Substituted oxazolidinones for combinational therapy

(54) Title: Pharmaceutical product containing combinations of substituted oxazolidinones, their use, their production process, and medicine (51) Int.CI .: A61 K31 / 422; A61 K31 / 435; A61 P7 / 00; A61 P9 / 00 (30) Unionist Priority: 20/06/2001 DE 101 29 725.4 (73) Holder (s): BAYER INTELLECTUAL PROPERTY GMBH, BAYER PHARMA AKTIENGESELLSOHAFT, BAYER SOHERING PHARMA AKTIENGESELLSOHAFT, Bayer Healthcare AG, Bayer Healthcare AG, Bayer Healthcare AG, Bayer Healthcare AG (72) Inventor (s): Alexander Straub, Elisabeth Perzborn, Jens Pohlmann, Josef Pernestorfer, Karl-Heinz Schlemmer, Susanne Roehrig, Thomas Lampe

Invention Patent Descriptive Report for PHARMACEUTICAL PRODUCT CONTAINING SUBSTITUTED OXAZOLIDINONE COMBINATIONS, THEIR USE, ITS PRODUCTION PROCESS, AND MEDICINE.

The present invention relates to combinations of A) oxazolidinones of formula (I) with B) other active substances, a process for producing these combinations and their use as a medicine, particularly for the prophylaxis and / or treatment of thromboembolic diseases.

Oxazolidinones of formula (I) act, in particular, as selective inhibitors of blood clotting factor Xa and as anticogulants.

An anthrithrombotic effect of factor Xa inhibitors has been demonstrated in numerous animal models (comp. WO 99/37304; WO 99/06371; J. Hauptmann, J. Stürzebecher, Thrombosis Research 1999, 93, 203; F. Al-Obeidi , JA Ostrem, Factor Xa inhibitors, Exp. Opin. Ther. Patents 1999, 9, 931; B.-Y. Zhu, RM Scarborough, Curr. Opin. Card. Pulm. Ren. Inv. Drugs 1999, 1 (1) 63, M. Samama, JM Walenga, B. Kaiser, J. Fareed, Specific Factor Xa Inhibitors, Cardiovascular Thrombosis: Thrombocardiology and Thromboneurology, Second Edition, edited by M. Verstraete, V. Fuster, EJ Topol, Lippincott-Raven Publishers, Philadelphia 1998), as well as in clinical studies in patients (The Ephesus Study , Blood, Vol 96, 490a, 2000; The Penthifra Study, Blood, Vol 96, 490a, 2000; The Pentamaks Study, Blood, Vol 96, 490a-491a, 2000; The Pentathlon 2000 Study, Blood, Vol 96, 491a, 2000). Therefore, factor Xa inhibitors can preferably be used in medications for prophylaxis and / or treatment of thromboembolic diseases.

Thromboembolic vascular diseases are the most frequent cause of pathology and mortality in industrialized countries (Thiemes Innere Medizin, Georg Thieme Verlag Stuttgart, New York; American Heart Association, 2000 heart and stroke statistical update, Dallas, TX: American Heart Association, 2000). Anticoagulatory therapy has been shown to be effective in the treatment of vascular diseases, to prevent thrombotic vessel occlusions or to unclog vessels with thrombotic occlusion again and assumes a target value in the prophylaxis and treatment of coronary, peripheral and cerebral vascular diseases, as well as in prophylaxis and / or treatment of venous thrombosis and pulmonary embolisms.

The cause of thromboembolic complications can be atherosclerotic changes in the vessel wall, particularly disorders of endothelial function, which can lead to acute thrombotic occlusions. Atherosclerosis is a multifactorial disease, which depends on a plurality of cardiovascular risk factors. Clinical studies have shown that prophylaxis with anticoagulants does not decisively influence the evolution of arterial vascular disease. For this reason, targeted treatment of risk factors in combination with antithrombotic therapy is advantageous.

Risk factors for coronary, peripheral and cerebral vascular diseases are, for example: increased serum cholesterol levels, arterial hypertonia, cigarette consumption, Diabetes mellitus (Allgemeine und spezielle Pharmakologie und Toxikologie, W. Forth, D. Henschler, W. Rummel, K. Starke: Spektrum Akademischer Verlag Heidelberg Berlin, Oxford; Thiemes Innere Medizin, Georg Thieme Verlag Stuttgart, New York). Principles of preventive medicine are based on the exclusion of these risk factors. In addition to changes in lifestyle, pharmacological measures are also part of this, such as, for example, antihypertensive therapy, lipid-lowering drugs or thrombosis prophylaxis. In addition, the combination with coronary therapeutic agents is appropriate for the treatment of existing coronary heart disease.

It has now surprisingly been discovered that combinations of oxazolidinones of formula (I) with certain other active substances have interesting properties and are better suited for the prophylaxis and / or treatment of various diseases than the individual active substances alone.

Therefore, combinations of

A) oxazolidinones of formula (I) with

B) other active substances, particularly with platelet aggregation inhibitors, anticoagulants, fibrinolytics, lipid reducers, coronary therapeutic agents and / or vasodilators.

By combinations in the sense of the invention are not only understood forms of administration that contain all the components (the so-called fixed combinations), and packages of combinations that contain the components separated from each other, but also components applied simultaneously or in a displaced way in time , provided they are used for prophylaxis and / or treatment of the same disease. In the same way, it is possible to combine two or more active substances with each other, in this case, therefore, respectively, double or multiple combinations.

Suitable oxazolidinones of the combination according to the invention comprise, for example, compounds of the formula (I)

<img file="BRPI0210941B1_D0001.tif" />

in which:

R¹ represents optionally benzocondensed thiophene (thienyl), which may optionally be mono- or polysubstituted;

R² represents any desired organic radical;

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are the same or different and represent hydrogen or (C_rC6) -alkyl, as well as the pharmaceutically acceptable salts, hydrates and prodrugs thereof.

In that case, compounds of formula (I) are preferred, in which

R¹ represents optionally benzocondensed thiophene (thienyl), which may optionally be mono- or polysubstituted by a radical of the halogen group; cyan; nitro; amino; aminomethyl; Ci-Cs-alkyl, which, in turn, can be optionally mono- or polysubstituted by halogen; (Ç₃-Ç₇) -cycloalkyl; CrCs-alkoxy; imidazolinyl; -C (= NH) NH₂; carbamoyl; and mono- and di- (Ci-G₄) -alkyl-aminocarbonyl,

R² represents one of the following groups:

THE-,

AM-,

DMA-,

BMA-,

B-,

BM-,

BMB-,

DMB-, of which:

the radical A represents (C₆-Ci₄) -aryl, preferably (Οβ-Οιο) aryl, particularly phenyl or naphthyl, particularly preferably phenyl;

radical B represents a 5- or 6-membered aromatic heterocycle, containing up to 3 heteroatoms and / or straight chain members, particularly up to 2 heteroatoms and / or straight chain members, of the S, N, NO (N-oxide series) ) it's the;

radical D represents a 4- to 9-membered heterocycle, saturated or partially unsaturated, mono- or bicyclic, optionally benzocondensed, containing up to three heteroatoms and / or straight chain members of the S, SO, SO series₂, N, NO (N-oxide) and O;

radical M represents -NH-, -CH₂-, -CH₂CH₂-, -O-, -NH-CH₂-, -CH₂-NH-, -OCH₂-, -CH₂O-, -CONH-, -NHCO-, -COO-, -OOC-, -S-, -SO₂- or represents a covalent bond;

the groups A, B and D defined above can optionally be respectively mono- or polysubstituted with a radical of the halogen group; trifluoromethyl; oxo; cyan; nitro; carbamoyl; pyridyl; (C1-C6) -alkaneyl; (Ç₃-C7) -cycloalkanoyl; (Ç₆-Ç₁₄) -arylcarbonyl; (C5-C10) heteroarylcarbonyl; (CrC₆) -alkanoyloxymethyloxy; (CrC₄) -hydroxyalkylcarbonyl; -COOR²⁷; -SO2 R²⁷; -C (NR²⁷R²⁸) = NR²⁹; -CONR²⁸R²⁹; -SO2NR²⁸R²⁹; -OR³⁰; -NR³⁰R³¹, (CrC6) -alkyl and (Ca-Czj-cycloalkyl, where (Ci-C6) -alkyl and (C₃-Ç₇) -cycloalkyl, in turn, can be optionally substituted by a cyano group radical; -OR²⁷; -NR²⁸R²⁹; -CO (NH) v (NR²⁷R²⁸) and -C (NR²⁷R²⁸) = NR²⁹, being that:

v represents 0 or 1 and

R²⁷, R²⁸ and R²⁹ are the same or different and, independently of each other, mean hydrogen, (CrC₄) -alkyl, (C₃-C7) -cycloalkyl, (C_rÇ₄) -alkanoyl, carbamoyl, trifluoromethyl, phenyl or pyridyl, and / or

R²⁷ and R²⁸ or R²⁷ and R²⁹, together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocycle, saturated or partially unsaturated, with up to three, preferably up to two, equal or different heteroatoms from the group of N, O and S and

R³⁰ and R³¹ are the same or different and, independently of each other, mean hydrogen, (CrC₄) -alkyl, (C₃-C7) -cycloalkyl, (CrC₄) -alkylsulfonyl, (Cq-Cfi-hydroxyalkyl, (Ci-C₄) -aminoalkyl, di- (CrC₄) -alkylamino (Ci-C₄) -alkyl, -CH₂C (NR²⁷R²⁸) = NR²⁹ or -COR³³, being that

R³³ means (CrC₆) -alkoxy, (C_rÇ₄) -alkoxy- (Ci-C₄) -alkyl, (C_rÇ₄) -alkoxycarbonyl- (Ci-C₄) -alkyl, (Ci-C₄) -aminoalkyl, (Ci-C₄) -alkoxycarbonyl, (CrC₄) -alkaneyla- (C₁-Ç₄) -alkyl, (C₃-Ç₇) -cycloalkyl, (C2-C₆) -alkenyl, (CrC₈) -alkyl, which may optionally be replaced by phenyl or acetyl, (C₆-Ç₁₄) -aryl, (C₅-Cio) -heteroaryl, trifluoromethyl, tetrahydrofuranyl or butyrolactone,

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are the same or different and represent hydrogen or (Ci-C₆) -alkyl, and their pharmaceutically compatible salts, hydrates and prodrugs.

Equally preferred are, in this case, the compounds of the general formula (I), in which

R¹ represents thiophene (thienyl), particularly 2-thiophene, which optionally may be mono- or polysubstituted by halogen, preferably chlorine or bromine, amino, aminomethyl or (C1-Csbalkyl, preferably methyl, with the radical (CrCsj-alkyl, in turn, it can be optionally mono- or polysubstituted by halogen, preferably fluorine,

R² represents one of the following groups:

THE-,

Α-Μ-,

DMA-,

Β-Μ-Α-,

Β-,

Β-Μ-,

Β-Μ-Β-,

DMB-, of which:

ο radical A represents (C6-C14) -aryl, preferably (C6-C10) aryl, particularly phenyl or naphthyl, particularly preferably phenyl;

radical B represents a 5- or 6-membered aromatic heterocycle, containing up to 3 heteroatoms and / or straight chain members, particularly up to 2 heteroatoms and / or straight chain members, of the S, N, NO (N-oxide series) ) it's the;

radical D represents a 4- to 7-membered heterocycle, saturated or partially unsaturated, containing up to three heteroatoms and / or straight chain members of the S, SO, SO series₂, N, NO (N-oxide) and O;

the radical M represents -NH-, CH₂-, CH₂CH₂-, -O-, -NH-CH₂-, -CH₂-NH-, -OCH₂-, -CH₂O, -CONH-, -NHCO-, -COO-, -OOC-, -S- or represents a covalent bond;

the groups A, B and D defined above can optionally be, respectively mono- or polysubstituted with a radical of the halogen group; trifluoromethyl; oxo; cyan; nitro; carbamoyl; pyridyl; (CrC₆) -alkaneyl; (Ç₃-C7) -cycloalkanoyl; (Ç₆-Ç₁₄) -arylcarbonyl; (Ç₅-Ci₀) -heteroarylcarbonyl; (CiC₆) -alkanoyloxymethyloxy; -COOR²⁷; -SO2 R²⁷; -C (NR²⁷R²⁸) = NR²⁹; -CONR²⁸R²⁹; -SO2NR²⁸R²⁹; -OR³⁰; -NR³⁰R³¹, (C1-C6) -alkyl and (C3-C7) -cycloalkyl, with (Ci-Cej-alkyl and (C3-C7) -cycloalkyl, in turn, optionally being substituted by a cyano group radical; OR²⁷; -NR²⁸R²⁹; -CO (NHv (NR²⁷R²⁸) and -C (NR²⁷R²⁸) = NR²⁹, being that:

v represents 0 or 1 and

R²⁷, R²⁸ and R²⁹ are the same or different and, independently of each other, mean hydrogen, (Ci-C₄) -alkyl or (C3-C₇) -cycloalkyl, and / or

R²⁷ and R²⁸ or R²⁷ and R²⁹, together with the nitrogen atom to which they are attached, form a 5- to 7-membered saturated or partially unsaturated heterocycle, with up to three, preferably up to two, equal or different heteroatoms of the group of N, O and S and r30 θ _R31 are the same or different and, independently of each other, mean hydrogen, (Ci-C₄) -alkyl, (C3-C₇) -cycloalkyl, (CrC₄) -alkylsulfonyl, (CrC₄) -hydroxyalkyl, (CrC₄) -aminoalkyl, di- (CiC₄) -alkylamino (CrC₄) -alkyl, (CrC₄) -alkaneyl, (C₆-Ç₁₄) -arylcarbonyl, (C₅-Cio) -heteroarylcarbonyl, (Ci-C₄) -alkylaminocarbonyl or -CH₂C (NR²⁷R²⁸) = NR²⁹, where R³, R⁴, R⁵, R⁶, R⁷ and R⁸ they are the same or different and represent hydrogen or (C1-C6) -alkyl, and their pharmaceutically compatible salts, hydrates and prodrugs.

Particularly preferred in this case are compounds of the general formula (I), in which

R¹ represents thiophene (thienyl), particularly 2-thiophene, which may optionally be mono- or polysubstituted by halogen, preferably chlorine or bromine, or (C1-Cs-alkyl, preferably methyl, with the radical C1-C₈-alkyl, in turn, may be optionally mono- or polysubstituted by halogen, preferably fluorine,

R² represents one of the following groups:

THE-,

AM-,

DMA-,

BMA-,

B-,

BM-,

BMB-,

DMB-, of which:

the radical A represents phenyl or naphthyl, particularly phenyl, the radical ”B represents an aromatic heterocycle of 5 or 6 members, containing up to 2 heteroatoms of the S, N, NO (N-oxide) and O series;

radical D represents a 5- or 6-membered heterocycle, saturated or partially unsaturated, containing up to two heteroatoms and / or straight chain members of the S, SO, SO2, N, NO (N-oxide) and O series;

radical M represents -NH-, -O-, -NH-CH₂-, -CH₂-NH-, -OCH₂-, -CH₂O.-CONH-, -NHCO-, or represents a covalent bond;

the groups A, B and D ”defined above can optionally be respectively mono- or polysubstituted with a radical of the halogen group; trifluoromethyl; oxo; cyan; pyridyl; (CrC3) -alkaneyl; (C6-C10) -arylcarbonyl; (Ç₅-Ç₆) -heteroarylcarbonyl; (C1 -C3) -alkanoyloxymethyloxy; -C (NR²⁷R²⁸) = NR²⁹; -CONR²⁸R²⁹; -SO2NR²⁸R²⁹; -OH; -NR³⁰R³¹, (CrC4) -alkyl; and cyclopropyl, cyclopentyl or cyclohexyl, and (CrC₄) -alkyl and cyclopropyl, cyclopentyl or cyclohexyl, in turn, can be optionally substituted by a cyano group radical; -OH; -OCH₃; -NR²⁸R²⁹; -CO (NH_V(NR²⁷R²⁸) and -C (NR²⁷R²⁸) = NR²⁹, being that:

v represents 0 or 1, preferably 0 and

R²⁷, R²⁸ and R²⁹ are the same or different and, independently of each other, mean hydrogen, (CrC₄) -alkyl or cyclopropyl, cyclopentyl or cyclohexyl, and / or

R²⁷ and R²⁸ or R²⁷ and R²⁹, together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocycle, saturated or partially unsaturated, with up to two heteroatoms equal or different from the group of N, O and S and r3 ° θ p3i _are jg_{uais or} djf_erand_nand, independently of each other, mean hydrogen, (Ci-C₄) -alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (C₁-Ç₄) -alkylsuifonyl, (CrC4) -hydroxyalkyl, (Ci-C₄) -aminoalkyl, di (CrC₄) -alkylamino- (CrC₄) -alkyl, (CrC3) -alkanoyl or phenylcarbonyl,

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are the same or different and represent hydrogen or (Ci-C₆) -alkyl, and their pharmaceutically compatible salts, hydrates and prodrugs.

Particularly preferred are, in this case, the compounds of the general formula (I), in which

R¹ represents 2-thiophene, which may optionally be substituted in position 5 by a radical of the group chlorine, bromine, methyl or trifluoromethyl,

R² represents one of the following groups:

THE-,

AM-,

DMA-,

BMA-,

B-,

BM-,

BMB-,

DMB-, of which:

the radical A represents phenyl or naphthyl, particularly phenyl, the radical B represents a 5- or 6-membered aromatic heterocycle, containing up to 2 heteroatoms of the S, N, NO (N-oxide) and O series;

the radical D represents a 5- or 6-membered heterocycle, saturated or partially unsaturated, containing one nitrogen atom and, optionally, another heteroatom and / or straight chain member of the S, SO, SO2 and O series; or contains up to two hetero atoms and / or straight chain members of the S, SO, SO2 and O series;

the radical M represents -NH-, -O-, -NH-CH₂-, -CH₂-NH-, -OCH₂-, -CH₂O -, - CONH-, -NHCO-, or represents a covalent bond;

the groups A, B and D defined above can optionally be respectively mono- or polysubstituted with a radical of the halogen group; trifluoromethyl; oxo; cyan; pyridyl; (Ci-C₃) -alkaneyl; (Ç₆-Cio) -arylcarbonyl; (Ç₅-Ç₆) -heteroarylcarbonyl; (Ci-C₃) -alkanoyloxymethyloxy; -CONR²⁸R²⁹; -SO2NR²⁸R²⁹; -OH; -NR³⁰R³¹, (C1 -C4) -alkyl; and cyclopropyl, cyclopentyl or cyclohexyl, and (C₁-Ç₄) -alkyl and cyclopropyl, cyclopentyl or cyclohexyl, in turn, can be optionally substituted by a cyano group radical; -OH; -OCH₃; -NR²⁸R²⁹; -CO (NH)_V(NR²⁷R²⁸) and -C (NR²⁷R²⁸) = NR²⁹, being that:

v represents 0 or 1, preferably 0 and

R²⁷, R²⁸ and R²⁹ are the same or different and, independently of each other, mean hydrogen, (CrC₄) -alkyl or cyclopropyl, cyclopentyl or cyclohexyl, and / or

R²⁷ and R²⁸ or R²⁷ and R²⁹, together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocycle, saturated or partially unsaturated, with up to two identical or different heteroatoms from the group of N, O and S and

R³⁰ and R³¹ are the same or different and, independently of each other, mean hydrogen, (CiC₄) -alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (Ci-C₄) -alkylsulfonyl, (Ci-C₄) -hydroxyalkyl, (Ci-C₄) -aminoalkyl, di (CrC₄) -alkylamino- (C- | -C₄) -alkyl, (C_rÇ₃) -alkanoyl or phenylcarbonyl,

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are the same or different and represent hydrogen or (CrC₄) -alkyl, and their pharmaceutically compatible salts, hydrates and prodrugs.

Particularly preferred are compounds of the general formula (I), in which

R¹ represents 2-thiophene, which is substituted in position 5 by a radical of the group chlorine, bromine, methyl or trifluoromethyl,

R² represents DA-: where:

the radical A represents phenylene;

the radical D represents a 5- or 6-membered, saturated heterocycle, which is linked with A through a nitrogen atom, which in the immediate vicinity of the bonding nitrogen atom has a carbonyl group, in which a ring carbon member may be replaced by a heteroatom of the S, N and O series;

the group A defined above can optionally be mono- or disubstituted in the meta position in relation to the bond with oxazolidinone, with a radical of the group of fluorine, chlorine, nitro, amino, trifluoromethyl, methyl or cyano,

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ represent hydrogen, and their pharmaceutically compatible salts, hydrates and prodrugs.

In this case, the compound with the following formula is also particularly preferred.

<img file="BRPI0210941B1_D0002.tif" />

and the pharmaceutically compatible salts, hydrates and prodrugs thereof.

To date, oxazolidinones are described, substantially, only as antibiotics, in isolation also as MAO inhibitors and fibrinogen antagonists (summary: Riedl, B., Endermann, R., Exp. Opin. Ther. Patents 1999,9 (5) , 625), and for the antibacterial effect a small 5- [acyl-aminomethyl] group (preferably 5- [acetylaminomethyl]) appears to be essential.

