5-hydroxymethyloxazolidin-2-one derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula , where R1 denotes OH, OPO3H2 or OCOR5; R2 denotes H, OH or OPO3H2; A denotes N or CR6; R3 denotes fluorine; R4 denotes H, C1-3alkyl or C3-6cycloalkyl; R5 denotes an alanine residue; R6 denotes H, C1-6alkoxy group or halogen; and n=0 or 1; and to pharmaceutically acceptable salts of compounds of formula I. The invention also relates to a pharmaceutical composition having antibacterial activity, and to use of compounds of formula I to obtain a medicinal agent for preventing or treating bacterial infections.

EFFECT: compounds of formula I, having antibacterial activity.

14 cl, 3 dwg, 2 tbl, 14 ex

 

The present invention relates to new hybrid antibiotics, which are obtained from derivatives oxazolidinone related chinolones or naphthyridinone through a spacer, a pharmaceutical antibacterial composition containing them and the use of these compounds to obtain drugs for the treatment of infections (e.g. bacterial infections). These hybrid compounds useful as antimicrobial agents, effective against various pathogens in humans and animals, including, among others, gram-positive aerobic bacteria, gram-negative bacteria, anaerobic organisms, and acid-fast organisms.

The intensive use of antibiotics has a selective developmental pressure on microorganisms, contributing to the production of genetically formed of the mechanisms of resistance. Modern medical and socio-economic behavior exacerbates the problem of resistance development, creating conditions for slow growth of pathogenic microorganisms, for example, artificial joints and in terms of long-term support of the reserves of the host, for example, immunological "compromised" patients.

In hospitals the increase of a number of strains of Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus spp. and Pseudomonas aeruginosa, the main sources of infecti is, makes them resistant and difficult, until a cure is not possible at all:

- S.aureus is resistant to β-lactam, chinolone and now even to vancomycin;

- S.pneumoniae is resistant to penicillin, chinolone and even to new macrolides;

- Enteroccocci are resistant to chinolone and vancomycin and β-lactams have no effective action on these strains.

In addition, the new recently introduced organisms-type Acinetobacter spp. or .difficile that are taken when conducting therapy with the use of modern antibiotics, have become a real problem in hospital treatment.

In addition, microorganisms that cause persistent infections, increasingly recognized as agents that cause or cofactors of various chronic diseases such as peptic ulcer or heart disease.

In the hybrid molecules of two or more molecules, which exist separately in their natural state, combine together to form a single object (i.e. molecules)having the desired functionality of all of its constituent molecules.

Molecules, which are two antibiotic with two different models of the actions presented in the literature (e.g., Journal of Antimicrobial Chemotherapy, (1994), 33, 197-200). Many of them, however, are those where the two h the activity of antibiotics act after biological activation (for example, removal of difficult-ether grouping, cleavage of β-lactam). Information about chemical and biochemical stability of hybrid molecules that are associated with two different targets, rarely found in the literature. For example, hybrids oxazolidinone-hinolan described as antimicrobial agents, effective against resistant pathogens, in publications: WO 03/032962, WO 03/031443 and WO 2004/096221, WO 2005/023801 and WO 2005/058888). In addition, synthetic and biological evaluation of these hybrids (Bioorg. & Med. Chem., (2003), 11, 2313-2319) and the effect of the Central spacer on antibacterial activity in vzaimootnoshenii structure-activity in a series of oxazolidinone-hinolan also investigated (Bioorg. Med. Chem. Lett. (2003), 13, 4229-4233). All these derivatives include 4-aminoethylethanolamine the remainder as part oxazolidinones of pharmacophore.

Recently it has been unexpectedly found that a hybrid derivative of the formula I according to the definition, the following are particularly effective as antimicrobial agents against a number of bacteria with multilocational resistance.

Thus, the present invention relates to compounds of formula I

where R1is a HE, ORO3H2or OCOR5;

R2represents H, HE or ORO3H2;

And represents N or CR6 ;

R3represents H or fluorine;

R4represents H, C1-3alkyl or cycloalkyl;

R5represents a residue of a natural amino acid, of the enantiomer of natural amino acids or dimethylaminopyridine;

R6represents H, alkoxygroup or halogen; and

n=0 or 1;

and to the salts (in particular pharmaceutically acceptable salts) of compounds of formula I.

The compounds of formula (I) can contain one or more stereo or asymmetric centers, such as one or more asymmetric carbon atoms. The compounds of formula (I) may thus be present as mixtures of stereoisomers or, preferably, in the form of pure stereoisomers. Mixture of stereoisomers can be separated using methods known to experts in the field of engineering.

In the following paragraphs presents the definitions of the various chemical fragments for compounds according to the invention. These definitions are intended for uniform application throughout the description and in the claims, unless otherwise specified and if the definitions are not subject to wider or, conversely, a narrower interpretation.

Unless otherwise specified, the term "alkyl", used alone or in combination, refers to a saturated linear or branched alkyl group containing is she from 1 to 6 carbon atoms, and preferably, from 1 to 3 carbon atoms. Typical examples of alkyl Grupp include, but not limit, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl and isohexyl. The term "C1-xalkyl" (x represents an integer) refers to a saturated linear or branched alkyl group containing from 1 to x carbon atoms.

The term "alkoxygroup" refers to saturated linear or branched alkoxygroup containing from 1 to 6 carbon atoms, preferably from 1 to 3 carbon atoms. Typical examples of alkoxygroup include, but not limit, a methoxy group, ethoxypropan, propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, sec-butoxypropyl, tert-butoxypropan or n-hexyloxy. The term "C1-xalkoxygroup" (x represents an integer) refers to a linear or branched alkoxygroup containing from 1 to x carbon atoms.

The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably by fluorine or chlorine.

The term "cycloalkyl", used alone or in combination, refers to a saturated cyclic fragment, containing from 3 to 6 carbon atoms, preferably from 3 to 5 carbon atoms. Typical examples cycloalkyl groups include, but are not limited to, cyclopropyl and Cyclops is Teal.

When it is noted that R5represents the balance of amino acids, this means that R5-COOH is an amino acid.

The term "pharmaceutically acceptable salts" refers to non-toxic, inorganic or organic acid and/or basic additive salts. Information about such salts can be naidni in the publication: "Salt selection for basic drugs". Int. J. Pharm. (1986), 33, 201-217.

When we are not talking about temperatures, the term "approximately", located in front of the numerical value "X" refers in the customary application to the interval of X minus 10% of X to X plus 10% of X, and preferably to an interval of X minus 5% of X to X plus 5% of X. In the special case regarding temperatures, the term "approximately" (or, alternatively, the term "about"), located in front of the temperature "Y"refers in the customary application to the temperature interval of Y minus 10°C. to Y plus 10°C., and preferably to an interval of Y minus 5°C. to Y plus 5°C; in addition, the room temperature in this specification means a temperature of about 25°C.

In particular, the invention relates to compounds of the formula I, which are also compounds of the formula ICE

where R1is a HE, ORO3H2or OCOR5;

R2represents H, HE or ORO H2;

And represents N or CR6;

R3represents fluorine;

R4represents H, C1-3alkyl or cycloalkyl;

R5represents the balance of the natural amino acids (in particular, the residue is alanine);

R6represents H or alkoxygroup; and

n=0 or 1;

and to the salts (in particular pharmaceutically acceptable salts) of compounds of formula ICE.

According to the first basic version of the implementation of the present invention, the compounds of formula I are compounds where n=0. Such compounds are referred hereinafter to compounds of the formula I5".

According to one particular variant of the first main variant of the invention, the compounds of formula I5are those compounds which have the following stereochemical formula:

According to another variant of the first main variant of the invention, the compounds of formula I5are those compounds which have the following stereochemical formula:

According to the second variant basic variant of the invention, the compounds of formula I are those compounds where n=1. Such compounds are referred hereinafter to compounds of the formula I6".

According to the next main version of the implementation is tvline of the present invention, compounds of formula I are those compounds, which are also compounds of the formula ID

where R2represents H or HE;

And represents N or CR6;

R3represents fluorine;

R4represents H, C1-3alkyl or cycloalkyl;

R6represents H or alkoxygroup; and

n=0 or 1.

According to another another main variant of implementation of the present invention, compounds of formula I are those compounds, which are also compounds of the formula IPDG

where R1HE is a and R2represents ORO3H2or R1represents ORO3H2or OCOR5and R2represents H, HE or ORO3H2;

And represents N or CR6;

R3represents fluorine;

R4represents H, C1-3alkyl or cycloalkyl;

R5represents the balance of the natural amino acids (in particular, the residue is alanine);

R6represents H or alkoxygroup; and

n=0 or 1.

According to a special variant of implementation of the present invention, compounds of formula I are those compounds where a is an n

According to others the Gomu special variant of implementation of the present invention, compounds of formula I are those compounds where a is a CR6. In this case, R6preferably represents N or alkoxygroup (and in particular H or a methoxy group).

According to an important variant of implementation of the present invention, compounds of formula I are those compounds where R1IT refers.

Another important variant of implementation of the present invention, compounds of formula I are those compounds where R1indicates ORO3H2or OCOR5.

According to another another important variant of implementation of the present invention, compounds of formula I are those compounds where R2denotes N.

According to another another important variant of implementation of the present invention, compounds of formula I are those compounds where R2IT refers.

According to the next important option of implementing the present invention, compounds of formula I are those compounds where R2indicates ORO3H2.

Preferably, the amino acid residue is R5is such that R5-COOH represents a natural amino acid (preferably alanine).

Preferred compounds of formula I are those compounds which contain, in kr is ina least one of the following characteristics:

- And represents CR6;

- R1is a HE or ORO3H2;

- R2represents H or HE;

- R3represents fluorine;

- R4represents a C1-3alkyl or cycloalkyl.

More preferred compounds of formula I are those compounds which contain at least one of the following characteristics:

- n=0;

- And represents CR6, R6this represents H or alkoxygroup (and preferably H or a methoxy group);

- R1represents IT;

- R2represents H or HE;

- R3represents fluorine;

- R4is cycloalkyl.

Even more preferred compounds of formula I are those compounds which contain at least one of the following characteristics:

- n=0;

- And represents CR6, R6this represents H or a methoxy group;

- R1represents IT;

- R2represents H or HE (and preferably ONE);

- R3represents fluorine;

- R4represents a C3-5cycloalkyl (and in particular, cyclopropyl).

The following compounds of formula I are particularly preferred:

1-Cyclops the sawdust-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-4-hydroxypiperidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]piperidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-4-hydroxypiperidine-1-yl}-4-oxo-1,4-dihydro-[1,8]naphthiridine-3-carboxylic acid;

7-(4-{4-[(R)-5-((S)-2-aminopropionitrile)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-2-oxo-5-phosphonomethylglycine-3-yl)phenoxymethyl]-4-hydroxypiperidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-cyclopropyl-6-fluoro-7-{(R)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-3-hydroxypyrrolidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-cyclopropyl-6-fluoro-7-{(S)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-3-hydroxypyrrolidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-cyclopropyl-6-fluoro-7-{(R)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-3-hydroxypyrrolidine-1-yl}-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-cyclopropyl-6-fluoro-7-{(S)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-3-hydroxypyrrolidine-1-yl}-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic Ki the lot;

1-cyclopropyl-6-fluoro-7-{(R)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]pyrrolidin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-cyclopropyl-6-fluoro-7-{(S)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]pyrrolidin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-cyclopropyl-6-fluoro-7-{(R)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]pyrrolidin-1-yl}-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-cyclopropyl-6-fluoro-7-{(S)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]pyrrolidin-1-yl}-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-4-phosphonoacetate-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-ethyl-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]piperidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

7-(4-{4-[(R)-5-((S)-2-aminopropionitrile)-2-oxoacridine-3-yl]-2-forfinancial}piperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-4-hydroxypiperidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)proximate the l]-4-hydroxypiperidine-1-yl}-4-oxo-1,4-dihydro-[1,8]naphthiridine-3-carboxylic acid;

and their salts (in particular pharmaceutically acceptable salts).

Hybrid derivative of the formula I suitable for use as medicines, especially as antimicrobial agents in medicine and in veterinary medicine for the treatment of animals such as pigs, ruminants, horses, dogs, cats and poultry.

Hybrid derivative of the formula I according to the present invention are also used for getting medicines for the treatment of infections (especially bacterial infections or protozoal infections) and diseases associated with infections (especially diseases related to bacterial infections or protozoal infections).

