Substituted oxazolidinones, methods for their preparing, medicinal agent based on thereof and using substituted oxazolidinones

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel oxazolidinones of the general formula (I): , their pharmaceutically acceptable salts, hydrates and salt hydrates that inhibit factor Xa selectively and possess anti-thrombosis effect. Also, invention relates to a method for synthesis of these compounds (variants) and using the known substituted oxazolidinones of the general formula (A): as agent inhibiting factor Xa selectively and possessing anti-thrombosis effect, and to a medicinal agent based on at least one compound of the formula (I) or at least one compound of the general formula (A). Values of substitutes R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are given in the invention claim.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and agent.

10 cl, 2 tbl, 252 ex

 

Description

The present invention relates to a new five-membered heterocyclic compounds with biological activity, in particular antithrombotic activity, and more particularly to substituted oxazolidinones, methods for their preparation, to a medicinal product on their basis and application of substituted oxazolidinones.

Blood clotting is a protective mechanism of the body, which can be quickly and reliably "sealed" defects in the vessel wall. So you can exclude or, respectively, to minimize blood loss. Stop bleeding after injury of the vessel is mainly due to the blood clotting system, which runs the enzymatic cascade of complex reactions of plasma proteins. This involved numerous coagulation factors, each of which, once activated, translates into an active form following inactive stage of the cascade. At the end of the cascade is the conversion of soluble fibrinogen into insoluble fibrin, which leads to the formation of blood clot. In blood coagulation traditionally distinguish between internal and external systems that converge in General, the final reaction pathways. The key role belongs combines both ways of coagulation factor XA, which is formed from preferment the th factor X. The activated serine protease XA cleaves prothrombin to thrombin. The formed thrombin, in turn cleaves fibrinogen to fibrin is a fibrous gel-like substance clotting. In addition, thrombin is a potent trigger of platelet aggregation, which also contribute to hemostasis.

The maintenance of normal hemostasis - between bleeding and thrombosis, is governed by a complex regulatory mechanism. Uncontrolled activation of the coagulation system or a defective lock activation process can cause the formation of local blood clots or emboli in the blood vessels (arteries, veins, lymph vessels) or in the volume of the heart. The result can be such diseases with severe outcomes such as myocardial infarction, angina (including angina), reocclusion and restenosis after angioplasticheskih operations or coronary artery bypass surgery, stroke, intermittent ischemic attacks, diseases associated with blocked peripheral arteries, pulmonary embolisms or deep venous thrombosis; these disease will continue to be in General be referred to as thromboembolic disease. In addition, blood clots in the system with respect of consumption coagulopathy may result in scattered vnutripuzarnom svartisen the Y.

These thromboembolic diseases represent the most common cause of morbidity and mortality in major industrial countries (Pschyrembel, Klynisches Wörterbuch, 257-nd edition, 1994, publishing house Walter de Gruyter, s FF., the keyword "Blutgerinnung"; Römpp Chemie Lexikon, version 1.5, 1998, published by Georg Thieme, Stuttgart, keyword Blutgerinnung"; Lubert Stryer, Biochemie, Spectrum der Wissenschaft, Verlagsgesellschaft mbH, Heidelberg, 1990, s FF.).

Have known from the prior art anticoagulants, i.e. preventing the coagulation of blood or blocking clotting substances are also some disadvantages, which often complicate their use. Therefore, in practice an effective method of treatment or prevention of thromboembolic diseases is very complex and unsatisfactory.

For therapy and prophylaxis of thromboembolic diseases finds the use of heparin, which is used for parenteral or subcutaneous administration. Currently, more and more preferred low molecular weight heparin, thanks to its good pharmacokinetic properties; however, its use persists described hereinafter known deficiencies that occur during treatment with heparin. So, for example, heparin is not active when taken by mouth and is characterized sravnitel is but a small time of half-transformation. Because heparin inhibits many factors cascade of blood clotting, it acts selectivity. In addition, there is a high risk of bleeding, and first of all can present with bleeding in the brain and bleeding in the gastrointestinal tract can occur trombopenia, medical hair loss or osteoporosis (Pschyrembel, Klynisches Wörterbuch, 257-nd edition, 1994, publishing house Walter de Gruyter, s, the keyword "Heparin"; Römpp Chemie Lexikon, version 1.5, 1998, published by Georg Thieme, Stuttgart, keyword "Heparin").

The second class of anticoagulants presents antagonists of vitamin K. these include, For example, 1,3-indandione, but above all, compounds such as warfarin, phenprocoumon, dicumarol and other coumarin derivatives, which selectivity block in the liver synthesis of various products of certain coagulation factors, the formation of which is dependent on vitamin K. due to the mechanism of action, their effects become apparent only very slowly (latent period before the onset of effect from 36 to 48 hours). These compounds can, of course, be taken through the mouth, but because of the high risk of bleeding and a narrow therapeutic index, they require careful selection of individual plants and the control of the patient. In addition, they described other side effects, e.g. the measures gastrointestinal disturbances, hair loss and necrosis of the skin (Pschyrembel, Klynisches Wörterbuch, 257-nd edition, 1994, publishing house Walter de Gruyter, s FF., the keyword "Cumarinderivate"; Ullmann''s Encyclopedia of Industrial Chemistry, 5th edition, VCH Verlagsgesellschaft, Weinheim, 1985-1996, the keyword "Vitamin K").

Recently described a new therapeutic direction in the treatment and prevention of thromboembolic diseases. The purpose of this new therapeutic direction is the inhibition of factor XA (application of international patent No. 99/373054 and No. 99/06371; J.Hauptmann, J.Stürzebecher, Thrombosis Research, 1999, 93, 203; F. Al-Obeidi, J.A.Ostrem, Factor XA inhibitors by classical and combinatorial chemistry, DDT 1998, 3, 223; F. Al-Obeidi, J.A.Ostrem, Factor XA inhibitors, Exp. Opin. Ther. Patents 1999, 9, 931; B.Kaiser, Thrombin and factor XA inhibitors, Drugs of the Future 1998, 23, 423; A.Uzan, Antithrombotic agents, Emerging Drugs 1998, 3, 189; B.-Y. Zhu, R.M.Scarborough, Curr. Opin. Card. Pulm. Ren. Inv. Drugs 1999, 1 (1), 63). It was shown that different peptide, and ones connection in animal experiments demonstrate the properties of the inhibitors of factor XA.

Accordingly, the present invention was to develop new drugs to combat diseases manifesting great therapeutic breadth.

First of all they must be suitable for more effective prevention and/or therapy of thromboembolic diseases and they should be deprived, at least partially, the above-described drawbacks of the level of technical and, the term "thromboembolic disease" in the sense of the present invention relates primarily to such serious diseases as myocardial infarction, angina (including angina), reocclusion and restenosis after angioplasticheskih operations or coronary artery bypass surgery, stroke, intermittent ischemic attacks, diseases associated with blocked peripheral arteries, pulmonary embolisms or deep venous thromboses.

Another objective of the present invention consisted in the development of new anticoagulants that have high selectivity inhibit coagulation factor XA and which should be excluded, at least partially, the problems known from the prior art methods of treatment of thromboembolic diseases.

In accordance with this object of the present invention are substituted oxazolidinone General formula (I)

where

R1means thiophene (thienyl), which may be condensed with benzene and which can be from one to several times substituted by a residue from the group of halogen atom and an alkyl group with the number of carbon atoms of from one to eight, unsubstituted or one to several times substituted by halogen atoms,

R2means one of the following group is:

And,

D-M-A-,

In-M-A-,

In-,

In-M -,

D-M-B-,

and

the remainder of "A" means aryl group with the number of carbon atoms from six to fourteen, preferably aryl group with the number of carbon atoms from six to ten, in particular phenyl group,

the remainder of the "In" means a five - or six-membered aromatic heterocycle containing up to three heteroatoms and/or chain-based heteroatoms, in particular it contains up to two heteroatoms and/or links in the chain based on heteroatoms from the series: the sulfur atom, nitrogen atom and oxygen atom

the remainder of the "D" means the residue of a saturated mono - or bicyclic heterocycle with the number of members in the cycle from four to nine, which may be condensed with benzene and which contains up to three heteroatoms and/or links in the chain based on heteroatoms from the series: the sulfur atom, sulfonylurea, sulfonylurea group, the nitrogen atom and the oxygen atom

the remainder of the "M" means the group-NH-, -CH2-, -CH2CH2-, -CONH-, -NHCO-, -SO2or does it mean covalent bond,

while the above groups "a", "b" and "D" in each case can be from one to several times substituted by a residue from the group of halogen atoms, triptorelin group, oxoprop, cyano, a nitro-group, carnemolla group, alcoolica group with the number of carbon atoms in alkylen the m residue from one to six, hydroxyethylpyrrolidine group with the number of carbon atoms in the hydroxyalkyl residue from one to four, the group-COOR27, -C(NR27R28)=NR29, -CONR28R29, -SO2NR28R29, -OR30, -NR30R31, an alkyl group with the number of carbon atoms of from one to six and cycloalkyl group with the number of carbon atoms from three to seven,

R27, R28and R29identical or different, independently of one another mean a hydrogen atom or alkyl group with the number of carbon atoms one to four,

and/or

R28and R29along with connecting the nitrogen atom form a saturated or partially unsaturated six-membered heterocycle comprising up to three, preferably up to two, nitrogen atoms, and

R30and R31identical or different, independently of one another denote an alkyl group with the number of carbon atoms one to four,

R3, R4, R5, R6, R7and R8means a hydrogen atom,

and their pharmaceutically acceptable salts, hydrates, hydrates of the salts, excluding the compounds of General formula (I)where the remainder R1means unsubstituted 2-titanovyi residue and remainder R2means from one to several times substituted phenyl residue and simultaneously each of the residues R3, R4/sup> , R5, R6, R7and R8means a hydrogen atom.

In the first group of preferred substituted oxazolidinones General formula (I) include compounds in which

R1mean 2-thiophene, which may be from one to several times substituted by halogen atoms, preferably chlorine or bromine, or alkyl group with carbon atoms of from one to eight, preferably methyl group, and the alkyl residue with the number of carbon atoms of from one to eight can be in turn from one to several times substituted by halogen atoms, preferably fluorine,

R2means one of the following groups:

And,

D-M-A-,

In-M-A-,

In-,

In-M -,

D-M-B-,

and

the remainder of "A" means aryl group with the number of carbon atoms from six to fourteen, preferably aryl group with the number of carbon atoms from six to ten, in particular phenyl group,

the remainder of the "In" means a five - or six-membered aromatic heterocycle containing up to three heteroatoms and/or chain-based heteroatoms, in particular it contains up to two heteroatoms and/or links in the chain based on heteroatoms from the series: the sulfur atom, nitrogen atom and oxygen atom

the remainder of the "D" means the residue of a saturated heterocycle with the number of members in the cycle from four to seven, containing up to three is heteroatoms and/or links in the chain based on heteroatoms from the series: the sulfur atom, sulfonylurea, sulfonylurea group, the nitrogen atom and the oxygen atom

the remainder of the "M" means the group-NH-, -CH2-, -CH2CH2, -CONH-, -NHCO - or means covalent bond,

while the above groups "a", "b" and "D" in each case can be from one to several times substituted by a residue from the group of halogen atoms, triptorelin group, oxoprop, cyano, a nitro-group, carnemolla group, alcoolica group with the number of carbon atoms in the alkyl residue of from one to six, -COOR27, -C(NR27R28)=NR29, -CONR28R29, -SO2NR28R29, -OR30, -NR30R31, an alkyl group with the number of carbon atoms of from one to six and cycloalkyl group with the number of carbon atoms from three to seven,

R27, R28and R29identical or different, independently of one another mean a hydrogen atom, alkyl group with the number of carbon atoms one to four

and/or

R28and R29along with connecting the nitrogen atom form a saturated or partially unsaturated six-membered heterocycle comprising up to three, preferably up to two, nitrogen atoms,

R30and R31identical or different, independently of one another denote an alkyl group with the number of carbon atoms one to four,

R3, R4, R5, R 6, R7and R8means a hydrogen atom,

and their pharmaceutically acceptable salts, hydrates and hydrates of salts, excluding the compounds of General formula (I)where the remainder R1means unsubstituted 2-titanovyi residue and remainder R2means from one to several times substituted phenyl residue and simultaneously each of the residues R3, R4, R5, R6, R7and R8means a hydrogen atom.

The second group preferred oxazolidinones General formula (I) include compounds in which

R1mean 2-thiophene, which may be from one to several times substituted by halogen atoms, preferably chlorine or bromine, or alkyl group with carbon atoms of from one to eight, preferably methyl group, and the alkyl residue with the number of carbon atoms of from one to eight can be in turn from one to several times substituted by halogen atoms, preferably fluorine,

R2means one of the following groups:

And,

D-M-A-,

In-M-A-,

In-,

In-M -,

D-M-B-,

and

the remainder of "A" means fanilo group,

the remainder of the "In" means a five - or six-membered aromatic heterocycle containing up to two heteroatoms from the series: the sulfur atom, nitrogen atom and oxygen atom

the remainder of the "D" means the remainder of Assenova five - or six-membered heterocycle, containing up to two heteroatoms and/or links in the chain based on heteroatoms from the series: the sulfur atom, sulfonylurea, sulfonylurea group, the nitrogen atom and the oxygen atom

the remainder of the "M" means the group-NH-, -CONH-, -NHCO - or means covalent bond,

while the above groups "a", "b" and "D" in each case can be from one to several times substituted by a residue from the group of halogen atoms, triptorelin group, oxoprop, cyano, alcoolica group with the number of carbon atoms in the alkyl residue of from one to three, group-C(NR27R28)=NR29, -CONR28R29, -SO2NR28R29the group-NR30R31, an alkyl group with the number of carbon atoms one to four, cyclopropyl, cyclopentene or tsiklogeksilnogo group,

R27, R28and R29identical or different, independently of one another mean a hydrogen atom, alkyl group with the number of carbon atoms one to four,

and/or

R28and R29along with connecting the nitrogen atom form a saturated or partially unsaturated six-membered heterocycle comprising up to two nitrogen atoms,

R30and R31identical or different, independently of one another denote an alkyl group with the number of carbon atoms one to four,

R3, R4, R5, R6R 7and R8means a hydrogen atom,

and their pharmaceutically acceptable salts, hydrates and hydrates of salts, excluding the compounds of General formula (I)where the remainder R1means unsubstituted 2-titanovyi residue and remainder R2means from one to several times substituted phenyl residue and simultaneously each of the residues R3, R4, R5, R6, R7and R8means a hydrogen atom.

In a third preferred group of oxazolidines General formula (I) include compounds in which

R1mean 2-thiophene, which may be substituted in the 5-position residue from the group of chlorine, bromine, metal or triptorelin group,

R2means one of the following groups:

And,

D-M-A-,

In-M-A-,

In-,

In-M -,

D-M-B-,

and

the remainder of "A" means phenyl group,

the remainder of the "In" means a five - or six-membered aromatic heterocycle containing up to two heteroatoms from the series: a sulfur atom, a nitrogen atom, and oxygen atom

the remainder of the "D" means the residue of a saturated five - or six-membered heterocycle that includes the nitrogen atom and may contain another heteroatom and/or link in the chain based on heteroatoms from the series: the sulfur atom, sulfonylurea, sulfonylurea group and the oxygen atom

the remainder of the "M" means the group-NH-, -CONH-, -NHCO - or oznacevalno communication

while the above groups "a", "b" and "D" in each case can be from one to several times substituted by a residue from the group of halogen atoms, triptorelin group, oxoprop, cyano, alcoolica group with the number of carbon atoms in the alkyl residue of one to three group-CONR28R29, -SO2NR28R29the group-NR30R31, an alkyl group with the number of carbon atoms one to four, cyclopropyl, cyclopentene or tsiklogeksilnogo group,

R28and R29identical or different, independently of one another mean a hydrogen atom or alkyl group with the number of carbon atoms one to four,

and/or

R28and R29along with connecting the nitrogen atom form a saturated or partially unsaturated six-membered heterocycle comprising up to two nitrogen atoms,

R30and R31identical or different, independently of one another denote an alkyl group with the number of carbon atoms one to four,

R3, R4, R5, R6, R7and R8means a hydrogen atom,

and their pharmaceutically acceptable salts, hydrates and hydrates of salts, excluding the compounds of General formula (I)where the remainder R1means unsubstituted 2-titanovyi residue and remainder R2means from one the go to several times substituted phenyl residue and simultaneously each of the residues R 3, R4, R5, R6, R7and R8means a hydrogen atom.

Most preferred is a compound of the following formula

and its pharmaceutically acceptable salts, hydrates and hydrates of salts.

To date oxazolidinone was described mainly as antibiotics, and in some cases, and as blockers monoamine oxidase and antagonists of fibrinogen (review on this topic: B.Riedl, R.Endermann, Exp. Opin. Ther. Patents, 1999, 9 (5), 625), and for the manifestation of antibacterial properties apparently is mandatory the presence of a small 5-[acyl-aminomethyl] group (preferably 5-[acetyl-aminomethyl] group).

Substituted aryl - and heterogenisation, in which the nitrogen atom oxazolidinone rings can be associated with substituted from one up to several times the phenyl residue and which may contain in the 5-position oxazolidinone ring unsubstituted N-methyl-2-thiophencarboxylic residue, in particular substituted oxazolidinone General formula (A)

in which

R9means unsubstituted 2-titanovyi the rest,

R10means phenyl, unsubstituted or substituted by 1-3 residues from the group comprising chlorine, fluorine, methoxy, trifluoromethyl,

or pharmaceuticas is acceptable salt, hydrates and hydrates of salts and their use as substances with antibacterial activity are known from U.S. patents№5929248, №5801246, №5756732, №5654435. No. 5654428 and No. 5565571.

Therefore, the second object of the invention is the use of known compounds of the formula (A) or their pharmaceutically acceptable salts, hydrates, hydrates of the salts as a means of selectively inhibiting factor XA and having an antithrombotic effect.

Corresponding to the invention compounds of General formula (I) depending on the set of substituents may exist in stereoisomeric forms which differ both an image and its mirror reflection (enantiomers) or do not like an image and its mirror reflection (diastereomers). The invention relates both to the enantiomers or diastereomers, and any of their mixtures. Racemic forms exactly like the diastereomers, can be separated by known methods on stereoisomers homogeneous components.

In addition, certain compounds of General formula (I) can exist in tautomeric forms. This phenomenon is known to the specialist, and such compounds are also included in the scope of claims of the invention.

Not cause concern from a physiological point of view salts, that is acceptable from a pharmaceutical point of view salts can be represented by the corresponding salts is obreteniyu compounds with inorganic or organic acids. Preference is given to salts with inorganic acids, for example hydrochloric acid, Hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic acids or sulphonic acids, for example acetic acid, triperoxonane acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or with methansulfonate, econsultation, benzosulfimide, toluensulfonate or naphthalenedisulfonate.

As pharmaceutically acceptable salts can be named and salts with customary bases, such as alkali metal salts (e.g. sodium or potassium salt), salts with alkaline earth metals (e.g. calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, diisopropylethylamine, procaine, dibenzylamine, N-methylmorpholine, dehydroabietylamine or methylpiperidin.

In accordance with the invention, the term "hydrate" refers to those forms of the compounds of the above General formula (I), in which solid or liquid state in the hydration of the form a molecular compound with water (MES). In Hydra the tah water molecules attached without the participation of valence bonds intermolecular forces in particular due to the formation of hydrogen bridge bonds. Solid hydrates contain water in the form of so-called water of crystallization in stoichiometric ratios, and water molecules on the condition of connectedness does not necessarily have to be equal. Examples of hydrates are single hydrates, monohydrate, dihydrate or trihydrate. Similarly this applies to the hydrates of the salts corresponding to the invention of compounds.

The term "halogen" refers to fluorine atoms, chlorine, bromine and iodine. Preference is given to chlorine atoms or fluorine.

The concept of alkyl groups with carbon atoms of from one to eight refers to linear or branched alkyl residue with the number of carbon atoms of from one to eight. As examples, metal, ethyl, n-sawn, ISO-propyl, n-boutelou, isobutylene, tert.-boutelou, n-pentelow and n-hexoloy group. Derived from this definition in the same way are the corresponding alkyl groups with fewer carbon atoms, for example alkyl groups with carbon atoms of from one to six alkyl groups with carbon atoms of from one to four. In General, preference is given to alkyl group with the number of carbon atoms one to four.

The concept cycloalkyl group number at the MOU carbon from three to seven refers to cyclic alkyl residue, comprising three to seven carbon atoms. As an example, you can call cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo or cycloheptyl group. Derived from this concept in a similar way are the corresponding cycloalkyl groups with fewer carbon atoms, for example cycloalkyl group with the number of carbon atoms from three to five. Preference is given cyclopropenes, cyclopentyloxy and tsiklogeksilnogo groups.

The concept alkanoyloxy group with the number of carbon atoms of from one to six refers to a linear or branched alkyl residue with the number of carbon atoms of from one to six, in which 1-position shall be connected by a double bond to the oxygen atom and is attached at the 1-position. As examples should be called formyl, acetyl, propionyl, n-butyryloxy, isobutyryloxy, pivaloyloxy, n-hexanoyl group. Derived from this concept in a similar way are the corresponding alcoholnye groups with fewer carbon atoms, for example alcoholnye group with the number of carbon atoms from one to five, alcoholnye group with the number of carbon atoms one to four and alcoholnye group with the number of carbon atoms and from one to three. In General, preference is given alkanoyl groups with the number of carbon atoms is kind of from one to three.

