Substituted oxazolidinones for combinational therapy

Substituted oxazolidinones for combination therapy

The present invention relates to combinations of A) oxazolidinones of formula (I) with B) other active ingredients, a process for the preparation of these combinations and their use as a medicament, especially for the prophylaxis and / or treatment of diseases thromboembolic

The oxazolidinones of formula (I) act in particular as selective inhibitors of blood coagulation factor Xa and as anticoagulants.

An antithrombotic activity of factor Xa inhibitors has been proven in numerous animal models (see WO 99/37304; WO 99/06371; J. Hauptmann,

J. Stürzebecher, Thrombosis Research 1999, 93, 203; F. AlObeidi, 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, Lippincot-Raven Publishers, Philadelphia 1998) as well as in clinical studies in patients (The Ephesus Study, blood, vol 96, 490a, 2000; The Penthifra Study, biood, vol 96,

490a, 2000; The Pentamarks Study, biood, vol 96, 490a-491a, 2000; The Pentathlon 2000 Study, biood, vol 96, 491a,

2000). Factor Xa inhibitors can therefore preferably be used in medicaments for the prophylaxis and / or treatment of thromboembolic diseases.

Thromboembolic vascular diseases are the most common cause of morbidity 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 proven in the treatment of vascular diseases to prevent thrombotic vascular occlusions or to re-open thrombotically occluded vessels and occupies a high position in the prophylaxis and treatment of coronary, peripheral and cerebral vascular diseases, as well as in the prophylaxis and / o treatment of venous thrombosis and pulmonary embolisms.

Atherosclerotic vascular wall abnormalities, especially endothelial function disorders, which can lead to acute thrombotic occlusions can cause thromboembolic complications. Atherosclerosis is a multifactorial disease that depends on multiple cardiovascular risk factors. Clinical studies have shown that prophylaxis with anticoagulants does not decisively influence the course of arterial vascular disease. A targeted treatment of risk factors in conjunction with an antithrombotic therapy is therefore advantageous.

Risk factors for coronary, peripheral and cerebral vascular diseases, for example: elevated serum cholesterol level, arterial hypertonia, tobacco smoke, 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). The principles of preventive medicine are based on the elimination of these risk factors. In addition to changing life habits, pharmacological measures are also included here, such as antihypertensive therapy, hypolipidemic drugs or prophylaxis against thrombosis. In addition to this, the combination with coronary therapeutic agents is suitable for the treatment of an existing coronary heart disease.

It has now surprisingly been found that combinations of oxazolidinones of formula (I) with certain other active ingredients have interesting properties and are more suitable for the prophylaxis and / or treatment of various diseases than the active ingredients alone.

Therefore, combinations of

A) oxaxolidinones of formula (I) with

B) other active ingredients, especially with platelet aggregation inhibitors, anticoagulants, fibrinolytics, hypolipidemic agents, coronary therapeutic agents and / or vasodilators.

Combinations within the meaning of the invention mean not only forms of administration containing all components (called fixed combinations) and combination packages containing components separated from one another, but also components administered simultaneously or temporarily offset as long as they are used for the prophylaxis and / or treatment of the same disease. It is also possible to combine two or more active principles with each other, then dealing respectively with double or multiple combinations.

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

<img file="CU23366B7_D0001.tif" />

in which

R¹ represents thiophene (thienyl) in the case of benzo condensate, which may be mono or polysubstituted;

R² represents a discretionary organic residue;

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ they are the same or different and represent hydrogen or Ci-C alkyl₆ as well as its pharmaceutically acceptable salts, hydrates and prodrugs.

Compounds of formula (I), in which

<td>represents thiophene</td><td>(thienyl)</td><td>dice</td><td>the case</td>

<td>benzo condensate, which</td><td>given the case</td><td>may</td><td>be cute or</td>

<td>polysubstituted with</td><td>a rest of</td><td>group</td><td>halogen;</td>

<td>cyano; nitro; Not me;</td><td>aminometyl;</td><td colspan="2">C ^ -C alkyl, which</td>

<td colspan="2">if necessary it may be to</td><td>his</td><td>time monkey or</td>

<td>polysubstituted with</td><td>halogen;</td><td colspan="2">cycloalkyl C₃-C₇;</td>

Ci-C alkoxy₈; imidazolinyl; -C (= NH) NH₂; carbamoyl; and mono and di- (Ci-C alkyl₄) -aminocarbonyl, represents one of the following groups:

TO-,

AM-,

DMA-,

BMA-,

B-,

BM-,

BMB-,

DMB-, in which:

the remainder A represents aryl C_s-C₁₄preferably aryl C₆-Cio, especially phenyl or naphthyl, with very special preference phenyl;

the remainder B represents an aromatic heterocycle of 5 or 6 links, containing up to 3 heteroatoms and / or hetero-members, especially up to 2 heteroatoms and / or hetero-members, of the series of S, N, NO (N-oxide) and O;

the remainder D represents a heterocycle of 4 to 9 links, saturated or partially unsaturated, mono or bicyclic, where appropriate benzocondensed, containing up to three heteroatoms and / or hetero-members of the series of S, SO, SO₂, N, NO (N-oxide) and O; the remainder M represents -NH-, -CH₂-, -CH₂CH₂-, -O-, 7

NH-CH₂-, -CH₂NH-, -OCH₂-, -CH₂O-, -CONH-, -NH-CO-, COO-, -OOC-, -S-, -SO₂- or represents a covalent bond;

groups A, B and D may be defined above, if appropriate, respectively mono or polysubstituted with a remainder of the halogen group;

trifluoromethium; oxo; cyano; nitro; carbamoyl;

pyridyl; Ci-C alkanoyl₆; cycloalkanoyl C₃-C₇;

arylcarbonyl C₆-Ci₄; heteroarylcarbonyl C₅-Ci₀;

Ci-C alkanoyloxy₆-methyloxy; Ci ~ C hydroxyalkylcarbonyl₄; -COOR²⁷; -SW₂R²⁷; -C (NR²⁷R²⁸) = NR²⁹; -CONR²⁸R²⁹;

SW₂NR²⁸R²⁹; -OR³⁰; -NR³⁰R³¹, C alkyl_x-C₆ and cycloalkyl

C₃-C₇, the Ci-C alkyl may be_s and cycloalkyl C₃-C₇ in turn, if necessary, substituted with a remainder of the cyano group; -OR²⁷; -NR²⁸R²⁹; -CO (NH)_v (NR²⁷R²⁸) and C (NR²⁷R²⁸) = NR²⁹, in which v means 0 or 1 and

R²⁷, R²⁸ and R²⁹ they are the same or different and independently of each other mean hydrogen, Ci-C alkyl₄, cycloalkyl C₃-C₇alca-Ο alkanoyl_4/carbamoyl, trifluoromethio, phenyl or pyridyl, and / or

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

R³⁰ and R³¹ they are the same or different and independently of each other mean hydrogen, Ci-C alkyl₄, cycloalkyl C₃-C₇, Ci-C alkylsulfonyl₄, Ci-C hydroxyalkyl₄, Cx-C aminoalkyl₄, di (Ci-C alkylamino₄) -Ci ~ C alkyl₄,

CH₂C (NR²⁷R²⁸) = NR²⁹ or -COR³³, in which

R³³ means Ci-C alkoxy₆, Ci-C alkoxy₄-Ci-C alkyl₄, Ci-C alkoxycarbonyl₄-Ci-C alkyl₄, Ci-C aminoalkyl₄, Ci-C alkoxycarbonyl₄Ci-C alkanoyl₄-Ci-C alkyl₄, cycloalkyl C₃C₇, alkenyl C₂-C₆, Ci-C alkyl₈, which may be substituted with phenyl or acetyl, aryl c₅-c₁₄, heteroaryl C₅-Ci₀, trifluoromethyl, tetrahydrofuranyl or butyrolactone,

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ they are the same or different and represent hydrogen or Ci.-C alkyl₆, and their pharmaceutically acceptable salts, hydrates and prodrugs.

Compounds of the general formula (I), in which

R¹ represents thiophene (thienyl), especially 2-thiophene, which may be mono or polysubstituted with halogen, preferably chlorine or bromine, amino, aminomethyl or C alkyl_x-C₈, preferably methyl, the C alkyl moiety may be_x-C₈ in turn, in the case of mono or polysubstituted with halogen, preferably fluorine,

R² It represents one of the following groups:

TO-,

A.M-,

DMA-,

BMA-,

B-,

BM-,

BMB-,

DMB-, in which:

the remainder A represents aryl C₆-C₁₄preferably aryl C₆-Cio, especially phenyl or naphthyl, with very special preference phenyl;

the remainder B represents an aromatic heterocycle of 5 or 6 links, containing up to 3 heteroatoms and / or hetero-members, especially up to 2 heteroatoms and / or hetero-members, of the series of S, N, NO (N-oxide) and O;

the remainder D represents a heterocycle of 4 to 7 links, saturated or partially unsaturated, containing up to three heteroatoms and / or hetero-members of the series of S, SO, SO₂, N, NO (N-oxide) and

0;

the remainder M represents -NH-, -CH₂-, -CH₂CH₂-, -O-, NH-CH₂-, -CH₂NH-, -OCH₂-, -CH₂O-, -CONH-, -NH-CO-, C00-, -OOC-, -S- or represents a covalent bond; groups A, B and D may be defined above, if appropriate, respectively mono or polysubstituted with a remainder of the halogen group;

trifluoromethyl; oxo; cyano; nitro; carbamoyl;

pyridyl; Ci-C alkanoyl₆; cycloalkanoyl C₃-C₇;

arylcarbonyl C₆-C₁₄; C5 heteroarylcarbonyl^_Cio;

Οχ-C alkanoyloxy₆-met and loxi; -COOR²⁷; -SW₂R²⁷;

C (NR²⁷R²⁸) = NR²⁹; -CONR²⁸R²⁹; -SW₂NR²⁸R²⁹; -OR³⁰; -NR³⁰R³¹, alkyl 0_χ-0₆ and cycloalkyl C₃-C₇, the 0χ-0 alkyl may be₆ and cycloalkyl C₃-C₇ in turn, if necessary, substituted with a remainder of the cyano group; -OR²⁷; -NR²⁸R²⁹; -CO (NH)_v(NR²⁷R²⁸) and C (NR²⁷R²⁸) = NR²⁹, in which:

v means 0 or 1 and

R²⁷, R²⁸ and R²⁹ they are the same or different and independently of each other mean hydrogen, Ci-C alkyl₄ or cycloalkyl C₃-C₇, me

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

R³⁰ and R³¹ they are the same or different and independently of each other mean hydrogen, Ci-C alkyl₄, cycloalkyl C₃-C₇, Ci-C alkylsulfonyl₄, Ci-C hydroxyalkyl₄, Ci-C aminoalkyl₄, di (Ci-C alkylamino₄) -Ci-C alkyl₄, Ci-C alkanoyl₄, arylcarbonyl C₆-Ci₄, heteroarylcarbonyl C₅-Ci₀, Ci-C alkylaminocarbonyl₄ or -CH₂C (NR²⁷R²⁸) = NR²⁹,

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ they are the same or different and represent hydrogen or Ci-C alkyl₆, and their pharmaceutically acceptable salts, hydrates and prodrugs.

Compounds of the general formula (I), in which it represents thiophene (thienyl), especially 2-thiophene, which may be mono or polysubstituted with halogen, preferably chlorine or bromine, or Ci-C alkyl, are especially preferred in this regard.₈, preferably methyl, the Ci-C alkyl moiety may be₈ in turn, given the case mono or polysubstituted with halogen, preferably fluorine, represents one of the following groups:

TO-,

AM-,

DMA-,

BMA-,

B-,

BM-,

BMB-,

DMB-, in which:

residue A represents phenyl or naphthyl, especially phenyl residue B represents an aromatic heterocycle of 5 or 6 links, containing up to 2 heteroatoms of the series of S, N, NO (N-oxide) and 0;

the remainder D represents a 5 or 6 link heterocycle, saturated or partially unsaturated, containing up to two heteroatoms and / or hetero-members of the series of S, SO, S0₂, N, NO (N-oxide) and O;

the remainder M represents -NH-, -O-, -NH-CH₂-, -CH₂NH-,

-OCH₂-, -CH₂O-, -CONH-, -NH-CO- or represents a covalent bond;

groups A, B and D may be defined above, if appropriate, respectively mono or polysubstituted with a remainder of the halogen group; trifluoromethyl; oxo; cyano; pyridyl; alkanoyl C_xC₃; arylcarbonyl C₆-Ci₀; heteroarylcarbonyl C₅-C₆; Ci-C alkanoyloxy₃-methyloxy; -C (NR²⁷R²⁸) = NR²⁹; -CONR²⁸R²⁹;

-SW₂NR²⁸R²⁹; -OH; -NR³⁰R³¹; C alkyl_x-C₄; and cyclopropyl, cyclopentyl or cyclohexyl, the Ci-C alkyl may be₄ and cyclopropyl, cyclopentyl or cyclohexyl, in turn, substituted with a cyano group moiety; -OH; OCH₃; -NR²⁸R²⁹; -CO (NH)_v(NR²⁷R²⁸) and -C (NR²⁷R²⁸) = NR²⁹, in which:

v means 0 or 1, preferably 0, and

R²⁷, R²⁸ and R²⁹ they are the same or different and independently of each other mean hydrogen, C alkyl_x-C₄ or cyclopropyl, cyclopentyl or cyclohexyl, and / or

R²⁷ and R²⁸ or R²⁷ and R²⁹ together with the nitrogen atom to which they are attached they can form a saturated or partially unsaturated heterocycle of 5 to 7 links with up to two heteroatoms equal or different from the group of N, O and S, and R³⁰ and R³¹ they are the same or different and independently of each other mean hydrogen, Ci-C alkyl₄, cyclopropyl, cyclopentyl, cyclohexyl, Ci-Cj alkylsulf onyl, Ci-C hydroxyalkyl₄, aminoalkyl C₃-C₄, di- (Cx-C alkylamino₄) -I rent

Ci-C₄, Ci-C alkanoyl₃ or phenylcarbonyl,

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ they are the same or different and represent hydrogen or Ci-C alkyl₆, and their pharmaceutically acceptable salts, hydrates and prodrugs.

Compounds of general formula (I), in which

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

R² It represents one of the following groups:

TO-,

AM-,

DMA-,

BMA-,

B-,

BM-,

Β-Μ-Β-,

DMB-, in which:

residue A represents phenyl or naphthyl, especially phenyl;

residue B represents an aromatic heterocycle of 5 or 6 links, containing up to 2 heteroatoms of the series of S, N, NO (N-oxide) and 0;

the remainder D represents a 5 or 6 link heterocycle, saturated or partially unsaturated, containing a nitrogen atom and, if necessary, another heteroatom and / or hetero-chain member of the series of S, SO, S0₂ and 0; or up to two heteroatoms and / or hetero-members of the series of S, SO, S0₂ and

OR;

the remainder M represents -NH-, -O-, -NH-CH₂-, -CH₂NH-,

-OCH₂-, -CH₂O-, -CONH-, -NH-CO- or represents a covalent bond;

groups A, B and D may be defined above, if appropriate, respectively mono or polysubstituted with a remainder of the halogen group; trifluoromethyl; oxo; cyano; pyridyl; noC alkanoyl₃; arylcarbonyl C₆-C₁₀; heteroarylcarbonyl C₅-C₆; Ci-C alkanoyloxy₃-methyloxy; -CONR²⁸R²⁹; -SW₂NR²⁸R²⁹; -OH;

-NR³⁰R³¹, Ci-C alkyl₄; and cyclopropyl, cyclopentyl or cyclohexyl, the Ci-C alkyl may be₄ and cyclopropyl, cyclopentyl or cyclohexyl, in turn, substituted with a cyano group moiety; -OH; OCH₃; -NR²⁸R²⁹; -CO (NH)_v (NR²⁷R²⁸) and -C (NR²⁷R²⁸) = NR²⁹, in which:

v means 0 or 1, preferably 0, and

R²⁷, R²⁸ and R²⁹ they are the same or different and independently of each other mean hydrogen, C alkyl₃-C₄ or cyclopropyl, cyclopentyl or cyclohexyl, and / or

R²⁷ and R²⁸ or R²⁷ and R²⁹ together with the nitrogen atom to which they are attached they can form a saturated or partially unsaturated heterocycle of 5 to 7 links with up to two heteroatoms equal or different from the group of N, 0 and S, and

R³⁰ and R³¹ they are the same or different and independently of each other mean hydrogen, C alkyl₃-C₄, cyclopropyl, cyclopentyl, cyclohexyl, Ci-C alkylsulfonyl₄, hydroxyalkyl C! -C₄, Ci-C aminoalkyl₄, di- (alkylamino C! -C₄) -Ci-C alkyl₄, C1-C3 alkanoyl or phenylcarbonyl,

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ they are the same or different and represent hydrogen or Ci-C alkyl₄, and their pharmaceutically acceptable salts, hydrates and prodrugs.

Compounds of general formula (I), in which

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

R² represents DA-: in which:

the remainder A represents phenylene;

the remainder D represents a saturated heterocycle of 5 or links, which may be linked through a nitrogen atom with A, which directly possesses a carbonyl group adjacent to the bonding nitrogen atom and in which a ring member carbon may be replaced by a heteroatom of the series of S, N and O;

the group A may be defined above, if appropriate mono or disubstituted in the meta position with respect to the bond with the oxazolid inone with a residue of the group of fluorine, chlorine, nitro, amino, trifluoromethyl, methyl or cyano,

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ they represent hydrogen, and its pharmaceutically acceptable salts, hydrates and prodrugs.

The compound of the following formula is also very particularly preferred in this regard.

<img file="CU23366B7_D0002.tif" />

and its pharmaceutically acceptable salts, hydrates and prodrugs.

So far oxazolidinones are described essentially only as antibiotics, occasionally also as MAO inhibitors and as fibrinogen antagonists (review: Riedl, B., Endermann, R., Exp. Opin. Ther. Patents 1999, 9 (5), 625), a small 5- [acylaminomethyl] group (preferably 5- [acetylaminomethyl]) appears to be essential for antibacterial activity.

The substituted aryl- and heteroarylphenyloxazolidinones in which at the N atom of the oxazolidinone ring a mono or polysubstituted phenyl moiety may be linked and which at the 5-position of the oxazolidinone ring may have an unsubstituted moiety of N-methyl-219 thioph Carboxamide, as well as its use as substances with antibacterial activity are known from United States patent publications US-A-5 929

248, US-A-5 801 246, US-A-5 756 732, US-A-5 654 435, US-A5 654 428 and US-A-5 565 571.

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

The compounds of formula (I) may, depending on the substitution pattern, exist in stereoisomeric forms that behave as an object and their mirror image (enantiomers), or that do not behave as an object and their mirror image (diastereomers). Both enantiomers or diastereomers are included as well as their respective mixtures. The racemic forms can be separated in a known manner, like the diastereomers, into the unit stereoisomeric components.