Compounds according to the present invention are particularly active against bacterial and similar bacteria organisms and are therefore particularly suitable for humans and animals in the prophylaxis and chemotherapy of local and systemic infections caused by these pathogens, and diseases associated with bacterial infections, including pneumonia, otitis media, sinusitis, bronchitis, tonsillitis, and mastoiditis related to infection caused by Streptococcus pneumoniae, Haemophilus influenzas, Moraxella catarrhalis, Staphylococcus aureus, Enterococcus faecalis, E.faecium, E.casseliflavus, S.epidermidis, S.haemolyticus or Peptostreptococcus spp.; pharyngitis, rheumatic fever and glomer anephric, associated with infection caused by Streptococcus pyogenes, groups C and G streptococci, Corynebacterium diphtheriae, or Actinobacillus haemolyticum; infections of the upper respiratory tract associated with infection caused by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae; infections of the blood and tissues, including endocarditis and osteomyelitis, caused by S.aureus, S.haemolyticus, E.faecalis, E.faecium, E.durans, including hereditary resistance to known antibacterial agents such as, not limited to, β-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracyclines and macrolides; uncomplicated skin infections and and soft tissue abscesses and postpartum sepsis associated with infection caused by Staphylococcus aureus, coagulability susceptible (that is, S.epidermidis, S.haemolyticus and the like). Streptococcus pyogenes, Streptococcus agalactiae, Streptococcal groups C-F (the smallest colony streptococci), viridans streptococci, Corynebacterium minutissimum, Clostridium spp. or Bartonella henselae; uncomplicated acute urinary tract infections related to infection caused by Staphylococcus aureus, coagulability species staphyloccocal or Enterococcus spp.; urethritis and cervicitis; sexually transmitted diseases related to infection caused by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrhoeae; toxicosis associated with infection caused by S.aureus (food poisoning and toxic shock syndrome), or groups a, b and C streptococci; ulcers related to infection, is called Helicobacter pylori; systemic febrile syndrome associated with infection caused by Borrelia recurrentis; Lyme disease related to infection caused by Borrelia burgdorferi; conjunctivitis, keratitis, and dacryocystitis associated with infection caused by Chlamydia trachomatis, Neisseria gonorrhoeae, S.aureus, S.pneumoniae, these bacteria to antibiotics, H.Influenzae, or Listeria spp.; disseminated Mycobacterium avium complex (MAC)associated with infection caused by Mycobacterium avium, or Mycobacterium intracellulare; infection caused by Mycobacterium tuberculosis, M.leprae, M.paratuberculosis, M.Kansasii or .chelonei; gastroenteritis related to infection caused by Campylobacter jejuni; intestinal protozoal infections associated with infection caused by Cryptosporidium spp.; dental infection associated with infection caused by viridans streptococci, persistent cough associated with infection caused by Bordetella pertussis; gas gangrene related to infection caused by Clostridium perfringens or Bacteroides spp.; and atherosclerosis or cardiovascular disease related to infection caused by Helicobacter pylori or Chlamydia pneumoniae.

The compounds of formula I according to the present invention are applied, in addition, to obtain drugs for the treatment of infections caused by such bacteria as E. coli, Klebsiella pneumoniae and other enterobacteria, Acinetobacter spp., Stenothrophomonas maltophilia, Neisseria meningitidis, Bacillus cereus, Bacillus anthracis, Corynebacterium spp., Propionibacterium acnes and bacteroids spp. In addition, the compounds of formula I according to the present image is the shadow applied in addition, to obtain drugs for the treatment of infections caused by Clostridium difficile.

The compounds of formula I according to the present invention are applied, in addition, for the treatment of protozoal infections caused by Plasmodium malaria, Plasmodium falciparum, Tokcoplasma gondii, Pneumocystis carinii, Trypanosoma brucei and Leishmania spp.

Presents a list of pathogens should be considered only as examples and in no way as limiting the list.

Just as in humans, bacterial infection can be treated and in other species of animals, for example, such as pigs, ruminants, horses, dogs, cats and poultry.

Therefore, the compounds of formula I or their pharmaceutically acceptable salts can be used to produce drugs, and are suitable for the prevention or treatment of bacterial infections (particularly infections caused by pathogenic microorganisms mentioned in the list above).

The compounds of formula I and their pharmaceutically acceptable salts can be used as medicines, for example in the form of pharmaceutical compositions for enteral and parenteral administration.

Manufacturing pharmaceutical kompozizii is carried out by a method known to anyone skilled in the art (see, for example, Mark Gibson, Editor, Pharmaceutical Preformuation and Formulation, IHS Health Group, Englewood, CO, USA, 2001; Remington, The Science and Practice of Pharmacy, 20th Edition, Philadelphia College of Pharmacy and Science), by introducing the described compounds of formula I or their pharmaceutically acceptable salts, optionally in combination with other pharmaceutically acceptable substances in dosage form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carriers and, if desired, usual pharmaceutical excipients.

Another aspect of the invention relates to a method of treating infection, comprising the administration to a patient pharmaceutically active amount of a compound of formula I or its pharmaceutically acceptable salt.

Moreover, the compounds of formula I can be used for cleaning purposes, for example for cleaning surgical instruments from pathogenic microbes and bacteria or aseptic clean room or surface. For these purposes the compounds of formula I can be used in the form of a solution or spray.

Any reference to a compound of formula I, I51, I52, I6, IDor IPDGimplies a reference to the salts (in particular pharmaceutically acceptable salts) of compounds of formula I, I51, I52, I6, IDor IPDG, respectively, as appropriate and expedient. In addition, any reference to the compounds of formula I (or connections, the x salt the compositions containing compounds or their salts, the use of the compounds or their salts and the like), of course, with the changes applicable to compounds of formula ICEcompounds of the formula I5compounds of the formula I51compounds of the formula I52compounds of the formula I6compounds of the formula IDand compounds of the formula IPDG.

According to the invention, the compounds of formula I (or of formula ICEcan be obtained using the methods described below.

Obtaining compounds of formula I

Abbreviations:

In the description and examples, the following abbreviations are used:

Asón - acetic acid, AD-mix α - 1,4-bis-(digitonin)phthalazine, K3Fe(CN)6To2CO3and K2OsO4·2H2O, AD-mix β - 1,4-bis-(digitonin)phthalazine, K3Fe(CN)6To2CO3and K2OsO4·2H2O, Alloc - allyloxycarbonyl, BnBr-benzylbromide, Side - tert-butoxycarbonyl, t-BuOK-tert-butyl potassium, CBS - benzyloxycarbonyl, DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene, DHM - dichloromethane, DYADS - diisopropylsalicylic, DIPEA - N,N-diisopropylethylamine, DMA - dimethylacetamide, DMAP - 4-dimethylaminopyridine, DMF is N,N-dimethylformamide, DMSO is dimethylsulfoxide, EA - ethyl acetate, EDC hydrochloride, 1-(dimethylaminopropyl)-3-ethylcarbodiimide, ESI - ionization elektrorazpredelenie, ether or Et2O - IER the silt ether, UH - Express chromatography, h - h, hexane - n-hexane, MeCN is acetonitrile, m-HPBK - m-chloroperbenzoic acid, Meon - methanol, MS is mass spectroscopy, NaOMe - methylate sodium N-MP - N-methylpyrrolidinone, Pd/C or Pd(OH)2/C-palladium or dihydroxypropyl coal PPh3- triphenylphosphine, CT room temperature, SiO2- silica gel, l - tert-butyldimethylsilyloxy, tea is triethylamine, TFA - triperoxonane acid, THF is tetrahydrofuran, TMCCl - trimethylsilane.

A common way of synthesis:

The new compounds of formula I can be obtained in accordance with the present invention by:

a) reaction of compounds of formula II

with the compound of the formula III

where n, A, R3and R4have the meanings indicated in formula I, and R7means

C1-3alkylsulfonyl (for example, methylsulphonyl), trifloromethyl or arylsulfonyl (for example, phenyl - or p-tamilselvan) and R2indicates HE or H, or R2and R7together form a bond (that is, R2and OR7form, together with carbon atoms, containing, epoxy ring), preferably in the temperature range from 10°C to 100°C (more preferably, from about 40°C to 80°C), in the presence of inorganic bases such as2CO 3or organic base such as tea, in an organic solvent (such as DMF);

or through

b) reaction of compounds of formula IV

where n indicated in formula I and R2denotes H or HE,

with the compound of the formula V

where A, R3and R4have the meanings indicated in formula I, Y represents halogen and R8denotes hydrogen, BF2or(OS(=O)(C1-4alkyl)2C1-5alkyl (e.g. methyl, ethyl, n-propyl, isopropyl or tert-botep), allyl, arils1-5alkyl (e.g. benzyl, p-nitrobenzyl or p-methoxybenzyl), three-(C1-5alkyl)silyl (for example, trimethylsilyl or tert-butyldimethylsilyl) or diaries1-5alkylsilane (for example, tert-butyldiphenylsilyl), preferably in the temperature range from 10°C to 100°C, more preferably, between approximately 40°C and 80°C, in the presence of an organic base such as tea or DIPEA, in an organic solvent, for example, N-MP;

or through

C) conversion of the compounds of formula I, where R1IT denotes, in the compound of formula I, where R1indicates ORO3H2or OCOR5while R5is a remnant of the natural amino acids, the enantiomer of natural amino acids or dimethylaminopyridine;

or through the

g) the conversion of compounds of formula IPG

where R1means OPG1(PG1this indicates a protective group for the hydroxyl functional group), R2IT denotes, and n, R3, R4and have the same values that are indicated in the formula I, the compound of formula I, where R2indicates ORO3H2and subsequent removal of the protective group PG1examples of suitable protective group PG1are alkylsilane or diarylethylene group such as trimethylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl (methods of introduction and removal of these protective groups are summarized in the publication: Protecting Groups, Kocienski, P.J., Thieme (1994));

or through

d) the conversion of compounds of formula VI

where R9stands With1-5alkyl (e.g. methyl, ethyl, n-propyl, isopropyl or tert-butyl), aryl-C1-5alkyl (e.g. benzyl, p-nitrobenzyl or p-methoxybenzyl), allyl, three(C1-5alkyl)silyl (for example, trimethylsilyl or tert-butyldimethylsilyl) or diaries1-5alkylsilane (for example, tert-butyldiphenylsilyl), and n, A, R1, R2, R3and R4have the meanings given in formula I, the corresponding compound of formula I by hydrolysis, saponification or hydrogenolysis (for example, to what it is stated in the publication Protecting Groups, Kocienski, P.J., Thieme (1994)).

Considering the above process, it is necessary to focus on several observations:

- on option a), the compound of the formula III can also be replaced by its complex ether, i.e. a compound of formula IIIE

where n, A, R2, R3, R4and R7have the meanings given for formula III, and R10represents an alkyl, allyl or arylalkyl, in this case the stage of removal of the protective hard-ester group must follow the reaction of the compound of formula IIIEwith the compound of the formula II (General methods of removal of the protective hard-ether group, see publication: Protecting Groups, Kocienski, P.J., Thieme (1994));

- on option a), the compound of the formula II can also be substituted silyl ether group, i.e. the compound of formula IIPG

where PG2is a silyl protective group for the hydroxyl functional group such as tri-C1-5alkylsilane (for example, trimethylsilyl or tert-butyldimethylsilyl) or diaries1-5alkylsilane (for example, tert-butyldiphenylsilyl), in this case the stage of removal of the protective group must follow the reaction of the compound of formula III or IIIEwith the compound of the formula IIPG(General methods for carrying out such reactions can be found publikacii: Protecting Groups, Kocienski, P.J., Thieme (1994)), it should be borne in mind that when R2denotes H, condensation between the compound of formula IIPGand the compound of the formula III or IIIEis carried out in the reaction conditions Mitsunobu, as described in the publication: Synthesis (1981), 1, 1-28, and especially in the presence of DYADS and PPh3;

- on option b), the compound of formula IV can also be substituted compound of formula IVp

where n and R2have the meanings given for formula IV, and PG2represents a protective group for the hydroxyl functional group (for example, alkylsalicylate or diarylalkylarsines group such as trimethylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl), in this case, the corresponding stage of removal of the protective group must follow the reaction of the compound of formula IVPwith the compound of the formula V (General methods for carrying out such reactions can be found in the publication: Protecting Groups, Kocienski, P.J., Thieme (1994));

- on option b), when R8is not H, requires an additional step of removal difficult ester group (General methods for carrying out such reactions can be found in the publication: Protecting Groups, Kocienski, P.J., Thieme (1994)), except when R denotes BF2or(OS(=O)1-4alkyl)2and where the Hydra is Liz is already at the stage acid treatment;

- on option), compound of formula I, where R1IT refers, may be substituted compound of formula VI, where R1IT denotes, and R2denotes H or HE in this case requires an additional step of removal difficult ester group (General methods for carrying out such reactions can be found in the publication: Protecting Groups, Kocienski, P.J., Thieme (1994));

- on options C) and d):

the compounds of formula I, where R1or R2denote ORO3H2can be obtained by removing the protective group from compounds where R1or R2means OPO(OR)2and R represents allyl or benzyl (data about the nature of R, about the different methods of removal of the protective groups can be found in the publication: Protecting Groups, Kocienski, P. J., Thieme (1994), an example of methods for removing protective groups can serve as catalytic hydrogenation over an appropriate catalyst such as palladium, or hydrolysis of Hydrobromic acid in a solvent such as Asón, when R represents benzyl);

the compounds of formula I, where R1means OCOR5can be obtained, for example, by reaction of compounds of formula I, where R1IT denotes, or compounds of the formula VI, where R1IT denotes and R2denotes H or HE, with dimethylaminophenol or N-protected amino acid with the subsequent removal of protective the group with the amino group under standard conditions, well-known specialist in the field of engineering (an additional step of removing hard-ether protective group is required in the case of the reaction with the compound of the formula (VI).

The compounds of formula I obtained according to the above General methods of synthesis can then be optionally converted into their salts, namely, their pharmaceutically acceptable salts.

In addition, when the compounds of formula I obtained as a mixture of enantiomers may be separated using methods known to the expert in the field of technology, for example by preparation and separation of the diastereomeric salts or by chromatography on a chiral stationary phase). When the compounds of formula I obtained as a mixture of diastereoisomers, they can be extracted using an appropriate combination of chromatography on silica gel, HPLC and crystallization.