The term aryl group with the number of carbon atoms from six to fourteen refers to an aromatic residue with the number of carbon atoms from six to fourteen. As an example, should be called phenyl, naftalina, phenanthroline and antarctilyne group. Derived from this concept in a similar way are the corresponding aryl groups with fewer carbon atoms, such as aryl group with the number of carbon atoms from six to ten. In General, preferred aryl groups with the number of carbon atoms from six to ten.

The concept of five - or six-membered aromatic heterocycle containing up to three heteroatoms and/or links in the chain based on heteroatoms from the series: the atom of sulphur, oxygen, nitrogen refers to a monocyclic heteroaromatic compound, which can be called pyridyl, pyrimidyl, pyridazinyl, furyl and thienyl.

A saturated mono - or bicyclic heterocycle with the number of members from four to nine, which may be condensed with benzene and which contains up to three heteroatoms and/or links in the chain based on heteroatoms from the series: the sulfur atom, sulfonylurea group, sulfonylurea group, a nitrogen atom, and oxygen atom, can be called tetrahydrofuryl, pyrrolidinyl, pyrrolyl, piperidinyl, 1,2-dihydropyridine, 1,4-digitop riginal, piperazinyl, morpholinyl, thiomorpholine, azepine and 1,4-diazepines. Preference is given piperidinyloxy, morpholinyl and pyrrolidinyl groups.

Substituted oxazolidinone the above General formula (I) can be obtained due to the fact that the compound of General formula (II)

in which

the remains of R2, R3, R4, R5, R6, R7and R8have given in claim 1 values

subjected to interaction with the carboxylic acid of General formula (III)

in which

the remainder R1has given in claim 1 value

or with the corresponding galogenangidridy carboxylic acid, preferably the acid chloride of carboxylic acid, or with a corresponding symmetric or mixed carboxylic acid anhydride, representing derivatives of the above carboxylic acids of General formula (III),

in an inert solvent in the presence of, if necessary, activating agent or condensing means and/or the Foundation,

moreover, in those cases where R2means saturated cyclic hydrocarbon residue with the number of members in a cycle of three to seven, including one or more identical or different heteroatoms from the group of nitrogen or sulfur, the compound obtained, for example, which indicate oxidation with a selective oxidizing agent to the corresponding sulfinil, sulfone or N-oxide,

and/or

in those cases, when the molecule of the compounds of formula (I) include cyano, in the molecule, the cyano can be converted into amedieval group,

and/or

in those cases, when the molecule of the compounds of formula (I) comprises the amino group with tert.-butoxycarbonyl protection, this protective group can be split in the usual way,

and/or

in those cases, when the molecule of the compounds of formula (I) include aniline or benzylamine residue, the amino group can be subjected to interaction with various reagents, for example with carboxylic acids, anhydrides of carboxylic acids, carboxylic acid anhydrides, isocyanates, chlorides of sulfosalt or alkylhalogenide with the formation of corresponding derivatives,

and/or

in those cases, when the molecule of the compounds of formula (I) include phenyl residue, this ostok can be subjected to interaction with chlorosulfonic acid and then with amines with formation of the corresponding sulfonamides (hereinafter: the method [A]).

In addition, substituted oxazolidinone the above General formula (I) can be obtained due to the fact that the compound of General formula (IV)

where

the remains of R1, R3, R4, R5, R6, R 7and R8have given in claim 1 values

under the action of a suitable selective oxidizing agent in an inert solvent is transferred into the corresponding epoxide of General formula (V)

where

the remains of R1, R3, R4, R5, R6, R7and R8have given in claim 1 values

which is then subjected to interaction with the amine of General formula (VI)

,

where

the remainder R2has given in claim 1 value

in an inert solvent in the presence of, if necessary, a catalyst, and first get the connection of General formula (VII)

where

the remains of R1, R2, R3, R4, R5, R6, R7and R8have given in claim 1 values

which is then subjected to cyclization in an inert solvent in the presence of phosgene or phosgene equivalent to substances, such as carbonyldiimidazole, with the formation of compounds of General formula (I),

moreover, in those cases where R2means saturated cyclic hydrocarbon residue with the number of members in a cycle of three to seven, including one or more identical or different heteroatoms from the group of nitrogen or sulfur, the compound obtained of the formula (I) is subjected to oxidation with the help of the selective oxidizing agent to the corresponding sulfinil, sulfone or N-oxide,

and/or

in those cases, when the molecule of the compounds of formula (I) include cyano, cyano this can be turned into amedieval group,

and/or

in those cases, when the molecule of the compounds of formula (I) comprises the amino group with tert.-butoxycarbonyl protection, this protective group can be split in the usual way,

and/or

in those cases, when the molecule of the compounds include aniline or benzylamine residue, the amino group can be subjected to interaction with various reagents, for example with carboxylic acids, anhydrides of carboxylic acids, carboxylic acid anhydrides, isocyanates, chlorides of sulfosalt or alkylhalogenide with the formation of corresponding derivatives,

and/or

in those cases, when the molecule of the obtained compound include phenyl residue, this residue can be subjected to interaction with chlorosulfonic acid and then with amines with formation of the corresponding sulfonamides (hereinafter "the way [B]").

Methods [A] and [B], which is an additional object of the invention, illustrated in the following reaction schemes:

The previously described oxidation process to the th may follow these transformations, can be illustrated following the next scheme of reactions:

As solvents for the implementation of the methods described above are suitable organic solvents which are inert under the reaction conditions. These include such halogen-substituted hydrocarbons like dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, tetrachlorethane, 1,2-dichloroethylene or trichloroethylene, such ethers like diethyl ether, dioxane, tetrahydrofuran, dimethyl ether glycol or dimethyl ether of diethylene glycol, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert.-butanol, hydrocarbons such as benzene, xylene, toluene, hexane or cyclohexane, as well as dimethylformamide, dimethylsulfoxide, acetonitrile, pyridine, hexamethylene phosphoric acid or water.

You can also use a solvent mixture consisting of the above-mentioned solvents.

At the same time as activating reagents or condensing means for the above methods are suitable commonly used reagents such as hydrochloride, N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide, N,N'-dicyclohexylcarbodiimide, hydrate 1-hydroxy-1H-benzotriazole and similar compounds. As grounds suitable conventional inorganic and organic bases of the deposits. To them preferably include hydroxides of alkali metals, such as sodium hydroxide or potassium hydroxide, or carbonates of alkali metals as sodium carbonate or potassium carbonate, and sodium methylate or potassium or sodium ethylate or potassium, or tert.-butyl potassium, amides such as sodium amide, bis(trimethylsilyl)amide lithium or diisopropylamide lithium, or amines such as triethylamine, diisopropylethylamine, Diisopropylamine, 4-N,N-dimethylaminopyridine or pyridine.

This base can be used in an amount of from 1 to 5 moles, preferably 1 to 2 moles, based on 1 mol of the compounds of General formula (II).

In General the reactions take place in the temperature range from -78°C to the boiling temperature of the reaction mass, preferably in the range from 0°C to the boiling temperature of the reaction mass.

Interactions can be carried out at normal, elevated or reduced pressure (for example in the range from 0.5 to 5 bar). In General if the work is carried out under normal pressure.

As a suitable selective oxidizing agents at the time of receipt of epoxides and for the possible case of the reaction of oxidation with the formation of a sulfone, sulfoxide or N-oxide, can be considered, for example, m-chlormadinone acid, metaperiodate sodium N-methyl who orfelin-N-oxide, monoperoxyphthalic acid or osmium tetroxide.

As far as getting epoxides, then use the usual conditions for reactions.

As for the more precise indications on the conditions of carrying out reactions for oxidation in sulfon, sulfoxide or N-oxide, if they are, then here we can refer to the following literature: M.R.Barbachyn etc., J. Med. Chem. 1996, 39, 680, as well as the application of international patent No. 97/10223.

In addition, you can refer to the examples in the experimental part, the examples 14 to 16.

Amidinopropane, if it occurs in normal conditions. Other details of the process can be found in examples 31 to 35 and from 140 to 147.

Compounds of General formula (II), (III), (IV) and (VI) generally known to the specialist or they can be obtained in the usual way. Getting oxazolidinones, in particular the required 5-(aminomethyl)-2-oxoacridine presented in the international patent applications No. 98/01446, No. 93/23384, No. 97/03072, J.A.Tucker and others; J. Med. Chem. 1998, 41, 3727; S.J.Brickner etc., J. Med. Chem. 1996, 39, 673; W.A.Gregory etc., J. Med. Chem. 1989, 32, 1673.

Corresponding to the invention compounds of General formula (I) show valuable spectrum of pharmacological activity, which could not be foreseen in advance, so they in particular can be used for the prevention and/or treatment of diseases.

Corresponding to the invention the connection is of the General formula (I), including compounds that cannot be protected as substance as the object of the invention are, in particular, as anticoagulants and therefore they preferably can be used in medicines for the prevention and/or treatment of thromboembolic diseases. In the sense of the present invention to thromboembo-" diseases" include, in particular, serious diseases such as myocardial infarction, angina (including angina), reocclusion and restenosis after angioplasticheskih operations or coronary artery bypass surgery, stroke, intermittent ischemic attacks, diseases associated with blocked peripheral arteries, pulmonary embolisms or deep venous thromboses.

In addition, corresponding to the invention compounds of General formula (I), including compounds that cannot be protected as substance as the object of the invention is suitable equally for the treatment of multiple part coagulation.

Finally, corresponding to the invention compounds of General formula (I), including compounds that cannot be protected as substance as the object of the invention, can also be considered as means for the prevention and/or treatment of atherosclerosis and arthritis, and in addition, and for the prevention and/or Le is placed Alzheimer's disease and cancer.

Corresponding to the invention compounds of General formula (I), including compounds that cannot be protected as substance as the object of the invention are, in particular as selective inhibitors of coagulation factor XA and they don't block, or block only at much higher concentrations, other serine proteases, such as thrombin, plasmin, or trypsin.

In the framework of the present invention, the term "selective" refers to inhibitors of coagulation factor XA, in which the values of the IC50for the inhibition of factor XA 100 times, preferably about 500 times, in particular 1000 times smaller than the values of the IC50for the inhibition of other serine proteases, including thrombin, plasmin and trypsin, as regards methods of experimental verification of selectivity, they are presented later in the described testing methods in examples a-1) A.1) and A.2).

In addition, corresponding to the invention compounds of General formula (I), including compounds that cannot be protected as substance as the object of the invention can also be used to prevent coagulation ex vivo, for example, when preserving blood or biological sample containing factor XA.

In accordance with the foregoing object of the present invention are oxazol dynany formula (I), which in particular suddenly have a strong and selective blocking action on factor XA, and this applies equally to compounds that cannot be protected as substance as the object of the invention.

Together with this, another object of the invention is a drug selectively inhibiting factor XA and having antithrombotic action, containing at least one compound of the above General formula (I) together with one or more pharmacologically acceptable excipients or carriers.

When considering ways of introduction into the organism corresponding to the invention of compounds into account can be taken all the usual pharmaceutical forms. Preferably, when the introduction is oral, lingual, sublingual, buccal, rectal or parenteral (this means without the involvement of the gastrointestinal tract, that is, intravenously, intraarterially, intracardiac, in the skin, subcutaneous, dermal, intraperitoneal or intramuscular injection). Particularly suited for this oral and intravenous. Particular preference is given to oral method of administration, which is another advantage compared with the known from the prior art therapy of thromboembolic diseases.

The new active substances of the General forms of the crystals (I) can be transferred in a known manner in such a conventional dosage forms, as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, nontoxic, suitable pharmaceutical respect to carriers or solvents. Thus therapeutically active compound in each individual case must be present in a concentration of from about 0.1 to 95 wt.%, preferably from 0.5 to 90 wt.%, in particular from 1 to 85 wt.%, from all of the mixture, i.e. in amounts which are sufficient to achieve the prescribed dosage interval.

However in some cases it may be necessary to deviate from the above quantities, namely depending on the body weight or, respectively, from the method of administration, depending on the individual's relationship to medicine, from the form of the dosage form and the time or interval at which it is receiving. Thus, in some cases, it may be sufficiently smaller than the aforementioned minimum amount, whereas in other cases there is a need to exceed the specified upper bound. In the case of ingestion of high quantities can recommend their distribution during the day on several separate doses.

Dosage forms get, for example, by dilution of the active compounds with solvents and/or carrier substances and using, if necessary, emulsifying means and/or dispersing funds, and, for example, in the case of use as diluent water, if necessary, may be used organic solvents as solubilization.

In the General case, certain advantages are obtained when the intravenous method of administration to achieve effective results prescribed amount from about 0.001 to 10 mg/kg, preferably from about 0.01 to 10 mg/kg, in particular from about 0.1 to 8 mg per kg of body weight.

In the General case, certain advantages are obtained when the oral method of administration to achieve effective results prescribed amount from about 0.01 to 50 mg/kg, preferably from about 0.1 to 10 mg/kg, in particular from about 0.5 to 8 mg per kg of body weight.

However in some cases it may be necessary to deviate from the above quantities with intravenous or oral introduction, namely depending on the body weight or, respectively, from the method of administration, depending on the individual's relationship to medicine, from the form of the dosage form and the time or interval at which it is receiving. Thus, in some cases, it may be sufficiently smaller than the above minimum is number, whereas in other cases there is a need to exceed the specified upper bound. In the case of ingestion of high quantities can recommend their distribution throughout the day, with the acquisition of several individual doses or using a slow infusion.

Corresponding to the invention compounds of General formula (I) differ from conventional drugs for the treatment of thromboembolic diseases in particular that due to selective blocking factor XA is large therapeutic range. For the patient this means a lower risk of bleeding, and for the attending physician is the best setting of the patients. In addition, due to the mechanism of action, the effect quickly. But above all relevant to the invention connections allow you to take them through the mouth, which is another advantage in the treatment corresponding to the invention of compounds.

The present invention is further illustrated by the following examples, which in no way can limit the amount of his claim.

Examples

A. Assessment of physiological activity

1. General methods of test

A particular advantage of the biological properties relevant to the invention compounds can be installed next following ways.

a) description of the experiments (in vitr)

A.1) Measurement of blocking factor Ha

The enzymatic activity of factor XA (FXa) of a person was measured by the results of the interaction is specific for FXa chromogenic substrate. When this factor Ha it from the chromogenic substrate n-nitroaniline. The measurements were carried out according to the following method on the plates for micrometrology.

Analyte dissolved in dimethyl sulfoxide at various concentrations and incubated them at a temperature of 25°C for 10 minutes with human FXa (0.5 nmol/l in the form of a solution in TRIS-buffer with a concentration of 50 mmol/l S,s,s-Tris-(hydroxymethyl)aminomethane, 150 mmol/l sodium chloride, 0.1% bovine serum albumin, pH 8.3). In the control experiment, we take a pure dimethylsulfoxide. Then add chromogenic substrate (150 µmol/l Pefachrome®FXa production Pentapharm). After incubation for 20 minutes at 25°To determine the extinction at 405 nm. Extinction experienced in the download with the test substances compared with the control loads without analyte and hence calculate the value of the IC50.

The test results are summarized in table 1.

Table 1
Compound of example No.IC50(µmol)
17 0,004
420,16
430,014
440,0007
450,0042
460,0003
550,04
560,004
570,58
580,007
950,0021
970,0014
1120,016
1130,0014
1140,0036
1150,0017
1160,026
1180,013
1190,033
1230,0046
1270,0007
1280,002
1290,001
1300,0033
130A0,0014
1620,0028

A.2) Determining selectivity

For evidence of selective inhibition of factor XA analyte was analyzed for the inhibition of other serine proteases in humans, such as thrombin, trypsin, plasmin. To determine the enzymatic activity of thrombin (75 mu/ml), trypsin (500 mu/ml) and plasmin (,2 nmol/l), these enzymes are dissolved in TRIS-buffer (100 mmol/l, 20 mmol/l of calcium chloride, pH 8.0) and within 10 minutes, incubated with the test substance or solvent. After the addition of appropriate specific chromogenic substrates (Chromozym Thrombin®production Boehringer Mannheim, Chromozym Trypsin®production Boehringer Mannheim, Chromozym Plasmin®production Boehringer Mannheim) start of the enzymatic reaction and after 20 minutes, determine the extinction at 405 nm. All determinations carried out at 37°C. Extinction experienced in the download with the test substances compared with the control sample without analyte and hence calculate the value of the IC50.

A3) Determining the anticoagulant action

Anticoagulation action of the investigated substances determined in vitro in plasma of human blood. For that human blood is collected in a receiver with the use of 0.11 molar solution of sodium citrate at a ratio in a mixture of sodium citrate/blood equal to 1/9. Immediately after sampling the blood, mix well and within 10 minutes, centrifuged at about 2000g. The liquid above the precipitate is taken with a pipette. Prothrombin time (synonyms: thromboplastin time, Express analysis) determine the presence of varying concentrations of the analyte or appropriate solvent with coming in about what even the test set (Neoplastin ®production Boehringer Mannheim). The compounds for 10 minutes, incubated with plasma at a temperature of 37°C. After the addition of thromboplastin cause coagulation and record the start time of the collapse. Determine the concentration of the analyte, which causes a twofold increase in prothrombin time.

b) determining the antithrombotic action (in vivo)

B.1) Model of arteriovenous bypass grafting (on rats)

Hungry male rats (strain HSD CPB:WU) weighing 200 to 250 g narcotizing solution Rompun/Ketavet (12 mg/kg/50 mg/kg). A blood clot is called on arteriovenous shunt, by analogy with the described Christopher N. Berry, Br. J. Pharmacol. (1994), 113, 1209-1214, methodology. For this dissect the left jugular vein and right carotid artery. Between the two vessels set extracorporeal shunt with polyethylene (PE 60) hose a length of 10 cm In the middle of this plastic hose inserted another polyethylene (PE 160) hose length 3 cm, in which as a thrombogenic surface placed the loop of frayed nylon thread. Extracorporeal circulation is maintained for 15 minutes. After that, remove the shunt and immediately weighed nylon thread with a blood clot. The original weight of nylon thread to determine the start of the experiment. Analyte waking give the LM is now before applying extracorporeal circulation intravenously through the tail vein or orally through the pharyngeal probe.

The results are shown in table 2.

Table 2.
Antithrombotic effect in the model of arteriovenous shunt (on rats after oral or intravenous administration.
ExampleED50(mg/kg) orallyED50(mg/kg) intravenously
110
176
443
953
1143
1153
1233
1623

6.2) Model of arterial thrombosis (rat)

Hungry male rats (strain HSD CPB:WU) narcoticyou as described above. The weight of rats in an average of about 200, the Left carotid artery dissect a length of about 2 see the Formation of blood clot induce by mechanical damage to the vessel by analogy with the described K.Meng and others, Naunyn Schmiedeberg''s Arch. Pharmacol. (1977), 301, 115-119, methodology. To do this, cut the carotid artery cut off from circulation clamps, two minutes cool metallicheskom the groove -12° With and to standardize the size of the thrombus at the same time compress the load 200, After this further reduces the flow of blood covering the carotid artery spring clip mounted at some distance from the damaged area of the vessel. The middle clamp is removed, close the wound and open it again after 4 hours to remove the damaged section of the vessel. Cut open vessel in the longitudinal direction and remove the thrombus from the damaged portion of the vessel. Immediately determine the mass of blood clots in the wet state. Analyte give awake animals intravenously through the tail vein or orally through the pharyngeal probe.

B.3) Model of venous thrombosis (rat)

Hungry male rats (strain HSD CPB:WU) narcoticyou as described above, the Weight of rats in an average of about 200, the Left jugular vein dissect a length of about 2 see the Formation of a venous thrombus induce by mechanical damage to the vessel by analogy with the described K.Meng and others, Naunyn Schmiedeberg''s Arch. Pharmacol. (1977), 301, 115-119, methodology. For this jugular vein cut off from circulation clamps, two minutes is cooled in a metal groove to -12°and to standardize the size of the thrombus at the same time compress the load 200, Again open circulation and close the wound. After 4 hours again open the wound to extract blood from a damaged handle the AC receptacle. Immediately determine the mass of blood clots in the wet state. Analyte give awake animals intravenously through the tail vein or orally through the pharyngeal probe.

B. Examples of receipt

The source connections

Obtaining 3-morpholino described in U.S. patent No. 5349045.

Obtaining N-(2,3-epoxypropyl)phthalimide described in J.-W. Chem. and other Tetrahedron Lett. 1998, 39, 8483.

Substituted anilines can be obtained as a result of interaction, for example, 4-peritrabecular, 2,4-deformirovannoe or 4-chloronitrobenzene with the corresponding amines or inorganic salts in the presence of a base. This reaction can also be carried out in the presence of palladium catalysts as palladium diacetate/DPPF/tert.-butyl sodium (Tetrahedron Lett. 1999, 40, 2035) or copper (Renger, Synthesis 1985, 856; Aebischer and others, Heterocycles 1998, 48, 2225). Halogen-substituted aromatic compounds without the nitro group can be first converted into the corresponding amides in order to carry out the nitration in the 4-position (U.S. patent No. 3279880).

