 4): rt = 0.72 minutes

III-6. [1- (4-Aminophenyl) -3-piperidinyl] methanol MS (ESI): m / z (%) = 207 (M + H, 100);

HPLC (method 4): rt = 0.60 minutes

III-7. [1- (4-Aminophenyl) -2-piperidinyl] methanol MS (ESI): m / z (%) = 207 (M + H, 100);

HPLC (method 4): rt = 0.59 minutes

III-8. 1- (4-Aminophenyl) -2-piperidinecarboxylic acid ethyl ester MS (ESI): m / z (%) = 249 (M + H, 35), 175 (100);

HPLC (method 4): rt = 2.43 minutes

III-9. [1- (4-Aminophenyl) -2-pyrrolidinyl] methanol MS (ESI): m / z (%) = 193 (M + H, 45);

HPLC (method 4): rt = 0.79 minutes

III-10. 4- (2-Methylhexahydro-5H-pyrrolo [3,4-d] isoxazol-5-yl) -phenylamine

This compound is prepared starting from 2-methylhexahydro-2H-pyrrolo [3,4-d] isoxazole (Ziegler, Carl B. et al; J. Heterocycl. Chem., 25, 2, 1988, 719-723)

MS (ESI): m / z (%) = 220 (M + H, 50), 171 (100);

HPLC (method 4): rt = 0.54 minutes

III-11. 4- (1-Pyrrolidinyl) -3- (trifluoromethyl) -aniline MS (ESI): m / z (%) = 231 (M + H, 100);

HPLC (method 7): rt = 3.40 minutes

III-12. 3-Chloro-4- (1-pyrrolidinyl) -aniline MS (ESI): m / z (%) = 197 (M + H, 100);

HPLC (method 4): rt = 0.78 minutes

III-13. 5-Amino-2- (4-morpholinyl) -benzamide MS (ESI): m / z (%) = 222 (M + H, 100); g HPLC (method 4): rt = 0.77 minutes

III-14. 3-Methoxy-4- (4-morpholinyl) aniline MS (ESI): m / z (%) = 209 (M + H, 100);

HPLC (method 4): rt = 0.67 minutes

III-15. 1- [5-Amino-2- (4-morpholinyl) -phenyl] -ethanone MS (ESI): m / z (%) = 221 (M + H, 100);

HPLC (method 4): rt = 0.77 minutes

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

<img file="PL201121B1_D0015.tif" />

The amide is dissolved in DMF and 1.5 equivalents of potassium t-butoxide are added. The mixture is stirred for 1 hour at room temperature, then 1.2 equivalents of 1-fluoro-4-nitrobenzene are added portionwise. The reaction mixture was stirred overnight at room temperature, diluted with ether and ethyl acetate and washed with saturated aqueous bicarbonate solution.

Of sodium. The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product can be purified by chromatography on silica gel (dichloromethane / ethanol mixtures).

For the subsequent reduction, the nitro compound is dissolved in ethanol (0.01 M to 0.5 M solution), palladium on carbon (10%) is added and the mixture is stirred overnight under normal hydrogen pressure. Then it is filtered and concentrated. The crude product can be purified by chromatography on silica gel (dichloromethane / ethanol mixtures) or by preparative reverse phase HPLC (acetonitrile / water mixtures).

Iron powder can also be used as a reducing agent. For this, the nitro compound is dissolved in acetic acid (0.1 M to 0.5 M solution) and 6 equivalents of iron powder and water (0.3-0.5 times the volume of acetic acid) are added in portions at 90 ° C. within 10-15 minutes. After a further 30 minutes at 90 ° C, it is filtered and the filtrate is concentrated. The residue was extracted with ethyl acetate and 2N sodium hydroxide solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product can be purified by chromatography on silica gel (dichloromethane / ethanol mixtures) or by preparative reverse phase HPLC (acetonitrile / water mixtures).

The following starting compounds are prepared in an analogous manner:

IV-1. 1- [4-Amino-2- (trifluoromethyl) -phenyl] -2-pyrrolidinone MS (ESI): m / z (%) = 245 (M + H, 100);

HPLC (method 4): rt = 2.98 minutes

IV-2. 4- [4-Amino-2- (trifluoromethyl) -phenyl] -3-morpholinone MS (ESI): m / z (%) = 261 (M + H, 100);

HPLC (method 4): rt = 2.54 minutes

IV-3. 4- (4-Amino-2-chlorophenyl) -3-morpholinone MS (ESI): m / z (%) = 227 (M + H, 100);

HPLC (method 4): rt = 1.96 minutes

IV-4. 4- (4-Amino-2-methylphenyl) -3-morpholinone MS (ESI): m / z (%) = 207 (M + H, 100);

HPLC (method 4): rt = 0.71 minutes

IV-5. 5-Amino-2- (3-oxo-4-morpholinyl) -benzonitrile MS (ESI): m / z (%) = 218 (M + H, 100);

HPLC (method 4): rt = 1.85 minutes

IV-6. 1- (4-Amino-2-chlorophenyl) -2-pyrrolidinone MS (ESI): m / z (%) = 211 (M + H, 100);

HPLC (method 4): rt = 2.27 minutes

IV-7. 4- (4-Amino-2,6-dimethylphenyl) -3-morpholinone is prepared starting from 2-fluoro-1,3-dimethyl-5-nitrobenzene (Bartoli et al., J. Org. Chem. 1975, 40, 872 )

MS (ESI): m / z (%) = 221 (M + H, 100);

HPLC (method 4): rt = 0.77 minutes

IV-8. 4- (2,4-Diaminophenyl) -3-morpholinone is prepared starting from 1-fluoro-2,4-dinitrobenzene

MS (ESI): m / z (%) = 208 (M + H, 100);

HPLC (method 4): rt = 0.60 minutes

IV-9. 4- (4-Amino-2-chlorophenyl) -2-methyl-3-morpholinone is prepared starting from 2-methyl-3-morpholinone (Pfeil, E .; Harder, U .; Angew. Chem. 1967, 79, 188 )

MS (ESI): m / z (%) = 241 (M + H, 100);

HPLC (method 4): rt = 2.27 minutes

IV-10. 4- (4-Amino-2-chlorophenyl) -6-methyl-3-morpholinone is prepared starting from 6-methyl-3-morpholinone (EP 350002)

MS (ESI): m / z (%) = 241 (M + H, 100);

HPLC (method 4): rt = 2.43 minutes

Synthesis examples

The following examples 1-13, 17-19 and 36-41 and 47-54 relate to variant [A]. Example 17 relates to compounds excluded from the scope of protection and merely describes the procedure cited in the following examples.

Example 1.

Preparation of 5-chloro-N - {[(5S) -3- (3-fluoro-4-morpholinophenyl) -2-oxo-1,3-oxazolidin-5-yl] -methyl} -2-thiophenecarboxamide

PL 201 121 B1

<img file="PL201121B1_D0016.tif" />

(5S) -5- (Aminomethyl) -3- (3-fluoro-4-morpholinophenyl) -1,3-oxazolidin-2-one (for preparation see SJ Brickner et al., J. Med. Chem. 1996, 39, 673 ) (0.45 g, 1.52 mmol), 3-chlorothiophene-2-carboxylic acid (0.25 g, 1.52 mmol) and 1-hydroxy-1H-benzotriazole hydrate (HOBT) (0.3 g, 1.3 eq.) Is dissolved in 9.9 ml DMF. 0.31 g (1.98 mmol, 1.3 eq.) Of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide (EDCI) is added and 0.39 g (0.53 ml, 3 05 mmol, 2 eq.) Diisopropylethylamine (DIEA). Stir overnight at room temperature. 2 g of silica gel are added and the mixture is evaporated to dryness in vacuo. The residue is chromatographed on silica gel with a toluene-ethyl acetate gradient. 0.412 g (61.5% of theory) of the target compound with a melting point (mp) of 197 ° C is obtained.

Rf (SiO2, toluene / ethyl acetate 1: 1) = 0.29 (educt = 0.0);

MS (DCI) 440.2 (M + H) pattern-Cl ¹H-NMR (d 6 -DMSO, 300 MHz) 2.95 (m, 4H), 3.6 (t, 2H), 3.72 (m, 4H), 3.8 (dd, 1H), 4.12 (t, 1H), 4.75-4.85 (m, 1H), 7.05 (t, 1H), 7.15-7.2 (m, 3H), 7.45 (dd, 1H), 7.68 (d, 1H), 8.95 (t, 1H).

Example 2.

5-Chloro-N - {[(5S) -3- (4-morpholinophenyl) -2-oxo-1,3-oxazolidin-5-yl] -methyl} -2-thiophenecarboxamide

<img file="PL201121B1_D0017.tif" />

is prepared analogously from benzyl 4-morpholinophenylcarbamate via the step (5S) -5- (aminomethyl) -3- (3-fluoro-4-morpholinophenyl) -1,3-oxazolidin-2-one (see example 1).

Melting point 198 ° C;

IC50 value = 43 nM;

Rf (SiO2, toluene / ethyl acetate 1: 1) = 0.24

Example 3.

5-Chloro-N - ({(5S) -3- [3-fluoro-4- (1,4-thiazinan-4-yl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -

<img file="PL201121B1_D0018.tif" />

PL 201 B1 is prepared analogously from (5S) -5- (aminomethyl) -3- [3-fluoro-4- (1,4-thiazinan-4-yl) -phenyl] -1,3-oxazolidin-2- onu (for preparation see MR Barbachyn et al., J. Med. Chem. 1996, 39, 680).

Melting point 193 ° C;

Yield: 82%;

Rf (SiO2, toluene / ethyl acetate 1: 1) = 0.47 (educt = 0.0);

Example 4.

5-Bromo-N - ({(5S) -3- [3-fluoro-4- (1,4-thiazinan-4-yl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide

<img file="PL201121B1_D0019.tif" />

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

Melting point 200 ° C.

Example 5.

N - ({(5S) -3- [3-Fluoro-4- (1,4-thiazinan-4-yl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) - 2-thiophenecarboxamide

<img file="PL201121B1_D0020.tif" />

is prepared analogously from 5-methylthiophene-2-carboxylic acid.

Melting point: 167 ° C.

Example 6.

5-Chloro-N - {[(5S) -3- (6-methylthieno [2,3-b] pyridin-2-yl) -2-oxo-1,3-oxazolidin-5-yl] -methyl} - 2-thiophenecarboxamide

<img file="PL201121B1_D0021.tif" />

prepared analogously from (5S) -5- (aminomethyl) -3- (6-methylthieno [2,3-b] pyridin-2-yl) -1,3-oxazolidin-2-one (for preparation see EP-A- 785,200).

Melting point: 247 ° C.

PL 201 121 B1

Example 7.

5-Chloro-N - {[(5S) -3- (3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2-oxo-1,3-oxazolidin- 5-yl] methyl} -2-thiophenecarboxamide

<img file="PL201121B1_D0022.tif" />

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

Melting point: 217 ° C.

Example 8.

5-Chloro-N - [((5S) -3- {3-fluoro-4- [4- (4-pyridinyl) -piperazine] -phenyl} -2-oxo-1,3-oxazolidin-5-yl) -methyl] -2-thiophenecarboxamide

<img file="PL201121B1_D0023.tif" />

prepared analogously from (5S) -5- (aminomethyl) -3- {3-fluoro-4- [4- (4-pyridinyl) -piperazine] -phenyl} -1,3-oxazolidin-2-one (analogous preparation to JA Tucker et al., J. Med. Chem. 1998, 41, 3727).

MS (ESI) 516 (M + H), pattern Cl.

Example 9.

5-Chloro-N - ({(5S) -3- [3-fluoro-4- (4-methylpiperazine) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -2- thiophenecarboxamide

<img file="PL201121B1_D0024.tif" />

The compound is prepared analogously to (5S) -5- (aminomethyl) -3- [3-fluoro-4- (4-methylpiperazine) -phenyl] -1,3-oxazolidin-2-one.

Example 10.

5-Chloro-N - ({(5S) -3- [3-fluoro-4-t-butoxycarbonylpiperazin-1-yl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide

<img file="PL201121B1_D0025.tif" />

prepared analogously from (5S) -5- (aminomethyl) -3- [3-fluoro-4- (4-t-butoxycarbonylpiperazin-1-yl) -phenyl] -1,3-oxazolidin-2-one (for preparation see already cited WO-A-93/23384).

Melting point: 184 ° C;

Rf (SiO2, toluene / ethyl acetate 1: 1) = 0.42. Example 11.

5-Chloro-N - ({(5S) -3- [3-fluoro-4- (piperazin-1-yl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) - 2-thiophenecarboxamide

<img file="PL201121B1_D0026.tif" />

prepared by reacting the compound of Example 12 with trifluoroacetic acid in methylene chloride. IC50 value = 140 nM;

¹H-NMR [d6-DMSO]: 3.01-3.25 (m, 8H), 3.5-3.65 (m, 2H), 3.7-3.9 (m, 1H), 4, 05-4.2 (m, 1H), 4.75-4.9 (m, 1H), 7.05-7.25 (m, 3H), 7.5 (dd, 1H), 7.7 ( d, 1H), 8.4 (broad s, 1H), 9.0 (t, 1H).