Obtaining various synthetic intermediates:

Obtaining compounds of formula II

The compounds of formula II can be obtained by hydrogenation of compounds of formula VII

over an appropriate catalyst such as palladium or platinum on charcoal, in a solvent such as THF, Meon or AcOEt, in the temperature range from 0°C to 40°C, or by hydrolysis in the presence of a solution of HBr in water or Asón, when temperature is round from 0°C to 80°C and in a solvent such as Asón.

Obtaining the compounds of formula III

The compounds of formula III can be obtained in accordance with the following scheme 1.

Scheme 1

Scheme 1 R8denotes H, alkyl, allyl or arylalkyl, while other symbols are marked previously.

The compounds of formula IIISwhere R2denotes H or HE, R7means SO2R11, R11this denotes alkyl, trifluoromethyl or aryl type, phenyl or p-tolil receive (scheme 1) from compounds of formula IIIAwhere R7denotes H, by reaction with the appropriate sulphonylchloride in the presence of an organic base such as tea in a solvent such as DHL or THF, in a temperature range from -10°C to 50°C. the compounds of formula IIIAreceive by reaction of compounds of formula V with piperidine formula VIII in the presence of an organic base such as tea or DIPEA, in the temperature interval from 40°C to 100°C, in a solvent such as THF, DMF or N-MP. In the case when R8denotes benzyl carboxylic acid of the formula IIISfreed from the protective groups, using standard methods described in the publication: Protecting Groups, Kocienski, P.J., Thieme (1994) (for example, by hydrogenation over Pd/C).

The compounds of formula III, where R2and R7together form a bond, i.e. compounds of formula III O

can be obtained by intramolecular cyclization of compounds of formula IIISwhere R2IT denotes, in the presence of an organic base (such as tea) or inorganic bases (For example, a2CO3or alkali methylate such as NaOMe, or alkali hydride such as NaH).

Obtaining compounds of formula IV

The compounds of formula IV can be obtained, as shown in the diagram below 2.

Scheme 2

The compounds of formula IV can be obtained by removing the protective group from compounds of formula X, where PG3is a nitrogen protective group such as alkoxycarbonyl (e.g., Side), benzyloxycarbonyl (for example, CBZ), allyloxycarbonyl or benzyl. Common methods of implementing a consistent introduction/removal of protection from secondary nitrogen group is described in the publication: Protecting Groups, Kocienski, P.J., Thieme (1994).

The compounds of formula X, where R2IT denotes, get through the reaction of compounds of formula II with a compound of formula IX, where either R2IT denotes and R7means SO2R11while R11denotes alkyl, trifluoromethyl or aryl type, phenyl or p-tolila, or R2and R7together form a bond (epoxide). These epoxide can bytevalue from compounds of formula IX, where R2IT denotes and R7means SO2R11by processing or organic base such as tea, pyridine or DBU, or inorganic base such as K2CO3, in a solvent such as THF or DHM, in the temperature range from -10°C to 40°C. the compounds of formula X, where R2denotes H, get through the reaction of compounds of formula II with a compound of formula IX, where R7means SO2R11. The compounds of formula IX are commercially available (for example, the compounds of formula IX, where PG3indicates the Side, n=0 and R2and R7form an epoxide, or where PG denotes the Side, n=1 and R2=R7=IT) or get them as described below. Alternatively, the compounds of formula X can be obtained by reaction of compounds of formula II with compounds of formula IX, where R7denotes H, the reaction conditions Mitsunobu.

Obtaining compounds of formula V

The compounds of formula V, where R8represents N and Y is halogen, commercially available (for example, compounds where R3denotes F, R4denotes cyclopropyl and a denotes CH, CF, or Soma, or R3denotes F, R4means Et and a denotes CH or CF, or R3denotes F, R4denotes cyclopropyl and N denotes). The compounds of formula V, where R denotes BF2or(Is(=O)(C 1-4alkyl)2receive from compounds of formula V, where R8denotes H, according to the publication WO 88/07998.

Obtaining compounds of formula VI

The compounds of formula VI can be obtained by condensing compounds of the formula IV or, alternatively, compounds of formula IVPaccording to the definition given earlier, with compounds of the formula V according to the definition given previously, except that R8represents a C1-5alkyl (e.g. methyl, ethyl, n-propyl, isopropyl or tert-butyl), aryl-C1-5alkyl (e.g. benzyl, p-nitrobenzyl or p-methoxybenzyl), allyl, Tris1-5alkylsilane (for example, trimethylsilyl or tert-butyldimethylsilyl) or diaryl-C1-5alkylsilane (for example, tert-butyldiphenylsilyl), in the same conditions described for the reaction of compounds of the formula IV with compounds of the formula V. In the case when using the compounds of formula IVP, stage of removal of the protective group may be carried out after the condensation reaction.

Obtaining compounds of formula VII

Compound of formula VII can be obtained according to the publication WO 2004/096221.

Obtaining compounds of formula VIII

The compounds of formula VIII are either commercially available (R2denotes H), or can be obtained by removing the protective group from compounds of formula IX (R2IT denotes and R7denotes H), for example, POS is edstam processing Side-secure connections using TFA or by hydrogenation of the corresponding CBZ-secure connections over Pd/C.

Obtaining compounds of formula IX

The compounds of formula IX can be obtained from methylidene derivatives of formula XI, as shown in the diagram below, 3.

Scheme 3

The compounds of formula HB, i.e. the compounds of formula IX, where R2denotes H or HE and R7means SO2R11receive from the corresponding compounds of formula A, where R7denotes H, using the same methods that were used in the conversion of compounds of formula IIIAin the compounds of formula IIIS. The compounds of formula Ha either commercially available (R2denotes H), or can be obtained from known methylidene derivatives of formula XI (for example, compounds where n=0 and PG3denotes benzyl, Side or benzyloxycarbonyl (see EP 241206 and EP 550025); or compounds where n=1 and PG3denotes benzyl, Side, which are commercially available). They can also be obtained by catalytic CIS-dihydroxypropane using osmium tetroxide as a catalyst or by its asymmetric version (Sharpless dihydroxypropane using AD-mix α or β), as described in the publication J. Am. Chem. Soc. (1988), 110, 1968, where R2IT denotes. The compounds of formula IXC, i.e. the compounds of formula IX, where R2and R7together form St is z (epoxide), get either by intramolecular cyclization of compounds of formula HB with an inorganic base such as2CO3or NaH, or with an organic base such as tea or DBU, or by epoxidation methylidene double bond by percolates such as m-CHPBK. Alternatively, the compounds of formula IXC may also be obtained by reaction of the corresponding oxaprozin (commercially available compounds, where n=0 or 1 and PG3denotes benzyloxycarbonyl or Side) with iodide trimethylsulfoxonium or iodide trimethylsilane in the presence of alkali such as KOH, in a polar solvent such as MeCN, in the temperature interval from 20 to 100°C (as described in the publications: J. Am. Chem. Soc. (1965), 87, 1353-1364 and Tetrahedron Lett. (1987), 28, 1877-1878).

Connections the following examples illustrate the obtaining of the pharmacologically active compounds according to the invention, without limiting its scope.

Examples

All temperatures are given in °C. All analytical and preparative HPLC studies on the organization of the achiral phases was carried out using RP-C18 columns. Analytical HPLC studies were conducted on two different devices with cycle times of about 2.5 min and about 3.5 min, respectively. Unless otherwise stated, the values given for MS, correspond to the main peak (M+H)+with a range of +/- 0.5 units). WAMR spectra constant interaction J are given in Hz.

Standard techniques for processing:

After dissolution in an appropriate organic solvent (see description of the corresponding example) the organic phase is separated and successively washed with water and brine. In the case of reactions carried out in water-soluble solvent (for example, Meon, THF or DMF), the combined aqueous layers washed with the same solvent that was used in the processing of the reaction mixture. The combined organic phases are dried over MgSO4and filtered. The filtrate is evaporated under reduced pressure.

Standard chromatographic methods:

The crude product is dissolved in a minimal amount of eluent (see description of the corresponding example) and chromatographic on SiO2. The appropriate fractions are combined and evaporated under reduced pressure.

Example 1: 1-cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-4-hydroxypiperidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

1.i (R)-3-(3-Fluoro-4-hydroxyphenyl)-5-hydroxymethylimidazole-2-he:

A solution of (R)-3-(4-benzyloxy-3-forfinal)-5-hydroxymethylimidazole-2-it (6,34 g, obtained according to WO 2004/096221) in a mixture of THF/Meon (in the ratio 1:1; 200 ml) hydronaut over 10%Pd/C (1 g) during the night. The catalyst is filtered off, the filtrate is evaporated under reduced pressure and the residue peremeci is up with EA. The crystals are separated by filtration, receiving, and 3.16 g (70% yield) of colorless solid.

1H NMR (DMSOd6; δ ppm): 3,5 (m, 1H), to 3.64 (m, 1H), 3,74 (dd, J=8,8, 6,4, 1 H), 3,99 (t, J=8,8, 1H), with 4.64 (m, 1H), 5,16 (t, J=5,6, 1H), 6,93 (dd, J=9,7, 8,8, 1 H), was 7.08 (ddd, J=8,8, 2,6, 1,2, 1H), 7,45 (dd, J=13,5, 2,6, 1H), to 9.66 (s, 1H).

MS (ESI): TO 228.1.

1.ii. Benzyl ester 4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-4-hydroxypiperidine-1-carboxylic acid:

A solution of intermediate compound (1.i) (1.27 g) and 1-oxa-6-Aza-Spiro[2.5]octane-6-carboxylic acid (1.60 g; obtained according to the US 4244961) dissolved in DMF (15 ml) and treated with Na2CO3(1,16 g). The mixture is then heated at a temperature of 100°C during the night. The residue obtained after processing (DHM), mix with EA, the solid is separated by filtration and sequentially washed with EA and hexane, obtaining 2,52 g (94.5% of yield) of a beige solid.

1H NMR (DMSOd6; δ ppm): 1.57 in (m, 4H), 3,14 (m, 2H), 3,54 (m, 1H), to 3.64 (m, 1H), 3,79 (m, 5H), is 4.03 (t, J=9,1, 1H), of 4.66 (m, 1H), 4,78 (s, 1H), of 5.05 (s, 2 H), 5,16 (t, J=5,6, 1H), 7,18 (m, 2H), 7,32 (m, 5H), 7,55 (d, J=12, 1H).

MC (ESI): 475,0.

1.iii. (R)-3-[3-Fluoro-4-(4-hydroxypiperidine-4-ylethoxy)phenyl]-5-hydroxymethylimidazole-2-he:

A suspension of intermediate compounds (1.ii) (2.5 g) in a mixture of EA/Meon (ratio 1:1; 100 ml) hydronaut over Pd/C for 48 hours Then the suspension is heated at a temperature of 40°C, after which the catalyst is filtered off. The filtrate viparita the t under reduced pressure, getting to 1.61 g (89% yield) of yellow powder.

1H NMR (DMSOd6; δ ppm): 1,4-of 1.63 (m, 4H), to 2.67 (m, 2H), and 2.83 (m, 2H), 3,53 (dd, J=4.0 and 12,0, 1H); 3,66 (dd, J=3.3 and to 12.0, 1H), 3,71 (s, 2H); of 3.80 (m, 1 H), of 4.05 (t, J=9,0, 1H), 4,48 (s, 1H), and 4.68 (m, 1H), 5,20 (s, 1H), 7,20 (m, 2H), EUR 7.57 (d, 1H).

MS (ESI): 341,5.

1.iv. 1-Cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-4-hydroxypiperidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

A solution of intermediate compound (1.iii) (200 mg), compound 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid with bardicechelon (241 mg; obtained according to WO 88/07998), DIPEA (100 μl) in N-MP (2 ml) was stirred at 85°C for 5 hours, the Reaction mixture was then evaporated under reduced pressure and the residue is transferred into a 5-molar solution of HCl in Meon (3 ml) and stirred. The formed solid substance was separated by filtration and washed with Meon, getting 230 mg (67% yield) of yellow solid.

1H NMR (DMSOd6; δ ppm): 1,66-of 1.35 (m, 4H), of 1.75 (d, J=12,8, 2H), 1,95 (m, 2H), 3.33 and (t advanced, J=11,0, 2H), 3,57 (m, 3H), to 3.67 (dd, J=12,3, 3,3, 1 H), 3,83 (m, 2H), 3,92 (s, 2H), 4,06 (t, J=9,0, 1H), 4,69 (m, 1H), 7,24 (m, 2H), 7,60 (m, 2H), of 7.90 (d, J=13.3-inch, 1H), 8,66 (s, 1H).

MC (ESI): 585,9.

Example 2: 1-Cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]piperidine-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

2.i. (R)-3-(4-Benzyloxy-3-forfinal)-5-(tert-butultimately-silnilar imethyl)oxazolidin-2-he:

The solution l (3.77 g) in DHM (5 ml) added dropwise at a temperature of 0°C. to a solution of (R)-3-(4-benzyloxy-3-forfinal)-5-hydroxymethylimidazole-2-it (6,35 g; obtained according to WO 2004/096221) and imidazole (2,04 g) in DMF (15 ml). After stirring at RT for 16 h, the reaction mixture was concentrated in vacuo. The residue is then transferred to DHM and sequentially washed with 1 normal HCl solution, saturated aqueous NaHCO3and brine, dried over MgSO4filter and concentrate, getting to 8.41 g (97% yield) of colorless solid.

