Oxazolidinone derivatives, method for preparing thereof (versions) and based pharmaceutical composition

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to oxazolidinone derivatives covered by general graphic formula (I) and to their pharmaceutically acceptable salts. In formula (I) R1, R2, R3 and R4 are independently chosen from a group including -H and halogen; A is chosen from a group including R5 and R6 are independently chosen from a group including -H, -F, -CI, -Br, -OH, alkyl(C1-C6), haloalkyl(C1-C6), alkoxygroup(C1-C6); R7 is chosen from a group including -H, alkyl(C1-C6); either R7 and R5 or R6 taken together form a cycle of 2 carbon atoms and include 1 group chosen from O which in turn can be substituted by one substitute chosen from alkyl(C1-C6); R12 is chosen from a group including -H, -COR14, -CSR14, -COOR14; R14 is chosen from a group including alkyl (C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), R16, R17 and R18 represent -H; R21 is chosen from a group including -H, alkyl(C1-C6); X is chosen from a group including O, S, and Y is chosen from a group including O, S, SO, SO2, and NR12; and optional substitutes of alkyl(C1-C6) groups can represent one or two groups chosen from the following: -OR21, -CN.

EFFECT: invention refers to methods for preparing the compounds of the invention, to application of oxazolidinone derivatives for preparing a drug for treating bacterial infections and to a pharmaceutical composition for treating bacterial infections, including a therapeutically effective amount of the compound of the invention.

36 cl, 10 tbl, 44 ex

 

The invention relates to oxazolidinones derived antimicrobial compounds that are active against gram-positive and some gram-negative bacteria in low activity of inhibition of monoamine oxidase (MAO).

The level of technology

Oxazolidinone stand out among new antimicrobial agents aimed at gram-positive organisms, which are now becoming available. Oxazolidinone contact 50S-subunit of prokaryotic ribosomes, preventing the formation of a complex of initiation of protein synthesis. This represents a new mechanism of action. Other inhibitors of protein synthesis or block the elongation of the polypeptide, or cause an erroneous reading of the mRNA. Linezolid (N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide) is the first approved oxazolidinone antimicrobial intended for clinical use in the United States and beyond.

The minimum inhibiting concentration (MIC) of linezolid slightly vary depending on the method of testing laboratories and values attributed to some uncertainties associated with the survival of bacteria, but all researchers find that the sensitivity distribution is narrow and homogeneous values MICK from 0.5 to 4 μg/ml of d is I streptococci, enterococci and staphylococci. Full activity is retained against gram-positive cocci resistant to other antibiotics, including methicillinsensitive staphylococci and vancomycinresistant enterococci. MICK amount of 2-8 μg/ml for Moxarella, Pasteurella spp. and Bacteroides spp., but other gram-negative bacteria are resistant to the activity of endogenous efflux and acquisitions undertaken by an outer cell membrane of gram-negative bacteria.

Linezolid indicated for the treatment of adult patients with the following infections:

nosocomial pneumonia caused by Staphylococcus aureus (metitillinciuvstiveny and-resistant strains) or Streptococcus pneumoniae (including strains with multidrug resistance [MDRSP]). MDRSP refers to isolates resistant to two or more of the following antibiotics: penicillins, cephalosporins second-generation macrolides, tetracyclines and trimethoprim/sulfamethoxazole;

complicated infections of skin and skin structures, including diabetic infection stop without concomitant osteomyelitis, caused by Staphylococcus aureus (metitillinciuvstiveny and-resistant strains), Streptococcus pyogenes or Streptococcus agalactiae;

uncomplicated infections of the skin and skin structures, caused by Staphylococcus aureus (methicillin-sensitive) or Streptococcus pyogenes;

vancomycinresistant info is of Enterococcus faecium, including cases with concurrent bacteremia, and

community-acquired pneumonia caused by Streptococcus pneumoniae (including strains with multidrug resistance [MDRSP]), also in cases with concurrent bacteremia, or caused by Staphylococcus aureus (only metitillinciuvstiveny strains).

Oxazolidinone was originally developed as MAO inhibitors for treatment of depression and Parkinson's disease. MAO is one of the main enzymes that are sensitive to the catabolism of catecholamines. In humans, MAO exists in two isoforms, MAO-a and MAO-Century MAO-AND mostly will desaminase serotonin (5-HT) and norepinephrine; MAO-b will mainly desaminase phenylethylamine, benzylamine and dopamine in men. Typically, MAO inhibitors, such as moclobemide or tranilcipromin, used as an antidepressant, then as MAO inhibitors, such as selegiline, preferably used in the treatment of Parkinson's disease. U.S. patent 3655687 discloses derivatives of 5-hydroxymethyl-3-substituted-2-oxazolidinone with significant antidepressant activity. Refer specifically to the compound disclosed in this patent, toloxatone, 5-(hydroxymethyl)-3-(3-were)-2-oxazolidinone.

Toloxatone is a selective reversible inhibitor of MAO-a and introduced into clinical practice. For this reason, special attention is paid to the issue, is there evidence of harmful interactions with drugs, which are known to be metabolized by monoamine oxidase in patients being treated with linezolid. In patients taking a number of adrenergicheskie, including phenylpropanolamine and pseudoephedrine, see the answer in the form of pressure and specifically noted that patients receiving linezolid, the doses of these drugs should be reduced. Animal studies suggest that linezolid moderate but potentiates the effects of pressure increase of endogenous and food Amin, tiramina and other sympathomimetic amines. The liner in the package for linezolid warns against its combination of rich in tyramine food and informs about potential interaction with adrenergic and serotonergic agents. Consequently, there is a need for new oxazolidinone antimicrobial compounds with minimal activity inhibition of MAO to exclude relevant side effects, potential interactions drug - drug.

Getting linezolid disclosed in PCT application WO 9507271.

The PCT application WO 03084534 discloses a method of treating diabetic infection stop oxazolidinone, especially 3-{4-[1-(2,3-dihydroxy opional)-1,2,3,6-tetrahydropyridine-4-yl] - for 3,5-differenl}-5-(isoxazol-3-intoximeter)-oxazolidin-2-one; 2.2-debtor-N-({(5S)-3-[3-fluoro-4-(4-glycolyl-piperazine-1-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl} methyl) acantholyda and linezolid.

The PCT application WO 03063862 discloses a method of treatment need in this patient the oxazolidinone by introducing an effective amount of oxazolidinone and an effective amount of at least one vitamin selected from the group consisting of vitamin B2, vitamin B6, vitamin B12 and folic acid.

Patent application DE 10105989 and US 2003/0153610 disclose obtain N-((2-oxo-3-phenyl-1,3-oxazolidin-5-yl)-methyl)-heterocyclic amides and their use for inhibiting blood coagulation in vitro, especially canned blood or biological samples, including factor XA. Heterocyclic amides disclosed in US 2003/0153610, limited dianilide, while DE 10105989 focused on N-[[3-[(4-substituted)-phenyl]-2-oxo-5-oxazolidinyl]-methyl]-Amidah with substituents including any oxo-, or N-oxide group. Moreover, these documents do not describe neither antibacterial nor MAO inhibitory activity.

WO 04007489 describes a number oxazolidinone derivatives which possess antibacterial activity against gram-positive and gram-negative bacteria. In this patent application contains a number of limitations, which appeared during the clinical study and application of linezolid and intially members of his class. It is shown that this class of compounds has the potential ability to induce myelosuppression, followed by thrombocytopenia and the inhibition of monoamine oxidase by oxazolidinone has prompted clinicians to recommend the use of representatives of this class with caution during concomitant use of adrenergic or serotonergic agents and selective inhibitors of re-absorption of serotonin.

WO 04089944 describes certain substituted phenyloxazolidine, which are effective antimicrobial agents against a number of human and veterinary pathogens, including gram-positive aerobic bacteria and anaerobic organisms. In this document there is no mention of activity inhibition of monoamine oxidase.

Thus, it is obvious that, in spite of all taken in the past, attempts of research, there remains a need in the search of new effective antibacterial agents with lower side effects than known in the field of engineering.

Disclosure of inventions

The inventors have discovered that compounds of the class disclosed in this application are particularly active antimicrobial agents, showing weak activity inhibition of MAO, which implies a significant reduction to meet the common side effects, due to potential interactions drug - drug. This is unexpected, since the inhibition of monoamine oxidase by oxazolidinone, as it is known, gives a number of side effects and, consequently, the competent person would not seek antibacterial agents with low side effects or lack of it among oxazolidinone derivatives. Moreover, the compounds corresponding to the present invention, showing selective activity against bacteria Staphylococcus compared to Enterococcus bacteria, which is a valuable property in the treatment of diseases that require special antibiotic against Staphylococcus infections such as community-acquired methicillinsensitive Staphylococcus aureus (CA-MRSA), which acquire a position in the community and, apparently, moving to epidemic levels in the United States according to recent research.

In General, the present invention is the evidence that the new compound N-[[(3-[4-substituted phenyl]-2-oxo-5-oxazolidinyl]methyl]-amine, have specific activity against gram-positive human and veterinary pathogens with weak activity of inhibiting monoamine oxidase.

The present invention describes a new class oxazolidinones roizvodnykh compounds, covered by the General structural formula (I):

or their pharmaceutically acceptable salts, where A, R1R2, R3and R4X and Y are defined below, which are antibacterial agents, which are specifically active against gram-positive and some gram-negative human and veterinary pathogens with weak activity of inhibition of monoamine oxidase (MAO).

Another object of this invention is the development of synthetic methods for obtaining these derivatives. Another object of the present invention relates to the use of compounds of formula (I) or their pharmaceutically acceptable salts to obtain medicines for treatment of bacterial infections in a mammal, including man. The latter can alternatively be formulated as a method of treatment of a mammal, including man, suffering from a bacterial infection by administration of a therapeutically effective amount of compounds of formula (I) or their pharmaceutically acceptable salts.