Aryl- and substituted heteroarylphenyloxazolidinones, in which a mono- or polysubstituted phenyl radical may be attached to the N atom of the oxazolidinone ring, and which at position 5 of the oxazolidinone ring may have an N-methyl-2-thiophenecarboxamide radical, as well as their use as substances with antibacterial effect, are known from US patent documents, US-A-5 929 248, US-A-5 801 246, US-A-5 756 732, US-A-5 654 435, US- A-5 654 428 and US-A-5 565 571.

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

The compounds of formula (I), depending on the substitution pattern, may exist in stereomeric forms, which behave as mirror image and image (enanciomers) or that do not behave as mirror image and image (diastereomers). Enanciomers or diastereomers are understood, as well as their respective mixtures. Racemic forms can be separated in a known manner, such as diastereomers, into individual stereoisomeric components.

In addition, certain compounds of formula (I) can be presented in tautomeric forms. This is known to the technician and these compounds are also understood.

Physiologically acceptable, i.e. pharmaceutically compatible, salts can be salts of the compounds according to 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 carboxylic or sulfonic acids, such as, for example, acetic acid, trifluoroacetic acid, propionic acid, maleic acid, are preferred , fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphthalindisulfonic acid.

As pharmaceutically compatible salts, salts with usual bases can also be mentioned, such as, for example, alkali metal salts (for example, sodium or potassium salts), alkaline earth salts (for example, calcium or magnesium salts) or salts ammonium derivatives, ammonia derivatives or organic amines, such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, n-methylmorpholine, dihydroabiethylamine or methylpiperidine.

Hydrates are the forms of the compounds of formula (I) above which in solid or liquid form a compound of molecules (solution) by hydration with water. In hydrates the water molecules are deposited with secondary valence by intermolecular forces, particularly hydrogen bonding, solid hydrates contain water as a so-called crystal water, in stoichiometric relationships, and the water molecules, with regard to their connection state, they do not need to have the same valence. Examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates. Also of interest are the salt hydrates of the compounds according to the invention.

Pro-drugs are the forms of the compounds of formula (I) above which can themselves be biologically active or inactive, but which can be transformed into the corresponding biologically active form (for example, metabolically, solvolytically or otherwise) .

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

(Ci-CsJ-Alkyl represents a linear or branched alkyl radical, with 1 to 8 carbon atoms. Exemplary are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and From this definition, the corresponding alkyl groups, with fewer carbon atoms, are similarly derived, such as, for example, (CiC₆) -alkyl and (CrC₄) -alkyl. In general, it is worth that (CrC ^ -alkyl is preferred.

This definition also derives the meaning of the corresponding component from other more complex substituents, such as, for example, in alkylsulfonyl, hydroxyalkyl, hydroxyalkylcarbonyl, alkoxy-alkyl, alkoxycarbonyl-alkyl, alkanoylalkyl, aminoalkyl or alkylaminoalkyl.

(C3-C₇) -Cycloalkyl represents a cyclic alkyl radical, with 3 to 7 carbon atoms. For example, the following are mentioned: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. From this definition, similarly, the corresponding cycloalkyl groups derive, with fewer carbon atoms, such as, for example, (C3-C₅) -cycloalkyl. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.

This definition also derives the meaning of the corresponding component from other more complex substituents, such as, for example, cycloalkanoyl.

(C2-C6) -Alkenyl represents a linear or branched alkenyl radical, with 2 to 6 carbon atoms. A straight or branched alkenyl radical having 2 to 4 carbon atoms is preferred. Exemplarily, cited are: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.

(CrCsj-Aloxy represents a straight or branched alkoxy radical, with 1 to 8 carbon atoms. For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n -hexoxy, n-heptoxy and n-octoxy. From this definition, the corresponding alkoxy groups with less carbon atoms are similarly derived, such as, for example, (Ci-Ce) -alkoxy and (CrCzú-alkoxy. In general, (C1 -C4) -alkoxy is preferred.

This definition also derives the meaning of the corresponding component from other more complex substituents, such as, for example, alkoxy-alkyl, alkoxycarbonyl-alkyl and alkoxycarbonyl.

Mono- or di- (CrC4) -alkylaminocarbonyl represents an amino group, which is linked through a carbonyl group and which has a linear or branched alkyl substituent or two identical or different, linear or branched alkyl substituents, with, respectively, 1 to 4 carbon atoms. For example, there are mentioned: methylamino, ethylamino, n-propylamino, isopropylamino, t-butylamino, N, N-dimethylamino, Ν, Ν-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl -Nn-propylamino and Nt-butyl-N-methylamino.

(C- | -C6) -Alkaneyl represents a straight or branched alkyl radical, with 1 to 6 carbon atoms, which in position 1 contains a double-bonded oxygen atom and is linked through position 1. Exemplarily, the following are mentioned: formila , acetyl, propionyl, n-butyryl, i-butyryl, pivaloyl, n-hexanoyl. From this definition, the corresponding alkanoyl groups with less carbon atoms are similarly derived, such as, for example, (CrCsbalcanoíla, (CrC₄) -alkaneyl and (C_rC3) -alkanoyl. In general, (CrC3) -alkanoyl is preferred.

This definition also derives the meaning of the corresponding component from other more complex substituents, such as, for example, cycloalkanoyl and alkanoylalkyl.

(C3-C7) -Cycloalkanoyl represents a cycloalkyl radical as defined above, with 3 to 7 carbon atoms, which is attached through a carbonyl group.

(C1-C6) -Alkanoyloxymethyloxy represents a linear or branched alkanoyloxymethyloxy radical, with 1 to 6 carbon atoms. Exemplified15, are mentioned: acetoxymethyloxy, propionoxymethyloxy, n-butyroxymethyloxy, i-butyroxymethyloxy, pivaloyloxymethyloxy, n-hexanoyloxymethyloxy. From this definition, similarly, the corresponding alkanoyloxymethyloxy groups, with fewer carbon atoms, are derived, such as, for example, (CrC3) -alkanoyloxymethyloxy. In general, (CrC3) -alkanoyloxymethyloxy is preferred.

(C6-Ci4) -Aryl represents an aromatic radical, with 6 to 14 carbon atoms. For example, the following are mentioned: phenyl, naphthyl, phenanthrenyl and anthracenyl. From this definition, correspondingly, the corresponding aryl groups with fewer carbon atoms are derived, such as, for example, (C6-C-io) -aryl. In general, it is worth that (C6-Ci₀) -aryl is preferred.

This definition also derives the meaning of the corresponding component from other more complex substituents, such as, for example, arylcarbonyl.

(Ç₅-C-io) -Heteroaryl or an aromatic heterocycle with 5 to 10 members, with up to 3 heteroatoms and / or straight chain members of the S, O, N and / or NO (N-oxide) series, represents a mono- or bicyclic, which is bonded through a ring carbon atom of the heteroaromat, optionally also through a ring nitrogen atom of the heteroaromat. Examples include: pyridyl, pyridyl-N-oxide, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl or isoxazolyl, indolizinyl, indolyl, benzo [b] thienyl, benzo indazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl. From this definition, correspondingly, the corresponding heterocyclics, with smaller ring size, such as, for example, aromatic 5- or 6-membered heterocyclenes, are derived. In general, it is worthwhile that 5- or 6-membered aromatic heterocycenes, such as, for example, pyridyl, pyridyl-N-oxide, pyrimidyl, pyridazinyl, furyl and thienyl are preferred.

This definition also derives the meaning of the corresponding component from other more complex substituents, such as, for example, (C5-Cio) -heteroarylcarbonyl.

A 3 to 9 membered heterocycle, saturated or partially unsaturated, mono- or bicyclic, optionally benzocondensed, with up to 3 heteroatoms and / or straight chain members of the S, SO, SO series₂, N, NO (N-oxide) and / or O represents a heterocycle, which may contain one or more double bonds, which may be mono- or bicyclic, in which a benzene ring may be condensed into two contiguous ring carbon atoms and that is attached via an annular carbon atom or an annular nitrogen atom. For example, the following are mentioned: tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide, thiomorpholinyl, azepinyl, 1,4-diazepin and cyclohexepine. Piperidinyl, morpholinyl and pyrrolidinyl are preferred.

From this definition, correspondingly, the corresponding cyclenes, with smaller ring size, such as, for example, 5- to 7-membered cyclene derive.

The compounds of the formula (I) can be produced by reacting according to a process alternative [A] compounds of the general formula (II)

<img file="BRPI0210941B1_D0003.tif" />

in which the radicals R^z, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ have the meanings indicated above, with carboxylic acids of the general formula (III)

<img file="BRPI0210941B1_D0004.tif" />

O in which the radical R¹ has the meaning indicated above, or else with the corresponding carboxylic acid halides, preferably carboxylic acid chlorides, or else with the corresponding symmetric or mixed carboxylic acid anhydrides of the carboxylic acids defined above of general formula (III), in inert solvents, optionally in the presence of an activating or conjugating agent and / or a base, for compounds of the general formula (I)

<img file="BRPI0210941B1_D0005.tif" />

in which the radicals R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ have the meanings indicated above, or else transforming, according to a process alternative [B] compounds of formula (IV)

<img file="BRPI0210941B1_D0006.tif" />

in which the radicals R¹, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ have the meanings indicated above, with an appropriate selective oxidizing agent, in an inert solvent, in the corresponding epoxide of the general formula (V)

<img file="BRPI0210941B1_D0007.tif" />

in which the radicals R¹, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ have the meanings indicated 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) in which the radical R² has the meaning indicated above, the compounds of the general formula (VII) are first produced

<img file="BRPI0210941B1_D0008.tif" />

in which the radicals R \ R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ have the meanings indicated above, and subsequently cycling them in an inert solvent, in the presence of phosgene or phosgene equivalent, such as, for example, carbonyldiimidazole (CDI), for the compounds of the general formula (I)

<img file="BRPI0210941B1_D0009.tif" />

in which the radicals R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ have the meanings indicated above, being that both for the process alternative [A], as well as for the process alternative [B], for the case of R² contain a 3 to 7-membered cyclic hydrocarbon radical, saturated or partially unsaturated, with one or more heteroatoms equal to or different from the group of N and S, an oxidation with a selective oxidizing agent for the corresponding sulfone may follow, sulfoxide or N-oxide, and / or both for the process alternative [A] and for the process alternative [B], in case the compound produced in this way contains a cyano group in the molecule, an amidination of that cyan group can follow with the usual methods, and / or both for the process alternative [A], as well as for the process alternative [B], in case the compound produced in this way presents a protection group of BOC-amino in the molecule, a separation of that protection group of BOC-amino can follow with the usual methods, and / or both for the process alternative [A], as well as for the alternative of process [B], in the event that the compound produced in this way contains an aniline or benzylamine radical in the molecule, a reaction of that amino group can follow with various reagents, such as carboxylic acids, carboxylic acid anhydrides, carboxylic acid chlorides, isocyanates, acid chlorides sulfonic or alkyl halides, for the corresponding derivatives, and / or both for the process alternative [A], as well as for the process alternative [B], in case the compound produced in this way has a phenyl ring in the molecule, a reaction with chlorosulfonic acid and a subsequent reaction with amines for the corresponding sulfonamides can follow.

The processes can be explained, for example, by the following formula schemes:

[THE]

<img file="BRPI0210941B1_D0010.tif" />

O

The oxidation step, described above, which takes place optionally, can be explained, by way of example, by the following formula scheme:

<img file="BRPI0210941B1_D0011.tif" />

As solvents for the processes described above, in this case, organic solvents are appropriate, which are inert under the reaction conditions. They include halogen hydrocarbons, such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethylene or trichlorethylene, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether and ethylene glycol dimethyl ether. , alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons, such as benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine, hexamethyl phosphoric acid triamide or water.

In the same way it is possible to use solvent mixtures of the solvents mentioned above.

As activating or conjugating agents for the processes described above, the reagents normally used for this purpose, for example, N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide.HCI, Ν, Ν'-dicyclohexylcarbodiimide, are suitable in this case. , 1-hydroxy-1H-benzotriazole.H2O and similar.

The usual inorganic or organic bases are suitable as bases. They preferably include alkali hydroxides, such as, for example, sodium or potassium hydroxide, or alkaline carbonates, such as sodium or potassium carbonate or sodium or potassium methanolate or sodium or potassium or tert-butylate ethanolate. potassium or amides, such as sodium amide, lithium bis- (trimethylsilyl) amide or lithium diisopropylamide or amines, such as triethylamine, diisopropylethylamine, diisopropylamine, 4-N, N'-dimethylaminopyridine or pyridine.

The base can be used, in this case, in an amount of 1 to 5 moles, preferably 1 to 2 moles, with respect to 1 mole of the compounds of the general formula (II).

The reactions take place, in general, in a temperature range of -78 ° C to the reflux temperature, preferably in the range of 0 ° C to the reflux temperature.

The reactions can be carried out at normal, high or low pressure (for example, in the range of 0.5 to 5 bar). In general, one works at normal pressure.

As selective oxidizing agents, suitable both for the production of epoxides, as well as for the oxidation optionally carried out for sulfone, sulfoxide or N-oxide, are of interest, for example, m-chloroperbenzoic acid (MCPBA), sodium metaperiodate, N-methylformolinoN-oxide (NMO), monoperoxyphthalic acid or osmium tetroxide.

As regards the production of epoxides, the usual production conditions are used for this purpose.

Regarding the more detailed process conditions for the oxidation optionally carried out for sulfone, sulfoxide or N-oxide, reference can be made to the following literature: MR Barbachyn et al., J. Med. Chem. 1996, 39, 680, as well as WO-A-97/10223.

In addition, reference is made to Examples 14 to 16, described in the experimental part.

The optionally performed amidination takes place under usual conditions. For other details, reference can be made to Examples 31 to 35 and 140 to 147.

The compounds of formulas (II), (III), (IV) and (VI) are themselves known to the person skilled in the art or can be produced according to usual methods. For oxazolidinones, particularly, the necessary 5- (aminomethyl) -2-oxooxazolidines, comp. WO-A-98/01446; WO-A-93/23384; WO-A-97/03072; JA Tucker 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.

A preferred compound A) of formula (I) for use in combinations is 5-chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] -1, 3-oxazolidin-5-yl} methyl) -2thiophenecarboxamide, the compound of Example 44.

The combinations according to the invention are particularly suitable for the prophylaxis and / or treatment of arterial thrombosis and embolisms in coronary heart disease, disorders of cerebrovascular circulation and disorders of peripheral arterial circulation. The combinations of oxazolidinones of formula (I) with platelet aggregation inhibitors, anticoagulants and / or fibrinolytics are also suitable for the prophylaxis and / or treatment of venous thrombosis and pulmonary embolisms.

The individual combination active substances are known from the literature and, for the most part, commercially obtainable. They can optionally be used, such as oxazolidinones of formula (I), in subtherapeutically effective doses.

For prophylaxis and / or treatment of arterial vessel diseases, a combination therapy of oxazoloidinones of formula (I) with lipid reducers, particularly with HMG-CoA- (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors, is appropriate. such as, for example, cerivastatin (Rivastatin, Baycol; US 5,177,080), lovastatin (Mevacor; US 4,231,938). simvastatin (Zocor; US 4,444,784), pravastatin (Pravachol; US 4,346,227), fluvastatin (Lescol; US 5,354,772), atorvastatin (Lipitor; US 5,273,995) or with coronary therapeutic agents; vasodilators, particularly ACE inhibitors (Angiotensin-Converting-Enzyme), such as, for example, captopril, lisinopril, enalapril, ramipril, cilazapril, benazepril, fosinopril, quinapril, perindopril; All receptor antagonists (Angiotensin

II), such as, for example, embusartan (US 5,863,930), losartan, valsartan, irbesartan, candesartan, eprosartan, temisartan; β-adrenoreceptor antagonists, such as, for example, carvedilol, alfprenolol, bisoprolol, acebutolol, atenolol, betaxolol, carteolol, metoprolol, nadolol, penbutolol, pindolol, propa23 nolol, timolol; alpha-1-adrenoreceptor antagonists, such as, for example, prazosin, bunazosin, doxazosin, terazosin; diuretics, such as, for example, hydrochlorothiazide, furosemide, bumetanide, pyretanide, torasemide, amiloride; dihydralazine; calcium channel blockers, such as, for example, verapamil, diltiazem or dihydropyridine derivatives, such as, for example, nifedipine (Adalat) or nitrendipine (Bayotensin); substances that cause an increase in cyclic guanosinmonophosphate (cGMP), such as, for example, stimulators of soluble guanylacyclase (WO 98/16223, WO 98/16507, WO 98/23619, WO 00/06567, WO 00/06568, WO 00 / 06569, WO 00/21954, WO 00/66582, WO 01/17998, WO 01/19776, WO 01/19355, WO 01/19780, WO 01/19778).

The pharmacotherapeutic objective of the treatment of an existing coronary heart disease is the elimination of the disproportion between oxygen supply and oxygen demand in the myocardial sectors affected by ischemia. For the treatment of an existing coronary heart disease, therefore, a combination therapy of an oxazolidinone of formula (I) with coronary therapeutic agents, particularly with β-adrenoreceptor antagonists, is particularly particularly appropriate; ACE inhibitors (Angiotensin-Converting Enzyme); A-ll receptor antagonists (Angiotensin II); nitro preparations, such as, for example, isosorbid-5-mononitrate, isosorbid-dinitrate, glyceroltrinitrate; substances that cause an increase in cyclic guanosinmonophosphate (cGMP); calcium channel blockers. Most of these compounds are also used for high blood pressure therapy.

To open thrombotically closed vessels again, success was achieved with thrombolytic therapy with plasminogen activators (thrombolytic / fibrinolytic agents), such as, for example, tissue plasminogen activator (t-PA), streptokinase, reteplase or urokinase. But the administration of plasminogen activators alone does not prevent further thrombus growth. High doses of plasminogen activators may, in addition, pose a higher risk of bleeding. The combined administration of a thrombolytic agent with an oxazolidinone of formula (I) for opening thrombotically closed vessels in coronary heart disease, transient ischemic attacks, apoplectic attack, peripheral arterial occlusive diseases and pulmonary embolisms prevents further thrombus growth by inhibiting the formation of thrombus thrombin and thereby reduces the risk of new occlusion. In addition, in combination therapy with a thrombolytic agent and an oxazolidinone of the formula (I), the required dose of the thrombolytic agent can be reduced, which leads to a reduction in bleeding complications and, therefore, represents a considerable advantage in relation to monotherapy.

Oxazolidinones of formula (I) can also be administered in combination with other substances of anticoagulatory efficacy (anticoagulants), for prophylaxis and / or treatment of arterial, intracardial and venous thromboembolic diseases. Combination therapy of oxazolidinones of formula (I), particularly with heparin (UFH), low molecular heparins (NMH), such as, for example, tinzaparin, certainparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin or inhibitors of direct thrombin, such as, for example, hirudin, leads to an enhanced antithrombotic effect.

Oxazolidinones of formula (I), in addition, can also be administered in combination with platelet aggregation inhibiting substances (platelet aggregation inhibitors, thrombocyte aggregation inhibitors), for prophylaxis and / or treatment of arterial, intracardial and thromboembolic diseases venous. In the case of adhesion of the endothelium, adhesion to the walls and activation of blood platelets occurs and the simultaneous stimulation of blood clotting. This leads to the formation of thrombi that contain platelets and fibrins, with platelets contributing to the stabilization of the fibrin structure (J. Hirch, EW Salzman, VJ Marder, RW Colman, OverView of the Thrombotic Process and its Therapy, page 11511163, in Hemostasis and Thrombosis: Basic Principies and Clinicai Practice, Third Edition, edited by RW Colman, J. Hirsh, VJ Marder, EW Salzman, JB Lippincott Company, Philadelphia, 1994). Simultaneous inhibition of blood clotting and platelet aggregation therefore leads to an enhanced antithrombotic effect. Suitable for combination therapy, particularly, combinations of an oxazolidinone of formula (I) with platelet aggregation inhibitors, such as, for example, aspirin, ticlopidine (Ticlid), clopidogrel (Plavix); fibrinogen receptor antagonists (glycoprotein llb / llla antagonists), such as, for example, abciximab, eptifibatide, tirofiban, lamifiban, lefradafiban.

For the application of the combinations according to the invention, all usual forms of application are of interest. Preferably, the application is by oral, lingual, sublingual, buccal, rectal, topical or parenteral (that is, avoiding the intestinal tract, therefore, by intravenous, intraarterial, intracardial, intracutaneous, subcutaneous, transdermal, intraperitoneal or intramuscular) .

Pharmaceutical preparations belong to the present invention which, in addition to suitable adjuvants and / or vehicles, pharmaceutically inert, non-toxic, contain one or more combinations according to the invention or which consist of a combination according to the invention, as well as processes for production of these preparations.

The combinations according to the invention must be present in the pharmaceutical preparations described above in a concentration of approximately 0.1 to 99.5, preferably approximately 0.5 to 95% by weight of the total mixture.

The pharmaceutical preparations described above can also contain other pharmaceutical active substances, in addition to the combinations according to the invention.