1H NMR (DMSOd6; δ ppm): 0,04 (6N, s); 0,79 (N, s); 3,69-of 3.78 (2H, m), 3,86 (1H, dd, J=3 and J=12); 4,07 (1H, t, J=9); 4,69-of 4.77 (1H, m); further 5.15 (2H, s); 7,15-7,21 (1H, m); of 7.25 (1H, t, J=9); 7,30 and 7.36 (1H, m); 7,37 is 7.50 (4H, m); EUR 7.57 (1H, dd, J=3 and J=14).

2.ii. (R)-5-(tert-Butyldimethylsilyloxy)-3-(3-fluoro-4-hydroxyphenyl)oxazolidin-2-he:

A solution of intermediate compound (2.i) (7,22 g) in a mixture of THF/Meon (ratio 1:1; 150 ml) hydronaut over 10%Pd/C (150 mg) within 3 hours the Catalyst is filtered off and the filtrate was concentrated in vacuo, receiving the 5.51 g (96% yield) of colorless solid.

1H NMR (DMSOd6; δ ppm): 0,04 (6N, s); 0,80 (N, s); 3,69-of 3.78 (2H, m), 3,86 (1H, dd, J=3 and J=12); 4,07 (1H, t, J=9); 4,68-of 4.75 (1H, m); 6,94 (1H, t, J=9);? 7.04 baby mortality-7,10 (1H, m); was 7.45 (1H, dd, J=3 and J=14); 9,65 (1H, s).

MS (ESI): 342,2.

2.iii. tert-Butyl ether 4-{4-[(R)-5-(tert-butyldimethylsilyloxy)-2-oxoacridine-3-yl]-2-fervency ethyl}piperidine-1-carboxylic acid:

To a suspension of tert-butyl methyl ether 4-hydroxyethylpiperazine-1-carboxylic acid (200 mg; commercially available), intermediate (2.ii) (317 mg) and PPh3(365 mg) in THF (5 ml) dropwise over 90 min add DYADS (0,294 ml). After stirring overnight at RT the reaction mixture is treated with a mixture of toluene/hexane (in the ratio 1:2) and chromatographic (hexane/EA in the ratio 2:1)to give 351 mg (70% yield) of off-white solid.

MS (ESI): 539,2.

2.iv. (R)-3-[3-Fluoro-4-(piperidine-4-ylethoxy)phenyl]-5-hydroxymethylimidazole-2-he:

A solution of intermediate compound (2.iii) (351 mg) in Meon (2 ml) is treated with 5-molar solution of HCl in Meon (1 ml) and stirred at RT for 3 h the Resulting solid is separated by filtration and washed with Meon (5 ml)to give 180 mg (85% yield) of colorless solid.

1H NMR (DMSOd6; δ ppm): to 1.48 (2H, m); 1,89 (2H, m); is 2.05 (1H, m); is 2.88 (2H, t, J=10); 3,10 (2H, m); 3,55 (1H, m); 3,63 (1H, m); of 3.78 (1H, dd, J=6.4 and J=8,8); 3,91 (2H, d, J=6,2); WAS 4.02 (1H, t, J=8,8); OF 4.66 (1H,t); 5,19 (1H, t, J=5,6); 7,20 (2H, m); 7,56 (1H, dd, J=2.35 and J=14).

MS (ESI): 325,5.

2.v. 1-Cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]piperidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

Named in the title compound obtained as colorless powder with a 12%yield, based on the intermediate (2.iv) (177 mg) and chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid/bordereth complex (205 mg), using the method of example 1, stage 1.iv.

1H NMR (DMSOd6; δ ppm): of 1.13 and 1.33 (m, 4H), of 1.45 to 1.6 (m, 2H), 1,94 (d1, J=12,0, 2H), 2,04 (m, 1H), 2,98 (t, J=12,0, 2H), 3,50 at 3.69 (m, 2H), of 3.73-to 3.89 (m, 4H), 3,98 (d, J=6,2, 2H), was 4.02 (t, J=9,3, 1H), of 4.66 (m, 1H), 5,18 (t, J=5,6, 1H), 7,21 (m, 2H), 7,56 (m, 2H), 7,88 (d, J=13,5, 1H), 8,64 (s, 1H).

MS (ESI): 570,2.

Example 3: 1-Cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-4-hydroxypiperidine-1-yl}-4-oxo-1,4-dihydro-[1,8]naphthiridine-3-carboxylic acid:

A solution of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid (166 mg; commercial) and intermediate (1.iii) (200 mg) in N-MP (5 ml) is treated with the tea (0,32 ml) and TMCCl and heated at 85°C for 5 hours, the Reaction mixture was then evaporated under reduced pressure and the residue is transferred into a 5-molar solution of HCl in Meon (3 ml), then stirred for 30 minutes the Solution is evaporated under reduced pressure, and the residue is transferred in the EA, the Formed solid substance was separated by filtration and washed with ethyl acetate, receiving 271 mg (78% yield) of yellow solid.

1H NMR (AMCOd6; δ ppm): 0,89-of 1.27 (4H, m); 1,78 (2H, d, J=12,8); 1,90-2,04 (2H, m); 3,53-3,88 (6N, m); 3,88 (2H, s), 4,06 (1H, t, J=9,0), 4,42 (2H, d advanced, J=13,2), OF 4.44 (1H, m); 7,11 (2H, m); at 7.55 (1H, d, J=14,5); 8,05 (1H, d, J=13,5); at 8.60 (1H, s).

MS (ESI): 586,8.

Example 4: the Hydrochloride of 7-(4-{4-[(R)-5-((S)-2-aminopropionitrile)-2-oxoacridine-3-yl]-2-forfinancial}-4-guide is oxopiperidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

4.i. Benzyl ester 1-cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-4-hydroxypiperidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

A suspension of intermediate compounds (1.iv) (300 mg) and K2CO3(77,8 mg) in DMF (10 ml) is treated with BnBr (82 μl) and stirred at 80°C for 2 days. The solvents are removed then under reduced pressure. The residue is treated (DHM) and purified using chromatography (DHM/Meon in the ratio 95:5)to give 219 mg (63% yield) of white powder.

1H NMR (DMSOd6; δ ppm): 1,0-1,25 (4H, m); 1,71 (2H, dd, J=0.6 and J=12,9); OF 1.92 (2H, m); of 3.25 (2H, m); 3,50 (3H, m); the 3.65 (2H, m); of 3.78 (1H, dd, J=6.4 and J=8,8); THE 3.89 (2H, s); a 4.03 (1H, t, J=9,1); THE 4.65 (1H, m); 4,82 (1H s); to 5.17 (1H, t, J=5,6); THE 5.25 (2H, s); 7,21 (2H, m); 7,35-of 7.60 (7H, m); 7,74 (1H, d, J=13,5); TO 8.45 (1H, s).

MS (ESI): 676,2.

4.ii. Benzyl ether of 7-(4-{4-[(R)-5-((S)-2-tert-butoxycarbonylmethylene)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

A solution of intermediate compound (4.i) (219 mg) in DMF (3 ml) is treated with BOC-L-Ala-OH (79,7 mg), EDC (81 mg) and DMAP (20 mg). The reaction mixture was stirred at RT for 2 h Then DMF is evaporated under reduced pressure and the residue purified via chromatography (DHM/Meon in the ratio 95:5). The appropriate fractions are evaporated under reduced pressure and the AC who're asked on the air. The solid is separated by filtration, getting 280 mg (100% yield) of a white foam.

1H NMR (DMSOd6; δ ppm): 1,06-1,11 (2H, m); 1,17-of 1.27 (5H, m); 1,34 (N, s); 1,67 to 1.76 (2H, d, J=12); 1,86 OF 1.99 (2H, m); 3,18-of 3.25 (2H, m); 3.40 in-3,50 (2H, m); 3,60-and 3.72 (1H, m); of 3.77-of 3.85 (1H, m); the 3.89 (2H, s); 3,96-4,04 (1H, t, J=7,3); 4,10 (1H, t, J=9); a 4.2-43 (1H, dd, J=4.7 and J=13,2); TO 4.38-OF 4.44 (1H, d, J=11,7); A 4.83-OF 4.95 (1H, m); of 5.26 (2H, s); 7,20-7,55 (N, m); of 7.75 (1H, d, J=12,6); 8,46 (1H, s).

MS (ESI): AT 847.5.

4.iii. 7-(4-{4-[(R)-5-((S)-2-tert-Butoxycarbonylmethylene)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

A solution of intermediate compound (4.ii) (285,3 mg) in a mixture of dioxane/Meon (in the ratio 1:1; 10 ml) hydronaut over 10%Pd/C (10 mg) for 4 hours, the Catalyst was then removed by filtration and washed with Meon (2 ml). The filtrate is evaporated under reduced pressure, getting 215 mg (84,4% yield) of a yellow foam.

MS (ESI): 757,3.

4.iv. The hydrochloride of 7-(4-{4-[(R)-5-((S)-2-aminopropionitrile)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

A solution of intermediate compound (4.iii) (193 mg) in dioxane (1 ml) is treated with 0.15 ml of HCl (5-molar in dioxane). The reaction mixture was stirred at RT for 14 h, the Solvent is then evaporated under reduced pressure. The residue is transferred in dioxane (10 ml) and formed the I, the solid is separated by filtration, getting 153 mg (86,7% yield) of yellow powder.

1H NMR (DMSOd6; δ ppm): 1,15-of 1.33 (4H, m); of 1.35 (3H, d, J=6,4); 1,73 (2H, d, J=13); l,93(2H, m); and 3.31 (2H, t, J=11); A-3.84 (4H, m); 4,13 (2H, m); of 4.35 (1H, dd, J=5 and J=12); 4,55 (2H, dd, J=2 and J=12); of 4.95 (1H, m); 7.23 percent (2H, m); 7,56 (2H, m); 7,88 (1H, d, J=13,2); 8,51 (2H, sl); 8,64 (1H, s).

MS (ESI): 657,3.

Example 5: 1-Cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-2-oxo-5-phosphonomethylglycine-3-yl)phenoxymethyl]-4-hydroxypiperidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

5.i. 7-(4-{4-[(R)-5-(bis-Benzyloxycarbonyloxy)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

A suspension of intermediate compounds (1.iv) (300 mg) and 4,5-dicyanoimidazole (109 mg) in DHM (3 ml) is treated at 0°With dibenzyl-N,N-diisopropylphosphoramidite (0,303 ml). The reaction is stirred at RT for 1 h, and then add 70%solution of tert-butylhydroperoxide in water (0,147 ml), and the solution was stirred for 1 h at RT. The solvent is then evaporated under reduced pressure, the residue is treated (DHM) and purified using chromatography (DHM/Meon in the ratio 95:5)to give 214 mg (49,45% yield) of off-white foam.

MS (ESI): 846,3.

5.ii. 1-Cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-2-oxo-5-phosphonomethylglycine-3-yl)phenoxymethyl]-4-hydroxypiperidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

a Solution of intermediate compound (5.i) (214 mg) in Asón (1.5 ml) is treated with HBr (1.5 ml; 33%solution in Asón). The reaction mixture was stirred at RT for 2 h, then transferred into water (20 ml). The resin is stirred for 1 h and decanted. The oily product is transferred into ethyl acetate (20 ml) and further stirred for 2 hours, the Solid is separated by filtration, stirred in DHM (10 ml) and again separated by filtration, receiving 110 mg (65% yield) of yellow powder.

1H NMR (DMSOd6; δ ppm): 1.18 to of 1.30 (4H, m); 1,73 (1H, d, J=13); of 1.95 (2H, m); 2.40 a (2H, d, J=13); 3,26 (2H, m); to 3.58 (2H, m); 3,76-a 3.87 (2H, m); 3,90 (1H, s); 3.95 to to 4.15 (3H, m); 4,47 (1H, s); a 4.86 (1H, m); 7,21 (2H, m); EUR 7.57 (2H, m); 7,89 (1H, dd, J=5.9 and J=13,2); 8,65 (1H, s).

MS (ESI): 666,2.

Example 6: 1-Cyclopropyl-6-fluoro-7-{(RS)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-3-hydroxypyrrolidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

6.i. Benzyl ether diallylbarbituric acid:

The benzoyl chloride (15,5 ml) added dropwise over 30 min to a solution of diallylamine (12.3 ml) and tea (21 ml) in DHM (100 ml) at 0°C. the Reaction mixture was then stirred at RT for 16 h the Residue obtained after processing (DHM), purified using chromatography (hexane/EA in the ratio 95:5), receiving 20,71 g (88% yield) as a colourless liquid.

1H NMR (DMSOd6; δ ppm): a 3.83 (4H, dt, J=1 and J=6); of 5.05-5,18 (6H, m); 5,70 and 5.86 (2H, m); 7,27-of 7.48 (5H, m).

6.ii. Benzyl ether of 2,5-dihydropyrrol-1-carboxylic acid:

p> Benzylidene-bis(tricyclohexylphosphine)dichloroethene (5 g) was added to a solution of intermediate compound (6.i) (17,56 g) in DHM (1.5 l) at RT under nitrogen atmosphere. The reaction mixture is then stirred at 40°C for 2 h, then concentrated in vacuo. The residue is purified via chromatography (hexane/EA in the ratio 90:10), receiving 14,08 g (91% yield) of a yellow liquid.