The implementation of the invention

The present invention relates to new oxazolidinones compounds of formula (I):

where R1R2, R3and R4independently from each other selected from H and halogen; a is selected from the group consisting of

R5and R6independently from each other selected from the group consisting of-H, -F, -Cl, -Br, -OH, -NO2, -CN, -CF3, -COR8, -CSR8, -SO2R8, -OCOR8, alkyl(C1-C6), halogenoalkane(C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), quinil(C2-C6), alkoxygroup(C1-C6), alkoxy(C1-C6)alkyl(C1-C6), -N-R21R22and T; or R5and R6, taken together, form a benzo-, pyrido-, furo-, thieno-, oxazolo-, isoxazole-, thiazole-, isothiazole-, pyrrole-, pyrazolo - or imidazolium group, said fused group, in turn, can be substituted by one, two or Tr is two substituents, selected from the group consisting of-F, -Cl, -Br, -OH, -NO2, -CN, -CF3, -COR8, -CSR8, -SO2R8, -OCOR8, alkyl(C1-C6), halogenoalkane(C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), quinil(C2-C6), alkoxygroup(C1-C6), alkoxy(C1-C6)alkyl(C1-C6and-N-R21R22or merged cycle selected from cyclopenta, cyclohexa-, cyclohepta, methylendioxy and Ethylenedioxy, with the specified merged cycle, in turn, can be substituted by one, two or three substituents selected from the group comprising alkyl(C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6and quinil(C2-C6);

R7selected from the group consisting of-H, optionally substituted alkyl(C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), quinil(C2-C6), alkoxygroup(C1-C6), -N-R21R22and T; or R7and R5or R6, taken together, form a, where possible, a series of 2-6 carbon atoms and 1-3 groups selected from O, N, S, SO and SO2that, in turn, can be substituted by one, two or three substituents selected from the group consisting of alkyl(C1-C6), cycloalkyl(C -C6), alkenyl(C2-C6and quinil(C2-C6);

R8selected from the group consisting of-H, alkyl(C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), quinil(C2-C6), alkoxygroup(C1-C6), alkoxy(C1-C6)alkyl(C1-C6), hydroxyalkyl(C1-C6), -N-R21R22and T;

R9and R10independently from each other selected from the group consisting of-H, -CN, -NO2, -COR11, -SO2R11, alkyl(C1-C6), halogenoalkane(C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), quinil(C2-C6), alkoxygroup(C1-C6), alkoxy(C1-C6)alkyl(C1-C6), -N-R21R22and T;

R11selected from the group consisting of-H, -HE, alkyl(C1-C6), halogenoalkane(C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), quinil(C2-C6), alkoxy(C1-C6)alkyl(C1-C6and T;

R12and R13independently from each other selected from the group consisting of-H, -OH, -CHR14R15, -CN, -COR14, CSR14, -COOR14, -CSOR14, -CONR14R15, -CSNR14R15, -CON(R16)N(R14R15, -SO2R14, -SO2OR14, -SO2NR1 R15, alkyl(C1-C6), halogenoalkane(C3-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), alkenyl(C2-C6), quinil(C2-C6), alkoxy(C1-C6)alkyl(C1-C6and T;

R14and R15independently from each other selected from the group consisting of-H, -OH, -COR16, -CSR16, -SO2R16, -NR17R18, optionally substituted alkyl(C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), quinil(C2-C6), alkoxygroup(C1-C6), phenyl,

R16represents-H, -HE, alkyl(C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), quinil(C2-C6), alkoxygroup (C1-C6), alkoxy(C1-C6)-alkyl(C1-C6), hydroxyalkyl(C1-C6and T;

R17and R18independently from each other selected from the group consisting of-H, -OH, -F, -Cl, -Br, -NO2, -CN, -NR19R20, -COR19, -CONR19R20, -SO2R19, -SO2NR19R20, optionally substituted alkyl(C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), quinil(C2-C6), alkoxygroup(C1-C6and T; or R17and R18with the locally taken, form bandolito group, which, in turn, can be substituted by one, two or three substituents selected from the group consisting of-F, -Cl, -Br, -OH, -NO2, -CN, -CF3, -COR8, -CSR8, -SO2R8, -OCOR8, alkyl(C1-C6), halogenoalkane(C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), quinil(C2-C6), alkoxygroup(C1-C6), alkoxy(C1-C6)alkyl(C1-C6and-N-R21R22or merged cycle selected from cyclopenta, cyclohexa-, cyclohepta, methylendioxy and Ethylenedioxy, and merged specified cycle, in turn, can be substituted by one, two or three substituents selected from the group consisting of alkyl(C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6and sarcinella(C2-C6);

R19and R20independently from each other selected from the group consisting of-H, -HE, optionally substituted alkyl(C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), quinil(C2-C6), alkoxygroup(C1-C6and T;

R21and R22independently from each other selected from-H, alkyl(C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), quinil(C2-C6and T, of the decree of the nye-N-R 21R22group may be a heterocyclic ring selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinil, optionally N-substituted by alkyl(C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6or quinil(C2-C6), morpholinium, thiomorpholine, thiomorpholine-S-oxide and thiomorpholine-S-dioxide;

T represents a phenyl or heteroaryl group, each of which is optionally substituted, with heteroaryl selected from the group consisting of pyridine, pyridazine, pyrimidine, pyrazine, furan, thiophene, oxazole, thiazole, imidazole, pyrazole, isoxazol, isothiazole, 1,2,5-thiadiazole, furazane, 1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole, tetrazole, 1,2,3,4-oxadiazole and 1,2,3,4-tetrazole, and deputies, is not necessarily present on the optionally substituted phenyl or optionally substituted heteroaryl group may be the one, two or three substituent selected from the group consisting of-F, -Cl, -Br, -OH, -NH2, -NO2, -CN, -CF3, -COR8, -CSR8, -SO2R8, -OCOR8, alkyl(C1-C6), halogenoalkane(C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), quinil(C2-C6), alkoxygroup(C 1-C6), alkoxy(C1-C6)alkyl(C1-C6), NH-alkyl(C1-C6), NH-cycloalkyl(C3-C6), -N-dialkyl(C1-C6), -N (alkyl(C1-C6))(cycloalkyl(C3-C6)), methylendioxy, Ethylenedioxy and heterocyclic ring selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinil, optionally N-substituted by alkyl(C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6or quinil(C2-C6), morpholinium, thiomorpholine, thiomorpholine S-oxide and thiomorpholine S-dioxide;

X is selected from O, S, NR9and CR9R10and

Y is selected from O, S, SO, SO2NO, NR12and CR12R13;

when this optional substituents are alkyl (C1-C6groups can consist of one, two or three groups selected from the following: -F, -Cl, -NO2, -OR21, -COR21, -N-R21R12oxoprop, cycloalkyl(C3-C6), alkenyl(C2-C6), quinil(C2-C6), -CN, T, -COO-R21, -OCOR21, -CON-R21R22, -N(R21)-CO-R22, -OCON-R21R22and-N(R21)-COO-R22;

or its pharmaceutically acceptable salt.

Preferably, when the present invention relates to new oxazolidinones formula (I), where R1before the hat is-F; each of R2, R3and R4represent-H; X is O, S or N-CN; Y represents O, S, SO, SO2and NR12; Rather it represents a quinoline group, selected from

,and

where each of R5and R6is a - H; or R5means methyl and R6means a methoxy group; or R5and R6selected from the group consisting of-F, -Cl and-Br; and R12selected from the group consisting of-H, methyl, ethyl, -CN, -COCH2CN, -PINES3-SOON3, -CONHCH3, -SO2CH3, -SOCH3, -SO2NHCH3,

,,

,,

,and

where R13selected from the group consisting of-H, methyl, ethyl, isopropyl, tert-butyl, -CH2HE, -CH2NH2, -COOH, - COON3, -SOOS2H5, -CH2Cl, -CONH2, -CH2-CH=CH2, -CH2-C≡CH, - CH=CH2, -C≡CH and-CH=CHN(CH3)2.

The term "pharmaceutically acceptable salt"used in this context, encompasses any salt formed from organic and inorganic acids, such as bromatologia what I hydrochloric, phosphoric, nitric, sulfuric, acetic, adipic, aspartic, benzolsulfonat, benzoic, citric, econsultancy, formic, fumaric, glutamic, lactic, maleic, malic, malonic, almond, methansulfonate, 1,5-naphthalenedisulfonate, oxalic acid, pellonula, propionic, n-toluensulfonate, succinic acid, tartaric acid, etc.

The compounds are suitable antimicrobial agents, effective against a number of microorganisms that infect humans and animals. Example 43 illustrates that the compounds corresponding to the present invention, show weak activity inhibition of MAO, which indicates that these compounds possess the ability to minimize or eliminate potential interaction type drug - drug, because of the strong inhibition of monoamine oxidase may result in altered rates of clearance for other compounds, normally metabolisable by monoamine oxidase, including some pharmaceuticals. In addition, it is especially important to avoid elevated levels neiromediatornykh amines, such as dopamine, serotonin and norepinephrine.

Example 43 also illustrates that the compounds corresponding to the present invention, showing izbirateljnostj against bacteria Staphylococcus compared to Enterococcus bacteria. This property clearly shows those compounds disclosed in this invention, which include the structure of quinoline type, in contrast to those compounds, which include other heterocycles, such as described in WO 04089944. For example, the compound corresponding to example 34 of the present invention, 100 times more active against Staphylococcus than Enterococcus. Selectivity is a valuable property in the treatment of diseases that require specific antibiotic therapy Staphylococcus. Among them infections caused by S. aureus, such as furunculosis, cellulitis, pyemia, pneumonia, osteomyelitis, endocarditis, suppuration of wounds and food poisoning; infections caused by S. epidermidis, such as small painful abscesses and other skin wounds that take place on infested skin and mucous membranes of humans and other animals; S. hycius, such as disease fatty pigs; these bacteria to antibiotics albus and S. pyogenes aureus. Consequently, these compounds are suitable antimicrobial agents, effective against a number of human and veterinary pathogens, with the benefits of being relatively well-known in the prior art.

Preferred compounds are enantiomers having the S-configuration at position C-5 oxazolidinone cycle.

