Gyrase inhibitors and application thereof

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

 

Cross-reference to related applications

In this application claims the priority of provisional patent application U.S. 60/443917, filed January 31, 2003, the contents of which are introduced in the present description by reference.

The technical field

The present invention relates to the field of medical chemistry and in particular to the compounds and to pharmaceutical compositions containing these compounds, which inhibit bacterial girazu and Topo IV. These compounds can be used as inhibitors of the activity of bacterial gyrase and Topo IV. The present invention also relates to methods for treating bacterial infections in mammals and to methods of reducing the number of bacteria in a biological sample.

The level of technology

It has long been known that bacteria are resistant to antibiotics, and this phenomenon is now seen as a serious public health problem worldwide. As a result, the resistance of some bacterial infections are difficult to cure with antibiotics or are even incurable. Recently, with the advent of some bacterial strains resistance to many drugs, such asStreptococcus pneumoniae (SP),Mycobacterium tuberculosisandEnterococcus,this problem became especially Aktualno the ü. The emergence of enterococci resistant to vancomycin, is a particular threat because currently vancomycin is the only effective antibiotic for the treatment enterococcal infection, and this drug is considered as a "last hope" in the treatment of many infections. Although many other drug-resistant bacteria, such as enterococci, does not cause disease, posing a threat to life, however, there are concerns that the genes that induce such resistance may be transferred to, and more dangerous microorganisms, such asStaphylococcus aureus, most of which have already developed resistance to methicillin (De Clerq et al., Current Opinion in Antiinfective Investigational Drugs, 1999, 1, 1; Levy, "The Challenge of Antibiotic Resistance", Scientific American, March, 1998).

Another problem is the speed of the spread of antibiotic resistance. For example, prior to 1960, all regions of the world streptococci (SP) were susceptible to penicillin, and in 1987 in the United States were resistant only 0.02% of the strains SP. However, in 1995 it was reported that SP resistance to penicillin is about seven percent, and in some areas of the USA, it reached 30%. (Lewis, FDA Consumer magazine (September, 1995); Gershman y inThe Medical Reporter1997).

In particular, the hospital served as foci for the occurrence and spread the care of drug-resistant microorganisms. Infection acquired in the hospital, known as hospital-acquired (nosocomial) infections are becoming an increasingly serious problem. Each year in hospitals catches two million Americans, and more than half of them has the infection may be resistant to at least one antibiotic. The center for disease control reported that in 1992 more than 13000 patients died of bacterial infections that were resistant to treatment with antibiotics (Lewis, "The Rise of Antibiotic-Resistance Infections", FDA Consumer magazine, Sept, 1995).

Therefore, the need to fight against bacteria that are resistant to medicines, and all the more noticeable drawback of the currently available drugs are causing an increasing interest in the development of new antibiotics. One of the most attractive strategies for the development of new antibiotics is the inhibition of DNA gyrase, a bacterial enzyme required for DNA replication, and therefore necessary for the growth of bacterial cells and their division. Girana activity is also associated with the processes of transcription, repair and recombination of DNA.

Gyrase is one of topoisomerases belonging to the group of enzymes that catalyze vzaimoprevrascheny topological isomers of DNA (in General, see Kornberg & Baker, DNA Replication, 2d Ed., Chapter 12,1992, W.H. Freeman & Co.,; Drlica, Molecular Microbiology, 1992, 6, 425; Drlica &Zhao, Microbiology and Molecular Biology Reviews, 1997, 61, 377). Itself gyrase regulates superspecialization DNA and weakens the topological stress arising in the case when DNA strands isodoro duplex untwine the replication process. Gyrase also catalyzes the transformation relacionado closed circular duplex DNA in a negative super-spiral shape, which is more favorable for recombination. The reaction mechanism supercoiling includes twisting around gyrase a specific region of DNA, the gap dual chain in this area, the passage of the second region of the DNA through the gap and repair broken chains. Such a mechanism of splitting characteristic of topoisomerase type II. The supercoiling reaction is initiated by the binding of ATP with Girasol. Then ATP is hydrolyzed during the reaction. This binding of ATP and its subsequent hydrolysis leads to conformational changes in gyrase associated with DNA, which are necessary for its activity. It was also found that the level of supercoiling (or relaxation) of the DNA depends on the ratio of ATP/ADP. In the absence of ATP gyrase are only able to relaxation superspiritual DNA.

