Inhibitors of bacterial gyrase and their applying

FIELD: organic chemistry, biochemistry, medicine, pharmacology.

SUBSTANCE: invention relates to gyrase inhibitors that reduce amount of microorganisms in biological sample by contacting the indicated sample with compound of the formula (I): , to a method for treatment of bacterial infection by using compounds of the formula (I), compounds of the formula (I) and a pharmaceutical composition comprising compounds of the formula (I). Invention provides the enhanced effectiveness of treatment.

EFFECT: valuable medicinal properties of gyrase.

54 cl, 5 tbl, 13 ex

 

The scope of the invention

This invention relates to the field of medicinal chemistry and relates to compounds and pharmaceutical compositions that inhibit gyrase bacteria. Compounds suitable as inhibitors activity giras bacteria. The present invention also relates to methods for treating bacterial infections in mammals. The present invention also relates to methods of reducing the number of bacteria in a biological sample.

Background of the invention

Has long been established bacterial resistance to antibiotics, and at the present time it is considered a serious public health problem worldwide. As a result of resistance of some bacterial infection or difficult to treat with antibiotics, either they are not treatable. This problem became particularly severe after the recent discovery of multidrug resistance in some strains of bacteria such as Streptococcus pneumoniae (SP), Mycobacterium tuberculosis, and Enterococcus. Especially alarming is the emergence of vancomycin-resistant of Enterococcus as previously vancomycin was the only effective antibiotic to treat the infection, and was considered a medication of last resort" for many infections. Despite the fact that many others are resistant to drugs bacteria do not cause dangerously what about for a life of disease, as enterococci, there is a fear that the genes that induce resistance can be distributed in a more dangerous microorganisms, such as Staphylococcus aureus, which is already a dominant resistance to methicillin (De Clerq et al., Current Opinion in Anti-infective Investigational Drugs, 1999, 1, 1; Levy, "The Challenge of Antibiotic Resistance", Scientific American, March, 1998).

Another alarming aspect is how quickly you receive antibiotic resistance. For example, until the 1960s SP was universal sensitive to penicillin, and in 1987, only 0.02% of the strains of SP in the United States were resistant. However, in 1995 it was reported that SP resistance to penicillin was approximately 7%, and in some parts of the USA was high and equal to 30% (Lewis, FDA Consumer magazine (September, 1995); Gershman y in The Medical Reporter, 1997).

Hospitals, in particular, serve as centers of education and transmission of drug-resistant microorganisms. Infections that occur in hospitals, known as nosocomial (hospital-acquired) infections are becoming increasingly growing problem. Of the two million Americans, inspired in hospitals each year, more than half of them are infected with infections that are resistant to at least one antibiotic. According to the Center for disease control in 1992, more than 13,000 former to treatment in hospital patients died from the bacterial infecti is, pathogens were resistant to treatment with antibiotics (Lewis, "The Rise of Antibiotic-Resistant Infections", FDA Consumer magazine, Sept, 1995).

As a result of having to fight drug-resistant bacteria and a growing lack of effectiveness of the available drugs, there is growing interest in the development of new antibiotics. One attractive strategy for the development of new antibiotics is the inhibition of DNA-gyrase, the enzyme of bacteria, necessary for DNA replication and, therefore, is essential for growth and division of bacterial cells. The gyrase activity is also associated with events occurring during the transcription, repair and recombination of DNA.

Gyrase is one of topoisomerases, group of enzymes that catalyze vzaimoprevrascheny topological isomers of DNA (mostly, see Kornberg and Baker, DNA Replication, 2d Ed., Chapter 12, 1992, W.H.Freeman and Co.; Drlica, Molecular Microbiology, 1992, 6, 425; Drlica and Zhao, Microbiology and Molecular Biology Reviews, 1997, 61, 377). Itself gyrase controls superspecialization DNA, and weakens the topological stress, which occurs when the DNA chain of the original duplex unwinding during replication. Gyrase also catalyzes the transformation relacionado, closed circular DNA duplex in a negative superstructure form, which is more favorable for recombination. Fur the lowland reaction supercoiling includes packaging around gyrase DNA, gap double chains in this area, the passage of the second region of the DNA through the gap and the connection is broken chains. A similar mechanism of splitting characteristic of topoisomerase type II. The supercoiling reaction is stimulated by the binding of ATP with Girasol. Then ATP is hydrolyzed during the reaction. This binding and subsequent hydrolysis of ATP causes conformational changes associated with DNA gyrase, which are necessary for the manifestation of its activity. It was also found that the level of supercoiling of DNA (or relaxation) depends on the ratio of ATP/ADP. In the absence of ATP gyrase only able to recover super-spiral DNA.

DNA gyrase bacteria is a protein tetramer weight of 400 kDa, consisting of two subunits (GyrA) and two subunits B (GyrB). Binding and DNA cleavage associated with GyrA, while ATP is bound and hydrolyzed protein GyrB. GyrB consists of aminoanisole domain, which possesses ATP-aznoe activity, and carboxykinase domain, which interacts with GyrA and DNA. In contrast, topoisomerase type II in eukaryotes are homodimers that can relax both negative and positive superwide, but can't enter a negative superwide. Ideally, antibiotics, mechanism of action of which is based on the inhibition of DNA gyrase bacteria, Bud is t selective for this enzyme is relatively inactive against topoisomerases type II in eukaryotes.

Widely used quinolone antibiotics inhibit DNA girazu bacteria. Examples of quinolones include pre-existing connection, such as nalidixic acid and oxolinic acid, as well as the later, more effective fluoroquinolones, such as norfloxacin, ciprofloxacin, trovafloxacin. These compounds are associated with GyrA and stabilize the split complex, inhibiting thus, the function of gyrase in General, leading to cell death. However, it is generally acknowledged drug resistance as a problem for this group of compounds (WHO Report, "Use of Quinolones in Food Animals and Potential Impact on Human Health, 1998). For quinolones, as well as other groups of antibiotics is characterized by the fact that bacteria exposed to earlier connections, often rapidly develop cross-resistance to more effective connections within the same group.

Less known inhibitors that are associated with GyrB. Examples include coumarins, novobiocin and kumaresan And, ciclacillin, Zinedin and claritin. It was shown that coumarin is very strongly linked with GyrB. For example, novobiocin forms a network of hydrogen bonds with the protein and several hydrophobic contacts. Although, as it turned out, novobiocin and ATP bound within the binding site of ATP, there is a minimum perekriti is in the relative orientation of the two compounds. Overlapping areas are sugar unit novomicin and the adenine of ATP (Maxwell, Trends in Microbiology, 1997, 5, 102).

For resistant coumarin bacteria are the most dominant point mutation is located on the surface of the arginine residue, which binds to the carbonyl coumarin ring (Arg136 in E. coli GyrB). Although enzymes with this mutation show a lower superspecialization and activity of ATP-ases, they are also less sensitive to inhibition under the action of coumarin drugs (Maxwell, Mol. Environ., 1993, 9, 681).

Despite the fact that coumarins are strong inhibitors of supercoiling under the action of gyrase, they are not widely used as antibiotics. Basically, they are not usable as such because of their poor penetration into bacteria, eukaryotic toxicity and low solubility in water (Maxwell, Trends in Microbiology, 1997, 5, 102). It would be desirable to have a new, efficient inhibitor GyrB to overcome these disadvantages, it is preferable not functioning on the basis of binding Arg136 for the activity. Such an inhibitor would be attractive to potential antibiotic without problems with the resistance characteristic of other groups of antibiotics.

Because bacterial resistance to antibiotics has become a serious public health problem, there is an urgent sweat ebest in the development of newer and more effective antibiotics. More specifically, there is a need for antibiotics, which are new compounds not previously used for treatment of bacterial infections. Such compounds are especially suitable for treatment nosocomial infections in hospitals, where education and dissemination of resistant bacteria is becoming more prevalent.

Description of the invention

Currently, it was found that the compounds of this invention and their pharmaceutical compositions suitable for the treatment of bacterial infections. One embodiment of the invention relates to a method of treating a bacterial infection in a mammal, in need thereof, comprising the stage of introduction of a given mammal therapeutically effective amounts of compounds of formula I:

or its pharmaceutically acceptable derivative or prodrug, in which:

Z represents O or N-R4;

W represents a nitrogen atom or CRand;

Randselected from a hydrogen atom, halogen atom, -CF3, R7, -OR7or-N(R7)2;

R1represents aryl or heteroaryl ring, where the aforementioned ring is optionally substituted up to four R9; where the substituent R9in ortho-position, R1if taken together with R2may form a con is Tserovani, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R2and R3each independently selected from R6, halogen atom, CN, SR6, OR6N(R6)2, NRCO2R6, NRCON(R6)2, CON(R6)2, NRCOR6, NRN(R6)2, COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or NRSO2R6; or R2and R3if taken together, form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R4selected from R6, CON(R6), COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or (CH2)YR2;

y is 1-6;

R5selected from R7, Ar, COAr, CON(R7)Ar, (CH2)YCO2R, (CH2)YN(R7)2C(=NR10)-N(R7)2C(=NR10)-NRCOR, C(=S)-N(R7)2, CON(R7)2, CO2R, COR, SO2R or SO2N(R7)2;

Ar represents a 5-membered heteroaryl, heterocyclic or carbocyclic ring, where the aforementioned ring is optionally substituted with up to three what zamestitelyami, selected from oxo, halogen atom, CN, NO2, R8, OR8, Other8, NHCOR8, NHCONHR8, COR8, CONHR8, SO2R8, NHSO2Other8or SO2Other8;

each R is independently selected from hydrogen or optionally substituted aliphatic groups containing from one to six carbon atoms;

each R6independently selected from R7or optionally substituted groups selected from alkoxy, hydroxyalkyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, Alcoxy, aryloxyalkyl, heteroaryl, heteroalkyl, heteroaromatic or heteroaromatic;

each R7independently selected from a hydrogen atom or optionally substituted aliphatic groups containing from one to six carbon atoms, or two R7at the same nitrogen atom, being taken together with the nitrogen atom, optionally form a 4-6-membered saturated or unsaturated heterocyclic ring containing one to three heteroatoms;

R8is1-C4aliphatic group, where two of R8in related provisions of Ar, or aryl or heteroaryl ring may be taken together with the intermediate atoms with the formation of a 3-6-membered condensed ring;

each R9independently selected from oxo, halogen atom, CN, NO2, n(halogenoalkane), R6, SR6, OR6, OR8N(R6)2, CON(R6)2, CON(R)COR6, COR6, CO2R6, CO2N(R6)2, COCOR6, SO2R6, SO2N(R6)2N(R)TnCO2R6N(R)TnCON(R6)2N(R)TnN(R6)2N(R)TnNRCO2R6N(R)TnNRCON(R6)2N(R)TnCOR6N(R)TnNRCOR6N(R)TnSO2N(R6)2N(R)TnSO2R6, TnPO(OR7)2, TnOPO(OR7)2, TnSP(OR7)2, TnPO(OR7)2or TnNPO(OR7)2;

each Q is independently selected from C1-C3branched or normal alkyl;

T is selected from-Q - or Qm-CH(Qm-R2)-;

each m and n is independently selected from zero or 1; and

R10selected from R7or Ar.

In the sense in which they are used in this description, unless otherwise specified, will be following definitions apply. In addition, unless otherwise indicated, the radicals of functional groups selected independently.

The term "aliphatic" in the sense in which it is used, means a normal, branched or cyclic With1-C12hydrocarbons which are completely saturated or contain one or more units of unsaturation, what about that are not aromatic. For example, suitable aliphatic groups include substituted or unsubstituted, normal, branched or cyclic alkyl, alkenyl, quinil and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. The terms "alkyl", "alkoxy", "hydroxyalkyl", "alkoxyalkyl and alkoxycarbonyl"used alone or as part of a larger group, include both normal and branched chain containing 1-12 carbon atoms. The terms "alkenyl" and "quinil"used alone or as part of a larger group, will include both normal and branched chain, containing 2-12 carbon atoms. The term "cycloalkyl"used alone or as part of a larger group, will enable circular With3-C12hydrocarbons which are completely saturated or which contain one or more units of unsaturation, but which are not aromatic.

The terms "halogenated", "halogenoalkanes and halogenoalkane" mean alkyl, alkenyl or alkoxy which may be substituted by one or more halogen atoms. The term "halogen" means F, Cl, Br or I.

The term "heteroatom" means an atom of N, O or S, and includes any oxidized form of nitrogen and sulfur, and stereoselectivity form of any basic nitrogen.

The term "carbocycle", "carbocycle" or "carbocyclic" in the sense in which onopolies, means aliphatic ring system containing 3 to 14 members. The term "carbocycle", "carbocycle" or "carbocyclic", saturated or partially unsaturated, also refers to rings that are optionally substituted. The terms "carbocycle" or "carbocyclic" also include aliphatic ring, which is condensed with one or more aromatic or nonaromatic rings, as in decahydronaphthalene or tetrahydronaphthyl, where the radical or the place of connection is aliphatic ring.

The term "aryl"used alone or as part of a larger group, as in "aralkyl", "arakaki" or "aryloxyalkyl", refers to aromatic ring groups containing from 5 to 14 members, such as phenyl, benzyl, phenethyl, 1-naphthyl, 2-naphthyl, 1-antracol and 2-antracol. The term "aryl" also refers to rings that are optionally substituted. The term "aryl" can be used interchangeably with the term "aryl ring". "Aryl" also includes a condensed polycyclic aromatic ring systems in which an aromatic ring condensed with one or more rings. Examples include 1-naphthyl, 2-naphthyl, 1-antracol and 2-antracol. Also included in the scope of the term "aryl", in the sense in which it is used herein, is a group in which an aromatic ring condensed the one or more non-aromatic rings so as in indanyl, phenanthridine or tetrahydronaphthyl, where the radical or the place of attachment is at an aromatic ring.

The term "heterocycle", "heterocyclyl" or "heterocyclic", in the sense in which it is used in this description, includes non-aromatic ring system containing from 5 to 14 members, preferably 5-10, in which one or more ring carbons, preferably from 1 to 4, is replaced by a heteroatom, such as N atom, O or S. Examples of heterocyclic rings include 3-1H-benzimidazole-2-(1-substituted)-2-oxopentanoate-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophene, 3-tetrahydrothiophene, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholine, 3-thiomorpholine, 4-thiomorpholine, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinil, 2-piperazinil, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidine, diisononyl, N-substituted of diisononyl, 1-phtalimide, benzoxazol, benzopyranyl, benzoperylene, benzocaine, benzothiophenes and sensational. Also included in the scope of the term "heterocyclyl" or "heterocyclic", in the sense in which it is used herein, is a group in which a non-aromatic, containing heteroatom ring condensed with one or more aromatic or nonaromatic rings that is, as in indolinyl, chromanol, phenanthridine or tetrahydroquinoline, where the radical or the place of connection is non-aromatic, containing heteroatom ring. The term "heterocycle", "heterocyclyl" or "heterocyclic", saturated or partially unsaturated, also refers to rings that are optionally substituted.

The term "heteroaryl"used alone or as part of a larger group, as in "heteroalkyl" or "heteroaromatics", refers to heteroaromatic ring groups containing from 5 to 14 members. Examples of heteroaryl rings include 2-furanyl, 3-furanyl, 3-furutani, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2 pirimidil, 4 pirimidil, 5 pirimidil, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothiazyl, benzofuranyl, indolyl, chinoline, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, ethenolysis, indolyl, isoindolyl, acridines or benzisoxazole. Also included in the scope of the term "heteroaryl", in the sense in which it is used in this description is the fast group, in which heteroaromatic ring condensed with one or more aromatic or nonaromatic rings, where the radical or the place of connection is a heteroaromatic ring. Examples include tetrahydroquinolin, tetrahydroisoquinoline and pyrido[3,4-d]pyrimidinyl. The term "heteroaryl" also refers to rings that are optionally substituted. The term "heteroaryl" can be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".

Aryl (including aralkyl, Alcoxy, aryloxyalkyl and the like) or heteroaryl (including heteroalkyl, heteroaromatics and the like) can include one or more deputies. Examples of suitable substituents at the unsaturated carbon atom of an aryl, heteroaryl, aralkyl or heteroalkyl include a halogen atom, -Rabout, -ORabout, -SRabout, 1,2-methylenedioxy, 1,2-Ethylenedioxy, HE protected (such as acyloxy), phenyl (Ph), substituted Ph, -O(Ph), substituted-O(Ph), -CH2(Ph), substituted-CH2(Ph), -CH2CH2(Ph), substituted-CH2CH2(Ph), -NO2, -CN, -N(Ro)2, -NRoC(O)Ro, -NRoC(O)N(Ro)2, -NRoCO2Ro, -NRoNRoC(O)Ro, -NRoNRoC(O)N(Ro)2, -NRoNRoCO2Ro, -C(O)C(O)Ro, -C(O)CH2C(O)Ro,-CO 2Ro, -C(O)Ro, -C(O)N(Ro)2, -OC(O)N(Ro)2, -S(O)2Ro, -SO2N(Ro)2, -S(O)Ro, -NRoSO2N(Ro)2, -NRoSO2Ro, -C(=S)N(Ro)2, -C(=NH)-N(Ro)2, -(CH2)YNHC(O)Ro, -(CH2)YNHC(O)CH(V-Ro)(Ro), where Rorepresents H, substituted or unsubstituted aliphatic group, an unsubstituted heteroaryl or heterocyclic ring, phenyl (Ph), substituted Ph, -O(Ph), substituted-O(Ph), -CH2(Ph), or substituted-CH2(Ph); y is 0-6; and V represents a linker group. Examples of substituents in the aliphatic group or the phenyl ring include amino, alkylamino, dialkylamino, aminocarbonyl, halogen atom, alkyl, alkylaminocarbonyl, dialkylaminoalkyl, alkylaminocarbonyl, dialkylaminoalkyl, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylsulphonyl, hydroxy, halogenoalkane or halogenated.