The preferred compounds, which is adequate to the present invention, are:

(a) 7-methoxy-2-methyl-N-[[(5S)-3-[3-fluoro-4-(4'-acetyl-4-piperazinil)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-chinainternational, of the formula:

(b) 7-methoxy-2-methyl-N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)-phenyl]-2-oxo-5-oxazolidinyl] methyl]-3-chinainternational formula:

(C) 7-methoxy-2-methyl-N-[[(5S)-3-[3-fluoro-4-(4-thiomorpholine)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-chinainternational formula:

(d) 7-methoxy-2-methyl-N-[[(5S)-3-[3-fluoro-4-(4'-diacetyl-4-piperazinil)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-chinainternational formula:

Compounds of General formula (I) can be obtained in several different ways depending on the nature of functional groups

a) Obtaining amide compounds (I, X=O):

Formally amides obtained by reaction aminomethyl intermediate compounds of General formula (II) with an activated form of the corresponding acid of formula (III):

where A, R1, R2, R3, R4and Y are defined above. An activated form of the acid (III) is selected from the group consisting of acid halides, imidazolides p-nitrophenolic esters acid and 2,4,5-trichlorophenyl esters. Other activated form of the acid (III) are obtained in situ in prisutstvie the reagent, selected from the group including triphenylphosphine, bromotrichloromethane, dicyclohexylcarbodiimide, cation 2-chloropyridine, cation 3-chlorzoxazone, diphenylphosphoryl, N-hydroxybenzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate, 1-mesitylene-2-sulfonyl)-3-nitro-1H-1,2,4-triazole, benzotriazole-1-yl-oxytriphenylamine hexaflurophosphate, 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate.

b) Obtaining thioamide compounds (I, X=S):

Getting thioamide compounds (I, X=S) of the corresponding amide compounds (I, X=O) can be done using several tianyoude reagents selected from:

,

,,

,and

Preferred tianyoude reagent is a compound (IVi), known as the reagent Losson.

Otherwise thioamide compounds can be obtained by condensation of the corresponding aminomethyl derivative (II) with alkyllithium (IIIi):

where a is as defined in General formula (I) and R represents alkyl(C1-C6).

C) Obtaining sulfoxide compounds (I, Y=SO):

Getting self XENYX compounds (I, Y=SO) can be done

from the corresponding compounds of General formula (I), Y=S) using a variety of oxidizing reagents selected from the group consisting of metaperiodate sodium, hypervalent iodine reagent, chromic acid in acetic acid, chromic acid in pyridine, leads to compounds, which lead, manganese dioxide, nitrate thallium (III) and ozone and the like, preferably of metaperiodate sodium.

d) obtaining the sulfonic compounds (I, Y=SO2):

Getting sulfonic compounds (I, Y=SO2) from the corresponding sulfide (I, Y=S) can be done with the help of a number of oxidizing reagents, such as an excess of hydrogen peroxide in acetic acid and catalytic osmium tetroxide in the presence of N-methylmorpholine N-oxide. The excess of hydrogen peroxide in acetic acid is preferred.

e) Receiving cyanoaniline compounds (I, X=N-CN):

Cyanoaniline compounds (I, X=N-CN) synthesized by

the interaction of the corresponding aminomethyl derivative (II) with cyanamide General formula (V):

where a is as defined in General formula (I), and R represents alkyl(C1-C6).

A number aminomethyl intermediate compounds of General formula (II) are known in the technical field and can be obtained according to the methods described in the literature. So, the PCT application WO 9507271 R who hides obtain N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)-phenyl]-2-oxo-5-oxazolidinyl]-methyl]amine (II, R1=F, R2=R3=R4=H, Y=O), PCT application WO 9854161 reveals obtain N-[[(5S)-3-[3-fluoro-4-(4-thiomorpholine)-phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (II, R1=F, R2=R3=R4=H, Y=S) and PCT application WO 0032599 reveals obtain N-[[(5S)-3-[3-fluoro-4-(4'-acetyl-4-piperazinil)-phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (II, R1=F, R2=R3=R4=N, Y=CH3-CON). PCT application WO 04/018439 discloses obtaining (S)-N-[3-[ftor-4-[N-t-butoxycarbonylmethyl-1-yl]-phenyl]-2-cookiepolicy-5-ylmethyl]azide and (S)-[3-[3-fluoro-4-[N-t-butoxycarbonylmethyl-1-yl]phenyl]-2-kookatonin-5-Eletropaulo]alcohol.

Compounds corresponding to the present invention can generally be obtained in accordance with standard pharmaceutical practice as a pharmaceutical composition.

Another aspect of the invention relates to pharmaceutical compositions comprising a therapeutically effective amount of the compounds of General formula (I)as defined above, together with appropriate amounts of pharmaceutical excipients or carriers.

Pharmaceutical compositions corresponding to the present invention, it is possible to introduce a standard way according to the condition you want to treat, for example, by oral, parenteral, inhalation, rectal, transdermal or local introduction the deposits. For these purposes the compounds corresponding to the present invention can be produced by means known in the technical field in the form, for example, tablets, capsules, syrups, aqueous or oil solutions or suspensions, emulsions, dispergiruyushchie powders, inhalation solutions, suppositories, ointments, creams, drops and sterile aqueous or oily solutions or suspensions for injection, etc. of the Pharmaceutical composition can include flavorings, sweeteners, etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form suspensions or solutions suitable for intravenous, subcutaneous or intramuscular injection. These compositions generally comprise from 1 to 40 wt.%, preferably 1-10 wt.% active compound, the remainder of the composition is a pharmaceutically acceptable carriers, diluents, solvents, etc.

The compounds of formula (I) is administered in an amount of 0.1-100 mg/kg body weight/day, preferably 1-50 mg/kg body weight/day.

Compounds corresponding to the present invention, used in the treatment of conditions such as nosocomial pneumonia, community-acquired pneumonia caused by methicillinsensitive Staphylococcus aureus (MRSA), including the accompanying bacteremia, pneumonia, called penicillinases the mi and sensitive streptococci, diabetic infections of the feet and infections of the skin and skin structures, and all other infections caused by bacteria sensitive to the compounds described in the invention. Compounds corresponding to the present invention, effective against a number of pathogens of human and animal clinical isolates, including vancomycinresistant organisms and methicillinsensitive organisms.

The following non-limiting examples illustrate the scope of the present invention.

Examples:

Some abbreviations used in this context, is defined the following way: "DCM" means dichloromethane, "DMAP" means 4-(dimethylamino) pyridine, "DMSO" means dimethyl sulfoxide, "EDCI" means 3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, "ESI" means electrospray ionization, "HOBt" means N-hydroxybenzotriazole, "HPLC" means high performance liquid chromatography, "MS" means mass spectroscopy and TLC" means thin layer chromatography.

Example 1

7-methoxy-2-methyl-N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-chinainternational

A solution of 110 mg (1.5 EQ.) 7-methoxy-2-methylinosine-3-carboxylic acid, 21 mg (0.5 EQ.) DMAP and 97 mg of 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (1.5 EQ.) in 5 ml of DCM was stirred at room temperature under argon for is of 30 minutes. Then add 100 mg (1 EQ.) N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl] amine in 5 ml of DCM and continue stirring for 12 hours, when you see a complete transformation of the original amine with TLC. The crude mixture was washed with 5% solution of the SPLA, saturated NaHCO3and a salt solution. The combined organic layers are dried (MgSO4) and concentrated in vacuo, getting 173 mg of the title product (Yield = 95%).

Data1H NMR (400 MHz, δ ppm, CDCl3): 2,75 (3H, s),3,03 (4H, m), 3,85 (4H, m), 3.9 to (m, 3H), OF 3.94 (3H, s), 4,13 (1H, t, J=9,2 Hz), to 4.92 (1H, m), of 6.52 (1H, t, NH), 6.89 in (1H, t, J=8,8 Hz), to 7.09 (1H, dd, J=2,4, and 8.4 Hz), 7,17 (1H, dd, J=2,8, 9,2 Hz), 7,33 (1H, d, J=2.4 Hz), 7,46 (1H, dd, J=2,8, 14.4 Hz), to 7.61 (1H, d, J=9,2 Hz), and 8.0 (1H, s).

HPLC (t, %): 8,9 min, 99%.

MC (ESI) m/z=495 (M+1)

Example 2

7-methoxy-2-methyl-N-[[(5S)-3-[3-fluoro-4-(4-thiomorpholine)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-chinainternational

Connection receive, following the same procedure as in example 1, starting from 370 mg of 7-methoxy-2-methylinosine-3-carboxylic acid and 350 mg of N-[[(5S)-3-[3-fluoro-4-(4-thiomorpholine)-phenyl]-2-oxo-5-oxazolidinyl]methyl]amine. After similar processing gain 244 mg of the compound corresponding to the desired 7-methoxy-2-methyl-N-[[(5S)-3-[3-fluoro-4-(4-thiomorpholine)-phenyl]-2-oxo-5-oxazolidinyl]-methyl]-3-chinainternational (Yield = 43%).

Data1H NMR spectroscopy is (400 MHz, δ, ppm, CDCl3): 2,69 (3H, s), 2,78 (4H, m), of 2.23 (4H, m), 3,86 (m, 3H), 3,90 (3H, s), of 4.05 (1H, t, J=8,8 Hz), 4,88 (1H, m), PC 6.82 (1H, t, J=8,8 Hz), 6,97 (1H, t), 7,07 (1H, dd, J=2,4, 8,8 Hz), 7,31 (1H, dd, J=3.2, and 14 Hz), 7,34 (1H, d, J=2 Hz), 7,49 (2H, d, J=8,8 Hz), and 8.0 (1H, s).

HPLC (t, %): 12,0 min, 99%.

MC (ESI) m/z=511 (M+1)

Example 3

7-methoxy-2-methyl-N-[[(5S)-3-[3-fluoro-4-(4'-acetyl-4-piperazinil)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-chinainternational

Connection receive, following the same procedure as in example 1, starting from 190 mg (1.5 EQ.) 7-methoxy-2-methylinosine-3-carboxylic acid and 200 mg (1 EQ.) N-[[(5S)-3-[3-fluoro-4-(4'-acetyl-4-piperazinil)-phenyl]-2-oxo-5-oxazolidinyl]methyl]amine. After a similar treatment receiving 120 mg of the compound corresponding to the desired 7-methoxy-2-methyl-N-[[(5S)-3-[3-fluoro-4-(4'-acetyl-4-piperazinil)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-chinainternational (Yield = 38%).