Bacterial DNA gyrase is a protein tetramer weight of 400 kilodaltons, consisting of two subunits (GyrA) and TLD the subunit B (GyrB). Binding and DNA cleavage associated with GyrA, whereas for binding and hydrolysis of ATP is responsible GyrB protein. GyrB consists of aminoanisole domain, which has ATPase activity, and carboxykinase domain, which interacts with GyrA and DNA. In contrast, eukaryotic topoisomerase type II are homodimer, which can expose the relaxation of the negative and positive supercoiling, but can't enter a negative superwide. Ideally, antibiotics acting on the mechanism of inhibition of bacterial DNA gyrase, must be selective with respect to this enzyme and relatively inactive with respect to the eukaryotic type II topoisomerases.

Widely used quinolone antibiotics inhibit bacterial DNA-girazu. Examples of quinolones are already known compounds, such as nalidixic acid and oxolinic acid, and also recently received more potent fluoroquinolones, such as norfloxacin, ciprofloxacin, trovafloxacin. These compounds are associated with GyrA and stabilize the split complex, resulting in inhibition of all functions gyrase and to cell death. However, it is known that the main problem associated with the use of this class of compounds, is produced to him resist Tosti bacteria (WHO Report, "Use of Quinolones in Food Animals and Potential Impact on Human Health, 1998). As for the quinolones, as well as other classes of antibiotics, in this connection, it should be noted that bacteria exposed to the processing of already previously used compounds, often getting quite a bit of cross-resistance to more potent compounds of the same class.

Inhibitors that are associated with GyrB, less well-known. Examples of such inhibitors are coumarins, novobiocin and kumaresan A1, ciclacillin, Zinedin and claritin. It was shown that coumarin is very tightly associated with GyrB. For example, novobiocin forms a network of hydrogen bonds with the protein and several hydrophobic contacts. Although novobiocin and ATP, in all probability, contacted the website of the ATP-binding, however, there is minimal overlap in a specific orientation of these two compounds. The overlapping parts is carbohydrate link novomicin and ATP adenine (Maxwell, Trends in Microbiology, 1997, 5, 102).

As for bacteria that are resistant to the coumarin, the most dominant point mutation is a mutation in the surface arginine residue, which binds to the carbonyl coumarin ring (Arg 136 in GyrBE. coli). Although enzymes with this mutation detect lower superspiritual and ATPase activity, but they are also less. is lny to inhibition 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. Coumarins are largely ineffective due to their low ability to penetrate into the bacteria, toxicity in eukaryotes and poor solubility in water (Maxwell, Trends in Microbiology, 1997, 5, 102). It is therefore necessary to develop a new effective inhibitor GyrB, who lacked these disadvantages. Such an inhibitor should be used as an antibiotic candidate, the history of which is not linked with the problems of resistance arising from the use of other classes of antibiotics.

Moving replicative fork along the circular DNA can generate topological changes as before replicative complex, and already replicated regions (Champoux, J.J., Annu.Rev.Biochem., 2001, 70, 369-413). Although DNA-gyrase can make a negative superwide to compensate for the topological stress before replicative fork, but some twisting may be distributed back into the already replicated region of DNA that leads to the formation of precutaneous. If these Picatinny not removed, their presence can lead to binding (catenarian) child of molecules after replication. The enzyme Topo IV is responsible is N. for sharing catenarian child plasmids and also for the removal of precutaneous formed in the replication process that ultimately leads to segregation of daughter molecules into daughter cells. The enzyme Topo IV consists of two subunits, ParC and two ParE subunits, which represents a tetramer With2E2(where the monomers C and E are homologous monomers gyrase a and b, respectively), and for re-admission of this enzyme in the catalytic cycle required ATP hydrolysis (at the N-Terminus of the a subunit E). Topo IV is highly conserved in bacteria and plays an important role in their replication (Drlica &Zhao, Environ., Mol. Biol. Rev., 1997, 61, 377).