Example 12.

5-Chloro-N - [((5S) -3- (2,4'-bipyridinyl-5-yl) -2-oxo-1,3-oxazolidin-5-yl) -methyl] -2-thiophenecarboxamide

<img file="PL201121B1_D0027.tif" />

PL 201 121 B1 is prepared analogously from (5S) -5-aminomethyl-3- (2,4'-bipyridinyl-5-yl) -2-oxo-1,3-oxazolidin-2-one (for preparation see EP-A -789026).

Rf (SiO2, ethyl acetate / ethanol 1: 2) = 0.6

MS (ESI) 515 (M + H), pattern Cl.

Example 13.

5-Chloro-N - {[(5S) -2-oxo-3- (4-piperidinophenyl) -1,3-oxazolidin-5-yl] -methyl} -2-thiophenecarboxamide

<img file="PL201121B1_D0028.tif" />

prepared from 5- (hydroxymethyl) -3- (4-piperidinephenyl) -1,3-oxazolidin-2-one (for preparation see DE 2708236) after mesylation, reaction with the potassium salt of phthalimide, hydrazinolysis and reaction with 5-chlorothiophene acid 2-carboxylic acid.

Rf (SiO2, ethyl acetate / toluene 1: 1) = 0.31;

Melting point: 205 ° C.

Example 17.

5-Chloro-N - ({(5S) -2-oxo-3- [4- (2-oxo-1-pyrrolidinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) -2- thiophenecarboxamide

<img file="PL201121B1_D0029.tif" />

From 1- (4-aminophenyl) -pyrrolidin-2-one (for preparation see Reppe et al., Justus Liebigs Ann. Chem .; 596; 1955; 209) analogously to a known synthesis scheme (see SJ Brickner et al., J. Med. Chem. 1996, 39, 673) after reaction with benzyloxycarbonyl chloride, subsequent reaction with R-glycidyl butyric acid ester, reaction with potassium phthalimide, hydrazinolysis in methanol and reaction with 5-chlorothiophene-2-carboxylic acid finally give 5-chloro N - ({(5S) -2-oxo-3- [4- (2-oxo-1-pyrrolidinyl) -phenyl] -1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide. Thus obtained 5-chloro-N - ({(5S) -2-oxo-3- [4- (2-oxo-1-pyrrolidinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl ) -2-thiophenecarboxamide has an IC50 value = 4 nM (Test method for IC50 values ​​according to Example A-1.a.1 described above) "Factor Xa inhibition measurement").

Melting point: 229 ° C;

Rf value (SiO2, toluene / ethyl acetate 1: 1) = 0.05 (educt = 0.0);

MS (ESI): 442.0 (21%, M + Na, pattern Cl), 420.0 (72%, M + H, pattern Cl), 302.3 (12%), 215 (52%), 145 (100%);

¹H NMR (d6-DMSO, 300 MHz): 2.05 (m, 2H), 2.45 (m, 2H), 3.6 (t, 2H), 3.77-3.85 (m, 3H) , 4.15 (t, 1H), 4.75-4.85 (m, 1H), 7.2 (d, 1H), 7.5 (d, 2H), 7.65 (d, 2H), 7.69 (d, 1H), 8.96 (t, 1H).

The individual steps of the above-described synthesis of Example 17 together with the respective preliminary steps are as follows:

To 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 slowly added at -20 ° C. C 4.27 g (25.03 mmol) chloroformic acid benzyl ester. The mixture is stirred for 30 minutes at -20 ° C and then allowed to reach room temperature. 0.5 liters are added

Of ethyl acetate and the organic phase is washed with 0.5 liters of saturated NaCl solution. The separated organic phase is dried over MgSO4 and the solvent is evaporated off in vacuo. The residue is triturated with diethyl ether and suction filtered. 5.2 g (73.8% of theory) of benzyl 4- (2-oxo-1-pyrrolidinyl) phenylcarbamate are obtained in the form of light beige crystals, m.p. 174 ° C.

7.27 ml of a 2.5 M solution of n-butyllithium (BuLi) in hexane are added dropwise to 1.47 g (16.66 mmol) of isoamyl alcohol in 200 ml of tetrahydrofuran under argon at -10 ° C. 8 ml of BuLi solution until the color of the added N-benzylidenebenzylamine indicator changes color. It is stirred for 10 minutes at -10 ° C, cooled to -78 ° C and a solution of 4.7 g (15.14 mmol) of benzyl 4- (2-oxo-1-pyrrolidinyl) phenylcarbamate is slowly added. . Then 4 ml of n-BuLi solution is added again until the indicator turns pink. The mixture is stirred for 10 minutes at -78 ° C, and 2.62 g (18.17 mmol) of butyric acid R-glycidyl ester are added and the mixture is stirred for 30 minutes at -78 ° C.

The mixture is allowed to reach room temperature overnight, 200 ml of water are added to the mixture and the THF is evaporated off in vacuo. The aqueous residue is extracted with ethyl acetate, the organic phase is dried over MgSO4 and evaporated down i. Vac. The residue is triturated with 500 ml of diethyl ether and the precipitated crystals are suction filtered.

3.76 g (90% of theory) of (5R) -5- (hydroxymethyl) -3- [4- (2-oxo-1-pyrrolidinyl) -phenyl] -1,3-oxazolidin-2-one at a temperature of mp 148 ° C and Rf value (SiO2, toluene / ethyl acetate 1: 1) = 0.04 (educt = 0.3).

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

The reaction mixture is washed with water and the aqueous phase is extracted again with methylene chloride. The combined organic extracts are dried over MgSO4 and evaporated. The residue (1.67 g) was then dissolved in 70 ml of acetonitrile, 2.62 g (14.16 mmol) of potassium phthalimide were added and the mixture was stirred in a sealed vessel in a microwave oven for 45 minutes at 180 ° C.

Undissolved components are filtered off from the mixture, the filtrate is evaporated in vacuo, the residue (1.9 g) is dissolved in methanol and 0.47 g (9.37 mmol) of hydrazine hydrate is added. The mixture was boiled for 2 hours, a saturated sodium bicarbonate solution was added and the mixture was extracted six times with a total of 2 liters of methylene chloride. The combined organic extracts of the crude (5S) -5- (aminomethyl) -3- [4- (2-oxo-1-pyrrolidinyl) -phenyl] -1,3-oxazolidin-2-one are dried over MgSO4 and evaporated in vacuo no.

Final compound, 5-chloro-N - ({(5S) -2-oxo-3- [4- (2-oxo-1-pyrrolidinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide, prepared by preparing 0.32 g (1.16 mmol) of the above-prepared (5S) -5- (aminomethyl) -3- [4- (2-oxo-1-pyrrolidinyl) -phenyl ] -1,3-oxazolidin-2-one, 5-chlorothiophene-2-carboxylic acid (0.19 g, 1.16 mmol) and 1-hydroxy-1H-benzotriazole hydrate (HOBT) (0.23 g, 1 , 51 mmol) is dissolved in 7.6 mL of DMF. 0.29 g (1.51 mmol) of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide (EDCI) is added and 0.3 g (0.4 ml, 2.32 mmol, 2 eq.) Is added dropwise at room temperature. diisopropylethylamine (DIEA). The mixture was stirred overnight at room temperature.

The mixture is evaporated to dryness in vacuo, the residue is dissolved in 3 ml of DMSO and chromatographed on RP-MPLC with a gradient of acetonitrile / water / 0.5% TFA. Acetonitrile is evaporated off from the appropriate fractions and the precipitated compound is suction filtered. 0.19 g (39% of theory) of the target compound is obtained.

The following is produced in an analogous way:

Example 18.

5-Chloro-N - ({(5S) -2-oxo-3- [4- (1-pyrrolidinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide

Analogously to example 17 from 4-pyrrolidin-1-yl-aniline (Reppe et al., Justus Liebigs Ann. Chem., 596, 1955, 151), 5-chloro-N - ({(5S) -2-oxo 3- [4- (1-pyrrolidinyl) phenyl] -1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide.

IC₅₀= 40 nM,

Melting point: 216 ° C,

Rf value (SiO2, toluene / ethyl acetate 1: 1) = 0.31 [educt = 0.0].

PL 201 121 B1

Example 19.

5-Chloro-N - ({(5S) -2-oxo-3- [4- (diethylamino) -phenyl] -1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide

5-Chloro-N - ({(5S) -2-oxo-3- [4- (diethylamino) -phenyl) is obtained analogously from N, N-diethylphenyl-1,4-diamine (US-A-2811555, 1955) ] -1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide.

IC50 = 270 nM,

Melting point: 181 ° C,

Rf value (SiO2, toluene / ethyl acetate 1: 1) = 0.25 [educt = 0.0].

Example 36.

5-Chloro-N - ({(5S) -3- [2-methyl-4- (4-morpholinyl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -2- thiophenecarboxamide is prepared starting from 2-methyl-4- (4-morpholinyl) -aniline (JELu Valle et al., J. Am. Chem. Soc. 1948, 70, 2223).

MS (ESI): m / z (%) = 436 ([M + H]⁺, 100), standard Cl,

HPLC (method 1): rt (%) = 3.77 (98),

IC₅₀: 1.26 µM

Example 37.

5-Chloro-N - {[(5S) -3- (3-chloro-4-morpholinophenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl} -2-thiophenecarboxamide is prepared starting from 3 -chloro-4- (4-morpholinyl) -aniline (HRSnyder et al., J.Pharm. Sci. 1977, 66, 1204).

MS (ESI): m / z (%) = 456 ([M + H]⁺, 100), standard Cl2,

HPLC (method 2): rt (%) = 4.31 (100),

IC₅₀: 33 nM

Example 38.

5-Chloro-N - ({(5S) -3- [4- (4-morpholinylsulfonyl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide is obtained starting from from 4- (4-morpholinylsulfonyl) aniline (Adams et al., J. Am. Chem. Soc. 1939, 61, 2342).

MS (ESI): m / z (%) = 486 ([M + H]⁺, 100), standard Cl,

HPLC (method 3): rt (%) = 4.07 (100)

IC50: 2 μM

Example 39.

5-Chloro-N - ({(5S) -3- [4- (1-azetidinylsulfonyl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide is prepared starting from from 4- (1-azetidinylsulfonyl) -aniline.

MS (DCI, NH 3): m / z (%) = 473 ([M + NH 4]⁺, 100), standard Cl,

HPLC (method 3): rt (%) = 4.10 (100)

IC₅₀: 0.84 μM

Example 40.

5-Chloro-N - [((5S) -3- {4 - [(dimethylamino) sulfonyl] phenyl} -2-oxo-1,3-oxazolidin-5-yl) methyl] -2-thiophenecarboxamide produces starting from 4-amino-N, N-dimethylbenzenesulfonamide (IK Khanna et al., J. Med. Chem. 1997, 40, 1619).

MS (ESI): m / z (%) = 444 ([M + H]⁺, 100), standard Cl,

HPLC (method 3): rt (%) = 4.22 (100)

IC₅₀: 90 μM

General method of acylating 5- (aminomethyl) -3- [4- (2-oxo-1-pyrrolidinyl) -phenyl] -1,3-oxazolidin-2-one with carboxylic acid chlorides

<img file="PL201121B1_D0030.tif" />

PL 201 121 B1

An approximately 0.1 molar solution of 5- (aminomethyl) -3- [4- (2-oxo-1-pyrrolidinyl) -phenyl] -1 is added dropwise under argon at room temperature to the appropriate acid chloride (2.5 eq.) At room temperature at room temperature. , 3-Oxazolidin-2-one (from Example 45) (1.0 eq.) And absolute pyridine (about 6 eq.) In absolute dichloromethane. The mixture is stirred for about 4 hours at room temperature, then about 5.5 equivalents of PS-Trisamine (Argonaut Technologies) are added. The suspension is stirred gently for 2 hours, after dilution with dichloromethane / DMF (3: 1), it is filtered (the resin is washed with dichloromethane / DMF) and the filtrate is concentrated. The resulting product is optionally purified by preparative RP-HPLC.

The following is produced in an analogous way:

Example 41.

N - ({2-Oxo-3- [4- (2-oxo-1-pyrrolidinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide LC-MS (method 6) : m / z (%) = 386 (M + H, 100),

LC-MS: rt (%) = 3.04 (100),

IC50: 1.3 μΜ

General method for the preparation of acyl derivatives starting from 5- (aminomethyl) -3- [4- (2-oxo-1-pyrrolidinyl) -phenyl] -1,3-oxazolidin-2-one and carboxylic acids

<img file="PL201121B1_D0031.tif" />

To 2.9 equivalents of resin bound carbodiimide (PS-Carbodiimide, Argonaut Technologies) was charged the appropriate carboxylic acid (about 2 equivalents) and an absolute dichloromethane / DMF mixture (about 9: 1). After about 15 minutes of gentle shaking at room temperature, 5- (aminomethyl) -3- [4- (2-oxo-1-pyrrolidinyl) -phenyl] -1,3-oxazolidin-2-one (from example 45) is added. (1.0 eq.) And the mixture was shaken overnight, the resin was filtered off (washed with dichloromethane) and the filtrate was concentrated. The resulting product is optionally purified by preparative RP-HPLC.