In addition, certain compounds of formula (I) may be presented in tautomeric forms. This is known to the person skilled in the art and such compounds are equally understood.

Physiologically safe salts, that is, pharmaceutically acceptable salts, can be salts of the compounds according to the invention with inorganic or organic acids. Preferably they are salts with inorganic acids such as hydrochloric, hydrobromic, phosphoric or sulfuric acid, or salts with organic carboxylic or sulfonic acids, such as acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or ethanesulfonic acid, acid methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid naphthalenedisulfonic acid.

Pharmaceutically acceptable salts may also be referred to as salts with customary bases, such as alkali metal salts (eg sodium or potassium salts), alkaline earth metal salts (eg calcium or magnesium salts) or ammonium salts, derived from ammonia or organic amines such as diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabyethylamine or methylpyridine.

Hydrates are those forms of the compounds of the formula (I) above that form a molecular compound (solvate) in a solid or liquid state by hydration with water. In hydrates, water molecules are added by secondary valence by intermolecular forces, especially hydrogen bonding. Solid hydrates contain water in the form of the so-called water of crystallization in stoichiometric ratios, the water molecules not having to be equivalent in terms of their binding state. Examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates. The salt hydrates of the compounds according to the invention are also considered.

Prodrugs are those forms of the compounds of the formula (I) above that in themselves can be biologically active or inactive, but which can be transformed into the corresponding biologically active form (for example metabolically, solvolitically or otherwise).

Halogen represents fluorine, chlorine, bromine and iodine.

Preferably they are chlorine or fluorine.

Ci-Cs alkyl represents a straight or branched chain alkyl moiety of 1 to 8 carbon atoms. Exemplary are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tere-butyl, n-pentyl and n-hexyl. From this definition, the corresponding alkyl groups with less carbon atoms, such as Ci-C alkyl, are similarly derived₆ and Ci-C alkyl₄. In general it is valid that Ci-C alkyl₄ It is preferred.

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

Cycloalkyl C₃-C₇ represents a cyclic alkyl moiety of 3 to 7 carbon atoms. By way of example, there are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. From this definition, the corresponding cycloalkyl groups with fewer carbon atoms, such as cycloalkyl C, are similarly derived₃-C₅. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.

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

Alkenyl C₂-C_s represents a straight or branched chain alkenyl moiety of 2 to 6 carbon atoms. A straight or branched chain alkenyl moiety of 2 to 4 carbon atoms is preferred. By way of example, vinyl, allyl, isopropenyl and n-but-2-en-1-yl are mentioned.

Ci-C alkoxy₈ represents a straight or branched chain alkoxy moiety of 1 to 8 carbon atoms. Exemplary are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, nhexoxy, n-heptoxy and n-octoxy. From this definition, the corresponding alkoxy groups with fewer carbon atoms are derived analogously, eg Ci-C alkoxy₆ and Ci-C alkoxy₄. In general it is valid that Ci-C alkoxy₄ It 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- (Ci ~ C alkyl₄) aminocarbonyl represents an amino group that is linked through a carbonyl group and that has one or two straight or branched chain alkyl substituents equal or different from respectively 1 to 4 carbon atoms. Exemplary are: methylamino, ethylamino, n-propylamino, isopropylamino, t-butylamino, N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino,

N-isopropyl-Nn-propylamino and Nt-butyl-N-methylamino.

Ci-C alkanoyl₆ represents a straight or branched chain alkyl moiety of 1 to 6 carbon atoms which in position 1 carries an oxygen atom bonded by double bond and which is linked by position 1. Exemplary are: formyl, acetyl , propionyl, n-butyryl, ibutyryl, pivaloyl, n-hexanoyl. From this definition, the corresponding alkanoyl groups with fewer carbon atoms, such as C1-C5 alkanoyl, Ci-C alkanoyl, are similarly derived₄ and C1-C3 alkanoyl. In general it is valid that Ci-C alkanoyl₃ It is preferred.

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

Cycloalkanoyl C₃-C₇ represents a cycloalkyl moiety of 3 to 7 carbon atoms as defined above that is linked through a carbonyl group.

Ci-C alkanoyloxy₆-methyloxy represents a straight or branched chain alkanoyloxymethyloxy moiety of 1 to 6 carbon atoms. By way of example, there are: acetoxymethyloxy, propionoxymethyloxy, n-butyloxymethyloxy, ibuthyloxymethyloxy, pivaloyloxymethyloxy, n-hexanoxymethyloxy. From this definition, the corresponding alkanoyloxymethyloxy groups with fewer carbon atoms are derived similarly, e.g.

Ci-C alkanoyloxy₃-methyloxy. In general it is valid that C-C alkanoyloxy₃-methyloxy is preferred.

Arilo C₆-C₁₄ represents an aromatic moiety of 6 to 14 carbon atoms. By way of example they are mentioned: phenyl, naphthyl, phenanthrenyl and anthracenyl. From this definition, the corresponding aryl groups with fewer carbon atoms, such as aryl C, are similarly derived₆-Ci₀. In general it is valid that aryl C₆-Ci₀ It is preferred.

The meaning of the corresponding component of other more complex substituents such as arylcarbonyl also derives from this definition.

Heteroaryl C₅-C₁₀ or an aromatic heterocycle of 5 to 10 links with up to 3 heteroatoms and / or hetero-members of the S, O, N and / or NO (N-oxide) series represents a mono or bicyclic heteroaromatic hydrocarbon which is attached to through a carbon atom of the heteroaromatic hydrocarbon ring, if necessary also through a nitrogen atom of the heteroaromatic hydrocarbon ring. Exemplary are: pyridyl, pyridyl-N-oxide, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl or isoxazolyl, indolizinyl, indolyl, benzo [b] thienyl, benzo [ b] furyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl. From this definition, the corresponding heterocycles with smaller ring sizes are derived analogously, such as, for example, 5 or 5 link aromatic heterocycles. In general, it is preferred that aromatic heterocycles of 5 or 6 links are preferred, eg pyridyl, pyridyl-N-oxide, pyrimidyl, pyridazinyl, furyl and thienyl.

This definition also derives the meaning of the corresponding component of other more complex substituents such as heteroaryl C₅-C₁₀-carbonyl.

A heterocycle of 3 to 9 saturated or partially unsaturated links, mono or bicyclic, if necessary benzocondensed, with up to 3 heteroatoms and / or chain heteromembers of the S, SO, SO series₂, N, NO (Nóxide) and / or O represents a heterocycle that can contain one or several double bonds, which can be mono or bicyclic, in which a benzene ring can be condensed to two adjacent carbon atoms of the ring and which it is attached through a ring carbon atom or through a ring nitrogen atom. Exemplary are: tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl N-oxide, thiomorpholinyl, azepinyl, 1,4-diazepinyl and cyclohexyl. Piperidinyl, morpholinyl and pyrrolidinyl are preferred.

From this definition the corresponding cycles of smaller ring size are similarly derived, such as

eg cycles of 5 to 7 links.

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

<img file="CU23366B7_D0003.tif" />

in which the remains R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ they have the meanings indicated above, with carboxylic acids of general formula (III)

HCf, R¹ (ΠΙ),

T

Or in which the rest R¹ it has the meaning indicated above, either with the corresponding halides of the carboxylic acids, preferably the chlorides of the carboxylic acids, or with the corresponding symmetric or mixed anhydrides of the carboxylic acids of general formula (III) defined above, in inert solvents , if necessary in the presence of an activation or coupling reagent and / or a base, to obtain compounds of general formula (I)

<img file="CU23366B7_D0004.tif" />

R — Ν.

R^and

R⁷

<img file="CU23366B7_D0005.tif" />

in which the remains R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ they have the meanings indicated above, or according to an alternative of the procedure [B] transforming compounds of general formula (IV) (IV), in which the R moieties¹, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ they have the meanings indicated above, with a suitable selective oxidant in an inert solvent, in the corresponding epoxy of general formula (V) (V), in which the R moieties¹, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ they have the meanings indicated above, and by reaction in an inert solvent, if necessary in the presence of a catalyst, with an amine of general formula (VI)

R²-NH₂ (VI), in which the rest R² It has the meaning indicated above, the compounds of the general formula (VII) are first obtained

<img file="CU23366B7_D0006.tif" />

in which the remains R¹, R², R³, R⁴, R⁵, R^s, R⁷ and R⁸ they have the meanings indicated above, and then, in inert solvents and in the presence of phosgene or phosgene equivalents such as eg carbonyldiimidazole (CDI), the compounds of general formula (I) are cyclized to obtain

<img file="CU23366B7_D0007.tif" />

in which the remains R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ they have the meanings indicated above, where, both in the alternative [A] of the procedure and also in the alternative [B] of the procedure, in the case that R² containing a cyclic hydrocarbon residue of 3 to 7 links, saturated or partially unsaturated with one or more heteroatoms equal or different from the group of N and S, oxidation can then be carried out with a selective oxidant to form the corresponding sulfone, sulfoxide or N -oxide, and / or where, both in the alternative [A] of the procedure and also in the alternative [B] of the procedure, in the case that the compound prepared in this way has a cyano group in the molecule, an amidination of this cyano group can then be carried out by conventional methods, and / or where, both in the alternative [A] of the process and also in the alternative [B] of the process, in the event that the compound prepared in this way has an amino protecting BOC group in the molecule, The elimination of this amino-protective BOC group can then be carried out by conventional methods, and / or where, both in the alternative [A] of the process and also in the alternative [B] of the process, in the event that the compound prepared in this way an aniline or benzylamine moiety present in the molecule, a transformation of this amino group can then be carried out with different reagents such as carboxylic acids, carboxylic acid anhydrides, carboxylic acid chlorides, isocyanates, sulfonic acid chlorides or alkyl halides, to obtain the corresponding derivatives and / or where, both in the alternative [A] of the process and also in the alternative [B] of the process, in the case that the compound thus prepared has a phenyl ring in the molecule, A reaction with chlorosulfonic acid and a subsequent transformation with amines can then be carried out to form the corresponding sulfonamides.

The methods according to the invention can be illustrated by way of example with the following formula scheme:

[TO]

<img file="CU23366B7_D0008.tif" />

<img file="CU23366B7_D0009.tif" />

<img file="CU23366B7_D0010.tif" />

The oxidation step described above, if necessary, can be illustrated by way of example by the following formula scheme:

<img file="CU23366B7_D0011.tif" />

Suitable solvents for the process described above are inert organic solvents under the reaction conditions. To these belong halogenated 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 or diethylene glycol dimethyl ether, ethanol, ethanol, ethanol, ethanol, ethanol, ethanol, ethanol, ethanol, ethanol -propanol, iso-propanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide, dimethylsulfoxide, acetonitrile, pyridine, hexamethylphosphorotriamide or water.

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

Suitable reactive or coupling reagents for the process described above are reagents commonly used for this purpose, for example N '- (3-dimethylaminopropyl) -Netylcarbodiimide · HCl, N, N'-dicyclohexylcarbodiimide,

1-hydroxy-lH-benzotriazolH₂O and the like.

Suitable bases are the usual inorganic or organic bases. To these belong preferably alkaline hydroxides such as sodium or potassium hydroxide or alkali carbonates such as sodium or potassium carbonate or sodium or potassium methanolate, sodium or potassium ethanolate or potassium tert-butylate, or amides such as sodium amide, lithium bis- (trimethylsilyl) amide or lithium diisopropylamide or amines such as triethylamine, diisopropylethylamine, diisopropylamine, 4N, N-dimethylaminopyridine or pyridine.

The base can be used in this regard in an amount of 1 to 5 mol, preferably 1 to 2 mol referred to 1 mol of the compounds of general formula (II).

The reactions are carried out 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, elevated or reduced pressure (eg in the range of 0.5 to 5 bar). In general it works at normal pressure.

As suitable selective oxidants both for the preparation of the epoxides and also for oxidation, in the case of sulfone, sulfoxide or N-oxide, for example, m-chloroperbenzoic acid (MCPBA), sodium metaperiodate, N-methylmorpholine- are considered. N-oxide (NMO), monoperoxiftalic acid or osmium tetroxide.

With regard to the preparation of epoxides, the usual preparation conditions are used for this.

With regard to the more detailed conditions of the oxidation process, in the case of sulfone, sulfoxide or N-oxide, refer to the following bibliography: MR Barbachyn et al., J. Med.

Chem. 1996, 39, 680 as well as WO-A-97/10223.

It also refers to Examples 14 to 16 set forth in the experimental part.

The amidination given the case carried out is carried out under usual conditions. For more details, refer to Examples 31 to 35 and 140 to 147.

The compounds of formulas (II), (III), (IV) and (V) are known per se by the person skilled in the art or can be prepared by usual methods. For oxazolidinones, especially the necessary 5- (aminomethyl) -2-oxooxazolidines, see WO-A-98/01446; WO-A93 / 23384; WO-A-97/03072; and 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-oxo3- [4- (3-oxo-4-morpholinyl) phenyl] -1, 3-oxazolinedin-5-yl} methyl) 2-thiophenecarboxamide, the compound of example 44.

The combinations according to the invention are especially suitable for the prophylaxis and / or treatment of arterial thrombosis and embolisms in coronary heart disease, cerebrovascular circulatory disorders and peripheral circulatory disorders.

The combinations of oxazolidinones of formula (I) with inhibitors of platelet aggregation, anticoagulants and / or fibrinolytics are also especially suitable for the prophylaxis and / or treatment of venous thrombosis and pu1moneal embolisms.

The various active ingredients of combination are known in the literature and can be obtained mostly commercially. If necessary, they can be used, like the idinone oxazole of formula (I), in subtherapeutically effective doses.

A combination therapy of oxazolidinones of formula (I) with hypolipidemic agents, especially with HMG37 fluvastatin inhibitors, is suitable for the prophylaxis and / or treatment of arterial vascular diseases.

CoA- (3-hydroxy-3-methylglutaryl-coenzyme A) -reductase such as cerivastatin (Rivastatin, Baycol; US 5,177,080), lovastatin (Mevacor; US document

4,231,938), simvastatin (Zocor, US 4,444,784), pravastatin (Pravachol; US document (Lescol; document

4,345,227) ,

5,354,772),

US atorvastatin (Lipitor; US 5,273,995), or with coronary / vasodilatory therapeutic agents, especially ACE inhibitors - (Angiotensin-ConvertingEnzyme, angiotensin conversion enzyme) -, such as captopril, lisinopril, enalapril, ramipril, cilazapril, benazepril, fosinopril, quinapril, perindopril; AII receptor antagonists - (angiotensin II) such as embusartan (US 5,863,930), losartan, valsartan, irbesartan, candesartan, eprosartan, temisartan; β-adrenergic receptor antagonists such as carvedilol, alprenolol, bisoprolol, acebutolol, atenolol, betaxolol, carteolol, metoprolol, nadolol, penbutolol, pindolol, propanolol, timolol; alpha-l-adrenergic receptor antagonists such as prazosin, bunazosin, doxazosin, terazosin; diuretics such as hydrochlorothiazide, furosemid, bumetanid, piretanid, torasemid, amilorid; dihydralazine; calcium antagonists such as verapamil, diltiazem or dihydropyridine derivatives such as nifedipine (Adalat) or nitrendipine (Bayotensin); substances that produce an increase in cyclic guanosine monophosphate (cGMP) such as soluble guanylate cyclase stimulators (WO 98/16223, WO 98/16507, WO 98/23169, 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 the need for oxygen in myocardial areas affected by ischemia. For the treatment of an existing coronary heart disease, a combination therapy of an oxazolidinone of formula (I) with coronary therapeutic agents, in particular with β-adrenergic receptor antagonists, is therefore especially suitable; ACE inhibitors - (AngiotensinConverting-Enzyme, angiotensin conversion enzyme) -; IIA receptor antagonists (angiotensin II) -; nitropreparations such as for example 5 isosorbide mononitrate, isosorbide dinitrate, glycerol trinitrate; substances that produce an increase in cyclic guanosine monophosphate (cGMP); calcium antagonists Most of these compounds are also used for hypertension therapy.

To reopen thrombotically occluded vessels, thrombolytic therapy with plasminogen activators (thrombolytic / fibrinolytic) has been accredited, such as the tissue plasminogen activator (t-PA), reteplase or urokinase. The administration of only plasminogen activators does not nevertheless prevent subsequent thrombus growth. High doses of plasminogen activators can also mean a high risk of bleeding. The combined taking of a thrombolytic with an oxazolidinone of formula (I) for the opening of thrombotically occluded vessels in coronary heart disease, transient ischemic attacks, cerebral apoplexy, peripheral arterial occlusive diseases and pulmonary embolisms prevents subsequent thrombus growth by inhibiting thrombus formation and consequently reduces the risk of a new occlusion. In addition to this, in a combination therapy with a thrombolytic and an oxazolidinone of formula (I) the precise therapeutic dose of thrombolytic can be reduced, which leads to a decrease in hemorrhagic complications and therefore represents a considerable advantage over monotherapy. .

The oxazolidinones of formula (I) can also be given in combination with other substances with anticoagulatory activity (anticoagulants) for the prophylaxis and / or treatment of arterial, intracardiac and venous thromboembolic diseases. The combination therapy of oxazolidinones of formula (I), especially with heparin (UFH), low molecular weight heparins (NMH) such as tinzaparin, certoparin, parnaparin, nadroparin, ardeparin, exoparin, reviparin, dalteparin or direct inhibitors of Thrombin, such as hirudin, leads to enhanced antithrombotic activity.

The oxazolidinones of formula (I) may also occur in combination with substances that inhibit platelet aggregation (platelet aggregation inhibitors, thrombocyte aggregation inhibitors) for the prophylaxis and / or treatment of arterial, intracardiac and venous thromboembolic diseases . In an endothelial lesion there is an adhesion of the wall and an activation of blood platelets and a simultaneous stimulation of blood clotting. This leads to the formation of thrombi containing platelets and fibrin, contributing platelets to the stabilization of the fibrin structure (J. Hirsch, EW Salzman, VJ

Marder, RW Colman, OverView of the Thrombotic Process and its Therapy, pages 1151-1163 in Hemostasis and Thrombosis: Basic Principies and Clinical Practice, third edition, edited by RW Colman, J. Hirsch, VJ Marder, EW Salzman, JB Lippincott Company , Philadelphia, 1994). Simultaneous inhibition of blood coagulation and platelet aggregation therefore leads to enhanced antithrombotic activity. Combinations of an oxazolidinone of formula (I) with platelet aggregation inhibitors such as aspirin, ticlopidine (Ticlid), clopidogrel (Plavix) are especially suitable for combination therapy. fibrinogen receptor antagonists; (Ilb / lIIa glycoprotein antagonists) such as abciximab, eptifibatide, tirofiban, lamifiban, lefradafiban.

For the administration of the combinations according to the invention all the usual forms of administration are considered. Preferably, the administration is carried out orally, lingually, sublingually, buccally, rectally, topically or parenterally (that is, bypassing the intestinal tract, that is, intravenously, intraarterially, intracardiac, intracutaneously, subcutaneously, transdermally, intraperitoneally or intramuscularly).