Aliphatic group or non-aromatic heterocyclic ring may contain one or more substituents. Examples of suitable substituents at a saturated carbon atom aliphatic group or non-aromatic heterocyclic ring include those listed above for the unsaturated carbon of an aryl or heteroaryl, and are as follows: =O, =S, =NNHR*,=NN(R *)2, =N-, =NNHC(O)R*, =NNHCO2(alkyl), =NNHSO2(alkyl), or =NR*where each R*independently selected from a hydrogen atom, an unsubstituted aliphatic group or substituted aliphatic group. Examples of substituents in the aliphatic group include amino, alkylamino, dialkylamino, aminocarbonyl, halogen atom, alkyl, alkylaminocarbonyl, dialkylaminoalkyl, alkylaminocarbonyl, dialkylaminoalkyl, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylsulphonyl, hydroxy, halogenoalkane or halogenated.

Suitable substituents at the nitrogen aromatic or non-aromatic heterocyclic ring include-R+, -N(R+)2, -C(O)R+, -CO2R+, -C(O)C(O)R+, -C(O)CH2C(O)R+, -SO2R+, -SO2N(R+)2, -C(=S)N(R+)2, -C(=NH)N(R+)2and-NR+SO2R+where R+represents H, an aliphatic group, substituted aliphatic group, phenyl (Ph), substituted Ph, -O(Ph), substituted-O(Ph), -CH2(Ph), substituted-CH2(Ph) or unsubstituted heteroaryl or heterocyclic ring. Examples of substituents in the aliphatic group or the phenyl ring include amino, alkylamino, dialkylamino, aminocarbonyl, halogen atom, alkyl, alkylaminocarbonyl, dialkylaminoalkyl, alkylaminocarbonyl dialkylaminoalkyl, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylsulphonyl, hydroxy, halogenoalkane or halogenated.

The term "linker group" or "linker" means an organic group that links the two parts of the connection. Typically, the linkers include atom such as an oxygen atom or a sulfur atom, a link, such as-NH-, -CH2-, -C(O)-, -C(O)NH - or a chain of atoms, such as alkyliden. Typically, the molecular weight of the linker is in the range of about 14-200. Examples of linkers include saturated or unsaturated With1-6alkyliden, which is optionally substituted, and in which one or two saturated carbon atom chain optionally substituted-C(O)-, -C(O)C(O)-, -CONH-, -CONHNH-, -CO2-, -OC(O)-, -NHCO2-, -O-, -NHCONH-, -OC(O)NH-, -NHNH-, -NHCO-, -S-, -SO-, -SO2-, -NH-, -SO2NH - or-NHSO2-.

The term "alkylidene" refers to optionally substituted normal or branched carbon chain, which may be fully saturated or have one or more units of unsaturation. Optional substituents are described above for the aliphatic group.

A valid combination of the substituents or variables, if only this combination leads to the formation of a stable or chemically possible connection. Stable or chemically possible connection represents a connection which substantially does not change aetsa at a temperature of 40° C or lower in the absence of moisture or other chemically reactive conditions, for at least a week.

Specialists in this field it is obvious that some compounds of this invention can exist in tautomeric forms, all such tautomeric forms of the compounds included in the scope of the invention.

Unless otherwise specified, it is assumed that the patterns presented here include all stereochemical forms of the structure, i.e. the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as mixtures of enantiomers and diastereoisomers these compounds are included in the scope of the invention. Unless otherwise specified, it shall also be understood that the structures described herein include compounds that differ only by the presence of one or more isotopically enriched atoms. For example, compounds having these structures, except for the substitution of a hydrogen atom by a deuterium or tritium, or the replacement of a carbon atom13With or14With the carbon included in the scope of this invention.

One preferred embodiment of the present invention relates to a method of treating a bacterial infection in a mammal, in need thereof, comprising the stage of introduction of a given mammal a therapeutically effective amount of compounds having f is rmula Ia or Ib.

or its pharmaceutically acceptable derivative or prodrug, where R1, R2, R3, R4and R5have the meanings given above.

Examples of preferred R1include optionally substituted phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thienyl, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazole-1-yl, aminopyrimidines, chinoline, aminobenzimidazole and indolyl. Preferred R9if there is in R1-aryl or heteroaryl ring include halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6N(R)TnCO2R6N(R)TnNRCO2R6N(R)TnN(R6)2, NO2, Tn(halogenated), CO2N(R6)2, COR6, SO2R6or SO2N(R6)2. Examples of such groups R9include, but are not limited to, pyrrole-2,5-dione, NR2, OR, CO2H, NO2, OH, NHCOR, NHCO2R, NHCH2CO2R NH(CH2)2NHCO2R, CH2CO2R, CF3, SO2R, NHCH(CH2OH)CO2H, N-SO2Me-piperidinyl, SMe, NH(CH2)2NH2and piperidinyl.

Preferred groups R2and R3include a halogen atom, CN, CO2R6, OR6and R6. Examples of preferred groups R3include Br, F, Cl, COOH, CN, OMe, methyl, ethyl, tert-butyl, CF3, OH and OBn.

Examples of preferred R5include CO2(aliphatic), C(=NH)-NH2and CON(R7)2such as WITH(piperidine-1-yl), CONHEt, CONHMe, CONH(cyclopropyl), CONH(isopropyl), CONH(propyl), CONH(pyrrolidinyl), CO2Et and CO2Me.

Preferred compounds of formula Ia and Ib include those having one or more, or most preferably all of the characteristics selected from the group consisting of:

(a) R1represents optionally substituted aryl or heteroaryl ring;

(b) R2and R3each independently selected from a halogen atom, CN, CO2R6, OR6or R6;

(C) R5is CO2R, COAr, COR, CON(R7)2, Ar, (CH2)YCO2R or (CH2)yN(R7)2; and

(d) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6N(R)TnCO2R6N(R)TnNRCO2R6N(R)TnN(R6)2, NO2, Tn(halogenated), CO2N(R6)2, COR6, SO2R6or SO2N(R6)2.

More preferred compounds of formula Ia and Ib include those having one or more, or most preferably all of the characteristics selected from the group comprised the soup from:

(a) R1is optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, teinila, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazole-1-yl, aminopyrimidine, chinoline, aminobenzimidazole or indolyl;

(b) R2represents a hydrogen atom, alkoxy, aminoalkyl or halogen atom;

(C) R3represents a hydrogen atom, alkoxy, Alcoxy or halogen atom;

(d) R4represents a hydrogen atom or (CH2)YR2;

(e) R5represents CON(R7)2, Ar, (CH2)YCO2R or (CH2)YN(R7)2; and

(f) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6orN(R)TnCO2R6.

Selected compounds of formula Ia are presented in table 1.

Table 1
Room Ia-StructureRoom Ia-Structure
12
34
5 6
78
910
1112
1314
1516

Room Ia-StructureRoom Ia-Structure
1718
1920
2122
23 24
2526
2728
2930
3132

Room Ia-StructureRoom Ia-Structure
3334
3536
3738
3940
4142
4344
4546
4748
4950
5152

Room Ia-StructureRoom Ia-Structure
5354
5556
5758
5960
6162
6364
6566
6768
6970
7172

Room Ia-StructureRoom Ia-Structure
7374
7576
7778
7980
8182
8384
8586
8788

Room Ia-StructureRoom Ia-Structure
8990
9192
9394
9596
97 98
99100
101102
103104

Room Ia-StructureRoom Ia-Structure
105106
107108
109110
111112
113114
115116
117118

Room Ia-StructureRoom Ia-Structure
119120
121122
123124
125126
127128
129130
131132

Room Ia-Structures the Room Ia-Structure
133134
135136
137138
139140
141142
143144
145146

Room Ia-StructureRoom Ia-Structure
147148
149150
151152
153154
155156
157158
159160

Room Ia-StructureRoom Ia-Structure
161162
163164
165166
167168
169170
171172
173174
175176

Room Ia-StructureRoom Ia-Structure
177178
179180
181182
183184
185186
187 188
189190
191192

Room Ia-StructureRoom Ia-Structure
193194
195196
197198
199200

Selected compounds of formula Ib are presented in table 2.

Table 2
Room Ia-StructureRoom Ia-Structure
12
34
Room Ia-StructureRoom Ia-Structure
56
78
910
1112
1314
1516
1718
1920
21 22
2324
2526
2728

Another embodiment of the present invention relates to compounds of the formula IIa or IIb.

or their pharmaceutically acceptable derivative or prodrug, in which:

W represents a nitrogen atom or CRa;

Randselected from a hydrogen atom, halogen atom, -CF3, R7, -OR7or-N(R7)2;

R1represents aryl or heteroaryl ring, where the aforementioned ring is optionally substituted up to four R9; where the substituent R9in ortho-position, R1if taken together with R2may form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R2and R3each independently selected from R6, the halogen atom is, CN, SR6, OR6N(R6)2, NRCO2R6, NRCON(R6)2, CON(R6)2, NRCOR6, NRN(R6)2, COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or NRSO2R6; or R2and R3if taken together, form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R4selected from R6, CON(R6), COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or (CH2)YR2;

y is 1-6;

each R is independently selected from hydrogen or optionally substituted aliphatic groups containing from one to six carbon atoms;

Ar represents a 5-membered heteroaryl, heterocyclic or carbocyclic ring, where the aforementioned ring is optionally substituted with up to three substituents selected from oxo, halogen atom, CN, NO2, R8, OR8, Other8, NHCOR8, NHCONHR8, COR8, CONHR8, SO2R8, NHSO2Other8or SO2Other8;

each R6independently selected from R7or optionally substituted groups selected from alkoxy, hydroxyalkyl, heterocyclyl, geterotsiklicheskikh aryl, aralkyl, Alcoxy, aryloxyalkyl, heteroaryl, heteroalkyl, heteroaromatic or heteroaromatic;

each R7independently selected from a hydrogen atom or optionally substituted aliphatic groups containing from one to six carbon atoms, or two R7at the same nitrogen atom, being taken together with the nitrogen atom, optionally form a 4-6-membered saturated or unsaturated heterocyclic ring containing one to three heteroatoms;

R8is1-C4aliphatic group, where two of R8in related provisions of Ar, or aryl or heteroaryl ring may be taken together with the intermediate atoms with the formation of a 3-6-membered condensed ring;

each R9independently selected from oxo, halogen atom, CN, NO2, Tn(halogenoalkane), R6, SR6, OR6, OR8N(R6)2, CON(R6)2, CON(R)COR6, COR6, CO2R6, CO2N(R6)2, COCOR6, SO2R6, SO2N(R6)2,N(R)TnCO2R6N(R)TnCON(R6)2N(R)TnN(R6)2N(R)TnNRCO2R6N(R)TnNRCON(R6)2N(R)TnCOR6N(R)TnNRCOR6N(R)TnSO2N(R6)2N(R)TnSO2R6, TnPO(ORsup> 7)2, TnOPO(OR7)2, TnSP(OR7)2, TnPO(OR7)2or TnNPO(OR7)2;

each Q is independently selected from C1-C3branched or normal alkyl;

T is selected from-Q - or Qm-CH(Qm-R2)-; and

each m and n is independently selected from zero or 1.

Examples of preferred R1include optionally substituted phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thienyl, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazole-1-yl, aminopyrimidines, chinoline, aminobenzimidazole and indolyl. Preferred R9if there is in R1-aryl or heteroaryl ring of formula IIa or IIb, includes a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6,CON(R)COR6and N(R)TnCO2R6. Examples of groups R9include, but are not limited to, pyrrole-2,5-dione, NR2, OR, CO2H, NO2, OH, NHCOR, NHCO2R, NHCH2CO2R NH(CH2)2NHCO2R, CH2CO2R, CF3, SO2R, NHCH(CH2OH)CO2H, N-SO2Me-piperidinium, SMe, NH(CH2)2NH2and piperidinium.

Preferred groups R2and R3include a halogen atom, CN, CO2R6, OR6and R6. Examples of preferred groups R3include Br, F, Cl, COOH, CN, OMe, is ethyl, ethyl, tert-butyl, CF3, OH and OBn.

Preferred compounds of formula IIa and IIb include those having one or more, or most preferably all of the characteristics selected from the group consisting of:

(a) R1represents optionally substituted aryl or heteroaryl ring;

(b) R2and R3each independently selected from a halogen atom, CN, CO2R6, OR6or R6;

(C) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6N(R)TnCO2R6N(R)TnNRCO2R6N(R)TnN(R6)2, NO2, Tn(halogenated), CO2N(R6)2, COR6, SO2R6or SO2N(R6)2;

More preferred compounds of formula IIa and IIb include those having one or more, or most preferably all of the characteristics selected from the group consisting of:

(a) R1is optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, teinila, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazole-1-yl, aminopyrimidine, chinoline, aminobenzimidazole and indolyl;

(b) R2represents a hydrogen atom, alkoxy, aminoalkyl or halogen atom;

(C) R3represents a hydrogen atom, ALK is XI, Alcoxy or halogen atom;

(d) R4represents a hydrogen atom or (CH2)YR2; and

(e) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6orN(R)TnCO2R6.

Another embodiment of the present invention relates to compounds of the formula IIIa or IIIb:

or their pharmaceutically acceptable derivative or prodrug, in which:

W represents a nitrogen atom or CRa;

Randselected from a hydrogen atom, halogen atom, -CF3, R7, -OR7or-N(R7)2;

ring And optionally substituted with up to three R9; where, when the substituent R9located in the ortho-position of the ring And the substituent R9may be taken together with R2education optionally substituted 5-7-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R2and R3each independently selected from R6, halogen atom, CN, SR6, OR6N(R6)2, NRCO2R6, NRCON(R6)2, CON(R6)2, NRCOR6, NRN(R6)2, COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or NRSO2R6; Il is R 2and R3if taken together, form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R4selected from R6, CON(R6), COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or (CH2)YR2;

y is 1-6;

R5selected from R7, Ar, COAr, CON(R7)Ar, (CH2)YCO2R, (CH2)YN(R7)2C(=NR10)-N(R7)2C(=NR10)-NRCOR, C(=S)-N(R7)2, CON(R7)2, CO2R, COR, SO2R or SO2N(R7)2;

Ar represents a 5-membered heteroaryl, heterocyclic or carbocyclic ring, where the aforementioned ring is optionally substituted with up to three substituents selected from oxo, halogen atom, CN, NO2, R8, OR8, Other8, NHCOR8, NHCONHR8, COR8, CONHR8, SO2R8, NHSO2Other8or SO2Other8;

each R is independently selected from hydrogen or optionally substituted aliphatic groups containing from one to six carbon atoms;

each R6independently selected from R7or optionally substituted groups selected from alkoxy, hydroxyalkyl, heterocyclyl, heterocy is lilacina, aryl, aralkyl, Alcoxy, aryloxyalkyl, heteroaryl, heteroalkyl, heteroaromatic or heteroaromatic;

each R7independently selected from a hydrogen atom or optionally substituted aliphatic groups containing from one to six carbon atoms, or two R7at the same nitrogen atom, being taken together with the nitrogen atom, optionally form a 4-6-membered saturated or unsaturated heterocyclic ring containing one to three heteroatoms;

R8is1-C4aliphatic group, where two of R8in related provisions of Ar, or aryl or heteroaryl ring may be taken together with the intermediate atoms with the formation of a 3-6-membered condensed ring;

each R9independently selected from oxo, halogen atom, CN, NO2, Tn(halogenoalkane), R6, SR6, OR6, OR8N(R6)2, CON(R6)2, CON(R)COR6, COR6, CO2R6, CO2N(R6)2, COCOR6, SO2R6, SO2N(R6)2,N(R)TnCO2R6N(R)TnCON(R6)2N(R)TnN(R6)2N(R)TnNRCO2R6N(R)TnNRCON(R6)2N(R)TnCOR6N(R)TnNRCOR6N(R)TnSO2N(R6)2N(R)TnSO2R6, Tn/sub> PO(OR7)2, TnOPO(OR7)2, TnSP(OR7)2, TnPO(OR7)2or TnNPO(OR7)2;

each Q is independently selected from C1-With3branched or normal alkyl;

T is selected from-Q - or Qm-CH(Qm-R2)-; and

each m and n is independently selected from zero or 1; and

R10selected from R7or Ar.

Preferred R9if you have the ring And formulas IIIa and IIIb, includes a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6,N(R)TnCO2R6. Examples of such groups R9include, but are not limited to, pyrrole-2,5-dione, NR2, OR, CO2H, NO2, OH, NHCOR, NHCO2R, NHCH2CO2R NH(CH2)2NHCO2R, CH2CO2R, CF3, SO2R, NHCH(CH2OH)CO2H, N-SO2Me-piperidinyl, SMe, NH(CH2)2NH2and piperidinyl.

Preferred groups R2and R3include a halogen atom, CN, CO2R6, OR6and R6. Examples of preferred groups R3include Br, F, Cl, COOH, CN, OMe, methyl, ethyl, tert-butyl, CF3, OH and OBn.

Examples of preferred R5include CO2(aliphatic), C(=NH)-NH2and CON(R7)2such as WITH(piperidine-1-yl), CONHEt, CONHMe, CONH(cyclopropyl), CONH(isopropyl), CNH(propyl), CONH(pyrrolidinyl), CO2Et and CO2Me.