Example 47.

5-Chloro-N - {[(5S) -3- (3-isopropyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2-oxo-1,3-oxazolidine- 5-yl] methyl} -2-thiophenecarboxamide

<img file="PL201121B1_D0032.tif" />

200 mg (0.61 mmol) 6 - [(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] -3-isopropyl-1,3-benzoxazol-2 (3H) hydrochloride -one (EP 738726) is suspended in 5 ml of tetrahydrofuran and 0.26 ml (1.83 mmol) of triethylamine and 132 mg (0.73 mmol) of 5-chlorothiophene acid chloride are added.

-carboxylic acid. The reaction mixture is stirred overnight at room temperature and then concentrated. The product was isolated by column chromatography (silica gel, methylene chloride / ethanol = 50/1 to 20/1). 115 mg (43% of theory) of the desired compound are obtained.

MS (ESI): m / z = 436 (M + H, 100);

HPLC (method 40: rt = 3.78 minutes.

The following compounds are prepared in an analogous manner:

<td>Example no</td><td>Building</td><td>Tt [° C]</td><td>IC50 [μΜ]</td>

<td> 48</td><td>□ S ^ IOw * XX 0-7 · * &lt;A $ ABOUT</td><td> 210</td><td> 0,12</td>

<td> 49</td><td>G «.</td><td> 234</td><td> 0,074</td>

<td> 50</td><td>1 CUM (Ηλ_α</td><td> 195</td><td> 1,15</td>

<td> 51</td><td></td><td> 212</td><td> 1,19</td>

<td> 52</td><td>n &lt;&gt; 2xyy,^-y.</td><td> 160</td><td> 0,19</td>

<td> 53</td><td> 0</td><td>MS (ESI): m / z (%) = 431 ([M + H]⁺, 100), standard Cl</td><td> 0,74</td>

<td> 54</td><td>0 «* · from 5-amino-2-pyrrolidine-benzonitrile (Grell, W., Humaus, R; Griss, G., Sauter, R; Rupprecht, E. et al .; J.Med.Chem. 1998, 41.5219)</td><td> 221</td><td> 0,13</td>

PL 201 121 B1

The following Examples 20-30 and 58-94, 96, 98-111, 117, 120-122, 124-126 and 131-139 relate to variant [B], while Examples 20 and 21 describe the preparation of the starting compounds.

Example 20.

Preparation of N-allyl-5-chloro-2-thiophenecarboxamide

<img file="PL201121B1_D0033.tif" />

5-Chloro-thiophene-2-carboxylic acid chloride (7.61 g, 42 mmol) is added dropwise to 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. Ice cooling is removed and the mixture is stirred for 3 hours at room temperature and then concentrated in vacuo. Water is added to the residue and the precipitate is filtered off. The crude product was purified by flash chromatography on silica gel (dichloromethane). Yield: 7.20 g (99% of theory);

MS (DCI, NH4): m / z (%) = 219 (M + NH4, 100), 202 (M + H, 32);

HPLC (method 1): rt (%) = 3.96 minutes (98.9).

Example 21.

Preparation of 5-chloro-N- (2-oxiranylmethyl) -2-thiophenecarboxamide

<img file="PL201121B1_D0034.tif" />

Meta-chloroperbenzoic acid (3.83 g, about 60% strength) is introduced into an ice-cooled solution of 2.0 g (9.92 mmol) of N-allyl-5-chloro-2-thiophene carboxamide in 10 ml of dichloromethane. . The mixture was stirred overnight while warming to room temperature and then washed (three times) with 10% sodium bisulfate solution. The organic phase is washed with saturated sodium hydrogen carbonate solution (twice) and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The product was purified by chromatography on silica gel (cyclohexane / ethyl acetate 1: 1).

Yield: 837 mg (39% of theory)

MS (DCI, NH4): m / z (%) = 253 (M + NH4, 100), 218 (M + H, 80);

HPLC (method 1): rt (%) = 3.69 minutes (about 80).

General method for the preparation of substituted N- (3-amino-2-hydroxypropyl) -5-chloro-2-thiophenecarboxamide derivatives starting from 5-chloro-N- (2-oxiranomethyl) -2-thiophenecarboxamide

<img file="PL201121B1_D0035.tif" />

For a solution of the primary amine derivative or aniline (1.5 to 2.5 equiv.) In 1,4-dioxane, 1,4-dioxane-water mixtures or in ethanol, ethanol-water mixtures (about 0.3 to 1.0 moles) / liter) is added portionwise at room temperature or up to 80 ° C 5-chloro-N- (2-oxiranylmethyl) -2-thiophenecarboxamide (1.0 eq.). The mixture was stirred for 2-6 hours then concentrated. The product can be isolated from the reaction mixture by chromatography on silica gel (cyclohexane-ethyl acetate mixtures, dichloromethane-methanol mixtures or dichloromethane-methanol-triethylamine mixtures).

The following is produced in an analogous way:

Example 22.

N- [3- (Benzylamino) -2-hydroxypropyl] -5-chloro-2-thiophenecarboxamide MS (ESI): m / z (%) = 325 (M + H, 100);

HPLC (method 1): rt (%) = 3.87 minutes (97.9)

Example 23.

5-Chloro-N- [3- (3-cyanoanilino) -2-hydroxypropyl] -2-thiophenecarboxamide

PL 201 121 B1

MS (ESI): m / z (%) = 336 (M + H, 100);

HPLC (method 2): rt (%) = 4.04 minutes (100).

Example 24.

5-Chloro-N- [3- (4-cyanoanilino) -2-hydroxypropyl] -2-thiophenecarboxamide

MS (ESI): m / z (%) = 336 (M + H, 100);

HPLC (method 1): rt (%) = 4.12 minutes (100).

Example 25.

5-Chloro-N- {3- [4- (cyanomethyl) -anilino] -2-hydroxypropyl} -2-thiophenecarboxamide

MS (ESI): m / z (%) = 350 (M + H, 100);

HPLC (method 4): rt (%) = 3.60 minutes (95.4).

Example 26.

5-Chloro-N- {3- [3- (cyanomethyl) -anilino] -2-hydroxypropyl} -2-thiophenecarboxamide

MS (ESI): m / z (%) = 350 (M + H, 100);

HPLC (method 4): rt (%) = 3.76 minutes (94.2).

Example 58.

T-butyl 4 - [(3 - {[(5-chloro-2-thienyl) carbonyl] amino} -2-hydroxypropyl) amino] benzyl carbamate

This compound is prepared starting from t-butyl 4-aminobenzylcarbamate (Bioorg. Med.

Chem. Lett .; 1997; 1921-1926):

MS (ES positive): m / z (%) = 440 (M + H, 100), (ES negative): m / z (%) = 438 (MH, 100);

HPLC (method 1): rt (%) = 4.08 (100).

Example 59.

T-butyl 4- [(3 - {[(5-chloro-2-thienyl) carbonyl] amino} -2-hydroxypropyl) amino] phenylcarbamate

This compound is prepared starting from Nt-butyloxycarbonyl-1,4-phenylenediamine:

MS (ESI): m / z (%) = 426 (M + H, 45), 370 (100);

HPLC (method 1): rt (%) = 4.06 (100).

Example 60.

T-butyl 2-hydroxy-3 - {[4- (2-oxo-1-pyrrolidinyl) -phenyl] -amino} -propylcarbamate

This compound is prepared starting from 1- (4-aminophenyl) -2-pyrrolidinone (Justus Liebigs Ann.

Chem .; 1955, 596, 204):

MS (DCI, NH 3): m / z (%) = 350 (M + H, 100);

HPLC (method 1): rt (%) = 3.57 (97).

Example 61.

5- Chloro-N- (3-fluoro-4- (3-oxo-4-morpholinyl) -phenyl] -amino} -2-hydroxypropyl) -2-thiophenecarboxamide

800 mg (3.8 mmol) 4- (4-amino-2-fluorophenyl) -3-morpholinone and 700 mg (3.22 mmol) 5-chloro-N- (2-oxiranylmethyl) -2-thiophenecarboxamide in 15 ml ethanol and 1 ml of water is refluxed for 5 hours. The mixture is evaporated in vacuo and the precipitated crystals are suction filtered after adding ethyl acetate, after chromatography of the mother liquor, 276 mg (17% of theory) of the target compound are obtained.

R f (ethyl acetate): 0.25

Example 62.

N- (3-Anilino-2-hydroxypropyl) -5-chloro-2-thiophenecarboxamide is obtained starting from aniline.

MS (DCI, NH 3): m / z (%) = 311 ([M + H]⁺, 100), standard Cl;

HPLC (method 3): rt (%) = 3.79 (100).

Example 63.

5-Chloro-N- (2-hydroxy-3 - {[4- (3-oxo-4-morpholinyl) -phenyl] -amino} propyl) -2-thiophenecarboxamide is prepared starting from 4- (4-aminophenyl) -3-morpholinone.

MS (ESI): m / z (%) = 410 ([M + H]⁺, 50), standard Cl;

HPLC (method 3): rt (%) = 3.58 (100).

Example 64.

N- [3 - ({4- [Acetyl- (cyclopropyl) amino] phenyl} amino) -2-hydroxypropyl] -5-chloro-2-thiophenecarboxamide is prepared starting from N- (4-aminophenyl) -N -cyclopropylacetamide.

MS (ESI): m / z (%) = 408 ([M + H]⁺, 100), standard Cl;

HPLC (method 3): rt (%) = 3.77 (100).

PL 201 121 B1

Example 65.

N- [3 - ({4- [Acetyl- (methyl) -amino] -phenyl} -amino) -2-hydroxypropyl] -5-chloro-2-thiophenecarboxamide is prepared starting from N- (4-aminophenyl) -N -methylacetamide.

MS (ESI): m / z (%) = 382 (M + H, 100);

HPLC (method 4): rt (%) = 3.31 minutes.

Example 66.

5-Chloro-N- (2-hydroxy-3 - {[4- (1H-1,2,3-triazol-1-yl) -phenyl] -amino} -propyl) -2-thiophenecarboxamide is obtained 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 (M + H, 100);

HPLC (method 4): rt = 3.55 minutes.

Example 67.

1- {4 - [(3 - {[(5-chloro-2-thienyl) carbonyl] amino} -2-hydroxypropyl) amino] -phenyl} -L-proline t-butyl ester

MS (ESI): m / z (%) = 480 (M + H, 100);

HPLC (method 4): rt = 3.40 minutes.

Example 68.

1- {4 - [(3 - {[(5-Chloro-2-thienyl) carbonyl] amino} -2-hydroxypropyl) amino] -phenyl} -4-piperidinecarboxamide

MS (ESI): m / z (%) = 437 (M + H, 100);

HPLC (method 4): rt = 2.39 minutes.

Example 69.

1- {4 - [(3 - {[(5-Chloro-2-thienyl) carbonyl] amino} -2-hydroxypropyl) amino] phenyl} -3-piperidinecarboxamide

MS (ESI): m / z (%) = 437 (M + H, 100);

HPLC (method 4): rt = 2.43 minutes.

Example 70.

5-Chloro-N- (2-hydroxy-3 - {[4- (4-oxo-1-piperidinyl) -phenyl] -amino} -propyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 408 (M + H, 100);

HPLC (method 4): rt = 2.43 minutes.

Example 71.

1- {4 - [(3 - {[(5-Chloro-2-thienyl) -carbonyl] -amino} -2-hydroxypropyl) -amino] -phenyl} -L-prolinamide MS (ESI): m / z ( %) = 423 (M + H, 100);

HPLC (method 4): rt = 2.51 minutes.

Example 72.

5-Chloro-N- [2-hydroxy-3 - ({4- [3- (hydroxymethyl) -1-piperidinyl] -phenyl} -amino) -propyl] -2-thiophenecarboxamide

MS (ESI): m / z (%) = 424 (M + H, 100);

HPLC (method 4): rt = 2.43 minutes.

Example 73.

5-Chloro-N- [2-hydroxy-3 - ({4- [2- (hydroxymethyl) -1-piperidinyl] -phenyl} -amino) -propyl] -2-thiophenecarboxamide

MS (ESI): m / z (%) = 424 (M + H, 100);

HPLC (method 4): rt = 2.49 minutes.

Example 74.

1- {4 - [(3 - {[(5-chloro-2-thienyl) -carbonyl] -amino} -2-hydroxypropyl) -amino] -phenyl} -2-piperidinecarboxylic acid ethyl ester MS (ESI): m / z (%) = 466 (M + H, 100);

HPLC (method 4): rt = 3.02 minutes.

Example 75.