Data1H NMR (400 MHz, δ, ppm, CDCl3): 2,69 (3H, s), only 2.91 (2H, m), 2,98 (2H, m), of 3.57 (2H, m), 3,70 (2H, CH), 3,86 (3H, CH), with 3.89 (3H, s), 4,07 (1H, t, J=8,8 Hz), 4,88 (1H, m), 6,79 (1H, t, J=9,2 Hz), 6,99 (1H, m), was 7.08 (1H, dd, J=2, 8,8 Hz), was 7.36 (2H, m), to 7.50 (1H, d, J=9,2 Hz), to 7.59 (1H, m), and 8.0 (1H, s).

HPLC (t, %): 7,9 min, 98%.

MC (ESI) m/z=511 (M+1).

Example 4

7-methoxy-2-methyl-N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-chinainternational

A solution of 50 mg of N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)-phenyl]-2-oxo-5-oxazolidine is]methyl]-7-methoxy-2-methylinosine-3-yl-amide, 123 mg (3 EQ.) agent Losson in 4 ml of 1,4-dioxane is heated at 65°C for 3 hours and at 100°C for 1 hour. The solvent is removed under reduced pressure and the crude purified column chromatography (Merck silica gel, ethyl acetate/hexane 99/1)to give 39 mg of the title product (Yield = 75%).

HPLC (t, %): 11.2 min, 96%.

MC (ESI) m/z=511 (M+1)

Example 5

7-methoxy-2-methyl-N-[[(5S)-3-[3-fluoro-4-(4-thiomorpholine)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-chinainternational

A solution of 50 mg of N-[[(5S)-3-[3-fluoro-4-(4-thiomorpholine)-phenyl]-2-oxo-5-oxazolidinyl] methyl]-7-methoxy-2-methylinosine-3-yl-amide, 149 mg (4 EQ.) agent Losson in 4 ml of 1,4-dioxane is heated at 65°C for 3 hours and at 100°C for 1 hour. The solvent is removed under reduced pressure and the crude purified by two successive column chromatographie (Merck silica gel, first column elute DCM/MeOH 95/5 and second - ethyl acetate)to give 20 mg of the title product with a purity of 99% (Yield = 50%).

HPLC (t, %): 13,8 min, 99%.

MC (ESI) m/z=527 (M+1).

Example 6

7-methoxy-2-methyl-N-[[(5S)-3-[3-fluoro-4-(4'-diacetyl-4-piperazinil)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-chinainternational

A solution of 50 mg of N-[[(5S)-3-[3-fluoro-4-(4'-acetyl-4-piperazinil)-phenyl]-2-oxo-5-oxazolidinyl] methyl]-7-methoxy-2-methylinosine-3-yl-amide, 113 mg (3 EQ.) the reagent Loss is in 4 ml of 1,4-dioxane is heated at 65°C for 3 hours and at 100°C for 1 hour. The solvent is removed under reduced pressure and the crude purified column chromatography (Merck silica gel, ethyl acetate/hexane 8/2)to give 27 mg of the title product (Yield = 53%).

HPLC (t, %): 12,3 min, 90%.

MC(ESI) m/z=568 (M+1).

Example 7

7-methoxy-2-methyl-N-[[(5S)-3-[3-fluoro-4-(1-Osotimehin-4-yl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-chinainternational

400 mg (10 EQ.) metaperiodate sodium dissolved in 1 ml of water and then cooled to 0°C (ice bath). Then add 100 mg (1 EQ.) N-[[(5S)-3-[3-fluoro-4-(4-thiomorpholine)-phenyl]-2-oxo-5-oxazolidinyl] methyl]-7-methoxy-2-methylinosine-3-yl-amide in 2.5 ml of methanol. To improve the solubility add 0.5 ml of DCM. The reaction was stirred at 0°C for 3 hours until TLC shows complete conversion of the starting material. The crude mixture is transferred into a separating funnel, add DCM and water to the formation of two clear layers, the organic layer is separated, and the aqueous layer was additionally extracted with DCM. The organic layers are combined, dried over MgSO4, filtered and concentrated under reduced pressure, obtaining 95 mg of This solid is purified column chromatography (10 g silica gel, DCM/MeOH with increasing polarity)to give 82 mg (Yield = 79%) of the title compound.

Data1H NMR (400 MHz, δ ppm, CDCl3): to 2.67 (3H, s), is 2.88 (4H, m), 3,13 (2 is, m), of 3.56 (2H, m), 3,83 (3H, m), with 3.89 (3H, s), of 4.05 (1H, t, J=8 Hz), 4,88 (1H, m), 6.87 in (1H, t, J=8,8 Hz), 6,92 (1H, d, J=8,8 Hz), 7,07 (1H, d, J=9.9 Hz), 7,44 (3H, m), 7,95 (1H, s),

HPLC (t, %): 6,80 min, 100 %.

MC (ESI) m/z=527 (M+1).

Example 8

7-methoxy-2-methyl-N-[[(5S)-3-[3-fluoro-4-(1,1-diocletianopolis-4-yl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-chinainternational

A solution of 388 mg (1 equiv.)

N-[[(5S)-3-[3-fluoro-4-(4-thiomorpholine)-phenyl]-2-oxo-5-oxazolidinyl]methyl]7-methoxy-2-methylinosine-3-yl-amide in 20 ml of acetic acid and 1.05 ml (12 EQ.) H2O230% is stirred at reflux over night. When TLC of the crude mixture shows the disappearance of the starting material, add 0.5 ml of H2O230% and stirred overnight at reflux. The solvent is evaporated, dissolved in DCM and washed with saturated solution of NaHCO3organic layers are dried Na2SO4and concentrate, getting 190 mg. Material purified column chromatography (10 g silica gel, DCM/MeOH with increasing polarity)to give 33 mg (Yield = 8%) of the title compound.

Data1H NMR (400 MHz, δ ppm, CDCl3): 2,69 (3H, s), 3,17 (4H, m), 3,52 (4H, m), 3,86 (3H, m), a 3.9 (3H, s), 4,08 (1H, t, J=8 Hz), 4,9 (1H, m), to 6.88 (1H, t, J=8 Hz), 7,02 (1H, m), 7,10 (1H, d, J=8,4 Hz), 7,27 (1H, m), the 7.43 (1H, m), 7,53 (1H, m), of 7.97 (1H, s),

HPLC (t, %): 8,7 min, 85 %.

MC (ESI) m/z=543 (M+1).

Connection, before the purposes of Table 1, receive, by following the same procedure as in Example 1:

ExampleStructureHPLC,MC (ESI)
t (min) (%) m/z
98.6 (88)338
1010.2 (90)501
118.9 (100)451
125.85 (93)559
135.91(92)451
145.05(88)485
15 4.39(98)465
165.41(99)510
174.08(95)467
184.6(100)495

Example 19:

N-[(5S)-[3-[3-fluoro-4-[(N-tert-butoxycarbonyl)piperazine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]Amin

This compound can be obtained in two ways:

Method a: To a solution of (S)-[3-[3-fluoro-4-[N-tert-butoxycarbonylmethyl-1-yl]phenyl]-2-oxoacridine-5-ylmethyl]azide (27.6 mmol) in EtOAc add 10% Pd/C (6.4 g) and allow the reaction mix at room temperature under H2. The reaction monitorium TLC, and when it is completed, the mixture is filtered through celite and concentrated under vacuum. The purity of the product is raw, which is kept under argon to avoid oxidation of the amine exceeds 95%.

Method B: To a solution of (5S)-[3-[3-fluoro-4-[N-tert-butoxycarbonyl-piperazine-1-yl]phenyl]-2-oxoacridine-5-Eletropaulo]alcohol (74,1 g at 0.19 mol) and triethylamine (36 ml, 0.26 mol) in DCM (750 ml) slowly add recipients who have 3-nitrobenzenesulfonamide (55,6 g, 0.25 mol). The reaction is stirred for 24 hours, then washed with water (500 ml), dried and evaporated, receiving (5S)-[3-[3-fluoro-4-[N-tert-butoxycarbonyl-piperazine-1-yl]phenyl]-2-oxoacridine-5-ylmethyl]nosrat (116 g), containing some amount of unreacted 3-nitro-benzosulfimide. To a solution of noselite (115 g) in acetonitrile (2 l) is added concentrated ammonia (d=0.88 / l, 100 ml) and heated the reaction mixture to 40°C for 3 hours. Add the second part of the ammonia (500 ml) and the mixture support at 40°C during the night. The third part of the ammonia (500 ml) added 8 hours after adding the last part of ammonia (500 ml) and then stirred overnight. The reaction mixture is cooled, divide into two parts and each half diluted with water (1 l) and extracted with DCM (2×1 l). The combined DCM extracts are dried and evaporated, receiving and 71.4 g of the target product.

Data1H NMR (400 MHz, δ, ppm, CD3OD): 1,48 (N, s), 2,96 (6N, m), of 3.57 (4H, m), 3,81 (1H, m), 4.09 to (1H, t, J=16 Hz), 4,7 (1H, m), 7,05 (1H, t, J=8 Hz), 7,19 (1H, m), 7,51 (1H, dd, J=2,4, 14 Hz).

HPLC (t, %): 4,8 min, 97 %.

MC (ESI) m/z=395 (M+1).

Example 20: 7-methoxy-2-methyl-N-[[(5S)-[3-[3-fluoro-4-[(N-tert-butoxycarbonyl)piperazine-1-yl]phenyl]-2-oxo-5-oxazolidinyl-methyl]-3-chinainternational

A mixture of 7-methoxy-2-methylinosine-3-carboxylic acid (1.24 g, 5,72 mmol), EDCI (1,09 g, 5,72 mmol), DMAP (0,23 g, 1,9 shall mol) and DCM (30 ml) is stirred for 30 minutes, then add a solution of N-[(5S)-[3-[3-fluoro-4-[(N-tert-butoxycarbonyl)piperazine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]amine (1.5 g, 3,81 mmol) in DCM. After stirring overnight the mixture was washed with 5% solution of acetic acid, saturated NaHCO3and finally brine. The solvent is evaporated under reduced pressure, obtaining 2.1 g of the target product (yield 93%).