Preferred compounds of formulas IIIa and IIIb include those having one or more, or most preferably all of the characteristics selected from the group consisting of:

(a) R2and R3each independently selected from a halogen atom, CN, CO2R6, OR6or R6;

(b) R5is CO2R, COAr, COR, CON(R7)2, Ar, (CH2)YCO2R or (CH2)yN(R7)2; and

(C) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6N(R)TnCO2R6N(R)TnNRCO2R6N(R)TnN(R6)2, NO2, Tn(halogenated), CO2N(R6)2, COR6, SO2R6or SO2N(R6)2.

More preferred compounds of formulas IIIa and IIIb include those having one or more, or most preferably all of the characteristics selected from the group consisting of:

(a) R2represents a hydrogen atom, alkoxy, aminoalkyl or halogen atom;

(b) R3represents a hydrogen atom, alkoxy, Alcoxy or halogen atom;

(c) R4represents a hydrogen atom or (CH2)YR2;

(d) R5represents CON(R7)2, Ar, (CH2)YCO2R or (CHsub> 2)YN(R7)2; and

(e) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6orN(R)TnCO2R6.

The compounds of this invention can mainly be obtained by methods known to experts in the field for similar compounds, as shown in the General schemes I-VII below. In detail the conditions used to obtain these compounds are given below in the examples.

Reagents and conditions: (a) Ar-baronova acid, PdCl2(dppf), K3PO4, DMF, 95°C, 18 h; (b) 40 pounds per square inch, 10% Pd/C, EtOAc; (c) ROCOCl, NaOH, H2O, 0°With; (d) p-TsOH, ROH, boiling under reflux, 1 h

Connection 2 receive treatment solution of 4-bromo-2-nitroaniline (1) in DMF arylboronic acid (1.2 EQ), potassium phosphate (1.3 EQ) and dichloro(diphenylphosphinomethyl)palladium (0.1 EQ). The resulting mixture is heated at 95°C for 18 h, then cooled to room temperature and diluted with ethyl acetate. The crude product are treated with water, then concentrated in vacuo. The concentrate is purified by chromatography on silica gel to obtain compound 2. This reaction will receive a wide range of substitution in the aryl ring. Examples of suitable substituted and nezameshchenny the aryl groups include, but not limited to, are presented in table 1 above.

Compound 3 is obtained by treatment of a solution of compound 2 in ethyl acetate 10% palladium on carbon (0.1 g/mmol) and the resulting suspension hydronaut at a pressure of 40 pounds per square inch while shaking at room temperature for 2 hours, the Catalyst was removed by filtration and the filtrate was concentrated in vacuo to obtain compound 3.

The compounds of formula 5 get first obtaining a solution of 2-methyl-5-thiopseudourea 4 (1 EQ) and alkylphosphonate (2 EQ) in water at 0°C. To the solution is added dropwise a 25% aqueous sodium hydroxide solution for 1 h until the pH stabilizes at 8. Then add acetic acid to bring the pH to 5, then add the trihydrate of sodium acetate (1 EQ) and a solution of compound 3 (1 EQ) in ROH. Add p-toluensulfonate acid (catalytic amount) and the resulting mixture is heated at boiling temperature under reflux for 1 h Then the reaction mixture is cooled to room temperature and diluted with ethyl acetate. After treatment with water, the crude product is purified preparative HPLC to obtain compound 5.

Reagents and conditions: (a) bis(pinacolato)dibor, COAs, PdCl2(dppf), DMSO, 80°With; (b) ArBr, K3PO4, PdCl2(dppf), DMSO, 95° C.

In scheme II above shows an alternative method of obtaining compounds 2. The original connection 1 (1 EQ) is mixed with bis(pinacolato)diboron (1.2 EQ), PdCl2(dppf) (0.1 EQ) and Kaas (3 EQ) in DMSO and the mixture was heated at 80°C for 18 hours the Reaction mixture is cooled to room temperature, then add arilbred (1.1 EQ) followed by the addition To a3RHO4(3 EQ) and PdCl2(dppf) (0.1 EQ). The resulting mixture is heated at 95°for 72 h, then allowed to cool to room temperature. Purification by chromatography gives compound 2.

Reagents and conditions: (a) Enrichment, THF, Meon, water, room temperature; (b) EtNCO, THF, boiling under reflux.

Using the connection number Ia-84 for illustration, in scheme III above shows a General method used to produce compounds of formula IIa. The original connection 6 is produced by a method described in scheme I to stages (a) and (b). Compound 7 is obtained by treating compound 6 methyl-cyanide in acetonitrile at room temperature over night. Treatment with water gives compound 7. Compound Ia-84 produced from compound 7 treatment utilitarianism in THF by heating at the boiling point under reflux overnight. The crude product is purified by preparative chromatography with floor is for Ia-84.

Reagents and conditions: (a) EtOH, 80°C, 4 h; (b) PdCl2(dppf), K3PO4, 95°C, 48 h; (C) Pd/C, H2, 50 pounds per square inch, 6 h; (d) 2-methyl-2-thiopseudourea (14), EtOCOCl, 80°C, 18 o'clock

Using the connection number Ia-86 to illustrate, in scheme IV above shows a General method that can be used to obtain compounds of the formula IIIa. Compound 10 is obtained from 5-bromo-2-chloropyrimidine (8) and N-Boc-Ethylenediamine (9) by heating a mixture of compounds 8 and 9 in ethanol at 80°C for 4 h Compound 12 obtained from compounds 10 and 11, shown in scheme II. The connection 12 is used for Ia-86 at stages (C) and (d) in stages (b) and (c) of scheme I.

Reagents and conditions: (a) Enrichment, THF, Meon, water, room temperature; (b) EtOCOCl, pyridine.

Using the connection number Ib-1 to illustrate, in scheme V above shows a General method that can be used to obtain the compounds of formula Ib. Compound 16 is obtained from the connection 15, shown in scheme III, step (a). Compound Ib-1 is produced by treating compound 16 etelcharge.com in pyridine.

Reagents and conditions: (a) (b) EtNCO, THF, boiling under reflux.

Using the connection number Ib-3 for illustration, the diagram VI videocase General way, which you can use to obtain the compounds of formula IIb. The connection handle 16 utilitarianism in THF by heating at the boiling point under reflux in scheme III, step (b), with Ib-3.

Scheme VII

Reagents and conditions: (a) NaH, THF, 0°With; (b) H2(45 psi), Pd-C, MeOH; (c) Enrichment, MeCN, MeOH, room temperature; (d) i EtNCO, DMSO, 80°; ii NH3, MeOH, 80°C.

In scheme VII above shows a General method of preparing compounds of this invention in which R1represents imidazol-1-yl. At the stage of (a) dinitropropanol (17) is mixed with methyl-4-imidazolecarboxamide (18) in THF and treated with sodium hydride at 0°C. After 3 h the reaction mixture was diluted with toluene and acidified with HCl. The phases are separated and the aqueous phase is washed with toluene, cooled to 0°and alkalinized with concentrated NH4OH. Add ethyl acetate and the resulting mixture was stirred to dissolve all solids. The phases are separated and the organic phase is washed with saturated salt solution, dried over Na2SO4, then filtered and the filtrate concentrated in vacuo. The mixture of regioisomers separated and purified flash chromatography (silica gel, gradientethanol/ethyl acetate) to give the desired adduct 19 in the form of not quite white substance is.

Compound 19 is used for compounds Ia-156, Ia-157 and Ia-170 by the way, is basically the same methods described above for scheme III.

The preferred embodiment of the present invention relates to a method of treating a bacterial infection in a mammal, in need thereof, comprising the stage of introduction of a given mammal a therapeutically effective amount of a compound having the formula IIa or IIb:

or its pharmaceutically acceptable derivative or prodrug, in which:

W represents a nitrogen atom or CRa;

Randselected from a hydrogen atom, halogen atom, -CF3, R7, -OR7or-N(R7)2;

R1represents aryl or heteroaryl ring, where the aforementioned ring is optionally substituted up to four R9; where the substituent R9in ortho-position, R1if taken together with R2may form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R2and R3each independently selected from R6, halogen atom, CN, SR6, OR6N(R6)2, NRCO2R6, NRCON(R6)2, CON(R6)2, NRCOR6, NRN(R6/sup> )2, COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or NRSO2R6; or R2and R3if taken together, form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R4selected from R6, CON(R6), COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or (CH2)YR2;

y is 1-6;

each R is independently selected from hydrogen or optionally substituted aliphatic groups containing from one to six carbon atoms;

Ar represents a 5-membered heteroaryl, heterocyclic or carbocyclic ring, where the aforementioned ring is optionally substituted with up to three substituents selected from oxo, halogen atom, CN, NO2, R8, OR8, Other8, NHCOR8, NHCONHR8, COR8, CONHR8, SO2R8, NHSO2Other8or SO2Other8;

each R6independently selected from R7or optionally substituted groups selected from alkoxy, hydroxyalkyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, Alcoxy, aryloxyalkyl, heteroaryl, heteroalkyl, heteroaromatic or heteroaromatic;

<> each R7independently selected from a hydrogen atom or optionally substituted aliphatic groups containing from one to six carbon atoms, or two R7at the same nitrogen atom, being taken together with the nitrogen atom, optionally form a 4-6-membered saturated or unsaturated heterocyclic ring containing one to three heteroatoms;

R8is1-C4aliphatic group, where two of R8in related provisions of Ar, or aryl or heteroaryl ring may be taken together with the intermediate atoms with the formation of a 3-6-membered condensed ring;

each R9independently selected from oxo, halogen atom, CN, NO2, Tn(halogenoalkane), R6, SR6, OR6, OR8N(R6)2, CON(R6)2, CON(R)COR6, COR6, CO2R6, CO2N(R6)2, COCOR6, SO2R6, SO2N(R6)2,N(R)TnCO2R6N(R)TnCON(R6)2N(R)TnN(R6)2N(R)TnNRCO2R6N(R)TnNRCON(R6)2N(R)TnCOR6N(R)TnNRCOR6N(R)TnSO2N(R6)2N(R)TnSO2R6, TnPO(OR7)2, TnOPO(OR7)2, TnSP(OR7)2, TnPO(OR7)2or TnNPO(ORsup> 7)2;

each Q is independently selected from C1-C3branched or normal alkyl;

T is selected from-Q - or Qm-CH(Qm-R2)-; and

each m and n is independently selected from zero or 1.

Another preferred embodiment of the present invention relates to a method of treating a bacterial infection in a mammal, in need thereof, comprising the stage of introduction of a given mammal therapeutically effective amounts of compounds of formula IIIa or IIIb:

or its pharmaceutically acceptable derivative or prodrug, in which:

W represents a nitrogen atom or CRa;

Randselected from a hydrogen atom, halogen atom, -CF3, R7, -OR7or-N(R7)2;

ring And optionally substituted with up to three R9; where, when the substituent R9located in the ortho-position of the ring And the substituent R9may be taken together with R2education optionally substituted 5-7-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R2and R3each independently selected from R6, halogen atom, CN, SR6, OR6N(R6)2, NRCO2R6, NRCON(R6)2, CON(R6)2, NRCOR6, NRN(R6)2, COR 6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or NRSO2R6; or R2and R3if taken together, form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R4selected from R6, CON(R6), COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or (CH2)YR2;

y is 1-6;

R5selected from R7, Ar, COAr, CON(R7)Ar, (CH2)YCO2R, (CH2)YN(R7)2C(=NR10)-N(R7)2C(=NR10)-NRCOR, C(=S)-N(R7)2, CON(R7)2, CO2R, COR, SO2R or SO2N(R7)2;

Ar represents a 5-membered heteroaryl, heterocyclic or carbocyclic ring, where the aforementioned ring is optionally substituted with up to three substituents selected from oxo, halogen atom, CN, NO2, R8, OR8, Other8, NHCOR8, NHCONHR8, COR8, CONHR8, SO2R8, NHSO2Other8or SO2Other8;

each R is independently selected from hydrogen or optionally substituted aliphatic groups containing from one to six carbon atoms;

each R6independently selected and is R 7or optionally substituted groups selected from alkoxy, hydroxyalkyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, Alcoxy, aryloxyalkyl, heteroaryl, heteroalkyl, heteroaromatic or heteroaromatic;

each R7independently selected from a hydrogen atom or optionally substituted aliphatic groups containing from one to six carbon atoms, or two R7at the same nitrogen atom, being taken together with the nitrogen atom, optionally form a 4-6-membered saturated or unsaturated heterocyclic ring containing one to three heteroatoms;

R8is1-C4aliphatic group, where two of R8in related provisions of Ar, or aryl or heteroaryl ring may be taken together with the intermediate atoms with the formation of a 3-6-membered condensed ring;

each R9independently selected from oxo, halogen atom, CN, NO2, Tn(halogenoalkane), R6, SR6, OR6, OR8N(R6)2, CON(R6)2, CON(R)COR6, COR6, CO2R6, CO2N(R6)2, COCOR6, SO2R6, SO2N(R6)2,N(R)TnCO2R6N(R)TnCON(R6)2N(R)TnN(R6)2N(R)TnNRCO2R6N(R)TnNRCON(R6)2 N(R)TnCOR6N(R)TnNRCOR6N(R)TnSO2N(R6)2N(R)TnSO2R6, TnPO(OR7)2, TnOPO(OR7)2, TnSP(OR7)2, TnPO(OR7)2or TnNPO(OR7)2;

each Q is independently selected from C1-C3branched or normal alkyl;

T is selected from-Q - or Qm-CH(Qm-R2)-; and

each m and n is independently selected from zero or one; and

R10selected from R7or Ar.

According to another embodiment of the invention provides a method of reducing the number of bacteria in a biological sample. This method involves the step of contacting the specified biological sample with the compound of the formula I:

or its pharmaceutically acceptable derivative or prodrug, in which:

Z represents O or N-R4;

W represents a nitrogen atom or CRand;

Randselected from a hydrogen atom, halogen atom, -CF3, R7, -OR7or-N(R7)2;

R1represents aryl or heteroaryl ring, where the aforementioned ring is optionally substituted up to four R9; where the substituent R9in ortho-position, R1if taken together with R2may form a condensed, unsaturated or partially unsaturated, it is certainly substituted 5-8-membered ring, containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R2and R3each independently selected from R6, halogen atom, CN, SR6, OR6N(R6)2, NRCO2R6, NRCON(R6)2, CON(R6)2, NRCOR6, NRN(R6)2, COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or NRSO2R6; or R2and R3if taken together, form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R4selected from R6, CON(R6), COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or (CH2)YR2;

y is 1-6;

R5selected from R7, Ar, COAr, CON(R7)Ar, (CH2)YCO2R, (CH2)YN(R7)2C(=NR10)-N(R7)2C(=NR10)-NRCOR, C(=S)-N(R7)2, CON(R7)2, CO2R, COR, SO2R or SO2N(R7)2;

Ar represents a 5-membered heteroaryl, heterocyclic or carbocyclic ring, where the aforementioned ring is optionally substituted with up to three substituents selected from oxo, halogen atom, CN, NO2, R8, OR8, Other 8, NHCOR8, NHCONHR8, COR8, CONHR8, SO2R8, NHSO2Other8or SO2Other8;

each R is independently selected from hydrogen or optionally substituted aliphatic groups containing from one to six carbon atoms;

each R6independently selected from R7or optionally substituted groups selected from alkoxy, hydroxyalkyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, Alcoxy, aryloxyalkyl, heteroaryl, heteroalkyl, heteroaromatic or heteroaromatic;

each R7independently selected from a hydrogen atom or optionally substituted aliphatic groups containing from one to six carbon atoms, or two R7at the same nitrogen atom, being taken together with the nitrogen atom, optionally form a 4-6-membered saturated or unsaturated heterocyclic ring containing one to three heteroatoms;

R8is1-C4aliphatic group, where two of R8in related provisions of Ar, or aryl or heteroaryl ring may be taken together with the intermediate atoms with the formation of a 3-6-membered condensed ring;

each R9independently selected from oxo, halogen atom, CN, NO2, Tn(halogenoalkane), R6, SR6, OR6, OR8N(R6 2, CON(R6)2, CON(R)COR6, COR6, CO2R6, CO2N(R6)2, COCOR6, SO2R6, SO2N(R6)2N(R)TnCO2R6N(R)TnCON(R6)2N(R)TnN(R6)2N(R)TnNRCO2R6N(R)TnNRCON(R6)2N(R)TnCOR6N(R)TnNRCOR6N(R)TnSO2N(R6)2N(R)TnSO2R6, TnPO(OR7)2, TnOPO(OR7)2, TnSP(OR7)2, TnPO(OR7)2or TnNPO(OR7)2;

each Q is independently selected from C1-C3branched or normal alkyl;

T is selected from-Q - or Qm-CH(Qm-R2)-;

each m and n is independently selected from zero or 1; and

R10selected from R7or Ar.

The term "biological sample", in the sense in which it is used here, includes culture cells or their extracts; biopsy material obtained from a mammal or extracts; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts. The term "biological sample" also includes living organisms, where in this case "contacting the compounds of this invention with the biological breakdown" is synonymous with the term "introduction of the compounds (or compositions containing at asanee connection) to a mammal".

The preferred embodiment includes contacting a specified biological sample with the compound of the formula Ia, Ib, IIa, IIb, IIIa, IIIb, or compound included in the list in tables 1 and 2. Pharmaceutical compositions suitable for these methods, described below.