The pharmaceutical preparations described above can be produced in the usual manner, according to known methods, for example, by mixing the active substance or active substances with the vehicle (s).

In general, it has been shown to be advantageous to administer the combinations according to the invention in total amounts of approximately 0.001 to 100 mg / kg, preferably approximately 0.01 to 100 mg / kg, particularly approximately 0.1 to 10 mg / kg of body weight, every 24 hours, optionally in the form of several individual administrations, to obtain the desired results.

Despite this, optionally it may be necessary to deviate from the amounts mentioned above, more precisely, depending on body weight, the type of route of application, the type and severity of the disease, the individual behavior in relation to the medication, the type of formulation and the time or interval at which administration takes place. Thus, in some cases it may be sufficient to use less than the minimum quantity mentioned above, while in other cases the upper limit mentioned must be exceeded. In the case of the application of larger amounts, it may be recommended, for example, to distribute them throughout the day, more precisely, in several individual administrations or as a permanent infusion.

Another objective of the invention is, therefore, the combinations defined above for prophylaxis and / or treatment of diseases.

Another object of the invention is drugs that contain at least one of the combinations defined above and, optionally, other pharmaceutical active substances.

Another objective of the invention is the use of the combinations defined above for the production of medications, for the prophylaxis and / or treatment of the diseases described above, preferably thromboembolic diseases, particularly, heart attack, Angina Pectoris (including unstable angina), arrest sudden cardiac arrest, reocclusions and restenosis after angioplasty or aortocoronary bypass, apoplectic attack, transient ischemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thrombosis.

The percentage data in the examples below refer to weight, respectively; parts are parts by weight.

Examples

Assessment of physiological efficacy

1. Physiological effectiveness of the compounds of formula (I)

The compounds of formula (I) act, in particular, as selective inhibitors of blood clotting factor Xa and do not inhibit, or only at markedly higher concentrations, also other serine proteases, such as thrombin, plasmin or trypsin.

Blood clotting factor Xa inhibitors are designated as selective, in which the IC values₅o for the inhibition of factor Xa, in relation to the CI values₅o for the inhibition of other serine proteases, particularly thrombin, plasmin and trypsin, are around 100 times, preferably around 500 times, particularly around 1000 times, less, with respect to the methods of test for selectivity, reference is made to the test methods of Examples A-1) a.1) and a.2), described below.

The particularly advantageous biological properties of the compounds of the formula (I) can be seen by the following methods, a) Test description (in vitro)

a.1) Measurement of factor Xa inhibition

The enzymatic activity of human factor Xa (FXa) was measured by converting a chromogenic substrate, specific for FXa. In this case, factor Xa dissociates from the chromogenic substrate p-nitroaniline. The determinations were carried out as follows on microtiter plates.

The test substances were dissolved in different concentrations in DMSO and incubated for 10 minutes with human FXA (0.5 nmol / l), dissolved in 50 mmol / l of tris buffer [C, C, C-tris (hydroxymethyl) - aminomethane], 150 mmol / l NaCI, 0.1% BSA (bovine serum albumine), pH = 8.3, at 25 ° C. As a control it serves pure DMSO. Subsequently, the chromogenic substrate (150 μιτιοΙ / Ι Pefachrome® FXa from Pentapharm) was added. After 20 minutes of incubation time at 25 ° C, quenching at 405 nm was determined. The extinctions of the test preparations with the test substance were compared with the control preparations without test substance and from there the iCsoa values ​​were calculated.2) Determination of selectivity

For evidence of selective FXa inhibition, test substances were examined for their inhibition of other human serine proteases, such as thrombin, trypsin, plasmin. To determine the enzymatic activity of thrombin (75 mU / nnl), trypsin (500 mU / ml) and plasmin (3.2 nmol / l), these enzymes were dissolved in tris buffer (100 mmol / l, 20 mmol / l CaCb, pH = 8.0) and incubated for 10 minutes with the test substance or solvent. Subsequently, by adding the corresponding specific chromogen substrates (Chromozym Thrombin® by Boehringer Mannheim, Chromozym Trypsin® by Boehringer Mannheim, Chromozym Plasmin® by Boehringer Mannheim), the enzymatic reaction was started and, after 20 minutes, it was determined extinction at 405 nm. All determinations were performed at 37 ° C. The extinctions of test preparations with test substance were compared with control preparations without test substance and from there the IC values ​​were calculated₅₀.

The. 3) Determination of the anticoagulatory effect

The anticoagulatory effect of the test substances was determined in vitro in human plasma. For this purpose, human blood was removed as a filler in a 0.11 mol sodium citrate solution, in a 1/9 sodium citrate / blood mixture ratio; Immediately after removal, the blood was mixed well and centrifuged for 10 minutes at approximately 2000 g. The supernatant was removed by pipette. The prothrombin time (PT, synonyms: thromboplastin time, Quick-Test) was determined in the presence of varying concentrations of test substance or the corresponding solvent, with a commercially available test kit (Neoplastin® from Boehringer Mannheim). the test compounds were incubated for 10 minutes at 37 ° C with plasma. Subsequently, by the addition of thromboplastin, coagulation was initiated and the moment of coagulation initiation was determined. The concentration of the test substance that causes a doubling of the prothrombin time was determined. b) Determination of the antithrombotic effect (in vivo)

B. 1) Arteriovenous deviation model (rat)

Male fasting rats (family: HSD CPB: WU) weighing 200-250 g were anesthetized with a Rompun / Ketavet solution (12 mg / kg / 50 mg / kg). The formation of a thrombus was caused by a nasous arterioveolar deviation, based on the method described by Christopher N. Berry et al., Br. J. Pharmacol. (1994), 113, 1209-1214. To this end, the left Vena jugularis and the right Artery carotis were exposed. An extracorporeal deviation was glued between the two vessels using a 10 cm polyethylene (PE 60) tube. This polyethylene tube was inserted in the middle in another polyethylene tube (PE 160) with a length of 3 cm, which for the production of a thrombogenic surface, contained an asperized nylon thread and folded into a handle. Extracorporeal circulation was maintained for 15 minutes. Then, the bypass was removed and the nylon thread with the thrombus was immediately weighed. The empty weight of the nylon thread was determined before the test started. The test substances were administered to the awakened animals, before the application of the extracorporeal circulation, either intravenously, through the caudal vein, or orally, through a gastric tube. The results are shown in Table 1:

Table 1: Antithrombotic effect in the model of arteriovenous bypass (rat), after oral or intravenous administration

<td>Example</td><td>ED₅o [mg / kg] po</td><td>ED₅₀ [mg / kg] iv</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 fasting rats (family: HSD CPB: WU) were anesthetized as described above. The rats had an average weight of 200 g. 20 The left carotid artery was exposed (approximately 2 cm). The formation of an arterial thrombus was induced by mechanical damage to the vessel, based on the method described by K. Meng et al., Naunyn-Schmiedeberg's Arch.

Pharmacol. (1977), 301, 115-119. For this purpose, the exposed Artery carotis was separated by blood flow pressure, refrigerated for 2 minutes at -12 ° C in a metallic trough and for standardization of the thrombus size, simultaneously compressed with a weight of 200 g. Subsequently, blood flow was further reduced by a clamp placed around the Artery carotis, distally from the injured vessel section. The proximal clamp was removed, the wound was closed and after 4 hours it was reopened to remove the injured vessel section. The vessel section was opened longitudinally and the thrombus was removed from the injured vessel section. The wet weight of the thrombi was immediately determined. The test substances were administered to animals awake at the beginning of the test, either intravenously through the caudal vein or orally, through a gastric tube. b.3) Venous thrombosis model (rat)

Male fasting rats (family: HSD CPB: WU) were anesthetized as described above. The rats had an average weight of 200 g. The left Vena jugularis was exposed (approximately 2 cm). The formation of an arterial thrombus was induced by mechanical damage to the vessel, based on the method described by K. Meng et al., Naunyn-Schmiedeberg's Arch. Pharmacol. (1977), 301, 115-119. For this purpose, Vena jugularis was separated, by pressure, from the blood flow, refrigerated for 2 minutes at -12 ° C in a metallic trough and for standardization of the thrombus size, simultaneously compressed with a weight of 200 g. The blood flow was opened again and the wound was closed. After 4 hours, the wound was reopened to remove thrombi from the injured vessel sections. The wet weight of the thrombi was immediately determined. The test substances were administered to animals awake at the beginning of the test, either intravenously, through the caudal vein, or orally, through a gastric tube.

2. Physiological effectiveness of combinations of compounds of formula (I)

a) In vivo examinations in a rat thrombosis model

Under anesthesia, Artery carotis was exposed in rats (HSD CPB: WU, Harlan Winkelmann). A piece of filter paper impregnated with an aqueous solution of FeCb with conc. 10% (dissolved in 1 N aqueous hydrochloric acid) was carefully inserted under the exposed vessel, according to the method described by Kurz et al. (Rat Model of Arterial Thrombosis Induced by Ferric Chloride, Thrombosis Research 60, 269-280, 1990). After 3 minutes, the piece of filter paper was removed. The carotis artery was removed after 15 minutes, the thrombus was released and immediately weighed. The animals (10 rats per group) had previously been treated with 1 mg / kg of individual substances, respectively (oxazolidinone of formula (I) or combination active substance) or with the combination of 1 mg / kg of oxazolidinone of formula (I) and 1 mg / kg of combination active substance. The animals in the control group were treated with the corresponding solvent. Statistical significance was calculated using Student's t test. As a statistically significant effect, values ​​with p &lt;0.05 are considered (Medical Statistics, MJ Campbell, D. Machin, Second Edition, John Wiley &amp; Sons). The results are shown in Table 2.

Table 2: Synergistic thrombotic effect of the combination of an oxazolidinone of formula (I) with platelet aggregation inhibitor

<td colspan="3">Reduction of thrombus weight after oral treatment with</td>

<td>Compound of Example 44 [1 mg / kg]</td><td>Clopidogrel [1 mg / kg]</td><td>Compound combination of Example 44 [1 mg / kg] with Clopidogrel [1 mg / kg]</td>

<td> 22%</td><td> 28%</td><td> 39%</td>

<td>no effect (p&gt; 0.05)</td><td>no effect (p&gt; 0.05)</td><td>effect (p &lt;0.05)</td>

As shown in Table 2, with the combination of an oxazolidinone of formula (I), such as the compound of Example 44, with a platelet aggregation inhibitor, such as Clopidogrel, a synergistic effect is obtained, that is, the two components intensify each other in their effect. At individual dosage, the two compounds were ineffective at the tested dose. The combination of the two compounds, on the other hand, led to a significant reduction in the weight of the thrombus. By combining oxazolidinones of formula (I) with a platelet aggregation inhibiting substance, antithrombotic therapy could therefore be considerably improved.

B Production examples

Basic compounds

The preparation of 3-morpholinone is described in the document US

349 045.

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

Substituted anilines can be obtained by reacting, for example, 4-fluomitrobenzene, 2,4-difluomitrobeene or 4-chloronitrobenzene with the corresponding amines or amides, in the presence of a base. This can also be done using Pd catalysts, such as Pd (OAc) 2 / DPPF / NaOt-Bu (Tetrahedron Lett. 1990, 40, 2035) or copper (Renger, Synthesis 1985, 856; Aebischer et al. , Heterocycles 1998, 48, 2225). Likewise, halogen aromats without a nitro group can first be transformed into the corresponding amides, to subsequently nitrate them in position 4 (US 3279,880).

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

<img file="BRPI0210941B1_D0012.tif" />

<img file="BRPI0210941B1_D0013.tif" />

in 2 l of N-methylpyrrolidone (NMP) 2 moles (202 g) of morpholin-3-one (E. Pfeil, U. Harder, Angew. Chem. 79, 1967, 188) are dissolved. Then, over a period of 2 h, 88 g (2.2 moles) of sodium hydride (60% in paraffin) are added in portions. After the completion of the development of hydrogen, 282 g (2 moles) of 4-fluornitrobenzene are added in drops within 1 hour under refrigeration at room temperature and the reaction mixture is further stirred overnight. Then, it is removed by distillation, at 12 mbar and 76 ° C, 1.7 I of the volume of the liquid, the residue is poured into 2 I of water and this mixture is extracted twice with, respectively 1 I of ethylacetate. After washing the unified organic phases with water, it is dried over sodium sulfate and the solvent is removed by vacuum distillation. Purification takes place by chromatography on silica gel with hexane / ethyl acetate (1: 1) and subsequent crystallization of ethyl acetate. The product yields 78 g as a colorless to brownish solid, in 17.6% of the theory.

¹H NMR (300 MHz, CDCI₃): 3.86 (m, 2 H, CH₂CH₂), 4.08 (m, 2 H, CH₂CH₂), 4.49 (s, 2 H, CH₂CO), 7.61 (d, 2H, ³J = 8.95 Hz, CHCH), 8.28 (d, 2H, ³J = 8.95 Hz, CHCH)

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

Similarly, the following compounds were synthesized:

3- fluorine-4- (4-morpholin-3-onyl) nitrobenzene

4- (N-piperidonyl) nitrobenzene

3- fluorine-4- (N-piperidonyl) nitrobenzene

4- (N-pyrrolidonyl) nitrobenzene 3-fluorine-4- (N-pyrrolidonyl) nitrobenzene

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

<img file="BRPI0210941B1_D0014.tif" />

In an autoclave 63 g (0.275 mol) of 4- (4morpholin-3-onyl) nitrobenzene are dissolved in 200 ml of tetrahydrofuran, mixed with

3.1 g of Pd / C (with conc. 5%) and hydrogenated for 8 h, at 70 ° C and a hydrogen pressure of 50 bar. After filtration of the catalyst, the solvent is removed by vacuum distillation and the product is purified by crystallization from ethyl acetate. The product is formed with 20 g as a colorless to bluish solid in 37.6% of the theory.

Purification can also take place by chromatography on silica gel34 with hexane / ethyl acetate.

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

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

Similarly, the following compounds were synthesized:

3- fluorine-4- (4-morpholin-3-onyl) aniline

4- (N-piperidonyl) aniline

3- fluorine-4- (N-piperidonyl) aniline

4- (N-pyrrolidonyl) aniline 3-fluorine-4- (N-pyrrolidonyl) aniline

General method for preparing 4-substituted anilines by reacting 1 fluorine-4-nitrobenzolene and 1-chloro-4-nitrobenzenolene with primary or secondary amines and subsequent reduction

<img file="BRPI0210941B1_D0015.tif" />

Equimolar amounts of fluornitrobenzene or chloronitrobenzene and amine are dissolved in dimethylsulfoxide or acetonitrile (0.1 M to 1 M solution) and stirred overnight at 100 ° C. After cooling to RT, the reaction mixture is diluted with ether and washed with water. The organic phase is dried using MgSO₄, filtered and concentrated. If a precipitation forms in the reaction mixture, then it is removed by filtration and washed with ether or acetonitrile. If the product is also found in the mother liquor, it is treated, as described, 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), mixed with palladium on charcoal (10%) and stirred overnight, under normal hydrogen pressure. Then, filter and concentrate. The crude product can be purified by chromatography on silica gel (mixtures of dichloromethane / ethanol) or preparative reversible phase HPLC (mixtures of acetonitrile / water).

Alternatively, iron powder can also be used as a reducing agent. For this purpose, the nitro compound is dissolved in acetic acid (0.1 M to 0.5 M solution) and at 90 ° C six equivalents of powder of 10-15 min are added in portions. iron and water (0.3 to 0.5 times the volume of acetic acid). After another 30 min, at 90 ° C, it is filtered and the filtration product is concentrated. The residue is treated extractively with acetic ester and 2 N of sodium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product can be purified by chromatography on silica gel (mixtures of dichloromethane / ethanol) or preparative reversible phase HPLC (mixtures of acetonitrile / water).

Similarly, the following basic compounds were produced:

111-1. Terc-butyl-1- (4-aminophenyl) -L-propionate

MS (ESI): m / z (%) = 304 (M + H + MeCN, 100), 263 (M + H, 20);

HPLC (Method 4): TA = 2.79 min

III-2.1- (4-Aminophenyl) -3-piperidincarboxamide

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

HPLC (method 4): TA = 0.59 min

III-3.1- (4-Aminophenyl) -4-piperidincarboxamide

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

HPLC (method 4): TA = 0.57 min

III-4.1- (4-Aminophenyl) -4-piperidinone

MS (ESI): m / z (%) = 191 (M + H, 100);

HPLC (method 4): TA = 0.64 min

ΙΙΙ-5.1- (4-Aminophenyl) -L-prolinamide

MS (ESI): m / z (%) = 206 (M + H, 100);

HPLC (method 4): TA = 0.72 min

III-6. Γ1 - (4-Aminophenyl) -3-piperidinyl1methanol

MS (ESI): m / z (%) = 207 (M + H, 100);

HPLC (method 4): TA = 0.60 min

III-7. Γ1 - (4-Aminophenyl) -2-piperidininmethanol

MS (ESI): m / z (%) = 207 (M + H, 100);

HPLC (method 4): TA = 0.59 min

III-8. Ethyl-1- (4-aminophenyl) -2-piperidincarboxylate

MS (ESI): m / z (%) = 249 (M + H, 35), 175 (100);

HPLC (method 4): TA = 2.43 min

III-9. ri- (4-Aminophenyl) -2-pyrrolidinillmethanol

MS (ESI): m / z (%) = 193 (M + H, 45);

HPLC (method 4): TA = 0.79 min

111-10. 4- (2-Methylhexahidro-5H-pyrrolor3,4-d1isoxazol-5-yl) phenylamine starting from 2-methylhexahidro-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): TA = 0.54 min

111-11. 4- (1-Pyrrolidinyl) -3-trifluormethyl) aniline

MS (ESI): m / z (%) = 231 (M + H, 100);

HPLC (method 7): TA = 3.40 min

111-12. 3-Chlorine-4- (1-pyrrolidinyl) aniline

MS (ESI): m / z (%) = 197 (M + H, 100);

HPLC (method 4): TA = 0.78 min

111-13. 5-Amino-2- (4-morpholinyl) benzamide

MS (ESI): m / z (%) = 209 (M + H, 100);

HPLC (method 4): TA = 0.77 min

111-14. 3-Methoxy-4- (4-morpholinyl) aniline

MS (ESI): m / z (%) = 209 (M + H, 100);

HPLC (method 4): TA = 0.67 min

111-15.1 - [5-Amiono-2- (4-morpholinyl) pheninetanone

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

HPLC (method 4): TA = 0.77 min

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

<img file="BRPI0210941B1_D0016.tif" />

<img file="BRPI0210941B1_D0017.tif" />

<img file="BRPI0210941B1_D0018.tif" />

The amide is dissolved in DMF and mixed with 1.5 equivalents of potassium tert-butylate. The mixture is stirred for 1 h at RT, then 1.2 equivalents of 1-fluor-4-nitrobenzene are added in batches. The reaction mixture is stirred overnight at RT, diluted with ether or acetic ester and washed with saturated aqueous sodium hydrogencarbonate 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).

For the subsequent reduction, the nitro compound is dissolved in ethanol (0.01 M to 0.5 M of solution), mixed with palladium on carbon (10%) and stirred overnight under normal pressure of hydrogen. Then, filter and concentrate. The crude product can be purified by chromatography on silica gel (dichloromethane / ethanol mixtures) or reversible phase preparation (acetonitrile / water mixtures).

Alternatively, iron powder can also be used as a reducing agent. For this purpose, the nitro compound is dissolved in acetic acid (0.1 M to 0.5 M solution) and at 90 ° C six equivalents of powder of 10-15 min are added in portions. iron and water (0.3 to 0.5 times the volume of acetic acid). After a further 30 min, at 90 ° C, it is filtered and the filtration product is concentrated. The residue is treated extractively with acetic ester and 2 N of sodium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product can be purified by chromatography on silica gel (mixtures of dichloromethane / ethanol) or preparative reversible phase HPLC (mixtures of acetonitrile / water).

Similarly, the following basic compounds were produced:

IV-1.1-f4-Amino-2- (trifluormethyl) phenin-2-pyrrolidinone

MS (ESI): m / z (%) = 245 (M + H.100);

HPLC (method 4): TA = 2.98 min

IV-2, 4- [4-Amino-2- (trifluoromethyl) phenin-3-morpholinone

MS (ESI): m / z (%) = 261 (M + H.100);

HPLC (method 4): TA = 2.54 min

IV-3. 4- (4-Amino-2-chlorophenyl) -3-morpholinone

MS (ESI): m / z (%) = 227 (M + H.100);

HPLC (method 4): TA = 1.96 min

IV-4. 4- (4-Amino-2-methylphenyl) -3-morpholinone

MS (ESI): m / z (%) = 207 (M + H.100);

HPLC (method 4): TA = 0.71 min

IV-5. 5-Amino-2- (3-oxo-4-morpholinyl) benzonitrile

MS (ESI): m / z (%) = 218 (M + H.100);

HPLC (method 4): TA = 1.85 min

IV-6. 1 - (4-Amino-2-chlorophenyl) -2-pyrrolidinone

MS (ESI): m / z (%) = 211 (M + H.100);

HPLC (method 4): TA = 2.27 min

IV-7. 4- (4-Amino-2,6-dimethylphenyl) -3-morpholinone 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): TA = 0.77 min

IV-8. 4- (2,4-Diaminophenyl) -3-morpholinone from 1-fluorine-2,4-dinitrobenzene:

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

HPLC (method 4): TA = 0.60 min

IV-9. 4- (4-Amino-2-chlorophenyl) -2-methyl-3-morpholinone 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): TA = 2.27 min

IV-10. 4- (4-Amino-2-chlorophenyl) -6-methyl-3-morpholinone starting from 6-methyl-3-morpholinone (EP 350 002):

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

HPLC (method 4): TA = 2.43 min

Synthesis examples

Examples 1 to 13, 17 to 19 and 36 to 57 refer to process variant [A].