Data1H NMR (400 MHz, δ ppm, CDCl3): 1,47 (N, s), is 2.74 (3H, s), 2,96 (4H, m), of 3.57 (4H, m), a 3.9 (3H, m), of 4.12 (1H, t, J=9 Hz), 4,9 (1H, m), 6,63 (1H, NH), to 6.88 (1H, t, J=9 Hz), 7,06 (1H, m), to 7.15 (1H, dd, J=2,4, 9,2 Hz), 7,32 (1H, m), 7,44 (1H, dd, J=3, 14 Hz), to 7.59 (1H, d, J=9 Hz), and 8.0 (1H, s).

HPLC (t, %): 6,6 min, 93%.

MC(ESI) m/z=594 (M+1).

Example 21:

7-methoxy-2-methyl-N-[[(5S)-[3-[3-fluoro-4-(piperazine-1-yl)phenyl]-2-oxo-5-oxazolidinyl]-3-chinainternational

To a solution of the BOC-protected derivative, corresponding to example 20, in DCM (80 ml) at 0°C add 50% solution triperoxonane acid for 10 minutes. After 15 minutes the mixture is allowed to warm to room temperature and stirred over night. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate (50 ml) before re-extraction with water (9×50 ml). Then the combined aqueous extracts fail to pH 12 (K2CO3), and extracted with ethyl acetate (9×50 ml). The organic extracts are dried and the solvent daring is t under reduced pressure, getting the product in the form of a solid white color that gives 1.6 g (60%).

Examples 22-27 and 37-42 (see table 2 below) receive, following the same General method. A suitable acid (0.21 mmol), EDCl.HCl (40 mg, 0.21 mmol), DMAP (8.5 mg, 70 mmol) and DMF (1,5 ml) is stirred for 30 minutes, then add the compound corresponding to Example 21 (70 mg, 0.14 mmol). The mixture is stirred for approximately 64 hours and add ethyl acetate (6 ml). The mixture was washed with 5% solution of acetic acid (3 ml), a saturated solution of NaHCO3(3 ml)and finally brine (3 ml). The organic phase is dried, and the solvent evaporated under reduced pressure, obtaining the product.

Examples 28-33 (see table 2 below) receive, following the same General method. To a mixture of the appropriate acid (0.24 mmol), the compound corresponding to Example 21 (80 mg, 0.16 mmol) and DMF (2 ml), added DMAP (10 mg, 0.08 mmol) and EDCl.HCl (46 mg, 0.24 mmol) (and only in the case of Example 33, HOBt (31 mg, 0.24 mmol)). The solution is stirred overnight and diluted DCM (4 ml). The mixture was washed with 5% solution of acetic acid (2 ml), a saturated solution of K2CO3(2 ml)and finally brine (2 ml). The organic phase is dried and the solvent evaporated under reduced pressure, obtaining a product which is then purified Express chromatography.

Example 34-36: Use the method that is used for connections 2-27, by quantity, increased to 0,183 mmol of the compound corresponding to Example 21.

Table 2
22Rl4Purity according to LCHPLC t (min)MC(ESI) m/z
2295.1%11.6576
2390.2%10.6562
2497.8%10.0548
2596.2%9.5566
2697.8%9.7580
2795.3%9.3616
2895.8%9.8600
2993.5%9,3618
3089.4%9.2588
3184.5%7.9588
3290.6%11.3604
3391.3%8.9605
34 97.9%10.6562
3591.2%9.1552
3691.3%8.6582
3796%5.35578
3892%4.1599
3985%4.9564
4094%4.2561
4180%4.7589
4287%4.1599

Example 43: Determination of biological data

(a) Antibacterial activity

The minimum inhibiting activity (MIC) is determined using the standard method microdesmidae according to The National Committee for Clinical Laboratory Standards (NCCLS), 5th Approved standard M7-A5 (5 approved standard M7-A5 of the National Committee for clinical laboratory standards), 2001, Wayne, PA, USA.

All compounds tested against gram-positive and gram-negative bacteria expressing the corresponding different specificity, sensitivity and stability. Used microorganisms are selected from the laboratory reference bacteria from clinical isolates.

The tested concentration, constitute a serial dilution from 0.06 μg/ml to 128 μg/ml in 96-well tablets for micrometrology. The study used the following microorganisms:

Aerobic gram-positive bacteria, consisting of Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium and Streptococcus pneumoniae and Moraxella catarrhalis, gram-negative bacterium associated with respiratory infections; it is also called demanding due to the growth environment.

MICK determined in blood is the ed for Brucella with additives for anaerobic strains and media for cultivation of Mueller-Hinton (summed cations) for aerobic bacteria.

Test compounds dissolved in DMSO and diluted up to 2560 μg/ml in different environments according to the specific requirements of each group of strains.

96-well sealed tablets for micrometrology containing bacteria, incubated in different laboratory conditions depending on the nature of the microorganism. So, aerobic bacteria incubated for 16-24 h at 35°C and the so-called fastidious bacteria, such as M. catarrhalis and S. pneumoniae, during 20-24 h at 35°C in microaerobic atmosphere containing 5% CO2(Anaerocult C, MERCK).

(b) Enzymatic activity in vitro MAO-a and MAO-b

The enzymatic activity of MAO-a and MAO-b was measured using membranes obtained from SF9 cells expressing either human MAO A, human MAO-b (Gentest, BD, USA). The analyses carried out in black 96-well tablets for micrometrology using tenormin as substrate and measuring the formation of 4-hydroxyquinoline solution fluorescence at 340 nm/465 nm. Briefly, membranes with MAO-A (0.006 mg/ml protein) and MAO-b (0.015 mg/ml protein) incubated with kynurenine, 30 μm at 37°C for 40 min in the presence of compounds in a final volume of 200 μl. The reaction stopped by the addition of 2N NaOH, and determine the reaction product, 4-hydroxyquinolin, fluorometry using reader Tecan Ultra.

Low Ki value indicates that the tested inhibitor possess the AET high affinity binding to the enzyme MAO, thus, it is a strong inhibitor of MAO.

Antibacterial activity and enzymatic activity of MAO-a and MAO-b are shown in Tables 3 and 4, respectively.

Table 3
Activity in vitro against bacteria MIC (mcg/ml)
BodyExample 8Example 31Example 34Example 42Linezolid
S. aureus was ATSS 25923 MS 3192,004,000,501,002,00
S. aureus was ATSS 43300 MR 2142,002,000,500,061,00
S. epidermidis was ATSS 12228 MR 112,002,000,500,51,00
S. pneumoniae ATCC 49619 PR 2151,004,00 0,501,002,00

Table 4
Activity inhibition of MAO man
Example 34Example 42LinezolidToloxatone
MAO-A % inhibition (10 μm)754177
MAO-A % inhibition (1 μm)87627

(C) Selective activity against bacteria Staphylococcus compared to Enterococcus bacteria:

The results obtained are given in tables below: 1.

The compounds of formula:

Table 5A
R2The geometric mean MIC Staphylococcus (µg/ml)The geometric mean MIC Enterococcus Selective Enterococcus/Sthaphylococcus
Example 10,6the 5.79,5
Example 181,08,08,0
Comparative example 1the 5.74,80,8
Comparative example 2a 12.73,40,3
Comparative example 30,80,70,9
Comparative example 46,74,80,7
Comparative example 5 4,04,01,0

2. The compounds of formula:

Table 5b
R2The geometric mean MIC Staphylococcus (µg/ml)The geometric mean MIC EnterococcusSelective Enterococcus/Sthaphylococcus
Example 30,4the 5.714,3
Comparative example 66,3the 5.70,9
Comparative example 74,02,50,6

3. The compounds of formula:

Table 5C
R2 The geometric mean MIC Stbaphylococos (µg/ml)The geometric mean MIC EnterococcusSelective Enterococcus/Sthaphylocoecus
Example 240,616,027,0
Comparative example 84,83,20,66

4. The compounds of formula:

Table 5d
R2The geometric mean MIC Sthaphylococcus (µg/ml)The geometric mean MIC EnterococcusSelective Enterococcus/Sthaphylococcus
Example 291,732,018,8
Comparative example 913,5 4,00,3

5. The compounds of formula:

Table 5e
R2The geometric mean MIC Staphylococcus (µg/ml)The geometric mean MIC EnterococcusSelective Enterococcus/Sthaphylococcus
Example 340,4of 40.3100
Comparative example 106,74,00,6

6. The compounds of formula:

Table 5f
R2The geometric mean MIC Sthaphylococcus (µg/ml)The geometric mean MIC EnterococcusSelective Enterococcus/Sthaphylococcus
Example 35 0,65,08,3
Comparative example 114,83,20,7

These results show that the compounds corresponding to the present invention, showing selective activity against bacteria Staphylococcus compared to Enterococcus bacteria.

Example 44: the Pharmaceutical composition

The following material illustrates representative pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt for antimicrobial use in humans or animals:

Tablet 1mg tablet
The active ingredient100
Lactose179
Croscarmellose sodium12
Polyvinylpyrrolidone6
Magnesium stearate3
Tablet 2 mg tablet
The active ingredient50
Lactose229
Croscarmellose sodium12
Polyvinylpyrrolidone6
Magnesium stearate3
Tablet 3mg tablet
The active ingredient1
Lactose92
Croscarmellose sodium4
Polyvinylpyrrolidone2
Magnesium stearate1
Capsulemg/capsule
The active ingredient10
Lactose389
Croscarmellose sodium100
Magnesium stearate1
Injectable drug50 mg/ml
The active ingredient5.0% weight./about.

Isotonic aqueous solutionup to 100%

Buffers, pharmaceutically acceptable co-solvents, such as glycol, polypropyleneglycol, glycerol or ethanol, or chelating agents can be used in the product as an accessory.

These drugs can be well-known methods customary in the pharmaceutical field. Tablets 1-3 may be intersolubility coating applied by known methods, for example, to obtain a coating of cellulitecellulite.

1. Oxazolidinone derivatives covered by the General structural formula (I)

where R1, R2, R3and R4independently from each other selected from the group comprising-H and halogen;
And selected from the group including

R5and R6independently from each other selected from the group comprising-H, -F, -Cl,
-Br, -HE, alkyl(C1-C6 ), halogenated(C1-C6), alkoxygroup(C1-C6);
R7selected from the group comprising H, alkyl(C1-C6); or R7and R5or R6, taken together, form a loop of 2 carbon atoms and include 1 group selected from Oh, which, in turn, can be substituted by one Deputy, selected from alkyl(C1-C6);
R12selected from the group comprising-H, -COR14, -CSR14, -COOR14;
R14selected from the group comprising alkyl(C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6),



R16, R17and R18represent-H;
R21selected from the group comprising H, alkyl(C1-C6);
X is selected from the group comprising O, S, and
Y is selected from the group comprising O, S, SO, SO2and NR12; and the optional substituents are alkyl (C1-C6) groups can be one or two groups selected from-OR21, -CN;
or their pharmaceutically acceptable salts.