1H NMR (DMSOd6; δ ppm): 4,05-4,16 (4H, m); to 5.08 (2H, s); 5,81-of 5.92 (2H, m); 7,27-7,41 (5H, m).

6.iii. Benzyl ether of (RS)-3-hydroxypyrrolidine-1-carboxylic acid:

1-Molar solution of borohydride in THF (9 ml) was added to a solution of intermediate compound (6.ii) (1,81 g) in THF (25 ml) at 0°C in an atmosphere of nitrogen. The reaction mixture was stirred at RT for 16 h and cooled to 0°C. a 20%NaOH solution (1.8 ml) is cautiously added dropwise, then add 35%aqueous hydrogen peroxide solution (1.2 ml). The mixture is stirred at 0°C for 30 min and then at RT for 2 hours then add EtaO and 40%aqueous solution of sodium bisulfite and the reaction mixture is vigorously stirred for 15 minutes the Residue obtained after treatment (Et2O), purified using chromatography (hexane/EA in a ratio of from 5:5 to 3:7)to give 1.01 g (51% yield) of colorless oil.

1H NMR (DMSOd6; δ ppm): 1,67-to 1.82 (1H, m); 1,82 is 1.96 (1H, m); 3,16-of 3.25 (1H, m); 3,28-3,44 (3H, m); 4,20-4,29 (1 is, extended); to 4.92 (1H, d, J=3); is 5.06 (2H, s); 7,27-7,41 (5H, m).

6.iv. Benzyl ester 3-oxopyrrolidin-1-carboxylic acid:

A solution of intermediate compound (6.iii) (1.10 g) in DHM (8 ml) cooled to 0°C and added dropwise, DIPEA (2.5 ml), and then the solution of a complex of sulfur trioxide/pyridine (1,79 g) in DMSO (6.5 ml). The reaction mixture was stirred at 0°C for 1 h and quenched with water (6 ml). The aqueous layer was extracted with a mixture of Et2O/hexane (1:1 ratio, three times 5 ml) and the combined organic layers concentrated in vacuo. The residue obtained after treatment (Et2O/hexane in the ratio 1:1), purified using chromatography (hexane/EA in the ratio 5:5), receiving of 1.05 g (96% yield) of a yellowish oil.

1H NMR (DMSO; δ ppm): 2,48-2,61 (2H, m); 3,61-of 3.80 (4H, m); 5,09 (2H, s); 7,27-7,41 (5H, m).

6.v. Benzyl ester 3-methyleneindoline-1-carboxylic acid:

t-BuOK (617 mg) was added in one portion to a suspension of bromide methyltriphenylphosphonium (1.98 g) in THF (10 ml) at RT under nitrogen atmosphere. The yellow suspension is stirred at RT for 1 h, and then cooled to a temperature of -10°C., then added dropwise a solution of intermediate compound (6.iv) (1,05 g) in THF (2 ml) for 10 min and the reaction mixture is left to spontaneously heated at RT for 2 h the Reaction is then quenched by adding saturated aqueous solution of NH4Cl (1 ml) and diluted with ethyl is the Etat. The residue obtained after processing (EA), purified using chromatography (hexane/EA in the ratio 90:10), receiving 633 mg (64% yield) of a yellowish liquid.

1H NMR (DMSOd6; δ ppm): 2,48-2,61 (2H, m); 3.36-of 3.53 (2H, m); 3,84-4,01 (2H, m); equal to 4.97-to 5.03 (2H, m); to 5.08 (2H, s); 7,27-7,41 (5H, m).

6.vi. Benzyl ester 1-oxa-5-Aza-Spiro[2,4]heptane-5-carboxylic acid:

A solution of intermediate compound (6.v) (7,21 g) in DHM (400 ml) is treated with m-HPBC (20,1 g) and NaHCO3(22,3 g) at RT. The reaction is stirred at RT for 2 h, diluted with DHM (200 ml) and transferred into a solution of Na2SO3(45 g) in water (400 ml). The mixture is then stirred for 10 minutes, then separate the organic layer. The residue obtained after processing (DHM), purified using chromatography (hexane/EA in the ratio 6:4), receiving 4,37 g (56% yield) of yellow oil.

1H NMR (DMSOd6; δ ppm): 1.70 to to 1.83 (1H, m); 2,22-is 2.37 (1H, m); 2,90-to 2.94 (1H, m); 2.95 and-2,99 (1H, m); 3.15 in (1H, t, J=11); 3,39-OF 3.77 (3H, m); 5,09 (2H, s); 7,27-7,41 (5H, m).

6.vii. Benzyl ether of (RS)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-3-hydroxypyrrolidine-1-carboxylic acid:

To2CO3(274 mg) was added to a suspension of intermediate compounds (1.i) (300 mg) and intermediate (6.vi) (338 mg) in DMF (3 ml). The reaction mixture is stirred at a temperature of 80°C for 3 h, after which the solvent is removed in vacuum. The residue obtained after processing(DHM), purify via chromatography (DHM/Meon in the ratio 95:5)to give 531 mg (87% yield) of a beige foam.

1H NMR (DMSOd6; δ ppm): 1,80-of 1.92 (1H, m); 1,96-of 2.08 (1H, m); 3,32-3,59 (5H, m); 3,66 (1H, ddd, J=3, J=6 and J=13); OF 3.80 (1H, dd, J=6 and J=9); OF 3.97-4.09 TO (3H, m); with 4.64-4.72 in (1H, m); 5,07 (2H, s); 5,19 (1H, t, J=6); 5,23 (1H, s); 7,18-of 7.23 (2H, m); 7,27-7,38 (5H, m); EUR 7.57 (1H, dd, J=2 and J=14).

MS (ESI): ARE 460.9.

6.viii. (R)-3-[3-Fluoro-4-((RS)-3-hydroxypyrrolidine-3-ylethoxy)phenyl]-5-hydroxymethylimidazole-2-he:

A solution of intermediate compound (6.vii) (259 mg) in a mixture of THF/Meon (in the ratio 1:1; 20 ml) hydronaut over 10%Pd/C (60 mg) for 20 h at RT. The reaction mixture was then concentrated in vacuo, transferred into a mixture DHM/Meon in the ratio of 90:10 (20 ml) and stirred at RT for 30 minutes, the Catalyst is filtered off and the filtrate was concentrated in vacuo, getting 184 mg (100% yield) of an orange foam.

MS (ESI): 327,3.

6.ix. 1-Cyclopropyl-6-fluoro-7-{(RS)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-3-hydroxypyrrolidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

A solution of intermediate compound (6.viii) (226 mg) and complex of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid with bardicechelon (270 mg; obtained according to WO 88/07998) in N-MP (5 ml) is treated with DIPEA (120 μl) and stirred at 60°C for 2 h, the Reaction mixture was then concentrated in vacuo and the residue is transferred into a 5-molar RA the HCl solution in the Meon (2 ml). After this, the solution is stirred at RT for 1 h, concentrated in vacuo and the residue purified via chromatography (DHM/Meon/Asón in a ratio of 95:4:1 to 90:9:1). Foamy residue is transferred in the Meon (2 ml), stirred for 1 h and filtered. The crystals are separated and dried in vacuum, obtaining 23 mg (6% yield) as beige solid.

1H NMR (DMSOd6; δ ppm): 1,10-of 1.34 (4H, m); 1.98-2,10 (1H, m); 2.14-of 2.26 (1H, m); 3,48-3,70 (3H, m); 3,71-to 3.89 (5H, m); of 4.05 (1H, t, J=9); 4.09 to 4,18 (2H, m); 4,66-4,74 (1H, m); 5,19 (1H, t, J=6); OF 5.40 (1H, s); to 7.09 (1H, d, J=8); 7,18-7,31 (2H, m); to 7.59 (1H, dd, J=2 and J=14); OF 7.82 (1H, d, J=14); 8,59 (1H, s); 15,52 (1H, s).

MS (ESI): 572,3.

Example 7: 1-Cyclopropyl-6-fluoro-7-{(RS)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-3-hydroxypyrrolidine-1-yl}-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

This compound is obtained as yellow solid with a 52%yield, based on the intermediate (6.viii) (85 mg), 1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid with bardicechelon (100 mg; receive according to Sakurai et al., Bioorg. Med. Chem. Lett. (1998), 8, 2185-2190), DIPEA (43 μl) and using the method of example 6, stage 6.ix. Foamy residue is stirred in EA (5 ml) and dried.

MS (ESI): 602,2.

Example 8: 1-Cyclopropyl-6-fluoro-7-{(RS)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]pyrrolidin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic Ki the lot:

8.i. Benzyl ether of (RS)-3-hydroxyethylpyrrolidine-1-carboxylic acid:

This compound is obtained as colorless oil from 68%yield, based on the intermediate (6.v) (630 mg) and 1-molar solution of borane in THF (9 ml), and applying the method of example 6, stage 6.iii.

1H NMR (DMSOd6; δ ppm): 1,51-1,71 (1H, m); 1,79-of 1.97 (1H, m); 2,19 to 2.35 (1H, m); 3.00 and is 3.15 (1H, m); 3,19-3,50 (5H, m); the 4.65 (1H, t, J=5); of 5.05 (2H, s); 7,27-7,40 (5H, m).

MS (ESI): 235,9.

8.ii. Benzyl ether of (RS)-3-{4-[(R)-5-(tert-butyldimethylsilyloxy)-2-oxoacridine-3-yl]-2-forfinancial}pyrrolidin-1-carboxylic acid:

A suspension of intermediate compounds (8.i) (456 mg), intermediate (2.ii) (630 mg) and h3(726 mg) in THF (8 ml) is treated DYADS (0,55 ml), adding it dropwise over 2 h at RT. The reaction mixture is further stirred at RT for 2 h, and then concentrated in vacuo. Then the residue purified via chromatography (hexane/EA in a ratio of from 7:3 to 6:4), receiving 966 mg (94% yield) of yellow oil.

1H NMR (DMSOd6; δ ppm): 0,04 (6N, s); 0,79 (N, s); 1,65-to 1.82 (1H, m); 1,93-of 2.08 (1H, m); 2,56-to 2.74 (1H, m); 3,14-of 3.25 (1H, m); 3,30-3,59 (3H, m); 3,69-of 3.78 (1H, m); 3,74 (1H, dd, J=3 and J=12); A 3.87 (1H, dd, J=3 and J=12); 3,95-4,12 (3H, m); 4,70 of 4.83 (1H, m); of 5.05-5,08 (2H, m); 7,16-7,21 (2H, m); 7,27-7,38 (5H, m); 7,56 (1H, dd, J=2 and J=14).

MS (ESI): 559,3.

S.iii. Benzyl ether of (RS)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethylpenicillin-1-carboxylic key is lots of:

A solution of intermediate compound (8.ii) (200 mg) in dioxane (1 ml) is treated with 6-molar solution of HCl in dioxane (0,30 ml) at RT. The reaction mixture was stirred at RT for 2 h, and then concentrated without dried. The residue is diluted with DHM, washed with saturated aqueous NaHCO3and process (DHM). The crude product is then purified using accelerated chromatography (DHM/Meon in a ratio of from 98:2 to 96:4)to give 258 mg (81% yield) of a yellowish oil.

1H NMR (DMSOd6; δ ppm): 1,66-to 1.82 (1H, m); 1,96-2,10 (1H, m); 2,58-to 2.74 (1H, m); 3,14-3,26 (1H, m); 3,28-to 3.38 (1H, m); 3,39-3,61 (3H, m); 3,66 (1H, ddd, J=4, J=6 and J=13); OF 3.80 (1H, dd, J=b and J=9); 3,94-4,08 (3H, m); 4,62-4,71 (1H, m); of 5.05 (2H, s); 5,19 (1H, t, J=6); 7,18-7,21 (2H, m); 7,27-7.38 (5H, m); EUR 7.57 (1H, dd, J=2 and J=14).

MS (ESI): 445,2.

8.iv. (R)-3-[3-Fluoro-4-((RS)-1-pyrrolidin-3-ylethoxy)phenyl]-5-hydroxymethylimidazole-2-he:

This connection is received with 100%yield in the form of a pinkish solid substances by hydrogenation of the intermediate compound (8.in) (230 mg) over 10%Pd/C (72 mg) using the method of example 6, stage 6.viii.

MS (ESI): 311,3.

8.v. 1-Cyclopropyl-6-fluoro-7-{(RS)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]pyrrolidin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

This connection receive 17%yield as a yellow solid, based on the intermediate (8.iv) (67 mg), compound 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro--oxo-quinoline-carboxylic acid with bardicechelon (80 mg; obtained according to WO 88/07998), DIPEA (36 μl) and using the method of example 6, stage 6.ix. The crude product is purified using chromatography (DHM/Meon/Asón in a ratio of 98:1:1 to 94:5:1) foamy residue is stirred in the Meon (1 ml).

1H NMR (DMSOd6; δ ppm): 1,10-of 1.34 (4H, m); 1.85 to a 2.01 (1H, m); 2,14-of 2.28 (1H, m); 2,75-2,90 (1H, m); 3,48-of 3.60 (2H, m); 3,60-3,88 (6N, m); of 4.05 (1H, t, J=9); 4.09 TO 4,18 (2H, m); 4.63 to-4,72 (1H, m); 5,19 (1H, t, J=6); 7,09 (1H, d, J=8); 7,18-7,29 (2H, m); 7,58 (1H, dd, J=3 and J=14); 7,80 (1H, d, J=14); 8,58 (1H, s); 14, 48mm (1H, s).