To the present invention belong pharmaceutical preparations which contain, in addition to non-toxic, inert, pharmaceutically suitable adjuvants and / or vehicles, one or more combinations according to the invention or which are constituted by a combination according to the invention, as well as processes for the preparation of these preparations.

The combinations according to the invention must be present in the above-mentioned pharmaceutical preparations in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% of the total mixture.

The pharmaceutical preparations mentioned above may contain, in addition to the combinations according to the invention, other pharmaceutical active ingredients.

The preparation of the aforementioned pharmaceutical preparations can be carried out in the usual way by known methods, eg by mixing the active ingredient or the active ingredients with the vehicle (s).

In general, it has proved advantageous to administer the combinations according to the invention in total amounts of about 0.001 to 100 mg / kg, preferably about 0.01 to 100 mg / kg, especially about 0.1 to 10 mg / kg of body weight, every 24 hours, if necessary in the form of several single doses, to achieve the desired results.

However, if necessary, it may be necessary to deviate from the amounts indicated above, and specifically depending on the body weight, the type of route of administration, the type and severity of the disease, the individual behavior against the medication, the type of formulation and the time or interval at which the administration is performed. Thus, in some cases it may be sufficient with less than the minimum amount indicated above, while in other cases it must exceed the upper limit indicated. It may be advisable, for example, in the case of the administration of larger quantities, to distribute these throughout the day, specifically in several unit doses or as a permanent infusion.

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

Other objects of the invention are medicaments containing at least one of the combinations defined above and, where appropriate, other pharmaceutical active ingredients.

Another object of the invention is the use of the combinations defined above for the manufacture of medicaments for the prophylaxis and / or treatment of the above-described diseases, preferably of thromoembolic diseases, especially myocardial infarction, angina pectoris (including unstable angina), sudden cardiac death, reocclusions and restenosis after angioplasty or aortocoronary bypass, cerebral apoplexy, transient ischemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thrombosis.

The percentage data of the following examples are respectively referred to by weight; The parts are parts by weight.

Examples

A. Assessment of physiological activity

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

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

Selective are those inhibitors of blood coagulation factor Xa in which IC values₅₀ for inhibition of factor Xa with respect to IC values₅₀ for the inhibition of other serine proteases, especially thrombin, plasmin and trypsin, they are about 100 times, preferably about 500 times, especially about 1,000 times, less, where the test methods for the selectivity refers to the test methods of Examples Al) a) and a.2) described below.

The especially advantageous biological properties of the compounds of formula (I) can be checked by the following methods.

a) Description of the test (in vitro)

al) Measurement of factor Xa inhibition

The enzymatic activity of human factor Xa (FXa) was determined by the reaction of a specific chroma substrate of FXa. In it, factor Xa follows from the chromogenic substrate p-nitroaniline. The determinations were performed as follows in microtiter plates.

The test substances were dissolved in DMSO at different concentrations and incubated at 25 ° C for 10 minutes with human FXa (0.5 nmol / 1 dissolved in tris mmol / 1 buffer [C, C, C-tris (hydroxymethyl) - aminomethane], 150 mmol / 1 NaCl, BSA (bovine serum albumin) 0.1%, pH = 8.3). As a control, pure DMSO was used. Then the chromogenic substrate (150 gmol / l of Pefachrorae * FXa from Pentapharm) was added. After 20 minutes incubation at

25 ° C the extinction at 405 nm was determined. The extinctions of the test preparations with test substance were compared with those of the control preparations without test substance and from these comparisons the IC50 values ​​were calculated.

a.2) Determination of selectivity

For the analysis of selective inhibition of FXa, the inhibitory effect of test substances on other human serine proteases such as thrombin, trypsin and plasmin was studied. For the determination of the enzymatic activity of thrombin (75 mU / ml), trypsin (500 mU / ml) and plasmin (3.2 nmol / 1) these enzymes were dissolved in tris buffer (100 mmol / 1, CaCl₂ 20 mmol / 1, pH = 8.0) and incubated for 10 minutes with test substance or solvent. The enzymatic reaction was then started by adding the corresponding specific chromogenic substrate (Chromozym Thrombin⁹ from Boehringer Mannheim, Chromozym Trypsin⁰ from Boehringer Mannheim, Chromozym Plasmin® from Boehringer Manhheim), and the extinction was determined after 20 minutes at 405 nm. All determinations were made at ° C. The extinctions of the test preparations with test substance were compared with the control samples without test substance and from these comparisons the IC values ​​were calculated₅₀.

a.3) Determination of anticoagulant activity

The anticoagulant activity of the test substances was determined in vitro in human plasma. For this, human blood was extracted using 0.11 molar sodium citrate solution as a receptor in a 1/9 sodium citrate / blood mixture ratio. The blood immediately after extraction was mixed well and centrifuged for 10 minutes at approx. 2000 g The supernatant was removed by pipette. Prothrombin time (PT, synonym: thromboplastin time, Quick test) was determined in the presence of different concentrations of test substance or the corresponding solvent with a commercial test kit (Neoplastin *⁵ from Boehringer Mannheim). Test compounds were incubated for 10 minutes at

<td>37 ° C with plasma</td><td>TO</td><td>continuation</td><td>he</td><td>caused</td><td>the</td>

<td>coagulation adding</td><td colspan="2">thromboplastin and</td><td>he</td><td>determined</td><td>he</td>

<td>start time</td><td>of the</td><td>coagulation.</td><td>He</td><td>determined</td><td>the</td>

<td colspan="2">substance concentration</td><td>of testing</td><td>what</td><td>it caused</td><td>a</td>

Prothrombin time doubling.

b) Determination of antithrombotic activity (in vivo)

bl) Arteriovenous communication model (in rat)

Fasting male rats (race: HSD CPB: WU) weighing 200-250 g with a rupun / ketavet solution (12 mg / kg / 50 mg / kg) were drugged. Thrombus formation was caused in an arteriovenous communication according to the method described by Christopher N. Berry et al., Br. J. Pharmacol. (1994), 113, 1209-1214. For this, the left jugular vein and the right carotid artery were exempt. Extracorporeal communication was arranged using a 10 cm long polyethylene (PE 60) flexible tube between the two vessels. This polyethylene tube was connected in the center with another flexible polyethylene tube (PE 160) 3 cm long that contained a thrombogenic surface a carded nylon wire and arranged in a loop. Extracorporeal circulation was maintained for 15 minutes. Then the communication was withdrawn and the nylon thread was immediately weighed with the thrombus. The empty weight of the nylon thread was determined before the start of the test. The test substances were administered to the awake animals before arranging the extracorporeal circuit either intravenously through the tail vein or orally by means of an esophageal probe. The results are shown in Table 1:

Table 1: Antithrombotic activity in arteriovenous communication model (in rat) after oral or intravenous intake

<td>Example</td><td>FROM₅₀ [mg / kg] po</td><td>SD50 [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) Model of arterial thrombosis (in rat)

Fasting male rats (race: HSD CPB: 15 WU) were drugged as described above. The rats weighed approximately 200 g on average. The left carotid artery was exempt (approx. 2 cm). The formation of an arterial thrombus was induced by mechanical vascular injury according to the method described by K. Meng et al., Naunyn Schmiedeberg's Arch. Pharmacol. (1977), 301, 115-119. To do this, the exempt carotid artery was strangulated by obstructing blood flow, cooled to -12 ° C for 2 minutes in a metal groove and for the standardization of the thrombus size, it was compressed simultaneously with a weight of 200 g. The blood flow was then further reduced by a clamp arranged around the carotid artery distal to the injured vascular segment. The proximal clamp was removed, the wound was closed and after 4 hours it was opened again to remove the injured vascular segment. The vascular segment was opened longitudinally and the thrombus was removed from the injured vascular segment. The wet weight of the thrombi was immediately determined. The test substances were administered to the animals awake at the beginning of the test either intravenously through the tail vein or orally by esophageal probe.

b.3) Model of venous thrombosis (in rat)

Fasting male rats (race: HSD CPB: WU) were drugged as described above. The rats weighed approximately 200 g on average. The left jugular vein was exempt (approx. 2 cm). The formation of a venous thrombus was induced by mechanical vascular injury according to the method described by K. Meng et al., Naunyn51

Schmiedeberg's Arch. Pharmacol. (1977), 301, 115-119. For this, the exempt jugular vein was strangled obstructing blood flow, cooled to -12 ° C for 2 minutes in a metal groove and for the standardization of the thrombus size it was compressed simultaneously with a weight of 200 g. The blood flow was opened again and the wound closed. After 4 hours the wound was opened again to remove the thrombi from the injured vascular segment. The wet weight of the thrombi was immediately determined. The test substances were administered to the animals awake at the beginning of the test either intravenously through the tail vein or orally by esophageal probe.

two. Physiological activity of the combinations of compounds of formula (I)

a) In vivo studies in a thrombosis model in rats

The carotid artery in rats was exempted under narcosis (HSD CPB: WU, Harlam Winkelmann). A piece of filter paper impregnated with a 10% aqueous solution was carefully slipped under the exempt vessel

FeCl₃ (dissolved in 1 N aqueous hydrochloric acid) 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. After 15 minutes the carotid artery was taken, the thrombus detached and weighed immediately. The animals (10 rats per group) had previously been treated with 1 mg / kg of the respective different active ingredient (oxazolidinone of formula (I) or active compound combination) or with the combination of 1 mg / kg of oxazolidinone of formula (I ) and 1 mg / kg of active substance combination. The animals in the control group had been treated with the corresponding solvent. Statistical significance was calculated using the Student test. As a statistically significant activity, values ​​with p &lt;0.05 (Medical Statistics, MJ Campbell, D. Machín, second edition, John Wiley &amp; Sons) are considered. The results are shown in Table 2:

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

<td colspan="3">Thrombus weight reduction 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) as the compound of

Example 44 with a platelet aggregation inhibitor such as clopidogrel a synergistic effect is obtained, that is to say both components reinforce each other in their effect. In the individual dosage both compounds were ineffective at the dose examined. The combination of both compounds led instead to a significant reduction in thrombus weight. By combining oxazolidinones of formula (I) with a substance that inhibits platelet aggregation, antithrombotic therapy can therefore be significantly improved.

B Preparation examples

Starting compounds

The synthesis of 3-morpholinone is described in US 5 349 045.

The synthesis of N- (2,3-epoxypropyl) phthalimide is described in J.-W. Chern et al., Tetrahedron Lett. 1988, 39,

8483 .

The substituted anilines can be obtained e.g.

by reacting 4-fluoronitrobenzene, 2,4-difluoronitrobenzene or 4-chloronitrobenzene with the corresponding amines or amides in the presence of a base. This can also be done using catalysts

Pd as Pd (OAc)₂/ DPPF / NaOt-Bu (Tetrahedron Lett. 1999, 40,

2035) or copper (Renger, Synthesis 1985, 856; Aebischer et al., Heterocycles 1998, 48, 2225). Likewise, halogenated aromatic hydrocarbons without a nitro group can be transformed first into the corresponding amides and then nitrated in position 4 (document

US3279880).

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

<img file="CU23366B7_D0012.tif" />

They were dissolved in 2 1 of N-methylpyrrolidone (NMP) 2 mol (202 g) of morpholin-3-one (E. Pfeil, U. Harder, Angew.

Chem. 79, 1967, 188). Then, within 2 h, 88 g (2.2 nol) of sodium hydride (60% paraffin) was added to portions. After completion of the evolution of hydrogen, 282 g (2 mol) of 4-fluoronitrobenzene was added dropwise over 1 hour and the reaction mixture was stirred overnight. Subsequently, they were removed by distillation at 12 mbar and 76 ° C 1.7 1 of the volume of liquid, the residue was poured onto 2 1 of water and this mixture was extracted twice with each 1 1 of ethyl acetate. After washing the combined organic phases with water, they were dried over sodium sulfate and the solvent was removed by vacuum distillation. Purification was performed by chromatography on silica gel with hexane / ethyl acetate (1: 1) and subsequent crystallization from ethyl acetate. The product, 78 g as a colorless to brownish solid, was obtained with a yield of 17.6% of theory.

NMR-¹H (300 MHz, CDCl₃): 3.86 (m, 2H, CH₂CH₂), 4.08 (m, 2H, CH₂CH₂), 4.49 (s, 2H, CH₂C0), 7.61 (d, 2H, ³J = 8.95 Hz, CHCH), 8.28 (d, 2H, ³J = 8.95 Hz, CHCíí)

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

Similarly, the following compounds were synthesized:

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

4- (N-Piperidonyl) nitrobenzene

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

4- (N-Pyrrolidonyl) nitrobenzene

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

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

<img file="CU23366B7_D0013.tif" />

63 g (0.275 mol) of 4- (4-morpholin-3onyl) nitrobenzene were dissolved in an autoclave in 200 ml of tetrahydrofuran, mixed with 3.1 g of Pd / C (5%) and hydrogenated for 8 ha 70 ° C and a hydrogen pressure of 50 bar. After filtration of the catalyst, the solvent was removed by vacuum distillation and the product was purified by crystallization from ethyl acetate. The product, 20 g as a colorless to brownish solid, was obtained with a yield of 37.6% of theory.

Purification can also be performed by chromatography on silica gel with hexane / ethyl acetate. NMR-¹H (300 MHz, CDC1₃): 3.67 (m, 2H, CH₂CH₂), 3.99 (m,

2H, CH₂CH₂), 4.27 (s, 2H, CH₂CO), 6.68 (d, 2H, ³J = 8.71 Hz, CHCH), 7.03 (d, 2H, ³J = 8.71 Hz, CHCHj

MS (Ir%) = 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- Fluoro-4- (4-morpholin-3-onyl) aniline

4- (N-Piperidonyl) aniline

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

4- (N-Pyrrolidonyl) aniline

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

General method for the synthesis of 4-substituted anilines by reaction of 1-fluoro-4-nitrobenzenes and 1-chloro-4-nitrobenzenes with primary or secondary amines and subsequent reduction

<img file="CU23366B7_D0014.tif" />

Fluoronitrobenzene or equimolar amounts of chloronitrobenzene and the amine are dissolved in dimethylsulfoxide or acetonitrile (0.1 M solution at 1 M) 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 over MgSO₄, is filtered and concentrated. A precipitate forms in the reaction mixture, then it is filtered and washed with ether or acetonitrile. If product is also found in the mother liquors, it is processed as described with ether and water. The crude products can be purified by chromatography on silica gel (dichloromethane / cyclohexane and dichloromethane / ethanol mixtures).

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

Alternatively, iron powder can also be used as a reducer. In this case, the nitro compound is dissolved in acetic acid (0.1 M solution at 0.5 M) and six equivalents of iron and water powder are added at 90 ° C to portions within 10-15 min (0, 3 to 0.5 times the volume of acetic acid). After an additional 30 min at 90 ° C it is filtered and the filtrate is concentrated. The residue is processed by extraction with ethyl acetate and 2N caustic soda solution. The organic phase is dried over MgSO.₄₍ It is filtered and concentrated. The crude product can be purified by silica gel chromatography (dichloromethane / ethanol mixtures) or preparative reverse phase HPLC (acetonitrile / water mixtures).

Similarly, the following starting compounds were prepared:

XII-1 1- (4-Aminophenyl) -L-tere-butyl prolinate

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

HPLC (Method 4): tr = 2.79 min.

III-2 1- (4-Aminophenyl) -3-piperidinecarboxamide

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

HPLC (Method 4): tr = 0.59 min.

III-3 1- (4-Aminophenyl) -4-piperidinecarboxamide

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

HPLC (Method 4): tr = 0.57 min.

III-4 1- (4-Aminophenyl) -4-piperidinone

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

HPLC (Method 4): tr = 0.64 min.

III-5 1- (4-Aminophenyl) -L-prolinamide

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

HPLC (Method 4): tr = 0.72 min.

III-6 [1- (4-Aminophenyl) -3-piperidinyl] methanol

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

HPLC (Method 4): tr = 0.60 min.

III-7. [1- (4-Aminophenyl) -2-piperidinyl] methanol

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

HPLC (Method 4): tr = 0.59 min.

III-8 ._1- (4-Aminophenyl) -2-ethyl piperidinecarboxylate

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

HPLC (Method 4): tr = 2.43 min.

III-9. [1- (4-Aminophenyl) -2-pyrrolididinyl] methanol

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

HPLC (Method 4): tr = 0.79 min.

III.10 4- (2-Methylhexahydro-5H-pyrrolo [3,4-d] isoxazol5-yl) phenylamine

Starting from 2-methylhexahydro-2H-pyrrolo [3,4d] isoxazole (Ziegler, Cari B., et al .; J. Heterocyclic.

Chem .; 25; two; 1988; 719-723)

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

HPLC (Method 4): tr = 0.54 min.

III-ll. 4- (1-Pyrrolidinyl) -3- (trifluoromethyl) aniline

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

HPLC (Method 7): tr = 3.40 min.

III-12 3-Chloro-4- (1-pyrrolidinyl) aniline

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

HPLC (Method 4): tr = 0.78 min.

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

MS (ESI): m / z (%) = 222 (M + H, 100);

HPLC (Method 4): tr = 0.77 min.

III-14, 3-Methoxy-4- (4-morpholinyl) aniline

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

HPLC (Method 4): tr = 0.67 min.

III-15 1- [5-Amino-2- (4-morpholinyl) phenyl] ethanone

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

HPLC (Method 4): tr = 0.77 min.

General method for the synthesis of 4-substituted anilines by reaction of l-fluoro-4-nitrobenzenes with amides and subsequent reduction

<img file="CU23366B7_D0015.tif" />

<img file="CU23366B7_D0016.tif" />

<img file="CU23366B7_D0017.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 equivalent portions of l-fluoro-4-nitrobenzene are added to portions. The reaction mixture is stirred overnight at RT, diluted with ether or ethyl acetate and washed with aq. sat. of sodium hydrogen carbonate. The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product can be purified by silica gel chromatography (dichloromethane / ethanol mixtures).

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

Alternatively, iron powder can also be used as a reducer. In this case, the nitro compound is dissolved in acetic acid (0.1 M solution at 0.5 M) and six equivalents of iron and water powder are added at 90 ° C to portions within 10-15 min (0, 3 to 0.5 times the volume of acetic acid). After an additional 30 min at 90 ° C it is filtered and the filtrate is concentrated. The residue is processed by extraction with ethyl acetate and 2N caustic soda solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product can be purified by silica gel chromatography (dichloromethane / ethanol mixtures) or preparative reverse phase HPLC (acetonitrile / water mixtures).

Similarly, the following starting compounds were prepared:

IV-1._1- [4-Amino-2- (trifluoromethyl) phenyl) -2pyrrolidone

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

HPLC (Method 4): tr = 2.98 min.

IV-2 ._4- [4-Amino-2- (trifluoromethyl) phenyl) -3morpholinone

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

HPLC (Method 4): tr = 2.54 min.