I. 4-(4-Morpholine-3-IMT)nitrobenzene

In 2 l of N-methylpyrrolidone dissolve 2 mol (202 g) morpholine-3-one (E.Pfeil, U.Harder, Angew. Chem. 79, 1967, 188). Within two hours of individual portions was added 88 g (2,2 mole) of sodium hydride (60% in paraffin). After the evolution of hydrogen during cooling, maintaining the room temperature is ur, within 1 hour added dropwise 282 g (2 mol) of 4-peritrabecular and the reaction mixture is stored overnight under stirring. Then in a vacuum of 12 mbar at a temperature of 76°With distilled 1.7 l of liquid volume, the residue is poured into 2 l of water and extracted with the mixture twice with 1 l of ethyl acetate. After washing the combined organic phases with water, dried with sodium sulfate and evaporated in vacuum solvent. Cleaning is performed by chromatographytandem on silica gel with hexane/ethyl acetate (1:1) followed by crystallization from ethyl acetate. The product is obtained as colourless or brownish solid with a yield of 78 g (17.6% of theory).

Range 1H-NMR (300 MHz, deuterochloroform): 3,86 (m, 2H, CH2CH2), 4,08 (m, 2H, CH2CH2), of 4.49 (s, 2H, CH2WITH), to 7.61 (D., 2H,3J=8,95 Hz, CHCH), 8,28 (D., 2H,3J=8,95 Hz, CHCH).

Mass spectrum (relative intensity in %): 222 (74, M+), 193 (100), 164 (28), 150 (21), 136 (61), 117 (22), 106 (24), 90 (37), 76 (38), 63 (32), 50 (25).

Similarly synthesized following connections:

3-fluoro-4-(4-morpholine-3-IMT)nitrobenzene,

4-(N-piperidinyl)nitrobenzene,

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

4-(N-pyrrolidinyl)nitrobenzene,

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

II. 4-(4-Morpholine-3-IMT)aniline

In the autoclave in 200 ml of tetrahydrofuran is dissolved in 63 g (0,275 mole) of 4-(4-Morpholine-3-IMT)n is tramasol, added 3.1 g of 5%palladium on coal and 8 hours hydronaut at a temperature of 70°and at hydrogen pressure of 50 bar. After separation of the catalyst by filtration distilled off in vacuum, the solvent and purify the product by crystallization from ethyl acetate. Get the product in the form of colorless or bluish solid with a yield of 20 g (37.6 per cent of theory).

Purification can also be carried out by chromatographytandem on silica gel with a mixture of hexane and ethyl acetate (1:1).

Range 1H-NMR (300 MHz, deuterochloroform): to 3.67 (m, 2H, CH2CH2), to 3.99 (m, 2H, CH2CH2), 4,27 (S., 2H, CH2WITH), 6,68 (D., 2H,3J=8,71 Hz, CHCH), 7,03 (D., 2H,3J=8,71 Hz, CHCH).

Mass spectrum (relative intensity in %): 192 (100, M+), 163 (48), 133 (26), 119 (76), 106 (49), 92 (38), 67 (27), 65 (45), 52 (22), 28 (22).

Similarly synthesized following connections:

3-fluoro-4-(4-morpholine-3-IMT)aniline,

4-(N-piperidinyl)aniline,

3-fluoro-4-(N-piperidinyl)aniline,

4-(N-pyrrolidinyl)aniline,

3-fluoro-4-(N-pyrrolidinyl)aniline.

A common way to obtain a 4-substituted anilines by the interaction of 1-fluoro-4-nitrobenzene and 1-chloro-4-nitrobenzol with primary and secondary amines and subsequent reduction

Equimolar amount of peritrabecular or, respectively, chloronitrobenzene and aniline are dissolved in dimethyl sulfoxide or in acetonic the Le (solution concentration from 0.1 M to 1.0 M) and left under stirring overnight at a temperature of 100° C. After cooling to room temperature the reaction mixture is diluted with ether and washed with water. The organic phase is dried over magnesium sulfate, filtered and evaporated. If precipitation of the reaction mixture, it is filtered and washed with ether or acetonitrile. If in the mother solution, found the product, then it is treated with ether and water, as described above. The crude products can be purified by chromatographytandem on silica gel using mixtures of dichloromethane/cyclohexane and dichloromethane/ethanol).

For the final recovery nitrosoaniline dissolved in methanol, in ethanol or mixtures of ethanol with dichloromethane (concentration in solutions of 0.01 M to 0.5 M)was added 10%palladium on coal and left overnight under stirring in a hydrogen atmosphere at normal pressure. Then filtered and evaporated. The crude product can be purified by chromatographytandem on silica gel (dichloromethane mixtures with ethanol) or by the method of preparative HPLC with treatment phases (mixtures of acetonitrile with water).

As an alternative reductant can be also used iron powder. For this nitrosoaniline dissolved in acetic acid (concentration in the solution is from 0.1 M to 0.5 M) and at 90°With separate portions add 10-15 minutes to six equivalents of iron powder and water (from 0,3 to 0,5 volume acetic acid). After 30 minutes at a temperature of 90°filtered and the filtrate evaporated. The residue is extracted with ethyl acetate with the addition of 2 n sodium hydroxide solution. The organic phase is dried over magnesium sulfate, filtered and evaporated. The crude product can be purified by chromatographytandem on silica gel (dichloromethane mixtures with ethanol) or by the method of preparative HPLC with treatment phases (mixtures of acetonitrile with water).

In a similar way obtained the following source connection.

III-1. Tert.-butyl-1(4-AMINOPHENYL)-L-prolinate have been obtained

Mass spectrum (electrospray ionization): m/z (%)=304(M+H+CH3CN, 100), 263 (M+H, 20).

HPLC (method 4): retention time 2,79 minutes

III-2. 1-(4-AMINOPHENYL)-3-piperidinecarboxylic

Mass spectrum (electrospray ionization): m/z (%)=220 (M+H, 100).

HPLC (method 4): retention time 0,59 minutes

III-3. 1-(4-AMINOPHENYL)-4-piperidinecarboxylic

Mass spectrum (electrospray ionization): m/z (%)=220 (M+H, 100).

HPLC (method 4): retention time 0,57 minutes

III-4. 1-(4-AMINOPHENYL)-4-piperidinol

Mass spectrum (electrospray ionization): m/z (%)=191 (M+H, 100).

HPLC (method 4): retention time of 0.64 minutes

III-5. 1-(4-AMINOPHENYL)-L-prolinamide

Mass spectrum (electrospray ionization): m/z (%)=206 (M+H, 100).

HPLC (method 4): retention time 0,72 minutes

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

Mass spectrum (ei El is spray): m/z (%)=207 (M+H, 100).

HPLC (method 4): retention time 0,60 minutes

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

Mass spectrum (electrospray ionization): m/z (%)=207 (M+H, 100).

HPLC (method 4): retention time 0,59 minutes

III-8. Ethyl ester of 1-(4-AMINOPHENYL)-2-piperidinecarboxylic acid

Mass spectrum (electrospray ionization): m/z (%)=249 (M+H, 35), 175 (100).

HPLC (method 4): retention time 2,43 minutes

III-9. [1-(4-AMINOPHENYL)-2-pyrrolidinyl]methanol

Mass spectrum (electrospray ionization): m/z (%)=193 (M+H, 45).

HPLC (method 4): retention time 0,79 minutes

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

Is obtained from 2-methylhexane-2H-pyrrolo[3,4-d]isoxazol (Ziegler, Carl C., and others, J. Heterocycl. Chem., 25, 2,1988, 719-723).

Mass spectrum (electrospray ionization): m/z (%)=220 (M+N, 50), 171 (100).

HPLC (method 4): retention time 0,54 minutes

III-11. 4-(1-Pyrrolidinyl)-3-(trifluoromethyl)aniline

Mass spectrum (electrospray ionization): m/z (%)=231 (M+H, 100).

HPLC (method 7): retention time 3,40 minutes

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

Mass spectrum (electrospray ionization): m/z (%)=197 (M+H, 100).

HPLC (method 4): retention time 0,78 minutes

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

Mass spectrum (electrospray ionization): m/z (%)=222 (M+H, 100).

HPLC (method 4): retention time 0,77 minutes

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

Mass spectrum (who anisate elektrorazpredelenie): m/z (%)=209 (M+H, 100).

HPLC (method 4): retention time 0,67 minutes

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

Mass spectrum (electrospray ionization): m/z (%)=221 (M+H, 100).

HPLC (method 4): retention time 0,77 minutes

A common way to obtain a 4-substituted anilines by the interaction of 1-fluoro-4-nitrobenzol with inorganic salts, followed by recovery

In dimethylformamide is dissolved amide and added 1.5 equivalent of tert.-the butyl potassium. A mixture of 1 hour and stirred at room temperature, then separate portions added 1, 2 equivalent of 1-fluoro-4-nitrobenzene. The reaction mixture is left under stirring overnight at room temperature, diluted with ether and ethyl acetate and washed with saturated sodium bicarbonate solution in water. The organic phase is dried over magnesium sulfate, filtered and evaporated. The crude product can be purified by chromatographytandem on silica gel (dichloromethane mixtures with ethanol).

For the final recovery nitrosoaniline dissolved in ethanol (concentration in solutions of 0.01 M to 0.5 M)was added 10%palladium on coal and left overnight under stirring in a hydrogen atmosphere at normal pressure. Then filtered and evaporated. The crude product can be purified by chromatographytandem on silica gel (dichloromethane mixtures with ethanol) or by the method of p is operativnoy HPLC with treatment phases (mixtures of acetonitrile with water).

As an alternative reductant can be also used iron powder. For this nitrosoaniline dissolved in acetic acid (concentration in the solution is from 0.1 M to 0.5 M) and at 90°With separate portions add 10-15 minutes to six equivalents of iron powder and water (0.3 to 0.5 of the volume of acetic acid). After 30 minutes at a temperature of 90°filtered and the filtrate evaporated. The residue is extracted with ethyl acetate with the addition of 2 n sodium hydroxide solution. The organic phase is dried over magnesium sulfate, filtered and evaporated. The crude product can be purified by chromatographytandem on silica gel (dichloromethane mixtures with ethanol) or by the method of preparative HPLC with treatment phases (mixtures of acetonitrile with water).

In a similar way obtained the following source connection.

IV-1. 1-[4-Amino-2-(trifluoromethyl)phenyl)]-2-pyrrolidinone

Mass spectrum (electrospray ionization): m/z (%)=245 (M+H, 100).

HPLC (method 4): retention time 2,98 minutes

IV-2. 4-[4-Amino-2-(trifluoromethyl)phenyl)]-3-morpholino

Mass spectrum (electrospray ionization): m/z (%)=261 (M+H, 100).

HPLC (method 4): retention time of 2.54 minutes

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

Mass spectrum (electrospray ionization): m/z (%)=227 (M+H, 100).

HPLC (method 4): retention time 1,96 minutes

IV-4. 4-(4-Amino-2-were)-3-morpho is Inon

Mass spectrum (electrospray ionization): m/z (%)=207 (M+H, 100).

HPLC (method 4): retention time 0,71 minutes

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

Mass spectrum (electrospray ionization): m/z (%)=218 (M+H, 100).

HPLC (method 4): retention time of 1.85 minutes

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

Mass spectrum (electrospray ionization): m/z (%)=211 (M+H, 100).

HPLC (method 4): retention time of 2.27 minutes

IV-7. 4-(4-Amino-2,6-dimetilfenil)-3-morpholino

Is obtained from 2-fluoro-1,3-dimethyl-5-nitrobenzol (by Bartoli and others, J. Org. Chem. 1975, 40, 872)

Mass spectrum (electrospray ionization): m/z(%)=221 (M+H, 100).

HPLC (method 4): retention time 0,77 minutes

IV-8. 4-(2,4-Diaminophenyl)-3-morpholino

Obtained from 1-fluoro-2,4-dinitrobenzene.

Mass spectrum (electrospray ionization): m/z (%)=208 (M+H, 100).

HPLC (method 4): retention time 0,60 minutes

IV-9. 4-(4-Amino-2-chlorophenyl)-2-methyl-3-morpholino

Is obtained from 2-methyl-3-morpholino (E.Pfeil, U.Harder, Angew. Chem. 1967, 79, 188).

Mass spectrum (electrospray ionization): m/z (%)=241 (M+H, 100).

HPLC (method 4): retention time of 2.27 minutes

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

Obtained from 6-methyl-3-morpholino (European patent No. 350002).

Mass spectrum (electrospray ionization): m/z (%)=241 (M+H, 100).

HPLC (method 4): retention time 2,43 minutes

Obtaining compounds of formula (I)

The following gave the f examples 1 to 13, from 17 to 19 and from 36 to 57 apply to method [A].

Example 1

Obtain N-{[(5S)-3-(3-Fluoro-4-morpholinyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophencarboxylic

9.9 ml of dimethylformamide is dissolved 0.45 g (1.52 mmole) of (5S)-5-(aminomethyl)-3-(3-fluoro-4-morpholinyl)-1,3-oxazolidin-2-it (obtained by the method S.J.Brickner etc., J. Med. Chem. 1996, 39, 673), 0.25 g (1.52 mmole) of 5-chlorothiophene-2-carboxylic acid and 0.3 g (1.3 equivalents) hydrate (1-hydroxy-1H-benzotriazole. To this mixture was added 0.31 g (1.98 mmole, 1.3 equivalent) of N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide and at room temperature is added dropwise 0.39 g (of 0.53 ml of 3.05 mmole, 2 equivalent) diisopropylethylamine. Left overnight under stirring at room temperature. Add 2 g of silica gel and evaporated mixture in vacuum to dryness. The remainder chromatographic on silica gel with a gradient of concentrations of toluene/ethyl acetate. Get 0,412 g (61.5% of theory) of the target compound with TPL 197°C.

Rf(on silica gel, toluene/ethyl acetate 1:1)=0,29 (the original product Rf=0,0).

Mass spectrum (desorption-chemical ionization): 440,2 (M+N), Cl-matrix.

Range1H-NMR (d6-sulfoxide, 300 MHz): 2,95 (m, 4H), and 3.6 (t, 2H), and 3.72 (m, 4H), 3,8 (Shostakovich, 1H), 4,12 (t, 1H), 4.75 V-is 4.85 (m, 1H), 7,05 (t, 1H), 7,15 to 7.2 (m, 3H), 7,45 (Shostakovich, 1H), 7,68 (D., 1H), 8,95 (t, 1H).

Example 2

N-{[(5S)-3-(4-Mor is AMINOPHENYL)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophencarboxylic

Receive by analogy with example 1 from benzyl-4-morpholinosydnonimine through the stage of formation of (5S)-5-(aminomethyl)-3-(3-fluoro-4-morpholinyl)-1,3-oxazolidin-2-it.

TPL°C.

The value of the IC50=43 nm.

Rf(on silica gel, toluene/ethyl acetate 1:1)=0,24.

Example 3

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

Get analogously from (5S)-5-(aminomethyl)-3-[3-fluoro-4-1,4-diazinon-4-yl)phenyl]-1,3-oxazolidin-2-it (its receipt described in M.R.Barbachyn etc., J. Med. Chem. 1996, 39, 680).

TPL 193°C.

Yield 82%.

Rf(on silica gel, toluene/ethyl acetate 1:1)=0,47 (the original product Rf=0,0).

Example 4

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

Get a similar 5-bromothiophene-2-carboxylic acid.

TPL 200°C.

Example 5

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

Get a similar 5-methylthiophene-2-carboxylic acid.

TPL 167°C.

Example 6

N-{[(5S)-3-(6-Methylthieno[2,3-b]pyridine-2-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophencarboxylic

what are square analogously from (5S)-5-(aminomethyl)-3-(6-methylthieno[2,3-b]pyridine-2-yl)-1,3-oxazolidin-2-it (its getting described in the application for the European patent No. 785200).

TPL 247°C.

Example 7

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

Get a similar 6-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-3-methyl-1,3-benzothiazol-2(3H)-she (receive it as described in the application for the European patent No. 738726).

TPL 217°C.

Example 8

N-[((5S)-3-{3-Fluoro-4-[4-(4-pyridinyl)piperazine derivatives]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophencarboxylic

Get analogously from (5S)-5-(aminomethyl)-3-{3-fluoro-4-[4-(4-pyridinyl)piperazine derivatives]phenyl}-1,3-oxazolidin-2-it (it is obtained similarly J.A.Tucker etc., J. Med. Chem. 1998, 41, 3727). Mass spectrum (electrospray ionization): 516 (M+H), Cl-matrix.

Example 9

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

Get analogously from (5S)-5-(aminomethyl)-3-[3-fluoro-4-(4-methylpiperazine)phenyl]-1,3-oxazolidin-2-it.

Example 10

N-({(5S)-3-[3-Fluoro-4-(4-tert.-butoxycarbonylmethyl-1-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophencarboxylic

Get analogously from (5S)-5-(aminomethyl)-3-[3-fluoro-4-(4-tert.-butoxycarbonyl-piperazine-1-yl)phenyl]-1,3-oxazolidin-2-she (it getting listed in the already cited C the turnout for the international patent No. 93/23384.

TPL 184°C.

Rf(silica, toluene/ethyl acetate 1:1)=0,42.

Example 11

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

Receive by trifluoroacetic acid in methylene chloride in the connection example 10.

The value of the IC50=140 nm.

Range1H-NMR (d6-dimethylsulfoxide): 3,01-of 3.25 (m, 8H), 3,5-of 3.65 (m, 2H), of 3.7-3.9 (m, 1H), 4,05-4,2 (m, 1H), 4.75 V-4,9 (m, 1H), 7,05-7,25 (m, 3H), 7.5 (a Shostakovich, 1H), 7,7 (D., 1H), 8.4V (Sh.S., 1H), and 9.0 (t, 1H).

Example 12

N-[((5S)-3-(2,4'-Bipyridinyl-5-yl)-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thio-fenerbache

Get analogously from (5S)-5-(aminomethyl)-3-(2,4'-bipyridinyl-5-yl)-1,3-oxazole-DIN-2-she (it getting listed in the application for the European patent No. 789026).

Rf(silica, toluene/ethyl acetate 1:2)=0,6.

Mass spectrum (electrospray ionization): 515 (M+H), Cl-matrix.

Example 13

N-{[(5S)-2-Oxo-3-(4-piperidinophenyl)-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophencarboxylic

Obtained from 5-(hydroxymethyl)-3-(4-piperidinophenyl)-1,3-oxazolidin-2-she (it getting listed in the Federal Republic of Germany patent No. 2708236) after its conversion into mesilate, interaction with phthalimide potassium, hydrazinolysis and reaction with 5-chlorothiophene-2-carboxylic acid.

Rf (silica, toluene/ethyl acetate 1:1)=0.31 in.

TPL 205°C.

Example 17

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

From 1-(4-AMINOPHENYL)pyrrolidin-2-it (receipt given by Reppe and others, Justus Liebigs Arm. Chem., 596, 1955, 209) by analogy with the known scheme of synthesis (S.J.Brickner etc., J. Med. Chem. 1996, 39, 673) after interaction with benzyloxycarbonylamino, subsequent reaction with R-glycidylether, becoming mesityl, interaction with phthalimide potassium, hydrazinolysis in methanol and reaction with 5-chlorothiophene-2-carboxylic acid is obtained in the end N-({(5S)-2-Oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-5-chloro-2-thiophencarboxylic. Thus obtained N-({(5S)-2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-5-chloro-2-thiophencarboxylic characterized by the value of the IC50=4 nm (determination of value IC50conducted in accordance with the above-described example A-1.a.1) "measuring the blocking factor Ha").

TPL 229°C.

The value of Rf(silica, toluene/ethyl acetate 1:1)=0,05 (the original product Rf=0,0).

Mass spectrum (electrospray ionization): 442,0 (21%, M+Na, Cl-matrix) 420,0 (72%, M+H, Cl-matrix), 302,3 (12%), 215 (52%), 145 (100%).

Range1H-NMR (d6-sulfoxide, 300 MHz): 2,05 (m, 2 is), of 2.45 (m, 2H), 3,6 (t, 2H). of 3.77-of 3.85 (m, 3H), 4,15 (t, 1H), and 4.75-4.85 (m, 1H), 7,2 (D., 1H), 7.5 (D., 2H), 7,65 (D., 2H), 7,69 (D., 1H). 8,96 (t, 1H).

Here are some stages of the above-described synthesis example 17 with the relevant preparatory operations.

To 4 g (22,7 mmole) of 1-(4-AMINOPHENYL)pyrrolidin-2-she and 3.6 ml (28,4 mmole) of N,N-dimethylaniline in 107 ml of tetrahydrofuran at -20°slowly add 4,27 g (25,03 mmole) of the benzyl ether of Harborview acid. Stirred for 30 minutes at -20°and then give the reaction mixture to warm to room temperature. Add 0.5 l of ethyl acetate and the organic phase is washed with 0.5 l of saturated solution of sodium chloride. The separated organic phase is dried with magnesium sulfate and evaporated the solvent in vacuo. The residue is triturated with diethyl ether and sucked off. Get 5,2 g (73.8% of theory) of benzyl-4-(2-oxo-1-pyrrolidinyl)-phenylcarbamate in the form of light beige crystals with a melting point of 174°C.