MC (ESI): 556,3.

Example 9: 1-Cyclopropyl-6-fluoro-7-{(RS)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]pyrrolidin-1-yl}-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

This compound is obtained as yellow solid with a 12%yield, based on the intermediate (8.iv) (65 mg), 1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid with boron diacetate (80 mg; obtained according to Sakurai et al., Bioorg. Med. Chem. Lett. (1998), 8, 2185-2190), DIPEA (27 μl), using the method of example 6, stage 6.ix. The crude product is purified using chromatography (DHM/Meon/Asón in a ratio of 98:1:1 to 94:5:1) and stirring foamy residue in a mixture of EA/Et2O (2:1 ratio; 1.5 ml).

1H NMR (DMSOd6; δ ppm): 0,90-of 1.18 (4H, m); 1,76-of 1.93 (1H, m); 2,10-of 2.24 (1H, m); 2,70-of 2.81 (1H, m); only 3.57 (3H, s); 3,56-3,83 (7H, m); 3,99-4,20 (4H, m); 4,62-to 4.73 (1H, m); 5,19 (1H, t, J=6); 7,18-7,29 (2H, m); 7,58 (1H, dd,, J=3 and J=14); to 7.68 (1H, d, J=14); 8,64 (1H, s); 15,13 (1H, s).

MC (ESI): 586,3.

Example 10: 1-Cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-4-postexperiment-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

10.i. Benzyl ether of 7-(4-{4-[5-(tert-butyldimethylsilyloxy)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

The imidazole (67 mg) and l (162 mg) are added to a solution of intermediate compound (4.i) (600 mg) in DMF (6 ml). The solution is stirred at RT for 6 h, the Solvent is then evaporated under reduced pressure, and the residue is treated (DHM) and purified using chromatography (DHM/Meon; in the ratio 95:5)to give 544 mg (75,6% yield) yellow solid.

1H NMR (DMSOd6; δ ppm): 0,03 (6N, s); 0,78 (N, s); 1,10 (2H, m); 1,22 (2H, m); 1.70 (2H, m); of 1.92 (2H, m); 3,2 (2H, m); of 3.45 (2H, m); 3.70 (3H, m); 3,83-3,88 (1H, dd, J=2.6 and J=12); the 3.89 (2H, s); 4,07 (1H, t, J=9); to 4.73 (1H, m); 4,82 (1H, s); of 5.26 (2H, s); then 7.20 (2H, m); 7,28-7,58 (7H, m); of 7.75 (1H, d, J=13,5); 8,46 (1H, s).

MC (ESI): 790,5.

10.ii. Petrol ether 7-(4-(bis-benzyloxycarbonyloxy)-4-{4-[(R)-5-(treue-butyldimethylsilyloxy)-2-oxoacridine-3-yl]-2-forfinancial}piperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

A suspension of intermediate compounds (10.i) (523 mg) in DHM (4 ml) was sequentially treated with 4,5-renomination (140 mg) and dibenzyl-N,N-diisopropylphosphoramidite the m (392 μl). After treatment for 1 h at RT, the reaction mixture is treated with 190 μl of tert-butylhydroperoxide (70%aqueous solution), and then stirred at RT for 1 h the Solvent is evaporated under reduced pressure, then the residue is treated (DHM) and purified using chromatography (DHM/Meon; ratio of 97.5:2.5 to). The resulting solid (369 mg) is stirred with ether (5 ml)to give 287 mg (41% yield) of yellow solid.

1H NMR (DMSOd6; δ ppm): 0,02 (6N, s); 0,77 (N. m); of 1.07 (2H, m); 1.19 (2H, dd, J=1,2 and J=6,4), 2,07 (2H, t advanced, J=9); to 2.29 (2H, d, J=13,5); 3,18 (2H, t, J=11); 3.49 (2H, m); 3,61 (1H, m); 3.73 (2H, m); of 3.85 (1H, dd, J=2.6 and J=12); 4,07 (1H, t, J=9,1); to 4.38 (2H, s); to 4.73 (1H, m); 5,02 (4H, d, J=7,6); 5.26 (2H, s); 7,17 (2H, m); 7,42 (17H, m); to 7.77 (1H, d, J=13,2); 8,46 (1H, s).

MS(ESI): 1050,3.

10.iii. Benzyl ether of 7-{4-[4-((R)-5-acetoxymethyl-2-oxoacridine-3-yl)-2-fortunecity]-4-phosphonoacetate-1-yl}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

A suspension of intermediate compounds (10.ii) (200 mg) in Asón (1.5 ml) is treated with HBr (1 ml, 33%solution in Asón), then stirred at RT for 2 h, after which the reaction mixture is transferred into cold water (10 ml). After processing (DHM) residue is stirred with ether (30 ml). The resulting yellow solid is separated by filtration (144,5 mg; 95% yield).

MS (ESI): 798,1.

10.iv. 1-Cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-ox is oxazolidin-3-yl)phenoxymethyl]-4-phosphonoacetate-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

A solution of intermediate compound (10.iii) (144,5 mg) in a mixture of dioxane/Meon/water (3 ml; in a ratio of 1:1:1) is treated with sodium acetate (29 mg) and hydronaut over Pd/C (10%, 10 mg) for 10 h at RT. The catalyst is filtered off and washed with water (5 ml). The filtrate is evaporated under reduced pressure, transferred into water (1 ml) and treated with 1 normal HCl solution (400 μl) until then, until you fall precipitate. The solid is separated by filtration, dissolved again in the Meon (10 ml) and treated To a2CO3(56,25 mg). After stirring the mixture at RT for 30 min the solvent is evaporated under reduced pressure and the residue dissolved in water (4 ml) and treated with 1 normal HCl solution (814 μl) until then, until you fall precipitate. The solid is separated by filtration, washed with water and dried under reduced pressure, getting 105 mg (82% yield) of yellow solid.

1H NMR (DMSOd6; δ ppm): 1,13-of 1.30 (4H, m); 1,95-2,11 (2H, t advanced, J=10); 2,24 (2H, d, J=12,5); 3,59 (3H, t, J=10); 3,5-OF 3.69 (3H, m); 3,74-a 3.87 (2H, m); was 4.02 (1H, t, J=9); OR 4.31 (2H, m); of 4.66 (1H, m); of 5.17 (1H, m); 7,19 (2H, m); 7,56 (2H, m); 7,87 (1H, d, J=13,2); 8,63 (1H, s).

MS (ESI): 666,2.

Example 11: 1-Ethyl-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethylpenicillin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

This connection receive similarly to obtain example 1, stage 1.iv, based on the sub-the face-to-face connections (2.iv) (250 mg) and complex of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid with boron (280 mg; obtained according to WO 87/03595). The residue obtained after evaporation of the solvent under reduced pressure, dissolved in water (100 ml) and the mixture DHM/Meon (500 ml; the ratio of 9:1). The organic phase is then dried over MgSO4and filtered. The filtrate is evaporated and stirred into the mixture DHM/Meon (10 ml; the ratio of 9:1). Yellow solid allocate using filtering (171 mg; 44% yield).

1H NMR (DMSOd6; δ ppm): 1,45 (3H, t, J=7); OF 1.57 (2H, dq, J=4.7 and J=9); 1.95 (2H, d, J=12,5); 2,01-of 2.09 (1H, m); 3,00 (2H, m); 3,62, (3H, dq, J=4 and J=13,2), to 3.73-of 3.78 (1H, m); of 3.80 (1H, dd, J=6.5 and J=9); 3,99-4,07 (3H, m); of 4.49 (2H, q, J=7)and 4.65 (1H, m); 7,16 (3H, m); 7,47-rate of 7.54 (1H, m); 7,88 (1H, d, J=13,8); 8,83 (1H, s),

MS (ESI): 558,2.

Example 12: the Hydrochloride of 7-(4-{4-[(R)-5-((S)-2-aminopropionitrile)-2-oxoacridine-3-yl]-2-forfinancial}piperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

12.i. Benzyl ester 1-cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethylpenicillin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

A solution of the compound of example 2 (600 mg) in DMF (10 ml) is treated To a2CO3(155 mg) and BnBr (160 μl) and stirred at 80°C for 24 hours the Solvent is evaporated under reduced pressure, and the residue is treated (DHM). Then the residue is mixed with ether (100 ml) and the resulting crystals are separated by filtration, getting 612 mg (90,6% yield) of off-white is th solids.

1H NMR (DMSOd6; δ ppm): 1,08-of 1.27 (4H, m); 1,45-to 1.60 (2H, m); 1,88-2,05 (3H, m); 2,89 (2H, t, J=10,8); 3,50 is 3.57 (1H, m); 3,62-3,71 (4H, m); of 3.78 (1H, dd, J=6.2 and J=8,8); 3,98 (2H, d, J=6,2); a 4.03 (1H, t, J=8,8); 4,62-4,71 (1H, m); of 5.17 (1H, t, J=5,9); THE 5.25 (2H, s); 7,19-7,22 (2H, m); 7,31-7,41 (3H, m); 7,43-7,49 (3H, m); 7,53-of 7.55 (1H, dd, J=2.0 and J=13,8); of 7.75(1H, d, J=13,8); 8,46 (1H, s).

MS (ESI): 660,3.

12.ii. Benzyl ether of 7-(4-{4-[(R)-5-((S)-2-tert-butoxycarbonylmethylene)-2-oxoacridine-3-yl]-2-forfinancial}piperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

This compound (307 mg; 81% yield) is obtained as colorless solid substance similar to obtaining compounds of example 4, step 4.ii, on the basis of the intermediate compound (12.i) (300 mg), BOC-L-Ala-OH (111 mg), EDC (113 mg) and DMAP (27 mg).

1H NMR (DMSOd6; δ ppm): 1,05-1,11 (2H, m);, 1,17-of 1.26 (5H, m); of 1.32 (9H, s); of 1.52 (2H, m); a 1.96 (3H, m); 2,90 (2H, t, J=11); 3,59-and 3.72 (3H, m); 3,81 (1H, dd, J=6.7 and J=9,7); 3,94-4,00 (3H, m); 4,12 (1H, t, J=9); of 4.25 (1H, dd, J=4.7 and J=11); however, 4.40 (1H, dd, J=2.6 and J=12,3); 4,85-of 4.95 (1H, m); 5.26 (2H, s); 7,18-of 7.23 (2H, m); 7,26-7,46 (7H, m); of 7.75 (1H, d, J=13,5); to 8.45 (1H, s).

MS (ESI): 831,3.

12.iii. 7-(4-{4-[(R)-5-((S)-2-tert-Butoxycarbonylmethylene)-2-oxoacridine-3-yl]-2-forfinancial}piperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

This compound (252 mg, 100% yield) are obtained in the form of a yellow solid is analogous to obtain compounds of example 4, stage 4.iii, by hydrogenation of the intermediate compound (12. ii) (279 m is) over Pd/C (10%, 10 mg).

1H NMR (DMSOd6; δ ppm): 1,12-1,22 (5H, m); 1.26 in-1,36 (11N, m); 1,47-to 1.59 (2H, m); 1,92 (2H, d, J=12); 1,98-2,10 (1H, m); 2,99 (2H, t, J=12); with 3.79 (4H, m); of 3.97 (3H, d, J=7,6); 4,10 (1H, t, J=9); 4.26 deaths (1H, dd, J=5.3 and J=12,6); 4,36-4,43 (1H, m); 4,84-4,96 (1H, m); 7,17-to 7.32 (3H, m); 7,52 (1H, d, J=12,9); rate of 7.54 (1H, d, J=8,2); 7,88 (1H, d, J=13,5); 8,64 (1H, s).

MS (ESI): 741,3.

12.iv. The hydrochloride of 7-(4-{4-[(R)-5-((S)-2-aminopropionitrile)-2-oxoacridine-3-yl]-2-forfinancial}piperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

This compound (84 mg; 97% yield) are obtained in the form of a yellow solid is analogous to obtain compounds of example 4, stage 4.iv, on the basis of the intermediate compound (12.iii) (100 mg) and 5-molar solution of HCl in dioxane (0.5 ml).

1H NMR (DMSOd6; δ ppm): 1,13-of 1.32 (4H, m); of 1.36 (3H, d, J=7,3); 1,46-TO 1.61 (2H, m); 1,92(2H, d advanced, J=12); 1,98-2,10 (1H, m); 2,99 (2H, t, J=12); 3,74-3,91 (5H, m); 3,98 (2H. d, J=6,4); 4,10-4,18 (1H, m); of 4.35 (1H, dd, J=5.3 and J=12,3); 4,55 (1H, dd, J=2.6 and J=12,3); 4,96 (1H, m); 7,19-7,24 (2H, m); 7,52-7,58 (2H, m); 7,88 (1H, d, J=13,5); of 8.47 (3H, m); 8,64 (1H, s).

MS (ESI): 641,2.

Example 13: 6-Fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-4-hydroxypiperidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

A solution of intermediate compound (1.iv) (150 mg) in DMA (10 ml) hydronaut over 20%Pd(OH)2/C (100 mg) for 5 days at a temperature of 80°C. the Reaction mixture was then concentrated in vacuo, transferred into a mixture DHM/Meon in the ratio of 90:10 (50 ml) and stirred for p and CT within 30 minutes The catalyst is filtered off and the filtrate was concentrated in vacuo. The residue is transferred in the Meon (0.2 ml) and added ethyl acetate (2 ml). The suspension is stirred at RT for 30 min and filtered. The crystals are separated and dried in vacuum, obtaining 48 mg (34% yield) yellow solid.