IV-3 ._4- (4-Amino-2-chlorophenyl) -3-morpholinone

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

HPLC (Method 4): tr = 1.96 min.

IV-4 ._4- (4-Amino-2-methylphenyl) -3-morpholinone

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

HPLC (Method 4): tr = 0.71 min.

IV-5 ._5-Amino-2 - (3-oxo-4-morpholinyl) benzonitrile

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

HPLC (Method 4): tr = 1.85 min.

IV-6 ._1- (4-Amino-2-chlorophenyl) -3-pyrrolidone

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

HPLC (Method 4): tr = 2.27 min.

IV-7 ._4- (4-Amino-2,6-dimethylphenyl) -3-morpholinone

Starting from 2-fluoro-l, 3-dimethyl-5-nitrobenzene (Bartoli et al., J. Org. Chem., 1975, 40,872):

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

HPLC (Method 4): tr = 0.77 min.

IV-8 ._4- (2,4-Diaminophenyl) -3-morpholinone

Starting from 1-fluoro-2,4-dinitrobenzene

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

HPLC (Method 4): tr = 0.60 min.

IV- 9 _4- (4-Amino-2-chlorophenyl) -2-methyl-3morpholinone

Starting from 2-methyl-3-morpholinone (Pfeil, E .; Harder,

OR.; Angew Chem. 1967, 79, 188);

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

HPLC (Method 4): tr = 2.27 min.

IV-10 ._4- (4-Amino-2-chlorophenyl) -6-methyl-3morpholinone

Starting from 6-methyl-3-morpholinone (EP 350 002);

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

HPLC (Method 4): tr = 2.43 min.

Synthesis Examples

The following examples 1 to 13, 17 to 19 and 36 to 57 refer to the variant [A] of the procedure.

Example 1

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

<img file="CU23366B7_D0018.tif" />

They were dissolved in 9.9 ml of DMF (5S) -5- (aminomethyl) -ΙΟ-fluoro-4-morph olinof enyl) -1,3-oxazolidin-2 -one (for preparation 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-hydroxy-lHbenzotriazole, hydrate ( HOBT) (0.3 g, 1.3 equivalents). 0.31 g (1.98 mmol, 1.3 equivalents) of Ν '- (3dimethylaminopropyl) -N-ethylcarbodiimide (EDCI) was added dropwise at room temperature 0.39 g (0.53 ml, 3, 05 mmol, 2 equivalents) of diisopropylamine (DIEA). It was stirred overnight at room temperature. 2 g of silica gel were added and the mixture was evaporated in vacuo to dryness. The residue was chromatographed on silica gel with a gradient of toluene-ethyl acetate. 0.412 g (61.5% of theory) of the desired compound were obtained with a melting point (mp) of 197 ° C.

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

MS (DCI) 440.2 (M + H), Cl pattern;

NMR-¹H (d₆-DMSO, 300 MHz) 2.95 (m, 4H), 3.6 (t, 2H),

<td> 3,72</td><td>(m,</td><td>4H),</td><td>3.8 (dd, IH),</td><td>4.12 (t, IH), 4.75-4.85</td><td>(m,</td>

<td>IH),</td><td> 7,05</td><td>(t,</td><td>IH), 7.15-7.2</td><td>(m, 3H), 7.45 (dd, IH),</td><td> 7,68</td>

<td>(d,</td><td>IH),</td><td> 8,95</td><td>(t, IH).</td><td></td><td></td>

Example 2

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

<img file="CU23366B7_D0019.tif" />

It was obtained analogously from benzyl 4morpholinophenylcarbamate through intermediate (5S) -5- (aminomethyl) -3- (3-fluoro-4-morpholinophenyl) -1,3oxazolidin-2-one (see Example 1).

Mp: 198 ° C;

CI value₅₀ = 43 nM;

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

Example 3

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

<img file="CU23366B7_D0020.tif" />

It was obtained analogously from (5S) -5 (aminomethyl) -3 - [3-fluoro-4 - (1,4-thiazinan-4-yl) phenyl] -1,3oxazolidin-2-one (for its preparation see MR Barbachyn et al., J. Med. Chem. 1996, 39, 680).

Mp: 193 ° C;

Yield: 82%;

Rf (SiO₂, toluene / ethyl acetate 1: 1) = 0.47 (reactant = 0.0).

Example 4

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

<img file="CU23366B7_D0021.tif" />

It was obtained analogously from 5-bromothiophene-2-carboxylic acid.

Mp: 200 ° C.

Example 5

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

<img file="CU23366B7_D0022.tif" />

It was obtained analogously from 5-methylthiophene-2-carboxylic acid.

Mp: 167 ° C

Example 6

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

<img file="CU23366B7_D0023.tif" />

Cl

It was obtained analogously from (5S) -5 (aminomethyl) -3- (6-methylthieno [2,3-b] pyridin-2-yl) -1,3oxazolidin-2-one (for preparation see document

EP-A-785 200).

Mp: 247 ° C.

Example 7

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

Cl '

It was obtained analogously from 6 - [(5S) -570 (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] -3-methyl-1,3 benzothiazol-2 (3H) -one (for its preparation see EP-A-738

726) .

Mp: 217 ° C

Example 8

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

<img file="CU23366B7_D0024.tif" />

It was obtained analogously from (5S) -5 (aminomethyl) -3- {3-fluoro-4- [4- (4-pyridinyl) piperazino] phenyl} -1,3-oxazolidin-2-one (preparation analogously as in JA Tucker et al., J.

Med. Chem. 1998, 41, 3727).

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

Example 9

5-Chloro-N- ({(5S) -3- [3-fluoro-4- (4methylpiperazino) phenyl] -2-oxo-1,3-oxazolidin-5-yl) methyl) -271 thiophenecarboxamide

<img file="CU23366B7_D0025.tif" />

It was obtained analogously from (5S) -5 (aminomethyl) -3- [3-fluoro-4- (4-methylpiperazino) phenyl] -1,3oxazolidin-2-one

Example 10

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

<img file="CU23366B7_D0026.tif" />

It was obtained analogously from (5S) -5 (aminomethyl) -3- [3-fluoro-4- (4-tert-butoxycarbonylpiperazin72

1- il) phenyl] -1,3-oxazolidin-2-one (for preparation see document WO-A-93/23384 already cited).

Mp: 184 ° C;

R_F(SiO₂, toluene / ethyl acetate 1: 1) = 0.42.

Example 11

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

<img file="CU23366B7_D0027.tif" />

It was obtained by reacting the compound of Example 12 with trifluoroacetic acid in methylene chloride.

CI value₅₀ = 140 nM;

NMR-¹!! [d₆-DMSO]: 3.01-3.25 (m, 8H), 3.5-3.65 (m, 2H),

3.7-3.9 (m, IH), 4.05-4.2 (m, IH), 4.75-4.9 (m, IH), 7.057.25 (m, 3H), 7, 5 (dd, IH), 7.7 (d, IH), 8.4 (wide s, IH),

9.0 (t, IH).

Example 12

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

<img file="CU23366B7_D0028.tif" />

It was obtained analogously from (5S) -5 (aminomethyl) -3- (2,4'-bipyridinyl-5-yl) -2-oxo-l, 3oxazolidin-2-one (for preparation see document

EP-A-789 026).

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

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

Example 13

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

<img file="CU23366B7_D0029.tif" />

It was obtained analogously from 5- (hydroxymethyl) -3 (4-piperidinophenyl) -1,3-oxazolidin-2-one (for preparation see DE 2708235) after mesylation, reaction with potassium phthalimide, hydrazinolysis and reaction with 5-chlorothiophene-2-carboxylic acid.

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

Mp: 205 ° C.

Example 17

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

<img file="CU23366B7_D0030.tif" />

It was obtained from 1- (4-aminophenyl) pyrrolidin-2-one (for its preparation see Reppe et al., Justus Liebigs Ann. Chem .; 596; 1955; 209) analogously to the known synthesis scheme (see SJ Brickner et al., J. Med.

Chem. 1996, 39, 673) after reaction with benzyloxycarbonyl chloride, subsequent reaction with glycidyl R-butyrate, mesylation, reaction with potassium phthalimide, hydrazinolysis in methanol and reaction with 5-chlorotiefen-2-carboxylic acid to finally reach 5-chloro- N - ({(5S) -2-oxo-3- [4- (2-oxo-1-pyrrolidinyl) phenyl] -1,375 oxazolidin-5-ylmethyl) -2-thiophenecarboxamide. The 5-chloro-N ({(5S) -2-oxo-3- [4- (2-oxo-1-pyrrolidinyl) phenyl] -1,3oxazolidin-5-yl} methyl) -2-thiophenecarboxamide obtained from this mode presented a CI value₅₀ = 4 nM (test method for the IC value₅₀ according to Example Al.al) above described measurement of inhibition of factor Xa).

Mp: 229 ° C;

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

<td></td><td>MS (ESI)</td><td> : 442,0 (21%,</td><td>M + Na,</td><td>Cl pattern</td><td> 1, 420,0</td><td> (72%,</td>

<td>M + H,</td><td>Pattern</td><td>of Cl), 302.3</td><td> (12%),</td><td colspan="2"> 215 (52%), 145 (100%)</td><td>i</td>

<td></td><td>NMR-¹!!</td><td>(d₆-DMSO, 300</td><td>MHz);</td><td>2.05 (m, 2H),</td><td>2.45 (m,</td><td>2H),</td>

<td> 3,6</td><td>(t, 2H),</td><td>3.77-3.85 (m,</td><td>, 3H),</td><td>4.15 (t, IH),</td><td colspan="2">4.75-4.85 (m,</td>

<td>IH),</td><td>7, 2 (d.</td><td>IH), 7.5 (d,</td><td>2H),</td><td>7.65 (d, 2H),</td><td>7.69 (d,</td><td>IH),</td>

<td> 8,96</td><td>(t, IH)</td><td> -</td><td></td><td></td><td></td><td></td>

<td></td><td colspan="3">The individual steps of</td><td>the synthesis</td><td colspan="2">previously</td>

<td colspan="2">described from</td><td colspan="2">Example 17 with the</td><td colspan="3">respective precursors are</td>

as follows:

4 g (22.7 mmol) of 1 (4-aminophenyl) pyrrolidin-2-one and 3.6 ml (28.4 mmol) of N, N-dimethylaniline in 107 ml of tetrahydrofuran were mixed slowly at -20 ° C , 27 g (25.03 mmol) of benzyl chloroformate. It was stirred for 30 minutes at -20 ° C and then the mixture was allowed to reach room temperature. 0.5 1 of ethyl acetate was added and the organic phase was washed with 0.5 1 of saturated NaCl solution. The separated organic phase was dried with MgSO₄ and the solvent was evaporated in vacuo. The residue was rubbed with diethyl ether and filtered with suction. 5.2 g (73.8% of theory) of benzyl 4- (2-oxo-pyrrolidinyl) phenylcarbamate were obtained as light beige crystals with a melting point of 174 ° C.

1.47 g (16.66 mmol) of isoamyl alcohol in 200 ml of tetrahydrofuran were mixed under argon at 10 ° C dropwise with 7.27 ml of a 2.5 M solution of n-butyllithium (BuLi) in hexane, another 8 ml of Bu-Li solution being necessary for the turn of the added Nbenzylidenebenzylamine indicator. It was stirred for 10 minutes at -10 ° C, cooled to -78 ° C and a solution of 4.7 g (15.14 mmol) of benzyl 4- (2-oxo-lpyrrolidinyl) phenylcarbamate was slowly added. Subsequently, 4 ml of η-BuLi solution was added until turning the indicator to pink. It was stirred for 10 minutes at -78 ° C and 2.62 g (18.17 mmol) of glycidyl R-butyrate was added and stirring was continued for 30 minutes at -78 ° C.

The mixture was allowed to reach room temperature overnight, 200 ml of water was added to the mixture and the THF content was evaporated in vacuo. The aqueous residue was extracted with ethyl acetate, the organic phase was dried with MgSO₄ and evaporated under vacuum. The residue was rubbed with 500 ml of diethyl ether and the crystals that precipitated were filtered under vacuum suction.

3.76 g (90% of theory) of (5R) -5 (hydroxymethyl) -3 - [4 - (2-oxo-1-pyrrolidinyl) phenyl] -1,3oxazolidinin-2-one with a point of fusion of 148 ° C and an R value_F(SiO₂, toluene / ethyl acetate 1: 1) = 0.04 (reactant = 0.3).

3.6 g (13.03 mmol) of (5R) -5 (hydroxymethyl) -3- [4- (2-oxo-1-pyrrolidinyl) phenyl] -1,3oxazolidinin-2-one and 2.9 g (28.67 mmol) of triethylamine in 160 ml of dichloromethane at 0 ° C with stirring. 1.79 g (15.64 mmol) of methanesulfonyl chloride was added with stirring and stirred for 1.5 hours at 0 ° C as well as 3 h at room temperature.

The reaction mixture was washed with water and the aqueous phase was repeatedly extracted with methylene chloride.

The combined organic extracts were dried with MgSO₄ and evaporated. The residue (1.67 g) was then dissolved in 70 ml of acetonitrile, mixed with 2.62 g (14.16 mmol) of potassium phthalimide and stirred in a closed container in a microwave oven for 45 minutes at 180 ° C

The insoluble residue was removed from the reaction mixture by filtration, the filtrate was evaporated in vacuo, the residue (1.9 g) was dissolved in methanol and mixed with 0.47 g (9.37 mmol) of hydrate. hydrazine He underwent

<td>boiling</td><td>during</td><td>2 hours,</td><td>he</td><td>cooled down</td><td>it mixed</td><td>with</td>

<td colspan="2">saturated solution of</td><td colspan="2">baking soda</td><td colspan="2">sodium and extracted</td><td>six</td>

<td>times with</td><td>a total</td><td>of 2 1</td><td>from</td><td>chloride</td><td>methylene</td><td>The</td>

<td>extracts</td><td>organic</td><td>together</td><td>from</td><td>the (5S) -5-</td><td>(aminomethyl</td><td> ) -3-</td>

[4- (2-Oxo-l-pyrrolidinyl) phenyl] -1,3-oxazolidinin-2-one crude was dried with MgSO₄ and evaporated in vacuo.

The final product, 5-chloro-N - ({(5S) -2-oxo-3- [4- (2oxo-1-pyrrolidinyl) phenyl] -1,3-oxazolidin-5-yl} methyl) -2 thiophenecarboxamide, was prepared by dissolving 0.32 g (1.16 mmol) of the (5S) -5- (aminomethyl) -3- [4- (2-oxo-lpyrrolidinyl) phenyl] -1,3-oxazolidinin-2- a previously synthesized one, 5-chlorothiophene-2-carboxylic acid (0.19 g;

1.16 mmol) and 1-hydroxy-lH-benzotriazole hydrate (HOBT) (0.23 g, 1.51 mmol) in 7.6 ml of DMF. 0.29 g (1.51 mmol) of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide (EDCI) was added dropwise at room temperature 0.3 g (0.4 ml; 2.32 mmol; 2 equivalents) of diisopropylethylamine (DIEA). It was stirred overnight at room temperature.

The reaction mixture was evaporated in vacuo to dryness, the residue was dissolved in 3 mL of DMSO and chromatographed by RP-MPLC with acetonitrile / water / 0.5% TFA gradients. From the convenient fractions, the acetonitrile content was evaporated and the precipitated compound was filtered off with suction. 0.19 g (39% of theory) of the desired compound were obtained.

Similarly, they prepared:

Example 18

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

Similarly to Example 17 from 4-pyrrolidin-lil-aniline (Reppe et al., Justus Liebigs Ann. Chem .; 596; 1955; 151) the compound 5-chloro-N - ({(5S) -2 was obtained -oxo-3 [4 - (1-pyrrolidinyl) phenyl] -1,3-oxazolidin-5-yl} methyl) -2 thiophenecarboxamide.

CI₅₀ = 40 nM;

Mp: 216 ° C;

R value_F(SiO₂, toluene / ethyl acetate 1: 1) = 0.31 (reactant = 0.0).

Example 19

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

Similarly, from Ν, Ν-diethylphenyl-l, 4-diamine (US-A-2 811 555; 1955) the compound 5-chloro-N ({(5S) -2-ΟΧΟ-3- [4 - (diethylamino) phenyl] -1,3-oxazolidin-5-ylmethyl) -2-thiophenecarboxamide.

CI₅₀ = 270 nM;

Mp: 181 ° C;

R value_F(SiO₂, toluene / ethyl acetate 1: 1) (reactant = 0.0).

Example 36

0,25

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

Starting from 2-methyl-4- (4-morpholinyl) aniline (JE Lu

Valle et al., J.Am.Chem.Soc. 1948, 70, 2223):

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

HPLC (Method 1): tr (%) = 3.77 (98).

CI₅₀: 1.26 μΜ

Example 37

5-Chloro-N- {[(5S) -3- (3-chloro-4-morpholinylphenyl) -2-oxo1,3-oxazolidin-5-yl] methyl} -2-thiophenecarboxamide

Starting from 3-chloro-4- (4-morpholinyl) aniline (HR

Snyder et al., J.Pharm.Sci. 1977, 66, 1204):

MS (ESI): m / z (%) = 456 ([M + H]⁺, 100), Cl pattern₂;

HPLC (Method 2): tr (%) = 4.31 (100).

CI₅₀: 33 nM

Example 38

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

Starting from 4- (4-morpholinyl sulfonyl) aniline (Adams and

<td>col., J.Am.Chem.Soc.</td><td> 1939,</td><td> 61, 2342) :</td>

<td>MS (ESI): m / z (%)</td><td> = 466</td><td>([M + H]⁺, 100), Cl pattern;</td>

<td>HPLC (Method 3):</td><td>tr (%)</td><td> = 4,07 (100) .</td>

CI₅₀: 2 μΜ

Example 39

5-Chloro-N - ({(5S) -3- [4- (4-azetidinylsulfonyl) phenyl] -281 oxo-1,3-oxazolidin-5-ylmethyl) -2-thiophenecarboxamide

Starting from 4 - (1-azetidinylsulfonyl) aniline:

MS (INN, NH₃): m / z (%) = 473 ([M + NH₄]⁺, 100), pattern

Cl;

HPLC (Method 3): tr (%) = 4.10 (100).

CI₅₀: 0.84 μΜ

Example 40

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

Starting from 4-amino-N, N-dimethylbenzenesulfonamide (IK Khana et al., J.Med.Chem. 1997, 40, 1619):

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

HPLC (Method 3): tr (%) = 4.22 (100).

CI₅₀: 90 nM

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

<img file="CU23366B7_D0031.tif" />

To the corresponding acid chloride (2.5 eq.) Is added dropwise under argon and at room temperature a solution approx. 1 molar of 5- (aminomethyl) -3- [4- (2-oxo-lpyrrolidinyl) phenyl] -1,3 -oxazolidin-2 -one (from Example 45) (1.0 eq.) And absolute pyridine (approx. 6 eq.) In absolute dichloromethane. The mixture is stirred for approx. 4 h at room temperature before adding approx. 5.5 eq. from PS-Trisamine (Argonaut Technologies). The suspension is gently stirred for 2 h, after dilution with dichloromethane / DMF (3: 1), it is filtered (the resin is washed with dichloromethane / DMF) and the filtrate is concentrated. The product obtained is purified as appropriate by preparative RP-HPLC.