2. Derivative according to claim 1, in which R1is a-F and each is of R 2, R3and R4means N.

3. Derivative according to claim 2, in which X represents O.

4. Derivative according to claim 2, in which X represents S.

5. Derivative according to claim 2 to 4, in which a represents a

6. Derivative according to claim 5, in which each of R5and R6means N.

7. Derivative according to claim 5, in which R5represents methyl.

8. Derivative according to claim 5, in which R5and R6selected from the group comprising-F, -Cl and-Br.

9. Derivative according to claim 2 to 4, And in which means

10. Derivative according to claim 9, in which each of R5and R6represents-N.

11. Derivative according to claim 9, in which R5represents methyl.

12. Derivative according to claim 9, in which R5and R6selected from the group comprising-F, -Cl and-Br.

13. Derivative according to claim 2 to 4, in which Y is selected from the group comprising O, S, SO and SO2.

14. Derivative according to claim 2 to 4, in which Y represents NR12.

15. Derivatives 14, in which R12selected from the group comprising-H.

16. Derivatives 14, in which R12selected from the group that includes the PINE trees3and SOON3.

17. Derivatives 14, in which R12represents a

18. Derivatives with respect to items 1, which is the enantiomer with S-Ko is the figuration in position C-5 oxazolidinone cycle.

19. Derivative according to claim 2, which correspond to the formula

20. Derivative according to claim 2, which correspond to the formula

21. Derivative according to claim 2, which correspond to the formula

22. Derivative according to claim 2, which correspond to the formula

23. The method of obtaining oxazolidinone derivatives covered by the General formula (I), where X means O, as defined in claim 1, in which the acylation aminomethyl intermediate compounds of General formula (II)

where R1, R2, R3, R4and Y are such as defined for General formula (I), using the activated form of the corresponding acid of formula (III)

where As the same as defined for General formula (I).

24. The method according to item 23, in which the activated form of the acid (III) is selected from the group comprising acidic halides, imidazoline p-nitrophenolate esters acid and 2,4,5-trichlorophenolate esters.

25. The method according to item 23, in which the activated form of the acid (III) are obtained in situ in the presence of a reagent selected from the group comprising triphenylphosphine, bromotrichloromethane, dicyclohexylcarbodimide, cation 2-chloropyridine, cation 3-chlorzoxazone, diphenylprop related, N-hydroxybenzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate, (1-mesitylene-2-sulfonyl)-3-nitro-1H-1,2,4-triazole, benzotriazole-1-yl-oxtriphylline-phosphonium hexaflurophosphate, 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate.

26. The method of obtaining oxazolidinone derivatives covered by the General formula (I), where X is S, as defined in claim 1, in which the interaction of the derivative of General formula (I), where X is Oh, with tianyoude reagent selected from the group


P4S10(IViv), Na2P4S11(IVv) and Na2P4S10O(IVvi)

27. The method according to p in which tianyoude reagent is a compound (IVi).

28. The method of obtaining oxazolidinone derivatives covered by the General formula (I), where X means SO as defined in claim 1, in which the oxidation of the corresponding derivative of General formula (I)where Y represents S, with a reagent selected from the group comprising metaperiodate sodium, hypervalent iodine reagent, chromic acid in acetic acid, chromic acid in pyridine, leads to compounds, which lead, manganese dioxide, nitrate thallium (III) and ozone.

29. The method according to p in which the reagent is metaperiodate sodium.

30. The method of obtaining oxazolidinone derivatives covered by the General formula (I)where Y represents the SO2as defined in claim 1, in which the oxidation of the corresponding derivative of General formula (I)where Y represents S, with a reagent selected from the group comprising excess hydrogen peroxide in acetic acid and catalytic osmium tetroxide in the presence of N-oxide N-methylmorpholine.

31. The method according to item 30, in which the reagent is an excess of hydrogen peroxide in acetic acid.

32. The use of derivatives according to claims 1 to 22 for receiving medicines for treatment of bacterial infections in human or animal.

33. Use p in which the drug is administered orally, parenteral, inhalation, rectal, transdermal or local path.

34. Use p or 33, in which the derivative is administered in an amount of from 0.1 to 100 mg/kg body weight/day.

35. The application of clause 34, in which the derivative is administered in an amount of from 1 to 50 mg/kg body weight/day.

36. Pharmaceutical composition for treating bacterial infections in human or animal, comprising a therapeutically effective amount oxazolidinones derived covered by the General formula (I) according to claims 1-22, together with the appropriate amounts of pharmaceutical excipients or carriers.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to (5H-pyrazolo[1,5-c][1,3]benzoxazin-5-yl)phenylmethanone derivatives (I), useful as HIV viral replication inhibitors, as well as pharmaceutical compositions, use thereof as medicinal agents.

EFFECT: disclosed compounds are meant for preventing or treating HIV infection and treating AIDS.

7 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula I and to their physiologically compatible salts. In general formula I , X denotes identical or different groups =C(-R)- or =N-, wherein at least one =C(-R-)- is substituted by =N-; Y is -O-; R denotes identical or different hydrogen, halogen, (C1-C6)-alkyl; R1 denoes (C4-C16-alkyl, (C1-C4)-alkylene-(C6-C10)-aryl, (C1-C4)-alkylene-(C3-C12)-cycloalkyl, (C9-C10)-bicyclic ring, wherein the aryl can be singly or multiply substituted with (C1-C6)-alkyl; R2 denotes hydrogen; or R1 and R2 together with the nitrogen atom which it is bonded form a monocyclic, saturated 6-member ring in which separate members of the ring system can be substituted with -CHR4-; R4 denotes (C1-C6)-alkyl. The invention also relates to a pharmaceutical composition having inhibiting action on endothelial lipase (EL) and containing one or more compounds of formula I, to use of the disclosed compounds to prepare a medicinal agent and to methods of producing compounds of formula I.

EFFECT: high effectiveness of derivatives.

11 cl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to azole derivatives of formula I , where: A denotes S, O; W denotes -(C=O)-; X are identical or different and denote =C(-R)- or =N-; Y denotes -O- or -NR1-; R denotes hydrogen, halogen, (C1-C6)-alkyl, nitro; R1 denotes hydrogen; R2 denotes (C5-C16)-alkyl, (C1-C4)alkyl-phenyl, where phenyl can be optionally mono- or poly-substituted with (C1-C6)-alkyl; R3 denotes hydrogen; or R2 and R3 together with the nitrogen atom bearing them can form a monocyclic saturated 6-member ring system, where separate members of this ring system can be substituted with 1 group selected from the following: -CHR5-, -NR5-; R5 denotes (C1-C6)-alkyl, trifluoromethyl; and physiologically acceptable salts thereof. The invention also pertains to methods of producing said compounds and a medicinal agent based on said compounds.

EFFECT: novel compounds and a medicinal agent based on said compounds are obtained, which can be used as hormone-sensitive lipase (HSL) or endothelial lipase (EL) inhibitors.

12 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of tetrahydrobenzoxazines

in which substitute R1 denotes a hydrocarbyl residue having 1-3000 carbon atoms, and substitutes R2, R3, R4 and R5 independently denote hydrogen atoms, hydroxyl groups or hydrocarbyl residues, having 1-3000 carbon atoms, respectively, and in which substitutes R3 and R4 or R4 and R5 with a partial structure -O-CH2-NR7-CH2-, bonded to the benzene ring, can also form a second tetrahydrooxazine ring, where R7 denotes hydrocarbyl residues having 1-3000 carbon atoms, provided that at least one of substitutes R1, R2, R3, R4, R5 or R7 are polyisobutenyl, having 3000 carbon atoms and the rest of the substitutes from the group R1, R2, R3, R4, R5 or R7, if they denote hydrocarbyl residues, have 1-20 carbon atoms, respectively, as anti-oxidants for stabilising mineral oil and fuel products against the effect of light, oxygen and heat. The invention also describes jet fuel and jet fuel additive concentrate containing tetrahydrobenzoxazine of formula (I).

EFFECT: preparation of stabilisers having improved stabilisation of nonliving organic material, particularly jet fuel against the effect of light, oxygen and heat.

9 cl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to methods for synthesis of compounds of formula (A), where R1 denotes halogen, C1-C6halogenalkyl, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2 denotes halogen, C1-C4alkyl or C1-C4alkoxy; R3 and R4 independently denote a branched C3-C6alkyl; and R5 denotes C3-C12cycloalkyl, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy(C1-C6)alkyl, C1-C6alkanoyloxy(C1-C6)alkyl, C1-C6aminoalkyl, C1-C6alkylamino(C1-C6)alkyl, C1-C6dialkylamino(C1-C6)alkyl, C1-C6alkanoylamino(C1-C6)alkyl, HO(O)C-(C1-C6)alkyl, C1-C6alkyl-O-(O)C-(C1-C6)alkyl, H2N-C(O)-(C1-C6)alkyl, C1-C6alkyl-HNC(O)-(C1-C6)alkyl or (C1-C6alkyl)2N-C(O)-(C1-C6)alkyl, or their pharmaceutically acceptable salts which have renin inhibiting activity, as well as to basic intermediate compounds obtained during steps for synthesis of the desired compounds and to methods for synthesis of said intermediate compounds.

EFFECT: alternative synthesis method.