Example 1

Production of 5-chloro-N - {[(5S) -3- (3-fluoro-4-morpholinophenyl) -2-oxo-1,3-oxazolidin

-5-inmethyl) -2-thiophenecarboxamide

<img file="BRPI0210941B1_D0019.tif" />

(5S) -5- (Aminomethyl) -3- (3-fluor-4-morpholinophenyl) -1,3-oxazolidin-2-one (production, see SJ Brickner et al., J. Med. Chem. 1996, 39 , 673) (0.45 g, 1.52 mmol), 5-chlorothiophene-2-carboxylic acid (0.25 g, 1.52 mmol) and 1-hydroxy1 H-benzotriazole hydrate (HOBT) (0.3 g, 1.3 equivalent) are dissolved in 9.9 ml of DMF. 0.31 g (1.98 mmol, 1.3 equivalent) of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide (EDCI) is added and 0.39 g (at room temperature) are added in drops. 0.53 ml, 3.05 mmoles, 2 equivalents) of diisopropylethylamine (DIEA). Stir overnight at room temperature. Silica gel g is added and concentrated by evaporation of the preparation in vacuo, until drying. The residue is chromatographed on silica gel with a gradient of toluene-acetic ester. 0.412 g (61.5% of theory) of the target compound are obtained, with a melting point (Smp.) Of 197 ° C.

Rf (SiO₂, toluene / acetic ester 1: 1) = 0.29 (extraction product = 0.0);

MS (DCI): 440.2 (M + H), Cl standard;

¹H NMR (ds-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-Chlorine-N ~ fr (5S) -3-4-morpholinopheniD-2-oxo-1,3-oxazolidin-5-inmethyl) -2-thiophene10 carboxamide

<img file="BRPI0210941B1_D0020.tif" />

similarly, benzyl-4-morpholinophenylcarbamate is obtained through the (5S) -5- (aminomethyl) -3- (3-fluoro-4-morpholinophenyl) -1,3-oxazolidin-2-one stage (see Example 1 ).

Smp .: 198 ° C

CI value₅o = 43 nM;

Rf (SiO₂, toluene / acetic ester 1: 1) = 0.24 Example 3

5-Chloro-N - ((((5S) -3-r3-fluor-4- (1,4-diazinan-4-yl) pheniH-2-oxo-1.3-oxazolidin-5-yl) methyl) -2- thiophenecarboxamide

<img file="BRPI0210941B1_D0021.tif" />

it is obtained, analogously, from (5S) -5- (aminomethyl) -3- [3-fluorine-4- (1,4-thiazinan-4-yl) phenyl] -1,3-oxazolidin-2-one (production , see MR Barbachyn et al., J. Med. Chem. 1996, 39, 680).

Smp .: 193 ° C;

Yield: 82%;

Rf (SiO2, toluene / acetic ester 1: 1) = 0.47 (extraction product = 0.0) Example 4

5-Bromo-N- (f (5S) -3-fluor-4- (1,4-thiazinan-4-yl) phenin-2-oxo-1,3-oxazolidin-5-yl) methyl) -2- thiophenecarboxamide

<img file="BRPI0210941B1_D0022.tif" />

it is similarly obtained from 5-bromothiophene-2-carboxylic acid.

SMP .: 200 ° C Example 5

N - ((((5S) -3-f3-fluor-4- (1,4-thiazinan-4-yl) phenyl1-2-oxo-1,3-oxazolidin-5-yl) methyl) -515 methyl-2 -thiophenecarboxamide

<img file="BRPI0210941B1_D0023.tif" />

similarly, it is obtained from 5-methylthiophenol-2-carboxylic acid. Smp .: 167 ° C

Example 6

5-Chloro-N-í [(5S) -3- (6-methylthieno [2,3-b1pyridin-2-yl) -2-oxo-1,3-oxazolidin-5-in methyl) -2-thiophenecarboxamide

<img file="BRPI0210941B1_D0024.tif" />

it is obtained, analogously, from (5S) -5- (aminomethyl) -3- (6-methylthieno [2,3-b] pyridin 5 2-yl) -1,3-oxazolidin-2-one (production, see EP -A-785 200).

Smp .: 247 ° C Example 7

5-Chloro-N- (í (5S) -3- (3-methyl-2-oxo-2,3-dihydro-1.3-benzothiazol-6-yl) -2-oxo-1.3oxazolidin-5-methyl} - 2-thiophenecarboxamide

<img file="BRPI0210941B1_D0025.tif" />

similarly, 6 - [(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] 3-methyl-1,3-benzothiazole-2- (3H) -one is obtained (production, see EP-A-738 726).

MP .: 217 ° C

Example 8

5-Chloro-Nf ((5S) -3- {3-fluor-4-f4- (4-pyridinyl) piperazine] phenyl} -2-oxo-1,3-oxazolidin-5-yl) methyl) -2- thiophenocarboxamide

<img file="BRPI0210941B1_D0026.tif" />

it is obtained, analogously, from (5S) -5- (aminomethyl) -3- {3-fluoro-4- [4- (4-pyridinyl) pipe5 razino] phenyl} -1,3-oxazolidin-2-one (production , analogously to JA Tucker et al., J. Med. Chem. 1998, 41, 3727).

MS (ESI): 516 (M + H), Cl standard Example 9

5-Chlorine-N - ({(5S) -3-r3-fluor-4-r4- (4-methylpiperazine) phenyl1-2-oxo-1.3-oxazolidin10 5-yl) methyl) -2-thiophenecarboxamide

<img file="BRPI0210941B1_D0027.tif" />

it is obtained, analogously, from (5S) -5- (aminomethyl) -3- [3-fluorine-4- (4-methylpiperazine] phenyl] -1,3-oxazolidin-2-one.

Example 10

5-Chloro-N - ({(5S) -3- {3-fluor-4- (4- (4-tert-butoxycarbonylpiperazin-1-yl) phenill-2oxo-1.3-oxazolidin-5-yl} methyl) - 2-thiophenecarboxamide

<img file="BRPI0210941B1_D0028.tif" />

it is obtained, analogously, from (5S) -5- (aminomethyl) -3- [3-fluoro-4- (4-terc.-butoxycarbonylpiperazin-1-yl) phenyl] -1,3-oxazolidin-2-one ( production, see document WO-A-93/23384, cited above).

Smp .: 184 ° C;

Rf (SiO₂, toluene / acetic ester 1: 1) = 0.42

Example 11

5-Chlorine-N - ((((5S) -3- [3-fluor-4-piperazin-1-yl) feniri-2-oxo-1,3-oxazolidin-5-iD methyl) -2-thiophenecarboxamide

<img file="BRPI0210941B1_D0029.tif" />

is obtained by reacting Example 12 with trifluoroacetic acid in 15 methylene chloride.

CI value₅₀ = 140 nM;

¹H-NMR [de-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), 8.4 ( broad s, 1H), 9.0 (t, 1H).

Example 12

5-Chloro-Nf ((5S) -3- (2.4'-bipyridinyl-5-yl) -2-oxo-1,3-oxazolidin-5-yl) metiri-2-thiophene-

<img file="BRPI0210941B1_D0030.tif" />

similarly is obtained from (5S) -5-aminomethyl-3- (2,4'-bipyridinyl-5-yl) -2-oxo1,3-oxazolidin-2-one (production, see EP-A-789 026 ).

Rf (SiO₂, toluene / acetic ester 1: 2) = 0.6;

MS (ESI): 515 (M + H), Cl standard.

Example 13

5-Chlorine-N-phen (5S) -2-oxo-3- (4-piperidinophenyl) -1,3-oxazolidin-5-iHmethyl} -2-thiophene-

<img file="BRPI0210941B1_D0031.tif" />

is obtained from 5- (hydrOxymethyl) -3- (4-piperidinophenyl) -1,3-oxazolidin-2-one (production, see DE 2708236) after mesylation, reaction with potassium phthalimide, hydrazinolysis and reaction with 5-chlorothiophene acid -2 carboxylic.

Rf (SiO₂, toluene / acetic ester 1: 1) = 0.31;

Sm p. 205 ° C.

Example 17

5-Chlorine-N - ((((5S) -2-oxo-3-F4-oxo-1-pyrrolidinyl) phenin-1.3-oxazolidin-5-yl) methyl) -2-

<img file="BRPI0210941B1_D0032.tif" />

From 1- (4-aminophenyl) pyrrolidin-2-one (production, see Reppe et al., Justus Liebigs Ann. Chem .; 596; 1955; 209), is obtained in analogy to the known synthesis scheme (see SJ Brickner et al., J. Med. Chem. 1996, 39 ,. 673), after reaction with benzyloxycarbonylchloride, subsequent reaction with R-glycidyl-butyrate, mesylation, reaction with phthalimide potassium, hydrazinolysis in methanol and reaction with 5-chlorothiophene-2 ​​carboxylic acid, finally, to 5-chloro-N - ({( 5S) -2-oxo-3- [4- (2-oxo-1-pyrrolidinyl) phenyl] -1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide. A 5-chloro-N - ({(5S) -2-oxo-3- [4- (2-oxo-1-pyrrolidinyl) phenyl] -1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide obtained in this way has an IC50 value = 4 nM (test method for the IC50 value according to Example A-1.a. 1) described above Measurement of factor Xa inhibition). Smp .: 229 ° C;

RXSIO2 value, toluene / acetic ester 1: 1) = 0.05 (extract: = 0.0);

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

¹H-NMR (de-DMSO, 300 MHz): 2.05 (m, 2H), 2.45 (m, 2H), 3.6 (t, 2H), 3,773.85 (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 stages of the synthesis described above in Example 17, with the respective precursors, are as follows:

g (22.7 mmoles) of 1- (4-aminophenyl) pyrrolidin-2-one and 3.6 ml (28.4 mmoles) of Ν, Ν-dimethylaniline are mixed slowly in 107 ml of tetrahydrofuran, at -20 ° C, with 4.27 g (25.03 mmoles) of chloroformic acid benzylester. Stir for 30 minutes at -20 ° C and subsequently allow everything to reach room temperature. 0.5 I of acetic acid is added and the organic phase is washed with 0.5 I of saturated NaCl solution. The separated organic phase is dried with MgSO₄ and the solvent is evaporated in vacuo. The residue is mixed with diethyl ether and aspirated. 5.2 g (73.8% of theory) of benzyl-4- (2-oxo-1-pyrrolidinyl) phenylcarbamate are obtained with light beige crystals, with a melting point of 174 ° C.

1.47 g (16.66 mmoles) of isoamyl alcohol are mixed in 200 ml of tetrahydrofuran, under argon at -10 ° C, in drops, with 7.27 M of nbutillithium solution (BuLi) in hexane, an additional 8 ml of the BuLi solution is needed until the change of the added indicator, N-benzylidenbenzylamine. Stir for 10 minutes at -10 ° C, cool to -78 ° C and slowly add a solution of 4.7 g (15.14 mmol) of benzyl-4- (2-oxo-) phenylcarbamate 1-pyrrolidinyl). Subsequently, 4 ml of η-BuLi solution are added once more, until the color of the indicator changes to pink. Stir for 10 minutes at -78 ° C and 2.62 g (18.17 mmoles) of R-glycidylbutyrate are added and further stirred at -78 ° C for 30 minutes.

Everything is allowed to come to room temperature overnight, 200 ml of water are added to the preparation and the THF fraction is evaporated in vacuo. The aqueous residue is extracted with acetic ester, the organic phase is dried with MgSO₄ and concentrated by vacuum evaporation. The residue is mixed with 500 ml of diethyl ether and the vacuum precipitated crystals are aspirated.

3.76 g (90% of theory) of (5R) -5- (hydroxymethyl) -3- [4 (2-oxo-1-pyrrolidinyl) phenyl] -1,3-oxazolidin-2-one are obtained, with a melting point of 148 ° C and an Rf value (SiO2, toluene / acetic ester 1: 1) = 0.04 (extract = 0.3).

3.6 g (13.03 mmoles) of (5R) -5- (hydroxymethyl) -3- [4- (2-oxo-1-pinOlidinyl) phenyl] -1,3-oxazolidin-2-one and 2, 9 g (28.67 mmoles) of triethylamine are loaded in 160 ml of dichloromethane, at 0 ° C, with stirring. 1.79 g (15.64 mmoles) of methanesulfonic acid chloride are added, with stirring, and stirred for 1.5 hours at 0 ° C, as well as for 3 hours, at room temperature.

The reaction mixture is washed with water and the aqueous phase is again extracted with methylene chloride. The unified organic extracts are dried with MgSO₄ and concentrated by evaporation. Subsequently, the residue (1.67 g) is dissolved in 70 ml of acetonitrile, mixed with 2.62 g (14.16 mmol) of potassium phthalimide and stirred for 45 minutes at 180 ° C in a closed container in a microwave oven.

The preparation is separated by filtration of non-soluble residue, the filtration product is concentrated by vacuum evaporation, the residue (1.9 g) is dissolved in methanol and mixed with 0.47 g (9.37 mmoles) of hydrate hydrazine. Boil for 2 hours, refrigerate, mix with saturated sodium bicarbonate solution and extract six times with a total of 2 l of methylene chloride. The unified organic extracts of the (5S) -5- (aminomethyl) -3 [4- (2-oxo-1-pyrrolidinyl) phenyl] -1,3-oxazolidin-2-one crude are dried with MgSO₄ and concentrated by vacuum evaporation.

The final stage, 5-chloro-N - ({(5S) -2-oxo-3- [4- (2-oxo-1-pyrrolidinyl) phenyl] -1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide, is produced by dissolving 0.32 g (1.16 mmol) of (5S) -5- (aminomethyl) -3- [4- (2-oxo-1-pyrrolidinyl) phenyl] -1, 3-oxazolidin-2-one described above, 5-chlorothiophene-2 ​​carboxylic acid (0.19 g; 1.16 mmol) and 1-hydroxy-1H-benzotriazole hydrate (HOBT) (0.23 g, 1.51 g mmol) in 7.6 ml of DMF. Add 0.29 g (1.51 mmol) of N '- (3dimethylaminopropyl) -N-ethylcarbodiimide (EDCI) and add, in drops, at room temperature, 0.3 g (0.4 ml; 2 , 32 mmoles, 2 equivalents) of diisopropylethylamine (DIEA). Stir overnight at room temperature.

The preparation is concentrated by vacuum evaporation until drying, the residue is dissolved in 3 ml of DMSO and chromatographed on an RP-MPLC with acetonitrile / water / 0.5% TFA gradients. From the appropriate fractions, the acetonitrile fraction is evaporated and the precipitated compound is aspirated. 0.19 g (39% of theory) of the desired compound is obtained.

Similarly, the following were produced:

Example 18

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

Analogously to Example 17, of 4-pyrrolidin-1-yl-aniline (Reppe et al., Justus Liebigs Ann. Chem .; 596; 1955; 151) the compound 5-chlorine is obtained

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

IC50 ⁼ 40 nM;

Smp.:216°C;

Rf (SiC&gt; 2, toluene / acetic ester 1: 1) = 0.31 [extract: = 0.0]

Example 19

5-Chloro-N - ((((5S) -2-oxo-3-r4- (diethylamino) feniri-1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide

Similarly, from N, N-diethylphenyl-1,4-diamine (US-A-2 811 555;

1955) 5-chloro-N - ({(5S) -2-oxo-3- [4- (diethylamino) phenyl] -1,3oxazolidin-5-yl} methyl) -2-thiophenecarboxamide is obtained.

IC₅₀ = 270 nM;

Smp .: 181 ° C;

Rf value (SiO₂, toluene / acetic ester 1: 1) = 0.25 [extract: = 0.0]

Example 36

5-Chloro-N - ((((5S) -3- [2-methyl-4- (4-morpholinyl) phenin-2-oxo-1.3-oxazolidin-5-yl) methyl) -2-thiophenecarboxamide starting from 2- methyl-4- (4-morpholinyl) aniline (JE LuValle et al. J.

Am. Chem. Soc. 1948, 70, 2223):

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

HPLC (method 1): TA (%) = 3.77 (98)

IC₅₀: 1.26 pM Example 37

5-Chloro-N- (T (5S) -3- (3-chloro-4-morpholinophenyl) -2-oxo-1,3-oxazolidin-5-inmethyl) -2thiophenecarboxamide starting from 3-chloro-4- (4 -morpholinyl) aniline (HR Snyder et al. J. Pharm. Sci. 1977, 66,1204):

MS (ESI): m / z (%) = 456 ([M + Hf, 100), Cl standard;

HPLC (method 2): TA (%) = 4.31 (100)

IC50: 33 nM

Example 38

5-Chloro-N - ({(5S) -3-f4- (4-morpholinylsulfonyl) phenyl1-2-oxo-1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide starting from 4- (4- morpholinylsulfonyl) aniline (Adams et al. J.Am. 5 Chem. Soc. 1939, 61.2342):

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

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

IC50: 2 μΜ

Example 39

5-Chloro-N - ((((5S) -3-f4- (1-azetidinylsulfonyl) phenyl1-2-oxo-1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide starting from 4- (1- azetidinylsulfonyl) aniline:

EM (DCI, NH₃): m / z (%) = 473 ([M + NH₄]⁺, 100), Cl standard;

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

IC₅₀: 0.84 μΜ

Example 40

5-Chloro-N - [((5S) -3- {4-f (dimethylamino) sulfoninfenil} -2-oxo-1,3-oxazolidin-5-yl) metin-2-thiophenecarboxamide starting from 4-amino-N , N-dimethylbenzenesulfonamide (IK Khanna 20 et al. J. Med. Chem. 1997, 40.1619):

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

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

IC50 '. 90 nM

General method for acylation of 5- (aminomethyl) -3- [4- (2-oxo-1-pyrrolidinyl) phenill25 1,3-oxazolidin-2-one with carboxylic acid chlorides

<img file="BRPI0210941B1_D0033.tif" />

To the corresponding acid chloride (2.5 eq.), A solution of approximately 0.1 mol of 5- (aminomethyl) -3- [4-oxo-1-pyrrolidinyl) is added dropwise under argon at room temperature phenyl] -1,3-oxazolidin-2one (from Example 45) (0.1 eq.) and absolute pyridine (approximately 6 eq.) in absolute dichloromethane. The mixture is stirred for approximately 4 h at room temperature, before approximately 5.5 eq of PS-Trisamine (Argonaut Technologies) is added. The suspension is stirred slightly for 2 h, filtered after dilution with dichloromethane / DMF (3: 1) (the resin is washed with dichloromethane / DMF) and the filtration product is concentrated. The product obtained is optionally purified by preparative RP-HPLC.

Similarly, it was produced:

Example 41

N - ((2-oxo-3-14- (2-oxo-1-pyrrolidinyl) phenill-1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide

LC-MS (method 6): m / z (%) = 386 (M + H, 100):

LS-MS: TA (%) = 3.04 (100)

IC50: 1.3 μΜ

General method for preparing acyl derivatives, starting from 5- (aminomethyl) -3-r4- (2-oxo-1-pyrrolidinyl) phenin-1.3-oxazolidin-2-one and carboxylic acids

<img file="BRPI0210941B1_D0034.tif" />

2.9 eq. resin-bound carbodiimide (PS-Carbodiimid, Argonaut Technologies) is added corresponding carboxylic acid (approximately 2 eq.) and a mixture of absolute dichloromethane / DMF (approximately 9: 1). After approximately 15 light shakes at room temperature, 5- (aminomethyl) -3- [4- (2-oxo-1-pyrrolidinyl) phenyl] is added 52

1,3-oxazolidin-2-one (from Example 45) (1.0 eq.) And the mixture is stirred overnight, before being separated by filtration of the resin (washed additionally with dichloromethane) and the filtration product is focused. The product obtained is optionally purified by preparative RP-HPLC.