In an argon atmosphere to 1.47 g (16,66 mmole) of isoamyl alcohol in 200 ml of tetrahydrofuran at a temperature of -10°With added dropwise 7,27 ml of 2.5 molar solution of n-utility in hexane, and to change the color added as an indicator of N-benzylideneaniline it took the addition of 8 ml utility. Stirred for 10 minutes at -10°C, cooled to -78°and slowly when ablaut solution of 4.7 g (15,14 mmole) benzyl-4-(2-oxo-1-pyrrolidinyl)phenylcarbamate. Once again add to the color change of the indicator to pink 4 ml of utility. Stirred 10 minutes at -78°C, add 2,62 g (18,17 mmole) of R-glycidylether and continue stirring for 30 minutes at -78°C.

The reaction mass is allowed to warm to room temperature and leave it on overnight, to the mixture was added 200 ml of water and distilled tertrahydrofuran ring component in a vacuum. The aqueous residue is extracted with ethyl acetate, the organic phase is dried with magnesium sulfate and evaporated it in a vacuum. The residue is triturated with 500 ml of diethyl ether and sucked off the drop-down crystals in vacuum.

Get 3,76 g (90% of theory) of (5R)-5-(hydroxymethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one with a melting point 148°and a value of Rf(silica, toluene/ethyl acetate 1:1)=0,04 (the original product Rf=0,3).

In 160 ml of dichloromethane at 0°mix With 3.6 g (13,03 mole) of (5R)-5-(hydroxymethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-she and 2.9 g (28,67 mmole) of triethylamine. Under stirring add to 1.79 g (15,64 mmole) of the acid chloride of methansulfonate and stirred for 1.5 hours at 0°and another 3 hours at room temperature.

The reaction mixture is washed with water, and extracted the aqueous phase is again methylene-chloride. The combined organic extracts are dried with magnesium sulfate and UPrev the Ute. After that, the remainder (1,67 g) dissolved in 70 ml of acetonitrile, add 2,62 g (14,16 mmole) phthalimide potassium and 45 minutes is stirred in a closed vessel when heated in a microwave oven at a temperature of 180°C.

The mixture is separated by filtration from the insoluble residue, the filtrate is evaporated in vacuo, the residue (1.9 g) is dissolved in methanol and added to 0.47 g (9,37 mmole) of hydrazine hydrate is added. Heated at boiling for 2 hours, cooled, added saturated sodium bicarbonate solution and extracted six times with a total volume of 2 l of methylene chloride. The combined organic extracts raw (5S)-5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-it is dried with magnesium sulfate and evaporated in vacuum.

At the final stage to obtain N-({(5S)-2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophencarboxylic 7.6 ml of dimethylformamide dissolving 0.32 g (1.16 mmole) obtained in the previous phase (5S)-5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-it, 0,19 g (1.16 mmole) 5-chlorothiophene-2-carboxylic acid and 0.23 g (1,51 mmole) hydrate (1-hydroxy-1H-benzotriazole. Add to 0.29 g (1,51 mmole) of N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide and at room temperature is added dropwise 0.3 g (0.4 ml, 2,32 mmole, 2 equivalent) diisopropylethylamine. Left overnight under stirring at room temperature.

The mixture is pariwat in vacuum to dryness, dissolve the residue in 3 ml of dimethyl sulfoxide and chromatographic by HPLC with treatment phases with a gradient mixture of acetonitrile/water/0.5% of triperoxonane acid. Last chromatograph fraction evaporated for the Department of acetonitrile and sucked off the drop-down connection. Get 0,19 g (39% of theory) of the target compound. Similarly obtained the following compounds.

Example 18

N-({(5S)-2-Oxo-3-[4-(1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-5-chloro-2-thiophencarboxylic

By analogy with example 17 from 4-pyrrolidin-1-yl-aniline (Reppe and others, Justus Liebigs Ann. Chem., 596, 1955, 151) receive the compound N-({(5S)-2-oxo-3-[4-(1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-5-chloro-2-thiophencarboxylic.

IC50=40 nm.

TPL 216°C.

The value of Rf(silica, toluene/ethyl acetate 1:1)=0.31 in (the original product Rf=0,0).

Example 19

N-({(5S)-2-Oxo-3-[4-(diethylamino)phenyl]-1,3-oxazolidin-5-yl} -methyl)-5-chloro-2-thiophencarboxylic

Similarly, from N,N-diethylphenyl-1,4-diamine (U.S. patent No. 2811555, 1955) receive the compound N-({(5S)-2-oxo-3-[4-(diethylamino)phenyl]-1,3-oxazolidin-5-yl}-methyl)-5-chloro-2-thiophencarboxylic.

IC50=270 nm.

TPL 181°C.

The value of Rf(silica, toluene/ethyl acetate 1:1)=0,25 (the original product Rf=0,0).

Example 36

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

Is obtained from 2-methyl-4-(4-morpholinyl)aniline (J.E.LuValle etc., J. Am. Chem. Soc. 1948, 70, 2223).

Mass spectrum (electrospray ionization): m/z (%)=436 ([M+H]+, 100), Cl-matrix.

HPLC (method 1): retention time(%)=3,77 (98).

IC50=1,26 mm.

Example 37

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

Obtained from 3-chloro-4-(4-morpholinyl)aniline (H.R.Snyder etc., J. Pharm. Sci. 1977, 66, 1204).

Mass spectrum (electrospray ionization): m/z (%)=456 ([M+H]+, 100), Cl2-matrix.

HPLC (method 2): retention time(%)=4,31 (100).

IC50=33 nm.

Example 38

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

Obtained from 4-(4-morpholinylcarbonyl)aniline (Adams and others, J. Am. Chem. Soc. 1939, 61, 2342).

Mass spectrum (electrospray ionization): m/z (%)=486 ([M+H]+, 100), Cl-matrix.

HPLC (method 3): retention time(%)=4,07 (100).

IC50=2 ám.

Example 39

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

Obtained from 4-(1-azetidinone)aniline.

Mass spectrum (desorption-chemical ionisation, ammonia): m/z (%)=473 ([M+NH4]+, 100), Cl-matrix.

HPLC (method 3): retention time(%)=4,10 (100).

IC50=0,84 mm.

Example 40

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

Obtained from 4-amino-N,N-dimethylbenzenesulfonamide (I.K.Khanna etc., J. Med. Chem. 1997, 40, 1619).

Mass spectrum (electrospray ionization): m/z (%)=444 ([M+H]+, 100), Cl-matrix.

HPLC (method 3): retention time(%)=4,22 (100).

IC50=90 nm.

A common way acylation of 5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)-phenyl]-1,3-oxazolidin-2-she carboxylic acid anhydrides.

To the corresponding acid chloride of acid (2.5 equivalents) at room temperature in an argon atmosphere is added dropwise in about decimally a solution of 5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-it (example 45) (1.0 equivalent) and absolute pyridine (about 6 equivalents) in absolute dichloromethane. The mixture is stirred for about 4 hours at room temperature, then add about 5.5 equivalents of PS-Trisamine (production Argonaut technologies). A suspension of weakly stirred for two hours, after dilution with a mixture of dichloromethane/dimethylformamide (3:1) filter (resin washed with a mixture of dichloromethane/dimethylformamide) and the filtrate evaporated. The resulting product, if necessary, purified by the method of preparative HPLC with treatment phases. On a similar scheme receive the following connection.

Example 41

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

Liquid / mass spectrometry (method 6): m/z (%)=386 (M+H, 100).

Liquid / mass spectrometry: retention time(%)=3,04 (100).

IC50=1,3 ám.

A common way to obtain acyl derivatives on the basis of 5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-she and carboxylic acids

To 2.9 equivalent associated with the carbodiimide resin (PS-Carbodiimid production Argonaut technologies) was added the corresponding carboxylic acid (about 2 equivalents) and the mixture of absolute dichloromethane and dimethylformamide (approximately 9:1). After a light shaking for about 15 minutes at room temperature was added 5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-he (example 45) (1.0 equivalent) and leave the mixture with shaking overnight. After that, the resin is filtered (washed with dichloromethane and the filtrate evaporated. The resulting product, if necessary, purified by the method of preparative HPLC with treatment phases. On a similar scheme receive the following connections.

Example 42

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

Liquid / mass spectrometry: m/z (%)=400 (M+H, 100).

Liquid / mass spectrometry (method 6): retention time(%)=3,23 (100).

IC50=0,16 mm.

<> Example 43

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

Liquid / mass spectrometry: m/z (%)=466 (M+H, 100).

Liquid / mass spectrometry (method 5): retention time(%)=3,48 (78).

IC50=0,014 mm.

Example 44

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

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

A suspension of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (A.Gutcait and others, Tetrahedron Asym. 1996, 7, 1641) (of 5.68 g of 27.9 mmole) and 4-(4-AMINOPHENYL)-3-Mohali-Nona (lower than the 5.37 g of 27.9 mmole) in ethanol-water (9:1, 140 ml) 14 hours refluxed (precipitate goes into solution again after a certain time, a precipitate). The precipitate (target product) is filtered off, washed three times with diethyl ether and dried. United uterine solutions are evaporated in vacuo and after adding the second portion of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (2,84 g, 14,0 mmole) is suspended in ethanol-water (9:1, 70 ml) and 13 hours refluxed (precipitate goes into solution again after a certain time, a precipitate). The precipitate (target product) is filtered off, washed three times with diethyl ether and dried. Total yield 10,14 g, 92% of theory.

Massspectra (electrospray ionization): m/z (%)=418 ([M+Na] +, 84), 396([M+H]+, 93).

HPLC (method 3): retention time(%)=3,34 (100).

b) 2-({(5S)-2-Oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione

To a suspension of amerosport (3.58 g, 9.05 mmole) in 90 ml of tetrahydrofuran in an argon atmosphere at room temperature was added N,N'-carbonyldiimidazole (2,94 g of 18.1 mmole) and dimethylaminopyridine (catalytic amount). The reaction suspension is stirred for 12 hours at 60° (precipitate goes into solution, after some time, the precipitate is again formed), add the second portion of N,N'-carbonyldiimidazole (2,94 g of 18.1 mmole) and stirred at 60°With a further 12 hours. The precipitate (target product) is filtered off, washed with tetrahydrofuran and dried. The filtrate is evaporated in vacuo and purify additional portion of product using flash chromatography (mixture of dichloromethane with methanol). The total yield of 3.32 g, 87% of theory.

Mass spectrum (electrospray ionization): m/z(%)=422 ([M+H]+, 100).

HPLC (method 4): retention time(%)=3,37 (100).

C) N-({(5S)-2-Oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-5-chloro-2-thiophencarboxylic

To a suspension of oxazolidinone (4,45 g, 10.6 mmole) in 102 ml of ethanol at room temperature was added dropwise methylamine (40%solution in water, of 10.2 ml, 0,142 mol). The reaction mixture for 1 hour, refluxed and evaporated in vacuum. Cheese is the first product used without additional purification in the next reaction.

To a solution of amine in 90 ml of pyridine in an argon atmosphere at 0°With added dropwise to the acid chloride 5-chlorothiophene-2-carboxylic acid (to 2.29 g, 12.7 mmole). The ice cooling ceased, the reaction mixture is stirred 1 hour at room temperature and add water. After addition of dichloromethane and phase separation the aqueous phase is extracted with dichloromethane. The combined organic phases are dried with sodium sulfate, filtered and evaporated in vacuum. The target product was then purified using flash chromatography (mixture of dichloromethane with methanol). The total yield to 3.92 g, 86% of theory.

TPL 232-C.

Range1H-NMR (d6-sulfoxide, 200 MHz): 9,05-of 8.90 (t, J=5.8 Hz, 1H), 7,70 (D., J=4,1 Hz, 1H), 7,56 (D., J=9.0 Hz, 2H), 7,41 (D., J=9.0 Hz, 2H), 7,20 (D., J=4,1 Hz, 1H), 4,93-of 4.75 (m, 1H), 4,27-4,12 (m, 3H), was 4.02-3,91 (m, 2H), 3,91-3,79 (Shostakovich, J=6,1 Hz and 9.2 Hz, 1H), 3,76-3,66 (m, 2H), 3,66-of 3.54 (m, 2H).

Mass spectrum (electrospray ionization): m/z (%)=436 ([M+H]+, 100, Cl-matrix).

HPLC (method 2): retention time(%)=3,60 (100).

(0,2985, dimethylsulfoxide), it: 99%.

IC50=0.7 nm

Similarly obtained the following compounds.

Example 45

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

Mass spectrum (electrospray ionization): m/z (%)=831 ([2M+H]+, 100), 416 ([M+H]+, 66).

HPLC (method 3): retention time (%)=3,65 (100.

IC50=4,2 nm

Example 46

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

Mass spectrum (electrospray ionization): m/z (%)=480 ([M+H]+, 100, Br-matrix).

HPLC (method 3): retention time(%)=3,87 (100).

IC50=0.3 nm

Example 47

N-{[(5S)-3-(3-Isopropyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl)-5-chloro-2-thiophencarboxylic

In 5 ml of tetrahydrofuran is suspended 200 mg (0,61 mmole) of the hydrochloride of 6-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-3-isopropyl-1,3-benzoxazol-2(3H)-it (European patent No. 738726) and gain of 0.26 ml (1,83 mmole) of triethylamine and 132 mg (0.73 mmole) of the acid chloride of 5-chlorothiophene-2-carboxylic acid. The reaction mixture was left overnight under stirring at room temperature and then evaporated. The product distinguish chromatographytandem on column (silica gel, methylene chloride/ethanol 50:1 to 20/1). Obtain 115 mg (43% of theory) of the target compound.

Mass spectrum (electrospray ionization): m/z (%)=436 (M+H, 100).

HPLC (method 4): retention time=3,78 (100).

Similarly obtained the following compounds.

The following examples from 20 to 30 and from 58 to 139 refer to option [B] method is get, moreover, examples 20 and 21 represent the initial connection.

Example 20 to Obtain N-allyl-5-chloro-2-thiophencarboxylic

To a cooled with ice to a solution 2,63 ml (35 mmol) of allylamine to 14.2 ml of absolute pyridine and 14.2 ml of absolute tetrahydrofuran are added to 7.61 g (42 mmole) of the acid chloride of 5-chlorothiophene-2-carboxylic acid. The ice cooling cease and 3 hours and stirred the mixture at room temperature before it was evaporated in vacuum. To the residue was added water and filtered off the solid. The crude product is purified using flash chromatography on silica gel (dichloromethane). The output of 7.20 g (99% of theory).

Mass spectrum (desorption-chemical ionization, NH4): m/z (%)=219 (M+NH4, 100), 202 (M+N, 32).

HPLC (method 1): retention time (%)=3,96 minutes (98,9).

Example 21

Obtaining N-(2-oxiranylmethyl)-5-chloro-2-thiophencarboxylic

To a cooled with ice to a solution of 2.0 g (9,92 mmole) of N-allyl-5-chloro-2-thiophencarboxylic in 10 ml of dichloromethane is added a 3.83 g m-chlormadinone acid (content of about 60%). The mixture is left under stirring overnight, it is heated to room temperature, and then washed three times its 10%solution of sodium bisulfate. The organic phase is twice washed with a saturated solution of bicarbonate is the atrium and a saturated solution of sodium chloride, dried with magnesium sulfate and evaporated. The product is distilled chromatographytandem on silica gel (cyclohexane/ethyl acetate 1:1).

The output of 837 mg (39% of theory)

Mass spectrum (desorption-chemical ionization, NH4): m/z (%)=253 (M+NH4, 100), 218 (M+H, 80).

HPLC (method 1): retention time (%)=3,69 minutes (about 80).

A common way of obtaining substituted derivatives of N-(3-amino-2-hydroxypropyl)-5-chloro-2-thiophencarboxylic of N-(2-oxiranylmethyl)-5-chloro-2-thiophencarboxylic

To a solution of the derived primary amine or aniline (1.5 to 2.5 equivalents) in 1,4-dioxane, mixtures of 1,4-dioxane with water or ethanol or mixtures of ethanol with water (concentration of from about 0.3 to 1.0 mol/l) at room temperature or at temperatures up to 80°add separate portions of N-(2-oxiranylmethyl)-5-chloro-2-thiophencarboxylic (1 equivalent). Before evaporation, the mixture is stirred for 2 to 6 hours. From the reaction product mixture can be separated by chromatography on silica gel (mixture of cyclohexane to ethyl acetate, dichloromethane with methanol or a mixture of dichloromethane, methanol and triethylamine). In a similar way we obtain the following connection.

Example 22

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

Mass spectrum (electrospray ionization): m/z (%)=325 (M+H, 100).

HPLC (meth the d 1): retention time 3.87 minutes (97,9).

Example 23

5-Chloro-N-[3-(3-cyanoaniline)-2-hydroxypropyl]-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=336 (M+H, 100).

HPLC (method 2): retention time of 4.04 minutes (100).

Example 24

5-Chloro-N-[3-(4-cyanoaniline)-2-hydroxypropyl]-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=336 (M+H, 100).

HPLC (method 1): retention time 4,12 minutes (100).

Example 25

5-Chloro-N-{3-[4-(cyanomethyl)aniline]-2-hydroxypropyl}-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=350 (M+H, 100).

HPLC (method 4): retention time of 3.60 minutes (95,4).

Example 26

5-Chloro-N-{3-[3-(cyanomethyl)aniline]-2-hydroxypropyl}-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=350 (M+H, 100).

HPLC (method 4): retention time 3,76 minutes (94,2).

Example 58A

tert.-Butyl-4-[(3-{[(5-chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)amino]-benzylcarbamoyl

Obtained from tert.-butyl-4-aminobenzoylglutamate (Bioorg. Med. Chem. Lett., 1997, 1921-1926).

Mass spectrum (electrospray ionization, cations): m/z (%)=440 (M+H, 100); (electrospray ionization, anions): m/z (%)=438 (M-H, 100).

HPLC (method 1): retention time 4,08 minutes (100).

Example 59

tert.-Butyl-4-[(3-{[(5-chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)amino]-phenylcarbamate

Obtained from N-tert.-butoxycarbonyl-1,4-phenylenediamine.

Mass spectrum(electrospray ionization): m/z (%)=426 (M+H, 45), 370 (100).

HPLC (method 1): retention time 4,06 (100).

Example 60

tert.-Butyl-2-hydroxy-3-{[4-(2-oxo-1-pyrrolidinyl)phenyl]amino} propyl-carbamate

Obtained from 1-(4-AMINOPHENYL)-2-pyrrolidinone (Justus Liebigs Ann. Chem. 1955, 596, 204).

Mass spectrum (desorption-chemical ionization, NH3): m/z (%)=350 (M+H, 100).

HPLC (method 1): retention time 3,57 (97).

Example 61

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

In 15 ml of ethanol and 1 ml water for 6 hours refluxed 800 mg (3.8 mmole) of 4-(4-amino-2-forfinal)-3-morpholino and 700 mg (3,22 mmole) of N-(2-oxiranylmethyl)-5-chloro-2-thiophencarboxylic. Evaporated in vacuo, after treatment with ethyl acetate sucked off from the precipitated crystals and chromatographytandem mother liquor obtain 276 mg (17% of theory) of the target compound. Rf(ethyl acetate)=0,25.

Example 62

N-(3-Aniline-2-hydroxypropyl)-5-chloro-2-thiophencarboxylic

Derived from aniline.

Mass spectrum (desorption-chemical ionization, NH3): m/z (%)=311 (M+H, 100),

Cl-matrix.

HPLC (method 3): retention time 3,79 (100).

Example 63

N-(2-Hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}-propyl)-5-chloro-2-thiophencarboxylic

Obtained from 4-(4-AMINOPHENYL)-3-morpholino.

Mass spectrum (electrospray ionization): m/z (%)=410 ([M+H]+, 50), Cl-matrix.

HPLC (method 3): in EMA holding to 3.58 (100).

Example 64

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

Obtained from N-(4-AMINOPHENYL)-N-cyclopropylacetic.

Mass spectrum (electrospray ionization): m/z (%)=408 ([M+H]+, 100), Cl-matrix.

HPLC (method 3): retention time of 3.77 (100).

Example 65

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

Obtained from 5(S)-5-(aminomethyl)-3-(4-morpholinyl)-1,3-oxazolidin-2-it.

Mass spectrum (electrospray ionization): m/z (%)=382 (M+H, 100).

HPLC (method 4): retention time of 3.31 minutes

Example 66

N-(2-Hydroxy-3-{[4-(1H-1,2,3-triazole-1-yl)phenyl]amino}propyl)-5-chloro-2-thiophencarboxylic

Obtained from 4-(1H-1,2,3-triazole-1-yl)aniline (Bouchet and others, J. Chem. Soc. Perkin Trans. 2, 1974, 449).

Mass spectrum (electrospray ionization): m/z (%)=378 ([M+H]+, 100).

HPLC (method 4): retention time 3,55 minutes

Example 67

tert.-Butyl-1-{4-[(3-{[(5-chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)-amino]-phenyl}-L-prolinate have been obtained

Mass spectrum (electrospray ionization): m/z (%)=480 (M+H, 100).

HPLC (method 4): retention time 3,40 minutes

Example 68

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

Mass spectrum (electrospray ionization): m/z (%)=437 (M+H, 100).

HPLC (method 4): retention time 2,39 minutes

Example 69

1-{4-[(3-{[(5-Chloro-2-Tien is l)carbonyl]amino}-2-hydroxypropyl)amino]phenyl}-3-piperidinecarboxylic

Mass spectrum (electrospray ionization): m/z (%)=437 (M+H, 100).