The compounds of this invention are effective inhibitors of gyrase, which is determined by enzymatic analysis. It was also shown that these compounds possess antimicrobial activity test of antimicrobial sensitivity. Details of the conditions used for enzymatic analysis and test of antimicrobial sensitivity given in the examples below.

The gyrase inhibitors of the present invention or their pharmaceutically acceptable salts can be included in pharmaceutical compositions for administration to animals or humans. Data pharmaceutical composition effective for the treatment and prevention of bacterial infections, containing the gyrase inhibitor in a quantity sufficient to determine the reduction in the number of bacteria, and a pharmaceutically acceptable carrier, are another embodiment of the present invention. The term "detectable decrease in the number of bacteria" in the sense in which it is used, means the designated change in the number of bacteria in the sample containing the specified inhibitor, compared with the sample containing only BA the criteria.

Known agents that increase the sensitivity of bacteria to antibiotics. For example, in U.S. patent 5523288, U.S. patent 5783561 and U.S. patent 6140306 describes how to use the bactericidal/increasing permeability of the protein (BPI) to increase the sensitivity of gram-positive and gram-negative bacteria to antibiotics. Agents that increase the permeability of the outer membrane of the bacteria described Vaara M. in Microbiological Reviews (1992), pp.395-411, and the sensitivity of gram-negative bacteria - described Tsubery et al. in J. Med. Chem. (2000), pp.3085-3092.

Another preferred embodiment of the present invention relates to a method as described above, the treatment of bacterial infections in a mammal, in need thereof, optionally including the stage of introduction of a given mammal an agent that increases the sensitivity of bacteria to antibiotics.

According to another preferred embodiment of the invention provides a method as described above, reducing the number of bacteria in a biological sample, optionally including the stage of contact specified biological sample with an agent that increases the sensitivity of bacteria to antibiotics.

Pharmaceutical compositions and methods of the present invention will be generally suitable for combating bacterial infections in vivo. Examples of bacteria that can fight through to the positions and methods of this invention include, but not limited to, the following microorganisms: Streptococcus pneumoniae, Streptococcus pyrogenes, Enterococcus fecalis, Enterococcus faecium, Klebsiella pneumoniae, Enterobacter sps. Proteus sps. Pseudomonas aeruginosa, E. coli, Serratia marcesens, Staphylococcus aureus, Coag. Neg. Staph, Haemophilus influenzae, Bacillus anthracis, Mycoplasma pneumoniae and Staphylococcus epidermitidis. Therefore, compositions and methods are suitable for combat, treatment and suppression of progression, severity or activity nosocomially and nanoscopically infections. Examples of applications in pathogenic infections include, but are not limited to, urinary tract infections, pneumonia, infections of surgical wounds and bacteremia. Examples of applications in community-acquired infections include, but are not limited to, urinary tract infections, pneumonia, prostatitis, infections of skin and soft tissue infection in the abdominal cavity and treatment of patients with febrile neutropenia.

In addition to the compounds of this invention can also be used pharmaceutically acceptable derivatives or prodrugs of the compounds of this invention in compositions for the treatment or prophylaxis of the above disorders.

"Pharmaceutically acceptable derivative or prodrug" means a pharmaceutically acceptable salt, ester, salt of ester or other derivative compounds of the present invention that when administered to the recipient is capable of providing, directly or OPOS edavanna, the compound of this invention or possessing inhibitory activity of the metabolite or residue. Particularly preferred derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention with the introduction of these compounds to a mammal (for example, when administered orally connection easier absorbed into the blood) or which increases the delivery of the parent compound in the biological cell (e.g., the brain or lymphatic system) compared to the parent compounds.

Pharmaceutically acceptable prodrugs of the compounds of this invention include, but are not limited to, esters, esters of amino acids, esters of phosphoric acids, metal salts and esters of sulfonic acids.

Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable salts of the acids include acetate, adipate, alginate, aspartate, benzoate, bansilalpet, bisulfate, butyrate, citrate, comfort, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulphate, aconsultant, formate, fumarate, glucoheptonate, glycyrrhizinate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic, lactate, maleate, alonet, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate. You can use other acids, such as oxalic acid, which are not in themselves pharmaceutically acceptable, to obtain salts useful as intermediates in obtaining the compounds according to the invention and their pharmaceutically acceptable additive salts of the acid.

Salts derived from appropriate bases include alkali metal salts (e.g. sodium and potassium), alkaline earth metals (e.g. magnesium), ammonium and N+(C1-4the alkyl)4. This invention also envisions the quaternization of any basic nitrogen-containing groups of the disclosed compounds. Such quaternization is possible to obtain water-soluble or soluble in oil or dispersible products.

The pharmaceutical compositions of this invention contain a compound of formula I or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier. Such compositions may optionally contain additional therapeutic agent. Such tools include, but are not limited to, antibiotic, anti-inflammatory agent, an inhibitor matp the SPE of metalloprotease, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, an anticancer agent, an antiviral agent, a cytokine, a growth factor, an immunomodulator, a prostaglandin or connection against vascular hyperproliferation.

The term "pharmaceutically acceptable carrier" refers to non-toxic carrier, which you can enter the patient together with the compound of the present invention, and which does not adversely affect its pharmacological activity.

Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as serum human albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as Protamine sulfate, intrigejosa, kalogeropoulos, chlorinate, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, compounds based on cellulose, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene copolymers, polyoxypropylene, lanolin and samoemulgirutisa system drug delivery is the R drugs (SEDDS), such as α-tocopherol and succinate polyethylene glycol 1000 or other similar polymeric matrix for delivery.

The term "pharmaceutically effective amount" refers to an amount effective for the treatment or improvement with a bacterial infection in a patient. The term "prophylactically effective amount" refers to an amount effective for prophylaxis and significant suppression of bacterial infection in the patient.

Depending on the specific condition or disease, which is subjected to treatment or prevention, together with the inhibitors of this invention it is possible to introduce additional therapeutic agents, which are usually used for the treatment or prevention of this condition. Such therapeutic agents include, but are not limited to, antibiotic, anti-inflammatory, ingebor matrix metalloprotease, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, antineoplastic agent, antiviral agent, cytokine, growth factor, an immunomodulator, a prostaglandin or connection against vascular hyperproliferation.

The compounds of this invention can be used in the normal way to fight bacterial infections in vivo and for the treatment or suppression of progression, or severity of effects mediated by the bacteria. Such methods of treatment, the dose and requirements may be selected by the specialists in this field from the available methods.

For example, the compound of this invention can be combined with a pharmaceutically acceptable adjuvant for administration to a patient suffering from a bacterial infection or disease, pharmaceutically acceptable manner and in an amount effective to reduce the severity of the infection or disease.

Alternatively, the compounds of this invention can be used in the compositions and methods of treatment or prophylaxis of individuals against bacterial infections or diseases over an extended period of time. The compounds can be used in such compositions either as such or together with other compounds of this invention in a way compatible with the normal use of enzyme inhibitors in pharmaceutical compositions. For example, the compound of this invention can be combined with pharmaceutically acceptable adjuvants commonly used in vaccines and entered into effective prevention amounts to protect individuals over an extended period of time against bacterial infections or diseases.

The compounds of formula I can also be entered in conjunction with other antibiotics to enhance therapeutic or pros who aktionscode actions against various bacterial infections. When the compounds of this invention is administered in combination therapy with other agents, they can be administered to the patient sequentially or simultaneously. Alternative pharmaceutical or prophylactic compositions of this invention contain a combination of compounds of formula I and another therapeutic or prophylactic agent.

Additional therapeutic agents described above can be entered separately, as part of a multiple dose containing the inhibitor composition. Alternatively, these funds can be part of a single dosage form, mixed together with the inhibitor in a single composition.

The pharmaceutical compositions of this invention can be administered orally, parenteral, inhalation, topically, rectally, internasals, buccal, vaginally or via an implanted reservoir. The pharmaceutical compositions of this invention can include any conventional non-toxic pharmaceutically acceptable carriers, adjuvants or diluents. In some cases, the pH of the composition can be brought pharmaceutically acceptable acids, bases or buffers to enhance the stability is included in the composition of the compound or its shape for delivery. The term "parenteral" in the sense in which it is used, includes subcutaneous, intracutaneous,intravenous, intramuscular, intra-articular, nutricentials, vnutriserdecnuu, intrathecal, in the lesion and intracranial injection or infusion.

The pharmaceutical compositions can be in the form of a sterile injectable preparation, for example, as sterile injectable aqueous or oily suspension. This suspension can be obtained using methods known in this field, using a dispersing or wetting agents (such as, for example, tween-80), and suspendida agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic, acceptable for injecting diluent or solvent, for example, in the form of a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are mannitol, water, ringer's solution and isotonic sodium chloride solution. In addition, as a solvent or suspendida environment usually are sterile, fatty oil. For this purpose you can use any soft fatty oils, including synthetic mono - or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives suitable for the preparation of injection preparations, as well as natural pharmaceutically-acceptable oils, such as olive oil, and castor oil, especially in their polyoxyethylene forms. Data oil solutions or suspensions may also include a diluent or dispersant, representing the alcohol with a long chain, such as described in the Pharmacopoeia Helvetica, or a similar alcohol.

The pharmaceutical compositions of this invention can be administered orally in any dosage form that is acceptable for oral administration, including but not limited to, capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral administration, the media that are commonly used include lactose and corn starch. Usually also add lubricants such as magnesium stearate. For oral administration in a capsule, suitable diluents include lactose and dried corn starch. When aqueous suspensions and solutions, and propylene glycol administered orally, the active ingredient is mixed with emulsifying and suspendresume agents. If you want, you can add sweeteners and/or flavoring and/or coloring agents.

The pharmaceutical compositions of this invention can also be introduced in the form of suppositories for rectal use. Song data can be obtained by mixing the compounds of this invention with a suitable, not irritant effect excipient, which is in solid state the research Institute at room temperature, but becomes liquid at rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

Topical application of the pharmaceutical compositions of the present invention is particularly suitable when the desired treatment involves areas or organs readily accessible for local applications. For local application on the skin of the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in the carrier. Carriers for topical application of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene derivatives of polyoxypropylene, emulsifying wax and water. Alternatively, the pharmaceutical composition can be with a suitable lotion or cream containing the active compound suspended or dissolved in the carrier. Suitable carrier materials include, but are not limited to, mineral oil, sorbitol monostearate, Polysorbate-60, citylove esters wax, Cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention can also skin the th locally in the lower part of the intestinal tract with the introduction of a suppository for rectal injection or by using a suitable enema. This invention also includes transdermal patches for local use.

The pharmaceutical compositions of this invention can be introduced in the form of a nasal aerosol or inhalation. Such compositions produced by methods well known in the field of pharmaceutical compositions, and may be obtained as solutions in saline, using benzyl alcohol or other suitable preservatives, substances that contribute to the absorption, to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the field.

Doses are in the range of about 0.01 to about 100 mg/kg of body weight per day, preferably from 0.5 to about 75 mg/kg of body weight per day and most preferably about 1 to 50 mg/kg of body weight per day of the active ingredient, suitable monotherapy for the prevention and treatment of bacterial infections caused by bacteria, such as Streptococcus pneumoniae, Streptococcus pyrogenes, Enterococcus fecalis, Enterococcus faecium, Klebsiella pneumoniae, Enterobacter sps. Proteus sps. Pseudomonas aeruginosa, E. coli, Serratia marcesens, S. aureus and Coag. Neg. Staph.

Typically, the pharmaceutical compositions of the present invention will type about 1 to 5 times per day or alternatively, as prolonged infusion. Or, alternatively, compositions of the present invention can be enter in the composition pulsiruuschiy release. Such introduction can be used for long-term or short-term therapy. The amount of active ingredient that can be mixed with carriers to obtain a single dosage form will vary depending upon the host being treated and the particular route of administration. A typical preparation will contain from about 5% to about 95% active compound (wt./wt.). Preferably, such preparations contain from about 20% to about 80% active compound.

When the compositions of this invention contain a combination of compounds of formula I and one or more additional therapeutic or prophylactic agents, the compound and the additional agent should be present in doses in the range of about from 10% to 80% of the dose usually introduced when alone.

The improvement of the patient can enter a maintenance dose of a compound, composition or combination of this invention, if necessary. Therefore, the dose or frequency of administration, or both factors can be reduced depending on the symptoms, to a level which maintains the superior condition, and when the symptoms are suppressed to a desired level, treatment ceased. For patients, however, it may be necessary intermittent treatment for an extended period of time at any relapse of symptoms is s disease.

Specialists in this field, it is obvious, of course, that may be necessary to lower or higher doses than presented above. Specific dosage and treatment regimen for any particular patient will depend upon a variety of factors including the activity used a specific compound, the age, body weight, General health, sex, diet, time of administration, rate of excretion, combination of drugs, the severity and course of the disease, and predisposition of the patient to the disease, and the opinion of the treating physician.

According to another embodiment of the invention provides methods of treatment or prevention of bacterial infection or disease, including stage of introduction of the patient of any disclosed compounds, pharmaceutical compositions or combination. The term "patient" in the sense in which it is used, means an animal, preferably a mammal, and most preferably, humans.

The compounds of this invention are also suitable as industrially available compounds which effectively bind with the enzyme Girasol Century as an industrial available reagents, the compounds of the present invention and their derivatives can be used for blocking the activity of gyrase In when setting biochemical or cellular tests for gyrase bacteria or eigomanga, or you can convert them to their derivatives for binding with a stable resin as an immobilized substrate for carrying out affinity chromatography. These and other applications, characterizing industrial available gyrase inhibitors, will be clear to experts in this field.

In order to better understand this invention, the following examples are cited. These examples are presented only to illustrate and not limit the scope of the invention.

Examples

Example 1

4-(Pyridin-3-yl)-2-nitroaniline (2): to a solution of 4-bromo-2-nitroaniline (217 mg, 1 mmol) in DMF (6 ml) was added 3-pyridineboronic acid (148 mg, 1.2 mmol), potassium phosphate (276 mg, 1.3 mmol) and dichloro(diphenylphosphinomethyl) palladium (75 mg, 0.1 mmol). The resulting mixture was heated at 95°C for 18 h, then cooled to room temperature and was diluted with ethyl acetate (80 ml). The resulting solution was sequentially washed with saturated aqueous sodium bicarbonate, water and saturated salt solution, dried over magnesium sulfate, and then concentrated in vacuum. The concentrate was purified by chromatography [silica gel, a mixture of ethyl acetate:hexane (1:3)→(1:2)] to obtain compound 2 (117 mg, 54%).1H NMR (CDCl3) δ and 8.8 (d, 1H), 8,55 (m, 1H), 8,35 (d, 1H), a 7.85 (DD, 1H), 7,65 (DD, 1H), 7,35 (m, 1H), 6,95 (d, 1H), 6,2 (USS, 2H).

Example 2

4-Pyridin-3-albenza-1,2-diamine (3): to a solution of compound 2 (117 mg, 0.54 mmol) in ethyl acetate (13 ml) was added 10% palladium on carbon (51 mg). The resulting suspension was placed in a Parr apparatus for hydrogenation under pressure of the hydrogen gas 40 psi with shaking at room temperature for 2 hours the Catalyst was removed by filtration and the filtrate was concentrated in vacuum to obtain compound 2 (115 mg, quantitative yield).1H NMR (CDCl3) δ 8,8 (m, 1H), 8,45 (m, 1H), to 7.75 (m, 1H), 7,25 (m, 1H), 6,95 (m, 2H), to 6.80 (m, 1H), 3,25 (USS, 4H).

Example 3

Ethyl ester (5-pyridin-3-yl-1H-benzimidazole-2-yl) carbamino acid (Ia-11): to a solution of 2-methyl-2-thiopseudourea (151 mg, 0.54 mmol) and ethylchloride (0,103 ml of 1.08 mmol) in water (2 ml) at 0°C was added dropwise a 25% aqueous sodium hydroxide solution for 1 h until the pH is stabilized at 8. Then add a sufficient quantity of acetic acid to bring the pH to 5, then added the trihydrate of sodium acetate (74 mg, 0.54 mmol) and a solution of compound 2 (0.54 mmol) in ethanol (3 ml). Added a catalytic amount of p-toluensulfonate acid and the resulting mixture was heated at the boiling point under reflux for 1 h Then the reaction mixture is cooled is about room temperature and was diluted with ethyl acetate (50 ml). The organic solution was washed with an aqueous solution of NaOH, water and saturated salt solution, then dried over magnesium sulfate and concentrated in vacuum. The crude product was purified preparative HPLC to obtain compound (Ia-11).1H NMR (CDCL3) δ 9.1 (c, 1H), up 8.75 (d, 1H), and 8.5 (d, 1H), and 7.9 (s, 1H), 7,8 (m, 1H), 7,65 (m, 2H), 4,3 (kV, 2H), 1,3 (t, 3H). (M+1) 283.

Example 4

5-Phenyl-1H-benzimidazole-2-ylamine (7): to a solution of biphenyl-3,4-diamine (0,99 ml) in a mixture of THF:MeOH:water (5 ml:10 ml: 10 ml) was added CYANOGEN bromide (5 M solution in acetonitrile, 1.06 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was distributed between EtOAc and aqueous sodium hydroxide solution, and the aqueous layer was re-extracted with EtAOc. United EtAOc extracts were washed with water, saturated salt solution, dried over MgSO4, then was concentrated in vacuum to obtain compound 7 (147 mg, 71%) as not quite white solid.