Similarly, the following were produced:

Example 42

5-Methyl-N- (f2-oxo-3-r4- (2-oxo-1-pyrrolidinyl) phenin-1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide

LC-MS: m / z (%) = 400 (M + H, 100):

LS-MS (method 6): TA (%) = 3.23 (100)

IC₅₀: 0.16 μΜ Example 43

5-Bromo-N - ({2-oxo-3-r4- (2-oxo-1-pyrrolidinyl) phenin-1,3-oxazolidin-5-i0methyl) -2thiophenecarboxamide

LC-MS: m / z (%) = 466 (M + H, 100):

LS-MS (method 5): TA (%) = 3.48 (78)

IC₅₀: 0.014 μΜ

Example 44

5-Chloro-N- (f (5S) -2-oxo-3-y4- (3-oxo-4-morpholinyl) phenin-1,3-oxazolidin-5-yl) methyl) 20 2-thiophenecarboxamide

<img file="BRPI0210941B1_D0035.tif" />

a) 2 - ((2R) -2-Hydroxy-3- {T4- (3-oxo-4-morpholinyl) pheninamino) propyl) -1 H-isoindole1,3 (2H) -dione:

A suspension of 2 - [(2S) -2-oxiranylmethyl] -1H-isoindol-1,3 (2H) -dione (A. Gutcait et al., Tetrahedron Asym. 1996, 7, 1641) (5.68 g, 27.9 mmoles) and 4- (4-aminophenyl) -3-morpholinone (5.37 g, 27.9 mmoles) in ethanol-water (9: 1, 140 ml) is refluxed for 14 h (precipitation comes into solution, after some time, new precipitation formation). The precipitation (desired product) is filtered off, washed three times with diethyl ether and dried. The unified mother liquors are concentrated in vacuo and, after adding a second portion of 2 - [(2S) -2-oxiranylmethyl] -1H-isoindol-1,3 (2H) -dione (2.84 g, 14, 0 mmoles), are suspended in ethanol-water (9: 1, 70 ml) and subjected to reflux for 13 h (the precipitation enters into solution, after some time, new precipitation formation). The precipitation (desired product) is filtered off, washed three times with diethyl ether and dried. Total yield: 10.14 g, 92% of theory.

MS (ESI): m / z (%) = 418 ([M + Naf, 84), 396 ([M + Hf, 93);

HPLC (method 3): TA (%) = 3.34 (100)

b) 2 - (((5S) -2-Qxo-3-f4- (3-oxo-4-morpholinyl) phenin-1,3-oxazolidin-5-yl) methyl) -1Hisoindol-1,3 (2H) -diona:

To a suspension of the amino alcohol (3.58 g, 9.05 mmoles) in tetrahydrofuran (90 ml) are added, under argon, at room temperature, N, N'-carbonyldiimidazole (2.94 g, 18.1 mmoles) and dimethylaminopyridine (catalytic amount). The reaction suspension is stirred for 12 h at 60 ° C (the precipitation enters into solution, after some time, a new precipitation forms), mixed with a second portion of N, N'-carbonyldiimidazole (2.94 g, 18, 1 mmoles) and stirred for another 12 h at 60 ° C. The precipitation (desired product) is filtered off, washed with tetrahydrofuran and dried. The filtration product is concentrated in vacuo and the remaining product is purified by means of flash chromatography (dichloromethane-methanol mixtures). Total yield: 3.32 g, 87% of theory.

MS (ESI): m / z (%) = 422 ([M + Hf, 100);

HPLC (method 4): TA (%) = 3.37 (100)

c) 5-Chloro-N - ((((5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl-1,3-oxazolidin-5-yl) methyl) 2-thiophenecarboxamide:

To a suspension of oxazolidinone (4.45 g, 10.6 mmoles) in ethanol (102 ml) is added, in drops, at room temperature, methylamine (40% conc. In water, 10.2 ml, 0.142 mole) . The reaction mixture is refluxed for 1 h and concentrated in vacuo. The crude product is used in the next reaction without further purification.

To a solution of the amine in pyridine (90 ml), 5-chloro-thiophene-2-carboxylic acid chloride (2.29 g, 12.7 mmoles) is added dropwise under argon at 0 ° C. Cooling with ice is removed and the reaction mixture is stirred for 1 h at room temperature and mixed with water. After adding dichloromethane and separating the phases, the aqueous phase is extracted with dichloromethane. The unified organic phases are dried (sodium sulphate), filtered and concentrated in vacuo. The desired product is purified by means of flash chromatography (dichloromethane-methanol mixtures). Total yield: 3.92 g, 86% of theory.

Smp .: 232-233 ° C;

¹H-NMR (DMSO-d6, 200 MHz): 9.05-8.90 (t, J = 5.8 Hz, 1H), 7.70 (d, J = 4.1 Hz, 1H), 7, 56 (d, J = 9.0 Hz, 2H), 7.41 (d, J = 9.0 Hz, 2H), 7.20 (d, J = 4.1 Hz, 1H), 4.93- 4.75 (m, 1H), 4.27-4.12 (m, 3H), 4.02-3.91 (m, 2H), 3.91-3.79 (dd, J = 6.1 Hz, 9.2 Hz, 1H), 3.76-3.66 (m, 2H), 3.66-3.54 (m, 2H);

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

HPLC (method 2): TA (%) = 3.60 (100);

[The]²¹ d = -38 ° (c 0.2985, DMSO); ee: 99%

IC50: 0.7 nM

Similarly, the following were produced:

Example 45

5-Methyl-N - ((((5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl1-1,3-oxazolidin-5-yl} methyl) 2-thiophenecarboxamide

MS (ESI): m / z (%) = 831 ([2M + H]⁺, 100), 416 ([M + H] *, 66);

HPLC (method 3): TA (%) = 3.65 (100)

IC50: 4.2 nM

Example 46

5-Bromo-N - ((((5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenill-1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide

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

HPLC (method 3): TA (%) = 3.87 (100)

IC50: 0.3 nM Example 47

5-Chloro-N- {f (5S) -3- (3-isopropyl-2-oxo-2.3-dihydro-1,3-benzoxazol-6-yl) -2-oxo1,3-oxazolidin-5-iHmethyl) -2-thiophencarboxamide

<img file="BRPI0210941B1_D0036.tif" />

200 6 - [(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] -3-isopropyl-1,3-benzoxazol-2 hydrochloride (0.61 mmol) 3H) -one hydrochloride (EP 738726) are suspended in 5 ml of tetrahydrofuran and mixed with 0.26 ml (1.83 mmol) of triethylamine and 132 mg (0.73 mmol) of 5-chlorothiophene-2-acid chloride carboxylic. The reaction mixture is stirred overnight at room temperature and subsequently concentrated. The product is 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 4): TA = 3.78 min.

Analogously, the following compounds were produced:

<td>Example No.</td><td>Structure</td><td>Smp. [° C]</td><td>IC₅o [μΜ]</td>

<td> 48</td><td>1 3 O* O cyz n. \ = / o O</td><td> 210</td><td> 0,12</td>

<td> 49</td><td>0 O</td><td> 234</td><td> 0,074</td>

<td> 50</td><td>ΥΥΊ ₀ «^uiral 4. ^VN Y ° ^sAç.</td><td> 195</td><td> 1,15</td>

<td> 51</td><td>\ =. Ko chiral ΛΗΧ »υβ- °</td><td> 212</td><td> 1,19</td>

<td> 52</td><td>_N &lt;1 chiral _?Ty^N-HERE^NLÇ&gt; l jÇ^1-0 yO</td><td> 160</td><td> 0,19</td>

<td> 53</td><td>/ = \ 1&gt; the chiral Γ N — v λ-NT ra n &lt;QZ JX &gt; —0 ΙΓ ^s 0</td><td>MS (ESI): m / z (%) = 431 ([M + H] *, 100), Cl standard</td><td> 0,74</td>

<td>Example No.</td><td>Structure</td><td>Smp. [° C]</td><td>IC₅₀ [μΜ]</td>

<td> 54</td><td>/ = \ chiral / O ⁵</td><td> 221</td><td> 0,13</td>

<td></td><td>of 5-Amino-2-pyrrolidino- benzonitrile (Grell, W., Hurnaus, R .; Griss, G., Sauter, R .; Rupprecht, E. et al .; J.Med.Chem.1988.41; 5219)</td><td></td><td></td>

<td> 55</td><td>V q-1-ι 0</td><td> 256</td><td> 0,04</td>

<td></td><td>3- (4-Amino-phenyl) - oxazolidin-2-one (Artico, M. et al .; Farmaco Ed.Sci. 1969, 24; 179)</td><td></td><td></td>

<td> 56</td><td>_ / = \ X The chiral⁰ O</td><td> 218</td><td> 0,004</td>

<td> 57</td><td>0. , - =. chiral IV-⁰ O ⁵</td><td> 226</td><td> 0,58</td>

<td> 58</td><td></td><td> 228-230</td><td></td>

Examples 20 to 30 and 58 to 139 below refer to the process variant [B], with Examples 20 and 21 describing the preparation of precursors:

Example 20

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

<img file="BRPI0210941B1_D0037.tif" />

To a chilled solution with ice of 2.63 ml (35 mmoles) of allylamine in 14.2 ml of absolute pyridine and 14.2 ml of absolute THF is added, in drops, 5-chloro-thiophene-2 ​​acid chloride -carboxylic (7.61 g, 42 mmoles). The ice cooler is removed and the mixture is stirred for 3 h at room temperature, before being concentrated in vacuo. The residue is mixed with water and the solid is filtered off. The crude product is purified by flash chromatography on silica gel (dichloromethane).

Yield: 7.20 g (99% of theory);

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

HPLC (method 1): TA (%) = 3.96 (98.9)

Example 21

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

<img file="BRPI0210941B1_D0038.tif" />

An ice-cooled solution of 2.0 g (9.92 mmoles) of Nalyl-5-chloro-2-thiophenecarboxamide in 10 ml of dichloromethane is mixed with meta-chloroperbenzoic acid (3.83 g, approximately 60 conc. %). The mixture is stirred overnight, in this case, warmed to room temperature and subsequently washed with 10% sodium hydrogen sulfate solution (three times). The organic phase is washed with saturated sodium hydrogencarbonate solution (twice) and with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The product is purified by chromatography on silica gel (cyclohexane / acetic ester 1: 1).

Yield: 837 mg (39% of theory);

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

HPLC (method 1): TA (%) = 3.69 min (approximately 80)

General method for preparing substituted N- (3-amino-2hydroxy-propyl) -5-chloro-2-thiophenecarboxamide derivatives, starting from 5-chloro-N- (2-oxiranylmethyl) -2-thiophenecarboxamide

<img file="BRPI0210941B1_D0039.tif" />

To a solution of primary amine derivative or aniline (1.5 to 2.5 eq.) In 1,4-dioxane, mixtures of 1,4-dioxane-water or ethanol, mixtures of ethanol-water (approximately 0.3 at 1.0 mol / l) is added at room temperature or at temperatures up to 80 ° C, in portions, 5-chloro-N- (2oxyranylmethyl) -2-thiophenecarboxamide (1.0 eq.). The mixture is stirred for 2 to 6 hours, before being concentrated. From the reaction mixture the product can be isolated by chromatography on silica gel (mixtures of cyclohexane-acetic ester, mixtures of dichloromethane-methanol or mixtures of dichloromethane-methanol-triethylamine).

Similarly, the following were produced:

Example 22

N-f3- (benzylamino) -2-hydroxypropyl1-5-chloro-2-thiophenecarboxamide

MS (ESI): m / z (%) = 325 (M + H, 100);

HPLC (method 1): TA (%) = 3.87 min (97.9)

Example 23

5-Chloro-N- [3- (3-cyanoanilino) -2-hydroxypropin-2-thiophenecarboxamide

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

HPLC (method 2): TA (%) = 4.04 min (100)

Example 24

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

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

HPLC (method 1): TA (%) = 4.12 min (100)

Example 25

5-Chloro-N- {3- [4- (cyanomethyl) anilino1-2-hydroxypropyl} -2-thiophenecarboxamide

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

HPLC (method 4): TA (%) = 3.60 min (95.4)

Example 26

5-Chloro-N- (3-r3- (cyanomethyl) anilino1-2-hydroxypropyl) -2-thiophenecarboxamide

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

HPLC (method 4): TA (%) = 3.76 min (94.2)

Example 58 tert-Butyl-4 - [(3 - ([(5-chloro-2-thienyl) carbonyl1amino) -2-hydroxypropyl) amino) -benzylcarbamate

Starting from tert-butyl-4-aminobenzylcarbamate (Bioorg. Med. Chem. Lett .; 1997; 1921-1926):

MS (ES-pos): m / z (%) = 440 (M + H, 100), (ES-neg): m / z (%) = 438 (MH, 100);

HPLC (method 1): TA (%) = 4.08 (100)

Example 59 tert-Butyl-4 - [(3- (r (5-chloro-2-thienyl) carboniriamino) -2-hydroxypropyl) aminolfenylcarbamate

Starting from N-tert-butyloxycarbonyl-1,4-phenylendiamine:

MS (ESI): m / z (%) = 425 (M + H, 45), 370 (100);

HPLC (method 1): TA (%) = 4.06 (100)

Example 60 tert-Butyl-2-hydroxy-3- (f4- (2-oxo-1-pyrrolidinyl) pheninamino) propyl-carbamate

Starting from 1- (4-aminophenyl) -2-pyrrolidinone (Justus Liebigs Ann. Chem .; 1955; 596; 204):

EM (DCI, NH₃): m / z (%) = 350 (M + H, 100);

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

Example 61

5-Chlorine-N- (3-ph3-fluorine-4- (3-oxo-4-morpholinyl) phenyr | amino) -2-hydroxypropyl) -2thiophenecarboxamide

800 mg (3.8 mmoles) of 4- (4-amino-2-fluorophenyl) -3-morpholinone and 700 mg (3.22 mmoles) of 5-chloro-N- (2-oxiranylmethyl) -2-thiophenecarboxamide are heated in 15 ml of ethanol and 1 ml of water for 6 hours, under reflux. Concentrate by vacuum evaporation, precipitated crystals are aspirated, after treatment with acetic ester and chromatography of the mother liquor are obtained

276 mg (17% of theory) of the desired compound.

Rf (acetic ester): 0.25.

Example 62 (N- (3-Anilino-2-hydroxypropyl) -5-chloro-2-thiophenecarboxamide starting from aniline:

EM (DCI, NH₃): m / z (%) = 311 ([M + NH₄]⁺, 100), Cl standard;

HPLC (method 1): TA (%) = 3.79 (100)

Example 63

5-Chloro-N- (2-hydroxy-3- (f4- (3-oxo-4-morpholinyl) pheninamino) propyl) -2thiophenecarboxamide starting from 4- (4-aminophenyl) -3-morpholinone:

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

HPLC (method 3): TA (%) = 3.58 (100)

Example 64

N-r3- (i4-fAcetyl (cyclopropyl) aminolfenyl} amino) -2-hydroxypropiH-5-chloro-2thiophenecarboxamide from N- (4-aminophenyl) -N-cyclopropiolacetamide:

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

HPLC (method 3): TA (%) = 3.77 (100)

Example 65

N- [3 - ({4- [Acetyl (methyl) amino1phenyl) amino) -2-hydroxypropin-5-chloro-2-thiophenecarboxamide starting from N- (4-aminophenyl) -N-methylacetamide:

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

HPLC (method 4): TA = 3.31 min Example 66

5-Chloro-N- (2-hydroxy-34T4- (1 H-1,2,3-triazol-1-yl) pheninamino) -2-2-thiophenecarboxamide starting from 4- (1 H-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): TA = 3.55 min

Example 67 tert-Butyl-1- (4-i (3-n (5-chloro-2-thienyl) carboninamino) -2-hydroxypropyl) aminol phenyl) -L-prolinate

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

HPLC (method 4): TA = 3.40 min

Example 68

1- (4 - [(3 - ([(5-Chloro-2-thienyl) carboninaminoy-2-hydroxypropyl) amino1phenyl&gt; -4piperidincarboxamide

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

HPLC (method 4): TA = 2.39 min

Example 69

1- (4-f (3 - {[(5-Chloro-2-thieniDcarbonyl1amino} -2-hydroxypropyl) amino] phenyl) -3piperidincarboxamide

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

HPLC (method 4): TA = 2.43 min

Example 70

5-Chloro-N- (2-hydroxy-3 - {[4- (4-oxo-1-piperidinyl) phenylamino) propyl) -2-thiophenecarboxamide

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

HPLC (method 4): TA (%) = 2.43 min

Example 71

1- {4-i (3- (f (5-Chloro-2-thienyl) carbonyl1amino) -2-hydroxypropyl) aminolfenyl) -L-prolinamide

MS (ESI): m / z (%) = 423 (M + H.100);

HPLC (method 4): TA = 2.51 min

Example 72

5-Chloro-N-1,2-hydroxy-3- «4-f3- (hydroxymethyl) -1-piperidininfenyl} -amino) propin-2thiophenecarboxamide

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

HPLC (method 4): TA = 2.43 min

Example 73

5-Chloro-N-1,2-hydroxy-3 - ({4- [2- (hydroxymethyl) -1-piperidinylphenyl) amino) propin-263 thiophenecarboxamide

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

HPLC (method 4): TA = 2.49 min

Example 74

Ethyl-1- {4-F (3- {f (5-chloro-2-thienyl) carboninamino} -2-hydroxypropyl) amino1phenyl) -2piperidincarboxylate

MS (ESI): m / z (%) = 466 (M + H, 100);

HPLC (method 4): TA = 3.02 min

Example 75

5-Chlorine-N-r2-hydroxy-3 - ((4-r2- (hydroxymethyl0-1-pyrrolidininfenyl! Amino) propin-2thiophenecarboxamide

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

HPLC (method 4): TA = 2.48 min

Example 76

5-Chloro-N- (2-hydroxy-3- {f4- (2-methylhexahydro-5H-pyrrolor3,4-d1isoxazol-5-yl) pheninamino) propyl) -2-thiophenecarboxamide

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

HPLC (method 5): TA = 1.74 min

Example 77

5-Chloro-N- (2-hydroxy-3 - ([4- (1-pyrrolidinyl) -3- (trifluormethyl ) pheninamino} propyl) -2thiophenecarboxamide

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

HPLC (method 4): TA = 3.30 min

Example 78

5-Chloro-N- (2-hydroxy-3- {f4- (2-oxo-1-pyrrolidinyl) -3- (trifluormethyl) pheninamino) propyl) -2-thiophenecarboxamide

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

HPLC (method 4): TA = 3.50 min

Example 79

5-Chloro-N- (3- {r3-chloro-4- (3-oxo-4-morpholinyl) pheninamino} -2-hydroxypropyl) -2thiophenecarboxamide

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

HPLC (method 4): TA = 3.26 min

Example 80

5-Chloro-N- (2-hydroxy-3- {F4- (3-oxo-4-morpholinyl) -3- (trifluormethyl) phenyl1aminol · propyl) -2-thiophenecarboxamide

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

HPLC (method 4): TA = 3.37 min

Example 81

5-Chloro-N- (2-hydroxy-3- {(3-methyl-4- (3-oxo-4-morpholinyl) pheninamino) propyl) -2-thiophenecarboxamide

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

HPLC (method 4): TA = 2.86 min

Example 82

5-Chloro-N- (3-U3-cyano-4- (3-oxo-4-morpholinyl) phenylamino) -2-hydroxypropyl) -2-thiophenecarboxamide

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

HPLC (method 4): TA = 3.10 min

Example 83

5-Chloro-N- (3 - {[3-chloro-4- (1-pyrrolidinyl) phenyl1amino} -2-hydroxyoxyOpyl) -2-thiophenecarboxamide

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

HPLC (method 4): TA = 2.49 min

Example 84

5-Chlorine-N- (3 - {[3-chloro-4- (2-oxo-1-pyrrolidinyl) pheninamino} -2-hydroxypropyl) -2thiophenecarboxamide

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

HPLC (method 4): TA = 3.39 min

Example 85

S-Chlorine-N-fS-ÍD.S-dimetM-fS-oxo ^ -morpholinylphenylIaminol ^ -hydiOxypiOpil) ^ thiophenecarboxamide

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

HPLC (method 4): TA = 2.84 min

Example 86

N- (3 - {[3- (Aminocarbonyl) -4- (4-morpholinyl) pheninamino) -2-hydroxypropyl) -5-chloro2-thiophenecarboxamide

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

HPLC (method 4): TA = 2.32 min

Example 87

5-Chloro-N- (2-hydroxy-3 - ([3-methoxy-4- (4-morpholinyl) pheninamino) propyl) -2thiophenecarboxamide

MS (ESI): m / z (%) = 426 (M + H.100):

HPLC (method 4): TA = 2.32 min

Example 88

N- (3- {3-Acetyl-4- (4-morpholinyl) phenyl1amino} -2-hydroxypropyl) -5-chloro-2-thiophenecarboxamide

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

HPLC (method 4): TA = 2.46 min

Example 89

N- (3 - {[3-Amino-4- (3-oxo-4-morpholinyl) pheninamino) -2-hydroxypropyl) -5-chloro-2thiophenecarboxamide

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

HPLC (method 4): TA = 2.45 min

Example 90

5-Chlorine-N- (3 - ([3-chloro-4- (2-methyl-3-oxo-4-morpholinyl) phenyl1amino) -2-hydroxypropyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 458 (M + H.100);

HPLC (method 4): TA = 3.44 min

Example 91

5-Chlorine-N- (3- (f3-chloro-4- (2-methyl-5-oxo-4-morpholinyl) pheninamino) -2-hydroxypropyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 458 (M + H.100);

HPLC (method 4): TA = 3.48 min

Example 91a

5-Chloro-N-f2-hydroxy-3 - ({4-r3-oxo-4-morpholinyl) metinfenyl) amino) propin-266 thiophenecarboxamide

Starting from 4- (4-amino-benzyl) -3-morpholinone (Surrey et al .: J.