HPLC (method 4): retention time 2,43 minutes

Example 70

N-(2-Hydroxy-3-{[4-(4-oxo-1-piperidinyl)phenyl]amino}propyl)-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=408 (M+H, 100).

HPLC (method 4): retention time 2,43 minutes

Example 71

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

Mass spectrum (electrospray ionization): m/z (%)=423 (M+H, 100).

HPLC (method 4): retention time of 2.51 minutes

Example 72

N-[2-Hydroxy-3-({4-[3-(hydroxymethyl)-1-piperidinyl]phenyl}amino)propyl]-5-chloro-

2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=424 (M+H, 100).

HPLC (method 4): retention time 2,43 minutes

Example 73

N-[2-Hydroxy-3-({4-[2-(hydroxymethyl)-1-piperidinyl] phenyl}amino)propyl]-5-chloro-

2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=424 (M+H, 100).

HPLC (method 4): retention time 2,49 minutes

Example 74

Ethyl ester of 1-{4-[(3-{[(5-chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)-amino]phenyl}-2-piperidinecarboxylic acid

Mass spectrum (electrospray ionization): m/z (%) = 466 (M+H, 100).

HPLC (method 4): retention time to 3.02 min

Example 75

N-[2-Hydroxy-3-({4-[2-(hydroxymethyl)-1-pyrrolidinyl]phenyl}amino)propyl]-5-chloro-2-thiophencarboxylic

M is SS-spectrum (electrospray ionization): m/z (%) = 410 (M+H, 100).

HPLC (method 4): retention time 2,48 minutes

Example 76

N-(2-Hydroxy-3-{[4-(2-methylhexane-5-N-pyrrolo[3,4-d]isoxazol-5-yl)phenyl]-amino}propyl)-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=437 (M+H, 100).

HPLC (method 5): retention time 1,74 minutes

Example 77

N-(2-Hydroxy-3-{[4-(1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]amino}propyl)-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=448 (M+H, 100).

HPLC (method 4): retention time 3,30 minutes

Example 78

N-(2-Hydroxy-3-{[4-(2-oxo-1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]amino}propyl)-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=462 (M+H, 100).

HPLC (method 4): retention time 3,50 minutes

Example 79

N-(3-{[4-(3-Oxo-4-morpholinyl)-3-chlorophenyl]amino}-2-hydroxypropyl)-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=444 (M+H, 100).

HPLC (method 4): retention time 3,26 minutes

Example 80

N-(2-Hydroxy-3-{[4-(3-oxo-4-morpholinyl)-3-(trifluoromethyl)phenyl]amino}propyl)-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=478 (M+H, 100).

HPLC (method 4): retention time 3,37 minutes

Example 81

N-(2-Hydroxy-3-{[3-methyl-4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=424 (M+ሺ, 100).

HPLC (method 4): retention time 2,86 minutes

Example 82

N-(3-{[4-(3-Oxo-4-morpholinyl)-3-cyanophenyl]amino}-2-hydroxypropyl)-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=435 (M+H, 100).

HPLC (method 4): retention time 3,10 minutes

Example 83

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

Mass spectrum (electrospray ionization): m/z (%)=414 (M+H, 100).

HPLC (method 4): retention time 2,49 minutes

Example 84

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

Mass spectrum (electrospray ionization): m/z (%)=428 (M+H, 100).

HPLC (method 4): retention time 3,39 minutes

Example 85

N-(3-{[3,5-Dimethyl-4-(3-oxo-4-morpholinyl)phenyl]amino}-2-hydroxypropyl)-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=438 (M+H, 100).

HPLC (method 4): retention time 2,84 minutes

Example 86

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

Mass spectrum (electrospray ionization): m/z (%)=439 (M+H, 100).

HPLC (method 4): retention time 2,32 minutes

Example 87

N-Hydroxy-3-{[3-methoxy-4-(4-morpholinyl)phenyl]amino}propyl)-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=426 (M+H, 100).

HPLC (method 4): retention time 2,32 mi is.

Example 88

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

Mass spectrum (electrospray ionization): m/z (%)=438 (M+H, 100).

HPLC (method 4): retention time 2,46 minutes

Example 89

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

Mass spectrum (electrospray ionization): m/z (%)=425 (M+H, 100).

HPLC (method 4): retention time of 2.45 minutes

Example 90

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

Mass spectrum (electrospray ionization): m/z (%)=458 (M+H, 100).

HPLC (method 4): retention time 3,44 minutes

Example 91

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

Mass spectrum (electrospray ionization): m/z (%)=458 (M+H, 100).

HPLC (method 4): retention time of 3.48 min

Example a

N-[2-Hydroxy-3-({4-[(3-oxo-4-morpholinyl)methyl]phenyl}amino)propyl]-5-chloro-2-thiophencarboxylic

Obtained from 4-(4-aminobenzyl)-3-morpholino (Surrey, etc., J. Am. Chem. Soc. 77,

1955, 633).

Mass spectrum (electrospray ionization): m/z (%)=424 (M+H, 100).

HPLC (method 4): retention time 2,66 minutes

General method for the preparation of 3-substituted derivatives of 5-chloro-N-[(2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophencarboxylic substituted derivatives of N-(3-amino-2-hydroxypropyl)-5-x is the PR-2-thiophencarboxylic

To a solution of substituted derivative of N-(3-amino-2-hydroxypropyl)-5-chloro-2-thiophenecarboxylate (1.0 equivalent) in absolute tetrahydrofuran (concentration of about 0.1 mol/l) at room temperature was added carbonyldiimidazole (from 1.2 to 1.8 equivalent) or comparable properties equivalent of phosgene. At room temperature or, if necessary, at elevated temperatures (up to 70° (C) the mixture is stirred for from 2 to 18 hours and evaporated in vacuum. The product can be purified by chromatography on silica gel using mixtures of dichloromethane and methanol or cyclohexane and ethyl acetate).

In a similar way we obtain the following connection.

Example 27

N-[(3-Benzyl-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophencarboxylic

Mass spectrum (desorption-chemical ionization, NH4): m/z (%)=372 (M+Na, 100), 351(M+H,45).

HPLC (method 1): retention time 4,33 minutes (100).

Example 28

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

Mass spectrum (desorption-chemical ionization, NH4): m/z (%)=362 (M+H, 42), 145 (100).

HPLC (method 2): retention time 4,13 minutes (100).

Example 29

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

Mass spectrum (ei-electroresistive): m/z (%)=376 (M+H, 100).

HPLC (method 4): ASU is holding 4,12 minutes

Example 30

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

Mass spectrum (electrospray ionization): m/z (%)=376 (M+H, 100).

HPLC (method 4): retention time of 4.17 min

Example 92

tert.-Butyl-4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]benzylcarbamoyl

Produced from compound according to example 58.

Mass spectrum (electrospray ionization): m/z (%)=488 (M+Na, 23), 349 (100).

HPLC (method 1): retention time 4,51 (98,5).

Example 93

tert.-Butyl-4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenylcarbamate

Produced from compound according to example 59.

Mass spectrum (electrospray ionization): m/z (%)=493 (M+Na, 70), 452 (M+H, 10), 395 (100).

HPLC (method 1): retention time to 4.41 (100).

Example 94

tert.-Butyl-2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methylcarbamate

Produced from compound according to example 60.

Mass spectrum (desorption-chemical ionization, NH3): m/z (%)=393 (M+NH4, 100).

HPLC (method 3): retention time(%)=3,97 (100).

Example 95

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

In 20 ml of dioxane for two hours refluxed 260 mg (0,608 mmole) of N-(3-{[3-fluoro-4-(3-oxo-4-morpholinyl)phenyl]amino}-2-hydroxypropyl)-5-chloro-2-t is afterbattle (obtained in example 61), 197 mg (1,22 mmole) of carbonyldiimidazole and 7 mg dimethylaminopyridine. Then add 20 ml of acetonitrile and stirred for 30 minutes in a microwave oven in a closed vessel at a temperature of 180°C. the Solution is evaporated on a rotary evaporator and chromatographic by HPLC on a column with treatment phases. Obtain 53 mg (19% of theory) of the target compound.

An NMR spectrum (300 MHz, d6-dimethylsulfoxide): δ up 3.6-3.7 (m, 4H), 3,85 (Shostakovich, 1H), 3,95 (m, 2H), 4,2 (m, 1H), 4,21 (S. 2N), is 4.85 (m, 1H), 4,18 (S., 2H), 7,19 (D., 1H, thiophene), 7,35 (Shostakovich, 1H), 7,45 (t, 1H), 7,55 (Shostakovich, 1H), to 7.67 (D., 1H, thiophene), 8,95 (so, 1H, CONH).

Example 96

N-[(2-Oxo-3-phenyl-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophencarboxylic

Receive from the compound from example 62.

Mass spectrum (electrospray ionization): m/z (%)=359 ([M+Na]+, 71), 337 ([M+H]+, 100), Cl-matrix.

HPLC (method 3): retention time 4,39 (100).

IC50=2 ám.

Example 97

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

Receive from the compound from example 63.

Mass spectrum (electrospray ionization): m/z (%)=458 ([M+Na]+, 66), 436 ([M+H]+, 100), Cl-matrix.

HPLC (method 3): retention time 3,89 (100).

IC50=1,4 nm.

Example 98

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

Receive from the compound from example 64.

The mass spectrum of the (electrospray ionization): m/z (%)=456 ([M+Na] +, 55), 434 ([M+H]+, 100), Cl-matrix.

HPLC (method 3): retention time of 4.05 (100).

IC50=50 nm.

Example 99

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

Mass spectrum (electrospray ionization): m/z (%)=408 (M+H, 30), 449 (M+H+CH3CN, 100).

HPLC (method 4): retention time 3,66 minutes

Example 100

N-({2-Oxo-3-[4-(1H-1,2,3-triazole-1-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=404 (M+H, 45), 445 (M+H+CH3CN, 100).

HPLC (method 4): retention time of 3.77 min

Example 101

tert.-Butyl-1-{4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl] phenyl}-L-prolinate have been obtained

Mass spectrum (electrospray ionization): m/z (%)=450 (M+H-56, 25), 506 (M+H, 100).

HPLC (method 4): retention time 5,13 minutes

Example 102

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

Mass spectrum (electrospray ionization): m/z (%)=463 (M+H, 100).

HPLC (method 4): retention time of 2.51 minutes

Example 103

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

Mass spectrum (electrospray ionization): m/z (%)=463 (M+H, 100).

HPLC (method 4): retention time to 2.67 minutes

Example 104

N-{2-Oxo-3-[4-(4-oxo-1-piperidinyl)phenyl]-1,3-oxazolidin-5-yl}IU who yl)-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%) = 434 (M+H, 40), 452 (M+h+H2O,100), 475 (M+H+CH3CN, 60).

HPLC (method 4): retention time 3,44 minutes

Example 105

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

Mass spectrum (electrospray ionization): m/z (%)=449 (M+H, 100).

HPLC (method 4): retention time of 3.54 min

Example 106

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

Mass spectrum (electrospray ionization): m/z (%)=450 (M+H, 100).

HPLC (method 5): retention time 2,53 minutes

Example 107

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

Mass spectrum (electrospray ionization): m/z (%)=450 (M+H, 100).

HPLC (method 5): retention time 2,32 minutes

Example 108

Ethyl ester of 1-{4-[5-({[(5-Chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-2-piperidinecarboxylic acid

Mass spectrum (electrospray ionization): m/z (%)=492 (M+H, 100).

HPLC (method 5): retention time of 4.35 min

Example 109

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

Mass spectrum (electrospray ionization): m/z (%)=436 (M+H, 100).

HPLC (method 4): retention time 2,98 minutes

Example 110

N-({2-Oxo-3-[4-(1-pyrrol dinyl)-3-(trifluoromethyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=474 (M+H, 100).

HPLC (method 4): retention time 4,63 minutes

Example 111

N-({3-[4-(2-Methylhexane-5H-pyrrolo[3,4-d]isoxazol-5-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=463 (M+H, 100).

HPLC (method 4): retention time of 2.56 minutes

Example 112

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

Mass spectrum (electrospray ionization): m/z (%)=488 (M+H, 100).

HPLC (method 4): retention time of 3.64 min

Example 113

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

Mass spectrum (electrospray ionization): m/z (%)=470 (M+H, 100).

HPLC (method 4): retention time 3,41 minutes

Example 114

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

Mass spectrum (electrospray ionization): m/z (%)=504 (M+H, 100).

HPLC (method 4): retention time 3,55 minutes

Example 115

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

Mass spectrum (electrospray ionization): m/z (%)=450 (M+H, 100).

HPLC (method 4): retention time 3,23 minutes

Example 116

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

Mass spectrum (electrospray ionization): m/z (%)=461 (M+H, 100).

HPLC (method 4): retention time of 3.27 min

Example 117

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

Mass spectrum (electrospray ionization): m/z (%)=440 (M+H, 100).

HPLC (method 4): retention time and 3.72 min

Example 118

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

Mass spectrum (electrospray ionization): m/z (%)=454 (M+H, 100).

HPLC (method 4): retention time 3,49 minutes

Example 119

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

Mass spectrum (electrospray ionization): m/z (%)=464 (M+H, 100).

HPLC (method 4): retention time 3,39 minutes

Example 120

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

Mass spectrum (electrospray ionization): m/z (%)=465 (M+H, 100).

HPLC (method 4): retention time of 3.07 min

Example 121

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

Mass spectrum (electrospray ionization): m/z (%)=452 (M+H, 100).

HPLC (method 4): retention time 2,86 minutes

Example 122

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

Mass spectrum (electrospray ionization): m/z (%)=464 (M+H, 100).

HPLC (method 4): retention time 3,52 minutes

Example 123

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

Mass spectrum (electrospray ionization): m/z (%)=451 (M+H, 100).

HPLC (method 6): retention time 3,16 minutes

Example 124

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

Mass spectrum (electrospray ionization): m/z (%)=484 (M+H, 100).

HPLC (method 4): retention time 3,59 minutes

Example 125

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

Mass spectrum (electrospray ionization): m/z (%)=484 (M+H, 100).

HPLC (method 4): retention time 3,63 minutes

Example 125

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

Mass spectrum (electrospray ionization): m/z (%)=450 (M+H, 100).

HPLC (method 4): retention time of 3.25 minutes

In the disclosure epoxy communication with the amine, followed by cyclization to the corresponding oxazolidinone obtained the following compounds.

In the following examples 14 to 16 shows examples of what realizatsii of the invention with the optional stage of oxidation, that is the reaction, which is a possible phase retrieval method.

Example 14

N-({(5S)-3-[3-Fluoro-4-(1-oxo-1[lambda]4,4-diazinon-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophencarboxylic

To a solution of periodate sodium (0.05 g to 0.23 mmole) of 0.54 ml of water are added at a temperature of 0°With 0.1 g (0.22 mmole) of N-({(5S)-3-[3-fluoro-4-(1,4-diazinon-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophencarboxylic obtained according to example 3, 0.77 ml of methanol. Then add 1 ml of dimethylformamide and stirred for 8 hours at room temperature. After adding 50 mg of periodate sodium again left overnight under stirring at room temperature. In conclusion, to the reaction mixture was added 50 ml of water and the insoluble product is sucked off. After washing with water and drying receive 60 mg (58% of theory) of crystals. TPL 257°C.

Rf(silica gel, toluene/ethyl acetate 1:1)=0,54 (the original product Rf=0,46).

The value of the IC50=1.1 µm.

Mass spectrum (desorption-chemical ionization): 489 (M+NH4), Cl-matrix.

Example 15

Obtain N-({(5S)-3-[4-(1,1-dioxo-1[lambda]6,4-diazinon-4-yl)-3-forfinal]-2-oxo-

1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophencarboxylic

To the obtained in example 3 N-({(5S)-3-[3-fluoro-4-(1,4-thiazine the-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophenecarboxylate (0.1 g, 0.22 mmole) of 3.32 ml of a mixture of 1 part water and 3 parts of acetone was added 80 mg (0,66 mmole) of N-methyl-morpholine-N-oxide and 0.1 ml of 2.5%solution of osmium tetroxide in 2-methyl-2-propanol. Left overnight under stirring at room temperature and again add 40 mg of N-methylmorpholin-N-oxide. Again left overnight under stirring at room temperature, pour the reaction mixture into 50 ml of water and extracted three times with ethyl acetate. From the organic phase after drying and evaporation obtain 23 mg, and from the aqueous phase after the extraction of the insoluble solids obtain 19 mg (total yield of 39% of theory) of the target compound.

TPL 238°C.

Rf(toluene/ethyl acetate 1:1)=0,14 (source product Rf=0,46).

The value of the IC50=210 nm.

Mass spectrum (desorption-chemical ionization): 505 (M+NH4), Cl-matrix.

Example 16

N-Oxide of N-{[(5S)-3-(3-fluoro-4-morpholinyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophencarboxylic

This substance is produced by the action of magnesium salts monoperoxyphthalic acid N-{[(5S)-3-(3-fluoro-4-morpholinyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophencarboxylic obtained in example 1.

Mass spectrum (electrospray ionization): 456 (M+H, 21%, Cl-matrix), 439 (100%).

The following examples 31 to 35 and from 140 to 147 relate to the implementation of the invention with the optional stage and is adenilovaya, that is the reaction, which is a possible phase retrieval method.

A common way to obtain amidines and derivatives amidino of cinematelevision derivatives of N-[2-oxo-1,3-oxazolidin-5-yl)-methyl]-5-chloro-2-thiophencarboxylic

Appropriate cyanomethylphosphonate derived N-[(2-oxo-1,3-oxazole-DIN-5-yl)-methyl]-5-chloro-2-thiophenecarboxylate (1.0 equivalent) together with triethylamine (8.0 equivalents) is stirred for one to two days at room temperature in a saturated hydrogen sulfide pyridine (concentration of about 0.05-0.1 mol/l). The reaction mixture was diluted with ethyl acetate and washed denormalize hydrochloric acid. The organic phase is dried with magnesium sulfate, filtered and evaporated in vacuum.

The crude product is dissolved in acetone (0.01-0.1 mol/l) and added methyliodide (40 equivalents). The reaction mixture was stirred at room temperature for two to five hours and then evaporated in vacuum.

The residue is dissolved in methanol (0.01-0.1 mol/l) and to obtain unsubstituted amidino added ammonium acetate (3 equivalents) and ammonium chloride (2 equivalents). To obtain substituted ajdinovic derivatives to a solution in methanol are added to the primary or secondary amine (1.5 equivalents) and acetic acid (2 equivalents). From 5-30 hours to remove the solvent in vacuo and purify the residue by chromatography on R8-column with silica gel (water/acetonitrile from 9/1 to 1/1+0.1% of triperoxonane acid). In a similar way we obtain the following connection.

Example 31

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

Mass spectrum (electrospray ionization): m/z (%)=393 (M+H, 100).

HPLC (method 4): retention time 2,63 minutes

Example 32

N-({3-[3-(4,5-Dihydro-1H-imidazol-2-ylmethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}-methyl)-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=419 (M+H, 100).

HPLC (method 4): retention time 2,61 minutes

Example 33

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

Mass spectrum (electrospray ionization): m/z (%)= 63 (M+H, 100).

HPLC (method 4): retention time 2,70 minutes

Example 34

N-[(3-{3-[2-Imino-2-(1-pyrrolidinyl)ethyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=447 (M+H, 100).

HPLC (method 4): retention time 2,82 minutes

Example 35

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

Mass spectrum (electrospray ionization): m/z (%)=393 (M+H, 100).

HPLC (method 4): retention time 2,60 minutes

Example 140

N-({3-[4-(4,5-Dihydro-1H-imidazol-2-ylmethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}-methyl)-5-chloro-2-thiophencarboxylic

Mass spectrum (ei electroral the tion): m/z (%)=419 (M+H, 100).

HPLC (method 4): retention time 2,65 minutes

Example 141

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

Mass spectrum (electrospray ionization): m/z (%)=463 (M+H, 100).

HPLC (method 4): retention time 2,65 minutes

Example 142

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

Mass spectrum (electrospray ionization): m/z (%)=461 (M+H, 100).

HPLC (method 4): retention time of 2.83 min

Example 143

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

Mass spectrum (electrospray ionization): m/z (%)=447 (M+H, 100).

HPLC (method 4): retention time was 2.76 minutes

Example 144

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

Mass spectrum (electrospray ionization): m/z (%)=461 (M+H, 100).

HPLC (method 4): retention time 2,89 minutes

Example 145

N-[-{[3-(4-{2-Imino-2-[(2,2,2-triptorelin)amino]ethyl}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=475 (M+H, 100). HPLC (method 4): retention time 2,79 minutes

Example 146

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

Mass spectrum (ionization electrorash what Elenium): m/z (%)=469 (M+H, 100).

HPLC (method 4): retention time of 2.83 min

Example 147

N-[(3-{4-[2-Imino-2-(2-pyridinylamino)ethyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=470 (M+H, 100).

HPLC (method 4): retention time 2,84 minutes

The following examples from 148 to 151 refer to removal from the amino protective tert.-butoxycarbonyl group.