Example 5

1-Ethyl-3-(5-phenyl-1H-benzimidazole-2-yl) urea (Ia-84): to a solution of compound 7 (40 mg, 0,19 mmol) in THF (1 ml) was added utilizationa (27 μl, 0.34 mmol) in solution in THF (0.5 ml). The reaction mixture was heated at the boiling point under reflux overnight, then concentrated in vacuo. The crude product is ciali preparative HPLC to obtain Ia-84.

Example 6

Tert-butyl ether [2-(5-bromopyrimidine-2-ylamino)ethyl]carbamino acid (10): a mixture of 5-bromo-2-chloropyrimidine (500 mg), N-BOC-Ethylenediamine (496 mg) and triethylamine (1 ml) in ethanol (10 ml) was heated at 80°C for 4 h Then the reaction mixture was concentrated in vacuo and the residue was purified preparative HPLC (hexane: EtAOc, 60:40) to give compound 10 (700 mg) in the form of a white solid.

Example 7

Methyl ester 1-(3,4-dinitrophenyl)-1H-imidazole-4-carboxylic acid (19): to a stirred solution of 1,2-dinitro-4-fervently (325 mg, of 1.74 mmol) and methyl-4-imidazolecarboxamide (200 mg, of 1.59 mmol) in THF (5 ml) at 0° (C) was added in one portion NaH (70 mg, of 1.74 mmol). The resulting mixture was stirred at 0°C for 3 h, then was diluted with toluene and acidified using 6 N HCl solution. The phases were separated and the aqueous phase was washed with toluene, cooled to 0°and podslushivaet concentrated NH4OH. Added ethyl acetate and the resulting mixture was stirred to dissolve all solids. The phases were separated, the organic phase is washed with saturated salt solution, dried over Na2SO4, filtered and concentrated in vacuum. The mixture of regioisomers were separated and purified flash chromatography (silica gel, gradienttanol/ethyl acetate) to give the desired adduct 19 (225 mg, 45%) in the form of not-quite-white solid.1H NMR (500 MHz, DMSO-d6): to 8.41 (1H, d); 8,13 (1H, d); 7,5 (1H, OSS); 7,28 (1H, s); 7,02 (1H, d); of 3.80 (3H, s).

Example 8

Methyl ether of 1-[2-(3-ethylurea)-3H-benzimidazole-5-yl]-1H-imidazole-4-carboxylic acid (Ia-156): a mixture of compound 19 (225 mg, 0,770 mmol) and 10% Pd-C (catalytic amount) in MeOH (10 ml) were placed in the atmosphere of H2at a pressure of 45 pounds per square inch (Parr apparatus) at night. The mixture was filtered, concentrated in vacuo, re-diluted with MeCN and MeOH (5 ml/5 ml) and was treated with methyl zian (168 mg, 1.54 mmol) at room temperature. The resulting mixture was stirred for 4 h (precipitation), then the reaction was suppressed by the addition of 7N NH3-MeOH. The crude reaction mixture was concentrated in vacuo and directly subjected to flash chromatography (silica gel, gradient 10%->35% 7H NH3-MeOH/CH2Cl2) to obtain the pure aminobenzimidazole in the form of a white solid.

Purified aminobenzimidazole was diluted in DMSO (1 ml), treated with excess utilizationof (0.5 ml) and was heated up to 80°C for 3 hours the Reaction mixture was cooled to room temperature, removed in vacuum excess utilizationof, conducted azeotropic distillation with MeOH (three times), was diluted Meon (5 ml)was treated with NH4OH (2 ml) and heated at 80°C for 3 is. The mixture was cooled to room temperature, concentrated in vacuo, diluted with a mixture of water/saturated salt solution 1/1 and was extracted twice with a mixture of ethyl acetate/ethanol 4/1. The combined organic extracts were dried over Na2SO4was filtered , concentrated in vacuo and subjected to flash chromatography (silica gel, gradient2 N NH3-EtOH/CH2Cl2c give the desired product Ia-156 mixed with utilmately. The solid is triturated with water and filtered to obtain pure Ia-156 (115 mg, 41% with four stages) in the form of a white solid.1H NMR (500 MHz, DMSO-d6): 11,81 (1H, OSS); 9,94 (1H, USD); 8,32 (1H, USD); compared to 8.26 (1H, USD); 7,58 (1H, USD); of 7.48 (1H, m), 7,28 (1H, d); for 7.12 (1H, USD); of 3.78 (3H, s); 3,20 (2H, DQC); of 1.12 (3H, t).

Example 9

1-[2-(3-Ethylurea)-3H-benzimidazole-5-yl]-1H-imidazole-4-carboxylic acid

1-[2-(Amiloride)-3H-benzimidazole-5-yl]-1H-imidazole-4-carboxylic acid (Ia-157): a solution of compound Ia-156 (95 mg, 0,289 mmol) in 6 N HCl (2 ml) was heated at the boiling point under reflux for 6 hours Then the solution was cooled to room temperature, concentrated in vacuum and thoroughly azeotropic distillation with MeOH (twice) and acetone (twice). The obtained solid particles suspended in acetone, filtered and washed with acetone posleduyushim by washing with hexane to obtain compound Ia-157 (115 mg, 100%) as a white solid.1H NMR (500 MHz, DMSO-d6): 8,77 (1H, m); charged 8.52 (1H, m), 7,79 (1H, s); 7,72 (1H, m); the 7.65 (2H, m); 5,6-4,0 (2H, OSS); 3,20 (2H, dt); a 1.11 (3H, t).

Example 10

A solution of compound Ia-157 (20 mg, 0,051 mmol) and research (0,050 ml, excess) in DMF (1 ml) was treated with PyBrop (20 mg, excess) at room temperature. The resulting mixture was stirred overnight, then was diluted with a mixture of ethyl acetate:ethanol 4:1, washed with a mixture of a saturated solution of salt water (5 times), dried over Na2SO4, was filtered, was subjected to flash chromatography (silica gel, gradient2 N NH3-EtOH/CH2Cl2) obtaining compounds Ia-170 (13 mg, 72%) as a white solid. LRMS: 384,5 (M+H).

Example 11

Were obtained with other compounds of formula I by the methods basically similar to that described in the above examples 1-6 and are presented in schemes I-VI. Data on the characteristics of these compounds are summarized in table 3 below and include mass spectra (M+1) and data1H NMR.

Data1H NMR are summarized in table 3 below, there is a "Y"indicating data1H NMR, and found that they are consistent with the structure. The numbers of the compounds correspond to the numbers of the compounds listed in table 1.

498
Table 3

Data on the characteristics of the selected compounds
Room Ia-M+11H NMRRoom Ia-M+11H NMR
1282Y2288Y
3283Y4283Y
6210Y7268Y
8292-9350Y
10296Y11283Y
12325Y13324Y
14336Y15326Y
16344Y17361Y
18313Y19360Y
20399Y21284Y
22314Y23312Y
24326Y26342Y
33249Y34298Y
35356Y36283Y
37428Y38294Y
39272Y40Y
41452Y42312Y
43295,1Y44338-
45368Y46320Y
47382-48389-
49418-50311Y
51299Y52343Y
53368Y54298Y
55395Y56406-
57366 Y58296Y
59354Y60326Y
61440Y62300Y
63403-64381-
465352-66326-
67409Y69468Y
70368Y71299Y
72299Y73267-
74253-75297-
76413Y77371-
78282Y78296Y
80357Y81340Y
82280Y84281Y
85321-86442Y
87370Y88342-
89359Y90298Y
91446Y92329-
93499Y94 387Y
97294Y98389-
100370-101280-
102370-103312Y
106409-108300Y
109394-110467Y
111367Y112343Y
113409-115298Y
116343-117369-
118282 Y119296Y
120296Y121322Y
122340Y124445-
125382-126328Y
127394-128432-
129368-130396Y
131316Y132312Y
133296Y134316Y
135410Y136300 Y
137310Y138388-
139352Y140401Y
141384Y142310Y
143511Y144311Y
145353-146400Y
147326Y148411Y
149370Y150--
151--152317Y
153362Y 154389Y
155299-156--
157--158--
159328-160--
161--162--
163326Y164367Y
165297Y166367Y
167350-168298Y
169-Y170--
171 --172--
173--174--
175365Y176-Y
177377-178-Y
179367Y180-Y
181315Y182366Y
183330Y184--
185--186--
187--188- -

Example 12

Analysis of the activity of gyrase-ATP-ases

The activity of DNA gyrase in respect of ATP hydrolysis was determined by a combination of production ADRs involving the pyruvate kinase/lactate dehydrogenase with NADH oxidation. The method described previously (Tamura and Gellert, 1990, J. Biol. Chem., 265, 21342).

The determination of the activity of ATP-ASE was carried out at 30°in buffered solutions containing 100 mm Tris, pH of 7.6, 1.5 mm MgCl2, 150 mm KCl. Combining the system consisted of (final concentration) of 2.5 mm phosphoenolpyruvate, 200 μm adenine dinucleotide (NADH), 1 mm DTT, 30 μg/ml pyruvate kinase and 10 μg/ml lactate dehydrogenase. Added 40 nm enzyme (subunit Gyr A2B2 weight 374 kDa from Staphylococcus aureus) and a solution of inhibitor in DMSO to a final concentration of 4%, and the reaction mixture was incubated for 10 min at 30°C. Then the reaction was started by adding ATP to a final concentration of 0.9 mm and was determined by the speed of decreasing NADH at 340 nm for 10 min Values of inhibition percentage was determined on the basis of the speed with respect to the concentration profile, and were expressed as the average of the two values.

Table 4 presents data on the inhibitory activity in the percent of selected compounds of this invention in the test of inhibition of gyrase activity at a concentration of 10 μm. The numbers of the compounds correspond to the numbers of the compounds in table 1 Compounds possessing activity and marked "A"provided a percent inhibition less than 50%; compounds with activity and marked "B"provided a percent inhibition between 50 and 75%, and compounds with activity and marked "C"provided a percent inhibition higher than 75%.

Table 4

Inhibiting girazu activity of selected compounds
Room Ia-ActivityRoom Ia-Activity
1In2In
3In4
6And7And
8And9And
10And11
12In13And
14In15 In
1617
1819
20And21
2223
2426In
33And34
3536And
3738In
3940
41And42
4344
4546And
4748
4950In
5253
5455
5657
5859
6061
6263
6465
6667
69In70
71And72
73 And74And
75And76
7778And
79And80
81In82And
8485And
8687
8889
9091And
9293
9497And
98 100
101And102
103106
108109
110111
112113
115And116In
117And118
119120In
121And122
124In125
126127
128129
130131
132133
134135
136137
138139
140141
142143
144145
146147 In
148149
150In151
152153In
154155And
156157
158159And
160161And
162163
164165
166167
168 169
170171
172173
174175
176And177
178179
180181In
182183In
184In183
186187
188--

Example 13

Testing the sensitivity Jew who their environments

The compounds of this invention were also tested for their antimicrobial activity testing of sensitivity in liquid media. A similar analysis was performed following the instructions of the most recent NCCLS document for practice: "M7-A5 Methods for dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Fifth Edition (2000)". Other publications, such as "Antibiotics in Laboratory Medicine" (Edited by V.Lorian, Publishers Williams and Wilkins, 1996), provided the basic practices during laboratory testing of antibiotics. Basically, a few isolated colonies of bacteria (3-7) with a Cup of fresh culture was transferred into a corresponding rich broth medium, such as MHB, suitably enriched for a more "demanding" of microorganisms. They were cultivated during the night to a high density with subsequent dilution in 1000-2000 times with obtaining inoculum density within a 5×105-5×106SOME on the ml Alternative, picked colonies can be incubated at 37°C for about 4-8 hours until the culture reached a turbidity equal to or greater than a 0.5 McFarland standard (approximately 1.5×108cells per ml), and diluted with obtaining the same value on SOME ml. More convenient method, the inoculum was prepared using commercial available devices (BBL system PROMPT), which includes the contact p is ti colonies directly with a stick, at the base of which are cross-cut grooves, and subsequent preparation of a suspension of bacteria in an appropriate volume of saline. Breeding to the appropriate cell density of the inoculum was performed from this cell suspension. The broth used for testing consisted of environment EOM with the addition of 50 mg of CA2+on l and 25 mg of Mg2+L. Preparing a series of standard dilutions of control antibiotics and kept as described in the standard M7-A5 NCCLS, usually a series of dilutions ranged from 128 μg per ml to 0.015 μg per ml (2-fold serial dilution). Compound was dissolved and diluted on the day of the experiments; they used the same or similar limits of concentrations, which are listed above. Compound and controls were placed in advance of the tablet and added the tested bacteria so that the final concentration of the inoculum was approximately 5×104CFU per well, and the final volume was 100 μl. The plates were incubated at 35°C overnight (16-20 h) and visually determined turbidity or conducted a quantitative assessment on the reader to advance tablets. The final minimum inhibitory concentration (MIC) is the lowest drug concentration at which the test microorganisms were grown. Result is you such definitions were compared with the corresponding tables, available in the above two publications, to ensure that the limits of antibacterial activity are taken within this standardized test.

Table 5 presents the results of the test for determination of MIC for selected compounds of the present invention. The numbers of the compounds correspond to the numbers of the compounds in table 1. Compounds with activity and marked "A", provided MIC equal to less than 10 µg/ml; compounds having an activity designated as "B", provided the MIC within 10-40 µg/ml; compounds having an activity designated as "C", provided the MIC higher than 40 µg/ml.

Table 5

The MIC values of selected compounds
Room Ia-ActivityRoom Ia-Activity
42In58And
90And92And
98In112And
116117
118And119
120121
122 133And
137138
139140And
141And142And
144In145In
146And147
148In149
150151
152In153
154156In
157158
159160
161162
163And164
165In166
167168And
169In170
171In173In
174175
177178 And
179180In
181182
183184
185186And
187In188And
196In197In
198In--

Although described a number of embodiments of the present invention, it is obvious that the basic embodiment can be modified for other embodiments that use the products and methods of this invention.

1. The way to reduce the number of bacteria in a biological sample, comprising the stage of contact specified biological sample with the compound of the formula I:

or its pharmaceutically acceptable salt, in which

Z represents O or N-R4;

W represents a nitrogen atom or CRa;

Raselected from a hydrogen atom, halogen atom, -CF3, R7, -OR7or-N(R7)2;

R1represents aryl or heteroaryl ring, where the aforementioned ring is optionally substituted up to four R9 ; where the substituent R9in ortho-position, R1if taken together with R2may form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R2and R3each independently selected from R6, halogen atom, CN, SR6, OR6N(R6)2, NRCO2R6, NRCON(R6)2, CON(R6)2, NRCOR6, NRN(R6)2, COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or NRSO2R6; or R2and R3if taken together, form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R4selected from R6, CON(R6), COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or (CH2)yR2;

y is 1-6;

R5selected from R7, Ar, COAr, CON(R7)Ar, (CH2)yCO2R, (CH2)yN(R7)2C(=NR10)-N(R7)2C(=NR10)-NRCOR, C(=S)-N(R7)2, CON(R7)2, CO2R, COR, SO2R or SO2N(R7)2;

2, R8, OR8, Other8, NHCOR8, NHCONHR8, COR8, CONHR8, SO2R8, NHSO2Other8or SO2Other8;

each R is independently selected from hydrogen or optionally substituted aliphatic groups containing from one to six carbon atoms;

each R6independently selected from R7or optionally substituted groups selected from alkoxy, hydroxyalkyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, Alcoxy, aryloxyalkyl, heteroaryl, heteroalkyl, heteroaromatic or heteroaromatic;

each R7independently selected from a hydrogen atom or optionally substituted aliphatic groups containing from one to six carbon atoms, or two R7at the same nitrogen atom, being taken together with the nitrogen atom, optionally form a 4-6-membered saturated or unsaturated heterocyclic ring containing one to three heteroatoms;

R8represents C1-C4aliphatic group, where two of R8in related provisions of Ar, or aryl or heteroaryl ring may be taken together with their sub is face-to-face atoms with the formation of a 3-6-membered condensed ring;

each R9independently selected from oxo, halogen atom, CN, NO2Tn(halogenoalkane), R6, SR6, OR8, OR6N(R6)2, CON(R6)2, CON(R)COR6, COR6, CO2R6, CO2N(R6)2, COCOR6, SO2R6, SO2N(R6)2N(R)TnCO2R6N(R)TnCON(R6)2N(R)TnN(R6)2N(R)TnNRCO2R6N(R)TnNRCON(R6)2N(R)TnCOR6N(R)TnNRCOR6N(R)TnSO2N(R6)2N(R)TnSO2R6, TnPO(OR7)2, TnOPO(OR7)2, TnSP(OR7)2, TnPO(OR7)2or TnNPO(OR7)2;

each Q is independently selected from C1-C3branched or normal alkyl;

T is selected from-Q - or Qm-CH(Qm-R2)-;

each m and n is independently selected from zero or 1;

R10selected from R7or Ar.

2. The method according to claim 1, where the specified compound has the formula Ia or Ib:

or its pharmaceutically acceptable salt.

3. The method according to claim 2, in which the specified connection has one or more characteristics selected from the group consisting of

(a) R1represents optionally substituted aryl or g is derouillee ring;

(b) R2and R3each independently selected from a halogen atom, CN, CO2R6, OR6or R6;

(c) R5is CO2R, COAr, COR, CON(R7)2, Ar, (CH2)yCO2R or (CH2)yN(R7)2; and

(d) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6N(R)TnCO2R6N(R)TnNRCO2R6N(R)TnN(R6)2, NO2Tn(halogenated), CO2N(R6)2, COR6, SO2R6or SO2N(R6)2.