Amer Chem. Soc .; 77; 1955; 633):

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

HPLC (method 4): TA = 2.66 min

General method for preparing 3-substituted 5-chloro-Nf (2oxo-1.3-oxazolidin-5-yl) methyl1-2-thiophenecarboxamide derivatives, starting from substituted N- (3-amino-2-hydroxypropyl) -5 derivatives -chloro-2-thiophenecarboxamide

<img file="BRPI0210941B1_D0040.tif" />

<img file="BRPI0210941B1_D0041.tif" />

Cl

To a solution of substituted N- (3-amino-2-hydroxypropyl) -5-chloro-2-thiocarboxamide derivative (1.0 eq.) In absolute THF (approximately 0.1 mol / l) is added at room temperature carbodiimidazole (1.2 to

1.8 eq.) Or a phosgene equivalent. The mixture is stirred at room temperature or, optionally, at the highest temperature (up to 70 ° C) for 2 to 18 hours, before being concentrated in vacuo. The product can be purified by chromatography on silica gel (mixtures of dichloromethane-methanol or mixtures of cyclohexane-acetic ester).

Similarly, the following were produced:

Example 27

Nr (3-Benzyl-2-oxo-1,3-oxazolidin-5-yl) metin-5-chloro-2-thiophenecarboxamide

EM (DCI, NH₄): m / z (%) = 372 (M + Na, 100), 351 (M + H, 45);

HPLC (method 1): TA (%) = 4.33 (100)

Example 28

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

EM (DCI, NH₄): m / z (%) = 362 (M + H, 42), 145 (100); HPLC (method 2): TA (%) = 4.13 min. (100)

Example 29

5-Chlorine-N - ({3-r4- (cyanomethyl) phenin-2-oxo-1,3-oxazolidin-5-yl} methyl) -2thiophenecarboxamide

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

HPLC (method 4): TA = 4.12 min Example 30

5-Chloro-N - (((3-r3- (cyanomethyl) phenin-2-oxo-1,3-oxazolidin-5-yl) methyl) -2thiophenecarboxamide

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

HPLC (method 4): TA = 4.17 min Example 92 tert-Butyl-4-f5 - (([(5-chloro-2-thienyl) carboninamino) methyl) -2-oxo-1,3-oxazolidin-3illbenzylcarbamate from Example 58:

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

HPLC (method 1): TA (%) = 4.51 (98.5)

Example 93 tert-Butyl-4- [5- (f [(5-chloro-2-thienyl) carboninamino) methyl-2-oxo-1,3-oxazolidin3-ill phenylcarbamate starting from Example 59:

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

HPLC (method 1): TA (%) = 4.41 (100)

Example 94 tert-Butyl-2-oxo-3-f4- (2-oxo-1-pyrrolidinyl) phenyl1-1.3-oxazolidin-5-yl) methylcarbate 25 starting from Example 60:

EM (DCI, NH₃): m / z (%) = 393 (M + NH₄,100);

HPLC (method 3): TA (%) = 3.97 (100)

Example 95

5-Chlorine-N - ({3-f3-fluorine-4- (3-oxo-4-morpholinyl) phenin-2-oxo-1,3-oxazolidin-5-yl) methyl) -2-thiophenecarboxamide

<img file="BRPI0210941B1_D0042.tif" />

260 mg (0.608 mmol) of 5-chloro-N - {[3-fluoro-4- (3-oxo-4-morpholinyl) phenyl] -amino} -2-hydroxypropyl-2-thiophenecarboxamide (from Example 61), 197 mg (1.22 mmol) of carbonylimidazole and 7 mg of dimethylaminopyridine are boiled in 20 ml of dioxane for 5 hours, under reflux. Subsequently, 20 ml of acetonitrile are added and stirred in a microwave oven in a closed container for 30 minutes at 180 ° C. The solution is concentrated by rotation and chromatographed on a RP-HPLC column, 53 mg (19% of theory) of the desired compound are obtained.

NMR (300 MHz; d₆-DMSO) δ: 3.6-3.7 (m, 4H), 3.85 (dd, 1H),

3.95 (m, 2H), 4.2 (m, 1H), 4.21 (s, 2H), 4.85 (m, 1H), 4.18 (s, 2H), 7.19 (d, 1H , thiophene), 7.35 (dd, 1H), 7.45 (t, 1H), 7.55 (dd, 1H), 7.67 (d, 1H, thiophene),

8.95 (t, 1H, CONH).

Example 96

5-Chloro-N-K2-oxo-3-phenyl-1,3-oxazolidin-5-yl) methyl1-2-thiophenecarboxamide starting from Example 62:

MS (ESI): m / z (%) = 359 ([M + Naf, 71), 337 ([M + Hf, 100), Cl standard; HPLC (method 3): TA (%) = 4.39 (100)

IC50: 2 μΜ

Example 97

5-Chloro-N- (f2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl1-1,3-oxazolidin-5-yl) -methyl) -2thiophenecarboxamide starting from Example 63:

MS (ESI): m / z (%) = 458 ([M + Na]⁺, 66), 436 ([M + H]⁺, 100), Cl standard; HPLC (method 3): TA (%) = 3.89 (100)

IC₅₀: 1.4 nM

Example 98

N-i (3- {4-rAcetyl (cyclopropyl) amino1-phenylD-2-oxo-1,3-oxazolidin-5-yl) metin-5-chloro2-thiophenecarboxamide starting from Example 64:

MS (ESI): m / z (%) = 456 ([M + Naf, 55), 434 ([M + Hf, 100), Cl standard; HPLC (method 3): TA (%) = 4.05 (100)

IC50: 50 nM

Example 99

N-i (3- {4-rAcetyl (methyl) amino1phenyl) -2-oxo-1,3-oxazolidin-5-yl) metin-5-chloro-2thiophenecarboxamide

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

HPLC (method 4): TA = 3.66 min

Example 100

5-Chlorine-N - ({2-oxo-3-r4- (1H-1,2,3-triazol-1-yl) phenill-1.3-oxazolidin-5-yl) -methyl) -2thiophenecarboxamide

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

HPLC (method 4): TA = 3.77 min

Example 101 tert-Butyl-1- {4-r5 - (([(5-chloro-2-thienyl) carboninamino} methyl) -2-oxo-1,3-oxazolidin

-S-infenill-L-prolinate

MS (ESI): m / z (%) = 450 (M + H-56, 25), 506 (M + H, 100);

HPLC (method 4): TA = 5.13 min

Example 102

1- (4-15 - ({r (5-chloro-2-thienyl) carbonyl1amino) methyl) -2-oxo-1,3-oxazolidin-3-yl1 phenyl)

-4-piperidincarboxamide

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

HPLC (method 4): TA = 2.51 min

Example 103

- (4-15 - ({f (5-chloro-2-thienyl) carboninamino) methyl) -2-oxo-1,3-oxazolidin-3-yl1-phenyl)

-3-piperidincarboxamide

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

HPLC (method 4): TA = 2.67 min

Example 104

5-Chloro-N - ({2-oxo-3-y4- (4-oxo-1-piperidinyl) phenin-1,3-oxazolidin-5-yl) -methyl) -2thiophenecarboxamide

MS (ESI): m / z (%) = 434 (M + H, 40), 452 (M + H + H₂O, 100), 475 (M + H + MeCN, 60);

HPLC (method 4): TA = 3.44 min

Example 105

1-í4- [5 - ({F (5-chloro-2-thienyl) carboninamino) methyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl}

-L-prolinamide

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

HPLC (method 4): TA = 3.54 min

Example 106

5-Chloro-NF (3- {4-f3-hydroxymethyl) -1-piperidininfenyl) -2-oxo-1,3-oxazolidin-5-yl) metin-2-thiophenecarboxamide

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

HPLC (method 5): TA = 2.53 min

Example 107

5-Chloro-NF (3- {4-f2-hydroxymethyl) -1-piperidininfenyl) -2-oxo-1,3-oxazolidin-5-yl) metill-2-thiophenecarboxamide

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

HPLC (method 5): TA = 2.32 min

Example 108

Ethyl 1- {4-F5 - ((((5-chloro-2-thienyl) carbonyl1amino} methyl) -2-oxo-1.3-oxazolidin-3-in phenyl) -4-piperidincarboxylate

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

HPLC (method 5): TA = 4.35 min

Example 109

5-Chloro-N- [3- {4-1,2- (hydroxymethyl) -1-pyrrolidinyl1-phenyl) -2-oxo-1.3-oxazolidin-5-yl) metin-2-thiophenecarboxamide

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

HPLC (method 4): TA = 2.98 min

Example 110

5-Chlorine-N - ((2-oxo-3-r4- (1-pyrrolidinyl) -3- (trifluormethyl) phenin-1.3-oxazolidin-5-ill · methyl) -2-thiophenecarboxamide

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

HPLC (method 4): TA = 4.63 min

Example 111

5-Chlorine-N - ((3- [4- (2-methylhexahydro-5H-pyrrolo [3,4-d] isoxazol-5-yl) phenin-2-oxo1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide

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

HPLC (method 4): TA = 2.56 min

Example 112

5-Chlorine-N - ((2-oxo-3-14- (2-oxo-1-pyrrolidinyl) -3- (trifluormethyl) phenin-1,3-oxazolidin

-5-yl) methyl) -2-thiophenecarboxamide

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

HPLC (method 4); TA = 3.64 min

Example 113

5-Chlorine-N - (((3-r3-chloro-4- (3-oxo-4-morpholinyl) phenin-2-oxo-1,3-oxazolidin-5-yl) methyl) -2-thiophenecarboxamide

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

HPLC (method 4): TA = 3.41 min

Example 114

5-Chloro-N - ({2-oxo-3- [4- (3-oxo-4-morpholinyl) -3- (trifluormethyl) phenyl1-1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 504 (M + H, 100);

HPLC (method 4): TA = 3.55 min

Example 115

5-Chlorine-N - ({3-f3-methyl-4- (3-oxo-4-morpholinyl) phenill-2-oxo-1,3-oxazolidin-5-yl) methyl!) - 2-t! Ofenocarboxamid3

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

HPLC (method 4): TA = 3.23 min

Example 116

5-CloiO-N - ((3-r3-cyano-4- (3-oxo-4-morpholinyl) phenin-2-oxo-1,3-oxazolidin-5-yl) methyl) -2-thiophenecarboxamide

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

HPLC (method 4): TA = 3.27 min

Example 117

5-Chloro-N- (f3-r3-chloro-4- (1-pyrrolidinyl) phenill-2-oxo-1,3-oxazolidin-5-yl} methyl) -2thiophenecarboxamide

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

HPLC (method 4): TA = 3.72 min

Example 118

5-Chlorine-N - ((3-3-chloro-4- (2-oxo-1-pyrrolidinyl) phenin-2-oxo-1.3-oxazolidin-5-ill · methyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 454 (M + H, 100);

HPLC (method 4): TA = 3.49 min

Example 119

5-Chlorine-N - (((3-r3,5-dimethyl-4- (3-oxo-4-morpholinyl) phenill-2-oxo-1,3-oxazolidin-5-yl) methyl) -2-thiophenecarboxamide

MS (ESI): m / z (%) = 464 (M + H, 100);

HPLC (method 4): TA = 3.39 min

Example 120

N - ({3-1,3- (aminocarbonyl) -4- (4-morpholinyl) phenyl1-2-oxo-1,3-oxazolidin-5-yl) methyl) 5-chloro-2-thiophenecarboxamide

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

HPLC (method 4): TA = 3.07 min

Example 121

5-Chloro-N - ({3-f3-methoxy-4- (4-morpholinyl) phenin-2-oxo-1,3-oxazolidin-5-yl} methyl) -2thiophenecarboxamide

MS (ESI): m / z (%) = 452 (M + H, 100);

HPLC (method 4): TA = 2.86 min

Example 122

N - ({3-f3-acetyl-4- (4-morpholinyl) phenill-2-oxo-1.3-oxazolidin-5-yl} methyl) -5-chlorothiophenecarboxamide

MS (ESI): m / z (%) = 464 (M + H, 100);

HPLC (method 4): TA = 3.52 min

Example 123

N - ({3-r3-amino-4- (3-oxo-4-morpholinyl) phenin-2-oxo-1,3-oxazolidin-5-yl) methyl) -5chloro-2-thiophenecarboxamide

MS (ESI): m / z (%) = 451 (M + H, 100);

HPLC (method 6): TA = 3.16 min

Example 124

5-Chlorine-N - ({3-3-chloro-4- (2-methyl-3-oxo-4-morpholinyl) phenin-2-oxo-1,3-oxazolidin-5-yl) methyl) -2- thiophenocarboxamide

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

HPLC (method 4): TA = 3.59 min

Example 125

5-Chlorine-N - ({3-f3-chloro-4- (2-methyl-5-oxo-4-morpholinyl) phenin-2-oxo-1,3-oxazolidin-5-yl} methyl) -2- thiophenocarboxamide

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

HPLC (method 4): TA = 3.63 min

Example 125a

5-Chloro-N-f2-oxo-3- / 4 - [(3-oxo-4-morylOlyl) metyriphenyl-1,3-oxazolidin-5-yl) methyl)

-2-thiophenecarboxamide

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

HPLC (method 4): TA = 3.25 min

Through the method of opening epoxide with an amine and subsequent cyclization to the corresponding oxazolidinone, in addition, the following compounds were produced:

<td>Example No.</td><td>Structure</td><td>Smp. [° CJ</td><td>EC₅₀ [μΜ]</td>

<td> 126</td><td>f ο Ίι s ^ClF</td><td>229Z</td><td> 3,013</td>

<td> 127</td><td>F 0⁰ I</td><td> 159</td><td> 0,0007</td>

<td> 128</td><td>θ O</td><td> 198</td><td> 0,002</td>

<td> 129</td><td>0 Qi-Qn ^ h / v_Br⁰ O</td><td> 196</td><td> 0,001</td>

<td> 130</td><td>⁰ O</td><td> 206</td><td> 0,0033</td>

<td>130a</td><td>F 0 r ~ λ&gt; = \ X_O ° ⁿA /) - n Y d FV-n 0 &amp;</td><td> 194</td><td></td>

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

<td> 132</td><td>0 &lt;/ γ</td><td> 206</td><td> 0,12</td>

<td> 133</td><td>F 0 ° v-,) —X Fn Χ3^Ν_/ ~ ν ·^Ν^ Α ^ Ν / ~ Y_Ç| O ^s</td><td> 217</td><td> 0,062</td>

<td>Example No.</td><td>Structure</td><td>Smp. [° C]</td><td>[Ç₅₀ [μΜ]</td>

<td> 134</td><td>OF θ 0 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>V 0 O</td><td> 202</td><td> 1,1</td>

<td> 136</td><td>O X</td><td> 239</td><td> 1,2</td>

<td> 137</td><td>0 T</td><td> 219</td><td> 0,044</td>

<td> 138</td><td>/ -Λ °^_Ο '“^^ΝιτΌ-α 0</td><td> 95</td><td> 0,42</td>

<td> 139</td><td>0 Ç^n_O ^ⁿ^ⁿkQ'c. O</td><td> 217</td><td> 1,7</td>

Examples 14 to 16 below are exemplary embodiments for the optional oxidation process step, that is, optionally occurring.

Example 14

5-Chlorine-N - «(5S) -3- [3-fluorine-4- (1 -oxo-1 Qambdal⁴, 4-thiazinan-4-yl) phenyl1-2-oxo1,3-oxo7! Idin-5-! Dmet !!) - 2-t! Ofenocarboxamide

<img file="BRPI0210941B1_D0043.tif" />

5-Chlorine-N - ({(5S) -3- [3-fluorine-4- (1,4-thiazinan-4-yl) phenyl] -2-oxo-1,3-oxazolidin-5-yl} methyl ) -2-thiophenecarboxamide (0.1 g, 0.22 mmol) of Example 3 in methanol (0.77 ml) is added at 0 ° C to a solution of sodium periodate (0.05 g, 0.23 mmol ) in water (0.54 ml) and stirred for 3 h at 0 ° C. Subsequently, 1 ml of DMF is added and stirred for 8 h at RT. After adding another 50 mg of sodium periodate, stir again at RT. Subsequently, the preparation is mixed with 50 ml of water and the non-soluble product is aspirated. After washing with water and drying, 60 mg (58% of theory) of crystals are obtained.

Smp .: 257 ° C;

Rf (silica gel, toluene / acetic ester 1: 1) = 0.54 (extract = 0.46);

CI value₅o -1.1 μΜ;

MS (INN) 489 (M + NH₄), standard of Cl.

Example 15

Preparation of 5-Chlorine-N- (f (5S) -3-14- (1,1-dioxo-1 Qambdal⁶, 4-thiazinan-4-yl) -320 fluorfenill-2-oxo-1,3-oxazolidin-5-yl) methyl) -2-thiophenecarboxamide

<img file="BRPI0210941B1_D0044.tif" />

5-Chlorine-N - ({(5S) -3- [3-fluor-4- (1,4-thiazinan-4-yl) phenyl] -2oxo-1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide from Example 3 (0.1 g, 0.22 mmol) in 3.32 m! of a mixture of 1 part water and 3 parts acetone with 80 mg (0.66 mmol) of N-methylmorpholin-N-oxide (NMO) and 0.1 ml of a solution with conc. 2.5% osmium tetroxide in 2-methyl-2-propanol. Stir overnight at room temperature and add 40 mg of NMO again. After being stirred for another night, the preparation is added to 50 ml of water and extracted three times with acetic ester. From the organic phase, after drying and concentration by evaporation, 23 mg are obtained and from the aqueous phase, after aspiration of the non-soluble solid, 19 mg (in total, 39% of theory) of the desired compound.

Smp .: 238 ° C;

Rf (toluene / acetic ester 1: 1) = 0.14 (extract = 0.46);

IC50 value = 210 nM;

MS (INN): 505 (M + NH₄), standard of Cl.

Example 16

5-Chloro-N- {f (5S) -3- (3-fluor-4-morpholinophenyl) -2-oxo-1,3-oxazolidin-5-inmethyl) -2thiophenecarboxamide N-oxide is obtained by treatment of 5- chloro-N - ([(5S) -3- (3-fluoro-4-morpholinopheniD-2-oxo-1,3-oxazolidin-5-ylmethyl) -2-thiophenecarboxamide of Example 1 with monoperoxyphthalic acid-magnesium salt.

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

Examples 31 to 35 and 140 to 147 below refer to the optional amidination process step, that is, which optionally occurs.

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

The 5-chloro-N - [(2-oxo-1,3-oxazolidin-5-yl) methyl] -2-thiophenecarboxamide derivative, substituted with cyanomethylphenyl (1.0 eq.) Is stirred together with triethylamine (8, 0 eq.) For one to two days at RT in a saturated solution of sulfuric acid in pyridine (approximately 0.05 - 0.1 mol / l). The reaction mixture is diluted with ethyl acetate (EtOAc) and washed with 2 N hydrochloric acid. The organic phase is dried with MgSO₄, filtered and concentrated by vacuum evaporation.

The crude product is dissolved in acetone (0.01-0.1 mol / l) and mixed with methyl iodide (40 eq.). The reaction mixture is stirred for 2 to 5 h at room temperature (RT) and then concentrated in vacuo.