5-Chloro-N- [2-hydroxy-3 - ({4- [2- (hydroxymethyl) -1-pyrrolidinyl] -phenyl} -amino) -propyl] -2-thiophenecarboxamide

MS (ESI): m / z (%) = 410 (M + H, 100);

HPLC (method 4): rt = 2.48 minutes.

PL 201 121 B1

Example 76.

5-Chloro-N- (2-hydroxy-3 - {[4- (2-methylhexahydro-5H-pyrrolo [3,4-d] isoxazol-5-yl) -phenyl] -amino} -propyl) -2- thiophenecarboxamide

MS (ESI): m / z (%) = 437 (M + H, 100);

HPLC (method 5): rt = 1.74 minutes.

Example 77.

5-Chloro-N- (2-hydroxy-3 - {[4- (1-pyrrolidinyl) -3- (trifluoromethyl) -phenyl] -amino} -propyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 448 (M + H, 100);

HPLC (method 4): rt = 3.30 minutes.

Example 78.

5-Chloro-N- (2-hydroxy-3 - {[4- (2-oxo-1-pyrrolidinyl) -3- (trifluoromethyl) -phenyl] -amino} -propyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 462 (M + H, 100);

HPLC (method 4): rt = 3.50 minutes.

Example 79.

5-Chloro-N- (3 - {[3-chloro-4- (3-oxo-4-morpholinyl) -phenyl] -amino} -2-hydroxypropyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 444 (M + H, 100);

HPLC (method 4): rt = 3.26 minutes.

Example 80.

5-Chloro-N- (2-hydroxy-3 - {[4- (3-oxo-4-morpholinyl) -3- (trifluoromethyl) -phenyl] -amino} -propyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 478 (M + H, 100);

HPLC (method 4): rt = 3.37 minutes.

Example 81.

5-Chloro-N- (2-hydroxy-3 - {[3-methyl-4- (3-oxo-4-morpholinyl) -phenyl] -amino} -propyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 424 (M + H, 100);

HPLC (method 4): rt = 2.86 minutes.

Example 82.

5-Chloro-N- (3 - {[3-cyano-4- (3-oxo-4-morpholinyl) -phenyl] -amino} -2-hydroxypropyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 435 (M + H, 100);

HPLC (method 4): rt = 3.10 minutes.

Example 83.

5-Chloro-N- (3 - {[3-chloro-4- (1-pyrrolidinyl) -phenyl] -amino} -2-hydroxypropyl) -2-thiophene carboxamide

MS (ESI): m / z (%) = 414 (M + H, 100);

HPLC (method 4): rt = 2.49 minutes.

Example 84.

5-Chloro-N- (3 - {[3-chloro-4- (2-oxo-1-pyrrolidinyl) -phenyl] -amino} -2-hydroxypropyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 428 (M + H, 100);

HPLC (method 4): rt = 5.39 minutes.

Example 85.

5-Chloro-N- (3 - {[3,5-dimethyl-4- (3-oxo-4-morpholinyl) -phenyl] -amino} -2-hydroxypropyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 438 (M + H, 100);

HPLC (method 4): rt = 2.84 minutes.

Example 86.

N- (3 - {[3- (aminocarbonyl) -4- (4-morpholinyl) -phenyl] -amino} -2-hydroxypropyl) -5-chloro-2-thiophenecarboxamide

MS (ESI): m / z (%) = 439 (M + H, 100);

HPLC (method 4): rt = 2.32 minutes.

PL 201 121 B1

Example 87.

5-Chloro-N- (2-hydroxy-3 - {[3-methoxy-4- (4-morpholinyl) -phenyl] -amino} -propyl) -2-thiophene carboxamide

MS (ESI): m / z {%) = 426 (M + H, 100);

HPLC (method 4): rt = 2.32 minutes.

Example 88.

N- (3 - {[3-Acetyl-4- (4-morpholinyl) -phenyl] -amino} -2-hydroxypropyl) -5-chloro-2-thiophene carboxamide

MS (ESI): m / z (%) = 438 (M + H, 100);

HPLC (method 4): rt = 2.46 minutes.

Example 89.

N- (3 - {[3-Amino-4- (3-oxo-4-morpholinyl) -phenyl] -amino} -2-hydroxypropyl) -5-chloro-2-thiophenecarboxamide

MS (ESI): m / z (%) = 425 (M + H, 100);

HPLC (method 4): rt = 2.45 minutes.

Example 90.

5-Chloro-N- (3 - {[3-chloro-4- (2-methyl-3-oxo-4-morpholinyl) -phenyl] -amino} -2-hydroxypropyl) -2-thiophenecarboxamide MS (ESI): m / z (%) = 458 (M + H, 100);

HPLC (method 4): rt = 3.44 minutes.

Example 91.

5-Chloro-N- (3 - {[3-chloro-4- (2-methyl-5-oxo-4-morpholinyl) -phenyl] -amino} -2-hydroxypropyl) -2-thiophenecarboxamide MS (ESI): m / z (%) = 458 (M + H, 100);

HPLC (method 4): rt = 3.48 minutes.

Example 91a.

5-Chloro-N- [2-hydroxy-2 - ({4 - [(3-oxo-4-morpholinyl) -methyl] -phenyl} -amino) -propyl] -2-thiophenecarboxamide

This compound is prepared starting from 4- (4-aminobenzyl) -3-morpholinone (Surrey et al; J.Amer.Chem. Soc., 77, 1955, 633):

MS (ESI): m / z (%) = 424 (M + H, 100);

HPLC (method 4): rt = 2.66 minutes.

General method for the preparation of 3-substituted 5-chloro-N - [(2-oxo-1,3-oxazolidin-5-yl) methyl] -2-thiophenecarboxamide derivatives starting from substituted N- (3-amino-2-hydroxypropyl derivatives) ) -5-chloro-2-thiophenecarboxamide

<img file="PL201121B1_D0036.tif" />

To a solution of the substituted N- (3-amino-2-hydroxypropyl) -5-chloro-2-thiophenecarboxamide derivative (1.0 eq.) In absolute THF (about 0.1 mol / l) carbodiimidazole (1 2-1.8 eq.) Or a comparable phosgene equivalent. The mixture is stirred at room temperature or, if appropriate, at elevated temperature (up to 70 ° C) for 2-18 hours and then evaporated down i. Vac. The product can be purified by chromatography on silica gel (dichloromethane-methanol mixtures or cyclohexane-ethyl acetate mixtures).

The following is produced in an analogous way:

Example 27.

N - [(3-Benzyl-2-oxo-1,3-oxazolidin-5-yl) -methyl] -5-chloro-2-thiophenecarboxamide MS (DCI, NH4): m / z (%) = 372 (M + Na, 100), 351 (M + H, 45);

HPLC (method 1): rt (%) 4.33 minutes (100).

Example 28.

5-Chloro-N - {[3- (3-cyanophenyl) -2-oxo-1,3-oxazolidin-5-yl] -methyl} -2-thiophenecarboxamide

PL 201 121 B1

MS (DCI, NH 4): m / z (%) = 362 (M + H, 42), 145 (100);

HPLC (method 2): rt (%) 4.13 minutes (100).

Example 29.

5-Chloro-N - ({3- [4- (cyanomethyl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 376 (M + H, 100);

HPLC (method 4): rt (%) 4.12 minutes.

Example 30.

5-Chloro-N - ({3- [3- (cyanomethyl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 376 (M + H, 100);

HPLC (method 4): rt (%) 4.17 minutes.

Example 92.

T-Butyl 4- [5 - ({[(5-chloro-2-thienyl) carbonyl] amino} methyl) -2-oxo-1,3-oxazolidin-3-yl] -benzyl carbamate is prepared starting from from Example 58.

MS (ESI): m / z (%) = 488 (M + Na, 23), 349 (100);

HPLC (method 1): rt (%) 4.51 (98.5).

Example 93.

T-Butyl 4- [5 - ({[(5-chloro-2-thienyl) carbonyl] amino} methyl) -2-oxo-1,3-oxazolidin-3-yl] phenylcarbamate is obtained starting from from example 59.

MS (ESI): m / z (%) = 493 (M + Na, 70), 452 (M + H, 10), 395 (100);

HPLC (method 1): rt (%) 4.41 (100).

Example 94.

T-Butyl 2-Oxo-3- [4- (2-oxo-1-pyrrolidinyl) -phenyl] -1,3-oxazolidin-5-yl] -methylcarbamate is prepared starting from Example 60.

MS (DCI, NH 3): m / z (%) = 393 (M + NH 4, 100);

HPLC (method 3): rt (%) 3.97 (100).

Example 96.

5-Chloro-N - [(2-oxo-3-phenyl-1,3-oxazolidin-5-yl) methyl] -2-thiophenecarboxamide is prepared starting from Example 62.

MS (ESI): m / z (%) = 359 ([M + Na]⁺, 71), 337 ([M + H]⁺, 100), standard Cl;

HPLC (method 3): rt (%) = 4.39 (100)

IC50- 2 µM.

Example 98.

N - [(3- {4- [Acetyl- (cyclopropyl) amino] -phenyl} -2-oxo-1,3-oxazolidin-5-yl) -methyl] -5-chloro-2-thiophenecarboxamide is prepared starting from from example 64.

MS (ESI): m / z (%) = 456 ([M + Na]⁺55), 434 ([M + H]⁺, 100), standard Cl;

HPLC (method 3): rt (%) = 4.05 (100)

IC₅₀: 50 nM.

Example 99.

N - [(3- {4- [Acetyl- (methyl) -amino] -phenyl} -2-oxo-1,3-oxazolidin-5-yl) -methyl] -5-chloro-2-thiophenecarboxamide

MS (ESI): m / z (%) = 408 (M + H, 30), 449 (M + H + MeCN, 100);

HPLC (method 4): rt = 3.66 minutes. Example 100.

5-Chloro-N - ({2-oxo-3- [4- (1H-1,2,3-triazol-1-yl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) - 2-thiophenecarboxamide

MS (ESI): m / z (%) = 404 (M + H, 45), 445 (M + H + MeCN, 100);

HPLC (method 4): rt = 3.77 minutes.

Example 101.

1- {4- [5 - ({[(5-chloro-2-thienyl) carbonyl] amino} methyl) -2-oxo-1,3-oxazolidin-3-yl] -phenyl t-butyl ester } -L-proline

MS (ESI): m / z (%) = 450 (M + H-56.25), 506 (M + H, 100);

HPLC (method 4): rt = 5.13 minutes.

PL 201 121 B1

Example 102.

1- {4- [5 - ({[(5-Chloro-2-thienyl) -carbonyl] -amino} -methyl) -2-oxo-1,3-oxazolidin-3-yl] -phenyl} -4- piperidinecarboxamide

MS (ESI): m / z (%) = 463 (M + H, 100);

HPLC (method 4): rt = 2.51 minutes.

Example 103.

1- {4- [5 - ({[(5-Chloro-2-thienyl) -carbonyl] -amino} -methyl) -2-oxo-1,3-oxazolidin-3-yl] -phenyl} -3- piperidinecarboxamide

MS (ESI): m / z (%) = 463 (M + H, 100);

HPLC (method 4): rt = 2.67 minutes.

Example 104.

5-Chloro-N - ({2-oxo-3- [4- (4-oxo-1-piperidinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 434 (M + H, 40), 452 (M + H + H2), 100), 475 (M + H + MeCN, 60);

HPLC (method 4): rt = 3.44 minutes.

Example 105.

1- {4- [5 - ({[(5-Chloro-2-thienyl) -carbonyl] -amino} -methyl) -2-oxo-1,3-oxazolidin-3-yl] -phenyl} -L- prolinamide

MS (ESI): m / z (%) = 449 (M + H, 100);

HPLC (method 4): rt = 3.54 minutes.

Example 106.

5-Chloro-N - [(3- {4- [3- (hydroxymethyl) -1-piperidinyl] -phenyl} -2-oxo-1,3-oxazolidin-5-yl) methyl] -2-thiophenecarboxamide

MS (ESI): m / z (%) = 450 (M + H, 100);

HPLC (method 5): rt = 2.53 minutes.

Example 107.

5-Chloro-N - [(3- {4- [2- (hydroxymethyl) -1-piperidinyl] -phenyl} -2-oxo-1,3-oxazolidin-5-yl) methyl] -2-thiophenecarboxamide

MS (ESI): m / z (%) = 450 (M + H, 100);

HPLC (method 5): rt = 2.32 minutes.

Example 108.

1- {4- [5 - ({[(5-chloro-2-thienyl) -carbonyl] -amino} -methyl) -2-oxo-1,3-oxazolidin-3-yl] -phenyl} acid ethyl ester -2-piperidinecarboxylic MS (ESI): m / z (%) = 492 (M + H, 100);

HPLC (method 5): rt = 4.35 minutes.

Example 109.

5-Chloro-N - [(3- {4- [2- (hydroxymethyl) -1-pyrrolidinyl] -phenyl} -2-oxo-1,3-oxazolidin-5-yl) methyl] -2-thiophenecarboxamide

MS (ESI): m / z (%) = 436 (M + H, 100);

HPLC (method 4): rt = 2.98 minutes.

Example 110.