4. The method according to claim 3, in which

(a) R1represents optionally substituted aryl or heteroaryl ring;

(b) R2and R3each independently selected from a halogen atom, CN, CO2R6, OR6or R6;

(c) R5is CO2R, COAr, COR, CON(R7)2, Ar, (CH2)yCO2R or (CH2)yN(R7)2;

(d) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6N(R)TnCO2R6N(R)TnNRCO2R6N(R)TnN(R6)2, NO2Tn(halogenated), CO2N(R6)2,COR 6, SO2R6or SO2N(R6)2.

5. The method according to claim 3, in which the specified connection has one or more characteristics selected from the group consisting of

(a) R1is optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, teinila, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazole-1-yl, aminopyrimidine, chinoline, aminobenzimidazole or indolyl;

(b) R2represents a hydrogen atom, alkoxy, aminoalkyl or halogen atom;

(c) R3represents a hydrogen atom, alkoxy, Alcoxy or halogen atom;

(d) R4represents a hydrogen atom or (CH2)yR2;

(e) R5represents CON(R7)2, Ar, (CH2)yCO2R or (CH2)yN(R7)2; and

(f) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6or N(R)TnCO2R6.

6. The method according to claim 5, in which

(a) R1is optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, teinila, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazole-1-yl, aminopyrimidine, chinoline, aminobenzimidazole or indolyl;

(b) R2represents the atom in Dorada, alkoxy, aminoalkyl or halogen atom;

(c) R3represents a hydrogen atom, alkoxy, Alcoxy or halogen atom;

(d) R4represents a hydrogen atom or (CH2)yR2;

(e) R5represents CON(R7)2, Ar, (CH2)yCO2R or (CH2)yN(R7)2;

(f) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6or N(R)TnCO2R6.

7. The method according to claim 1, in which the indicated compound has the formula IIa and IIb:

or its pharmaceutically acceptable salt, in which

W represents a nitrogen atom or CRa;

Raselected from a hydrogen atom, halogen atom, -CF3, R7, -OR7or-N(R7)2;

R1represents aryl or heteroaryl ring, where the aforementioned ring is optionally substituted up to four R9; where the substituent R9in ortho-position, R1if taken together with R2may form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R2and R3 6, halogen atom, CN, SR6, OR6N(R6)2, NRCO2R6, NRCON(R6)2, CON(R6)2, NRCOR6, NRN(R6)2, COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or NRSO2R6; or R2and R3if taken together, form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from atoms of Izotov, oxygen, or sulfur;

R4selected from R6, CON(R6), COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or (CH2)yR2;

y is 1-6;

each R is independently selected from hydrogen or optionally substituted aliphatic groups containing from one to six carbon atoms;

Ar represents a 5-membered heteroaryl, heterocyclic or carbocyclic ring, where the aforementioned ring is optionally substituted with up to three substituents selected from oxo, halogen atom, CN, NO2, R8, OR8, Other8, NHCOR8, NHCONHR8, COR8, CONHR8, SO2R8, NHSO2Other8or SO2Other8;

each R6independently selected from R7or optionally substituted groups selected from alkoxy, g is drocella, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, Alcoxy, aryloxyalkyl, heteroaryl, heteroalkyl, heteroaromatic or heteroaromatic;

each R7independently selected from a hydrogen atom or optionally substituted aliphatic groups containing from one to six carbon atoms, or two R7at the same nitrogen atom, being taken together with the nitrogen atom, optionally form a 4-6-membered saturated or unsaturated heterocyclic ring containing one to three heteroatoms;

R8represents C1-C4aliphatic group, where two of R8in related provisions of Ar, or aryl or heteroaryl ring may be taken together with the intermediate atoms with the formation of a 3-6-membered condensed ring;

each R9independently selected from oxo, halogen atom, CN, NO2Tn(halogenoalkane), R6, SR6, OR6, OR8N(R6)2, CON(R6)2, CON(R)COR6, COR6, CO2R6, CO2N(R6)2, COCOR6, SO2R6, SO2N(R6)2N(R)TnCO2R6N(R)TnCON(R6)2N(R)TnN(R6)2N(R)TnNRCO2R6N(R)TnNRCON(R6)2N(R)TnCOR6N(R)TnNRCOR6N(R)TnSO2 6)2N(R)TnSO2R6, TnPO(OR7)2, TnOPO(OR7)2, TnSP(OR7)2, TnPO(OR7)2or TnNPO(OR7)2;

each Q is independently selected from C1-C3branched or normal alkyl;

T is selected from-Q -, or-Om-SN (Qm-R2)-;

and each of m and n is independently selected from zero or 1.

8. The method according to claim 7, in which the specified connection has one or more characteristics selected from the group consisting of

(a) R1represents optionally substituted aryl or heteroaryl ring;

(b) R2and R3each independently selected from a halogen atom, CN, CO2R6, OR6or R6; and

(c) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6N(R)TnCO2R6N(R)TnNRCO2R6N(R)TnN(R6)2, NO2Tn(halogenated), CO2N(R6)2, COR6, SO2R6or SO2N(R6)2.

9. The method according to claim 8, in which

(a) R1represents optionally substituted aryl or heteroaryl ring;

(b) R2and R3each independently selected from a halogen atom, CN, CO2R6 , OR6or R6; and

(c) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6N(R)TnCO2R6N(R)TnNRCO2R6N(R)TnN(R6)2, NO2Tn(halogenated), CO2N(R6)2, COR6, SO2R6or SO2N(R6)2.

10. The method according to claim 8, in which the specified connection has one or more characteristics selected from the group consisting of

(a) R1is optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, teinila, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazole-1-yl, aminopyrimidine, chinoline, aminobenzimidazole and indolyl;

(b) R2represents a hydrogen atom, alkoxy, aminoalkyl or halogen atom;

(c) R3represents a hydrogen atom, alkoxy, Alcoxy or halogen atom;

(d) R4represents a hydrogen atom or (CH2)yR2; and

(e) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6or N(R)TnCO2R6.

11. The method according to claim 10, in which

(a) R1is optionally substituted ring selected from Fe the sludge, 2-pyridyl, 3-pyridyl, 4-pyridyl, teinila, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazole-1-yl, aminopyrimidine, chinoline, aminobenzimidazole and indolyl;

(b) R2represents a hydrogen atom, alkoxy, aminoalkyl or halogen atom;

(c) R3represents a hydrogen atom, alkoxy, Alcoxy or halogen atom;

(d) R4represents a hydrogen atom or (CH2)yR2; and

(e) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CO(R6)2, CO2R6, CON(R)COR6or N(R)TnCO2R6.

12. The method according to claim 1, in which the indicated compound has the formula IIIa and IIIb:

or its pharmaceutically acceptable salt, in which

W represents a nitrogen atom or CRa;

Raselected from a hydrogen atom, halogen atom, -CF3, R7, -OR7or-N(R7)2;

ring And optionally substituted with up to three R9; where, when the substituent R9located in the ortho-position of the ring And the substituent R9may be taken together with R2education optionally substituted 5-7-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R2and R 3each independently selected from R6, halogen atom, CN, SR6, OR6N(R6)2, NRCO2R6, NRCON(R6)2, CON(R6)2, NRCOR6, NRN(R6)2, COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or NRSO2R6; or R2and R3if taken together, form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R4selected from R6, CON(R6), COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or (CH2)yR2;

y is 1-6;

R5selected from R7, Ar, COAr, CON(R7)Ar, (CH2)yCO2R, (CH2)yN(R7)2C(=NR10)-N(R7)2C(=NR10)-NRCOR, C(=S)-N(R7)2, CON(R7)2, CO2R, COR, SO2R or SO2N(R7)2;

Ar represents a 5-membered heteroaryl, heterocyclic or carbocyclic ring, where the aforementioned ring is optionally substituted with up to three substituents selected from oxo, halogen atom, CN, NO2, R8, OR8, Other8, NHCOR8, NHCONHR8, COR8, CONHR8, SO2R8, NHSO2 8or SO2Other8;

each R is independently selected from hydrogen or optionally substituted aliphatic groups containing from one to six carbon atoms;

each R6independently selected from R7or optionally substituted groups selected from alkoxy, hydroxyalkyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, Alcoxy, aryloxyalkyl, heteroaryl, heteroalkyl, heteroaromatic or heteroaromatic;

each R7independently selected from a hydrogen atom or optionally substituted aliphatic groups containing from one to six carbon atoms, or two R7at the same nitrogen atom, being taken together with the nitrogen atom, optionally form a 4-6-membered saturated or unsaturated heterocyclic ring containing one to three heteroatoms;

R8represents C1-C4aliphatic group, where two of R8in related provisions of Ar, or aryl or heteroaryl ring may be taken together with the intermediate atoms with the formation of a 3-6-membered condensed ring;

each R9independently selected from oxo, halogen atom, CN, NO2Tn(halogenoalkane), R6, SR6, OR6, OR8N(R6)2, CON(R6)2, CON(R)COR6, COR6, CO R6, CO2N(R6)2, COCOR6, SO2R6, SO2N(R6)2N(R)TnCO2R6N(R)TnCON(R6)2N(R)TnN(R6)2N(R)TnNRCO2R6N(R)TnNRCON(R6)2N(R)TnCOR6N(R)TnNRCOR6N(R)TnSO2N(R6)2N(R)TnSO2R6, TnPO(OR7)2, TnOPO(OR7)2, TnSP(OR7)2,; TnPO(OR7)2or TnNPO(OR7)2;

each Q is independently selected from C1-C3branched or normal alkyl;

T is selected from-Q - or Qm-CH(Qm-R2)-; and

each m and n is independently selected from zero or 1, and

R10selected from R7or Ar.

13. The method according to item 12, in which the specified connection has one or more characteristics selected from the group consisting of:

(a) R2and R3each independently selected from a halogen atom, CN, CO2R6, OR6or R6;

(b) R5is CO2R, COAr, COR, CON(R7)2, Ar, (CH2)yCO2R or (CH2)yN(R7)2; and

(c) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6N(R)TnCO2R6N()T nNRCO2R6N(R)TnN(R6)2, NO2Tn(halogenated), CO2N(R6)2, COR6, SO2R6or SO2N(R6)2.

14. The method according to item 13, in which:

(a) R2and R3each independently selected from a halogen atom, CN, CO2R6, OR6or R6;

(b) R5is CO2R, COAr, COR, CON(R7)2, Ar, (CH2)yCO2R or (CH2)yN(R7)2; and

(C) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6N(R)TnCO2R6N(R)TnNRCO2R6N(R)TnN(R6)2, NO2Tn(halogenated), CO2N(R6)2, COR6, SO2R6or SO2N(R6)2.

15. The method according to item 13, in which the specified connection has one or more characteristics selected from the group consisting of:

(a) R2represents a hydrogen atom, alkoxy, aminoalkyl or halogen atom;

(b) R3represents a hydrogen atom, alkoxy, Alcoxy or halogen atom;

(c) R4represents a hydrogen atom or (CH2)yR2;

(d) R5represents CON(R7)2, Ar, (CH2)yCO2R or (CH2)yN(R7/sup> )2; and

(e) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6or N(R)TnCO2R6.

16. The method according to item 15, in which:

(a) R2represents a hydrogen atom, alkoxy, aminoalkyl or halogen atom;

(b) R3represents a hydrogen atom, alkoxy, Alcoxy or halogen atom;

(c) R4represents a hydrogen atom or (CH2)yR2;

(d) R5represents CON(R7)2, Ar, (CH2)yCO2R or (CH2)yN(R7)2; and

(e) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6or N(R)TnCO2R6.

17. The method according to claim 1, in which the indicated compound selected from those listed in tables 1 or 2.

18. The method according to claim 1, further comprising a stage of contacting the specified biological sample with an agent that increases the sensitivity of bacteria to antibiotics.

19. A method of treating a bacterial infection in a mammal, in need thereof, comprising the stage of introduction of a given mammal therapeutically effective amounts of compounds of formula I:

or its pharmaceutically acceptable salts, in which

Z represents O or N-R4;

W represents a nitrogen atom or CRa;

Raselected from a hydrogen atom, halogen atom, -CF3, R7, -OR7or-N(R7)2;

R1represents aryl or heteroaryl ring, where the aforementioned ring is optionally substituted up to four R9; where the substituent R9in ortho-position, R1if taken together with R2may form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R2and R3each independently selected from R6, halogen atom, CN, SR6, OR6V(R6)2, NRCO2R6, NRCON(R6)2, CON(R6)2, NRCOR6, NRN(R6)2, COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or NRSO2R6; or R2and R3if taken together, form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R4selected from R6, CON(R6), COR 6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or (CH2)yR2;

y is 1-6;

R5selected from R7, Ar, COAr, CON(R7)Ar, (CH2)yCO2R, (CH2)yN(R7)2C(=NR10)-N(R7)2C(=NR10)-NRCOR, C(=S)-N(R7)2, CON(R7)2, CO2R, COR, SO2R or SO2N(R7)2;

Ar represents a 5-membered heteroaryl, heterocyclic or carbocyclic ring, where the aforementioned ring is optionally substituted with up to three substituents selected from oxo, halogen atom, CN, NO2, R8, OR8, Other8, NHCOR8, NHCONHR8, COR8, CONHR8, SO2R8, NHSO2Other8or SO2Other8;

each R is independently selected from hydrogen or optionally substituted aliphatic groups containing from one to six carbon atoms;

each R6independently selected from R7or optionally substituted groups selected from alkoxy, hydroxyalkyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, Alcoxy, aryloxyalkyl, heteroaryl, heteroalkyl, heteroaromatic or heteroaromatic;

each R7independently selected from a hydrogen atom or optionally substituted aliphatic group containing the t one to six carbon atoms, or two R7at the same nitrogen atom, taken together with the nitrogen atom, optionally form a 4-6-membered saturated or unsaturated heterocyclic ring containing one to three heteroatoms;

R8represents C1-C4aliphatic group, where two of R8in related provisions of Ar, or aryl or heteroaryl ring may be taken together with the intermediate atoms with the formation of a 3-6-membered condensed ring;

each R9independently selected from oxo, halogen atom, CN, NO2Tn(halogenoalkane), R6, SR6, OR8, OR6N(R6)2, CON(R6)2, CON(R)COR6, COR6, CO2R6, CO2N(R6)2, COCOR6, SO2R6, SO2N(R6)2N(R)TnCO2R6N(R)TnCON(R6)2N(R)TnN(R6)2N(R)TnNRCO2R6N(R)TnNRCON(R6)2N(R)TnCOR6N(R)TnNRCOR6N(R)TnSO2N(R6)2N(R)TnSO2R6, TnPO(OR7)2, TnOPO(OR7)2, TnSP(OR7)2, TnPO(OR7)2or TnNPO(OR7)2;

each Q is independently selected from C1-C3branched or normal alkyl;

T is selected from-Q - or Qm -CH(Qm-R2)-;

each m and n is independently selected from zero or 1; and

R10selected from R7or Ar.

20. The method according to claim 19, in which the indicated compound has the formula Ia or Ib;

or its pharmaceutically acceptable salt.

21. The method according to claim 20, in which the specified connection has one or more characteristics selected from the group consisting of:

(a) R1represents optionally substituted aryl or heteroaryl ring;

(b) R2and R3each independently selected from a halogen atom, CN, CO2R6, OR6or R6;

(c) R5is CO2R, COAr, COR, CON(R7)2, Ar, (CH2)YCO2R or (CH2)yN(R7)2; and

(d) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6N(R)TnCO2R6N(R)TnNRCO2R6N(R)TnN(R6)2, NO2Tn(halogenated), CO2N(R6)2, COR6, SO2R6or SO2N(R6)2.

22. The method according to item 21, in which

(a) R1represents optionally substituted aryl or heteroaryl ring;

(b) R2and R3each independently selected from and what Ohm halogen, CN, CO2R6, OR6or R6;

(c) R5is CO2R, COAr, COR, CON(R7)2, Ar, (CH2)yCO2R or (CH2)yN(R7)2; and

(d) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6N(R)TnCO2R6N(R)TnNRCO2R6N(R)TnN(R6)2, NO2Tn(halogenated), CO2N(R6)2, COR6, SO2R6or SO2N(R6)2.

23. The method according to item 21, in which the specified connection has one or more characteristics selected from the group consisting of

(a) R1is optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, teinila, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazole-1-yl, aminopyrimidine, chinoline, aminobenzimidazole and indolyl;

(b) R2represents a hydrogen atom, alkoxy, aminoalkyl or halogen atom;

(c) R3represents a hydrogen atom, alkoxy, Alcoxy or halogen atom;

(d) R4represents a hydrogen atom or (CH2)yR2;

(e) R5represents CON(R7)2, Ar, (CH2)yCO2R or (CH2)yN(R7)2; and

(f) R9/sup> represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6or N(R)TnCO2R6.

24. The method according to item 23, in which

(a) R1is optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, teinila, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazole-1-yl, aminopyrimidine, chinoline, aminobenzimidazole and indolyl;

(b) R2represents a hydrogen atom, alkoxy, aminoalkyl or halogen atom;

(c) R3represents a hydrogen atom, alkoxy, Alcoxy or halogen atom;

(d) R4represents a hydrogen atom or (CH2)yR2;

(e) R5represents CON(R7)2, Ar, (CH2)yCO2R or (CH2)yN(R7)2; and

(f) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6or N(R)TnCO2R6.