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

Similarly, the following were produced:

Example 31:

N-í (3-í4- (2-Amino-2-iminoethyl) phenin-2-oxo-1,3-oxazolidin-5-yl | methyl) -5-chloro-2thiophenecarboxamide

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

HPLC (method 4): TA = 2.63 min

Example 32:

5-Chloro-N - ({3-r3- (4,5-dihydro-1H-imidazol-2-ylamethyl) phenin-2-oxo-1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide

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

HPLC (method 4): TA = 2.61 min

Example 33:

5-Chlorine-N - [(3- {3-r2-imino-2- (4-morpholinyl) ethynphenyl} -2-oxo-1,3-oxazolidin-5-yl) metin-2-thiophenecarboxamide

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

HPLC (method 4): TA = 2.70 min

Example 34:

5-Chloro-Nf (3- (3-r2-imino-2- (1-pyrrolidinyl) ethyl1-phenyl) -2-oxo-1,3-oxazolidin-5-yl) metin-2-thiophenecarboxamide

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

HPLC (method 4): TA = 2.82 min

Example 35:

N - ({3- (2-amino-2-iminoethyl) phenin-2-oxo-1.3-oxazolain-5-yl) methyl) -5-chloro-2-thiophenecarboxamide

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

HPLC (method 4): TA = 2.60 min

Example 140:

5-Chlorine-N - ((3-f4- (4,5-dihydro-1H-imidazol-2-ylmethyl) phenyl1-2-oxo-1,3-oxazolidin5-yl) methyl) -2-thiophenecarboxamide

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

HPLC (method 4): TA = 2.65 min

Example 141:

5-Chlorine-N-R3- {4- [2-imino-2- (4-morpholinyl) ethylphenyl} -2-oxo-1₁3-oxazolidin-5-yl) metin-2-thiophenecarboxamide

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

HPLC (method 4): TA = 2.65 min

Example 142:

5-Chloro-N-i (3- (4-f2-imino-2- (1-piperidinyl) ethyl1-phenyl} -2-oxo-1.3-oxazolidin-5-yl) metin-2-thiophenecarboxamide

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

HPLC (method 4): TA = 2.83 min

Example 143:

5-Chloro-N-i (3- {4-1,2-imino-2- (1-pyrrolidinyl) ethinfenyl) -2-oxo-1,3-oxazolidin-5-yl) methyl-2-thiophenecarboxamide

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

HPLC (method 4): TA = 2.76 min

Example 144:

5-Chloro-Nr (3-f4-r2- (cyclopentylamino) -2-iminoethyriphenyl} -2-oxo-1,3-oxazolidin-5iDmetin-2-thiophenecarboxamide

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

HPLC (method 4): TA = 2.89 min

Example 145:

5-Chloro-N- {f3- (4- {2-imino-2-R2,2.2-trifluorethyl) amino1ethyl) phenyl) -2-oxo-1.3oxazolidin-5-methylmethyl} -2-thiophenecarboxamide

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

HPLC (method 4): TA = 2.79 min

Example 146:

N - ((3- [4- (2-Anilino-2-iminoethyl) phenill-2-oxo-1,3-oxazolidin-5-yl) methyl) -5-chloro-2thiophenecarboxamide

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

HPLC (method 4): TA = 2.83 min

Example 147:

5-Chloro-Nf (3-f4-1,2-imino-2- (2-pyridinylamino) ethylphenyl) -2-oxo-1,3-oxazolidin-5yl) metin-2-thiophenecarboxamide

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

HPLC (method 4): TA = 2.84 min

Examples 148 to 151 below refer to the separation of BOC-amino protecting groups:

General method for separating Boc protection groups (tert-butyloxycarbonyl):

RN OH

To an ice-cooled solution of a compound protected by tert-butyloxycarbonyl (Boc) in chloroform or dichloromethane (approximately 0.1 to 0.3 mol / l) is added, in drops, trifluoroacetic acid (TFA, approximately 90%). After 15 min, the refrigeration with ice is removed and the mixture is stirred for approximately 2-3 h at room temperature, before the solution is concentrated and dried in a high vacuum. The residue is added to dichloromethane or dichloromethane / methanol and washed with saturated sodium hydrogencarbonate solution or 1N sodium hydroxide solution. The organic phase is washed with a saturated sodium chloride solution, dried with a little magnesium sulfate and concentrated. Optionally, purification is carried out by crystallization from ether or ether / dichloromethane mixtures.

Similarly, the corresponding Boc-protected precursors were produced:

Example 148

N - ({3- [4- (Aminomethyl) phenyl1-2-oxo-1.3-oxazolidin-5-yl) -methyl) -5-chloro-2-thiophenecarboxamide starting from Example 92:

MS (ESI): m / z (%) = 349 (M-NH₂, 25), 305 (100);

HPLC (method 1): TA (%) = 3.68 (98)

IC50: 2.2 μΜ Example 149

N- (f3-r4- (Aminophenyl) -2-oxo-1,3-oxazolidin-5-yl) -methyl) -5-chloro-2-thiophenecarboxamide starting from Example 93: MS (ESI): m / z ( %) = 352 (M + H, 25); HPLC (method 1): TA (%) = 3.50 (100) IC50: 2 μΜ

An alternative synthesis, of enanciomeric purity, of this compound is described in the following scheme (compare also Delalande SA, DE

<img file="BRPI0210941B1_D0045.tif" />

<img file="BRPI0210941B1_D0046.tif" />

Cl

1. ) Fitalimide DEAD / PPh₃ θ_χ

2. ) nh, nh..h ~ O ⁱⁿ ethanol ^ no

3. ) 5-chloro-2-thiophenecarboxylic acid

<img file="BRPI0210941B1_D0047.tif" />

O

Example 150

5-Chloro-N - (((3-f4- (glycylamino) phenyl-2-oxo-1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide starting from Example 152:

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

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

IC50: 2 μΜ

Example 151

5- (Aminomethyl) -3- [4- (2-oxo-1-pyrrolidinyl) phenin-1,3-oxazolidin-2-one starting from Example 60:

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

HPLC (method 3): TA (%) = 2.99 (100)

IC50: 2 μΜ

Examples 152 to 166 below refer to the derivatization of amino groups of oxazolidinones substituted with aniline or benzylamine, with several reagents:

Example 152

5-Chloro-N - ({3-- (N-tert-butyloxycarbonyl-qlicylamino) phenill-2-oxo-1,3-oxazoli20 din-5-yl) methyl) -2-thiophenecarboxamide

<img file="BRPI0210941B1_D0048.tif" />

To a solution of 751 mg (4.3 mmoles) of Boc-glycine, 870 mg (6.4 mmoles) of HOBT (1-hydroxy-1H-benzotriazole x H₂O), 1790 mg (4.7 mmoles) of HBTU [O- (benzotriazol-1-yl) -N, N, N ', N'tetramethyluroniumhexafluorphosphate] and 1.41 ml (12.9 mmoles) of N-methylmorfolin in 15 ml of DMF / CH2 Cl2 (1: 1) 754 mg (2.1 mmol) of N - {[3- (4-aminophenyl) -2-oxo-1,3-oxazolidin-5 are added at 0 ° C -yl] methyl} -5-chloro-2thiophenecarboxamide (from Example 149). The mixture is stirred overnight at room temperature, before dilution with water. The precipitated solid is filtered off and dried. Yield: 894 mg (79.7% of theory):

EM (DCI, NH₃): m / z (%) = 526 (M + NH₄,100);

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

Example 153

N-í (3-f4-r (Acetylamino) metinfenil} -2-oxo-1,3-oxazolidin-5-yl) rnetin-5-chloro-2-thio-

<img file="BRPI0210941B1_D0049.tif" />

O

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 10 pius 148) in 1.5 ml of absolute THF and 1.0 ml of absolute dichloromethane, 0.02 ml of absolute pyridine is mixed at 0 ° C with acetane hydride (0.015 ml, 0.164 mmol). The mixture is stirred overnight at room temperature. After adding ether and crystallization, the product is obtained. Yield: 30 mg (87% of theory).

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

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

IC50: 0.6 μΜ

Example 154

N- {f3- (4 - {[(Aminocarbonyl) aminolmethyl) phenyl) -2-oxo-1.3-oxazolidin-5-in-methyl) 20 5-chloro-2-thiophenecarboxamide

<img file="BRPI0210941B1_D0050.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 Exem84 pio 148) in 1.0 ml of dichloromethane, 0.19 ml (0.82 mmol) of trimethylsilylisocyanate are added dropwise to the room temperature. Stir overnight before adding the product by ether by filtration. Yield: 21.1 mg (52% of theory),

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

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

IC50: 1.3 μΜ

General method for acylation of N- {(3-- 4-aminophenyl) -2-oxo-1,3-oxazolidin-5-illmetyl) -5-chloro-2-thiophenecarboxamide with carboxylic acid chlorides:

<img file="BRPI0210941B1_D0051.tif" />

Under argon, a solution of approximately 0.1 mol of N - {[3- (4aminophenyl) -2-oxo-1,3-oxazolidin-5 is added dropwise to the corresponding acid chloride (2.5 eq.) -yl] -methyl} -5-chloro-2-thiophenecarboxamide (from Example 149) (1.0 eq.) in absolute dichloromethane / pyridine (19: 1). The mixture is stirred overnight, before mixing with approximately 5 eq. in

PS-Tris-amine (Argonaut Technologies) and 2 ml of absolute dichloromethane. After a slight stirring for 1 h, it is filtered and the filtration product is concentrated. Optionally, the products are purified by preparative RP-HPLC.

Similarly, the following were produced:

Example 155

N - (((3-44- (acetylamino) phenill-2-oxo-1,3-oxazolidin-5-yl) -methyl) -5-chloro-2-thiophenecarboxamide

LC-MS: m / z (%) = 394 (M + H, 100): LS-MS (method 6): TA (%) = 3.25 (100)

IC50: 1.2 μΜ Example 156

5-Chlorine-N - [(2-oxo-3-f4-i (2-thienylcarbonii) amino1phenyl) -1.3-oxazolidin-5-yl) metin-2-thiophenecarboxamide

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

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

IC50: 1.3 μΜ

Example 157

5-chloro-Nr (3-f4 - [(nnethoxyacetyl) amino1phenyl) -2-oxo-1,3-oxazolidin-5-yl) -metin-210 thiophenecarboxamide

LC-MS: m / z (%) = 424 (M + H, 100):

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

IC50: 0.73 μΜ

Example 158

N- {4-5 - ((r (5-chloro-2-thienyl) carboninamino} methyl) -2-oxo-1,3-oxazolidin-3-ill-phenyl)

-3,5-dimethyl-4-isoxazolcarboxamide

LC-MS: m / z (%) = 475 (M + H, 100):

IC50: 0.46 μΜ Example 159

5-Chloro-N - ([3- (4- (f (3-chloropropyl) sulfoninamino} phenyl) -2-oxo-1.3-oxazolidin-5in-methyl) -2-thiophenecarboxamide

<img file="BRPI0210941B1_D0052.tif" />

To an ice-cooled solution of 26.4 mg (0.15 mmol) of 3-chloro-1-chloride of propanesulfonic acid and 0.03 ml (0.2 mmol) of triethyl25 lamine in 3.5 ml of absolute dichloromethane 35 mg (0.1 mmol) of N - {[3- (4- (aminophenyl) -2-oxo-1,3-oxazolidin-5-yl] -methyl} -5-chloro-2thiophenecarboxamide (from Example 149). After 30 min, the ice cooler is removed and the mixture is stirred overnight at room temperature, before adding 150 mg (approximately 5.5 eq.) Of PSTrisamine (Argonaut Technologies) and 0.5 ml of dichloromethane . The suspension is stirred slightly for 2 h, filtered (the resin is washed further with dichloromethane / methanol) and the filtration product is concentrated. The product is purified by preparative RP-HPLC. Yield: 19.6 mg (40% of theory). LC-MS: m / z (%) = 492 (M + H, 100):

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

IC50: 1.7 μΜ

Example 160

5-Chloro-N - ((3- [4- (1.1-dioxide-2-isothiazolidinyl) phenill-2-oxo-1,3-oxazolidin-5-yl) methyl) -2-thiophenecarboxamide

<img file="BRPI0210941B1_D0053.tif" />

A mixture of 13.5 mg (0.027 mmol) of 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 is heated for 2 h to 100 ° C. After cooling, dilute with dichloromethane and wash 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): TA (%) = 3.81 (90)

IC₅₀: 0.14 μΜ Example 161

5-Chlorine-N - [((5S) -3- (4-f (5-chloropentanoyl) amino1phenyl} -2-oxo-1.3-oxazolidin-5yl) -metin-2-thiophenecarboxamide

<img file="BRPI0210941B1_D0054.tif" />

0.5 g (1.29 mmol) of N - {[(5S) -3- (4-aminophenyl) -2-oxo-1,3-oxazolidin-5-ylmethyl} -5-chloro-2-thiophenecarboxamide ( of Example 149) are dissolved in 27 ml of tetrahydrofuran and mixed with 0.2 g (1.29 mmol) of 5-chloro-valerianic chloride, as well as 0.395 ml (2.83 mmol) of triethylamine. The preparation is concentrated by vacuum evaporation and chromatographed on silica gel with a gradient of toluene / acetic ester = 1: 1 -&gt; acetic ester. 315 mg (52% of theory) of a solid are obtained.

Smp.:211°C.

Example 162

5-Chlorine-N - ((((5S) -2-oxo-3-f4- (2-oxo-1-piperidinyl) phenyl1-1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide

<img file="BRPI0210941B1_D0055.tif" />

Under inert conditions, 5 ml of DMSO 30 mg NaH with conc. 60% in paraffin oil and heat for 30 min to 75 ° C, until the end of gas formation. Subsequently, a 290 mg (0.617 mmol) solution of 5-chloro-N - [((5S) -3- {4 - [(5chloropentanoyl) amino] phenyl} -2-oxo-1 is added in drops , 3-oxazolidin-5-yl) methyl] -2thiophenecarboxamide (from Example 161) in 5 ml of methylene chloride and stir overnight at room temperature. The reaction is stopped and the mixture is poured into 100 ml of water and extracted with acetic ester. The concentrated organic phase by evaporation is chromatographed on an RP-8 column and extracted with acetonitrile / water. 20 mg (7.5% of theory) of the desired compound are obtained.

Smp .: 205 ° C;

NMR (300 MHz, d₆-DMSO) δ: 1.85 (m, 4H), 2.35 (m, 2H), 3.58 (m, 4H), 3.85 (m, 1H), 4.2 (t, 1H), 4.82 (m, 1H), 7.18 (d, 1H, thiophene), 7.26 (d, 2H), 7.5 (d, 2H), 2.68 (d, 1H, thiophene), 9 , 0 (t, 1H, CONH).

IC50- 2.8 ηΜ

Example 163

5-Chloro-Nf ((5S) -3- {4-i (3-bromopropionyl) amino1phenyl} -2-oxo-1,3-oxazolidin-5yl) -methyl-2-thiophenecarboxamide

<img file="BRPI0210941B1_D0056.tif" />

is obtained analogously to Example 149.

Example 164

5-Chlorine-N - ({(5S) -2-oxo-3- [4- (2-oxo-1-azetidinyl) phenin-1,3-oxazolidin-5-inmetiO-2-thiophenecarboxamide

<img file="BRPI0210941B1_D0057.tif" />

it is obtained in an analogous manner, by cyclizing the open chain bromopropionyl compound of Example 163 by means of NaH / DMSO.

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

IC50: 380 nM

Example 165 tert-Butyl-4- {4- [5- (í (5-chloro-2-thienyl) carbonylamino) methyl) -2-oxo-1,3-oxazolidin3-infenyl) -3,5-dioxo-1 -piperazincarboxylate

<img file="BRPI0210941B1_D0058.tif" />

To a solution of 199 mg (0.85 mmol) of Boc iminodiacetic acid, 300 mg (2.2 mmoles) of HOBT, 0.66 ml (6 mmoles) of N-methylmor89 folin and 647 mg (1.7 mmol ) of HBTU are added 300 mg (0.85 mmol) of N - {[3- (4-aminophenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl} -5-chloro-2-thiophenecarboxamide in 6 m! of a mixture of DMF and dichloromethane (1: 1). The mixture is stirred overnight, before washing, after dilution with dichloromethane, with water, saturated ammonium chloride solution, saturated sodium hydrogencarbonate solution, water and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The crude product is 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): TA (%) = 4.39 (90)

IC50: 2 μΜ

Example 166

Nf ((5S) -3- {4-r (3R) -3-Amino-2-oxo-1-pinOlidininfenyl} -2-oxo-1,3-oxazolidin-5-yl) metin-5-chloro-2 -thiophencarboxamide trifluoracetate

<img file="BRPI0210941B1_D0059.tif" />

O

N2- (tert-Butoxycarbonyl) -N1- {4 - [(5S) -5- (f [(5-chloro-2-thienyl) carbonyl1amino} methyl)

-2-oxo-1.3-oxazolidin-3-infenyl) -D-methioninamide

429 mg (1.72 mmol) of N-BOC-D-methionine, 605 mg (1.72 mmol) of N - {[(5S) -3- (4-aminophenyl) -2-oxo-1,3-oxazolidin -5-yl] methyl} -5-chloro-2-thiophenecarboxamide and 527 mg (3.44 mmoles) of HOBT-hydrate are dissolved in 35 ml of DMF, mixed with 660 mg (3.441 mmoles) of EDCI hydrochloride and subsequently , mixed, in drops, with 689 mg (5.334 mmoles) of N-ethyl-diisopropylamine. Stir at room temperature for two days. The obtained suspension is aspirated and the residue is washed with DMF. The unified filtration products are mixed with a little silica gel, concentrated by vacuum evaporation and chromatographed on silica gel with a gradient of toluene -&gt; T10EE7. 170 mg (17% of theory) of the desired compound are obtained, with a melting point of 183 ° C.

Rf (SiO₂, toluene / acetic ester 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 an AB system, 2H), 7.6 (d, part of an AB system, 2H), 7.7 (d, 1H, thiophene), 8.95 (t, 1H, CH₂NHCO), 9.93 (bs, 1H, NH).

tert-Butyl (3) -1 - {4-r (5S) -5 - ({r (5-chloro-2-thienyl) carboninamino} methyl) -2-oxo-1,3oxazolidini-3-infenyl) -2 -oxo-3-pyrrolidinylcarbamate

170 mg (0.292 mmol) of N2- (tert-butoxycarbonyl) -N1- {4 - [(5S) -5 ({[(5-chloro-2-thienyl) carbonyl] amino} methyl) -2-oxo-1, 3-oxazolidin-3-yl] phenyl} -D-methioninamide are dissolved in 2 ml of DMSO and mixed with 178.5 mg (0.875 mmol) of trimethylsulfonium iodide, as well as 60.4 mg (0.437 mmol) of carbonate potassium and stirred for 3.5 hours at 80 ° C. Subsequently, it is concentrated by evaporation in a high vacuum and the residue is washed with ethanol. 99 mg of the desired compound remains.

¹H-NMR (300 MHz, d_and-DMSO): δ = 1.4 (s, 1H, BOC), 1.88-2.05 (m, 1H), 2.32.4 (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 an AB system, 2H), 7.65 (d, part of a system of AB, 2H), 7.65 (d, 1H, thiophene), 9.0 (broad s, 1H).

Nr (((5S) -3- (4-f (3R) -3-Amino-2-oxo-1-pyrrolidininfenyl) -2-oxo-1.3-oxazolidin-5yl) metill-5-chloro-2-thiophenecarboxamide trifluoracetate mg (0.181 mmol) of tert-butyl (3R) -1- {4 - [(5S) -5 - ({[(5-chloro-2-thienyl) carbonyl] amino} methyl) -2-oxo-1,3-oxazolidin -3-yl] phenyl} -2-oxo-3-pyrrolidinylcarbamate are suspended in 4 ml of methylene chloride, 1.5 ml of trifluoroacetic acid are added and stirred for 1 hour at room temperature. Subsequently, it is concentrated by vacuum evaporation and purified on an RP-HPLC (gradient of acetonitrile / water / 0.1% TFA). After concentration by evaporation of the corresponding fraction, 29 mg (37% of theory) of the desired compound are obtained, with a melting point of 241 ° C (decomposition).

RXSiO₂, 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 an AB system, 2H), 7.7 (d, part of an AB system, 2H), 7.68 (d, 1H, thiophene), 8.4 (wide s, 3H , NH3), 8.9 (t, 1H, NHCO).

Examples 167 to 170 below refer to the introduction of sulfonamide groups in oxazolidinones substituted with phenyl:

General method for preparing substituted sulfonamides starting from 5-chlorine

-N-K2-oxo-3-phenyl-1,3-oxazolidin-5-yl) metin-2-thiophenecarboxamide

<img file="BRPI0210941B1_D0060.tif" />

O

Chlorosulfonic acid (12 eq.) Is added, under argon to

5 ° C, 5-chloro-N - [(2-oxo-3-phenyl-1,3-oxazolidin-5-yl) methyl] -2-thiophenecarboxamide (from Example 96). The reaction mixture is stirred for 2 h at room temperature and subsequently poured over ice water. The precipitated precipitation is filtered, washed with water and dried.

Subsequently, it dissolves under argon, at room temperature, in tetrahydrofuran (0.1 mol / l) and mixed with the corresponding amine (3 eq.) Triethylamine (1.1 eq.) And dimethylaminopyridine (0.1 eq. .). The reaction mixture is stirred for 1-2 h and subsequently concentrated in vacuo. The desired product is purified by means of flash chromatography (dichloromethane-methanol mixtures).

Similarly, the following were produced:

Example 167

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

MS (ESI): m / z (%) = 492 ([M + Naf, 100), 470 ([M + Hf, 68), Cl HPLC standard (method 3): TA (%) = 4.34 ( 100);

IC₅₀: 0.5 μΜ

Example 168

5-Chloro-Nf (3- (4-r (4-methyl-1-piperazinyl) sulfonyl-phenyl) -2-oxo-1,3-oxazolidin-5-yl) metin-2-thiophenecarboxamide

MS (ESI): m / z (%) = 499 ([M + Naf, 100), Cl standard;

HPLC (method 2): TA (%) = 3.3 (100)

Example 169

5-Chloro-N- (f2-oxo-3- [4- (1-piperidinylsulfonyl) pheniri-1,3-oxazolidin-5-yl) methyl) -2thiophenecarboxamide

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

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

Example 170

5-Chloro-N - [(- 3- {4-r (4-hydroxy-1-piperidinyl) sulfonin-phenyl) -2-oxo-1,3-oxazolidin5-yl) metin-2-thiophenecarboxamide

MS (ESI): m / z (%) = 500 ([M + Naf, 100), Cl standard;

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

Example 171

5-Chloro-N - (((2-oxo-3- [4- (1-pyrrolidinyl) phenin-1,3-oxazolidin-5-yl) methyl) -2-thiophenecarboxamide

<img file="BRPI0210941B1_D0061.tif" />

780 mg (1.54 mmol) of tert-butyl-1- {4- [5 - ({[(5-chloro-2-thienyl) carbonyl] amino} 5 methyl) -2-oxo-1,3-oxazolidin- 3-yl] phenyl} prolinate are dissolved in 6 ml of dichloromethane and 9 ml of trifluoroacetic acid and the mixture is stirred for two days at 40 ° C. Then, the reaction mixture is concentrated and mixed with ether and 2 N sodium hydroxide. The aqueous phase is concentrated and mixed with ether and 2 N hydrochloric acid. The organic phase of this extraction is dried using MgSCL, filtered and concentrated. The crude product is chromatographed on silica gel (CH₂CI₂/ EtOH / sol. from NH₃-LSG. = 100/1 / 0.1 to 20/1 / 0.1). 280 mg (40% of product theory) are obtained.