Similarly, it was prepared:

Example 41

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

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

LC-MS: tr (%) = 3.04 (100).

CI₅₀: 1.3 μΜ

General method for the synthesis of acylated derivatives starting with 5- (aminomethyl) -3- [4- (2-oxo-lpyrrolidinyl) phenyl] -1,3-oxazolidin-2-one and carboxylic acids

<img file="CU23366B7_D0032.tif" />

At 2.9 eq. Resin-fixed carbodiimide (PSCarbodiimid, Argonaut Technologies) were added the corresponding carboxylic acid (approx. 2 eq.) and a mixture of absolute dichloromethane / DMF (approx. 9: 1). After approx. 15 min of gentle stirring at room temperature, 5- (aminomethyl) -3- [4- (2-oxo-l-pyrrolidinyl) phenyl] 1,3-oxazolidin-2-one (from Example 45) is added (1 , 0 eq.) And the mixture is stirred overnight before removing the resin by filtration (then washed with dichloromethane), and the filtrate is concentrated. The product obtained is purified as appropriate by preparative RP-HPLC.

Similarly, they prepared:

Example 42

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

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

LC-MS (Method 6): tr (%) = 3.23 (100).

CI₅₀: 0.16 μΜ

Example 43

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

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

LC-MS (Method 5): tr (%) = 3.48 (78).

CI₅₀: 0.014 μΜ

Example 44

5-Chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4morpholinyl) phenyl] -l, 3-oxazolidin-5-yl} methyl) -2t iofcarboxamide

<img file="CU23366B7_D0033.tif" />

<img file="CU23366B7_D0034.tif" />

OR

<img file="CU23366B7_D0035.tif" />

a) 2 - ((2R) -2-Hydroxy-3 - {[4- (3-oxo-4-morpholinyl) phenyl] amino} propyl) -lH-isoindole-1,3 (2H) -dione:

A suspension of 2- [(2S) -2-oxyranylmethyl] -1Hisoindole-1,3 (2H) -dione (A. Gutcait et al., Tetrahedron Asym. 1996, 7, 1641) (5.68 g, 27, 9 mmol) and 4- (4aminophenyl) -3-morpholinone (5.37 g, 27.9 mmol) in ethanolagua (9: 1, 140 ml) was heated at reflux for 14 h (the precipitate dissolved, after some time a precipitate formed again). The precipitate (desired product) was filtered off, washed three times with diethyl ether and dried. The combined mother liquors were concentrated in vacuo and after adding a second portion of 2 - [(2S) -2-oxyranylmethyl] -lH-isoindole-1,3 (2H) -dione (2.84 g, 14.0 mmol) they were suspended in ethanol-water (9: 1, 70 ml) and heated at reflux for 13 h (the precipitate dissolved, after some time a precipitate formed again). The precipitate (desired product) was filtered off, washed three times with diethyl ether and dried. Total yield: 10.14 g, 92% of theory.

MS (ESI): m / z (%) = 418 ([M + Na]⁺, 84), 396 ([M + H]⁺, 93);

HPLC (Method 3): tr (%) = 3.34 (100).

b) 2 - ({(5S) -2-Oxo-3- {4- (3-oxo-4-morpholinyl) phenyl] -1,3oxazolidin-5-yl} methyl-lH-isoindole-l, 3 (2H ) -Diona:

To a suspension of the amino alcohol (3.58 g, 9.05 mmol) in tetrahydrofuran (90 ml) was added under argon at room temperature Ν, N'-carbonyldiimidazole (2.94 g, 18.1 ml) and dimethylaminopyridine ( catalytic amount). The reaction suspension was stirred at 60 ° C for 12 h (the precipitate dissolved, after some time a precipitate formed again), mixed with a second portion of Ν, N'-carbonyldiimidazole (2.94 g, 18 , 1 ml) and stirred for a further 12 h at 60 ° C. The precipitate (desired product) was filtered off, washed with tetrahydrofuran and dried. The filtrate was concentrated in vacuo and more product was purified by flash chromatography (dichloromethane-methanol mixtures). Total yield: 3.32 g, 87% of theory.

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

HPLC (Method 4): tr (%) = 3.37 (100).

c) 5-Chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] -l, 3-oxazolidin-5-yl} methyl) -2- thiophencarboxamide:

To a suspension of oxazolidinone (4.45 g, 10.6 mmol) in ethanol (102 ml) was added dropwise at room temperature methylamine (40% in water, 10.2 ml, 0.142 mol). The reaction mixture was heated at reflux for 1 h and concentrated in vacuo. The crude product was used without further purification in the next reaction.

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

Mp: 232-233 ° C;

NMR of ³H (DMSO-d⁶, 200 Mhz): 9.05-8.90 (t, J = 5.8

<td>Hz</td><td>, IH)</td><td> /</td><td> 7,70</td><td>(d,</td><td>J = 4.1</td><td>Hz,</td><td>IH), 7.56</td><td>(d, J =</td><td> 9,</td><td>0 Hz</td>

<td>2H</td><td> ) , 7,</td><td> 41</td><td>(d,</td><td>J =</td><td>9.0 Hz,</td><td>2H)</td><td>, 7.20 (d,</td><td>J = 4.1</td><td>Hz,</td><td>IH)</td>

<td> 4,</td><td> 93-4,</td><td> 75</td><td>(m,</td><td>IH),</td><td> 4,27-4,</td><td> 12</td><td>(m, 3H), 4,</td><td> 02-3,91</td><td>(m,</td><td>2H)</td>

<td> 3,</td><td> 91-3,</td><td> 79</td><td>(dd,</td><td>J =</td><td>6.1 Hz,</td><td> 9,2</td><td>Hz, IH), 3</td><td> , 76-3,66</td><td>(m,</td><td>2H)</td>

3.66 (m, 2H);

MS (ESI): m / z (%) = 436 ([M + H]⁺, 100, Cl pattern); HPLC (Method 2): tr (%) = 3.60 (100);

[to] ²¹d = -38 ° (c 0.2885, DMSO); ee: 99%.

CI₅₀: 0.7 nM

In a similar way they were prepared.

Example 45

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

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

66);

HPLC (Method 3): tr (%) = 3.65 (100).

CI₅₀: 4.2 nM

Example 46

5-Bromo-N - ({(5S) -2-oxo-3- {4- (3-oxo-4-morpholinyl) 10 phenyl] -1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide

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

HPLC (Method 3): tr (%) = 3.87 (100).

CI₅₀: 0.3 nM

Example 47

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

<img file="CU23366B7_D0036.tif" />

200 mg (0.61 mmol) of hydrochloride were suspended.

6- [(5S) -5- (aminomethyl) -2-oxo-l, 3-oxazolidin-3-yl] -3isopropyl-1,3-benzoxazol-2 (3H) -one (EP 738726) in 5 ml of tetrahydrofuran and mixed with 0.26 ml (1.83 mmol) of triethylamine and 132 mg (0.73 mmol) of chloro-thiophene-2-carboxylic acid chloride. The reaction mixture was stirred overnight at room temperature and then concentrated. The product was isolated by column chromatography (silica gel, methylene chloride / ethanol = 50/1 to 20/1). 115 mg (43% of theory) of the desired compound were obtained.

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

HPLC (Method 4): tr = 3.78 min.

Similarly, the following compounds were prepared:

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

<td> 48</td><td>Or S- ^^CI Chiral OR 0</td><td> 210</td><td> 0,12</td>

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

<td> 50</td><td>1 or ^ChiralΛ_οχΛ_νλ_οX.</td><td> 195</td><td> 1,15</td>

<td> 51</td><td>9. Chiral 0</td><td> 212</td><td> 1,19</td>

<td> 52</td><td>„&lt;5 Chiral ₀W-ΧγΟ-- y »</td><td> 160</td><td> 0,19</td>

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

<td>Example N "</td><td>Structure</td><td>Pf [° C]</td><td>CI₅₀ [μΜ]</td>

<td> 54</td><td>/ “\ E Quiral N °</td><td> 221</td><td> 0,13</td>

<td></td><td>from 5-aimno-2-pyrrolidino- benzonitrile (Grell, W., Humaus, R .; Griss, G., Sauter, R .; Rupprecht, E. et al .; J.Med.Chem. 1998,41; 5219)</td><td></td><td></td>

<td> 55</td><td>Chiral 0</td><td> 256</td><td> 0,04</td>

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

<td> 56</td><td>rA / = \ Chiral or 5</td><td> 218</td><td> 0,004</td>

<td> 57</td><td>_ L Chiral⁰ s</td><td> 226</td><td> 0,58</td>

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

The following Examples 20 to 30 and 58 to 139 refer to the variant [B] of the process, Examples 20 and 21 describing the synthesis of precursors.

Example 20

<img file="CU23366B7_D0037.tif" />

To an ice-cold solution of 2.63 ml (35 mmol) of allylamine in 14.2 ml of absolute pyridine and 14.22 ml of absolute THF was added dropwise 5-chloro-thiophene-2-carboxylic acid chloride ( 7.61 g, 42 mmol). The ice bath was removed and the mixture was stirred for 3 h at room temperature before concentrating in vacuo. The residue was mixed with water and the solids filtered off. The crude product was purified by flash chromatography on silica gel (dichloromethane).

Yield: 7.20 g (99% of theory);

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

32) ;

HPLC (Method 1): tr (%) = 3.96 (98.9).

Example 21

Synthesis of 5-chloro-N- (2-oxyranylmethyl) -2thiophenecarboxamide

An ice-cold solution of 2.0 g (9.92 mmol) of N-allyl-5-chloro-2-thiophenecarboxamide in 10 ml of dichloromethane was mixed with meta-chloroperbenzoic acid (3.83 g, approx. 60 %). The mixture was stirred overnight, warming to room temperature, and then washed with 10% sodium hydrogen sulfate solution (three times). The organic phase was washed with saturated sodium hydrogen carbonate solution (twice) and with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The product was purified by silica gel chromatography (cyclohexane / ethyl acetate 1: 1).

Yield: 837 mg (39% of theory):

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

80) ;

HPLC (Method 1): tr (%) = 3.69 (approx. 80).

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

<img file="CU23366B7_D0038.tif" />

To a solution of the primary amine or aniline derivative (1.5 to 2.5 eq.) In 1,4-dioxane, 1,4-dioxane-water or ethanol mixtures, ethanol-water mixtures (approx. 0.3 to 1 .0 mol / 1) is added to portions at room temperature or at temperatures up to 80 ° C 5-chloro-N- (2-oxyranylmethyl) -2thiophenecarboxamide (1.0 eq.). The mixture is stirred for 2 to 6 hours before concentrating. The product can be isolated from the reaction mixture by silica gel chromatography (cyclohexane-ethyl acetate mixtures, dichloromethane-methanol mixtures or dichloromethane-methanol-triethylamine mixtures.

Similarly, they prepared:

Example 22

N- [3- (Benzylamino) -2-hydroxypropyl] -5-chloro-2-thiophenecarboxamide

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

HPLC (Method 1): tr (%) = 3.87 min (97.9).

Example 23

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

Example 24

5-Chloro-N- [3- (4-cyanoanilino) -2-hydroxypropyl] -295 thiocarboxamide

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

HPLC (Method 1): tr (%) = 4.12 min (100).

Example 25

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

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

HPLC (Method 4): tr (%) = 3.60 min (95.4).

Example 26

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

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

HPLC (Method 4): tr (%) = 3.76 min (94.2).

Example 58

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

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

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

HPLC (Method 1): tr (%) = 4.08 (100).

Example 59

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

Starting from N-tert-butyloxycarbonyl-1,4 96 phenylenediamine:

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

HPLC (Method 1): tr (%) = 4.06 (100).

Example 60

2-Hydroxy-3 - {[4- (2-oxo-l-pyrrolidinyl) phenyl] amino} propyl) tere-butyl carbamate

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

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

HPLC (Method 1): tr (%) = 3.57 (97).

Example 61

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

They were heated at reflux in 15 ml of ethanol and 1 ml of water for 6 hours 800 mg (3.8 mmol) of 4- (4-amino-2-fluorophenyl) -3-morpholinone and 700 mg (3.22 mmol) of 5 -chloroN- (2-oxyranylmethyl) -2-thiophenecarboxamide. It was evaporated in vacuo, the precipitated crystals were filtered off with suction after treatment with ethyl acetate and 276 mg (17% of theory) of the desired compound was obtained by chromatography of the mother liquor.

R_F (ethyl acetate): 0.25.

Example 62 (N- (3-Anilino-2-hydroxypropyl) -5-chloro-297 thiophenecarboxamide

Starting from aniline:

MS (INN, NH₃): m / z (%) = 311 ([M + H]⁺, 100), pattern

Cl;

HPLC (Method 3): tr (%) = 3.79 (100).

Example 63

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

Starting from 4- (4-aminophenyl) -3-morpholinone:

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

HPLC (Method 3): tr (%) = 3.58 (100).

Example 64

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

Starting from N- (4-aminophenyl) -N-cyclopropylacetamide: MS (ESI): m / z (%) = 408 ([M + H]⁺, 100), Cl pattern;

HPLCI Method 3): tr (%) = 3.77 (100).

Example 65

N- [3 - ({4 - [Acetyl (methyl) amino] phenyl) amino) -2 hydroxypropyl] -5-chloro-2-thiophenecarboxamide

Starting from N- (4-aminophenyl) -N-methylacetamide:

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

HPLC (Method 4): tr = 3.31 min.

Example 66

5-Chloro-N- (2-hydroxy-3 - {[4- (1 H-1,2,3-triazol-198 yl) phenyl] amino} propyl) -2-thiophenecarboxamide

Starting from 4- (IH-1,2,3-triazol-1-yl) aniline (Bouchet et al., J. Chem. Soc. Perkin Trans. 2; 44 9:

MS (ESI): m / z (%) = 378 (M + H, 100);

HPLC (Method 4): tr = 3.55 min.

Example 67 l- {4 - [(3 - {[(5-Chloro-2-thienyl) carbonyl] amino} -2hydroxypropyl) amino] phenyl} -L-tere-butyl prolinate

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

HPLC (Method 4): tr = 3.40 min.

Example 68 l- {4 - [(3 - {[(5-Chloro-2-thienyl) carbonyl] amino} -2hydroxypropyl) amino] phenyl} -4-piperidinecarboxamide

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

HPLC (Method 4): tr = 2.39 min.

Example 69 l- {4 - [(3 - {[(5-Chloro-2-thienyl) carbonyl] amino} -2hydroxypropyl) amino] phenyl} -3-piperidinecarboxamide

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

HPLC (Method 4): tr = 2.43 min.

Example 70

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

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

HPLC (Method 4): tr = 2.43 min.

Example 71 l- {4- [(3- {[(5-Chloro-2-thienyl) carbonyl] amino} -2hydroxypropyl) amino] phenyl} -L-prolinamide

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

HPLC (Method 4): tr = 2.51 min.

Example 72

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

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

HPLC (Method 4): tr = 2.43 min.

Example 73

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

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

HPLC (Method 4): tr = 2.49 min.

Example 74 l- {4 - [(3 - {[(5-Chloro-2-thienyl) carbonyl] amino} -2hydroxypropyl) amino] phenyl} -2-piperidinecarboxylate

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

HPLC (Method 4): tr = 3.02 min.

Example 75

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

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

HPLC (Method 4): tr = 2.48 min.

100

Example 76

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

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

HPLC (Method 5): tr = 1.74 min.

Example 77

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

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

HPLC (Method 4): tr = 3.30 min.

Example 78

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

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

HPLC (Method 4): tr = 3.50 min.

Example 79

5-Chloro-N- (3 - {[3-chloro-4- (3-oxo-4morpholinyl) phenyl] amino} -2-hydroxypropyl) -220 thiophenecarboxamide

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

HPLC (Method 4): tr = 3.26 min.

Example 80

5-Chloro-N- (2-hydroxy-3 - {[4- (3-oxo-4-morpholinyl-325 (trifluoromethyl) phenyl] amino} propyl) -2-thiophenecarboxamide

101

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

HPLC (Method 4): tr = 3.37 min.

Example 81

5-Chloro-N- (2-hydroxy-3 - {[3-methyl-4- (3-oxo-45 morpholinyl) phenyl] amino} propyl) -2-thiophenecarboxamide

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

HPLC (Method 4): tr = 2.86 min.

Example 82

5-Chloro-N- (3 - {[3-cyano-4- (3-oxo-410 morpholinyl) phenyl] amino} -2-hydroxypropyl) -2thiophenecarboxamide

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

HPLC (Method 4): tr = 3.10 min.

Example 83

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

2-hydroxypropyl) -2-thiophenecarboxamide

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

HPLC (Method 4): tr = 2.49 min.

Example 84

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

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

HPLC (Method 4) · tr = 3.3 9 min.

Example 85

102

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

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

HPLC (Method 4): tr = 2.84 min.

Example 86

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

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

HPLC (Method 4): tr = 2.32 min.

Example 87

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

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

HPLC (Method 4): tr = 2.32 min.

Example 88

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

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

HPLC (Method 4): tr = 2.46 min.

Example 89

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

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

HPLC (Method 4): tr = 2.45 min.

103

Example 90

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

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

HPLC (Method 4): tr = 3.44 min.

Example 91

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

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

HPLC (Method 4): tr = 3.48 min.

Example 91 a

5-Chloro-N- [2-hydroxy-3 - ({4 - [(3-oxo-4morpholinyl) methyl] phenyl} amino) propyl) -2-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): tr = 2.66 min.

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

104

<img file="CU23366B7_D0039.tif" />

<img file="CU23366B7_D0040.tif" />

of the substituted derivative of N- (3-amino2-hydroxypropyl) -5-chloro-2-thiophenecarboxamide (1.0 eq.) in absolute THF (approx. 0.1 mol / 1) carbodiimidazole (1 is added at room temperature) , 2 to 1.8 eq.) Or an equivalent phosgene equivalent. The mixture is stirred at room temperature or if necessary at elevated temperature (up to

70 ° C) for 2 to 18 h, before concentrating in vacuo. The product can be purified by silica gel chromatography (dichloromethane-methanol mixtures or cyclohexane-ethyl acetate mixtures).

Similarly, they prepared:

Example 27

N - [(3-Benzyl-2-oxo-l, 3-oxazolidin-5-yl) methyl] -5-chloro-2-thiophenecarboxamide

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

HPLC (Method 1): tr (%) = 4.33 min (10).

Example 28

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

MS (DCI, NHJ: m / z (%) = 352 (M + H, 42), 145 (100);

HPLC (Method 2): tr (%) = 4.13 min (10).