5-Chloro-N - ({2-oxo-3- [4- (1-pyrrolidinyl] -3- (trifluoromethyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 474 (M + H, 100);

HPLC (method 4): rt = 4.63 minutes.

Example 111.

5-Chloro-N - ({3- [4- (2-methylhexahydro-5H-pyrrolo [3,4-d] isoxazol-5-yl) -phenyl] -2-oxo-1,3-oxazolidin-5- yl} -methyl) -2-thiophenecarboxamide MS (ESI): m / z (%) = 463 (M + H, 100);

HPLC (method 4): rt = 2.56 minutes.

Example 117.

5-Chloro-N - ({3- [3-chloro-4- (1-pyrrolidinyl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 440 (M + H, 100);

HPLC (method 4): rt = 3.72 minutes.

PL 201 121 B1

Example 120.

N - ({3- [3- (Aminocarbonyl) -4- (4-morpholinyl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} methyl) -5-chloro-2-thiophenecarboxamide

MS (ESI): m / z (%) = 465 (M + H, 100);

HPLC (method 4): rt = 3.07 minutes.

Example 121.

5-Chloro-N - ({3- [3-methoxy-4- (4-morpholinyl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide MS (ESI ): m / z (%) = 452 (M + H, 100);

HPLC (method 4): rt = 2.86 minutes.

Example 122.

N - ({3- [3-Acetyl-4- (4-morpholinyl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -5-chloro-2-thiophenecarboxamide MS (ESI ): m / z (%) = 464 (M + H, 100);

HPLC (method 4): rt = 3.52 minutes.

Example 124.

5-Chloro-N - ({3- [3-chloro-4- (2-methyl-3-oxo-4-morpholinyl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl ) -2-thiophenecarboxamide MS (ESI): m / z (%) = 484 (M + H, 100);

HPLC (method 4): rt = 3.59 minutes.

Example 125.

5-Chloro-N - ({3- [3-chloro-4- (2-methyl-5-oxo-4-morpholinyl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl ) -2-thiophenecarboxamide MS (ESI): m / z (%) = 484 (M + H, 100);

HPLC (method 4): rt = 3.63 minutes.

Example 125a.

5-Chloro-N - [(2-oxo-3- {4 - [(3-oxo-4-morpholinyl) -methyl] -phenyl} -1,3-oxazolidin-5-yl) -methyl] -2- thiophenecarboxamide MS (ESI): m / z (%) = 450 (M + H, 100);

HPLC (method 4): rt = 3.25 minutes.

The following compounds are also prepared by opening the epoxy bond with an amine and then cyclizing to the corresponding oxazolidinone:

<td>Example no</td><td>Building</td><td>Tt [° C]</td><td>IC50 [μΝΙ]</td>

<td> 126</td><td>Ύ-</td><td>229 schedule</td><td> 0,013</td>

<td> 131</td><td></td><td> 195</td><td> 0,85</td>

<td> 132</td><td>Αρ</td><td> 206</td><td> 0,12</td>

<td> 133</td><td></td><td> 217</td><td> 0,062</td>

To be continued

<td> 134</td><td>from 1- (4-Amino-phenyl) -piperidin-3-ol (Tong, LKJ et al .; J.Amer.Chem. Soc 1960; 82.1988)</td><td> 207</td><td> 0,48</td>

<td> 135</td><td></td><td> 202</td><td> 1,1</td>

<td> 136</td><td>oAo</td><td> 239</td><td> 1,2</td>

<td> 137</td><td>f £ f 0S&gt;</td><td> 219</td><td> 0,044</td>

<td> 138</td><td>'' · Ο ^._Λ,</td><td> 95</td><td> 0,42</td>

<td> 139</td><td></td><td> 217</td><td> 1,7</td>

The following examples 14-16 are examples of optional embodiment, i.e., oxidation step that may be present.

Example 14.

5-Chloro-N - ({(5S) -3- [3-fluoro-4- (1-oxo-1 [lambda]⁴, 4-thiazinan-4-yl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide

PL 201 121 B1

<img file="PL201121B1_D0037.tif" />

5-Chloro-N - ({(5S) -3- [3-fluoro-4- (1,4-thiazinan-4-yl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide (0.1 g, 0.22 mmol) from Example 3 in methanol (0.77 ml) was introduced at 0 ° C to a solution of sodium periodate (0.05 g, 0.23 mmol) ) in water (0.54 ml) and stirred for 3 hours at 0 ° C. Then 1 ml of DMF is added and the mixture is stirred for 8 hours at room temperature. After addition of a further 50 mg of sodium periodate, the mixture was stirred again overnight at room temperature. Then 50 ml of water are added to the mixture and the insoluble product is filtered off with suction. After washing with water and drying, 60 mg (58% of theory) of crystals are obtained.

Melting point: 257 ° C;

Rf (silica gel, toluene / ethyl acetate 1: 1) = 0.54 (educt = 0.46);

IC value₅₀ = 1.1 μΜ;

MS (DCI) 489 (M + NH 4), pattern Cl.

Example 15.

Preparation of 5-chloro-N - ({(5S) -3- [4- (1,1-dioxo-1 [lambda])⁶, 4-thiazinan-4-yl) -3-fluorophenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide

<img file="PL201121B1_D0038.tif" />

Do 5-chloro-N - ({(5S) -3- [3-fluoro-4- (1,4-thiazinan-4-yl) -phenyl] -2-oxo-1,3-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 are added 80 mg (0.66 mmol) of N-N-oxide. methylmorpholine (NMO) and 0.1 ml of a 2.5% solution of osmium tetroxide in 2-methyl-2-propanol. The mixture is stirred overnight at room temperature and 40 mg NMO are added again. After stirring overnight, the mixture is poured into 50 ml of water and extracted three times with ethyl acetate. The organic phase after drying and evaporation yields 23 mg, and from the aqueous phase after suction of the insoluble precipitate 19 mg (39% of theory in total) of the target compound.

Melting point: 238 ° C;

R f (toluene / ethyl acetate 1: 1) = 0.14 (educt = 0.46);

IC50 value = 210 nM;

MS (DCI): 505 (M + NH 4), pattern Cl.

Example 16.

5-chloro-N - {[(5S) -3- (3-fluoro-4-morpholinophenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl} -2-thiophenecarboxamide N-oxide is obtained by treating 5-chloro-N - {[(5S) -3- (3-fluoro-4-morpholinophenyl) -2-oxo-1,3-oxazolidin-5-yl] -methyl} -2-thiophenecarboxamide from Example 1 magnesium salt of monoperoxy phthalic acid.

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

PL 201 121 B1

The following Examples 31 to 35 and 140 to 147 relate to an optional, i.e. optionally applicable, amidination step.

General method for the preparation of amidines and amidine derivatives starting from 5-chloro-N - [(2-oxo-1,3-oxazolidin-5-yl) -methyl] -2-thiophenecarboxamide substituted with a cyanomethylphenyl group

Each 5-chloro-N - [(2-oxo-1,3-oxazolidin-5-yl) -methyl] -2-thiophenecarboxamide derivative substituted with cyanomethylphenyl group (1.0 eq.) Along with triethylamine (8.0 eq.) Was mixed for 1-2 days at room temperature in a saturated solution of hydrogen sulfide in pyridine (about 0.05-0.1 mol / liter). The reaction mixture was diluted with ethyl acetate (EtOAc) and washed with 2N hydrochloric acid. The organic phase is dried over MgSO4, filtered and concentrated in vacuo.

The crude product was dissolved in acetone (0.01-0.1 mol / L) and methyl iodide (40 eq.) Was added. The reaction mixture was stirred for 2-5 hours at room temperature (RT) and then concentrated in vacuo.

The residue is dissolved in methanol (0.01-0.1 mol / L) and treated with ammonium acetate (3 eq.) And ammonium chloride (2 eq.) To obtain unsubstituted amidine. To obtain the substituted amidine derivatives, primary or secondary amines (1.5 eq.) And acetic acid (2 eq.) Are added to the methanolic solution. After 5-30 hours the solvent is removed in vacuo and the residue is purified by chromatography on an RP8 silica gel column (water / acetonitrile 9 / 1-1 / 1 + 0.1% trifluoroacetic acid).

The following is produced in an analogous way:

Example 31.

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

MS (ESI): m / z (%) = 393 (M + H, 100);

HPLC (method 4): rt = 2.63 minutes.

Example 32.

5-Chloro-N - ({3- [3- (4,5-dihydro-1H-imidazol-2-ylmethyl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) - 2-thiophenecarboxamide

MS (ESI): m / z (%) = 419 (M + H, 100);

HPLC (method 4): rt = 2.61 minutes.

Example 33.

5-Chloro-N - [(3- {3- [2-imino-2- (4-morpholinyl) -ethyl] -phenyl} -2-oxo-1,3-oxazolidin-5-yl) -methyl] - 2-thiophenecarboxamide

MS (ESI): m / z (%) = 463 (M + H, 100);

HPLC (method 4): rt = 2.70 minutes.

Example 34.

5-Chloro-N - [(3- {3- [2-imino-2- (1-pyrrolidinyl) -ethyl] -phenyl} -2-oxo-1,3-oxazolidin-5-yl) -methyl] - 2-thiophenecarboxamide

MS (ESI): m / z (%) = 447 (M + H, 100);

HPLC (method 4): rt = 2.82 minutes.

Example 35.

N - ({3- [3- (2-Amino-2-iminoethyl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -5-chloro-2-thiophenecarboxamide

MS (ESI): m / z (%) = 393 (M + H, 100);

HPLC (method 4): rt = 2.60 minutes.

Example 140.

5-Chloro-N - ({3- [4- (4,5-dihydro-1H-imidazol-2-ylmethyl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) - 2-thiophenecarboxamide

MS (ESI): m / z (%) = 419 (M + H, 100);

HPLC (method 4): rt = 2.65 minutes.

Example 141.

5-Chloro-N - [(3- {4- [2-imino-2- (4-morpholinyl) -ethyl] -phenyl} -2-oxo-1,3-oxazolidin-5-yl) -methyl] - 2-thiophenecarboxamide

MS (ESI): m / z (%) = 463 (M + H, 100);

HPLC (method 4): rt = 2.65 minutes.

PL 201 121 B1

Example 142.

5-Chloro-N - [(3- {4- [2-imino-2- (1-piperidinyl) ethyl] phenyl} -2-oxo-1,3-oxazolidin-5-yl) methyl] - 2-thiophenecarboxamide

MS (ESI): m / z (%) = 461 (M + H, 100);

HPLC (method 4): rt = 2.83 minutes.

Example 143.

5-Chloro-N - [(3- {4- [2-imino-2- (1-pyrrolidinyl) -ethyl] -phenyl} -2-oxo-1,3-oxazolidin-5-yl) -methyl] - 2-thiophenecarboxamide

MS (ESI): m / z (%) = 447 (M + H, 100);

HPLC (method 4): rt = 2.76 minutes.

Example 144.

5-Chloro-N - [(3- {4- [2- (cyclopentylamino) -2-iminoethyl] -phenyl} -2-oxo-1,3-oxazolidin-5-yl) methyl] -2-thiophenecarboxamide

MS (ESI): m / z (%) = 461 (M + H, 100);

HPLC (method 4): rt = 2.89 minutes.

Example 145.

5-Chloro-N - {[3- (4- {2-imino-2 - [(2,2,2-trifluoroethyl) -amino] -ethyl} -phenyl) -2-oxo-1,3-oxazolidin5- yl] methyl} -2-thiophenecarboxamide

MS (ESI): m / z (%) = 475 (M + H, 100);

HPLC (method 4): rt = 2.79 minutes.

Example 146.

N - ({3- [4- (2-Anilino-2-iminoethyl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -5-chloro-2-thiophenecarboxamide

MS (ESI): m / z (%) = 469 (M + H, 100);

HPLC (method 4): rt = 2.83 minutes.

Example 147.

5-Chloro-N - [(3- {4- [2-imino-2- (2-pyridinylamino) -ethyl] -phenyl} -2-oxo-1,3-oxazolidin-5-yl) methyl] -2 -thiophenecarboxamide

MS (ESI): m / z (%) = 470 (M + H, 100);

HPLC (method 4): rt = 2.84 minutes.

The following Examples 148-151 relate to the cleavage of the BOC amino protecting groups:

General method for cleaving Boc (t-butyloxycarbonyl) protecting groups:

<img file="PL201121B1_D0039.tif" />

R ~ N Ό Η

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

The corresponding Boc-protected compounds are prepared in an analogous manner:

Example 148.

N - ({3- [4- (Aminomethyl) phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -5-chloro-2-thiophenecarboxamide is prepared starting from Example 92.

MS (ESI): m / z (%) = 349 (M-NH 2, 25), 305 (100);

HPLC (method 1): rt (%) = 3.68 (98).

IC50- 2.2 μΜ

Example 149.

N - {[3- (4-Aminophenyl) -2-oxo-1,3-oxazolidin-5-yl] -methyl} -5-chloro-2-thiophenecarboxamide is prepared starting from Example 93.