A common way off tert.-butoxycarbonyl protective groups

To a cooled with ice to a solution of the compound with tert.-butoxycarbonyl protective group in chloroform or dichloromethane (concentration of from about 0.1 to 0.3 mol/l) are added dropwise water triperoxonane acid (about 90%). After about 15 minutes the ice cooling is removed and stirred the mixture for about 2-3 hours at room temperature, then evaporated solution and dried in high vacuum. The residue is dissolved in dichloromethane or in mixtures of dichloromethane and methanol and washed with a saturated solution of sodium bicarbonate or odnomomentnym solution of sodium hydroxide. The organic phase is washed with a saturated solution of sodium chloride, dried over a small amount of magnesium sulfate and concentrate it. Cleaning, if required, is carried out by crystallization from diethyl ether or mixtures of diethyl E. the Ira with dichloromethane.

By analogy with that of the predecessors with tert.-butoxycarbonylamino protective groups receive the following connections.

Example 148

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

Produced from compound according to example 92.

Mass spectrum (electrospray ionization): m/z (%)=349 (M-NH2, 25), 305 (100).

HPLC (method 1): retention time 3,68 (98).

IC50: 2,2 mm.

Example 149

N-{[3-(4-AMINOPHENYL)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophencarboxylic

Produced from compound according to example 93.

Mass spectrum (electrospray ionization): m/z (%)=352 (M+H, 25).

HPLC (method 1): retention time 3,50 (100).

IC50:2 ám.

An alternative synthesis of this compound with obtaining pure enantiomers represented by the following further schema transformations (see also S.A.Delalande, the Federal Republic of Germany patent No. 2836305, 1979; Chem. Abstr. 90, 186926):

Example 150

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

thiophencarboxylic

Produced from compound according to example 152.

Mass spectrum (electrospray ionization, cations): m/z(%)=408 (100).

HPLC (method 3): retention time of 3.56 (97). IC50: 2 ám.

Example 151

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

Produced from compound according to example 60.

Mass spectrum (ei El is spray): m/z (%)=276 (M+H, 100). HPLC (method 3): retention time 2,99 (100). IC50:2 ám.

The following examples from 152 to 166 are transformations on the amino group anilinopiperidine or benzylaminopurine of oxazolidinones under the action of various reagents.

Example 152

N-({3-[4-(N-tert.-Butyloxycarbonyl-glycylamino)phenyl] -2-oxo-1,3-oxazolidin-5-

yl}methyl)-5-chloro-2-thiophencarboxylic

To a solution of 751 mg (4.3 mmole) of tert.-butyloxycarbonyl, 870 mg (6.4 mmole) of hydrate 1-hydroxy-1H-benzotriazole, 1790 mg (4.7 mmole) of hexaflurophosphate O-benzo-triazole-1-yl-N,N,N',N'-tetramethylurea and 1.41 ml (12.9 mmole) N-methylmorpholine in 15 ml of a mixture of dimethylformamide and dichloromethane (1:1) at a temperature of 0°To give 754 mg (2.1 mmole) of N-{[3-(4-AMINOPHENYL)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophenecarboxylate (obtained from example 149). The mixture is left overnight under stirring at room temperature, then diluted with water. Precipitated solid is filtered off and dried. Output 894 mg (79,7% of theory). Mass spectrum (desorption-chemical ionization, NH3): m/z (%)=526 (M+NH4, 100). HPLC (method 3): retention time 4,17 (97).

Example 153

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

To a mixture of 30 mg (0,082 mmole) of N-({3-[4-(aminomethyl)phenyl]-2-oxo-1,3-OK who solidin-5-yl}methyl)-5-chloro-2-thiophenecarboxylate (obtained in example 148) in 1.5 ml of absolute tetrahydrofuran, 1.0 ml absolute dichloromethane and 0.02 ml of absolute pyridine at a temperature of 0°add 0,015 ml (0,164 mmole) of acetic anhydride. The mixture is left overnight under stirring at room temperature. After addition of ether and crystallization receive the product. Yield 30 mg (87% of theory)

Mass spectrum (electrospray ionization): m/z (%)=408 (M+H, 18), 305 (85).

HPLC (method 1): retention time of 3.78 (97). IC50: 0.6 microns.

Example 154

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

To a mixture of 30 mg (0,082 mmole) of N-({3-[4-(aminomethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophenecarboxylate (obtained in example 148) and 1.0 ml of dichloromethane at room temperature is added dropwise to 0.19 ml (about 0.82 mmole) trimethylsilyltriflate. Left under stirring overnight and after addition of ether to produce the product by filtration. The output of 21.1 mg (52% of theory).

Mass spectrum (electrospray ionization): m/z (%)=409 (M+H, 5), 305 (72).

HPLC (method 1): retention time to 3.67 (83).

IC50: 1,3 ám.

A common way acylation of N-{[3-(4-AMINOPHENYL)-2-oxo-1,3-oxazolidin-5-yl]methyl]-5-chloro-2-thiophencarboxylic carboxylic acid anhydrides

In an argon atmosphere to the corresponding acid chloride of acid (2,5 equivalent is enta) are added dropwise to about decimally a solution of N-{[3-(4-AMINOPHENYL)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophenecarboxylate (obtained from example 149) (1.0 equivalent) in a mixture of absolute dichloromethane and pyridine (19:1). The mixture is left under stirring overnight, add about 5 equivalents of PS-Trisamine (production Argonaut technologies) and 2 ml of absolute dichloromethane. After the weak mixing for 1 hour, filtered and concentrated the filtrate. If necessary, the product was then purified by the method of preparative HPLC with treatment phases. A similar technique get the following connection.

Example 155

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

Liquid / mass spectrometry: m/z (%)=394 (M+H, 100).

Liquid / mass spectrometry (method 6): retention time(%)=3,25 (100).

IC50: 1.2 microns.

Example 156

N-[(2-Oxo-3-{4-[(2-thienylboronic)amino]phenyl}-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophencarboxylic

Liquid / mass spectrometry: m/z (%)=462 (M+H, 100).

Liquid / mass spectrometry (method 6): retention time(%)=3,87 (100).

IC50: 1,3 ám.

Example 157

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

Liquid / mass spectrometry: m/z (%)=424 (M+H, 100).

Liquid / mass spectrometry (method 6): retention time(%)=3,39 (100).

IC50: to 0.73 ám.

Example 158

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

Liquid / mass spectrometry: m/z (%)=475 (M+H, 100).

IC50: 0,46 mm.

Example 159

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

To a cooled with ice to a solution of 26.4 mg (0.15 mmole) of 3-chloro-1-propanesulfonate and 0.03 ml (0.2 mmole) of triethylamine in 3.5 ml of absolute dichloromethane was added 35 mg (0.1 mmole) of N-{[3-(4-AMINOPHENYL)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophenecarboxylate (obtained from example 149). After 30 minutes, remove the ice cooling and leave the mixture overnight under stirring at room temperature, then added 150 mg (about 5.5 equivalents) of PS-Trisamine (production Argonaut technologies) and 0.5 ml of dichloromethane. A suspension of weakly stirred for two hours, filtered (the resin is washed with a mixture of dichloromethane with methanol and the filtrate evaporated. The product was then purified by the method of preparative HPLC with treatment phases. The output of 19.6 mg (40% of theory).

Liquid / mass spectrometry: m/z (%)=492 (M+H, 100).

Liquid / mass spectrometry (method 5): retention time(%)=3,82 (91).

IC50: 1,7 mm.

Example 160

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

A mixture of 13.5 mg (0,027 mmole) of N-{[3-(4-{[(3-chlorpropyl)sulfonyl]amino}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-type the carboxamide (obtained in example 159) and 7.6 mg (by 0.055 mmole) of potassium carbonate in 0.2 ml of dimethylformamide for 2 hours, heated at a temperature of 100° C. After cooling, diluted with dichloromethane and washed with water. The organic phase is dried and evaporated. The residue is purified by the method of preparative thin-layer chromatography (silica gel, dichloromethane/methanol, 95:5).

Output 1.8 mg (14.4% of theory).

Mass spectrum (electrospray ionization): m/z (%)=456 (M+H, 15), 412 (100). Liquid / mass spectrometry (method 4): retention time(%)=3,81 (90).

IC50: 0,14 m.

Example 161

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

In 27 ml of tetrahydrofuran was dissolved 0.5 g (1,29 mmole) of N-{[(5S)-3-(4-AMINOPHENYL)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophenecarboxylate (obtained from example 149) and add 0.2 g (1,29 mmole) of the acid chloride of 5-haralanova acid, and 0,395 ml and 2.83 mmole) of triethylamine. The reaction mixture was evaporated in vacuum and chromatographic on silica gel with a gradient of solvents from a mixture of toluene/ethyl acetate (1:1) to pure ethyl acetate. Get 315 mg (52% of theory) of a solid substance.

TPL 211°C.

Example 162

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

In an inert atmosphere to 5 ml of dimethyl sulfoxide was added 30 mg of 60%sodium hydride in paraffin oil and within 30 minutes the heating of the Ute at 75° With before the end of veseleny gas. Then add dropwise a solution of 290 mg (0,617 mmole) of N-[((5S)-3-{4-[(5-Charpentier)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)-methyl]-5-chloro-2-thiophenecarboxylate (obtained in example 161) in 5 ml of methylene chloride and left overnight under stirring at room temperature. The reaction is stopped and pour the mixture into 100 ml of water, extracted with ethyl acetate. One stripped off the organic phase chromatographic on column RP-8, elwira a mixture of acetonitrile/water. Receive 20 mg (7.5% of theory) of the target compound.

TPL 205°C.

An NMR spectrum (300 MHz, d6-dimethylsulfoxide): δ=1,85 (m, 4H), to 2.35 (m, 2H), to 3.58 (m, 4H), 3,85 (m, 1H), 4,2 (t, 1H), 4,82 (m, 1H), 7,18 (D., 1H, thiophene), 7,26 (D., 2H), 7,50 (D., 2H), 2,68 (D., 1H, thiophene), and 9.0 (t, 1H, CONH).

IC50: 2,8 nm.

Example 163

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

This substance get by analogy with example 149.

Example 164

N-({(5S)-2-Oxo-3-[4-(2-oxo-1-azetidine)phenyl]-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophencarboxylic

Get a similar manner, by cyclization obtained in example 163 bromopropionyl connection with an open circuit by the action of sodium hydride in dimethyl sulfoxide.

Mass spectrum (electrospray ionization): m/z (%)=406 (M+H, 100), Cl-is atrica.

IC50: 380 nm.

Example 165

tert.-Butyl ether 4-{4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl} - for 3,5-dioxo-1-piperazinecarboxamide acid

To a solution of 199 mg of 0.85 mmole) of tert.-butoxycarbonylmethylene acid, 300 mg (2.2 mmole) of hydroxybenzotriazole, of 0.66 ml (6 mmol) N-methylmorpholine and 647 mg (1.7 mmole) of HBTU are added to 300 mg of 0.85 mmole) of N-{[3-(4-AMINOPHENYL)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophencarboxylic in 6 ml of a mixture of dimethylformamide and dichloromethane (1:1). The mixture is left under stirring overnight, then diluted with dichloromethane and washed with water, saturated solution of ammonium chloride, saturated sodium bicarbonate solution, water and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and evaporated. The crude product is purified by chromatography on silica gel (mixture of dichloromethane and methanol 98:2). Yield 134 mg (29% of theory).

Mass spectrum (electrospray ionization): m/z (%)=571 (M+Na, 82), 493 (100).

HPLC (method 3): retention time(%)=4,39 (90).

IC50: 2 ám.

Example 166

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

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

In 35 ml of dimethylformamide is dissolved 429 mg (1,72 mmole) of N-tert.-butoxycarbonyl-D-methionine, 605 mg (1,72 mmole) of N-{[(5S)-3-(4-AMINOPHENYL)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophencarboxylic and 527 mg (3,44 mmole) hydrate (1-hydroxy-1H-benzotriazole give 660 mg (3,441 mmole) of the hydrochloride of N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide and then added dropwise 689 mg (5,334 mmole) of N-ethyldiethanolamine. Leave for two days under stirring at room temperature. The resulting suspension is sucked off and washed the rest of dimethylformamide. To the combined filtrates added a little silica gel, evaporated in vacuum and chromatographic on silica gel with a gradient of concentrations of toluene to a mixture of 10 parts of toluene and 7 parts of ethyl acetate. Obtain 170 mg (17% of theory) of the target compound with TPL 183°C.

Rf(silica, toluene/ethyl acetate 1:1)=0,2.

Range1H-NMR (300 MHz, d6-dimethylsulfoxide): δ=1,4 (C., 1H, tert.-butoxycarbonyl), 1,88-of 1.95 (m, 2H), 2,08 (C., 3H, SCH3), 2,4-2,5 (m, 2H, partially obscured by the signal from the dimethyl sulfoxide), and 3.6 (m, 2H), and 3.8 (m, 1H), 4,15 (m, 2H), and 4.8 (m, 1H), 7,2 (1H, thiophene), 7,42 (doctor, part of AB-system, 2H), 7,6 (doctor, part of AB-system, 2H), 7,7 (D., 1H, thiophene), of 8.95 (t, 1H, CH2NHCO), to 9.93 (d.n., 1H, NH).

tert.-Butyl(3R)-1-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}-methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-2-oxo-3-pyrrolidinyl the Mat

In 2 ml of dimethyl sulfoxide was dissolved 170 mg (0,292 mmole) of N2-(tert.-butoxy-carbonyl)-N1-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}-methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-D-methioninamide and add 178,5 mg (0,875 mmole)iodide trimethylsilane and 60,4 mg (0,437 mmole) of potassium carbonate and stirred for 3.5 hours at a temperature of 80°C. then evaporated under high vacuum and washing the residue with ethanol. In balance to get 99 mg of the target compound.

Range1H-NMR (300 MHz, d6-dimethylsulfoxide): δ=1,4 (C., 1H, tert.-butoxycarbonyl), 1,88-2,05 (m, 1H), 2.3 to 2.4 (m, 1H), of 3.7-3.8 (m, 3H), 3,8-3,9 (m, 1H), 4,1-of 4.25 (m, 1H), 4,25 is 4.45 (m, 1H), 4.75 V-of 4.95 (m, 1H), 7,15 (1H, thiophene), 7,25 (D., 1H), 7,52 (doctor, part of AB-system, 2H), 7,65 (doctor, part of AB-system, 2H), 7,65 (D., 1H, thiophene), and 9.0 (d.n., 1H).

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

In 4 ml of methylene chloride are suspended 97 mg (0,181 mmole) of tert.-butyl(3R)-1-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}-methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-2-oxo-3-pyrrolidinylcarbonyl. Add 1.5 ml triperoxonane acid and 1 hour and stirred at room temperature. Then evaporated in vacuum and purified by HPLC with a treatment phase (gradient acetonitrile/water /0.1% of triperoxonane acid). After evaporation of the appropriate fractions obtain 29 mg (37% of theory) of the target compound is TPL 241°C (decomp.).

Rf(silicon dioxide, ethanol/triethylamine 17:1)=0,19.

Range1H-NMR (300 MHz, d6-dimethylsulfoxide): δ=1,92-2,2 (m, 1H), 2,4-by 2.55 (m, 1H, partially overlapped with a signal of DMSO), 3,55-the 3.65 (m, 2H), 3.75 to 3,95 (m, 3H), 4,1-4,3 (m, 2H), 4.75 V-4,9 (m, 1H), 7,2 (1H, thiophene), 7,58 (doctor, part of AB-system, 2H), 7,7 (doctor, part of AB-system, 2H), to 7.68 (D., 1H, thiophene), and 8.4 (d.n., 3H, NH3), 8,9 (t, 1H, NHCO).

The following examples from 167 to 170 refer to the introduction sulfonamidnuyu groups in phenylsilane oxazolidinone.

A common way of obtaining substituted sulfonamides of N-[(2-oxo-3-phenyl-1,3-oxazolidin-5-yl)methyl]5-chloro-2-thiophencarboxylic

In an argon atmosphere to chlorosulfonic acid (12 equivalents) at a temperature of 5°With added N-[(2-oxo-3-phenyl-1,3-oxazolidin-5-yl)methyl]5-chloro-2-thiophencarboxylic (obtained in example 96). The reaction mixture is stirred for 2 hours at room temperature and then poured into ice water. The precipitation is filtered off, washed with water and dried.

Then in an argon atmosphere at room temperature was dissolved in tetrahydrofuran (concentration 0.1 mol/l) and added the appropriate amine (3 equivalents), tri-ethylamine (1.1 equivalent) and dimethylaminopyridine (0.1 equivalent). The reaction mixture is stirred for 1-2 hours and then UPrev the Ute in a vacuum. The target product was then purified using flash chromatography (mixture of dichloromethane with methanol).

Similarly receive the following connections.

Example 167

N-({2-Oxo-3-[4-(1-pyrrolidinylcarbonyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=492 ([M+Na]+, 100), 470 ([M+H]+, 68), Cl-matrix.

HPLC (method 3): retention time(%)=4,34 (100).

IC50=0.5 µm.

Example 168

N-[(3-{4-[(4-Methyl-1-piperazinil)sulfonyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)-methyl]-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=499 ([M+H]+, 100), Cl-matrix.

HPLC (method 2): retention time(%)=3,3 (100).

Example 169

N-({2-Oxo-3-[4-(1-piperidinylcarbonyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=484 ([M+H]+, 100), Cl-matrix.

HPLC (method 2): retention time(%)=4,4 (100).

Example 170

N-[(3-(4-[(4-Hydroxy-1-piperidinyl)sulfonyl] phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophencarboxylic

Mass spectrum (electrospray ionization): m/z (%)=500 ([M+H]+, 100), Cl-matrix.

HPLC (method 3): retention time(%)=3,9 (100).

Example 171

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

In 6 ml dig armeana and 9 ml triperoxonane acid are dissolved 780 mg (1,54 mmole) of tert.-butyl-1-{4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-prolinate have been obtained and stirred the mixture for two days at a temperature of 40° C. Then the reaction mixture is evaporated and stirred with ether and 2 N. a solution of sodium hydroxide. The aqueous phase is evaporated and stirred with ether and 2 N. hydrochloric acid. Obtained in this extraction, the organic phase is dried over magnesium sulfate, filtered and evaporated. The crude product chromatographic on silica gel (dichloromethane/ethanol/concentrated aqueous ammonia solution in a ratio of from 100/1/0,1 to 20/1/0,1). Get 280 mg (40% of theory) of product.

Mass spectrum (electrospray ionization): m/z (%)=406 (M+H, 100).

HPLC (method 4): retention time (%)=3,81 minutes

The HPLC parameters and parameters of liquid chromatography / mass spectrometry in the above data HPLC and liquid chromatography / mass spectrometry in the above examples (retention time is specified in minutes):

[1] column Kromasil C18, L-R temperature 30°S, the flow velocity of 0.75 ml/min, eluent A=0.01 M HClO4, B=acetonitrile, gradient → for 0.5 min 98% A → a 4.5 min 10% A → 6,5 min 10% A;

[2] column Kromasil C18 60*2, L-R temperature 30°S, the flow velocity of 0.75 ml/min, eluent A = 0.01 M H3RHO4, B = acetonitrile, gradient → 0,5 min 90% A → a 4.5 min 10% A → 6,5 min 10% A;

[3] column Kromasil C18 60*2, L-R temperature 30°S, the flow velocity of 0.75 ml/min, eluent A=0.005 M HClO4, B=acetonitrile, gradient → for 0.5 min 98% A → a 4.5 min 10% A → 6,5 min 10% A;

[4] the column is Symmetry C18 2.1 a× 150 mm, column heater 50°S, the flow velocity of 0.6 ml/min, eluent A=0.6 g of 30%hydrochloric acid in 1 l of water, B=acetonitrile, gradient of 0.0 min 90% A → to 4.0 min 10% A → 9 min 10% A;

[5] MHZ-2Q, instrument Micromass Quattro LCZ column Symmetry C18, 50 mm × 2.1 mm, 3.5 µm, temperature 40°S, the flow velocity of 0.5 ml/min, eluent A=acetonitrile+0.1% of formic acid, B=water+0.1% of formic acid, gradient of 0.0 min 10% A → 4 min 90% A → 6 min 90% A;

[6] MHZ-2P, instrument Micromass Platform LCZ column Symmetry C18, 50 mm × 2.1 mm, 3.5 µm, temperature 40°S, the flow velocity of 0.5 ml/min, eluent A=acetonitrile+0.1% of formic acid, B=water+0.1% of formic acid, gradient of 0.0 min 10% A → 4 min 90% A → 6 min 90% A;

[7] MHZ-7Q, instrument Micromass Quattro LCZ column Symmetry C18, 50 mm × 2.1 mm, 3.5 µm, temperature 40°S, the flow velocity of 0.5 ml/min, eluent A=acetonitrile+0.1% of formic acid, B=water+0.1% of formic acid, gradient of 0.0 min 5% A → 1 min 5% A → 5 min 90% A → 6 min 90% A.

A common way to obtain oxazolidinones General formula B solid-phase synthesis of Interaction associated with different resin products proceeded without stepwise selection in separate reaction vessels.