So far, inhibitors directed against ParE Topo IV, was not given much attention, while the newer quinolones, aimed at the region of ParC, has been widely studied (D. Hooper, C., Clin. Infect. Dis., 2000, 31(Suppl.2):S24-28). It was demonstrated that moxifloxacin and Gatifloxacin have a more balanced activity against gyrase and Topo IV, which allows to provide a broader coverage of gram-positive bacteria, and reduce the levels of mutation primary target, causing resistance. In these cases, the sensitivity is limited by the sensitivity of the secondary target in relation to the antimicrobial agent. Thus, tools that are able to inhibit many of the major targets can JV is to encourage the extension of the range of activities, the increase in antibacterial activity, increase effectiveness against mutants one target and/or the decrease in the spontaneous level of resistance.

Bacterial resistance to antibiotics is becoming an important problem of modern health care, and it is therefore necessary to develop new and stronger antibiotics. More specifically, it is necessary to get these antibiotics, which would represent a new class of compounds not previously used for treatment of bacterial infections. Such compounds should be particularly effective for the treatment of nosocomial infections in hospitals, where the emergence and spread of resistant infections is becoming more widespread.

The invention

It was found that the compounds of the present invention and their pharmaceutically acceptable salts are effective inhibitors of gyrase and/or Topo IV. These compounds or their pharmaceutically acceptable salts have the General formula I

where R1, R2, W, X, Z and ring As defined below.

These compounds and their pharmaceutically acceptable compositions can be used to treat or ameliorate the severity of bacterial infections. In particular, the compounds of the present invention can be used to treat or ameliorate the severity of infections is Chepalova ways, pneumonia, prostatitis, skin infections and soft tissue infections, abdominal infections, infections of the circulatory system or infections in patients with neutropenia accompanied by fever.

Detailed description of the invention

The present invention relates to a compound of formula I

or its pharmaceutically acceptable salt,

where W is selected from nitrogen, CH or CF;

X is selected from CH or CF;

Z represents O or NH;

R1represents phenyl or 5-6-membered heteroaryl ring containing 1-3 heteroatoms independently selected from oxygen, nitrogen or sulfur, and where

R1substituted by 0-3 groups independently selected from -(T)y-Ar, R', oxo, C(O)R', CO2R', OR', N(R')2, SR', NO2, halogen, CN, C(O)N(R')2, NR'r C(O)R', SO2R', SO2N(R')2or NR'r SO2R';

y is 0 or 1;

T is a straight or branched C1-4alkylidene chain, where one methylene link T optionally replaced by-O-, -NH - or-S-;

each R' is independently selected from hydrogen, C1-4aliphatic group or a 5-6-membered saturated, unsaturated or aryl ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where

R' is substituted by 0-3 groups independently selected from halogen, oxo, R°N R°)2, OR° , CO2R°, NR°C(O)R°, C(O)N(R°)2, SO2R°, SO2N R°)2or NR°SO2R°, where

each R° is independently selected from hydrogen, C1-4aliphatic group or a 5-6-membered saturated, unsaturated or aryl ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, and where

two Deputy in related provisions of R1taken together can form a 5-7 membered saturated, partially unsaturated, or aryl ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Ar represents a 3-8-membered saturated, unsaturated or aryl ring, a 3-7-membered heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, and where

Ar is substituted by 0-3 groups independently selected from R', oxo, CO2R', OR', N(R')2, SR', NO2, halogen, CN, C(O)N(R')2, NR'r C(O)R', SO2R', C(O)R', SO2N(R')2or NR'r SO2R';

R2selected from hydrogen or C1-3aliphatic group; and

ring a is a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, provided that at asanee ring has a hydrogen bond acceptor in the position adjacent to the position of joining to the ring In, and where

ring And substituted 0-3 groups independently selected from R', oxo, CO2R', OR', N(R')2, SR', NO2, halogen, CN, C(O)N(R')2, NR'r C(O)R', SO2R', SO2N(R')2or NR'r SO2R', where

two Deputy in the adjacent positions of the ring And, taken together, may form a 5-7-membered saturated, partially unsaturated, or aryl ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Used herein, the terms, if it is not specifically mentioned, have the meanings given above.

The term "optionally substituted" is synonymous with the term "substituted or unsubstituted". If it is not specifically mentioned, optionally substituted group may have a substituent at each substitutable position of the group, and each of these substitutions are not dependent on each other.