PL 201 121 B1

MS (ESI): m / z (%) = 352 (M + H, 25);

HPLC (method 1): rt (%) = 3.50 (100).

IC50: 2 µM

An enantiomerically pure alternative synthesis of these compounds is shown in the following scheme (see also Delalande SA, DE 2836305, 1979; Chem. Abstr. 90, 186926):

<img file="PL201121B1_D0040.tif" />

Example 150.

5-Chloro-N - ({3- [4- (glycylamino) phenyl] -2-oxo-1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide is prepared starting from Example 152.

MS (ES positive): m / z (%) = 408 (100);

HPLC (method 3): rt (%) = 3.56 (97);

IC50: 2 µM

Example 151.

5- (Aminomethyl) -3- [4- (2-oxo-1-pyrrolidinyl) -phenyl] -1,3-oxazolidin-2-one was prepared starting from Example 60.

MS (ESI): m / z (%) = 276 (M + H, 100);

HPLC (method 3): rt (%) = 2.99 (100);

IC50: 2 µM

The following examples 152-161 and 163-166 relate to the derivatization of the amine groups of anilino- or benzylamino-substituted oxazolidinones with various reagents:

Example 152.

5-Chloro-N - ({3- [4- (Nt-butyloxycarbonylglycylamino) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide

<img file="PL201121B1_D0041.tif" />

For a solution of 751 mg (4.3 mmol) Boc-glycine, 870 mg (6.4 mmol) HOBT (1-hydroxy-1H-benzotriazole x H2O), 1790 mg (4.7 mmol) HBTU [hexafluorophosphate O- (benzotriazole) -1-yl) -N, N, N ', N'-tetramethyluronium] and 1.41 ml (12.9 mmol) of N-methylmorpholine in 15 ml of DMF / CH2Cl2 (1: 1) are introduced at 0 ° C 754 mg (2.1 mmol) N - {[3- (4-aminophenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl} -5-chloro-2-thiophenecarboxamide (from example 149) . The mixture is stirred for

Overnight at room temperature, then diluted with water. The precipitated solid is filtered off and dried.

Yield: 894 mg (79.7% of theory).

MS (DCI, NH 3): m / z (%) = 526 (M + NH 4, 100);

HPLC (method 3): rt (%) = 4.17 (97).

Example 153.

N - [(3- {4 - [(Acetylamino) methyl] phenyl} -2-oxo-1,3-oxazolidin-5-yl) methyl] -5-chloro-2-thiophenecarboxamide

<img file="PL201121B1_D0042.tif" />

To a mixture of 30 mg (0.082 mmol) of N - ({3- [4- (aminomethyl) phenyl] -2-oxo-1,3-oxazolidin-5-yl} methyl) -5-chloro-2-thiophenecarboxamide ( from Example 148) in 1.5 mL absolute THF, 1.0 mL absolute dichloromethane and 0.02 mL absolute pyridine were added at 0 ° C acetic anhydride (0.015 mL, 0.164 mmol). The mixture was stirred overnight at room temperature. The product is obtained after adding ether and crystallization. Yield: 30 mg (87% of theory).

MS (ESI): m / z (%) = 408 (M + H, 18), 305 (85);

HPLC (method 1): rt (%) = 3.78 (97);

IC50: 0.6 μΜ

Example 154.

N - {[3- (4 - {[(Aminocarbonyl) amino] methyl} phenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl} -5-chloro-2-thiophenecarboxamide

<img file="PL201121B1_D0043.tif" />

To a mixture of 30 mg (0.082 mmol) of N - ({3- [4- (aminomethyl) phenyl] -2-oxo-1,3-oxazolidin-5-yl} methyl) -5-chloro-2-thiophenecarboxamide ( from Example 148) in 1.0 ml of dichloromethane, 0.19 ml (0.82 mmol) of trimethylsilyl isocyanate is added dropwise at room temperature. After the mixture was stirred overnight, ether was added and the product was filtered off.

Yield: 21.1 mg (52% of theory).

MS (ESI): m / z (%) = 409 (M + H, 5), 305 (72);

HPLC (method 1): rt (%) = 3.67 (83);

IC50: 1.3 μΜ

General method of acylating N - {[3- (4-aminophenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl} -5-chloro-2-thiophenecarboxamide with carboxylic acid chlorides:

<img file="PL201121B1_D0044.tif" />

PL 201 121 B1

An approximately 0.1 molar solution of N - {[3- (4-aminophenyl) -2-oxo-1,3-oxazolidin-5-yl] -methyl is added dropwise to the appropriate acid chloride (2.5 eq) under argon. } -5-chloro-2-thiophenecarboxamide (from Example 149) (1.0 eq.) In absolute dichloromethane / pyridine (19: 1). The mixture is stirred overnight then about 5 equivalents of PS-Tris-amine (Argonaut Technologies) and 2 ml of absolute dichloromethane are added. After gently stirring for 1 hour, it was filtered, and the filtrate was concentrated. Optionally, the products are purified by preparative RP-HPLC.

The following is produced in an analogous way:

Example 155.

N - ({3- [4- (Acetylamino) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -5-chloro-2-thiophenecarboxamide

LC-MS: m / z (%) = 394 (M + H, 100);

LC-MS (method 6): rt (%) = 3.25 (100);

IC50: 1.2 μΜ

Example 156.

5-Chloro-N - [(2-oxo-3- {4 - [(2-thienylcarbonyl) -amino] -phenyl} -1,3-oxazolidin-5-yl) -methyl] -2-thiophenecarboxamide

LC-MS: m / z (%) = 462 (M + H, 100);

LC-MS (method 6): rt (%) = 3.87 (100);

IC50: 1.3 µM

Example 157.

5-Chloro-N - [(3- {4 - [(methoxyacetyl) amino] phenyl} -2-oxo-1,3-oxazolidin-5-yl) methyl] -2-thiophenecarboxamide LC-MS: m / z (%) = 424 (M + H, 100);

LC-MS (method 6): rt (%) = 3.39 (100);

IC50: 0.73 µM

Example 158.

N- {4- [5 - ({[(5-Chloro-2-thienyl) -carbonyl] -amino} -methyl) -2-oxo-1,3-oxazolidin-3-yl] -phenyl} -3, 5-dimethyl-4-isoxazole carboxamide LC-MS: m / z (%) = 475 (M + H, 100);

IC50: 0.46 µM

Example 159.

5-Chloro-N - {[3- (4 - {[(3-chloropropyl) sulfonyl] -amino} -phenyl) -2-oxo-1,3-oxazolidin-5-yl] -methyl} -2- thiophenecarboxamide

<img file="PL201121B1_D0045.tif" />

To an ice-cooled solution of 26.4 mg (0.15 mmol) of 3-chloro-1-propanesulfonic acid chloride and 0.03 ml (0.2 mmol) of triethylamine in 3.5 ml of absolute dichloromethane, 35 mg (0.1 mmol) N - {[3- (4-aminophenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl} -5-chloro-2-thiophenecarboxamide (from example 149). After 30 minutes, ice cooling is removed and the mixture is stirred overnight at room temperature, then 150 mg (about 5.5 eq.) Of PS-Trisamine (Argonaut Technologies) and 0.5 ml of dichloromethane are added. The suspension was stirred gently for 2 hours, filtered (the resin was washed with dichloromethane / methanol) and the filtrate was concentrated. The product was purified by preparative RP-HPLC. Yield: 19.6 mg (40% of theory).

LC-MS: m / z (%) = 492 (M + H, 100);

LC-MS (method 5): rt (%) = 3.82 (91);

IC50: 1.7 µM

Example 160.

5-Chloro-N - ({3- [4- (1,1-dioxygen-2-isothiazolidinyl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide

PL 201 121 B1

<img file="PL201121B1_D0046.tif" />

A mixture of 13.5 mg (0.027 mmol) 5-chloro-N - {[3- (4 - {[(3-chloropropyl) sulfonyl] -amino} -phenyl) -2-oxo-1,3-oxazolidin-5 -yl] -methyl} -2-thiophenecarboxamide (from Example 159) and 7.6 mg (0.055 mmol) of potassium carbonate in 0.2 ml of DMF are heated to 100 ° C. for 2 hours. After cooling, it 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 (M + H, 15), 412 (100);

LC-MS (method 4): rt (%) = 3.81 (90);

IC50: 0.14 μΜ

Example 161.

5-Chloro-N - [((5S) -3- {4 - [(5-chloropentanoyl) -amino] -phenyl} -2-oxo-1,3-oxazolidin-5-yl) methyl] -2-thiophenecarboxamide

<img file="PL201121B1_D0047.tif" />

0.5 g (1.29 mmol) N - {[(5S) -3- (4-aminophenyl) -2-oxo-1,3-oxazolidin-5-yl] -methyl} -5-chloro-2- The thiophenecarboxamide (from Example 149) was dissolved in 27 ml of tetrahydrofuran and 0.2 g (1.29 mmol) of 5-chlorovaleric acid chloride and 0.395 ml (2.83 mmol) of triethylamine were added. The mixture is evaporated in vacuo and chromatographed on silica gel using gradients toluene / ethyl acetate 1: 1 / ethyl acetate. 315 mg (52% of theory) of solid are obtained.

Melting point 211 ° C.

Example 163.

5-Chloro-N - [((5S) -3- {4 - [(3-bromopropionyl) -amino] -phenyl} -2-oxo-1,3-oxazolidin-5-yl) methyl] -2-thiophenecarboxamide

<img file="PL201121B1_D0048.tif" />

prepared analogously from Example 149.

Example 164.

5-Chloro-N - ({(5S) -2-oxo-3- [4- (2-oxo-1-azetidinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) -2- thiophenecarboxamide

<img file="PL201121B1_D0049.tif" />

prepared analogously by cyclization of the open chain bromopropionyl compound of Example 163 with NaH / DMSO.

MS (ESI): m / z (%) = 406 ([M + H] +, 100), pattern Cl;

IC50: 380 nM

PL 201 121 B1

Example 165.

4- {4- [5 - ({[(5-chloro-2-thienyl) -carbonyl] -amino} -methyl) -2-oxo-1,3-oxazolidin-3-yl] - acid t-butyl ester phenyl} -3,5-dioxo-1-piperazinecarboxylic acid

<img file="PL201121B1_D0050.tif" />

300 mg (2.2 mmol) of HOBT, 0.66 ml (6 mmol) of N-methylmorpholine and 647 mg (1.7 mmol) of HBTU are introduced into a solution of 199 mg (0.85 mmol) of Boc-iminodiacetic acid, 300 mg (2.2 mmol) of HOBT. (0.85 mmol) N - {[3- (4-aminophenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl} -5-chloro-2-thiophenecarboxamide in 6 ml of a mixture of DMF and dichloromethane (1: 1). After stirring overnight, the mixture was diluted with dichloromethane and washed with water, saturated ammonium chloride, saturated sodium bicarbonate, water, and saturated sodium chloride. The organic phase is dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (dichloromethane / methanol 98: 2). Yield: 134 mg (29% of theory).

MS (ESI): m / z (%) = 571 (M + Na, 82), 493 (100);

HPLC (method 3): rt (%) = 4.39 (90);

IC50: 2 µM

Example 166.

N - [((5S) -3- {4 - [(3R) -3-amino-2-oxo-1-pyrrolidinyl] -phenyl} -2-oxo-1,3-oxazolidin-5-yl) - trifluoroacetate trifluoroacetate methyl] -5-chloro-2-thiophenecarboxamide

<img file="PL201121B1_D0051.tif" />

N2- (t-Butoccarbonyl) -N1- {4 - [(5S) -5 - ({[(5-chloro-2-thienyl) carbonyl] amino} methyl) -2-oxo-1,3- oxazolidin-3-yl] -phenyl} -D-methioninamide

PL 201 121 B1

429 mg (1.72 mmol) N-BOC-D-methionine, 605 mg (1.72 mmol) N - {[(5S) -3- (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 DMF, 660 mg (3.441 mmol) of EDCI hydrochloride are added and then 689 mg ( 5.334 mmol) N-ethyl-diisopropylamine. The mixture was stirred for 2 days at room temperature. The resulting suspension is suction filtered and the residue is washed with DMF. The combined filtrates are treated with a little silica gel, evaporated in vacuo and chromatographed with a gradient of toluene&gt; T10EE7. 170 mg (17% of theory) of the target compound are obtained, m.p. 183 ° C.

Rf (SiO2, toluene / ethyl acetate 1: 1): 0.2 ¹H-NMR (300 MHz, d6-DMSO): δ = 1.4 (s, 1H, BOC), 1.88-1.95 (m, 2H), 2.08 (s, 3H, SMe), 2 , 4-2.5 (m, 2H, partially covered by DMSO), 3.6 (m, 2H), 3.8 (m, 1H), 4.15 (m, 2H), 4.8 (m, 1H), 7.2 (1H, thiophene), 7.42 (d, part of AB system, 2H), 7.6 (d, part of AB system, 2H), 7.7 (d, 1H, thiophene),

8.95 (t, 1H, CH₂NHCO), 9.93 (bs, 1H, NH).