25. The method according to claim 19, in which the indicated compound has the formula IIa or IIb:

or its pharmaceutically acceptable salt, in which

W represents a nitrogen atom or CRa;

Raselected from a hydrogen atom, halogen atom, -CF3,R 7, -OR7or-N(R7)2;

R1represents aryl or heteroaryl ring, where the aforementioned ring is optionally substituted up to four R9; where the substituent R9in ortho-position, R1if taken together with R2may form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R2and R3each independently selected from R6, halogen atom, CN, SR6, OR6N(R6)2, NRCO2R6, NRCON(R6)2, CON(R6)2, NRCOR6, NRN(R6)2, COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or NRSO2R6; or R2and R3if taken together, form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R4selected from R6, CON(R6), COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or (CH2)yR2;

y is 1-6;

each R is independently selected from hydrogen or optionally substituted aliphatic is the group containing from one to six carbon atoms;

Ar represents a 5-membered heteroaryl, heterocyclic or carbocyclic ring, where the aforementioned ring is optionally substituted with up to three substituents selected from oxo, halogen atom, CN, NO2, R8, OR8, Other8, NHCOR8, NHCONHR8, COR8, CONHR8, SO2R8, NHSO2Other8or SO2Other8;

each R6independently selected from R7or optionally substituted groups selected from alkoxy, hydroxyalkyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, Alcoxy, aryloxyalkyl, heteroaryl, heteroalkyl, heteroaromatic or heteroaromatic;

each R7independently selected from a hydrogen atom or optionally substituted aliphatic groups containing from one to six carbon atoms, or two R7at the same nitrogen atom, being taken together with the nitrogen atom, optionally form a 4-6-membered saturated or unsaturated heterocyclic ring containing one to three heteroatoms;

R8represents C1-C4aliphatic group, where two of R8in related provisions of Ar, or aryl or heteroaryl ring may be taken together with the intermediate atoms with the formation of a 3-6-membered, conden the new ring;

each R9independently selected from oxo, halogen atom, CN, NO2Tn(halogenoalkane), R6, SR6, OR6, OR8N(R6)2, CON(R6)2, CON(R)COR6, COR6, CO2R6, CO2N(R6)2, COCOR6, SO2R6, SO2N(R6)2N(R)TnCO2R6N(R)TnCON(R6)2N(R)TnN(R6)2N(R)TnNRCO2R6N(R)TnNRCON(R6)2N(R)TnCOR6N(R)TnNRCOR6N(R)TnSO2N(R6)2N(R)TnSO2R6, TnPO(OR7)2, TnOPO(OR7)2, TnSP(OR7)2, TnPO(OR7)2or TnNPO(OR7)2;

each Q is independently selected from C1-C3branched or normal alkyl;

T is selected from-Q - or Qm-CH(Qm-R2)-; and each of m and n is independently selected from zero or 1.

26. The method according A.25 in which the specified connection has one or more characteristics selected from the group consisting of

(a) R1represents optionally substituted aryl or heteroaryl ring;

(b) R2and R3each independently selected from a halogen atom, CN, CO2R6, OR6or R6; and

(c) R9represents a halogen atom, CN, oxo, R6, SR 6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6N(R)TnCO2R6N(R)TnNRCO2R6N(R)TnN(R6)2, NO2Tn(halogenated), CO2N(R6)2, COR6, SO2R6or SO2N(R6)2.

27. The method according to p, in which

(a) R1represents optionally substituted aryl or heteroaryl ring;

(b) R2and R3each independently selected from a halogen atom, CN, CO2R6, OR6or R6; and

(c) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6N(R)TnCO2R6N(R)TnNRCO2R6N(R)TnN(R6)2, NO2Tn(halogenated), CO2N(R6)2, COR6, SO2R6or SO2N(R6)2.

28. The method according to p in which the specified connection has one or more characteristics selected from the group consisting of:

(a) R1is optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, teinila, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazole-1-yl, aminopyrimidine, chinoline, aminobenzimidazole and indolyl;

(b) R2represents the atom in which aroda, alkoxy, aminoalkyl or halogen atom;

(c) R3represents a hydrogen atom, alkoxy, Alcoxy or halogen atom;

(d) R4represents a hydrogen atom or (CH2)yR2; and

(e) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6or N(R)TnCO2R6.

29. The method according to p, in which

(a) R1is optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, teinila, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazole-1-yl, aminopyrimidine, chinoline, aminobenzimidazole and indolyl;

(b) R2represents a hydrogen atom, alkoxy, aminoalkyl or halogen atom;

(c) R3represents a hydrogen atom, alkoxy, Alcoxy or halogen atom;

(d) R4represents a hydrogen atom or (CH2)yR2; and

(e) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6or N(R)TnCO2R6.

30. The method according to claim 19, in which the indicated compound has the formula IIIa or IIIb:

or its pharmaceutically acceptable salt, in which

W pre which is a nitrogen atom or CR a;

Raselected from a hydrogen atom, halogen atom, -CF3, R7, -OR7or-N(R7)2;

ring And optionally substituted with up to three R9; where, when the substituent R9located in the ortho-position of the ring And the substituent R9may be taken together with R2education optionally substituted 5-7-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R2and R3each independently selected from R6, halogen atom, CN, SR6, OR6N(R6)2, NRCO2R6, NRCON(R6)2, CON(R6)2, NRCOR6, NRN(R6)2, COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or NRSO2R6; or R2and R3if taken together, form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R4selected from R6, CON(R6), COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or (CH2)yR2;

y is 1-6;

R5selected from R7, Ar, COAr, CON(R7)Ar, (CH2)yCO2R, (CH2) N(R7)2C(=NR10)-N(R7)2C(=NR10)-NRCOR, C(=S)-N(R7)2, CON(R7)2, CO2R, COR, SO2R or SO2N(R7)2;

Ar represents a 5-membered heteroaryl, heterocyclic or carbocyclic ring, where the aforementioned ring is optionally substituted with up to three substituents selected from oxo, halogen atom, CN, NO2, R8, OR8, Other8, NHCOR8, NHCONHR8, COR8, CONHR8, SO2R8, NHSO2Other8or SO2Other8;

each R is independently selected from hydrogen or optionally substituted aliphatic groups containing from one to six carbon atoms;

each R6independently selected from R7or optionally substituted groups selected from alkoxy, hydroxyalkyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, Alcoxy, aryloxyalkyl, heteroaryl, heteroalkyl, heteroaromatic or heteroaromatic;

each R7independently selected from a hydrogen atom or optionally substituted aliphatic groups containing from one to six carbon atoms, or two R7at the same nitrogen atom, being taken together with the nitrogen atom, optionally form a 4-6-membered saturated or unsaturated heterocyclic ring containing from one is about three heteroatoms;

R8represents C1-C4aliphatic group, where two of R8in related provisions of Ar, or aryl or heteroaryl ring may be taken together with the intermediate atoms with the formation of a 3-6-membered condensed ring;

each R9independently selected from oxo, halogen atom, CN, NO2Tn(halogenoalkane), R6, SR6, OR6, OR8N(R6)2, CON(R6)2, CON(R)COR6, COR6, CO2R6, CO2N(R6)2, COCOR6, SO2R6, SO2N(R6)2N(R)TnCO2R6N(R)TnCON(R6)2N(R)TnN(R6)2N(R)TnNRCO2R6N(R)TnNRCON(R6)2N(R)TnCOR6N(R)TnNRCOR6N(R)TnSO2N(R6)2N(R)TnSO2R6, TnPO(OR7)2, TnOPO(OR7)2, TnSP(OR7)2, TnPO(OR7)2or TnNPO(OR7)2;

each Q is independently selected from C1-C3branched or normal alkyl;

T is selected from-Q - or Qm-CH(Qm-R2)-; and

each m and n is independently selected from zero or 1; and

R10selected from R7or Ar.

31. The method according to item 30, in which the specified connection has one or more characteristics, using the data from the group consisting of:

(a) R2and R3each independently selected from a halogen atom, CN, CO2R6, OR6or R6;

(b) R5is CO2R, COAr, COR, CON(R7)2, Ar, (CH2)yCO2R or (CH2)yN(R7)2; and

(c) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6N(R)TnCO2R6N(R)TnNRCO2R6N(R)TnN(R6)2, NO2Tn(halogenated), CO2N(R6)2, COR6, SO2R6or SO2N(R6)2.

32. The method according to p, in which

(a) R2and R3each independently selected from a halogen atom, CN, CO2R6, OR6or R6;

(b) R5is CO2R, COAr, COR, CON(R7)2, Ar, (CH2)yCO2R or (CH2)yN(R7)2; and

(c) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6N(R)TnCO2R6N(R)TnNRCO2R6N(R)TnN(R6)2, NO2Tn(halogenated), CO2N(R6)2, COR6, SO2R6or SO2N(R6)2.

33. The method according to p, the which the specified connection has one or more characteristics, selected from the group consisting of

(a) R2represents a hydrogen atom, alkoxy, aminoalkyl or halogen atom;

(b) R3represents a hydrogen atom, alkoxy, Alcoxy or halogen atom;

(c) R4represents a hydrogen atom or (CH2)yR2;

(d) R5represents CON(R7)2, Ar, (CH2)yCO2R or (CH2)yN(R7)2; and

(e) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6or N(R)TnCO2R6.

34. The method according to p, in which

(a) R2represents a hydrogen atom, alkoxy, aminoalkyl or halogen atom;

(b) R3represents a hydrogen atom, alkoxy, Alcoxy or halogen atom;

(c) R4represents a hydrogen atom or (CH2)yR2;

(d) R5represents CON(R7)2, Ar, (CH2)yCO2R or (CH2)yN(R7)2; and

(e) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6or N(R)TnCO2R6.

35. The method according to claim 19, in which the indicated compound selected from the group comprising the following compounds Ia and Ib:

36. The method according to claim 19, in which the disease in mammals is facilitated by the introduction of the gyrase inhibitor.

37. The method according to claim 19, in which a bacterial infection that is being treated, characterized by the presence of one or more of the following: Streptococcus pneumoniae, Streptococcus pyrogenes, Enterococcus fecalis, Enterococcus faecium, Klebsiella pneumoniae, Enterobacter sps. Proteus sps. Pseudomonas aeruginosa, E. coli, Serratia marcesens, S.aureus or Coag. Neg. Staph.

38. The method according to claim 19, in which the bacterial infection, which is subjected to a treatment selected from one or more of the following: urinary tract infections, pneumonia, prostatitis, skin infections and soft tissue infections of the abdominal cavity or infection in patients with febrile neutropenia.

39. The method according to claim 19, further comprising a stage of introduction of the uke is anomo the mammal additional therapeutic agent, selected from an antibiotic, anti-inflammatory agent, an inhibitor of matrix metalloprotease, lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, anti-cancer agents, antiviral agents, cytokine, growth factor, an immunomodulator, a prostaglandin or compounds against vascular hyperproliferation, or as part of a multiple dosage form together with specified connection or in separate dosage forms.

40. The method according to claim 19, further comprising a stage of introduction of a given mammal an agent that increases the sensitivity of bacteria to antibiotics.

41. The compound of the formula I:

or its pharmaceutically acceptable salt, in which

W represents a nitrogen atom or CRa;

Z is O or NR4;

Raselected from a hydrogen atom, halogen atom, -CF3, R7, -OR7or-N(R7)2;

R1represents aryl or heteroaryl ring, where the aforementioned ring is optionally substituted up to four R9; where the substituent R9in ortho-position, R1if taken together with R2may form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring, the content is the future 0-2 ring heteroatoms, selected from nitrogen atoms, oxygen or sulfur;

R2and R3each independently selected from R6, halogen atom, CN, SR6, OR6N(R6)2, NRCO2R6, NRCON(R6)2, CON(R6)2, NRCOR6, NRN(R6)2, COR6, CO2R6, COCOR6, SO2R6, SO2N (R62 or NRSO2R6; or R2and R3if taken together, form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R4selected from R6, CON(R6), COR6, CO2R6, COCOR6, SO2R6, SO2N (R6)2or (CH2)yR2;

R5represents CON(R7)2;

y is 1-6;

each R is independently selected from hydrogen or optionally substituted aliphatic groups containing from one to six carbon atoms;

Ar represents a 5-membered heteroaryl, heterocyclic or carbocyclic ring, where the aforementioned ring is optionally substituted with up to three substituents selected from oxo, halogen atom, CN, NO2, R8, OR8, Other8, NHCOR8, NHCONHR8, COR8, CONHR8, SO2R8, NHSO2/sub> Other8or SO2Other8;

each R6independently selected from R7or optionally substituted groups selected from alkoxy, hydroxyalkyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, Alcoxy, aryloxyalkyl, heteroaryl, heteroalkyl, heteroaromatic or heteroaromatic;

each R7independently selected from a hydrogen atom or optionally substituted aliphatic groups containing from one to six carbon atoms, or two R7at the same nitrogen atom, being taken together with the nitrogen atom, optionally form a 4-6-membered saturated or unsaturated heterocyclic ring containing one to three heteroatoms;

R8represents C1-C4aliphatic group, where two of R8in related provisions of Ar, or aryl or heteroaryl ring may be taken together with the intermediate atoms with the formation of a 3-6-membered condensed ring;

each R9independently selected from oxo, halogen atom, CN, NO2Tn(halogenoalkane), R6, SR6, OR6, OR8N(R6)2, CON(R6)2, CON(R)COR6, COR6, CO2R6, CO2N(R6)2, COCOR6, SO2R6, SO2N(R6)2N(R)TnCO2R6N(R)TnCON(R6 )2N(R)TnN(R6)2N(R)TnNRCO2R6N(R)TnNRCON(R6)2N(R)TnCOR6N(R)TnNRCOR6N(R)TnSO2N(R6)2N(R)TnSO2R6, TnPO(OR7)2, TnOPO(OR7)2, TnSP(R7)2, TnPO(OR7)2or TnNPO(OR7)2;

each Q is independently selected from C1-C3branched or normal alkyl;

T is selected from-Q - or Qm-CH(Qm-R2)-; and

each m and n is independently selected from zero or 1.

42. The connection at paragraph 41, where the specified connection has one or more characteristics selected from the group consisting of:

(a) R1represents optionally substituted aryl or heteroaryl ring;

(b) R2and R3each independently selected from a halogen atom, CN, CO2R6, OR6or R6; and

(c) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6N(R)TnCO2R6N(R)TnNRCO2R6N(R)TnN(R6)2, NO2Tn(halogenated), CO2N(R6)2, COR6, SO2R6or SO2N(R6)2.

43. Connection § 42, in which:

(a) R1predstavljaet optionally substituted aryl or heteroaryl ring;

(b) R2and R3each independently selected from a halogen atom, CN, CO2R6, OR6or R6; and

(c) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6N(R)TnCO2R6N(R)TnNRCO2R6N(R)TnN(R6)2, NO2Tn(halogenated), CO2N(R6)2, COR6, SO2R6or SO2N(R6)2.

44. Connection § 42, where the specified connection has one or more characteristics selected from the group consisting of:

(a) R1is optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, teinila, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazole-1-yl, aminopyrimidine, chinoline, aminobenzimidazole and indolyl;

(b) R2represents a hydrogen atom, alkoxy, aminoalkyl or halogen atom;

(c) R3represents a hydrogen atom, alkoxy, Alcoxy or halogen atom;

(d) R4represents a hydrogen atom or (CH2)yR2; and

(e) R9represents a halogen atom, CN, oxo, R6, SR6, OR6V(R6)2, CON(R6)2, CO2R6, CON(R)COR6or N(R)TnCO2R6.

45. The connection is on item 44, where:

(a) R1is optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, teinila, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazole-1-yl, aminopyrimidine, chinoline, aminobenzimidazole and indolyl;

(b) R2represents a hydrogen atom, alkoxy, aminoalkyl or halogen atom

(e) R3represents a hydrogen atom, alkoxy, Alcoxy or halogen atom;

(d) R4represents a hydrogen atom or (CH2)yR2; and

(C) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6or N(R)TnCO2R6.