In 70 ml of dimethyl sulfoxide was dissolved 1.2 g of (3.75 mmole) 5-(methyl bromide)-3-(4-fluoro-3-nitrophenyl)-1,3-oxazolidin-2-it is A (obtained from epibromohydrin and 4-fluoro-3-nitrophenylacetate with bromide whether the Oia and tributyltinoxide in xylene by analogy with U.S. patent No. 4128654, example 2) and at 1.91 ml (4,13 mmole) of diisopropylethylamine, add secondary amine (1.1 equivalent of amine component 1) and provide interaction for 5 hours at a temperature of 55°C. To this solution was added the resin TentaGel Sam (5,00 g, 0.25 mmol/g) and the reaction incubated for 48 hours at 75°C. the Resin is filtered off and repeatedly washed with methanol, dimethylformamide, methanol, dichloromethane and diethyl ether and dried. The resin (5,00 g) is suspended in dichloromethane (80 ml), added diisopropylethylamine (10 equivalents) and the acid chloride of 5-chlorothiophene-2-carboxylic acid [obtained by the reaction of 5-chlorothiophene-2-carboxylic acid (5 equivalents) of 1-chloro-1-dimethylamino-2-methylpropanol (5 equivalents) in dichloromethane (20 ml) at room temperature for 15 minutes] and leave for 5 hours at room temperature for reaction. The resulting resin is filtered off and repeatedly washed with methanol, dichloromethane and diethyl ether and dried. After that, the resin is suspended in a mixture of dimethylformamide and water (volume ratio of 9:2, 80 ml), added dihydrate tin dichloride (5 equivalents) and provide interaction for 18 hours at room temperature. The resin is again washed repeatedly with methanol, dimethylformamide, water, methanol, dichloromethane and diethyl ether and dried. This resin with spenderat in dichloromethane, add diisopropylethylamine (10 equivalents) and at 0°add the acid chloride of acid (5 equivalents derived acid 1) and the reaction left overnight at room temperature. Carboxylic acid before the interaction is translated into the corresponding acid chlorides by the action of 1-dimethylamino-1-chloro-2-methylpropene (1 equivalent based on carboxylic acid) in dichloromethane at room temperature for 15 minutes. Resin was repeatedly washed with dimethylformamide, water, dimethylformamide, methanol, dichloromethane and diethyl ether and dried. In the case of use as derived acid 1 amino acids with 9-fluorenylmethoxycarbonyloxy protective group, the protective group at the last stage of the reaction is removed by the action of piperidine in dimethylformamide (volume ratio of 1/4) at room temperature for 15 minutes, and the resin washed with dimethylformamide, methanol, dichloromethane and diethyl ether and dried. After that, the product otscheplaut from the solid phase triperoxonane acid in dichloromethane (volume ratio 1:1), the resin is filtered and evaporated, the reaction solutions. Raw food is filtered through silica gel (dichloromethane and methanol in the ratio 9:1) and evaporated to obtain a portion of the products B.

By way of solid-phase synthesis get the following connection.

Example 172

N - [(3-{3-(β-Alaninemia)-4-[(3-hydroxypropyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophencarboxylic

By analogy with the General method of obtaining derivatives of B spend interaction 5 g (1.25 mmole) of resin TentaGel SAM with azetidinol as amine derivative 1 and protected fluorenylmethoxycarbonyl group β-alanine as a function of acid 1. Obtained after removal of the crude product is stirred for 48 hours in methanol at room temperature and evaporated to dryness. This crude product was then purified by HPLC with treatment phases, using a gradient mixture of water, triperoxonane acid and acetonitrile.

Range1H-NMR (400 MHz, watermethanol): 2,31 (TT, 2H), on 3.36 (t, 2H), 3,54 (t, 2H), 3,62 (t, 2H), 3.72 points Shostakovich, 1H), 3,79 (Shostakovich, 1H), 4,01 (Shostakovich, 1H), 4,29 (Shostakovich, 2H), 4,43 (t, 2H), 4,85-of 4.95 (m, 1H), 7,01 (D., 1H), 4,48-of 7.55 (m, 2H), to 7.61 (D., 1H), 7,84 (D., 1H).

Example 173

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

By analogy with the General method of obtaining derivatives of B spend the interaction of 130 mg (32.5 mmol) of resin TentaGel SAM with tert.-butyl-3-pyrrolidinylcarbonyl as amine derivative 1. Received after the acyl is of the 5-fortifikatsionnoy acid derivative of nitrobenzene otscheplaut from the solid phase and evaporated. This crude product was then purified by HPLC with treatment phases, using a gradient mixture of water, triperoxonane acid and acetonitrile.

Range1H-NMR (400 MHz, watermethanol): 2,07-2,17 (m, 1H), 2,39-2,49 (m, 1H), 3,21 is 3.40 (m, 2H), 3.45 points (Shostakovich, 1H), 3,50-3,60 (m, 1H), 3,67 (Shostakovich, 1H), 3,76 (Shostakovich, 1H), 3,88-4,00 (m, 2H), 4,14-is 4.21 (t, 1H), 4,85-of 4.95 (m, 1H), 7,01 (D., 1H), 7,11 (D., 1H), 7,52 (D., 1H), 7,66 (Shostakovich, 1H), 7,93 (D., 1H).

Example 174

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

By analogy with the General method of obtaining derivatives of B spend the interaction of 130 mg (32.5 mmol) of resin TentaGel SAM with pyrrolidine as amine derivative 1 and acetylchloride as derived acid 1. The crude product is stirred with ethyl acetate and sodium bicarbonate solution, the organic phase is vymalivayut sodium chloride, decanted and evaporated to dryness. This crude product is purified by vacuum flash chromatography on silica gel (mixture of dichloromethane and ethyl acetate in ratios from 1:1 to 0:1).

Range1H-NMR (400 MHz, watermethanol): 1,93-2,03 (wide band, 4H), of 2.16 (s, 3H), 3,20-3,30 (wide band, 4H), 3,70 (D., 2H), 3,86 (Shostakovich, 1H), 4,10 (Shostakovich, 1H), 4,14 (Shostakovich, 1H), 4.80 to the 4.90 (m, 1H), 7,00 (D., 1H), 7,07 (D., 1H), 7,31 (Shostakovich, 1H), 7,51 (D., 1H), 7,60 (D., 1H).

By analogy with the General method of obtaining synthesize the following compounds.

All the products of solid-phase synthesis have been characterized using liquid chromatography / mass spectrometry. For this purpose, in accordance with the standard used on the following division: device HP 1100 with UV detector (208-400 nm), the temperature of the heater 40°C, column Waters Symmetry C18 (50 mm × 2.1 mm, 3.5 µm), mobile phase A: 99.9% acetonitrile/0.1% of formic acid, mobile phase B: to 99.9% water/0.1% of formic acid, gradient:

TimeA (%)B (%)Stream
0,0010,090,00,50
4,0090,010,00,50
6,0090,010,00,50
6,1010,090,01,00
7,50 10,090,00,50

Analysis of the substances was carried out using the instrument Micromass Quattro LCZ MS, electrospray ionization (cations/anions).

In the above structures, which contain the remainsorit is always about the functional groupsor

Examples of drugs, we offer drugs
TabletsComposition (mg/tablet
The compound of formula (I), such as example 44, micronized20
Microcrystalline cellulose35
The lactose monohydrate22,9
Croscarmellose (trade product of AC-Di-Sol)3,0
Sodium lauryl sulfate0,5
Magnesium stearate0,6
The viscosity hypromellose 15 SP1,5
Polyethylene glycol with molecular weight of 33500,5
Titanium dioxide0,5
84,5

Obtaining tablets

the Hypromellose and sodium lauryl sulfate dissolved in water. In the obtained suspended solution of the compound of formula (I) as active substance. Thus obtained suspension nabryzgivajut method of granulation in a fluidized bed with a mixture consisting of microcrystalline cellulose, lactose monohydrate and croscarmelose.

After drying and sieving through a sieve with openings of 0.8 mm) of the obtained granulate add magnesium stearate and mix. Thus obtained mixture is pressed into tablets with a diameter of 6 mm, the Subsequent coating of the tablets are carried out with titanium dioxide, which is suspended in the aqueous solution hydroxypropylmethylcellulose and polyethylene glycol.

The granulesThe composition of the granulate in mg/capsule
The compound of formula (I), for example, example 112, micronized20,0
Microcrystalline cellulose30,0
The lactose monohydrate79,5
Corn starch25,0
The hypromellose4,5
Sodium lauryl sulfate0,5
Highly dispersed silicon dioxide (trade product Aerosoil 200)0,5
160,00

Obtaining granules

The hypromellose and sodium lauryl sulfate dissolved in water. In the obtained suspended solution of the compound of formula (I) as active substance. Thus obtained suspension nabryzgivajut method of granulation in a fluidized bed with a mixture consisting of microcrystalline cellulose, lactose monohydrate and corn starch.

After drying and sieving through a sieve with openings of 0.8 mm) of the obtained granulate add highly dispersed silicon dioxide and mixed. The obtained mixture in an amount of 160 mg fill in capsules of hard gelatin size 2.

1. Substituted oxazolidinone General formula (I)

where R1means thiophene (thienyl), which may be condensed with benzene and which can be from one to several times substituted by a residue from the group of halogen atom and an alkyl group with the number of carbon atoms of from one to eight, unsubstituted or one to several times substituted by halogen atoms,

R2means one of the following groups:

A-, D-M-A-In-M-A-, b-, b-M-B-, D-M-B-, and residue And means aryl group with the number of carbon atoms from six to fourteen, preferably aryl group with the number of carbon atoms from six to ten, the company and phenyl group, balance means a five - or six-membered aromatic heterocycle containing up to three heteroatoms and/or chain-based heteroatoms, in particular it contains up to two heteroatoms and/or links in the chain based on heteroatoms from the series: the sulfur atom, nitrogen atom and oxygen atom

the residue D is the residue of a saturated mono - or bicyclic heterocycle with the number of members in the cycle from four to nine, which may be condensed with benzene and which contains up to three heteroatoms and/or links in the chain based on heteroatoms from the series: the sulfur atom, sulfonylurea, sulfonylurea group, the nitrogen atom and the oxygen atom, the remainder of the M stands for the group-NH-, -CH2, -CH2CH2-, -CONH-, -NHCO-, -SO2or does it mean covalent bond,

while the above groups a, b and D in each case can be from one to several times substituted by a residue from the group of halogen atoms, triptorelin group, oxoprop, cyano, a nitro-group, carnemolla group, alcoolica group with the number of carbon atoms in the alkyl residue of from one to six, hydroxyethylpyrrolidine group with the number of carbon atoms in the hydroxyalkyl residue from one to four, the group-COOR27, -C(NR27R28)=NR29, -CONR28R29, -SO2NR28R29, -OR30, -NR30R31 , an alkyl group with the number of carbon atoms of from one to six and cycloalkyl group with the number of carbon atoms from three to seven,

R27, R28and R29identical or different, independently of one another mean a hydrogen atom or alkyl group with the number of carbon atoms one to four,

and/or R28and R29along with connecting the nitrogen atom form a saturated or partially unsaturated six-membered heterocycle comprising up to three, preferably up to two nitrogen atoms, and

R30and R31identical or different, independently of one another denote an alkyl group with the number of carbon atoms one to four,

R3, R4, R5, R6, R7and R8means a hydrogen atom,

and their pharmaceutically acceptable salts, hydrates, hydrates of the salts, excluding the compounds of General formula (I)where the remainder R1means unsubstituted 2-titanovyi residue and remainder R2means from one to several times substituted phenyl residue and simultaneously each of the residues R3, R4, R5, R6, R7and R8means a hydrogen atom.

2. Substituted oxazolidinone General formula (I) according to claim 1, in which R1mean 2-thiophene, which may be from one to several times substituted the volumes of halogen, preferably chlorine or bromine, or alkyl group with carbon atoms of from one to eight, preferably methyl group, and the alkyl residue with the number of carbon atoms of from one to eight can be, in turn, from one to several times substituted by halogen atoms, preferably fluorine, R2means one of the following groups:

A-, D-M-A-In-M-A-, b-, b-M-B-, D-M-B-, and residue And means aryl group with the number of carbon atoms from six to fourteen, preferably aryl group with the number of carbon atoms from six to ten, in particular phenyl group, a residue means a five - or six-membered aromatic heterocycle containing up to three heteroatoms and/or chain-based heteroatoms, in particular it contains up to two heteroatoms and/or links in circuit-based heteroatoms from the series: the sulfur atom, nitrogen atom and oxygen atom, residue D is the residue of a saturated heterocycle with the number of members in the cycle from four to seven, containing up to three heteroatoms and/or links in the chain based on heteroatoms from the series: the sulfur atom, sulfonylurea, sulfonylurea group, the nitrogen atom and the oxygen atom

the remainder of the M stands for the group-NH-, -CH2-, -CH2CH3-, -CONH-, -NHCO - or means covalent bond,

while the above groups a, b and D each from the preliminary case may be from one to several times substituted by a residue from the group of halogen atoms, triptorelin group, oxoprop, cyano, a nitro-group, carnemolla group, alcoolica group with the number of carbon atoms in the alkyl residue of from one to six, the group-COOR27, -C(NR27R28)=NR29, -CONR28R29, -SO2NR28R29, -OR30, -NR30R31, an alkyl group with the number of carbon atoms of from one to six and cycloalkyl group with the number of carbon atoms from three to seven,

R27, R28and R29identical or different, independently of one another mean a hydrogen atom, alkyl group with the number of carbon atoms one to four, and/or

R28and R29along with connecting the nitrogen atom form a saturated or partially unsaturated six-membered heterocycle comprising up to three, preferably up to two nitrogen atoms,

R30and R31identical or different, independently of one another denote an alkyl group with the number of carbon atoms one to four,

R3, R4, R5, R6, R7and R8means a hydrogen atom,

and their pharmaceutically acceptable salts, hydrates and hydrates of salts, excluding the compounds of General formula (I)where the remainder R1means unsubstituted 2-titanovyi residue and remainder R2means from one to discolicious substituted phenyl residue and simultaneously each of the residues R 3, R4, R5, R6, R7and R8means a hydrogen atom.

3. Substituted oxazolidinone General formula (I) according to claim 1, in which R1mean 2-thiophene, which may be from one to several times substituted by halogen atoms, preferably chlorine or bromine, or alkyl group with carbon atoms of from one to eight, preferably methyl group, and the alkyl residue with the number of carbon atoms of from one to eight can be, in turn, from one to several times substituted by halogen atoms, preferably fluorine, R2means one of the following groups:

A-, D-M-A-In-M-A-, b-, b-M-B-, D-M-B-, and the remainder indicates a phenyl group,

balance means a five - or six-membered aromatic heterocycle containing up to two heteroatoms from the series: the sulfur atom, nitrogen atom and oxygen atom

the residue D is the residue of a saturated five - or six-membered heterocycle containing up to two heteroatoms and/or links in the chain based on heteroatoms from the series: the sulfur atom, sulfonylurea, sulfonylurea group, the nitrogen atom and the oxygen atom

the remainder of the M stands for the group-NH-, -CONH-, -NHCO - or means covalent bond,

while the above groups a, b and D in each case can be from one to several times substituted by a residue isgroup: halogen atoms, triptorelin group, oxoprop, cyano, alcoolica group with the number of carbon atoms in the alkyl residue of from one to three, group-C(NR27R28)=NR29, -CONR28R29, -SO2NR28R29the group-NR30R31, an alkyl group with the number of carbon atoms one to four, cyclopropyl, cyclopentene or tsiklogeksilnogo group,

R27, R28and R29identical or different, independently of one another mean a hydrogen atom, alkyl group with the number of carbon atoms one to four

and/or R28and R29along with connecting the nitrogen atom form a saturated or partially unsaturated six-membered heterocycle comprising up to two nitrogen atoms,

R30and R31identical or different, independently of one another denote an alkyl group with the number of carbon atoms one to four,

R3, R4, R5, R6, R7and R8means a hydrogen atom,

and their pharmaceutically acceptable salts, hydrates and hydrates of salts, excluding the compounds of General formula (I)where the remainder R1means unsubstituted 2-titanovyi residue and remainder R2means from one to several times substituted phenyl residue and simultaneously each of the residues R3, 4, R5, R6, R7and R8means a hydrogen atom.

4. Substituted oxazolidinone General formula (I) according to claim 1, in which R1mean 2-thiophene, which may be substituted in the 5-position residue from the group of chlorine, bromine, methyl or triptorelin group, R2means one of the following groups:

A-, D-M-A-In-M-A-, b-, b-M-B-, D-M-B-, and the remainder indicates a phenyl group,

balance means a five - or six-membered aromatic heterocycle containing up to two heteroatoms from the series: the sulfur atom, nitrogen atom and oxygen atom

the residue D is the residue of a saturated five - or six-membered heterocycle that includes the nitrogen atom and may contain another heteroatom and/or link in the chain based on heteroatoms from the series: the sulfur atom, sulfonylurea, sulfonylurea group and the oxygen atom

the remainder of the M stands for the group-NH-, -CONH-, -NHCO - or means covalent bond,

while the above groups a, b and D in each case can be from one to several times substituted by a residue from the group of halogen atoms, triptorelin group, oxoprop, cyano, alcoolica group with the number of carbon atoms in the alkyl residue of one to three group-CONR28R29, -SO2NR28R29the group-NR30R31, an alkyl group with the number of the volumes of carbon from one to four, cyclopropyl, cyclopentene or tsiklogeksilnogo group,

R28and R29identical or different, independently of one another mean a hydrogen atom or alkyl group with the number of carbon atoms one to four,

and/or R28and R29along with connecting the nitrogen atom form a saturated or partially unsaturated six-membered heterocycle comprising up to two nitrogen atoms,

R30and R31identical or different, independently of one another denote an alkyl group with the number of carbon atoms one to four, R3, R4, R5, R6, R7and R8means a hydrogen atom,

and their pharmaceutically acceptable salts, hydrates and hydrates of salts, excluding the compounds of General formula (I)where the remainder R1means unsubstituted 2-titanovyi residue and remainder R2means from one to several times substituted phenyl residue and simultaneously each of the residues R3, R4, R5, R6, R7and R8means a hydrogen atom.

5. Substituted oxazolidinone General formula (I) according to claim 1, in which R1mean 2-thiophene, which may be substituted in the 5-position residue from the group of chlorine, bromine, methyl or triptorelin group, R2mean D-A-, and the remainder And means phenylene is a new group,

the remainder of D means a saturated five - or six-membered heterocycle which is linked to And through the nitrogen atom and which in the immediate vicinity of the linking nitrogen atom is a carbonyl group and in which the carbon atom in the cycle can be replaced by a heteroatom from the series: the atom of sulphur, nitrogen and oxygen,

moreover, the above group in meta-position with respect to the junction with the oxazolidinone can be from one to two times substituted by a residue from the group of fluorine atoms, chlorine, nitro-group, amino group, triptorelin group, methyl group, or cyano,

R3, R4, R5, R6, R7and R8means a hydrogen atom,

and their pharmaceutically acceptable salts, hydrates and hydrates of salts.

6. Substituted oxazolidinone according to claim 1, which represents a compound of formula

and its pharmaceutically acceptable salts, hydrates and hydrates of salts.

7. The method of obtaining substituted oxazolidinones General formula (I) according to claim 1 by reacting compounds of General formula (II)

in which R2, R3, R4, R5, R6, R7and R8have given in claim 1 values, with a carboxylic acid of General formula (III)

in which the residue R1has given in claim 1 value

or conduct liaison with relevant galogenangidridy carboxylic acid, preferably the acid chloride of carboxylic acid, or with a corresponding symmetric or mixed carboxylic acid anhydride, representing derivatives of the above carboxylic acids of General formula (III), in an inert solvent in the presence of, if necessary, activating agent or condensing means and/or grounds, and in those cases where R2means saturated cyclic hydrocarbon residue with the number of members in a cycle of three to seven, including one or more identical or different heteroatoms from the group of nitrogen or sulfur, the compound obtained is subjected to oxidation with a selective oxidizing agent to the corresponding sulfinil, sulfone or N-oxide,

and/or in cases where the molecule of the compounds of formula (I) include cyano, cyano this can be turned into amedieval group,

and/or in cases where the molecule of the compounds of formula (I) comprises the amino group with tert.-butoxycarbonyl protection, this protective group can be split in the usual way,

and/or in cases where the molecule is perceived by the tion of the compounds of formula (I) include aniline or benzylamine residue, this amino group can be subjected to interaction with various reagents, for example, with carboxylic acids, anhydrides of carboxylic acids, carboxylic acid anhydrides, isocyanates, chlorides of sulfonic acids or alkylhalogenide with the formation of corresponding derivatives, in cases where the molecule of the compounds of formula (I) include phenyl residue, this residue can be subjected to interaction with chlorosulfonic acid and then with amines with formation of the corresponding sulfonamides.

8. The method of obtaining substituted oxazolidinones General formula (I) according to claim 1, where the compound of General formula (IV)

where the residues R1, R3, R4, R5, R6, R7and R8have given in claim 1 values, under the action of a suitable selective oxidizing agent in an inert solvent is transferred into the corresponding epoxide of General formula (V)

where the residues R1, R3, R4, R5, R6, R7and R8have given in claim 1 values, which are then subjected to interaction with the amine of General formula (VI)

where

the remainder R2has given in claim 1 is, in an inert solvent in the presence of the tvii, if necessary, a catalyst, and first get the connection of General formula (VII)

where the residues R1, R2, R3, R4, R5, R6, R7and R8have given in claim 1 values, which are then subjected to cyclization in an inert solvent in the presence of phosgene or phosgene equivalent to substances, such as carbonyldiimidazole, with the formation of compounds of General formula (I), and in those cases where R2means saturated cyclic hydrocarbon residue with the number of members in a cycle of three to seven, including one or more identical or different heteroatoms from the group of nitrogen or sulfur, the compound obtained is subjected to oxidation with a selective oxidizing agent to the corresponding sulfinil, sulfone or N-oxide,

and/or in cases where the molecule of the compounds of formula (I) include cyano, cyano this can be turned into amedieval group,

and/or in cases where the molecule of the compounds of formula (I) comprises the amino group with tert.-butoxycarbonyl protection, this protective group can be split in the usual way,

and/or in cases where the molecule of the compounds include aniline or benzylamine balance, this amino group which can be subjected to interaction with various reagents, for example, with carboxylic acids, anhydrides of carboxylic acids, carboxylic acid anhydrides, isocyanates, chlorides of sulfonic acids or alkylhalogenide with the formation of corresponding derivatives,

and/or in cases where the molecule of the obtained compound include phenyl residue, this residue can be subjected to interaction with chlorosulfonic acid and then with amines with formation of the corresponding sulfonamides.