1H NMR (DMSOd6; δ ppm): 1,64-to 1.77 (2H, m); 1,82-to 1.98 (2H, m); 3,14-3,30 (2H, m); 3,38-3,59 (3H, m); 3,59-3,71 (1H, m); of 3.78 (1H, dd, J=6 and J=9); the 3.89 (2H, s); a 4.03 (1H, t, J=9); 4,62-to 4.73 (1H, m); 4,84 (1H, s); 5.17 to (1H, t, J=6); 7,16-of 7.23 (2H, m); 7,28 (1H, d, J=8); 7,51-of 7.60 (1H, m); 7,81 (1H, d, J=13); 8,79 (1H, s); to 13.09 (1H, extended); 15,44 (1H, s),

MS (ESI): 546,2.

Example 14: 6-Fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-4-hydroxypiperidine-1-yl}-4-oxo-1,4-dihydro-[1,8]naphthiridine-3-carboxylic acid:

A solution of intermediate compound (3.i) (110 mg) in DMA (10 ml) hydronaut over 10%Pd/C (35 mg) for 16 h at a temperature of 80°C. the Reaction mixture was concentrated in vacuo, transferred into a mixture DHM/Meon in the ratio of 90:10 (25 ml) and stirred at RT for 30 minutes, the Catalyst is filtered off and the filtrate was concentrated in vacuo. The residue is transferred into ethyl acetate (2 ml), stirred at RT for 16 h and filtered. The crystals are separated and dried in vacuum, obtaining 35 mg (34% yield) yellow solid.

1H NMR (DMSOd6; δ ppm): 1,62-of 1.92 (4H, m); 3,41-of 3.60 (3H, m); 3,60 at 3.69 (1H, m); of 3.78 (1H, dd, J=6 and J=9); 3,86 (2H, s); was 4.02 (1H, t, J=8); 4,22-4,37 (2H, m); 4,60-4,72 (1H, m); of 4.95 (1H, increasing the Enen); by 5.18 (1H, extended); 7,13-of 7.23 (2H, m); 7,50-to 7.59 (1H, m); 8,01 (1H, d, J=14); 8,79 (1H, extended); 13,26 (1H, extended); 15,34 (1H, advanced).

MS (ESI): 547,3.

Biological assays

In vitro analysis

Experimental methods:

These analyses are carried out in accordance with the description given in: "Methods for dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, 4th ed.; Approved standard NCCLS Document M7-A4; National Committee for Clinical Laboratory Standards: Villanova, PA, USA, 1997". The minimum inhibition concentration (MICs; mg/l) were determined in cation-regulated nutrient medium Mueller-Hinton Broth (BBL) using the method of microrasbora according to the NCCLS guidelines (National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility). The pH-value of the test environment was 7,2-7,3.

In the special case where the connection is to be checked, is a compound of formula IPDGin which at least one of R1and R2is a group of ORO3H2testing was performed in the presence of human alkaline phosphatase (concentration: 1 unit/ml).

In the special case where the connection is to be checked, is a compound of formula IPDGin which R1is a group OCOR5testing was performed in the presence of 50% human serum. However, it is not necessary for the compounds of examples 4 and 12, which are already znachitelbnoj in the absence of human serum.

The results:

Join all of the above examples are tested regarding the effects on gram-positive and gram-negative bacteria. Typical antibacterial spectrum is shown in the table below (MIC in mg/l).

ExampleS.aureus A798S.Pneumoniae 49619M.catarrhalis A894
30,250,1250,5
710,250,063

In addition, the following results were obtained for compounds of the formula IDacting on S.aureus A798 (MIC in mg/l):

ExampleS.aureus A798ExampleS.aureus A798
10,2580,125
20,2591
30,2511 >16
61132
71144

Additionally, the compound of example 11 has a MIC of 8 mg/l against E. faecalis 29212 bacteria.

Moreover, in the physiological environment (including phosphatase and esterase) the compounds of formula IPDGrapidly converted into the corresponding compounds of formula ID. Indeed:

connection examples 5 and 10 in the presence of human alkaline phosphatase have the MIC, respectively, 0.25 and 0.5 mg/l against S.aureus A798, whereas the same compounds have the MIC accordingly >16 mg/l and 16 mg/l against S.aureus A798 when phosphatase is absent; and

connection examples 4 and 12, even in the absence of human serum, each has a MIC of 0.5 mg/l against S.aureus A798.

1. The compound of the formula I
,
where R1is a HE, ORO3H2or OCOR5;
R2represents H, HE or ORO3H2;
And represents N or CR6;
R3represents fluorine;
R4represents H, C1-3alkyl or C3-6cycloalkyl;
R5represents the residue of alanine;
R6represents H, C1-6 alkoxygroup or halogen; and
n=0 or 1;
or pharmaceutically acceptable salt of such compounds.

2. The compound of formula I according to claim 1, which is a compound of the formula ID
,
where R2represents H or HE;
And represents N or CR6;
R3represents fluorine;
R4represents H, C1-3alkyl or C3-6cycloalkyl;
R6represents N or C1.6alkoxygroup; and
n=0 or 1;
or pharmaceutically acceptable salt of such compounds.

3. The compound of formula I according to one of claims 1 or 2, where R2is a HE;
or pharmaceutically acceptable salt of such compounds.

4. The compound of formula I according to claim 1 or 2, where n=0;
or pharmaceutically acceptable salt of such compounds.

5. The compound of formula I according to claim 1 or 2, where n=1;
or pharmaceutically acceptable salt of such compounds.

6. The compound of formula I according to claim 1 or 2, where a denotes CR6, R6represents N or C1-6alkoxygroup;
or pharmaceutically acceptable salt of such compounds.

7. The compound of formula I according to claim 6, where a denotes CR6, R6represents H or methoxy;
or pharmaceutically acceptable salt of such compounds.

8. The compound of formula I according to claim 1, where R4denotes cycloalkyl; lifemates acceptable salt of such compounds.

9. The compound according to claim 1, which is selected from the following compounds:
1-cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-4-hydroxypiperidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]piperidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-4-hydroxypiperidine-1-yl}-4-oxo-1,4-dihydro-[1,8]naphthiridine-3-carboxylic acid;
7-(4-{4-[(R)-5-((S)-2-aminopropionitrile)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-2-oxo-5-phosphonomethylglycine-3-yl)phenoxymethyl]-4-hydroxypiperidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-{(R)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-3-hydroxypyrrolidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-{(S)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-3-hydroxypyrrolidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-{(S)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-3-hydroxypyrrolidine-1-yl}-8-methoxy-oxo-1,4-dihydroquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-{(S)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-3-hydroxypyrrolidine-1-yl}-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-{(R-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]pyrrolidin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-{(S)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]pyrrolidin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-{(R)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]pyrrolidin-1-yl}-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-{(S)-3-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]pyrrolidin-1-yl}-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-4-phosphonoacetate-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
1-ethyl-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]piperidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
7-(4-{4-[(R)-5-((S)-2-aminopropionitrile)-2-oxoacridine-3-yl]-2-forfinancial}piperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)shall taximeter]-4-hydroxypiperidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-4-hydroxypiperidine-1-yl}-4-oxo-1,4-dihydro-[1,8]naphthiridine-3-carboxylic acid;
or pharmaceutically acceptable salt of such compounds.

10. The connection according to claim 9, which is a 1-cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxoacridine-3-yl)phenoxymethyl]-4-hydroxypiperidine-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
or pharmaceutically acceptable salt of such compounds.

11. The compound of formula I according to claim 1 or its pharmaceutically acceptable salt as a drug, possess antibacterial activity.

12. Pharmaceutical composition having antibacterial activity, containing as an active ingredient a compound of the formula I according to claim 1 or its pharmaceutically acceptable salt, and at least one therapeutically inert excipient.

13. The use of the compounds of formula I according to claim 1 or its pharmaceutically acceptable salt for a medicinal product intended for the prevention or treatment of bacterial infections.

14. The compound of formula I according to claim 1 or its pharmaceutically acceptable salt for the prevention or treatment of bacterial infections.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a compound having chemical structure of formula II , all salts and stereoisomers thereof, where the value of radicals D, A2 and B are as described in paragraph 1 of the claim. The invention also relates to a composition having activity as a c-kit and c-fms modulator, a method of treating a subject suffering from a disease or condition mediated by c-kit and c-fms and a kit for modulating c-kit and c-fms.

EFFECT: novel compounds which can be useful in treating c-kit-mediated diseases or conditions and/or c-fms-mediated diseases or conditions are obtained and described.

21 cl, 44 ex

Polycyclic compound // 2451685

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a new polycyclic compound with general formula (I-1) and (1-3) or a pharmaceutically acceptable salt thereof where X1- -CR1 =CR2 - where R1 and R2 independently stand for hydrogen or C1-6 alkyl while Het stands for a radical of the following formulae: that may be substituted 1-3 times additionally described is a pharmaceutical composition containing such compound and intended for prevention or treatment of diseases caused by β-amyloid.

EFFECT: production of a pharmaceutical composition prevention or treatment of diseases caused by β-amyloid.

7 cl, 392 ex, 12 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to substituted imidazopyridine derivatives of general formula (I) or enantiomers, diastereomers and tautomers and pharmaceutically acceptable salts thereof, in which A denotes -NH-, -CH2-, -CH2-CH2- or a bond; X denotes phenyl, phenyl condensed with a saturated heterocyclic 5- or 6-member ring, where the heterocyclic ring can contain one or two heteroatoms selected from O and N, and where the heterocyclic ring can further be substituted with an oxo group, a 6-member saturated heterocyclyl containing O as a heteroatom, a 5-6-member heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, and where each phenyl and heteroaryl is possibly substituted with 1 to 2 R14 and/or 1 substitute R4b and/or 1 substitute R5; R1 and R2 are independently selected from the following groups: C1-6-alkyl and C1-6-alkylene-C3-7-cycloalkyl, and where each alkyl is possibly substituted with a OH group, or R1 and R2 together with the nitrogen atom with which they are bonded form a 5-6-member ring which is possibly substituted with one substitute selected from C1-6-alkyl and O-C1-6-alkyl; R4b denotes C(O)NH2, C(O)OH, C(O)NH-C1-6-alkyl, C(O)N-(C1.6-alkyl)2, SO2-C1-6-alkyl, oxo group, and where the ring is at least partially saturated, NH2, NH-C1-6-alkyl, N-(C1-6-alkyl)2; R5 denotes a 6-member heteroaryl containing N as a heteroatom; R3 denotes -(CR8R9)n-T; R8 and R9 are independently selected from the following groups: H and C1-6-alkyl; n equals 1, 2, 3, 4, 5 or 6; T denotes or NR12R13; R10 denotes H, NH2, OH, C1-6-alkyl, possibly substituted with one OH, a halogen atom, NH(C1-6-alkyl) or N(C1-6-alkyl)2; q equals 1 or 2; Y denotes CH2, NR11 or O; R11 denotes H, or C1-6-alkyl; R12 and R13 are independently selected from the following groups: H, C1-6-alkyl, C1-6-alkynyl, (CH2)0-2-C3-7-cycloalkyl, and C1-6-alkylene-O- C1-6-alkyl, where C1-6-alkyl is possibly substituted with one halogen; R14 denotes a halogen atom, CN, C1-6-alkyl, possibly substituted with 1-3 substitutes selected from halogen atom, OH, O- C1-6-alkyl, O-C(O)C1-6-alkyl, O- C1-6-alkyl, possibly substituted with one substitute selected from OH, O- C1-6-alkyl, and O-C(O) C1-6-alkyl, or OH. The invention also relates to a pharmaceutical composition based on the compound of formula (I).

EFFECT: novel imidazopyridine derivatives are obtained, which can be used as melanocortin-4 receptor modulators.

17 cl, 8 tbl, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to compounds that may be applied for HIV infection treatment or prevention or for AIDS or AIDS-associated complex treatment. According to the invention, the compounds represent compounds with formula I, where A stands for A1 , A2 , A3 or A4 and R1, R2, R3, R4a, R4b, R5, R6, Ar, X1, X2, X4, X4 and X5 having values specified in the patent claim. Additionally, this invention relates to a pharmaceutical composition containing the said compounds.

EFFECT: production of compounds possessing inhibition activity with regard to HIV reverse transcriptase.

22 cl, 3 tbl, 29 ex

Polymorphic form // 2448966

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is novel polymorphic form B N-[3-tret-butyl-1-(3-chlor-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-{2-[(2-hydroxyethyl)sulfanyl]phenyl}-[1,2,4]triazolo[4,3-a]pyridin-6-yl)sulfanyl]benzyl]}carbamide, method of its obtaining.

EFFECT: possibility to apply composition in treatment of various states, especially in treatment of inflammatory conditions, such as chronic obstructive lung disease.

4 cl, 12 ex, 9 tbl, 11 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 1-azabicycloalkyl derivatives of formula (I): wherein A represents O or N(R1); Y represents a group of formulas: or R represents substituted or unsubstituted phenyl or indolylradical, to their use as pharmaceutical agents, to pharmaceutical compositions containing them, to methods of treating and preventing mental and neurodegenerative diseases.