105

Example 29

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

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

HPLC (Method 4): tr = 4.12 min.

Example 30

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

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

HPLC (Method 4): tr = 4.17 min.

Example 92

4- [5 - ({[5-Chloro-2-thienyl) carbonyl] amino} methyl) 1,3-oxazolidin-3-yl] tere-butyl benzylcarbamate

Starting from Example 58:

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

HPLC (Method 1): tr (%) = 4.51 (98.5).

Example 93

4- [5 - ({[5-Chloro-2-thienyl) carbonyl] amino} methyl) 1,3-oxazolidin-3-yl] phenylcarbamate tere-butyl

Starting from Example 59:

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

HPLC (Method 1): tr (%) = 4.41 (100).

Example 94

2-Oxo-3- [4- (2-oxo-l-pyrrolidinyl) phenyl] -1,3-oxo-oxo395

106 tere-butyl oxazolidin-5-ylmethylcarbamate

Starting from Example 60:

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

HPLC (Method 3): tr (%) = 3.97 (100).

Example 95

5-Chloro-N - ({3- [3-fluoro-4- (3-oxo-4-morpholinyl) phenyl] 2-oxo-1,3-oxazolidin-5-ylmethyl) -2-thiophenecarboxamide

Cl

They were heated at reflux for 5 hours in 2.0 ml of dioxane 260 mg (0.608 mmol) of 5-chloro-N- (3 - {[3-fluoro-4 (3-oxo-4-morpholinyl) phenyl] amino} - 2-hydroxypropyl) -2thiophenecarboxamide (from Example 61), 197 mg (1.22 mmol) of carbinylimidazole and 7 mg of dimethylaminopyridine. Then 20 ml of acetonitrile was added and stirred in a microwave in a closed container for minutes at 180 ° C. The solution was evaporated on a rotary evaporator and chromatographed on an RP-HPLC column. Mg (19% of theory) of the desired compound were obtained.

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

IH), 3.95 (m, 2H), 4.2 (m, IH), 4.21 (s, 2H), 4.85 (m, IH),

107

4.18 (s, 2H), 7.19 (d, IH, thiophene), 7.35 (dd, IH), 7.45 (t, IH), 7.55 (dd, IH), 7.67 (d, IH, thiophene), 8.95 (t, IH,

CONH).

Example 96

5-Chloro-N - [(2-oxo-3-phenyl-l, 3-oxazolidin-5-yl) methyl] 2-thiophenecarboxamide

Starting from Example 62:

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

100), Cl pattern;

HPLC (Method 3): tr (%) = 4.39 (100).

CI₅₀: 2 μΜ

Example 97

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

Starting from Example 63:

MS (ESI): m / z (%) = 458 ([M + Na]⁺, 66), 436 ([M + H]⁺,

100), Cl pattern;

HPLC (Method 3): tr (%) = 3.89 (100).

CI₅₀: 1.4 μΜ

Example 98

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

Starting from Example 64:

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

100), Cl pattern;

108

HPLC (Method 3): tr (%) = 4.05 (100).

CI₅₀ : 50 μΜ

Example 99

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

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

HPLC (Method 4): tr = 3.66 min.

Example 100

5-Chloro-N - ({2-oxo-3- [4- (1H-1,2,3-triazol-l-yl) phenyl] 10 1,3-oxazolidin-5-yl} methyl] -2- thiophenecarboxamide

MS (ESI): m / z (%) = 404 (M + H, 30), 445 (M + H + MeCN, 100);

HPLC (Method 4): tr = 3.77 min.

Example 101 l- {4- [5 - ({[(5-Chloro-2-thienyl) carbonyl] amino} methyl) -215 oxo-l, 3-oxazolidin-3-yl] phenyl} -L-prolinate of tere -butyl

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

HPLC (Method 4): tr = 5.13 min.

Example 102 l- {4- [5- ({[(5-Chloro-2-thienyl) carbonyl] amino} methyl) -220 oxo-l, 3-oxazolidin-3-yl] phenyl} -4-piperidinecarboxamide

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

HPLC (Method 4): tr = 2.51 min.

Example 103 l- {4- [5 - ({[(5-Chloro-2-thienyl) carbonyl] amino} methyl) -225 oxo-l, 3-oxazolidin-3-yl] phenyl} -3-piperidinecarboxamide

109

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

HPLC (Method 4): tr = 2.67 min.

Example 104

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

MS (ESI): m / z (%) = 434 (M + H, 40), 452 (M + H + H₂Or, 100),

475 (M + H + MeCN, 60);

HPLC (Method 4): tr = 3.44 min.

Example 105 l- {4- [5 - ({[(5-Chloro-2-thienyl) carbonyl] aminojmethyl) -2oxo-1,3-oxazolidin-3-yl] phenyl} -L-prolinamide

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

HPLC (Method 4): tr = 3.54 min.

Example 106

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

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

HPLC (Method 5): tr = 2.53 min.

Example 107

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

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

HPLC (Method 5): tr = 2.32 min.

110

Example 108 l- {4- [5 - ({[(5-Chloro-2-thienyl) carbonyl] aminojmethyl) -2oxo-1,3-oxazolidin-3-yl] phenyl} -2-piperidinecarboxylate ethyl

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

HPLC (Method 5): tr = 4.35 min.

Example 109

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

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

HPLC (Method 4): tr = 2.98 min.

Example 110

5-Chloro-N - ({2-ΟΧΟ-3- [4- (1-pyrrolidinyl) -3 (trifluoromethyl) phenyl] -l, 3-oxazolidin-5-yl} methyl) -2t iofcarboxamide

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

HPLC (Method 4): tr = 4.63 min.

Example 111

5-Chloro-N - ({3 - [4 - (2-methylhexahydro-5H-pyrrolo [3,4d] isoxazol-5-yl) phenyl] -2-oxo-l, 3-oxazolidin-5-i} methyl ) -2thiophenecarboxamide

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

HPLC (Method 4): tr = 2.56 min.

Example 112

111

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

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

HPLC (Method 4): tr = 3.64 min.

Example 113

5-Chloro-N - ({3- [3-chloro-4- (3-oxo-4-morpholinyl) phenyl] -2 oxo-1,3-oxazolidin-5-ylmethyl) -2-thiophenecarboxamide

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

HPLC (Method 4): tr = 3.41 min.

Example 114

5-Chloro-N - ({2-ΟΧΟ-3- [4- (3-oxo-4-morpholinyl) -3 (trifluoromethyl) phenyl] -1,3-oxazolidin-5-yl} methyl) -2t iof acarboxamide

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

HPLC (Method 4): tr = 3.55 min.

Example 115

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

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

HPLC (Method 4): tr = 3.23 min.

Example 116

5-Chloro-N - ({3- [3-cyano-4- (3-oxo-4-morpholinyl) phenyl] -2 oxo-1,3-oxazolidin-5-i1} methyl) -2-thio fcarboxamide

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

112

HPLC (Method 4): tr = 3.27 min.

Example 117

5-Chloro-N- ({3- [3-chloro-4- (1-pyrrolidinyl) phenyl] -2-oxo1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide

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

HPLC (Method 4): tr = 3.72 min.

Example 118

5-Chloro-N - ({3- [3-chloro-4- (2-oxo-l-pyrrolidinyl) phenyl] 2-oxo-l, 3-oxazolidin-5-ylmethyl) -2-thiophenecarboxamide

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

HPLC (Method 4): tr = 3.49 min.

Example 119

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

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

HPLC (Method 4): tr = 3.39 min.

Example 120

N - ({3- [3- (Aminocarbonyl) -4- (4-morpholinyl) phenyl] -2-oxo1.3-oxazolidin-5-yl} methyl) -5-chloro-2-thiophenecarboxamide

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

HPLC (Method 4): tr = 3.07 min.

Example 121

5-Chloro-N - ({3- [3-methoxy-4- (4-morpholinyl) phenyl] -2-oxo1,3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide

113

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

HPLC (Method 4): tr = 2.86 min.

Example 122

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

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

HPLC (Method 4): tr = 3.52 min.

Example 123

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

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

HPLC (Method 6): tr = 3.16 min.

Example 124

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

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

HPLC (Method 4): tr = 3.59 min.

Example 125

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

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

HPLC (Method 4): tr = 3.63 min.

Example 125 a

114

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

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

HPLC (Method 4): tr = 3.25 min.

Through the route of the epoxy opening with an amine and subsequent cyclization to the corresponding oxazolidinone, the following compounds were also prepared:

115

<td>Example No.</td><td>Structure</td><td>Pf [° C]</td><td>CI₅₀[p.m]</td>

<td> 126</td><td>^F5 ^ o F</td><td>229D</td><td> 0,013</td>

<td> 127</td><td>F 0 xv_B^roo ⁵</td><td> 159</td><td> 0,0007</td>

<td> 128</td><td>FO Q^N^ tE^NAND_v.N_&gt;/ Q '^Br0 or</td><td> 198</td><td> 0,002</td>

<td> 129</td><td>θ O</td><td> 196</td><td> 0,001</td>

<td> 130</td><td>Q-tEvO XX&gt;⁰ 0</td><td> 206</td><td> 0,0033</td>

<td>130th</td><td>° Q-tE \ X.ifJV_Ci or 5</td><td> 194</td><td></td>

<td> 131</td><td>Vo qX&gt;ⁿ^ V &lt;E_c,</td><td> 195</td><td> 0,85</td>

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

<td> 133</td><td>v Ό^ν-Ο '^ΝΈν 7A_CIor ^s</td><td> 217</td><td> 0,062</td>

116

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

<td> 134</td><td>0 from l- (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> 0</td><td> 202</td><td> 1,1</td>

<td> 136</td><td>PV and o ^ o</td><td> 239</td><td> 1,2</td>

<td> 137</td><td>0 T O'XJ</td><td> 219</td><td> 0,044</td>

<td> 138</td><td>° “\ - Vo 0</td><td> 95</td><td> 0,42</td>

<td> 139</td><td>0 C^N-O ^ '^N^-^Nr^JQ^kci 0</td><td> 217</td><td> 1,7</td>

117

The following Examples 14 to 16 are examples of ralization for the optional oxidation step of the process, that is, if necessary, it is performed.

Example 14

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

<img file="CU23366B7_D0041.tif" />

5-Chloro-N - ({(5S) -3 - [3-fluoro-4- (1,4-thiazinan-4-yl) phenyl] -2-oxo-l, 3-oxazolidin-5-yl} methyl was added ) -2-thiocarboxamide (0.1 g, 0.22 mmol) of Example 3 in methanol (0.77 ml) 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. Then 1 ml of DMF was added and stirred for 8 h at RT. After adding another 50 mg of sodium periodate it was stirred overnight at RT. Then 50 ml of water was added to the reaction mixture and the insoluble product was filtered off with suction. After washing with water and drying, 60 were obtained.

118 mg (58% of theory) of crystals.

Mp: 257 ° C;

R_F(silica gel, toluene / ethyl acetate 1: 1) = 0.54 (reactant = 0.46);

CI value₅₀ = 1.1 μΜ;

MS (INN) 489 (M + NH₄), Cl pattern.

Example 15

Synthesis of 5-chloro-N - ({(5S) -3 - [4 - (1,1-dioxo1 [lambda]⁶, 4-thiazinan-4-yl) -3-fluorophenyl] -2-oxo-l, 310 oxazolidin-5-yl} methyl) -2-thiophenecarboxamide

<img file="CU23366B7_D0042.tif" />

5-Chloro-N - ({(5S) -3- [3-fluoro-4- (l, 4-thiazinan-4-yl) phenyl] -2-oxo-l, 3-oxazolidin-5-yl} methyl was mixed ) -220 thiophenecarboxamide of Example 3 (0.1 g, 0.22 mmol) in 3.32 ml of a mixture of 1 part of water and 3 parts of acetone with 80 mg (0.66 mmol) of N-methylmorpholine- N-oxide (NMO) and

0.1 ml of a 2.5% solution of osmium tetroxide in 2-methyl-2-propanol. It was stirred overnight at room temperature and 4.0 mg of NMO was still added. After

119 This was stirred another night, the reaction mixture was poured into 50 ml of water and extracted three times with ethyl acetate. From the organic phase, 23 mg were obtained after drying and evaporation and from the aqueous phase after suction filtration of the 19 mg insoluble solids (in total 39% of theory) of the desired compound.

Mp: 238 ° C;

Rf (toluene / ethyl acetate 1: 1) = 0.14 (reactant =

0,46);

CI value_E0 = 210 μΜ;

MS (INN) 5 05 (M + NH₄), Cl pattern.

Example 16

5-Chloro-N- {[(5S) -3-fluoro-4- (4-morpholinophenyl) -2-oxo1,3-oxazolidin-5-yl] methyl} -2-thiophenecarboxamide N-oxide

It was obtained by treating 5-chloro-N {[(5S) -3- (3fluoro-4-morpholinophenyl) -2-oxo-l, 3-oxazolidin-5-yl] methyl} 2-thiophenecarboxamide of Example 1 with salt of magnesium of monoperoxiftálic acid.

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

The following Examples 31 to 35 and 140 to 147 refer to the optional step of amidination of the procedure, that is, if necessary, it is performed.

General method for the synthesis of amidines and amidine derivatives from 5-chloro-N120 [(2-oxo-l, 3-oxazolidin-5-yl) methyl] -2-thiophenecarboxamide cyanomethylphenyls derivatives

The respective derivative of 5-chloro-N - [(2-oxo-l, 3oxazolidin-5-yl) methyl] -2-thiophenecarboxamide cyanomethylphenyls substituted (1.0 eq.) Is stirred together with triethylamine (8.0 eq.) for one to two days at RT in a saturated solution of hydrogen sulfide in pyridine (approx. 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 MgSO.₄, filtered and evaporated in vacuo.

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 hours at room temperature (RT) and then concentrated in vacuo.

The residue is dissolved in methanol (0.01-0.1 mol / l) and for the synthesis of unsubstituted amidines it is mixed with ammonium acetate (3 eq.) And ammonium chloride (2 eq.). For the synthesis of 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, they prepared:

121

Example 31;

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

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

HPLC (Method 4): tr = 2.63 min.

Example 32;

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

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

HPLC (Method 4): tr = 2.61 min.

Example 33;

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

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

HPLC (Method 4): tr = 2.70 min.

Example 34:

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

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

HPLC (Method 4): tr = 2.82 min.

Example 35;

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

122

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

HPLC (Method 4): tr = 2.60 min.

Example 140

5-Chloro-N- ({3- [4- (4,5-dihydro-lH-imidazol-25-ylmethyl) phenyl] -2-oxo-l, 3-oxazolidin-5-yl} methyl) -2thiopheneboxamide

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

HPLC (Method 4): tr = 2.65 min.

Example 141

5-Chloro-N- [(3- {4- [2-imino-2- (4-morpholinyl) ethyl] phenyl}

2-oxo-l, 3-oxazolidin-5-yl) methyl] -2-thiophenecarboxamide

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

HPLC (Method 4): tr = 2.65 min.

Example 142

5-Chloro-N - [(3- {4- [2-imino-2- (1-piperdinyl) ethyl] phenyl}

2-oxo-l, 3-oxazolidin-5-yl) methyl] -2-thiophenecarboxamide

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

HPLC (Method 4): tr = 2.83 min.

Example 143

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

MS (ESI): m / z (%) = 447 (M + H, 100); HPLC (Method 4): tr = 2.76 min.

Example 144

123

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

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

HPLC (Method 4): tr = 2.89 min.

Example 145

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

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

HPLC (Method 4): tr = 2.79 min.

Example 146

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

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

HPLC (Method 4): tr = 2.83 min.

Example 147

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

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

HPLC (Method 4): tr = 2.84 min.

The following Examples 148 to 151 refer to the removal of amino BOC protecting groups:

General method for removing groups

124 BOC (tert-butyloxycarbonyl) protectors:

<img file="CU23366B7_D0043.tif" />

R-NH₂

To an ice-cold solution of a compound protected with tert-butoxycarbonyl (Boc) in chloroform or dichloromethane (approx. 0.1 to 0.3 mol / l) is added dropwise aqueous trifluoroacetic acid (TFA, approx. 90%) After approx. 50 min the ice bath is removed and the mixture is stirred for approx. 2-3 h at room temperature before concentrating the solution and drying it under high vacuum. The residue is suspended in dichloromethane or in dichloromethane / methanol and washed with saturated sodium hydrogen carbonate solution or 1 N sodium hydroxide. The organic phase is washed with saturated sodium chloride solution, dried over a little magnesium sulfate and concentrated.

If necessary, purification is carried out by crystallization from ether or ether / dichloromethane mixtures.

Similarly, from the corresponding precursors protected with Boc were prepared:

Example 148

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

From Example 92:

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

125

HPLC (Method 1): tr (%) = 3.68 (98).

CI₅₀: 2.2 μΜ

Example 149

N - {[3 - (4-Aminophenyl) -2-oxo-l, 3-oxazolidin-5-yl] methyl} 5 5-chloro-2-thiophenecarboxamide

From Example 93:

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

HPLC (Method 1): tr (%) = 3.50 (100).

C15 or: 2 μΜ

An alternative synthesis of pure enantiomer of this compound is represented in the following scheme (see also Delalande SA, DE 2836305, 1979; Chem. Abstr. 90,

186926) :

<img file="CU23366B7_D0044.tif" />

1-) Phthalimide DEAD / PPh₃

2.) NH₂NH₂.H₂Or in ethanol

0 3.) 5-Chloro-2-thiophenecarboxylic acid, EDC / HOBT

<img file="CU23366B7_D0045.tif" />

Zrt / HCI - »« ·

<img file="CU23366B7_D0046.tif" />

126

Example 150

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

From Example 152:

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

HPLC (Method 3): tr (%) = 3.56 (97).

CIs or: 2 μΜ

Example 151

5- (Aminomethyl) -3- [4- (2-oxo-l-pyrrolidinyl) phenyl] -1,3oxazolidin-2-one

From Example 60:

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

HPLC (Method 3): tr (%) = 2.99 (100).

CI₅₀. 2 μΜ

The following Examples 152 to 166 refer to the formation of derivatives of the amino groups of oxazolidinones substituted with aniline or benzylamine with different reagents:

Example 152

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

127

<img file="CU23366B7_D0047.tif" />

Cl

To a solution of 751 mg (4.3 mmol) of Boc-glycine, 870 mg (6.4 mmol) of HOBT (1-hydroxy-lH-benzotriazole x H₂O), 1790 mg (4.7 mmol) of HBTU [hexaf luorof osf ato of O (benzotriazol-1-yl) -N, N, Ν ', N'-tetramethyluronium] and 1.41 ml (12.9 mmol ) of N-methylmorf oline in 15 ml of DMF / CH₂Cl₂(1: 1) 754 mg (2.1 mmol) of N - {[3- (4aminophenyl) -2-oxo-l, 3-oxazolidin-5-yl] methyl} -5- were added at 0 ° C chloro-2 thiophenecarboxamide (from Example 149). The mixture was stirred overnight at room temperature before diluting it with water. The precipitated solid was filtered off and dried. Yield: 894 mg (79.7% of theory);

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

HPLC (Method 3): tr (%) = 4.17 (97).