43 cl, 8 dwg, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula pharmaceutically acceptable salts thereof, where ---- independently denotes a single or double bond; ring Q is imidazole, triazole (for example 1,2,3-triazole or 1,3,4-triazole), tetrazole or oxadiazole; B denotes C(R7)(R8) or C(R7), where if the bond between B and Y is a single bond, B denotes C(R7)(R8), and when the bond between B and Y is a double bond, B denotes C(R7); Y denotes C(R7), C(R7)(R8) or O, where if the bond between B and Y is a single bond, Y denotes C(R7)(R8) or O, and when the bond between B and Y is a double bond, B denotes C(R7); Z1 denotes -CH2-, -(CH2)2-, -CH2CH-CH3-, where Z1 is bonded on the left side to a nitrogen atom or -(CH2)3-; X denotes C(R1) or N; A denotes quinolyl, quinazolinyl or benzofuranyl, any of which is optionally substituted with 1-4 substitutes, which can be identical or different and are selected from a group comprising halogen, cyano, C1-6-alkyl, halogen-C1-6-alkyl, C(O)N(R3)(R4), 5-member heterocyclic ring containing 1-3 heteroatoms selected from N or O. The heterocyclic ring is optionally substituted with C1-6-alkyl; when R is present, each independently denotes halogen, C1-6-alkyl; each R1 denotes hydrogen or methyl; each R2 denotes cyano, C1-6-alkyl, C1-6-alkoxy, halogen-C1-6-alkyl, =O, -C(O)N(R3)(R4), -C(O)N(R3)-C1-6-alkoxy, -C(NOR5)R6, -C(O)R6, -C(O)OR7, -C(O)NHNHC(O)R6, 5-member heterocyclic ring containing 1-3 heteroatoms selected from N or O. The heterocyclic ring is optionally substituted with C1-6-alkyl; R3 and R4 independently denote hydrogen; C1-6-alkyl; C3-7-cycloalkyl; C3-7-cycloalkyl-C1-6-alkyl; or when R3 and R4 are bonded to the same nitrogen atom, they, together with the nitrogen atom, they form a 4-, 5- or 6-member ring which optionally contains one extra O atom in the ring; R5 denotes C1-4-alkyl; R6 denotes C3-7-cycloalkyl or C1-6-alkyl; R7 and R8 independently denote hydrogen or C1-6-alkyl; p equals 0, 1 or 2; r equals 0, 1, 2 or 3; s equals 0, 1, 2 or 3. The invention also relates to 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide, 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperidinyl]ethyl}imidazo-[1,5-a]quinoline-3-carboxamide, dihydrochloride 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxamide, 7-methyl-6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide, to use of the compound in any of claims 1-16, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, having 5-HT1 receptor mediated activity.

23 cl, 195 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of a compound of formula , where R1 is an alkyl or aryl group, or a pharmaceutically acceptable salt or solvate thereof, including hydrate, involving reaction of a compound of formula with a Grignard reagent of formula , where X is a halogen selected from Cl, Br and I, and R1 is an alkyl or aryl group; and optional conversion of the obtained free base compound of formula (I) to a pharmaceutically acceptable salt. The invention also relates to a compound of formula II; a compound of formula , where X is a halogen selected from O, Br and I and to use of formula II and IIIA compounds in synthesis of delmopinol and a derivative of the formula I compound.

EFFECT: novel method for synthesis of a compound of formula I using novel intermediate compounds of formulae II and IIIA.

18 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I or its pharmaceutically acceptable salt , where R, R9, Z, X, Q and Y are defined in the formula of invention. The compounds are chemokine receptor 2 and chemokine receptor 5 antagonists and can be used as a medicinal agent for preventing, relieving or treating autoimmune or inflammatory diseases or conditions.

EFFECT: obtaining a formula (I) compound, a pharmaceutical composition based on the formula (I) compound, use of the compound in paragraph 1 to prepare a medicinal agent for treating an autoimmune or inflammatory disease or condition, as well as use of the compound in paragraph 1 to prepare a medicinal agent for treating HIV infection or AIDS.

11 cl, 181 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula I. In general formula I A is C or N; B, D and E independently represent CR4, NR5, N, O or S; and a ring containing groups A, B, D, E, selected from thienyl, furan, imidazole, oxazole, isothiazole, thiazole, pyrrol, pyrazole; provided that: b) when A is N, not any of B, D, E can be O or S; and c) when A is C, B is CR4 and one of D or E is N or NR5, when any of D or E cannot be NR5 or N; G is N or C; R1 represents one or more substitutes selected from H, Ra halogen, -OH and -ORa; R2 represents one or more substitutes selected from H, halogen and C1-6-alkyl, and also one of substitutes R2 can be -ORb' , -NRb' Rb', -SRb', -SORb', -SO2Rb', -SO2NRb' Rb'; R3 is H, or Cy, selected from phenyl optionally substituted with one or more substitutes selected from Rc , where Rc independently represents halogen, -ORg', where Rg' independently represents a Rg group, where Rg is C1-6-alkyl; each R4 independently represents H, Re, halogen, -CORe', -CO2Re', -CONRe'Re', -NRe'Re'; R5 independently represents H, Re, -CORe, -CONReRe, -SORe or -SO2Re; each Ra independently represents C1-6-alkyl or halogen- C1-6-alkyl; each R independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rb' independently represents H or Rb; each Rc independently represents halogen, -ORg', -CONRg'Rg', -NRg'Rg'; Rd is Cy optionally substituted with one or more Rf substitutes; each Rc independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rc and Cy*, or Re is Cy, where any of the groups Cy or Cy* can optionally be substituted with one or more substitutes selected from Rc and Rg ; each Re' independently represents H or Re; each Rf independently represents a halogen, -ORh', -CO2Rh; each Rg independently represents Rd or C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rg' independently represents H or Rg; each Rh independently represents C1-6-alkyl, halogen-C1-6-alkyl or hydroxy- C1-6-alkyl; each Rh' independently represents H or Rh; and Cy or Cy* given in definitions above is a partially saturated, saturated or aromatic 3-7-member monocyclic carbocyclic ring which optionally contains 1-2 heteroatoms selected from N and O, and where the ring or rings can be bonded to the remaining part of the molecule through a carbon or nitrogen atom.

EFFECT: obtaining formula I compounds with p38-kinase inhibitory properties which can be used in making drugs for treating such diseases as tumour immune and autoimmune diseases etc.

21 cl, 10 dwg, 8 tbl, 57 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazoquinoline derivatives or pharmaceutically acceptable salts thereof, tautomers thereof and pharmaceutically acceptable salts of tautomers, having general formula where R1 is -NR6R7, -(CH2)mCH=CH(CH2)nR9, -(CH2)mC=C(CH2)nR9 or -S(O)qR10; R2 is C1-6alkyl or C1-6alkyl which is substituted with one group selected from -OH and -OMe; each R4 and R5 is independently H, C6aryl-C1alkyl or a protective group; each of R6 and R7 is independently H, C1-6alkyl, C1-6alkyl which is substituted with one group selected from -OH and -OMe, C1-6alkoxy-C1-2alkyl or -(CH2)mCH=CH(CH2)nR9; each R9 is independently H, C1-6alkyl, or C6-10aryl; each R10 is independently C1-3alkyl or C6-10aryl-C1-6alkyl; each of m and n is independently equal to 0 or 1; and each q is independently equal to 0; provided that if R1 is -S-Me, R2 is isobutyl. The invention also relates to specific compounds, methods for synthesis of compounds of formulae and which are versions of formula I, a pharmaceutical composition based on formula I compounds and compositions based on formula I compounds and an additional immunogenic composition or antigen.

EFFECT: novel imidazoquinoline derivatives, which are suitable for modulating immune response in a subject, are obtained.

37 cl, 4 dwg, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the following compounds: 4-[1-(2-chlorophenyl)-3-methyl-4-oxo-5-piperidin-1-yl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]phenyl ether 3,3,3-trifluoropropane-1-sulphonic acid; 4-[1-(2,4-dichlorophenyl)-3-methyl-4-oxo-5-piperidin-1-yl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]phenyl ether 3,3,3-trifluoropropane-1-sulphonic acid; 4-[1-(2-chloro-4-fluorophenyl)-3-methyl-4-oxo-5-piperidin-1 -yl-4,5,6,7-tetrahydro-1 H-pyrrolo[3,2-c]pyridin-2-yl] phenyl ether 3,3,3-trifluoropropane-1-sulphonic acid; 1-(2-chlorophenyl)-3-methyl-5-piperidin-1-yl-2-[4-(4,4,4-trifluorobutoxy)phenyl]-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one; a pharmaceutical composition based on said compounds, having CB1(cannabinoid)-modulator activity, as well as use of said compounds in preparing a medicinal agent for treating diabetes or obesity.

EFFECT: possibility of using compounds in treating psychiatric and neurological disorders.

7 cl, 15 ex

FIELD: chemistry.

SUBSTANCE: compounds are suitable for use as kinase 1β-adrenergic receptor (βARK-1) inhibitors. The invention also relates to compositions containing such compounds and to use of compounds of formula to treat and prevent chronic heart failure, hypertension myocardial ischemia and hepatitis C viral infections (HCV) and for preventing opiate addiction. The invention also pertains to methods of producing formula (I) compounds.

EFFECT: more effective use of the compounds.

11 cl, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described 3,4-substituted piperidines applicable in diagnostics and drug therapy of a warm-blooded animal, preferentially for therapy of a disease which depends on renin activity; application of a compound of such kind for preparing a pharmaceutical composition for therapy of the disease which depends on renin activity; application of the compound of such kind for therapy of the disease which depends on renin activity; the pharmaceutical compositions containing 3,4-substituted piperidine, and/or a therapeutic mode involving administration of 3,4-substituted piperidine, a method for producing 3,4-substituted piperidine. The preferential compound (which also can be presented in the form of salts) are described by formula I' wherein R1, R2, T, R3 and R4 are such as described by the patent claim.

EFFECT: production of the compounds for therapy of the disease which depends on renin activity.

28 cl, 1 tbl, 375 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel pyrazole derivatives of formula (I) or pharmaceutically acceptable salts thereof, having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths accompanied by high level of Trk, to a method of producing said derivatives, use thereof to prepare a medicinal agent, pharmaceutical compositions based on said derivatives, a method of inhibiting Trk activity and a method of obtaining antiproliferative action. where A denotes a single bond or C1-2alkylene; where the said C1-2alkylene can be optionally substituted with one R22; ring C is a phenyl or a 5-6-member heterocyclic ring with 1-2 heteroatoms selected from N or S. Values of R1-R7, R22 and n are given in the formula of invention.

EFFECT: obtaining pharmaceutically acceptable salts having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths.