EFFECT: preparing pharmaceutical agents for treating and preventing mental and neurodegenerative diseases.

17 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula (I) or its pharmaceutically acceptable salts which have action of mTOR inhibitors. What is also declared is preparing a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or diluent; besides, what is declared is the use of the compound of formula (I) or its pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

EFFECT: preparing the pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

11 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrido[2,3-d]pyrimidines of formula (V) and use of compounds of formula (I), containing a compound of formula (V), to prepare a medicinal agent used for inhibiting HCV replication in mammals infected with HCV, as well as a pharmaceutical composition based on said compounds. In formula (I)

R1 denotes hydrogen, amino, mono- or disubstituted amino, where amino group substitute(s) can be selected from C1-6alkyl, C1-4alkyloxyC1-4alkyl, diC1-4alkylaminoC1-4alkyl/piperidin-1-ylC1-4alkyl, phenylC1-4alkyl, where the phenyl group can further be substituted with C1-4alkoxy; L denotes -NR8-; R2 denotes Het2, where said Het2 denotes an aromatic monocyclic 6-member heterocycle which contains one nitrogen atom and is optionally substituted with one or more substitutes selected from C1-4alkyl; polyhalogenC1-4alkyl, halogen, -COOR7, -CONR4aR4b, -OR7, -SR5, and where C1-4alkyl can further be substituted with -COOR7; R3 denotes phenyl which is optionally substituted with one or two halogen atoms; each of R4a and R4b independently denotes hydrogen, C1-4alkyl, hydroxyC1-4alkyl; each R5 independently denotes C1-4alkyl; each R7 independently denotes hydrogen or C1-4alkyl; and each R8 independently denotes hydrogen or C1-10alkoxycarbonyl. The values of radicals in formula (V) are given in the claim.

EFFECT: improved method.

18 cl, 4 dwg, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

where the ring X represents benzole or pyridine; R1 represents substituted alkyl; R2 represents optionally substituted aryl or optionally substituted 4-7-member monocyclic heterocyclic group or optionally substituted condensed group of heterocyclic group with the benzole ring where the substitutes of optionally substituted aryl, optionally substituted 4-7-member monocyclic heterocyclic group and optionally substituted condensed group of heterocyclic group with the benzole ring are selected from a group consisting of; (1) alkyl optionally substituted by a group selected from halogen and alkoxycarbonyl, (2) alkoxy optionally substituted by halogen, (3) halogen, (4) 4-7-member monocyclic heterocyclic group or (5) amino, optionally mono- or disubstituted alkyl, and (6) hydroxyl, R3 represents hydrogen or alkyl: R4 represents hydrogen, halogen or alkyl; R5 represents hydrogen or alkyl; R6 and R7 are identical or different, and each represents hydrogen or halogen; or pharmaceutically acceptable salt. Also, the invention refers to a IKur blocker containing the compounds described above as an active ingredient, and also to a preventive and therapeutic agent for cardiac arrhythmia and atrial fibrillation.

EFFECT: there are produced and described new compounds applicable as a IKur blocker effective for preventing or treating cardiac arrhythmia, such as atrial fibrillation.

12 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted methyl-amines of general formula 1, having serotonin 5-HT6 receptor antagonist properties. In formula 1 , W is naphthalene, indolysin or quinoline; R1 is hydrogen, fluorine, chlorine, methyl; R2 is hydrogen, fluorine, methyl, phenyl, thiophen-2-yl, furan-2-yl, pyridyl, piperazin-1-yl or 4-methylpiperazin-1-yl; R3 is methyl; or W is benzene, R3 assumes the value given above; R1 is 3-Cl, R2 is 3-piperazin-1-yl or 3-(4-methylpiperazin-1-yl); or R1 is hydrogen, R2 is phenyl or pyridyl; or R1 is hydrogen, fluorine, chlorine, methyl; R2 is 4-piperazin-1-yl or 4-(4-methylpiperazin-1-yl); or W is oxazole, R3 is optionally substituted methyl; R1 is chlorine or fluorine, R2 is methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is piperazin-1-yl, 4-methylpiperazin-1-yl, or R1 is chlorine, fluorine or methyl; R2 is furan-2-yl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is furan-2-yl, R3 is (tetrahydrofuran-2-yl)methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is thiophen-2-yl, R3 is 2-methoxyethyl, or R1 is chlorine or fluorine, R2 is thiophen-2-yl, R3 is methyl.

EFFECT: compounds can be used to treat central nervous system (CNS) diseases, such as psychiatric disorders, schizophrenia, anxiety disorders, as well as for improving mental capacity, for treating obesity or for studying the molecular mechanism of inhibiting serotonin 5-HT6 receptors.

15 cl, 27 dwg, 2 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I):

, where: R=NO2, or and Het denotes an azolyl radical selected from nitroazolyl and tetrazolyl radicals; except 3- and nitro-4-(4-nitro-1,2,3-triazol-1-yl)furazan. The invention also describes a method of producing a compound of formula I and an energy composition based on said compounds.

EFFECT: compounds have high energy characteristics, low sensitivity and high thermal stability.

11 cl, 7 ex, 3 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention describes isoxazolines of formula (I), in which A denotes C or N; R denotes C1-4 haloalkyl; X denotes identical or different halogens or C1-4 haloalkyl; l equals 0, 1 or 2; Y denotes halogen or C1-4 alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, nitro, amino, C1-4 alkylcarbonylamino, benzoylamino or C1-4 alkoxycarbonylamino; m equals 1 or 1; and G denotes any group selected from heterocyclic groups given in the description, and a method of producing said compounds and use as insecticides for controlling the population of harmful insects or arthropods.

EFFECT: high efficiency of using said compounds.

11 cl, 28 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel azoles of general formula 1A and 1B and pharmaceutically acceptable salts thereof, having activity on hepatitis C and hepatitis GBV-C virus. Said compounds have NS5A viral protein ligand properties and can be used as active components for a pharmaceutical composition and a medicinal agent for treating diseases caused by said viruses. In general formula 1A and 1B, the solid lines accompanied by dotted lines denote a single or double bond, wherein if one of them is a single bond, the other is a double bond; X and Y optionally assume different values and denote a nitrogen, oxygen or sulphur atom or a NH group; R1 and R2 optionally denote identical radicals 2.1-2.20, in which the asterisk (*) indicates site of the bond to azole fragments. Said fragments and values of A and B are given in the claim.

EFFECT: more value of the compounds.

10 cl, 1 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, where: n equals 0, 1, 2; G denotes CH2, CHR3; R1 denotes H, C1-C6-alkyl, C3-C6-alkenyl, -CH2Ph; R2, R3, R4 independently denote H, CH3, -CH2F, -CHF2, CF3; A denotes 1,4-Ph, 1,3-Ph, which can be optionally substituted with 1-4 substitutes selected from halogen, C1-C4-alkyl, C1-C4alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4alkoxy; E denotes NR5, where R5 denotes H, C1-C3-alkyl; Ar denotes a radical of formula

and

where: Ra denotes halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, phenyl sulphonyl, CN, -NR6R7, where R6 and R7, together with an N atom, form a 5- or 6-member saturated ring or denotes a 5-member saturated or unsaturated aromatic or non-aromatic heterocyclic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heterocyclic ring can carry 1, 2 or 3 substitutes selected from halogen and C1-C6-alkyl, or denotes a 6-member saturated heterocyclic ring containing, as ring members, one N and one O atom; Rb and Rc independently denote H, halogen, CH3, OCH3, CH2F, OCH2F, CHF2, OCHF2, CF3, OCF3, CH2CH2F, OCH2CH2F, CH2CHF2, OCH2CHF2, CH2CF3 or OCH2CF3; Rd denotes Ra or a 5- or 6-member heteroaromatic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heteroaromatic ring can carry 1 substitute selected from C1-C6-alkyl and C1-C6-alkylthio; Re denotes H or is defined as Ra; Rf is defined as Ra; k equals 0, 1, 2, 3; j equals 0, 1, 2, 3, 4; provided that Ra does not denote F, CH2F, CHF2, CF3, OCF3, if A denotes 1,4-Ph, Ar denotes a radical of formula (A) and Rb and Rc denote H, halogen; except compounds, where R1 denotes propyl, G denotes CH2, n equals 1, A denotes 1,4- Ph, E denotes NH, Ar denotes a radical of formula (F) and Rd denotes halogen, C1-C6-alkyl, C2-C6-alkenyl or a 5-member heteroaromatic ring; and physiologically acceptable acid addition salts thereof.

EFFECT: compounds exhibit 5HT6 receptor simulating activity, which allows for their use in a pharmaceutical composition.

25 cl, 6 tbl, 107 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds specified in cl. 1, and also to a pharmaceutical composition possessing binding activity with respect to Bcl proteins, to applying the declared compounds for preparing a drug for treating cancer and for treating a bcl-mediated disorder.

EFFECT: use of the compounds as Bcl protein inhibitors.

18 cl, 2 tbl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I): or pharmaceutically acceptable salt thereof, or stereoisomer, in which: n equals 0 or 1; X denotes CH2, C=O; R1 denotes a) -(CH2)mR3 or -CO(CH2)mR3, where m equals 0, 1; and R3 denotes a 5-10-member aryl or heteroaryl, where the heteroaryl denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected oxygen, nitrogen or sulphur, optionally substituted with one or more halogens; b) -C=YR4, where Y denotes O; and R4 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; (C0-C10)alkyl-(5-10-member heteroaryl), where "heteroaryl" denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected from oxygen, nitrogen or sulphur, said heteroaryl is optionally substituted with one or more substitutes selected from halogen, oxo or 2-(C1-C6)alkyl, where Z denotes S; (C0-C10)alkyl-(5-10-member aryl), said aryl is optionally substituted with one or more substitutes selected from halogen; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; or -Z-(C1-C6)alkyl, where Z denotes S or SO2, and where said (C1-C6)alkyl can be optionally substituted with one or more halogens; or (C1-C6)alkyl-CO-O-R12, where R12 denotes H or (C1-C6)alkyl; or c) -C=ZNHR6, where Z denotes O or S; and R6 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; 5-10-member aryl or heteroaryl, where "heteroaryl" denotes a bicyclic aromatic ring containing 9 ring atoms, from which at least one or two atoms are oxygen atoms; optionally substituted with one or more substitutes selected from halogen; cyano; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; and R2 denotes H or (C1-C6)alkyl. Also described is a pharmaceutical composition for inhibiting TNFα, based on the compound of formula I.

EFFECT: novel compounds which can regulate production of certain cytokines, including TNF-α, are obtained and described.

27 cl, 81 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (IB) or to their pharmaceutically acceptable salts:

, wherein R means formula: R1 means -C(O)NR3R4, -C(O)R3 and -C(O)OR3; each R3 and R4 independently means H, C1-10 alkyl, wherein alkyl is optionally substituted by one -OH; R3 and R4 are bound together with N atoms to form a 5-6-member heterocyclic ring which additionally contains one O heteroatom; R5 means H; R6 means CN; R7 means H; W means C. What is described is a method for producing both them and intermediate compounds of formula (1-1c): , wherein: R1 means -C(O)NR3R4; R3 and R4 are specified above.

EFFECT: compounds (IB) shows DPP-IV inhibitory activity that allows them being used in a pharmaceutical composition.

9 cl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula (I) or its pharmaceutically acceptable salts which have action of mTOR inhibitors. What is also declared is preparing a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or diluent; besides, what is declared is the use of the compound of formula (I) or its pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

EFFECT: preparing the pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

11 cl, 25 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, obstetrics, gynecology and includes estimation of puerperas' state, depending on which treatment tactics is selected. Severity of state is estimated by two groups of criteria of table No 3, presented in the description, by 1 point: absence of factors of risk of purulent-septic complications (PSC), subfebrile condition with single rise to 38°C, arrested by antibacterial therapy (ABT), absence of easily arrested intestine paresis after Cesarean section, the cervix of uterus is formed, presence of uterus involution in hysteroscopy at the background of treatment with endometrectomy or vacuum-aspiration, USE-data - increase and extension of uterus cavity by 0.5-1.0 cm, absence of deformation in the area of scar or deformation up to 0.5 cm, on uterus walls - linear echo-positive structures up to 0.2-0.3 cm thick, local sections of reduced myometrium echogenicity in the region of scars not larger than 1.5x1.5 cm, absence of infiltration, hematoma in the region of scars, improvement of laboratory indices in dynamics. Criteria of group 2 are estimated in 2 points: presence of PSC risk factors, long-lasting fever with resumption after finishing ABT, intestine paresis with absence of effect from intensive or repeated treatment courses, absence of tendency to formation of uterus cervix, stable uterus subinvolution, by USE data: extension of uterus cavity ≥1 cm, deformation in scar ≥0.5 cm, echopositive structures ≥0.4 cm, reduces echogenicity in scar zone ≥2.5×1.5 cm, hematoma or infiltrate in retrovesical space, in area of scars, absence of positive dynamics or change of laboratory indices to the worse. If state of puerpera is characterised by criteria of the first group to 7 points, it is estimated as uncomplicated form of disease, if - more than 7 points or at least by one criterion from group 2, as complicated form.

EFFECT: method ensures reliable justification of adequate tactics of patient management, strict control of their state in dynamics, reduction of frequency of complicated generalised forms of PSC, terms of staying in hospital.

2 ex, 3 tbl

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