Example 153

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

OR.

Cl

128

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

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

HPLC (Method 1): tr (%) = 3.78 (97).

CI₅₀: 0.6 μΜ

Example 154

N - {[3- (4- {[(Aminocarbonyl) amino] methyljphenyl) -2-oxo1,3-oxazolidin-5-yl] methyl} -5-chloro-2-thiophenecarboxamide

<img file="CU23366B7_D0048.tif" />

To a mixture of 30 mg (0.082 mmol) of N - ({3- [4 (aminomethyl) phenyl] -2-oxo-l, 3-oxazolidin-5-yl} methyl) -5 chloro-2-thiophenecarboxamide (del Example 148) in 1.0 ml of dichloromethane 0.19 ml (0.82 mmol) of trimethylsilylisocyanate was added dropwise at room temperature. He

129 stirred overnight before adding ether and the product was obtained by filtration. Yield: 21.1 mg (52% of theory),

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

HPLC (Method 1): tr (%) = 3.67 (83).

CI₅₀: 1.3 μΜ

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

<img file="CU23366B7_D0049.tif" />

Under argon, a solution of approx. 0.1 molar of N- {[3 - (4-aminophenyl) -2-oxo-1,3oxazolidin-5-yl] methyl} -5-chloro-2-thiophenecarboxamide (from Example 149) (1.0 eq. ) in absolute dichloromethane / pyridine (19: 1). The mixture is stirred overnight before adding approx. 5 eq. of PS-Trisamine (Argonaut Technologies) and 2 ml of absolute dichloromethane. After 1 h of gentle stirring, it is filtered and the filtrate is concentrated. Dice

130 the case proceeds to a purification of the products by

RP-HPLC preparative.

Similarly, they prepared:

Example 155

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

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

LC-MS (Method 6): tr (%) = 3.25 (100).

IC50: 1.2 μΜ

Example 156

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

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

LC-MS (Method 6): tr (%) = 3.87 (100).

CI₅₀: 1.3 μΜ

Example 157

5-Chloro-N - [(3- {4 - [(methoxyacetyl) amino] phenyl} -2-oxo1,3-oxazolidin-5-yl) methyl] -2-thiophenecarboxamide

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

LC-MS (Method 6): tr (%) = 3.39 (100).

CI₅₀ : 0.73 μΜ

Example 158

N- {4- [5 - ({[(5- (Chloro-2-thienyl) carbonyl] amino} methyl) -2oxo-1,3-oxazolidin-3-yl] phenyl} -3,5-dimethyl-4131 isoxazolcarboxamide

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

CI₅₀: 0.46 μΜ

Example 159

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

Cl

To an ice-cold solution of 26.4 mg (0.15 mmol) of 3-chloro-l-propanesulfonic acid chloride and

0.03 ml (0.2 mmol) of triethylamine in 3.5 ml of absolute dichloromethane was added 35 mg (0.1 mmol) of N - {[3- (4-aminophenyl) -2-oxo-l, 3-oxazolidin-5-yl] methyl} -5-chloro-2-thiophenecarboxamide (from Example 149). After 30 min the ice bath was removed and the mixture was stirred overnight at room temperature before adding 150 mg (approx. 5.5 eq.) Of PS-Trisamine (Argonaut Technologies) and

0.5 ml dichloromethane. The suspension was gently stirred for 2 h, filtered (the resin was then washed with dichloromethane / methanol) and the filtrate was concentrated. The product was purified by preparative RP-HPLC. Performance:

132

19.6 mg (40% of theory),

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

LC-MS (Method 5): tr (%) = 3.82 (91).

CI₅₀: 1.7 μΜ

Example 160

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

<img file="CU23366B7_D0050.tif" />

A mixture of 13.5 g (0.027 mmol) of 5-chloro-N - {[3- (4- {[(3-chloropropyl) sulfonyl] -amino} phenyl) -2oxo-1,3-oxazolidin-5- was heated il] methyl} -2-thiophenecarboxamide (del

Example 159) and 7.6 mg (0.055 mmol) of potassium carbonate in 0.2 ml of DMF at 100 ° C for two hours. After cooling it was diluted with dichloromethane and washed with water. The organic phase was dried and concentrated. The residue was 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): tr (%) = 3.81 (90).

133

CI₅₀: 0.14 μΜ

Example 161

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

<img file="CU23366B7_D0051.tif" />

0.5 g (1.29 mmol) of N - {[(5S) -3- (4aminophenyl) -2-oxo-l, 3-oxazolidin-5-yl] methyl} -5-chloro-2-thiocarboxamide were dissolved (from Example 149) in 27 ml of tetrahydrofuran and mixed with 0.2 g (1.29 mmol) of 5-chlorovaleric acid chloride as well as 0.395 ml (2.83 mmol) of triethylamine. The reaction mixture was evaporated in vacuo and chromatographed on silica gel with a gradient of toluene / ethyl acetate = 1: 1 -&gt; ethyl acetate. 315 mg (52% of theory) of a solid were obtained.

Example 162

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

134

<img file="CU23366B7_D0052.tif" />

5 ml of DMSO 30 mg of 60% NaH in paraffin oil were added in inert conditions and heated for 30 min at 75 ° C until the end of gas evolution. A solution of 290 mg (0.617 mmol) of 5-chloro-N10 [((5S) -3- {4- [(5-chloropentanoyl) amino] phenyl} -2-oxo-l, was then added dropwise. 3 oxazolidin-5-yl) methyl] -2-thiophenecarboxamide (from Example 161) in 5 ml of methylene chloride and stirred overnight at room temperature. The reaction was interrupted and

<td>the mixture is</td><td>poured</td><td>in 100 ml</td><td>of water</td><td>and</td><td>it was extracted</td><td>with</td>

<td>acetate</td><td>ethyl.</td><td>The phase</td><td colspan="2">organic</td><td>evaporated</td><td>he</td>

<td>chromatography</td><td>in a</td><td>column</td><td>from RP-8</td><td>and</td><td>eluded</td><td>with</td>

<td colspan="2">acetonitrile / water He</td><td>they got</td><td>20 mg i</td><td> (7,</td><td colspan="2">5% of theory)</td>

of the compound sought.

Mp: 205 ° C;

<td></td><td>NMR (300</td><td>MHz, d₆-DMSO)</td><td>: δ</td><td> = 1,85</td><td>(m,</td><td>4H), 2.35 (m,</td>

<td>2H),</td><td>3.58 (m,</td><td>4H), 3.85 (m,</td><td>IH),</td><td>4.2 (t,</td><td>IH),</td><td>4.82 (m, IH),</td>

<td> 7,18</td><td>(d, IH,</td><td>thiophene), 7.26</td><td>(d,</td><td>2H), 7.5</td><td>(d,</td><td>2H), 2.68 (d,</td>

<td>IH,</td><td>thiophene),</td><td colspan="2">9.0 (t, IH, CONH).</td><td></td><td></td><td></td>

CI₅₀ : 2.8 nM

Example 163

135

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

<img file="CU23366B7_D0053.tif" />

It was obtained analogously to that of Example 149.

Example 164

5-Chloro-N - ({(5S) -2-OXO-3- [4- (2-oxo-l10 azetidinyl) phenyl] -1,3-oxazolidin-5-yl} methyl) -2 thiophenecarboxamide

<img file="CU23366B7_D0054.tif" />

The open chain bromopropionyl compound of Example 163 was obtained analogously by cyclisation by NaH / DMSO.

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

CI₅₀: 380 nM

Example 165

4- {4- [5 - ({[(5-Chloro-2-thienyl) carbonyl] amino} methyl) -2oxo-1,3-oxazolidin-3-yl] phenyl} -3,5-dioxo-125 piperazinecarboxylate tere-butyl

136

<img file="CU23366B7_D0055.tif" />

To a solution of 199 mg (0.85 mmol) of Bociminodiacetic acid, 300 mg (2.2 mmol) of HOBT, 0.66 ml (6 mmol) of N-methylmorpholine and 647 mg (1.7 mmol) of HBTU 300 mg (0.85 mmol) of N - {[3- (4-aminophenyl) -2-oxo1,3-oxazolidin-5-yl] -methyl} -5-chloro-2-thiophenecarboxamide was added in 6 ml of a mixture of DMF and dichloromethane (1: 1). The mixture was stirred overnight before diluting with dichloromethane with water and then washing with saturated ammonium chloride solution, saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography (dichloromethane / methanol 98: 2). Yield: 134 mg (29% of theory);

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

HPLC (Method 3): tr (%) = 4.39 (90).

CI₅₀: 2 μΜ

Example 166

N - [((5S) -3- {4- [(3R) -3-Amino-2-oxo-lpyrrolidinyl] phenyl} -2-oxo-l, 3-oxazolidin-5-yl) methyl] -5137

<img file="CU23366B7_D0056.tif" />

chloro-2-thiophenecarboxamide, trifluoroacetate

BOCNH,

<img file="CU23366B7_D0057.tif" />

h₂n

<img file="CU23366B7_D0058.tif" />

ch₃ hn ^

<img file="CU23366B7_D0059.tif" />

N2- (tert-Butoxycarbonyl) -Nl- {4 - [(5S) -5 - ({[(5-chloro-2-thienyl) carbonyl] amino} methyl) -2-oxo-l, 3-oxazolidin-3yl)] phenyl} -D-methioninamide &lt;

&gt; They were dissolved in 35 ml of DMF 429 mg (1.72 mmol) of

N-BOC-D-methionine, 605 mg (1.72 mmol) of N - {[(5S) -3- (4aminophenyl) -2-oxo-l, 3-oxazolidin-5-yl] methyl} -5- Chloro-2-thiophencarboxamide and 527 mg (3.44 mmol) of HOBT-hydrate were mixed with 660 mg (3,441 mmol) of EDCI hydrochloride and then dropwise with 689 mg (5,334 mmol) of NMMWMKMMNMΜΟβ * ·! * · » * W · Μ ·· ΛίΜΐδ * • W * ·· »······· ^ * '· ***' *******

ΤΓββΙΧη'y 'l¿..iduo' and washed with DMF. The combined filtrates were mixed with a little silica gel, evaporated in vacuo and chromatographed on silica gel with a gradient of toluene -&gt; T10AE7, 170 mg (17% of theory) of the desired compound were obtained with a dot of fusion of 183'C.

<td colspan="7">R_F(SiO₂, toluene / ethyl acetate = 1: 1): 0.2</td>

<td colspan="2">βΜΝ ^ Η (300 MHz, d₆-DMSO)</td><td>: δ</td><td> = 1,4</td><td colspan="3">(S, IH, BOC), 1.88-</td>

<td>1.95 (m, 2H), 2.08</td><td>(Y,</td><td>3H,</td><td>SMe),</td><td> 2,4-2,5</td><td>(m,</td><td>2H,</td>

<td>partially hidden by</td><td colspan="2">the DMSO),</td><td colspan="2">3.6 (m, 2H), 3.8</td><td>(m,</td><td>IH),</td>

<td>4.15 (m, 2H), 4.8 (m,</td><td>IH),</td><td> 7,2</td><td>(IH,</td><td>thiophene),</td><td> 7,42</td><td>&lt;d,</td>

part of an AB system, 2H), 7.6 (d, part of an AB system, 2H), 7.7 (d, IH, thiophene), 8.95 (t, IH, CH₂NHCO), 9.93 (sa, IH, NH).

&lt;3R) -l- {4 - [(5S) -5 - ({[(5-Chloro-2-thienyl) carbonyl] amino} methyl) -2-oxo-l, 3-oxazolidin-3yl] phenyl} -2- tere-butyl oxo-3-pyrrolidinylcarbamate

170 mg (0.292 mmol) of N2- (tert-butoxycarbonyl) -Ni- {4 - [(5S) -5 - ({[(5-chloro-2-thienyl) carbonyl] amino} methyl) was dissolved in 2 ml of DMSO -2-oxo-l, 3-oxazolidin-3-yl] phenyl} -D-methioninamide and mixed with 178.5 mg (0.875 mmol) of trimethylsulfonium iodide as well as 60.4 mg (0.437 mmol) of potassium carbonate and stirred for 3.5

139 hours at 80 ° C. It was then evaporated under high vacuum and the residue was washed with ethanol. 99 mg of the desired compound remained.

Y-NMR (300 MHz, d_s-DMSO): δ = 1.4 (s, IH, BOC), 1,882.05 (m, IH), 2.3-2.4 (m, IH), 3.7-3.8 (m, 2H ), 3.8-3.9 (m,

IH), 4.1-4.25 (m, IH), 4.25-4.45 (m, IH), 4.75-4.95 (m,

IH), 7.15 (IH, thiophene), 7.25 (d, IH), 7.52 (d, part of an AB system, 2H), 7.65 (d, part of an AB system, 2H) , 7.65 (d, IH, thiophene), 9.0 (broad s, IH).

N- [((5S) -3- {4 - [(3R) -3-Amino-2-oxo-lpyrrolidinyl] phenyl} -2-oxo-l, 3-oxazolidin-5-yl) methyl] -5chloro- 2-thiophenecarboxamide, trifluoroacetate

97 mg (0.181 mmol) of (3R) -l- {4 - [(5S) -5 - ({[(5-chloro-2-thienyl) carbonyl] amino} methyl) -2 were suspended in 4 ml of methylene chloride -2 -oxo-l, 3-oxazolidin-3-yl] phenyl} -2-oxo-3-pyrrolidinylcarbamate tere-butyl, 1.5 ml of trifluoroacetic acid was added and stirred for 1 hour at room temperature. It was then evaporated in vacuo and purified by RP-HPLC (acetonitrile / water gradient / 0.1% TFA). After evaporating the corresponding fraction, 29 mg (37% of theory) of the desired compound were obtained with a melting point of 241 ° C (das.).

R_F(YES₂, EtOH / TEA = 17: 1): 0.19.

NMR-¹H (300 MHz, d_s-DMSO): δ = 1.92-2.2 (m, IH), 2.42.55 (m, IH, partially hidden by the DMSO peak),

140

3.55-3.65 (m, 2H), 3.75-3.95 (m, 3H), 4.1-4.3 (τη, 2Η),

4.75-4.9 (m, 1Η), 7.2 (IH, thiophene), 7.58 (d, part of an AB system, 2H), 7.7 (d, part of an AB system, 2H ), 7.68 (d, IH, thiophene), 8.4 (broad s, 3H, NH3), 8.9 (t, IH,

NHCO).

The following Examples 167 to 170 refer to the introduction of sulfonamide groups in phenyl substituted oxazolidinones:

General method for the synthesis of substituted sulfonamides from 5-chloro-N - [(2-oxo-3-phenyl-l, 3oxazolidin-5-yl) methyl] -2-thiophenecarboxamide

<img file="CU23366B7_D0060.tif" />

<img file="CU23366B7_D0061.tif" />

It is added to chlorosulfonic acid (12 eq.) Under argon at

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 at room temperature for 2 h and then poured onto ice water. The precipitate

141 which is formed is filtered, washed with water and dried.

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

Similarly, they prepared:

Example 167

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

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

68), Cl pattern;

HPLC (Method 3): tr (%) = 4.34 (100).

CI₅₀: 0.5 μΜ

Example 168

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

MS (ESI): m / z (%) = 499 ([M + H]⁺, 100), Cl pattern;

HPLC (Method 2): tr (%) = 3.3 (100).

Example 169

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

142

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

HPLC (Method 2): tr (%) = 4.4 (100).

Example 170

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

MS (ESI): m / z (%) = 500 ([M + H]⁺, 100), Cl pattern;

HPLC (Method 3): tr (%) = 3.9 (100).

Example 171

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

Cl

780 mg (1.54 mmol) of 1 - {4- [5- ({[(5 chloro-2-thienyl) carbonyl] amino} methyl) -2- were dissolved in 5 ml of dichloromethane and 9 ml of trifluoroacetic acid tere-butyl oxo-1,3-oxazolidin3-yl] phenyl} prolinate and the mixture was stirred for two days at 40 ° C. The reaction mixture was then concentrated and stirred with ether and 2N solution of caustic soda. The aqueous phase was concentrated and stirred with ether and 2 N hydrochloric acid. The organic phase of this extraction.

143 dried over MgSO₄, was filtered and concentrated. The crude product was chromatographed on silica gel (CH₂Cl₂/ EtOH / sun.

ac. conc. from NH₃ = 100/1 / 0.1 to 20/1 / 0.1).

280 mg (40% of theory) of the product were obtained.

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

HPLC (Method 4): tr = 3.81 min.

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

[1] Column: Kromasil C-18, Temperature LR: 30 ° C, Flow = 0.75 mlmin¹, Eluent: A = HC1O₄ 0.01 Μ, B = CH₃CN, Gradient: -&gt; 0.5 min 98% A -&gt; 4.5 min 10% A -&gt; 6.5 min 10% A [2] Column: Kromasil C-18 60 * 2, Temperature LR:

30 ° C, Flow = 0.75 mlmin '¹, Eluent: A = H₃PO₄ 0.01 Μ, B = CH₃CN, Gradient: -&gt; 0.5 min 90% A -&gt; 4.5 min 10% A -&gt; 6.5 min 10% A [3] Column: Kromasil C-18 60 * 2, Temperature LR:

30 ° C, Flow = 0.75 mlmin¹, Eluent: A = HC1O₄ 0.005 Μ, B = CH₃CN, Gradient: -&gt; 0.5 min 98% A -&gt; 4.5 min 10% A -&gt; 6.5 min 10% A [4] Column: Symmetry C-18 2.1x150 mm, Column stove: 50 ° C, Flow = 0.6 mlmin '¹, Eluent: A = 0.6 g of 30% HCl / l of 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

144

Symmetry C-18 column, 50 mm x 2.1 mm, 3.5 pm,

Temperature: 40 ° C, Flow = 0.5 mlmin '¹, Eluent A = CH₃CN + 0.1% formic acid, Eluent 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 C-18 column, 50 mm x 2.1 mm, 3.5 pm,

Temperature: 40 ° C, Flow = 0.5 mlmin '¹, Eluent A = CH₃CN + 0.1% formic acid, Eluent 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 C-18 column, 50 mm x 2.1 mm, 3.5 pm,

Temperature: 40 ° C, Flow = 0.5 mlmin '¹, Eluent A = CH₃CN + 0.1% formic acid, Eluent 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 the synthesis of oxazolidinones of general formula B by solid phase supported synthesis

Reactions with different products fixed to resins take place in a series of different reaction vessels.