20 cl, 5 dwg, 193 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to the following compounds: N-(1-{4-[2-(1-acetylamino-ethyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2,-trofluoro-1-methyl-ethoxy)-benzamide, N-(1-{4-[2-(1-methyl-1-hydroxy-ethyl)-1-ethyl-1H-imidazole-4-yl}-benzyl}-3-hydroxy-propyl)-3-chloro-4-(,2,2,2-trifluoro-1-methyl-ethoxy)-benzamide, N-(1-{4-[2-(1-hydroxy-1-methyl-ethyl)-1-methyl-1H-imidazole-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2,-trifluoro-1-methyl-ethoxy)-benzamide, 3-chloro-N-[2-[(N,N-dimethylglicyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridine-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide, 3-chloro-N-(1-(2-(dimethylamino)acetamido)-3-(4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl)propan-2-yl)-4-isopropoxybenzamide, 3-chloro-N-(2-[(2-methylalanyl)amino]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide, 3-chloro-N-[(3-hydroxy)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridine-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide, as well as to their pharmaceutically acceptable salts.

EFFECT: obtained compounds and salts can be used for treatment cell proliferative diseases and disorders by modulating activity of mitotic kinesin CENP-E.

26 cl, 102 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel acetylenyl-pyrazole-pyrimidine derivatives of general formula (I), having mGluR2 (metabotropic glutamate receptor) antogonist properties). In compounds of general formula (I): either E and J denote N, G denotes C and L denotes N, M denotes CH, or M denotes N, L denotes CH; or L and G denote N, E denotes C, and J and M denote CH; or J, G and L denote N, E denotes C, and M denotes CH; or E and L denote N, J and M denote CH, and G denotes C; R1 denotes H, halogen, CF3, CHF2 or C1-6alkyl; R2 denotes H, halogen, C1-6-alkyl, C1-6-alkoxy, CF3 or CHF2, wherein R1=R2≠H; R3 denotes H; -C(CH3)2OH; linear C1-4-alkyl or C3-4-cycloalkyl, which are possibly substituted with one or more substitutes selected from a group comprising 1-3 F and 1-2 OH; A is selected from a group comprising phenyl or a 5- or 6-member heteroaryl having in the ring 1-2 heteroatoms selected from nitrogen, sulphur or nitrogen and sulphur in the 5-member ring, and 1-2 nitrogen atoms i the 6-member ring, and possibly substituted with 1-3 Ra; Ra denotes halogen; hydroxy; cyano; CF3; NReRf; C1-C6-alkyl, possibly substituted amino or hydroxy; ; C1-6-alkoxy; C3-4-cycloalkyl; CO-NRbRc, SO2-NRbRc; or SO2-Rd-; Rb and RC can be identical or different and are selected from a group comprising H; normal or branched C1-6-alkyl, possibly substituted with one or more substitutes selected from a group comprising F, cyano, hydroxy, C1-6-alkoxy, -NH-C(O)-O-C1-6-alkyl, amino, (C1-6-alkyl)amino, di(C1-6-alkyl)amino, heterocycloalkyl having 6 ring atoms, from which 1-2 heteroatoms are selected from nitrogen or nitrogen and oxygen, or a 6-member heteroaryl with one nitrogen heteroatom in the ring; or a 6-membeer heteroaryl with one nitrogen heteroatom in the ring; or Rb and Rc, together with the nitrogen atom with which they are bonded, can form a heterocyclic ring having 6 members in the ring, from which 1-2 atoms are selected from nitrogen and/or oxygen, and which can be substituted with C1-6-alkyl; Rd denotes OH or C1-6-alkyl; Re and Rf denote H, C1-6-alkyl, possibly substituted hydroxy, -C(O)- C1-6-alkyl; S(O)2-C1-6-alkyl.

EFFECT: compounds can be used in preparing medicinal agents for treating central nervous system (CNS) disorders, such as Huntington's chorea, amyotrophic lateral sclerosis, dementia caused by AIDS, parkinsonism etc.

55 cl, 6 dwg, 321 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel derivatives of 1H-imidazo [4,5-c]quinolines of formula II or pharmaceutically acceptable salts thereof, where R3 is selected from a group comprising -Z-Y-R4, -Z-Y-X-Y-R4, -Z-R5, -Z-Het, -Z-Het'-R4, and -Z-Het'-Y-R4; Z is selected from a group which includes C1-C6alkylene; n equals 0; R1 is selected from a group comprising R4, -X-R4 and -X-Y-R4; R2 is selected from a group comprising C1-C6alkyl, C1-C6alkoxy, hydroxyC1-C6alkyl and C1-C6alkoxy-C1-C6alkyl; X is selected from a group comprising C1-C6alkylene, C6arylene, heteroarylene which is thienyl, and heterocyclylene which is piperzinyl, where the alkylene group can be optionally broken by -O- group; Y is selected from a group comprising -S(O)0-2-, -C(R6)-, -C(R6)-O-, -O-C(R6)-, -N(R8)-Q-, -C(R6)-N(R8)-, and R4 is selected from a group comprising hydrogen, C1-C6alkyl, C2alkenyl, C1-C10aryl, C6aryl-C1alkylenyl, and heteroaryl selected from pyridyl, thienyl, benzodioxanyl and others (see claim 1), where C1-C6alkyl, C2alkenyl and C6-C10aryl can be unsubstituted or substituted with one or two substitutes which are independently selected from a group comprising C1-C6alkyl, C1-C4alkoxy, CF3-O-; halogen, nitro, hydroxy, mercapto, cyano, C6-10aryl, C6aryloxy, C6aryl-C1alkyleneoxy, thienyl, morpholinyl, amino, C1alkylamino, di-C1alkylamino, heterocyclyl group and an oxo-group; R5 is selected from a group comprising and R6 is selected from a group comprising =O and =S; R7 is C2-3akylene; R8 is selected from a group comprising hydrogen and C1-C3alkyl; R10 is C4alkylene; A is selected from a group comprising -O-, -C(O)-, -S(O)0-2-, and -N(R4)-; Het is heterocyclyl selected from morpholinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl and others (see claim 1), which can be unsubstituted or substituted with one or more substitutes which are independently selected from a group comprising C1-C2alkyl, hydroxy, hydroxy-C1-C2alkyl, amino, C1-C2alkylamino, di-C1-C2alkylamino, heterocyclyl group and oxo; Het' is heterocyclylene selected from imidazolinyl and piperidinyl; Q is selected from a group comprising a covalent bond, -C(R6)-, -C(R6)-C(R6)-, -S(O)2-, -C(R6)-N(R8)-W-, -S(O)2-N(R8)- and -C(R6)-O-; V is selected from a group comprising -C(R6)-, -O-C(R6)-, -N(R8)-C(R6)-, and -S(O)2-; W is selected from a group comprising a covalent bond, , -C(O)-, and -S(O)2-; a and b are independently integers from 1 to 6, provided that a+b≤7; provided that Z can also denote a covalent bond when R3 is -Z-Het, -Z-Het'-R4, or -Z-Het'-Y-R4, or R3 is -Z-Y-R4 or -Z-Y-X-Y-R4, and Y is selected from a group comprising -S(O)0-2-, -C(R6)-, -C(R6)-O-, -C(R6)-N(R8)- and The invention also relates to a pharmaceutical composition based on the formula II compound, a method of inducing biosynthesis of cytokines, a method of treating a viral disease and an oncological disease using the compound of formula II.

EFFECT: novel derivatives of 1H-imidazo [4,5-c]quinoline, which are useful in treating viral and oncological diseases, are obtained.

37 cl, 130 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) in form of (R) or (S) isomers, separately or in a mixture, as well as their physiologically acceptable salts and hydrates, having vitronectin receptor antagonist properties. In formula (I)

G denotes Het-NH-CO-, Het-NH-CH2-, Het-; Het denotes a mono- or bicyclic system, where each ring is a 5- or 6-member aromatic or non-aromatic ring, where at least one of the rings contains 1-2 nitrogen atoms as heteroatoms, where Het is unsubstituted or substituted with R9 groups; R1 denotes H, (C6-C14)-aryl, (C6-C14)aryl(C1-C4)alkyl; amino, unsubstituted, mono-or disubstituted with alkyl and/or acyl, containing 1-4 C atoms; R2 denotes H, halogen, nitro-group; alkyl containing 1-4 C atoms; amino, unsubstituted, mono- or disubstituted with alkyl and/or acyl containing 1-4 C atoms; a -(CH2)0-2-OR5 group; R3 denotes H, -CO2R5, -SO2R5 or mono- or bicyclic system, where each ring denotes a 5- or 6-member aromatic or non-aromatic ring, where at least one of the rings contains 1-4 heteroatoms selected from N, O or S, unsubstituted or substituted with R9 radicals; R4 denotes OH, (C1-C8)alkoxy-; amino, unsubstituted, mono- or disubstituted with (C1-C4)alkyl; or an aminoacid residue; R5 denotes (C1-C8)alkyl; (C6-C14)aryl; (C6-C14)aryl(C1-C4)alkyl; (C3-C12)cycloalkyl or (C3-C12)cycloalkyl(C1-C4)alkyl; bi- and tricycloalkyl(C1-C4)alkyl. Aryls, alkyls, cycloalkyls are not substituted or substituted with R9 groups; R9 denotes halogen, amino, nitro, hydroxyl, (C1-C4)alkyloxy-, carboxy, (C1-C4)alkyloxycarbonyl-, (C1-C8)alkyl, unsubstituted or substituted with halogen atoms; phenyl. The invention also relates to a methods for synthesis of formula (I) compounds, a medicinal agent and a pharmaceutical composition containing said compounds, as well as use thereof in preparing the medicinal agent.

EFFECT: improved properties of the compound.

21 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates or tautomers thereof, where substitute M is selected from groups D1 and D2, having structural formulae given below, and R1, E, A and X are as described in the formula of invention. Disclosed also are pharmaceutical compositions which contain these compounds, methods for synthesis of these compounds, intermediate compounds and synthesis methods thereof, as well as use of compounds of formula (I) in preventing or treating diseases mediated by CDK kinases, GSK-3 kinases or Aurora kinases.

EFFECT: high effectiveness of the compounds.

40 cl, 8 dwg, 18 tbl, 84 ex

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