9. The use of substituted oxazolidinones General formula (A)

in which R9means unsubstituted 2-titanovyi the rest,

R10means phenyl, unsubstituted or substituted by 1-3 residues from the group comprising chlorine, bromine, fluorine, methoxy, trifluoromethyl,

or their pharmaceutically acceptable salts, hydrates, hydrates of the salts, as a means of selectively inhibiting factor XA and having an antithrombotic effect.

10. Drug selectively inhibiting factor XA and having antithrombotic action, containing at least one compound of General formula (I) according to one of claims 1 to 5, along with one or more pharmacologically acceptable excipients or carriers or at least one compound of the substituted oxazolidinones General form is s (A) according to claim 9, along with one or more pharmacologically acceptable excipients or carriers.



 

Same patents:

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (1): and their salts wherein values R1, k, Ar, n, j, Y, R and R2 are determined in the invention claim. Novel compounds are able to modulate activity of chemokine receptors. Also, invention relates to using indicated compounds for treatment of human immunodeficiency virus or feline immunodeficiency virus and to a pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 100 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds represented by the general formula (I): and their pharmaceutically acceptable salts and esters possessing agonistic activity with respect to peroxisome proliferator receptors PPARα and/or PPARγ, to a pharmaceutical composition based on thereof and their using for preparing medicines wherein R1 means thiophenyl or phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkoxy-group, (C1-C8)-alkyl and (C1-C8)-alkyl substituted with one-three halogen atoms; R2 means hydrogen atom or (C1-C8)-alkyl; R3 means phenoxy-, (C2-C8)-alkenyloxy- or (C1-C8)-alkoxy-group; R4 means hydrogen atom or (C1-C8)-alkyl wherein one of substitutes R5 and R6 means compound of the formula and another one means hydrogen atom and wherein the bond between carbon atoms Ca and Cb means a carbon-carbon simple or double bond; R7 means hydrogen atom or (C1-C8)-alkyl; R8 means hydrogen atom or (C1-C8)-alkyl being any of A and A1 means nitrogen atom and another means oxygen or sulfur atom; n means 1, 2 or 3.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

30 cl, 1 tbl, 14 sch, 86 ex

FIELD: organic chemistry, chemical technology, insecticides.

SUBSTANCE: invention relates to derivatives of N-heteroaryl-4-(halogenalkyl)nicotinamide represented by the general formula (I): wherein R represents (C1-C6)-alkyl group that can be substituted with one or some halogen atoms; R1 represents hydrogen atom, (C1-C6)-alkyl group that can be substituted with one or some substituted chosen from group of substitutes A, (C2-C6)-alkenyl group or acyl group; X represents group of the formula -C-R2 or nitrogen atom; each among R2 and R3 represents independently hydrogen atom, halogen atom, (C1-C6)-alkyl group that can be substituted with one or some substitutes chosen from group of substitutes A, (C3-C7)-cycloalkyl group, (C2-C6)-alkenyl group, (C3-C7)-cycloalkenyl group, formyl group, group of the formula: -CH=NOR4 (wherein R4 represents hydrogen atom or (C1-C6)-alkyl group, cyano-group, phenyl group that can be substituted with one or some substitutes chosen from group of substitutes B, 5- or 6-membered heterocyclic group (heterocycle comprising 1-2 heteroatoms that are similar and chosen from nitrogen atom), (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group or phenoxy-group. The group of substitutes A represents group consisting of halogen atom, (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group, cyano-group and phenyl group. The group of substitutes B represents group consisting of halogen atom, (C1-C6)-alkyl group that can be substituted with one or some substitutes chosen from above given group of substitutes A, (C1-C6)-alkoxy-group that can be substituted with one or some substitutes chosen from above given group of substitutes A, or its salt. Also, invention relates to insecticide comprising a derivative of N-heteroaryl-4-(halogenalkyl)nicotinamide or its salt as an active component and a carrier optionally. Also, invention relates to a method for synthesis of derivative of N-heteroaryl-4-(halogenalkyl)nicotinamide. Invention provides synthesis of derivatives of N-heteroaryl-4-(halogenalkyl)nicotinamide possessing the high insecticide activity.

EFFECT: improved method of synthesis, valuable properties of derivatives.

18 cl, 3 tbl, 91 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 18 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (1): wherein Y means -O-, -S- or -N(R2)- wherein R2 means hydrogen atom, (C1-C10)-alkyl or aralkyl; Z means 2,5-furanyl, 2,5-thiophenyl, 4,4'-stilbenyl or 1,2-ethyleneyl residue; R1 means hydrogen or halogen atom, (C1-C10)-alkyl, (C1-C10)-alkoxy-group, cyano-group, -COOM or -SO3M wherein M means hydrogen atom or alkaline or alkaline-earth metal atom. Method for synthesis involves carrying out the reaction of compound of the formula (2): with dicarboxylic acid of the formula: HOOC-Z-COOH (3) or with it ester wherein Y, Z and R1 have values given above in N-methylpyrrolidone or N,N-dimethylacetamide medium in the presence of an acid catalyst and optionally in the presence of an accessory solvent able to remove water from the reaction mixture.

EFFECT: improved method of synthesis.

11 cl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of sulfonamide of the general formula (I): wherein A means a substitute chosen from 5- or 6-membered heteroaromatic ring comprising 1 or 2 heteroatoms chosen from oxygen (O), nitrogen (N) or sulfur (S) optionally substituted with 1 or 2 halogen atoms, (C1-C4)-alkyl or phenyl radical, or 5- or 6-membered heteroaryl radical comprising 1 or 2 atoms of O, N or S; bicyclic heteroaromatic ring comprising from 1 to 3 heteroatoms chosen from O, N or S and optionally substituted with 1 or 2 halogen atoms or (C1-C4)-alkyl; R1 means hydrogen atom (H), (C1-C4)-alkyl, benzyl; n means 0, 1, 2, 3 or 4; R2 means -NRR5 or the group of the formula: wherein a dotted line means optional chemical bond; R, R4 and R5 mean independently H or (C1-C4)-alkyl; or one of its physiologically acceptable salts. Compounds of the formula (1) possess antagonistic activity with respect to serotonin HT6-receptors that allows their using in pharmaceutical composition and for preparing a medicament.

EFFECT: valuable medicinal properties of derivatives and pharmaceutical composition.

10 cl, 2 tbl, 7 ex

FIELD: organic chemistry, anti-microbial preparations.

SUBSTANCE: invention relates to compounds useful as anti-microbial agents. Claimed compounds are effective against to certain human and animal pathogens, including Gram-positive aerobic bacteria such as multi-resistant staphylococcus, streptococcus and enterococcus, as well as anaerobic organisms such as species Bacterioides spp. and Clostridia spp., and acid resistant organisms such as Mycobacterium tuberculosis, Mycobacterium avium, and Mycobacterium spp.

EFFECT: new anti-microbial agents.

2 ex, 5 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel class of 5-membered heterocyclic compounds of the general formula (I): or cosmetically acceptable salts. Invention describes a compound represented by the formula (I) and its pharmaceutically or cosmetically acceptable salt wherein R1 is chosen from linear or branched (C1-C12)-alkyl, (C3-C7)-cycloalkyl, phenyl, naphthyl, C3-, C4-, C5- or C8-heteroaryl wherein one or some heteroatoms when they present are chosen independently from oxygen (O), nitrogen (N) or sulfur (S) atom and substituted optionally wherein substitutes are chosen from the first group comprising halogen atom, hydroxy0, nitro-, cyano-, amino- oxo-group and oxime, or from the second group comprising linear or branched (C1-C8)-alkyl wherein a substitute from indicated second group is optionally substituted with R10, or wherein heteroaryl is substituted with -CH2-C(O)-2-thienyl; Y is absent or chosen from the group consisting of (C1-C12)-alkyl-Z or (C2-C8)-alkyl wherein Z is chosen from sulfur, oxygen or nitrogen atom; A and B are chosen independently from nitrogen atom (N), -NH, -NR6, sulfur, oxygen atom to form heteroaromatic ring system; R2, R3 and R4 are chosen independently from the first group comprising hydrogen, halogen atom, or R3 and R4 form phenyl ring in adjacent positions; R5 is absent or chosen from the group comprising -CH2-phenyl, -CH2(CO)R7, -CH2(CO)NHR8 and -CH2(CO)NR8R9 that are substituted optionally with R10; R6, R7, R8 and R are chosen independently from the group comprising linear or branched (C1-C8)-alkyl, (C3-C7)-cycloalkyl, C5-heterocycloalkyl, benzylpiperidinyl, phenyl, naphthyl, heteroaryl, alkylheteroaryl, adamantyl, or R8 and R9 form piperidine ring, and R means 3,4-ethylenedioxyphenyl wherein substitutes in indicated group are substituted optionally with R10, and heteroaryl means C3-, C4-, C5- or C8-heteroaryl wherein one or some heteroatom when they present are chosen independently from O, N or S; R10 is chosen from halogen atom, hydroxy-, nitro-, cyano-, amino-, oxo-group, perhalogenalkyl-(C1-C6) or oxime; X means halide ion under condition that when groups/substitutes present at the same or at adjacent carbon or nitrogen atoms then can form optionally 5-, 6- or 7-membered ring optionally containing one o some double bonds and containing optionally one or some heteroatoms chosen from O, N or S. Also, invention describes a method for synthesis of these compounds, their therapeutic and cosmetic using, in particular, in regulation of age and diabetic vascular complications. Proposed compounds show effect based on the triple effect as agent destroying AGE (terminal products of enhanced glycosylation), inhibitors of AGE and scavengers of free radicals that do their suitable in different therapeutic and cosmetic using. Also, invention relates to pharmaceutical and cosmetic compositions comprising these compounds and to methods for treatment of diseases caused by accumulation of AGE and/or free radicals in body cells. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds.

73 cl, 4 tbl, 63 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1):

and their salts wherein ring A comprises optionally heteroatom oxygen (O); dotted lines represent the optional unsaturation; R1 represents (C1-C4)-alkoxy-group; R2 and R3 represent independently hydrogen atom (H), optionally halogenated (C1-C4)-alkyl, optionally substituted aromatic group, or R2 and R3 in common can form substituted or unsubstituted 5-7-membered ring condensed with ring E; k = 0-4; L1 represents a covalent bond or (C1-C6)-alkyl optionally comprising nitrogen atom (N); X represents unsubstituted or substituted carbon © atom or N, or represents O or sulfur (S) atom; Ar represents phenylene; each n = 0-2 independently; each R represents independently H or (C1-C6)-alkyl; Y represents optionally substituted aromatic or heteroaromatic group or 5-11-membered heterocyclic group comprising 1-4 heteroatoms cgosen from N, O and S that are bound with chemokine receptors comprising CXCR4 and CCR5, and elicit the protective affect against damage of host-cells by human immunodeficiency virus (HIV).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

FIELD: organic chemistry, chemical technology, insecticides.

SUBSTANCE: invention relates to derivatives of N-heteroaryl-4-(halogenalkyl)nicotinamide represented by the general formula (I): wherein R represents (C1-C6)-alkyl group that can be substituted with one or some halogen atoms; R1 represents hydrogen atom, (C1-C6)-alkyl group that can be substituted with one or some substituted chosen from group of substitutes A, (C2-C6)-alkenyl group or acyl group; X represents group of the formula -C-R2 or nitrogen atom; each among R2 and R3 represents independently hydrogen atom, halogen atom, (C1-C6)-alkyl group that can be substituted with one or some substitutes chosen from group of substitutes A, (C3-C7)-cycloalkyl group, (C2-C6)-alkenyl group, (C3-C7)-cycloalkenyl group, formyl group, group of the formula: -CH=NOR4 (wherein R4 represents hydrogen atom or (C1-C6)-alkyl group, cyano-group, phenyl group that can be substituted with one or some substitutes chosen from group of substitutes B, 5- or 6-membered heterocyclic group (heterocycle comprising 1-2 heteroatoms that are similar and chosen from nitrogen atom), (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group or phenoxy-group. The group of substitutes A represents group consisting of halogen atom, (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group, cyano-group and phenyl group. The group of substitutes B represents group consisting of halogen atom, (C1-C6)-alkyl group that can be substituted with one or some substitutes chosen from above given group of substitutes A, (C1-C6)-alkoxy-group that can be substituted with one or some substitutes chosen from above given group of substitutes A, or its salt. Also, invention relates to insecticide comprising a derivative of N-heteroaryl-4-(halogenalkyl)nicotinamide or its salt as an active component and a carrier optionally. Also, invention relates to a method for synthesis of derivative of N-heteroaryl-4-(halogenalkyl)nicotinamide. Invention provides synthesis of derivatives of N-heteroaryl-4-(halogenalkyl)nicotinamide possessing the high insecticide activity.

EFFECT: improved method of synthesis, valuable properties of derivatives.

18 cl, 3 tbl, 91 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

FIELD: organic chemistry, anti-microbial preparations.

SUBSTANCE: invention relates to compounds useful as anti-microbial agents. Claimed compounds are effective against to certain human and animal pathogens, including Gram-positive aerobic bacteria such as multi-resistant staphylococcus, streptococcus and enterococcus, as well as anaerobic organisms such as species Bacterioides spp. and Clostridia spp., and acid resistant organisms such as Mycobacterium tuberculosis, Mycobacterium avium, and Mycobacterium spp.

EFFECT: new anti-microbial agents.

2 ex, 5 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted indoles or its pharmaceutically acceptable salts of the formula (I): , wherein R1 means hydrogen (H) atom, halogen atom, -CN, nitro-group, -SO2R4, -OH, -OR4, -SO2NR5R6, -CONR5R6, -COOH, -COOCH3, -NR5R6, phenyl, naphthyl or (C1-C6)-alkyl wherein the latter group is possibly substituted with one or more substitutes chosen independently from halogen atom, -OR8 and -NR5R6 wherein x = 2; R2 means (C1-C7)-alkyl; R3 means phenyl, naphthyl or heteroaryl and each of them is possibly substituted with one or more substitutes chosen independently from H, halogen atom, -CN, -OH, -SO2R4, -OR4, -SO2NR5R6, -CONR5R6, phenyl, naphthyl, (C1-C6)-alkyl wherein the latter group is possibly substituted with one or more substitutes chosen independently from halogen atoms, -OR8 and -NR5R6, -S(O)xR7 wherein x = 2; R4 means (C1-C6)-alkyl; R5 and R6 mean independently H, (C1-C6)-alkyl, or R5 and R6 in common with nitrogen atom to which they are bound can form 6-membered saturated heterocyclic ring comprising one atom chosen from -NR16; R7 means (C1-C6)-alkyl; R8 means H, (C1-C6)-alkyl; R16 means H, -COY-(C1-C4)-alkyl wherein Y means oxygen atom (O) and wherein alkyl group in the substitute group can be direct, branched or cyclic, and wherein heteroaryl means 5-6-membered heteroaromatic ring comprising from 1 to 3 heteroatoms chosen from nitrogen (N), oxygen (O) and sulfur (S) atoms, or means 6,6-condensed bicyclic aromatic ring system comprising one nitrogen atom. Compounds of the formula (I) can be used in production of a medicinal agent used in treatment of asthma and chronic obstructive disease.

EFFECT: valuable medicinal properties of compounds.

7 cl, 2 tbl, 59 ex

FIELD: chemistry of heterocyclic organic compounds, medicine.

SUBSTANCE: invention relates to a novel heterocyclic derivative of the formula (I'): , wherein R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents-CO-C(R4)=C(R4)-R5 wherein R4 represents hydrogen atom; R5 represents (C2-C8)-alkenyl; R3 represents hydrogen atom or (C1-C4)-alkyl; X represents oxygen atom or sulfur atom; R20 represents phenyl substituted with unsubstituted (C1-C6)-alkyl, (C1-C6)-alkyl substituted with fluorine atom, (C1-C4)-alkoxy-group, phenyl-(C1-C4)-alkoxy-group, hydroxyl group, halogen atom, nitro-group, unsubstituted amino-group or amino-group substituted with (C1-C4)-alkyl; n means a whole number from 1 to 4, or to its pharmaceutically acceptable salt. Also, invention relates to heterocyclic derivative of the formula (I): , wherein R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents -CO-C(R4)=C(R4)-R5 wherein R4 represents hydrogen atom; R represents (C4-C8)-alkyl or (C2-C8)-alkenyl or -CO-C≡C-R6 wherein R6 represents (C1-C8)-alkyl; R3 represents hydrogen atom or (C1-C4)-alkyl; X represents oxygen atom or sulfur atom; n means a whole number from 1 to 4, or its pharmaceutically acceptable salt. Compounds of the formulas (I') and (I) are effective as a hypoglycemic agent, hypolipidemic agent, agent improving resistance to insulin, therapeutic agent in treatment of diabetes mellitus, therapeutic agent in treatment of diabetes mellitus complications, agents enhancing tolerance to glucose, anti-arteriosclerotic agent, agents against obesity or agent for X syndrome.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 2 tbl, 56 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 2-phenylaminoimidazoline phenylketone that can be used as IP antagonists. Invention describes 2-phenylaminoimidazoline phenylketone of the general formula (I): wherein R1 mean optionally substituted aryl wherein R1 is optionally substituted with 1, 2 or 3 substitutes chosen independently from series including alkoxy-group, aryl aryloxy-, aralkyloxy-group, halogen atom, ethylenedioxy-group or optionally substituted heterocyclyl that means a monovalent saturated carbocyclic radical comprising from 3 to 7 atoms in cycle and comprising one or two heteroatoms chosen independently from nitrogen and oxygen atoms, and can be optionally substituted with one or more substitutes chosen independently from alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkyl sulfonyl, furanyloxy-group; R2 means hydrogen atom; A means -C(O)-(CH2)n- or -C(O)-CH2-O-; index n means a whole number from 2 to 6, or its pharmaceutically acceptable salt or solvate. Invention provides preparing novel compounds showing useful biological properties.

EFFECT: valuable properties of compounds.

16 cl, 1 tbl, 23 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel amino- and hydroxy-derivatives of phenyl-3-aminomethylquinolone-2 of the general formula (1):

wherein R1, R2, R3 and R4 are independently similar or different and R1 is chosen from hydrogen atom (H), Alk, OAlk; R2 is chosen from H, Alk, OAlk, -OCF3; R3 is chosen from H, Alk, OAlk, -SCH3; R4 is chosen from H. Alk, OAlk, or R2 and R3 are chosen from -(CH2)3, -OCH2O-, -OCH2CH2O-; R5 means H or Alk; R6, R7 and R9 mean H; R8 is chosen independently from the following substitutes:

wherein n = 1, 2, 3; Het represents furan; R represents hydrogen atom or alkyl. In case of hydroxy-derivatives at least one among R6, R7, R8 or R9 is -OH and other represent H. Also, invention relates to methods for synthesis of these compounds and to a pharmaceutical composition based on these compounds inhibiting activity of NO-synthase. Invention provides preparing novel compounds and pharmaceutical compositions based on thereof in aims for treatment of diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

32 cl, 1 tbl, 132 ex

FIELD: medicine, organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of formula I , or pharmaceutically acceptable salt or solvates thereof, wherein X and Z represent CH or N; Y represents O; R1, R2, and R3 are identical or different and represent hydrogen atom, C1-C6-alkoxy; R5 represents hydrogen atom; R5, R6, R7, and R8 are identical or different and represent hydrogen atom, halogen atom, C1-C4-alkyl, trifluoromethyl; R9 and R10 represent hydrogen atom; R11 represents optionally substituted azolyl. Also disclosed are pharmaceutical composition with inhibiting activity in relates to KDR phosphorylation and method for inhibiting of target blood-vessel angiogenesis.

EFFECT: new pharmaceuticals useful in treatment of tumors, diabetic retinopathy, chronic rheumatism, psoriasis, arteriosclerosis, and Kaposi's sarcoma.

33 cl, 5 tbl, 75 ex

FIELD: medicine.

SUBSTANCE: method involves administering Thyroxin at a dose of 50 mg/day in a combination with Metformin at a dose of 500 mg/day, Detralex at a dose of 800 mg/day within a month before forthcoming operation to patients. Low molecular weight heparin is subcutaneously introduced two hours before surgical intervention. Hydroxyethylized starch infusion is carried out at a dose of 0.5-1.0 ml/kg during operation. Low molecular weight heparin is subcutaneously introduced 7 days long after the surgical intervention.

EFFECT: enhanced effectiveness of treatment; prevented thrombogenetic complications and hemodynamic instability; improved metabolic processes in blood platelets, blood vessel walls; decreased thrombophilic orientations of hemostasis system.

2 tbl

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