They are dissolved in DMSO (70 ml) 5- (bromoethyl) -3- (4fluoro-3-nitrophenyl) 1,3-oxazolidin-2-one A (synthesized from epibromhydrin and 4-fluoro-3-nitrophenyl isocyanate

145 with LiBr / Bu₃PO in xylene analogously as in US 4128654, Ex. 2) (1.20 g, 3.75 mmol) and ethyldiisopropylamine (DIEA, 1.91 ml, 4.13 mmol), are mixed with a secondary amine ( 1.1 eq., Amine component 1) and allowed to react for 5 h at 55 ° C. To this solution is added TentaGel SAM resin (5.00 g, 0.25 mmol / g) and reacts for 48 h at 75 ° C. The resin is filtered, washed repeatedly with methanol (MeOH), dimethylformamide (DMF), MeOH, dichloromethane (DCM) and diethyl ether and dried. The resin (5.00 g) is suspended in dichloromethane (80 ml), mixed with DIEA (10 eq.) And 5-chlorothiophene-2-carboxylic acid chloride [prepared by reaction of 5-chlorothiophene-2-carboxylic acid (5 eq. ) and l-chloro-l-dimethylamino-2-methylpropene (5 eq.) in DCM (20 ml) at room temperature for 15 minutes] and allowed to react at room temperature for 5 h. The resin obtained is filtered and washed repeatedly with MeOH, DCM and diethyl ether and dried. The resin is then suspended in DMF / water (9: 2 v / v, 80 ml), mixed with SnCl₂* 2H₂O (5 eq.) And allowed to react for 18 h at room temperature for 5 h. The resin is repeatedly washed with MeOH, DMF, water, MeOH, DCM and diethyl ether and dried. This resin is suspended in DCM, mixed with DIEA (10 eq.) And at 0 ° C with an acid chloride (5 eq. Of acid derivative 1) and allowed to react overnight at room temperature. The carboxylic acids are

146 they convert the corresponding acid chlorides before the reaction by reaction with l-dimethylamino-l-chloro-2-methylpropene (1 eq. referred to carboxylic acid) in DCM at room temperature for 15 min. The resin is repeatedly washed with DMF, water, DMF, MeOH, DCM and diethyl ether and dried. If 1 Fmoc protected amino acid is used as an acid derivative, the Fmoc protecting group is removed in the last reaction step by reaction with piperidine / DMF (1/4, v / v) at room temperature for 15 minutes and the Resin is washed with DMF, MeOH, DCM and diethyl ether and dried. The products are then separated from the solid phase with trifluoroacetic acid (TFA) / DCM (1/1, v / v), the resin is filtered off and the reaction solutions are evaporated. The crude products are filtered through silica gel (DCM / MeOH), 9: 1) and evaporated to obtain a series of products B.

147

<img file="CU23366B7_D0062.tif" />

TentaGelSAM 'NHL

0₂N

<img file="CU23366B7_D0063.tif" />

N

OR

X,

TentaGelSAM

<img file="CU23366B7_D0064.tif" />

<img file="CU23366B7_D0065.tif" />

TFA / DCM,

1/1

148

Compounds prepared by solid phase supported synthesis:

Example 172

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

<img file="CU23366B7_D0066.tif" />

Similar to the general operational description for the preparation of derivatives B, 5 g (1.25 mmol) of TentaGel SAM resin were reacted with pyrrolidine as the amine derivative 1. The aniline obtained after reduction with

SnCl₂* 2H₂Or it was separated from the solid phase without further acylation step and concentrated. The crude product was partitioned between ethyl acetate and NaHC0 solution.₃, the salts of the organic phase were removed with NaCl, decanted and evaporated to dryness. This crude product was purified by flash chromatography under vacuum on silica gel (dichloromethane / ethyl acetate, 3: 1-1: 2).

ΕΜΝ ^ Η (300 MHz, CDClj: 1.95-2.08, a, 4H; 3.15-3.30, a, 4H; 3.65-3.81, m, 2H; 3.89, ddd , IH; 4.05, dd, IH; 4.81, dddd, IH; 6.46, dd, IH; 6.72, dd, IH; 6.90, dd, IH; 6.99, dd, IH ; 7.03, dd, IH; 7.29, d, IH.

149

Example 173

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

<img file="CU23366B7_D0067.tif" />

Similar to the general operational description for the preparation of derivatives B, 5 g (1.25 mmol) of TentaGel SAM resin were reacted with azetidine as derivative amine 1 and Fmoc ~ p-alanine as derivative of acid 1. The crude product obtained After separation, it was stirred for 48 h in methanol at room temperature and evaporated to dryness. This crude product was purified by reverse phase HPLC with a water / TFA / acetonitrile gradient.

<td></td><td>NMR-¹H</td><td>(400 MHz,</td><td>CD₃0D): 2.31</td><td>, tt, 2H;</td><td>3.36, t</td><td>, 2H;</td>

<td> 3,54</td><td>, t, 2H;</td><td>3.62, t,</td><td>2H; 3.72, dd,</td><td>IH; 3.79,</td><td>dd, IH;</td><td> 4,01,</td>

<td>dd,</td><td>IH; 4.29</td><td>, dd, 2H;</td><td>4.43, t, 2H;</td><td> 4,85-4,95,</td><td>my h;</td><td> 7,01,</td>

d, IH; 4.48-7.55, m, 2H; 7.61, d, IH; 7.84, d, IH.

Example 174

N - ({3- [4- (3-Amino-1-pyrrolidinyl) -3-nitrophenyl] -2-oxo1,3-oxazolidin-5-yl} methyl) -5-chloro-2-thiophenecarboxamide

150

<img file="CU23366B7_D0068.tif" />

Similarly to the general operational description for the preparation of derivatives B, 130 mg (32.5 μιηοΐ) of TentaGel SAM resin was reacted with tere-butyl 3-pyrrolidinylcarbamate as the amine derivative 1.

The nitrobenzene derivative obtained after acylation with 5-chlorothiophenecarboxylic acid was separated from the solid phase and concentrated. This crude product was purified by reverse phase HPLC with a water / TFA / acetonitrile gradient.

ΚΜΝ ^ Η (400 MHz, CD₃OH): 2.07-2.17, m, IH; 2.39-2.49, m, IH; 3.21-3.40, m, 2H; 3.45, dd, IH; 3.50-3.60, m, IH;

3.67, dd, IH; 3.76, dd, IH; 3.88-4.00, m, 2H; 4.14-4.21, t,

IH; 4.85-4.95, m, IH; 7.01, d, IH; 7.11, d, IH; 7.52, d,

IH; 7.66, dd, IH; 7.93, d, IH.

Example 175

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

<img file="CU23366B7_D0069.tif" />

Similarly to the general operational description for

151 The preparation of derivatives B was reacted 13.0 mg (32.5 μπιοί) of TentaGel SAM resin with piperidine as an amine derivative 1. The aniline obtained after reduction was separated from the solid phase without further acylation step and concentrated. This crude product was purified by reverse phase HPLC with a water / TFA / acetonitrile gradient.

NMR -'- H (400 MHz, CD₃OH): 1.65-1.75, m, 2H; 1.84-1.95,

<td>m</td><td>4H;</td><td> 3,20-3,</td><td> 28,</td><td>m, 4H; 3.68,</td><td>dd, IH; 3.73,</td><td>dd,</td><td>IH;</td>

<td>dd,</td><td>IH;</td><td> 4,17,</td><td>dd,</td><td>IH; 4.80-4.90</td><td>, my h; 7.00,</td><td>- d,</td><td>IH;</td>

<td>dd,</td><td>IH;</td><td> 7,30-7</td><td> ,38,</td><td>m, 2H; 7.50,</td><td>d, IH.</td><td></td><td></td>

Example 176

N - ({3- [3- (Acetylamino) -4- (1-pyrrolidinyl) phenyl] -2-oxo1,3-oxazolidin-5-ylmethyl) -5-chloro-2-thiophenecarboxamide

<img file="CU23366B7_D0070.tif" />

Similar to the general operational description for the preparation of derivatives B, 130 mg (32.5 μπιοί) of TentaGel SAM resin were reacted with pyrrolidine as the amine derivative 1 and acetyl chloride as the acid derivative 1. The crude product was partitioned between acetate

152 ethyl and NaHCO solution₃, the organic phase was desalinated with NaCl, decanted and evaporated to dryness. This crude product was purified by flash chromatography under vacuum on silica gel (dichloromethane / ethyl acetate,

1:1-0:1) .

<td></td><td>NMR-¹!! (400</td><td>MHz,</td><td>CD₃OH):</td><td>1.93-2.03, a, 4H; 2.16,</td><td>s,</td>

<td>3H;</td><td>3.20-3.30, to,</td><td>4H;</td><td>3.70, d,</td><td>2H; 3.86, dd, IH; 4.10,</td><td>dd,</td>

<td>IH;</td><td>4.14, dd, IH;</td><td colspan="2">4.80-4.90, m</td><td>, IH; 7.00, d, IH; 7.07,</td><td>d,</td>

<td>IH;</td><td>7.31, dd,</td><td>IH;</td><td> 7,51,</td><td>d, IH; 7.60 d</td><td>IH</td>

153

Similarly to the general operational description, they obtained the following compounds:

he

<td>Example</td><td>Structure</td><td>Ret time</td><td>HPLC [%]</td>

<td> 177</td><td>0 p '⁰z 7 = or</td><td> 2,62</td><td> 79,7</td>

<td> 178</td><td>o oj tr OR</td><td> 2,49</td><td> 33,7</td>

<td> 179</td><td>cvO CC OR</td><td> 4,63</td><td> 46,7</td>

<td> 180</td><td>₀ r / 0</td><td> 3,37</td><td> 44,8</td>

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

154

<td>Example</td><td>Structure</td><td>Ret time</td><td>HPLC [%]</td>

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

<td> 183</td><td>0γ ° ° j- °, ςτ ^ K N</td><td> 2,7</td><td> 100</td>

<td> 184</td><td>OS&gt; yT^NXp ° = N_O^r bl 0</td><td> 3,91</td><td> 51</td>

<td> 185</td><td> 2=0 ⁰ c</td><td> 2,72</td><td> 75,2</td>

<td> 186</td><td>o4 0</td><td> 3,17</td><td> 46</td>

<td> 187</td><td>cit-u v Q-ⁿ 0</td><td> 4,61</td><td> 50,2</td>

155

<td>Example</td><td>Structure</td><td>Ret time</td><td>HPLC [%]</td>

<td> 188</td><td>«Λ) w OR</td><td> 3,89</td><td> 56,6</td>

<td> 189</td><td>&gt; Κϊ °</td><td> 3,37</td><td> 52,9</td>

<td> 190</td><td>^ci'~' íÍZ ^ⁿ'' 'Y \ x&gt; 0</td><td> 3,6</td><td> 63,9</td>

<td> 191</td><td>, 4 / X 8í-J / I nc 7 — n] ° Ύ '' '“ή 0</td><td> 2,52</td><td> 70,1</td>

<td> 192</td><td>AAT V ° □ Aj ξν * OR</td><td> 3,52</td><td> 46,6</td>

156

<td>Example</td><td>Structure</td><td>Ret time</td><td>HPLC [%]</td>

<td> 193</td><td>0 sÁ &lt;W^N N^{C | Z}^ \ OR</td><td> 2,87</td><td> 50,1</td>

<td> 194</td><td>o ^ ° r °_c, to&gt; Ός k&gt;</td><td> 3,25</td><td> 71,1</td>

<td> 195</td><td>sv ^,_cl- &lt;3 ^ .r N</td><td> 2,66</td><td> 67</td>

<td> 196</td><td>&gt; J&gt;² °&lt; ^oAthat or</td><td> 2,4</td><td> 52,1</td>

<td> 197</td><td> ,₈ΑνΡ_&gt; °^cHj7 N</td><td> 3,13</td><td> 48,9</td>

157

<td>Example</td><td>Structure</td><td>Ret time</td><td>HPLC [%]</td>

<td> 198</td><td>tC</td><td> 2,67</td><td> 75,5</td>

<td> 199</td><td>tt Q N</td><td> 2,72</td><td> 65,7</td>

<td> 200</td><td> 0-^zX or</td><td> 2,71</td><td> 57,3</td>

<td> 201</td><td>θ ⁰⁼ζι^ci^^ Qd ^ a_N 0</td><td> 2,22</td><td> 100</td>

<td> 202</td><td>_S&gt; XT ° VQ OR</td><td> 3,89</td><td> 75,7</td>

158

<td>Example</td><td>Structure</td><td>Ret time</td><td>HPLC [%1</td>

<td> 203</td><td>ο, λΓ tr o</td><td> 3,19</td><td> 49,6</td>

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

<td> 205</td><td>&lt;λ&gt; tr N</td><td> 2,44</td><td> 68,6</td>

<td> 206</td><td>you £&gt;^zX or</td><td> 2,86</td><td> 71,8</td>

<td> 207</td><td>yrN °° W Xf &lt;T ς&gt; N</td><td> 2,8</td><td> 63,6</td>

159

<td>Example</td><td>Structure</td><td>Ret time</td><td>HPLC [%]</td>

<td> 208</td><td>Z OR OR ⁰⁼^ í^CIAND\^S'Í / W Γ N ^ fy — Ν 1 ο ^ Λ = Λ \ A_n 0</td><td> 2,41</td><td> 77</td>

<td> 209</td><td>or 4^οΎ / Γ ”'^Νν ^ 7 WI n- &lt;Vn j or</td><td> 2,56</td><td> 57,9</td>

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

<td> 211</td><td>° = h^C,'^^TON-YA_N ς, or</td><td> 2,54</td><td> 69,8</td>

<td> 212</td><td>_clxf U_Q</td><td> 3,84</td><td> 59,2</td>

160

<td>Example</td><td>Structure</td><td>Ret time</td><td>HPLC [%]</td>

<td> 213</td><td>iXC / rO 'U3 Cr' Cl N</td><td> 2,41</td><td> 67,8</td>

<td> 214</td><td>or X^οΛρ or</td><td> 2,41</td><td> 75,4</td>

<td> 215</td><td>J-_NvQ οΛί wo</td><td> 4,01</td><td> 81,3</td>

<td> 216</td><td>° P_C, K tr o</td><td> 3,46</td><td> 49,5</td>

<td> 217</td><td>Ογ ° ° V⁰\ &lt;ra_cl</td><td> 4,4</td><td> 60,2</td>

161

<td>Example</td><td>Structure</td><td>Ret time</td><td>HPLC [%]</td>

<td> 218</td><td>" and or</td><td> 3,79</td><td> 70,9</td>

<td> 219</td><td>0 &lt;yN 'Οί /' λ &amp; ° v cr&gt; or</td><td> 4,57</td><td> 51,5</td>

<td> 220</td><td>=, - or O N</td><td> 2,68</td><td> 100</td>

<td> 221</td><td>&gt; Χϊ1ν °</td><td> 4,53</td><td> 63,5</td>

<td> 222</td><td>tr N</td><td> 2,66</td><td> 89,2</td>

162

<td>Example</td><td>Structure</td><td>Ret time</td><td>HPLC [%]</td>

<td> 223</td><td>αΛΓ W Ό</td><td> 4,76</td><td> 69,3</td>

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

<td> 225</td><td>&lt;4 OR</td><td> 3,97</td><td> 63,2</td>

<td> 226</td><td>0 ° yj V / VN T = X</td><td> 3,94</td><td> 61,4</td>

<td> 227</td><td>-h you OR</td><td> 4,15</td><td> 56,3</td>

163

<td>Example</td><td>Structure</td><td>Ret time</td><td>HPLC [%]</td>

<td> 228</td><td>, ι -'- όΓ'Τ</td><td> 4,41</td><td> 55,1</td>

<td> 229</td><td>or ο = Τ “ΪΡ'Ύ'ύΪ V ¿n— &lt;ζ YN} 0</td><td> 2,83</td><td> 41,1</td>

<td> 230</td><td>n N</td><td> 2,7</td><td> 83</td>

<td> 231</td><td>h-, or X °^jhere or</td><td> 4,39</td><td> 54,2</td>

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

164

<td>Example</td><td>Structure</td><td>Ret time</td><td>HPLC [% j</td>

<td> 233</td><td>or</td><td> 4,17</td><td> 41</td>

<td> 234</td><td>? ° KT W O- ^^N 0</td><td> 4,21</td><td> 61,8</td>

<td> 235</td><td>_αΛ&gt; W N</td><td> 2,75</td><td> 100</td>

<td> 236</td><td>Jv &lt;r^ORor</td><td> 3,94</td><td> 50</td>

<td> 237</td><td>d To cr OR</td><td> 4,65</td><td> 75,8</td>

165

<td>Example</td><td>Structure</td><td>Ret time</td><td>HPLC [%]</td>

<td> 238</td><td>/ OR or θ =? or</td><td> 4,4</td><td> 753</td>

<td> 239</td><td></td><td> 4,24</td><td> 62,2</td>

<td> 240</td><td>&gt; Xí ° vO Nf Q- Ό</td><td> 4,76</td><td> 75,1</td>

<td> 241</td><td>ο, λΓ tr Oo</td><td> 4,17</td><td> 72,5</td>

<td> 242</td><td>&gt; Χϊ ° M? OR OR</td><td> 4,6</td><td> 74,8</td>

166

<td>Example</td><td>Structure</td><td>Ret time</td><td>HPLC [%]</td>

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

<td> 244</td><td>₈K^z~ Cf ° ° r ^ Ό</td><td> 4,71</td><td> 66,2</td>

<td> 245</td><td>° V ° \ Ct_cl</td><td> 4,86</td><td> 62</td>

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

<td> 247</td><td>€ r c, xf tr o</td><td> 4,17</td><td> 72,4</td>

167

<td>Example</td><td>Structure</td><td>Ret time</td><td>HPLC [%]</td>

<td> 248</td><td>AND ° ΐ z or</td><td> 3,35</td><td> 59,6</td>

<td> 249</td><td>77 and 'ύ or</td><td> 2,41</td><td> 60,3</td>

<td> 250</td><td>ο-γ-θ W'L'Yy cX N TO</td><td> 3,31</td><td> 65,2</td>

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

<td> 252</td><td>&gt; ΚΤ ° Y © „Λ&gt; € t © N</td><td> 2,69</td><td> 89,8</td>

168

<td>Example</td><td>Structure</td><td>Ret time</td><td>HPLC [%]</td>

<td> 253</td><td>c, K tr N</td><td> 2,81</td><td> 67,4</td>

<td> 254</td><td>«Xi a; or</td><td> 2,19</td><td> 75,4</td>

All solid phase supported synthesis products were characterized by EM-LC. For this, the following separation system was used as standard: HP 1100 with UV detector (208-400 nm), stove temperature 40 ° C, Waters-Symmetry C18 column (50 mm x 2.1 mm, 3.5 μτη ), eluent A: 99.9% acetonitrile / 0.1% formic acid, eluent B: 99.9% water / 0.1% formic acid; gradient:

<td>Weather</td><td>TO: %</td><td>B:%</td><td>Flow</td>

<td> 0,0</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>

169

The identification of the substances was carried out by MS with a Micromass Quattro LCZ, ionization: positive / negative ESI.

In the structures previously exposed the remains (s) ^wn or -O contents in them always mean a function Jr&gt; ^ NH or -OH

H 2