(3R) -1- {4 - [(5S) -5 - ({[(5-chloro-2-thienyl) -carbonyl] -amino} -methyl) -2-oxo-1,3 acid t-butyl ester -oxazolidin-3-yl] -phenyl} -2-oxo-3-pyrrolidinylcarbamic

170 mg (0.292 mmol) N2- (t-butoxycarbonyl) -N1- {4 - [(5S) -5 - ({[(5-chloro-2-thienyl) carbonyl] amino} methyl) -2-oxo The -1,3-oxazolidin-3-yl] -phenyl} -D-methioninamide is dissolved in 2 ml of DMSO and 178.5 mg (0.875 mmol) of trimethylsulfonium iodide and 60.4 mg (0.437 mmol) of potassium carbonate are added and the mixture is stirred. for 3.5 hours at 80 ° C. Then it is evaporated down under high vacuum and the residue is washed with ethanol. 99 mg of the target compound are obtained.

¹H-NMR (300 MHz, d6-DMSO): δ = 1.4 (s, 1H, BOC), 1.88-2.05 (m, 1H), 2.3-2.4 (m, 1H) , 3.7-3.8 (m, 3H), 3.8-3.9 (m, 1H), 4.1-4.25 (m, 1H), 4.25-4.45 (m, 1H), 4.75-4.95 (m, 1H), 7.15 (1H, thiophene), 7.25 (d, 1H), 7.52 (d, part of AB system, 2H), 7.65 (d, AB system part, 2H), 7.65 (d, 1H, thiophene), 9.0 (broad s, 1H).

N - [((5S) -3- {4 - [(3R) -3-amino-2-oxo-1-pyrrolidinyl] -phenyl} -2-oxo-1,3-oxazolidin-5-yl) - trifluoroacetate trifluoroacetate methyl] -5-chloro-2-thiophenecarboxamide

97 mg (0.181 mmol) of (3R) -1- {4 - [(5S) -5 - ({[(5-chloro-2-thienyl) -carbonyl] -amino} -methyl) acid t-butyl ester are suspended. -2-oxo-1,3-oxazolidin-3-yl] -phenyl} -2-oxo-3-pyrrolidinylcarbamic in 4 ml of methylene chloride, 1.5 ml of trifluoroacetic acid are added and the mixture is stirred for 1 hour at room temperature . It is then evaporated in vacuo and purified by RP-HPLC (gradient acetonitrile / water / 0.1% TFA). After evaporation of the appropriate fraction, 29 mg (37% of theory) of the target compound are obtained, m.p. 241 ° C (decomposition).

Rf (SiO2, EtOH / TEA = 17: 1) 0.19 ¹H-NMR (300 MHz, d6-DMSO): δ = 1.92-2.2 (m, 1H), 2.4-2.55 (m, 1H, partially covered by DMSO peak), 3.55- 3.65 (m, 2H), 3.75-3.95 (m, 3H), 4.1-4.3 (m, 2H), 4.75-4.9 (m, 1H), 7. 2 (1H, thiophene), 7.58 (d, part of AB system, 2H), 7.7 (d, part of AB system, 2H), 7.68 (d, 1H, thiophene), 8.4 (broad s . 3H

NH3), 8.9 (t, 1H, NHCO).

The following examples 167 to 170 relate to the introduction of sulfonamide groups into phenyl substituted oxazolidinones.

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

<img file="PL201121B1_D0052.tif" />

PL 201 121 B1

5-Chloro-N - [(2-oxo-3-phenyl-1,3-oxazolidin-5-yl) methyl] -2-thiophenecarboxamide is added to chlorosulfonic acid (12 eq) under argon at 5 ° C (from example 96). The reaction mixture was stirred for 2 hours and then poured into ice water. The precipitated solid is filtered off, washed with water and dried.

The resulting product is then dissolved in tetrahydrofuran (0.1 mol / L) under argon at room temperature and the appropriate amine (3 eq.), Triethylamine (1.1 eq.) And dimethylaminopyridine (0.1 eq.) Are added. The reaction mixture was stirred for 1-2 hours then concentrated in vacuo. The desired product is purified by flash chromatography (dichloromethane-methanol mixtures).

The following is produced in an analogous way:

Example 167.

5-Chloro-N - ({2-oxo-3- [4- (1-pyrrolidinylsulfonyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 492 ([M + Na]⁺0.1 100), 470 ([M + H]⁺, 68) Cl pattern;

HPLC (method 3): rt (%) = 4.34 (100);

IC50: 0.5 µM

Example 168.

5-Chloro-N - [(3- {4 - [(4-methyl-1-piperazinyl) sulfonyl] -phenyl} -2-oxo-1,3-oxazolidin-5-yl) -methyl] -2- thiophenecarboxamide MS (ESI): m / z (%) = 499 ([M + H]⁺, 100) Cl standard;

HPLC (method 2): rt (%) = 3.3 (100).

Example 169.

5-Chloro-N - ({2-oxo-3- [4- (1-piperidinylsulfonyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 484 ([M + H]⁺, 100) Cl standard;

HPLC (method 2): rt (%) = 4.4 (100).

Example 170.

5-Chloro-N - [(3- {4 - [(4-hydroxy-1-piperidinyl) sulfonyl] phenyl} -2-oxo-1,3-oxazolidin-5-yl) methyl] -2- thiophenecarboxamide MS (ESI): m / z (%) = 500 ([M + H]⁺, 100) Cl standard;

HPLC (method 3): rt (%) = 3.9 (100).

Example 171.

5-Chloro-N - ({2-oxo-3- [4- (1-pyrrolidinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide

<img file="PL201121B1_D0053.tif" />

780 mg (1.54 mmol) 1- {4- [5 - ({[(5-chloro-2-thienyl) carbonyl] -amino} methyl) -2-oxo-1,3-oxazolidine t-butyl ester -3-yl] -phenyl} -proline is dissolved in 6 ml of dichloromethane and 9 ml of trifluoroacetic acid and the mixture is stirred for 2 days at 40 ° C. The reaction mixture was then concentrated and mixed with ether and 2N sodium hydroxide solution. The aqueous phase is concentrated and mixed with ether and 2N hydrochloric acid. The organic phase from this extraction is dried over MgSO4, filtered and concentrated. The crude product is chromatographed over silica gel (CH2Cl2 / EtOH / concentrated aqueous NH3 = 100/1 / 0.1 to 20/1 / 0.1).

280 mg (40% of theory) of product are obtained.

MS (ESI): m / z (%) = 406 (M + H, 100);

HPLC (method 4): rt (%) = 3.81 minutes.

PL 201 121 B1

HPLC parameters and LC-MS parameters given in the HPLC and LC-MS method examples above (retention time unit (rt) is minutes):

[1] column: Kromasil C18, LR temperature: 30 ° C, flow = 0.75 ml. Min^-1, eluent: A = 0.01 Μ HClO4, B = CH3CN, gradient: 0.5 min 98% A? 4.5 min 10% A? 6.5 min 10% A;

[2] column: Kromasil C18 60 * 2, LR temperature: 30 ° C, flow = 0.75 ml.min^-1, eluent: A = 0.01 M H3PO4, B = CH3CN, gradient: 0.5 min 90% A? 4.5 min 10% A? 6.5 min 10% A;

[3] column: Kromasil C18 60 * 2, LR temperature: 30 ° C, flow = 0.75 ml.min^-1, eluent: A = 0.005 M HClO4, B = CH3CN, gradient: 0.5 min 98% A? 4.5 min 10% A? 6.5 min 10% A;

[4] Column: Symmetry C18 2.1x150mm, column heating: 50 ° C, flow = 0.6ml.min^-1, eluent: A = 0.6 g 30% HCl / l water, B = CH3CN, gradient: 0.0 min 90% A 4.0 min 10% A?

10% A minimum;

[5] MHZ-2Q, Instrument Micromass Quattro

LCZ Symmetry C18 column, 50mm x 2.1mm, 3.5μm, temperature: 40 ° C, flow = 0.5ml. Min^-1, eluent A = CH3CN -1- 0.1% formic acid, eluent B = water + 0.1% formic acid, gradient: 0.0 min 10% A 4 mins 90% A? 6 min 90% A;

[6] MHZ-2P, Instrument Micromass Platform LCZ Symmetry C18 column, 50mm x 2.1mm, 3.5μ ^ ι, temperature: 40 ° C, flow = 0.5ml.min^- , eluent A = CH3CN + 0.1% formic acid, eluent B = water + 0.1% formic acid, gradient: 0.0 min 10% A 4 mins 90% A? 6 min 90% A;

[7] MHZ-7Q, Instrument Micromass Quattro LCZ Symmetry C18 column, 50mm x 2.1mm, 3.5μm, temperature: 40 ° C, flow = 0.5ml.min^-1, eluent A = CH3CN + 1% formic acid, eluent B = water + 0.1% formic acid, gradient: 0.0 min 5% A 1 min 5% A? 5 mins 90% A? 6 min 90% A;

General method for the preparation of oxazolidinones of general formula B by solid phase synthesis

Reactions with the various resin related products take place in one batch in separate reaction vessels.

5- (Bromomethyl) -3- (4-fluoro-3-nitrophenyl) -1,3-oxazolidin-2-one A (prepared from epibromohydrin and 4-fluoro-3-nitrophenyl isocyanate with LiBr / Bu3PO in xylene analogously to U.S. Patent 4,128,654, Example 2) (1.20g, 3.75mmol) and ethyldiisopropylamine (DIEA, 1.91ml, 4.13mmol) are dissolved in DMSO (70ml), a secondary amine (1 1 equivalents, amine component 1) and reacted for 5 hours at 55 ° C. To this solution was added TentaGel SAM resin (5.00 g, 0.25 mmol / g) and reacted for 48 hours at 75 ° C. The resin was filtered off and washed several times with methanol (MeOH), dimethylformamide (DMF), MeOH, dichloromethane (DCM) and diethyl ether and dried. The resin (5.00 g) is suspended in dichloromethane (80 ml), DIEA (10 eq.) And 5-chlorothiophene-2-carboxylic acid chloride [prepared by reacting 5-chlorothiophene-2-carboxylic acid (5 eq.) Are added and 1-chloro-1-dimethylamino-2-methylpropene (5 eq.) In DCM (20 ml) at room temperature for 15 minutes] and reacted for 5 hours at room temperature. The resulting resin was filtered off and washed several times with MeOH, DCM and diethyl ether and dried. The resin was then suspended in DMF / water (v / v 9: 2, 80 ml), SnCl2 * 2H2O (5 eq.) Was added and reacted for 18 hours at room temperature. The resin was washed several times with MeOH, DMF, water, MeOH, DCM and diethyl ether and dried. The resin is suspended in DCM, DIEA (10 eq.) Is added and at 0 ° C acid chloride (5 eq., Acid derivative 1) is added and reacted overnight at room temperature. The carboxylic acids before this process are converted into the corresponding acid chlorides by reaction with 1-dimethylamino-1-chloro-2-methylpropene (1 eq, with respect to the carboxylic acid) in DCM at room temperature for 15 minutes. The resin was washed again with DMF, water, DMF, MeOH, DCM and diethyl ether and dried. When using Fmoc-protected amino acids as acid derivative, the Fmoc protecting group in the last step is cleaved by reaction with piperidine / DMF (v / v, 1/4) at room temperature for 15 minutes and the resin is washed with DMF, MeOH, DCM and diethyl ether and dried. The products are then cleaved from the solid phase with trifluoroacetic acid (TFA) / DCM (v / v, 1/1), the resin is filtered off and the reaction solutions are evaporated. The crude products are filtered through silica gel (DCM / MeOH, 9: 1) and evaporated to give product batch B.

PL 201 121 B1

<img file="PL201121B1_D0054.tif" />

Compounds obtained by solid phase synthesis:

Example 172.

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

<img file="PL201121B1_D0055.tif" />

Analogously to the general preparation of derivative B, 5 g (1.25 mmol) of TentaGel SAM resin are reacted with pyrrolidine as the amine derivative 1. The aniline obtained after reduction with SnCl2 * 2H2O without further acylation step is separated from the solid phase and evaporated. The crude product is partitioned between ethyl acetate and NaHCO3 solution, the organic phase

The mixture is salted out with NaCl, decanted and evaporated to dryness. The crude product was purified by flash vacuum chromatography on silica gel (dichloromethane / ethyl acetate, 3: 1 - 1: 2).

¹H-NMR (300 MHz, CDCl 3): 1.95 - 2.08, br, 4H; 3.15-3.30, br, 4H; 3.65-3.81, m, 2H; 3.89, ddd,

1H; 4.05, dd, 1H; 4.81, dddd, 1H; 6.46, dd, 1H; 6.72, dd, 1H; 6.90, dd, 1H; 6.99, dd, 1H; 7.03, dd, 1H;

7.29, d, 1H.

Example 173.