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

HPLC (method 4): TA = 3.81 min.

HPLC parameters and LC-EM parameters of the HPLC and LC-EM data indicated in the preceding examples (the unit of the retention time (TA) is minutes):

[1] Column: Kromasil C18, LR temperature: 30 ° C, flow = 0.75 mlmiri¹, extraction agent: A = 0.01 M HCIO₄, B = CH₃CN, gradient: -&gt;

0.5 min 98% A -&gt; 4.5 min 10% A -&gt; 6.5 min 10% A.

[2] Column: Kromasil C18 60 * 2, LR temperature: 30 ° C, flow = 0.75 mlmiri¹, extracting agent: A = 0.01 M H₃POWDER₄, B = CH₃CN, gradient: -&gt; 0.5 min 90% A -&gt; 4.5 min 10% A -&gt; 6.5 min 10% A.

[3] Column: Kromasil C18 60 * 2, LR temperature: 30 ° C, flow =

0.75 mlmin '¹, extracting agent: A = 0.005 M HCIO4, B = CH₃CN, gradient: -&gt; 0.5 min 98% A .-&gt; 4.5 min 10% A -&gt; 6.5 min 10% A.

[4] Column: Symmetrv G18 2.1x150 mm, column oven: 50 ° C, flow = 0.6 ml / min¹, extracting agent: A = 0.6 g HCI conc. 30% / l water, B = CH₃CN, gradient: 0.0 min 90% A -&gt; 4.0 min 10% A -&gt; 9 min 10% A.

[5] MHZ-2Q, Instrument Micromass Quattro LCZ

Symmetry C18 column, 50 mm x 2.1 mm, 3.5 μιτι, temperature: 40 ° C, flow = 0.5 ml min '¹, extracting agent A = CH₃CN + 0.1% formic acid, extraction agent B = water + 0.1% formic acid, gradient: 0.0 min 10% A -&gt; 4 min 90% A-&gt; 6 min 90% A [6 ] MHZ-2P, Instrument Micromass Platform LCZ

Symmetry C18 column, 50 mm x 2.1 mm, 3.5 μιτι, temperature: 40 ° C, flow = 0.5 ml / min¹, extracting agent A = CH₃CN + 0.1% formic acid, extraction agent B = water + 0.1% formic acid, gradient: 0.0 min 10% A -&gt; 4 min 90% A-&gt; 6 min 90% A [7 ] MHZ-7Q, Instrument Micromass Quattro LCZ

Symmetry C18 column, 50 mm x 2.1 mm, 3.5 μιτι, temperature: 40 ° C, flow = 0.5 ml / min¹, extracting agent A = CH₃CN + 0.1% formic acid, extraction agent B = water + 0.1% formic acid, gradient: 0.0 min 5% A -&gt; 1 min 5% A -&gt; 5 min 90% A-&gt; 6 min 90% A

General method for preparing oxazolidinones of general formula B by solid phase assisted synthesis

Reactions with different resin-bonded products occurred in a set of separate reaction vessels.

5- (Bromomethyl) -3- (4-fluor-2-nitrophenyl) -1,3-oxazolidin-2-one A (prepared from epibromhydrin and 4-fluor-3-nitrophenylisocyanate with LiBr / Bu₃PO in xylene, analogously to US 4128654, Ex. 2) (1.20 g, 3.75 mmoles) and ethyldiisopropylamine (DIEA, 1.91 ml, 4.13 mmoles) were dissolved in DMSO (70 ml), mixed with a secondary amine (1.1 eq., amine component 1) and reacted for 5 h at 55 ° C. To this solution, TentaGel SAM resin (5.00 g, 0.25 mmol / g) was added and reacted for 48 h at 75 ° C. The resin was filtered and repeatedly washed with methanol (MeOH), dimethylformamide (DMF), MeOH, dichloromethane (DCM) and diethyl ether and dried. The resin (5.00 g) was suspended in dichloromethane (80 ml), mixed with DIEA (10 eq) and 5-chlorothiophene-2-carboxylic acid chloride [produced by reaction of 5-c! Orothiophene-2-carboxylic acid (5 eq.) And 1-chloro-1-dimethylamino-2-methylpropene (5 eq.) In DCM (20 ml) at room temperature for 15 minutes] and reacted for 5 h at room temperature. The obtained resin was filtered and repeatedly washed with MeOH, DCM and diethyl ether and dried. Subsequently, the resin was suspended in DMF / water (v / v 9: 2, 80 ml), mixed with SnCI₂* 2H₂O (5 eq.) And reacted for 18 h at room temperature. The resin was again washed repeatedly with MeOH, DMF, water, MeOH, DCM and diethyl ether and dried. This resin was suspended in DCM, with DIEA (10 eq.) And mixed at 0 ° C with an acid chloride (5 eq. Of acid derivative 1) and reacted overnight at room temperature. The carboxylic acids were transformed before the reaction, by reaction with 1-dimethylamino-1-chloro-2-methylpropene (1 eq., With respect to the carboxylic acid) in DCM at room temperature, for 15 min, in the corresponding acid chlorides. The resin was repeatedly washed with DMF, water, DMF, MeOH, DCM and diethyl ether and dried. In the case of the use of Fmoc protected amino acids as an acid derivative 1, the Fmoc protection group was separated in the last reaction step by reaction with piperidine / DMF (v / v, 1/4) at room temperature, for 15 minutes and the resin was washed with DMF ,. MeOH, DCM and diethyl ether and dry. The products were subsequently separated with trifluoroacetic acid (TFA) / DCM (v / v, 1/1) from the solid phase, the resin was filtered and the reaction solutions were concentrated by evaporation. The crude products were filtered through silica gel (DCM / MeOH, 9: 1) and concentrated, to obtain a set of B products.

<img file="BRPI0210941B1_D0062.tif" />

<img file="BRPI0210941B1_D0063.tif" />

TFA / DCM,

1/1 ^ = ο

<img file="BRPI0210941B1_D0064.tif" />

Compounds produced by solid phase assisted synthesis

Example 172

Ν - (((3-Γ3-Απιϊηο-4- (1-pyrrolidinyl) phenin-2-oxo-1,3-oxazolidin-5-yl) methyl) -5-chloro-2-

<img file="BRPI0210941B1_D0065.tif" />

Similarly to the general work instruction for the production of derivatives B, 5 g (1.25 mmol) of TentaGel SAM resin were reacted with pyrrolidine as an amine derivative 1. The aniline obtained after reduction with SnCl2 * 2H2o was separated from the solid phase without another acylation step and concentrated. The crude product was distributed between ethyl acetate and

NaHCO3, the organic phase was desalted with NaCI, decanted and concentrated to dryness. This crude product was purified by vacuum flash chromatography on silica gel (dichloromethane / ethyl acetate, 3: 1 -1: 2).

¹H-NMR (300 MHz, CDCI₃): 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

Nf (3-f3- (8-Alanylamino) -4í (3-hydrOxypropyl) amino1phenyl) -2-oxo-1,3-oxazolidin5-iD-metin-5-chloro-2-thiophenecarboxamide

<img file="BRPI0210941B1_D0066.tif" />

Similarly to the general work instruction for the production of the 20 derivatives B, 5 g (1.25 mmol) of TentaGel SAM resin were reacted with azetidine as an amine derivative 1 and Fmoc-p-alanine as an acid derivative 1. The crude product obtained after separation it was stirred for 48 h in methanol at room temperature and concentrated by evaporation until dry. This crude product was purified by Reversed Phase HPLC with a water / TFA / acetonitrile gradient.

<img file="BRPI0210941B1_D0067.tif" />

<img file="BRPI0210941B1_D0068.tif" />

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-nitrophenin-2-oxo-1.3-oxazolidin-5-yl} -methyl) -5chloro-2-thiophenecarboxamide

Cl

AT THE.

<img file="BRPI0210941B1_D0069.tif" />

N

Similarly to the general work instruction for the production of B derivatives, 130 g (32.5 pmoles) of TentaGel SAM resin were reacted with tert-butyl 3-pyrrolidinylcarbamate as amine derivative 1. The nitrobenzene derivative obtained after acylation with acid 5 -chlorothiophenocarboxylic was separated from the solid phase and concentrated by evaporation. This crude product was purified by Reversed Phase HPLC with a water / TFA / acetonitrile gradient.

<img file="BRPI0210941B1_D0070.tif" />

Example 175

N - ((3-1,3-amino-4- (1-piperidinyl) phenin-2-oxo-1,3-oxazolidin-5-yl) -methyl) -5-chloro2-thiophenecarboxamide

<img file="BRPI0210941B1_D0071.tif" />

Cl

O

Analogous to the general work instruction for the production of B derivatives, 130 mg (32.5 pmoles) of TentaGel SAM resin were reacted with piperidine as an amine derivative 1. The aniline obtained after reduction was separated without another solid phase acylation step and was concentrated by evaporation. This crude product was purified by Reversed Phase HPLC with a water / TFA / acetonitrile gradient.

¹H-NMR (400 MHz, CD₃OD): 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 176

N - ({3-f3- (Acetylamino) -4- (1-pyrrolidinyl) phenin-2-oxo-1,3-oxazolidin-5-yl) -methyl)

-5-chloro-2-thiophenecarboxamide

<img file="BRPI0210941B1_D0072.tif" />

Similarly to the general work instruction for the production of derivatives B, 130 mg (32.5 pmoles) of TentaGel SAM resin were reacted with pyrrolidine as an amine derivative 1 and acetyl chloride as an acid derivative 1. The crude product was divided between ethyl acetate and NaHCO3 solution, the organic phase was desalted with NaCI, decanted and concentrated by evaporation until drying. This crude product was purified by vacuum chromatography on silica gel (dichloromethane / ethyl acetate, 1: 1-0: 1). ¹H-NMR (400 MHz, CD₃OD): 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.

Analogously to the general work instruction, the following compounds were produced:

100

<td>Example</td><td>Structure</td><td>Time Ret.</td><td>HPLC [%]</td>

<td> 182</td><td>J 0^ciThe\^sz^J)'ⁿV · PL % ^Λ=^ΓO</td><td> 2,31</td><td> 93,3</td>

<td> 183</td><td>^Oy °. WAf p X N</td><td> 2,7</td><td> 100</td>

<td> 184</td><td>^ yr-y ò- ° ^Cl</td><td> 3,91</td><td> 51</td>

<td> 185</td><td>θ-ν ^ _ o N ^ y ° M * y = o ° α</td><td>f2.72</td><td> 75,2</td>

<td> 186</td><td>Q O</td><td> 3,17</td><td> 46</td>

<td> 187</td><td>οΧ^ΝΧχΧ ~ &lt;Q-ⁿ 0</td><td> 4,61</td><td> 50,2</td>

101

<td>Example</td><td>Structure</td><td>Time Ret.</td><td>EÍPLC [%]</td>

<td> 188</td><td>jxr ° rO c, xf tr ü</td><td> 3,89</td><td> 56,6</td>

<td> 189</td><td>_αΛ) W υ</td><td> 3,37</td><td> 52,9</td>

<td> 190</td><td>i oo = &lt; Q-Oa 0</td><td> 3,6</td><td> 63,9</td>

<td> 191</td><td>»4 V2 / I NA Vn 1 ο_ύΛ = Τ u._n 0</td><td> 2,52</td><td> 70,1</td>

<td> 192</td><td>_s YYr ° _v^u° 0</td><td> 3,52</td><td> 46,6</td>

102

<td>Example</td><td>Structure</td><td>Time Ret.</td><td>HPLC [Grandfather]</td>

<td> 193</td><td>Q s ^N^Ç,/^ \ Μ</td><td> 2,87</td><td>cr \ i Or, i</td>

<td> 194</td><td>ν \ ϊ ° r ^ e, XS Dr^N^Ul</td><td> 3,25</td><td> 71,1</td>

<td> 195</td><td>ϊ s O</td><td> 2,66</td><td> 67</td>

<td> 196</td><td>. X X O</td><td> 2,4</td><td> 52,1</td>

<td> 197</td><td>sΛα_&gt; ° oy ~^clAj CK 9 N</td><td> 3,13</td><td> 48,9</td>

103

<td>Example</td><td>Structure</td><td>Time 1 Ret. [</td><td>PLC %]</td>

<td> 198</td><td>Hz cr X O</td><td> 2,67</td><td> 75,5</td>

<td> 199</td><td>C £ r · X ° c O</td><td> 2,72</td><td> 65,7</td>

<td> 200</td><td>c, Xf cr r N</td><td> 2,71</td><td> 57,3</td>

<td> 201</td><td>O ⁰⁼^· 0</td><td> 2,22</td><td> 100</td>

<td> 202</td><td>&gt; xr w c, rf rr o</td><td> 3,89</td><td> 75,7</td>

104

<td>Example</td><td>Structure</td><td>Time Ret.</td><td>HPLC [% I</td>

<td> 203</td><td>jXx ° yc ° c, Xf w O</td><td> 3,19</td><td> 49,6</td>

<td> 204</td><td>Y ος N</td><td> 2,55</td><td> 88,2</td>

<td> 205</td><td>Vyí ° v^o4° ο, λΓ w^NÇ&gt; N</td><td> 2,44</td><td> 68,6</td>

<td> 206</td><td>X O</td><td> 2,86</td><td> 71,8</td>

<td> 207</td><td>V-yT cXÍ w Q N</td><td> 2,8</td><td> 63,6</td>

105

<td>Example</td><td>Structure</td><td>Time Ret.</td><td>HPLC [%]</td>

<td> 208</td><td> / 0 0 °=\ ^ci'T \^sz^Anv ^ y^N_ 0</td><td> 2,41</td><td> 77</td>

<td> 209</td><td>0 ° = ^ Va 1 N-? ') —N 1 O</td><td> 2,56</td><td> 67,9</td>

<td> 210</td><td>j-XZ ° z ο, Λ) W O</td><td> 3,67</td><td> 78,4</td>

<td> 211</td><td>y o ° \^α'ί ^ rL · ^ζί ví ι n- # yN 1 ° ί: y 0</td><td> 2,54</td><td> 69,8</td>

<td> 212</td><td>the yy ° γΐ^νΝγ? γΜ V y</td><td> 3,84</td><td> 59,2</td>

106

<td>Example</td><td>Structure</td><td>Time Ret.</td><td>EÍPLC [% J</td>

<td> 213</td><td> 9</td><td> 2,41</td><td>£ 7 R</td>

<td> 214</td><td>sh cr a-θ N</td><td> 2,41</td><td> 75,4</td>

<td> 215</td><td>0X0 vO οΛΓ cr O</td><td> 4,01</td><td> 81,3</td>

<td> 216</td><td>j-XC x x cr O</td><td> 3,46</td><td> 49,5</td>

<td> 217</td><td>Ο'γ ° ° v ° \ WX ° The_cl</td><td> 4,4</td><td> 60,2</td>

107

<td>Example</td><td>Structure</td><td>Time Ret.</td><td>HPLC [%]</td>

<td> 218</td><td>'• /' Τς-Χ-ο 0</td><td>O J, /&gt;</td><td>H r \ r \ / u, 9</td>

<td> 219</td><td>d X ° cr) O</td><td> 4,57</td><td> 51.5</td>

<td> 220</td><td>'Sz Cr^ziP X ° x O</td><td> 2,68</td><td> 100</td>

<td> 221</td><td>va ° vo .Λ) w 0</td><td> 4,53</td><td> 63,5</td>

<td> 222</td><td>c&gt; JV³ ° Jçc, A&gt; “X Q N</td><td> 2,66</td><td> 89,2</td>

108

<td>Example</td><td>Structure</td><td>Time l Ret. |</td><td>IPLC %]</td>

<td> 223</td><td>JvaT MO ο, Λ) w 0</td><td> 4,76</td><td> 69,3</td>

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

<td> 225</td><td>i 0 fy ° r V O</td><td> 3,97</td><td> 63,2</td>

<td> 226</td><td> 0 _M° Y ° ψ_Ç, X&gt;</td><td> 3,94</td><td> 61,4</td>

<td> 227</td><td>° Z c, there CT 0</td><td> 4,15</td><td> 66,3</td>

109

<td>Example</td><td>Structure</td><td>Time Ret.</td><td>HPLC % J</td>

<td> 228</td><td>O</td><td> 4,41</td><td> 55,1</td>

<td> 229</td><td>N oo = C i / \ _y ^N\ _ / O</td><td> 2,83</td><td> 41,1</td>

<td> 230</td><td>n ^NO y ~ N _Nc, X&gt; «_O</td><td> 2,7</td><td> 83</td>

<td> 231</td><td>&gt; Xr ° ° Λ c, xf Cf O</td><td> 4,39</td><td> 64,2</td>

<td> 232</td><td>0 ^ ° Y ° ° vV O</td><td> 4,85</td><td> 74,9</td>

110

<td>Example</td><td>Structure</td><td>Time Ret.</td><td>HPLC [%]</td>

<td> 233</td><td>«Λ) ζΓ 0</td><td> 4,17</td><td> 41</td>

<td> 234</td><td>O S 11 Ν 0</td><td> 4,21</td><td> 61,8</td>

<td> 235</td><td>3- · —CC / to U u; 7</td><td> 7,75</td><td> 100</td>

<td> 236</td><td>XO vÚ? O</td><td> 3,94</td><td> 50</td>

<td> 237</td><td>_TheA&gt; cr 0</td><td> 4,65</td><td> 75,8</td>

111

<td>Example</td><td>Structure</td><td>Time 1 Ret. |</td><td>TPLC %]</td>

<td>hó ' CO</td><td>/ 0 0 O =? s 11 N 0</td><td>Λ A</td><td> 75,3</td>

<td> 239</td><td>O Sn ⁰y ° ^sR_CIFO 0 ^U</td><td> 4,24</td><td> 62,2</td>

<td> 240</td><td>vXf ° U3 ο, Λ) W O</td><td> 4,76</td><td> 75,1</td>

<td> 241</td><td>c, xf Or^NQ</td><td> 4,17</td><td> 72,5</td>

<td> 242</td><td>νϊ M? nr O</td><td> 4,6</td><td> 74,8</td>

112

<td>Example</td><td>Structure</td><td>Time Ret.</td><td>HPLC [%]</td>

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

<td> 244</td><td>X X O</td><td> 4,71</td><td> 66,2</td>

<td> 245</td><td>0γ ° ° yo^Νγγ^Ν''^/Ν4 ° X</td><td> 4,86</td><td> 62</td>

<td> 246</td><td>Y s O</td><td> 5,23</td><td> 58,3</td>

<td> 247</td><td>go v £ = -0 cr O</td><td> 4,17</td><td> 72,4</td>

113

<td>Example</td><td>Structure</td><td>Time Ret.</td><td>HJPLC %]</td>

<td> 248</td><td>_C1X&gt; N</td><td>T</td><td>SQ A t- '✓, w</td>

<td> 249</td><td>ο_Ύ° X THE ^UQ N ° = \</td><td> 2,41</td><td> 60,3</td>

<td> 250</td><td>OX ° Y ^ / X N O = aÇ</td><td> 3,31</td><td> 65,2</td>

<td> 251</td><td>O ^N</td><td> 2,86</td><td> 36,5</td>

<td> 252</td><td>&gt; Xt ° vO cXf cr N</td><td> 2,69</td><td> 89,8</td>

114

<td>Example</td><td>Structure</td><td>Time Ret.</td><td>HPLC í%]</td>

<td> 253</td><td>a) Uⁿq N</td><td> 2,81</td><td> 67,4</td>

<td> 254</td><td>cr υ</td><td> 2,19</td><td> 75,4</td>

All products of solid phase assisted synthesis were characterized by LC-EM. For this purpose, the following separation system was used as standard: HP 1100 with UV detector (208 - 400 nm), 40 ° C oven temperature, Waters-Symmetry C18 column (50 mm x 2.1 mm, 3 , 5 μίτι), extracting agent A: 99.9% acetonitrile / 0.1% formic acid, extracting agent B: 99.9% water / 0.1% formic acid; gradient:

<td>Time</td><td>THE: %</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>

The substances were checked by means of a Micromass Quattro LCZ EM, ionization: positive / negative ESI.

In the structures mentioned above, which contain either the radicals or -O, it always means ^{H NH}* or an -OH function.