46. The compound of the formula I:

or its pharmaceutically acceptable salt, in which

W represents a nitrogen atom or CRa;

Z represents O or N-R4;

Raselected from a hydrogen atom, halogen atom, -CF3, R7, -OR7or-N(R7)2;

R1is the ring pyrimidine-5-yl, optionally substituted with up to three R9; where, when the substituent R9located in the ortho-position of the specified ring pyrimidine-5-Il, the substituent R9may be taken together with R2with established who eat optionally substituted 5-7-membered ring, containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R2and R3each independently selected from R6, halogen atom, CN, SR6, OR6N(R6)2, NRCO2R6, NRCON(R6)2, CON(R6)2, NRCOR6, NRN(R6)2, COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or NRSO2R6; or R2and R3if taken together, form a condensed, unsaturated or partially unsaturated, optionally substituted 5-8-membered ring containing 0-2 ring heteroatoms selected from nitrogen atoms, oxygen or sulfur;

R4selected from R6, CON(R6), COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2or (CH2)yR2;

y is 1-6;

R5selected from R7, Ar, COAr, CON(R7)Ar, (CH2)yCO2R, (CH2)yN(R7)2C(=NR10)-N(R7)2C(=NR10)-NRCOR, C(=S)-N(R7)2, CON(R7)2, CO2R, COR, SO2R or SO2N(R7)2;

Ar represents a 5-membered heteroaryl, heterocyclic or carbocyclic ring, where the aforementioned ring is optionally substituted with up to three substituents selected from oxo, halogen atom, CN, NO 2, R8, OR8, Other8, NHCOR8, NHCONHR8, COR8, CONHR8, SO2R8, NHSO2Other8or SO2Other8;

each R is independently selected from hydrogen or optionally substituted aliphatic groups containing from one to six carbon atoms;

each R6independently selected from R7or optionally substituted groups selected from alkoxy, hydroxyalkyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, Alcoxy, aryloxyalkyl, heteroaryl, heteroalkyl, heteroaromatic or heteroaromatic;

each R7independently selected from a hydrogen atom or optionally substituted aliphatic groups containing from one to six carbon atoms, or two R7at the same nitrogen atom, being taken together with the nitrogen atom, optionally form a 4-6-membered saturated or unsaturated heterocyclic ring containing one to three heteroatoms;

R8represents C1-C4aliphatic group, where two of R8in related provisions of Ar, or aryl or heteroaryl ring may be taken together with the intermediate atoms with the formation of a 3-6-membered condensed ring;

each R9independently selected from oxo, halogen atom, CN, NO2Tn(halage which the alkyl), R6, SR6, OR6, OR8N(R6)2, CON(R6)2, CON(R)COR6, COR6, CO2R6, CO2N(R6)2, COCOR6, SO2R6, SO2N(R6)2N(R)TnCO2R6N(R)TnCON(R6)2N(R)TnN(R6)2N(R)TnNRCO2R6N(R)TnNRCON(R6)2N(R)TnCOR6N(R)TnNRCOR6N(R)TnSO2N(R6)2N(R)TnSO2R6, TnPO(OR7)2, TnOPO(OR7)2, TnSP(OR7)2, TnPO(OR7)2or TnNPO(OR7)2;

each Q is independently selected from C1-C3branched or normal alkyl;

T is selected from-Q - or Qm-CH(Qm-R2)-; and

each m and n is independently selected from zero or 1; and

R10selected from R7or Ar.

47. Connection p.46, where the specified connection has one or more characteristics selected from the group consisting of:

(a) R2and R3each independently selected from a halogen atom, CN, CO2R6, OR6or R6;

(b) R5is CO2R, COAr, COR, CON(R7)2, Ar, (CH2)yCO2R or (CH2)yN(R7)2; and

(c) R9represents a halogen atom, CN, oxo, R6, SR6,OR 6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6N(R)TnCO2R6N(R)TnNRCO2R6N(R)TnN (R6)2, NO2Tn(halogenated), CO2N(R6)2, COR6, SO2R6or SO2N(R6)2.

48. Connection p, in which:

(a) R2and R3each independently selected from a halogen atom, CN, CO2R6, OR6or R6;

(b) R5is CO2R, COAr, COR, CON(R7)2, Ar, (CH2)yCO2R or (CH2)yN(R7)2; and

(c) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6N(R)TnCO2R6N(R)TnNRCO2R6N(R)TnN(R6)2, NO2Tn(halogenated), CO2N(R6)2, COR6, SO2R6or SO2N(R6)2.

49. Connection p, where the specified connection has one or more characteristics selected from the group consisting of

(a) R2represents a hydrogen atom, alkoxy, aminoalkyl or halogen atom;

(b) R3represents a hydrogen atom, alkoxy, Alcoxy or halogen atom;

(c) R4represents a hydrogen atom or (CH2)yR2

(d) R5represents CON(R7)2, Ar, (CH2)yCO2R or (CH2)yN(R7)2; and

(e) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6or N(R)TnCO2R6.

50. Connection § 49, in which

(a) R2represents a hydrogen atom, alkoxy, aminoalkyl or halogen atom;

(b) R3represents a hydrogen atom, alkoxy, Alcoxy or halogen atom;

(c) R4represents a hydrogen atom or (CH2)yR2;

(d) R5represents CON(R7)2, Ar, (CH2)yCO2R or (CH2)yN(R7)2; and

(e) R9represents a halogen atom, CN, oxo, R6, SR6, OR6N(R6)2, CON(R6)2, CO2R6, CON(R)COR6or N(R)TnCO2R6.

51. Pharmaceutical composition for treatment or prevention of bacterial infection that contains the connection at one PP-50, and a pharmaceutically acceptable carrier.

52. The pharmaceutical composition according to § 51, in which the specified connection is made in the composition of a pharmaceutically acceptable way for the introduction of the patient.

53. The pharmaceutical composition according to § 51 or 52, additionally the containing additional therapeutic agent, selected from an antibiotic, anti-inflammatory agent, an inhibitor of matrix metalloprotease, lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, anti-cancer agents, antiviral agents, cytokine, growth factor, an immunomodulator, a prostaglandin or compounds against vascular hyperproliferation.

54. The pharmaceutical composition according to § 51 or 53, optionally containing an agent that increases the sensitivity of bacteria to antibiotics.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

26 cl, 1 tbl, 119 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

wherein R1, R2 and R3 have above given values; R6 is a group RR9N-; R7 is a group R10R11N-; each among R8, R, R10 and R11 means independently of one another hydrogen atom or (C1-C6)-alkyl in inert organic solvent being optionally with the presence of a base with compound of the formula (IV) ,

(IVa)

or (IVb) ,

wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

9 cl, 12 ex

The invention relates to the field of organic chemistry, namely to new individual compounds of class benzoxazines that exhibit fluorescent properties and can be used as starting products for the synthesis of new heterocyclic systems, as well as substances for sample labeling and additives for reflective paints

The invention relates to new nitrogen-containing aromatic 6-membered cyclic compounds of the formula (I) or their pharmaceutically acceptable salts, demonstrating excellent selective PDE V inhibitory activity

The invention relates to new physiologically active substituted oxazolo[4,5-d]pyridazine General formula (1), (2) or (3) and combinatorial library designed to search among them physiologically active substances, compounds leaders and candidates (drug-candidates) on the basis of screening

The invention relates to new cyclic diamine compounds of the formula I, where

< / BR>
represents an optionally substituted divalent residue of benzene, where the substituents are selected from unsubstituted lower alkyl groups, unsubstituted lower alkoxygroup, unsubstituted lower acyl group, a lower allylthiourea, lower alkylsulfonyl group, halogen atom, etc. or unsubstituted pyridine; Ar represents a phenyl group which may be substituted by one to four groups selected from unsubstituted lower alkyl group, the unsubstituted alkoxygroup, low allylthiourea, lower alkylsulfonyl group, and so on, optional substituted amino group, alkylenedioxy; X is-NH-, oxygen atom or sulfur atom; Y is a sulfur atom, sulfoxide or sulfon; Z represents a single bond or-NR2-; R2- the atom of hydrogen or unsubstituted lower alkyl group; l = 2 or 3; m = 2 or 3; n = 1, 2, or 3, or their salts, or their solvate

FIELD: organic chemistry, medicinal biochemistry, pharmacy.

SUBSTANCE: invention relates to substituted benzimidazoles of the formula (I): and/or their stereoisomeric forms, and/or their physiologically acceptable salts wherein one of substitutes R1, R2, R3 and R4 means a residue of the formula (II): wherein D means -C(O)-; R8 means hydrogen atom or (C1-C4)-alkyl; R9 means: 1. (C1-C6)-alkyl wherein alkyl is linear or branched and can be free of substituted by one-, bi- or tri-fold; Z means: 1. a residue of 5-14-membered aromatic system that comprises from 1 to 4 heteroatoms as members of the cycle that represent nitrogen and oxygen atoms wherein aromatic system is free or substituted; 1.1 a heterocycle taken among the group of oxadiazole or oxadiazolone that can be unsubstituted or substituted; 2. (C1-C6)-alkyl wherein alkyl is a linear or branched and monosubstituted with phenyl or group -OH; or 3. -C(O)-R10 wherein R10 means -O-R11, -N(R11)2 or morpholinyl; or R8 and R9 in common with nitrogen atom and carbon atom with that they are bound, respectively, form heterocycle of the formula (IIa): wherein D, Z and R10 have values given in the formula (II); A means a residue -CH2-; B means a residue -CH-; Y is absent or means a residue -CH2-; or X and Y in common form phenyl. The cyclic system formed by N, A, X, Y, B and carbon atom is unsubstituted or monosubstituted with (C1-C8)-alkyl wherein alkyl is monosubstituted with phenyl, and other substitutes R1, R2, R3 and R4 mean independently of one another hydrogen atom, respectively; R5 means hydrogen atom; R6 means the heteroaromatic cyclic system with 5-14 members in cycle that comprises 1 or 2 nitrogen atoms and can be unsubstituted or substituted. Also, invention relates to a medicinal agent for inhibition of activity of IkB kinase based on these compounds and to a method for preparing the indicated agent. Invention provides preparing new compounds and medicinal agents based on thereof for aims for prophylaxis and treatment of diseases associated with the enhanced activity of NFkB.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 7 tbl, 224 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives if azaindole of the formula (I)

or its pharmaceutically acceptable salts wherein the formula is taken among the group consisting of , , and and wherein each among R1, R2, R3 and R4 is taken independently among the group consisting of hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, halogen atom, cyano-group (CN), phenyl, nitro-group, -OC(O)R15, -C(O)R15, -C(O)OR16, -OR19, -SR20 and NR21R22 wherein R15 is taken independently among the group including hydrogen atom (H),(C1-C6)-alkyl and (C2-C6)-alkenyl; each among R16, R19 and R0 is taken independently among the group including hydrogen atom (H), (C1-C6)-alkyl or (C1-C6)-alkyl substituted with from 1 to 3 halogen atoms; each among R21 and R22 is taken among the group including hydrogen atom(H), hydroxy-group (OH), (C1-C6)-alkyl; R5 represents the group (O)m wherein m = 0 or 1; n = 1 or 2; R6 is taken among the group including hydrogen atom (H), (C1-C6)-alkyl, -C(O)R24 and -C(O)OR5 under condition that carbon atoms comprising carbon-carbon double bond of indicated (C3-C6)-alkenyl are not the addition point to nitrogen atom to which R6 is joined; R24 is taken among the group consisting of hydrogen atom (H), and (C1-C6)-alkyl; R25 represents (C1-C6)-alkyl; each among R7, R8, R9, R10, R11, R12, R13 and R14 is taken independently among the group including hydrogen atom (H) and (C1-C6)-alkyl; Ar is taken among the group including:

, and . Compounds of the formula (I) inhibit HIV-1 that allows proposing their applying in medicine.

EFFECT: valuable medicinal and antiviral properties of compounds.

22 cl, 13 sch, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

26 cl, 1 tbl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

FIELD: organic chemistry, medicine, psychiatry, pharmacy.

SUBSTANCE: invention relates to medicinal agents used for prophylaxis and treatment of schizophrenia by inhibition or suppression of neurodegenerative disease caused by hypofunction of glutamic acid receptors. As an active component agents comprise derivative of 5-substituted 3-oxadiazolyl-1,6-naphthiridine-2(1H)-one of the formula (I):

wherein Het represents oxadiazolyl group; R1 represents hydrogen atom, lower alkyl group, lower cycloalkyl group, trifluoromethyl group, lower alkenyl group, lower alkynyl group, lower alkoxyl group, lower alkoxy-(lower)-alkyl group, lower hydroxyalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group; R2 represents hydrogen atom, lower alkyl group, lower cycloalkyl group, lower cycloalkylmethyl group, lower alkenyl group, lower cycloalkenyl group, lower alkynyl group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group wherein indicated groups represent phenyl or naphthyl and indicated heteroaryl groups represents furyl, thienyl or pyridyl, or their physiologically acceptable acid-additive salts.

EFFECT: valuable medicinal properties of agents.

10 cl, 1 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines of the general formula (1)

that are effective inhibitors if caspase-3 that can be used for preparing medicinal agents and for experimental (in vitro, in vivo) investigation of apoptosis processes as "pharmacological tools". Also, invention proposes pharmaceutical composition and a method for their preparing and applying. In the general formula (1) radicals R1, R2, R3 and R8 represent independently of one another hydrogen atom, halogen atom, CF3, CN, inert substitute, optionally substituted hydroxyl group, optionally substituted carboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group; R4 represents hydrogen atom, halogen atom, inert substitute, optionally substituted amino-group, substituted hydroxyl group; R5 represents hydrogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; R6 and R7 represent independently of one another hydrogen atom, inert substitute, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; or R6 and R7 in common with nitrogen atom to which they are bound represent optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur, 3-10-membered cycle; or R6 and R7 in common with nitrogen atom to which they are bound represent condensed heterocycle being optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur.

EFFECT: improved preparing method and treatment.

9 cl, 19 sch, 7 tbl, 25 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

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

SUBSTANCE: invention relates to a new improved method for preparing 6-methyl-2-(4-methylphenyl)-imidazolo[1,2-a]pyridine-3-(N,N-dimethylacetamide) of the formula (I) or its pharmaceutically acceptable acid additive salts. Method involves interaction of ester of the general formula (II) (wherein R is a lower alkyl or phenyl-lower alkyl) with dimethylamine in polar aproton solvent and if necessary conversion of synthesized compound of the formula (I) to pharmaceutically acceptable acid additive salt. Compound of the formula (I) is the known effective sedative agent used in therapy. Also, invention relates to intermediate compounds of the general formula (II) wherein R is a lower alkyl or phenyl-lower alkyl using in this method. Method provides preparing highly pure product for a single stage being without applying harmful and toxic reagents.

EFFECT: improved method for preparing.

16 cl, 15 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compound of the formula (I): wherein cycle A represents imidazo[1,2-a]pyrid-3-yl or pyrazole[2,3-a]pyrid-3-yl; R2 is joined to cyclic carbon atom and taken among halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkyl-S(O)a wherein a = 0, phenyl, phenylthio- or (heterocyclic group)-thio-group wherein any (C1-C6)-alkyl, phenyl or heterocyclic group can be substituted optionally by carbon atom with one or some G wherein heterocyclic group represents saturated, partially saturate or unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least atom is taken among nitrogen, sulfur or oxygen atom that can be bound if another variants are not specified with unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least one atom is taken among nitrogen, sulfur or oxygen atoms that can be bound if another variants are not specified with carbon or nitrogen atom wherein group -CH2- can be substituted optionally with -C(O)- and cyclic atom can carry optionally (C1-C6)-alkyl group and to form quaternary compound, or cyclic atom of nitrogen and/or sulfur can be oxidized to form N-oxide and/or S-oxides; m = 0-2 and R2 values can be similar or different; R1 means halogen atom, (C1-C3)-alkyl-S(O)a wherein a = 0 wherein any (C1-C3)-alkyl can be substituted optionally by carbon atom with one or some J; n = 0-1; cycle B represents phenyl or phenyl condensed with (C5-C7)-cycloalkyl cycle; R3 means halogen atom or sulfamoyl; p = 0-2 and R3 values can be similar or different; R4 means group A-E- wherein A is taken among (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heterocyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl wherein (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heteroccyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl can be substituted optionally by carbon atom with one or some D and wherein above mentioned heterocyclic group comprises fragment -NH- then nitrogen atom can be substituted optionally with group taken among R; E means a simple bond or -O-, -C(O)-, -N(Ra)C(O)- or -N(Ra)SO2-, -S(O)r wherein Ra means hydrogen atom or (C1-C6)-alkyl and r = 0-2; D is taken independently among hydroxy-, amino- (C1-C6)-alkoxy-, N-(C1-C6-alkyl)-amino-, N,N-(C1-C6-alkyl)-amino-, (C1-C6)-alkoxycarbonylamino- and benzyloxycarbonylamino-group wherein any (C1-C6)-alkyl or phenyl can be substituted optionally by carbon atom with one or some K; q = 0-1; G, J and K are taken independently among hydroxy-, dimethylamino-, diethylamino-group; R is taken among (C1-C4)-alkyl; or its pharmaceutically acceptable salt. Invention proposes applying pyrimidine compounds for inhibition of activity of kinases CDK2, CDK4 and CDK6 in cellular cycle eliciting anti-proliferative properties. Indicated properties have value in treatment of cancer diseases (solid tumors and leukemia), fibroproliferative and differential disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, atherosclerosis, arterial repeated stenosis, osseous and ophthalmic diseases with proliferation of cellular tissue in vessels.

EFFECT: valuable medicinal properties of compounds.

22 cl, 99 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to a new method for preparing quinazoline compound of the formula (A) or its pharmaceutically acceptable salt or solvate wherein R1 represents (C1-C4)-alkoxy-group; R2 represents (C1-C6)-alkoxy-group; R3 represents 6-membered heterocyclic ring comprising at least one heteroatom taken among nitrogen atom (N); R4 represents 6-membered heterocyclic ring comprising at least one heteroatom taken among N and wherein this ring is optionally condensed with benzene ring. This ring system is optionally substituted with group NHSO2-(C1-C4-alkyl). Proposed method for preparing involves condensation of compound of the formula (B): wherein R1-R3 have above given values with compound of the formula (C): wherein R5 and R6 taken in common with nitrogen atom (N) to which they are bound represent 6-membered N-containing heterocyclic ring comprising at least one heteroatom taken among nitrogen atom (N). This ring is obligatory condensed with benzene ring and ring system if optionally substituted with group NHSO2-(C1-C4-alkyl). The condensation reaction is carried out in the presence of a base taken among tert.-butoxide sodium and tert.-pentoxide sodium and wherein conversion of prepared compound (A) to pharmaceutically acceptable salt or solvate is necessary or desirable, or conversion of prepared salt or solvate to compound of the formula (A). Except for, invention relates to methods for preparing compound of the formula (C) and compound of the formula (B) and compound of formulae (B) and (C). Invention provides minimal numbers of synthesis stages, elimination of carrying out competitive reactions and using danger materials.

EFFECT: improved preparing method.

23 cl, 7 ex

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