N - [(3- {3- (e-Alanylamino) -4- [3-hydroxypropyl) -amino] -phenyl} -2-oxo-1,3-oxazolidin-5-yl) methyl] -5-chloro -2-thiophenecarboxamide

<img file="PL201121B1_D0056.tif" />

Analogously to the general preparation of derivative B, 5 g (1.25 mmol) of TentaGel SAM resin are reacted with azetidine as the amine derivative 1 and Fmoc-e-alanine as the acid derivative 1. The crude product obtained after cleavage is stirred for 48 hours at methanol at room temperature and evaporated to dryness. The crude product was purified by reverse phase HPLC using a water / TFA / acetonitrile gradient.

¹H-NMR (400 MHz, CD 3 OD): 2.31, tt, 2H; 3.36, t, 2H; 3.54, t, 2H; 3.62, t, 2H; 3.72, dd, 1H; 3.79, dd, 1H; 4.01, dd, 1H; 4.29, dd, 2H; 4.43, t, 2H; 4.85-4.95, m, 1H; 7.01, d, 1H; 4.48-7.55, m, 2H; 7.61, d, 1H; 7.84, d, 1H.

Example 174.

N - ({3- [4- (3-Amino-1-pyrrolidinyl) -3-nitrophenyl] -2-oxo-1,3-oxazolidin-5-yl} methyl) -5-chloro-2-thiophenecarboxamide

<img file="PL201121B1_D0057.tif" />

Analogously to the general preparation of derivative B, 130 mg (32.5 μmol) of TentaGel SAM resin are reacted with 3-pyrrolidinylcarbamic acid t-butyl ester as the amine derivative 1. The nitrobenzene derivative obtained after acylation is cleaved from the solid phase and evaporated. The crude product was purified by reverse phase HPLC using a water / TFA / acetonitrile gradient.

¹H-NMR (400 MHz, CD3OH): 2.07-2.17, m, 1H; 2.39-2.49, m, 1H; 3.21-3.40, m, 2H; 3.45, dd, 1H; 3.50-3.60, m, 1H; 3.67, dd, 1H; 3.76, dd, 1H; 3.88-4.00, m, 2H; 4.14-4.21, t, 1H; 4.85-4.95, m, 1H; 7.01, d, 1H; 7.11, d, 1H; 7.52, d, 1H; 7.66, dd, 1H; 7.93, d, 1H.

Example 175.

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

<img file="PL201121B1_D0058.tif" />

Analogously to the general method for the preparation of derivative B, 130 mg (32.5 μmol) of the TentaGel SAM resin are reacted with piperidine as the amine derivative 1. Aniline obtained after reduction

The solid phase is cleaved off without further acylation and evaporated. The crude product was purified by reverse phase HPLC using a water / TFA / acetonitrile gradient.

¹H-NMR (400 MHz, CD3OH): 1.65-1.75, m, 2H; 1.84-1.95, m, 4H; 3.20-3.28, m, 4H; 3.68, dd,

1H; 3.73, dd, 1H; 3.90, dd, 1H; 4.17, dd, 1H; 4.80-4.90, m, 1H; 7.00, d, 1H; 7.05, dd, 1H; 7.30-7.38, m,

2H; 7.50, d, 1H.

Example 176.

N - ({3- [3- (Acetylamino) -4- (1-pyrrolidinyl) -phenyl] -2-oxo-1,3-oxazolidin-5-yl} -methyl) -5-chloro-2-thiophenecarboxamide

<img file="PL201121B1_D0059.tif" />

Analogously to the general preparation of derivative B, 130 mg (32.5 mol) of TentaGel SAM resin are reacted with pyrrolidine as the amine derivative 1 and with acetyl chloride as the acid derivative 1. The crude product is partitioned between ethyl acetate and NaHCO3 solution, the organic phase is salted out. with NaCl, it is decanted and evaporated to dryness. The crude product was purified by silica gel flash chromatography (dichloromethane / ethyl acetate, 1: 1 - 0: 1).

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

The following compounds are also prepared analogously to the general procedure:

<td>Example</td><td>Building</td><td>Time retention</td><td>HPLC [%]</td>

<td> 177</td><td>N 0 0</td><td> 2,62</td><td> 79,7</td>

<td> 178</td><td>A, χ</td><td> 2,49</td><td> 33,7</td>

<td> 179</td><td>at 0 ^ 0 o- ^ 0</td><td> 4,63</td><td> 46,7</td>

<td> 180</td><td>«Ύ φ-Γ 0</td><td> 3,37</td><td> 44,8</td>

To be continued

<td> 181</td><td></td><td> 2,16</td><td> 83</td>

<td> 182</td><td>0 about</td><td> 2,31</td><td> 93,3</td>

<td> 183</td><td>0γ ° ° yo W ^ w p ^ α_α·</td><td> 2,7</td><td> 100</td>

<td> 184</td><td></td><td> 3,91</td><td> 51</td>

<td> 185</td><td>P? Rt</td><td> 2,72</td><td> 75,2</td>

<td> 186</td><td>p</td><td> 3,17</td><td> 46</td>

<td> 187</td><td></td><td> 4,61</td><td> 50,2</td>

<td> 188</td><td>_s&gt; Gf ° yO oO W ABOUT</td><td> 3,89</td><td> 56,6</td>

<td> 189</td><td>u-cfF "&lt;&lt;R ABOUT</td><td> 3,37</td><td> 52,9</td>

To be continued

<td> 190</td><td> 5</td><td> 3,6</td><td> 63,9</td>

<td> 191</td><td>Ο</td><td> 2,52</td><td> 70,1</td>

<td> 193</td><td>0 er Ζ</td><td> 2,87</td><td> 50,1</td>

<td> 194</td><td>% τ7Χ ° «Λ»</td><td> 3,25</td><td> 71,1</td>

<td> 195</td><td>_s Λγ ° γΛ α-0 Ρ Ν</td><td> 2,66</td><td> 67</td>

<td> 196</td><td>and ^ 0C cr ^ from ιτχ Ν</td><td> 2,4</td><td> 52,1</td>

<td> 197</td><td> ?</td><td> 3,13</td><td> 48,9</td>

To be continued

<td> 198</td><td>... zy Υ w</td><td> 2,67</td><td> 75,5</td>

<td> 199</td><td>aYL νο ς&gt; Ν</td><td> 2,72</td><td> 65,7</td>

<td> 200</td><td>&gt;. · ΖΎ “X _andjf W. 'ł</td><td> 2,71</td><td> 57,3</td>

<td> 201</td><td>X ΧχΧος 0</td><td> 2,22</td><td> 100</td>

<td> 202</td><td>uAAA Ο</td><td> 3,89</td><td> 75,7</td>

<td> 203</td><td>WAF ° rO «Λγ w ο</td><td> 3,19</td><td> 49,6</td>

<td> 204</td><td>Q z-fV ° J} ClXx N</td><td> 2,55</td><td> 88,2</td>

<td> 205</td><td>XCX uf er N</td><td> 2,44</td><td> 68,6</td>

To be continued

<td> 206</td><td>-t Q-^r</td><td> 2,86</td><td> 71,8</td>

<td> 207</td><td>k:</td><td> 2,8</td><td> 63,6</td>

<td> 208</td><td> „ 4 ^and~ t #^łrYvfS-N^/about -p = /</td><td> 2,41</td><td> 77</td>

<td> 209</td><td>o o = ^_N“^ ΏΤΌ-ΧΧ about</td><td> 2,56</td><td> 67,9</td>

<td> 210</td><td>about</td><td> 3,67</td><td> 78,4</td>

<td> 211</td><td>o ° kt ~ 0</td><td> 2,54</td><td> 69,8</td>

<td> 212</td><td>wOi °, V -</td><td> 3,84</td><td> 59,2</td>

<td> 213</td><td>7¾ ° N</td><td> 2,41</td><td> 67,8</td>

To be continued

<td> 214</td><td>yKCy</td><td> 2,41</td><td> 75,4</td>

<td> 215</td><td>ΑΎ Ο</td><td> 4,01</td><td> 81,3</td>

<td> 216</td><td>° Υ 'Υ&gt;</td><td> 3,46</td><td> 49,5</td>

<td> 217</td><td>CXf ° ° νο_γρ</td><td> 4,4</td><td> 60,2</td>

<td> 218</td><td>1 FY / PPo Ο</td><td> 3,79</td><td> 70,9</td>

<td> 219</td><td>ρ-? ° χ Ά ° α⁷^⁷ &gt;</td><td> 4,57</td><td> 51,5</td>

<td> 220</td><td>ΥΡί η Ν</td><td> 2,68</td><td> 100</td>

<td> 221</td><td>γΧΐΡΡ Α</td><td> 4,53</td><td> 63,5</td>

To be continued

<td> 222</td><td>ο ΑΑ °</td><td> 2,66</td><td> 89,2</td>

<td> 223</td><td>“-Ο W Ο</td><td> 4,76</td><td> 69,3</td>

<td> 224</td><td> 0</td><td> 3,45</td><td> 77,4</td>

<td> 225</td><td>"= 4 ^ AcYo Ο</td><td> 3,97</td><td> 63,2</td>

<td> 226</td><td>0 ΥΑ ° Μ KYJ &lt;λ&gt;</td><td> 3,94</td><td> 61,4</td>

<td> 227</td><td>Ύ</td><td> 4,15</td><td> 66,3</td>

<td> 228</td><td>νΎ ° Α = -ο w Ό</td><td> 4,41</td><td> 55,1</td>

<td> 229</td><td>.γ Α “ΎΑοΥΟ 0</td><td> 2,83</td><td> 41,1</td>

To be continued

<td> 230</td><td>&gt;% ρ ο γ α</td><td> 2,7</td><td> 83</td>

<td> 231</td><td></td><td> 4,39</td><td> 64,2</td>

<td> 232</td><td></td><td> 4,85</td><td> 74,9</td>

<td> 233</td><td>0 = λ&gt; cr ο</td><td> 4,17</td><td> 41</td>

<td> 234</td><td>ρ °⁼^^_ 0</td><td> 4,21</td><td> 61,8</td>

<td> 235</td><td>ΥΥζ °</td><td> 2,75</td><td> 100</td>

<td> 236</td><td>Α , / ν ° Α α-U 0Α Ο</td><td> 3,94</td><td> 50</td>

<td> 237</td><td>% - &lt;y ° Α at? cr ο</td><td> 4,65</td><td> 75,8</td>

To be continued

<td> 238</td><td>Ρ</td><td> 4,4</td><td> 75,3</td>

<td> 239</td><td>Μ ' / ¾ S ^and</td><td> 4,24</td><td> 62,2</td>

<td> 240</td><td>what in about</td><td> 4,76</td><td> 75,1</td>

<td> 241</td><td>_syF ~ ^ (° rO m in. at</td><td> 4,17</td><td> 72,5</td>

<td> 242</td><td></td><td> 4,6</td><td> 74,8</td>

<td> 243</td><td> 0</td><td> 4,12</td><td> 51,6</td>

<td> 244</td><td>about</td><td> 4,71</td><td> 66,2</td>

<td> 245</td><td>0γ ° ° γ- ° ν c? A.</td><td> 4,86</td><td> 62</td>

To be continued

<td> 246</td><td>about</td><td> 5,23</td><td> 58,3</td>

<td> 247</td><td>ABOUT</td><td> 4,17</td><td> 72,4</td>

<td> 248</td><td>_W ° Oyf</td><td> 3,35</td><td> 59,6</td>

<td> 249</td><td>ο_Ύ° &lt;ά Υγ</td><td> 2,41</td><td> 60,3</td>

<td> 250</td><td>0γ ° 0 &lt;s&gt;</td><td> 3,31</td><td> 65,2</td>

<td> 251</td><td></td><td> 2,86</td><td> 36,5</td>

<td> 252</td><td>ζν¹</td><td> 2,69</td><td> 89,8</td>

<td> 253</td><td>Λ¹⁰</td><td> 2,81</td><td> 67,4</td>

To be continued

254

<img file="PL201121B1_D0060.tif" />

2,19

75,4

All products of the solid phase synthesis are characterized by LC-MS. The following separation system is typically used for this purpose: HP 1100 with UV detector (208-400 nm), oven temperature 40 ° C, Waters-Symmetry C18 column (50 mm x 2.1 mm, 3.5 μm), eluent A : 99.9% acetonitrile / 0.1% formic acid, eluent B: 99.9% water / 0.1% formic acid; gradient:

<td>Time</td><td>A:%</td><td>B:%</td><td>Flow</td>

<td> 0,00</td><td> 10,0</td><td> 90,0</td><td> 0,50</td>

<td> 4,00</td><td> 90,0</td><td> 10,0</td><td> 0,50</td>

<td> 6,00</td><td> 90,0</td><td> 10,0</td><td> 0,50</td>

<td> 6,10</td><td> 10,0</td><td> 90,0</td><td> 1,00</td>

<td> 7,50</td><td> 10,0</td><td> 90,0</td><td> 0,50</td>

Detection of substances is carried out with a Micromass Quattro LCZ MS, ionization: ESI positive / negative.

In the above-mentioned structures containing one or more * or -O residues, always mean a function