Used herein, the term "aliphatic" or "aliphatic group" refers to a straight or branched hydrocarbon With1-C8the chain that is completely saturated or which contains one or more unsaturated chains or monocyclic3-C8the hydrocarbon or bicyclic8-C12the hydrocarbon that is completely saturated or which contains one or more unsaturated chains, but is not Aro eticheskim (referred to here as the "carbocycle" or "cycloalkyl"), and that has one connection to the rest of the molecule, where any individual ring in the specified bicyclic system contains 3-7 members. For example, suitable aliphatic groups include, but are not limited to, straight or branched alkyl, alkeline, alkyline groups 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 molecule, include straight and branched chains containing one to twelve carbon atoms. The terms "alkenyl" and "quinil", used alone or as part of a larger molecule, include both straight and branched chain, containing from two to twelve carbon atoms.

The term "heteroatom" means an atom of nitrogen, oxygen or sulfur and includes any oxidized form of nitrogen and sulfur and stereoselectivity form of any of the nitrogenous base. The term "nitrogen" also includes substituted nitrogen atom of the heterocyclic ring. For example, in a saturated or partially unsaturated ring containing 0-3 heteroatoms selected from oxygen atoms, sulfur or nitrogen indicated by the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted the th pyrrolidinyl).

Used herein, the term "unsaturated" means that the molecule contains one or more unsaturated chains, and also refers to aryl rings.

The term "aryl"used herein alone or as part of a larger molecule, such as aralkyl", "arakaki" or "aryloxyalkyl", refers to monocyclic, bicyclic and tricyclic systems containing a total of five to fourteen ring members, where at least one ring in the system is aromatic and where each ring in the system contains 3-7 ring members. The terms "aryl" and "aryl ring" are used interchangeably. The term "aryl" also means a heteroaryl ring system as defined below.

Used herein, the terms "heterocycle", "heterocyclyl" or "heterocyclic" refers to non-aromatic, monocyclic, bicyclic or tricyclic systems having five to fourteen ring members in which one or more ring members represent a heteroatom, where each of the rings in this system has 3-7 ring members.

The term "heteroaryl", used alone or as part of a larger molecule, such as heteroalkyl" or "heteroaromatics", refers to monocyclic, bicyclic and tricyclic system having only five to chetyrnadcat and ring members, where at least one of the rings in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and where each ring in the system contains 3-7 ring members. The terms "heteroaryl", "heteroaryl ring" and "heteroaromatic ring" are used interchangeably.

Used herein, the term "hydrogen bond acceptor" means an atom that can accept a hydrogen bond. A typical hydrogen bond acceptor atom is sulfur, oxygen or nitrogen, and in particular, a nitrogen atom, which is sp2-hybridizing, the oxygen atom of a simple ester or the sulfur atom of tiefer. The preferred acceptor hydrogen bond is a nitrogen atom, which is sp2-hybridizing.

The combination of the substituents or radicals is valid only if this combination forms a stable or chemically valid connection. A stable compound or chemically valid connection is the connection that does not undergo significant changes when keeping at a temperature of 40°or lower in the absence of moisture or other chemically reactive conditions, at least during the week.

It should also be noted that some compounds of the present invention can prisutstvovat is in tautomeric forms, and all tautomeric forms of these compounds are included in the scope of the present invention.

Pictured here is the structure, if it is not specifically mentioned, include all stereochemical forms of the structure, i.e. the R and S configurations for each asymmetric center. Therefore, the scope of the present invention includes single stereochemical isomers as well as enantiomeric and diastereoisomeric mixture of compounds of the present invention. Pictured here is the structure, if it is not specifically mentioned, also include compounds that differ only by the presence of one or more enriched isotopes of atoms. For example, in the scope of the present invention includes compounds having the structure of the present invention, except for those structures in which the hydrogen atom is replaced by deuterium or tritium, or structures in which the carbon atom replaced by13With or14C-enriched carbon atom. Such compounds can be used, for example, as analytical tools or probes in biological assays.

Examples of suitable rings And groups are presented below in table 1,

Table 1

In accordance with one variant of the invention, ring a of formula I is a 5-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen atoms, oxygen or sulfur, provided that on the specified ring acceptor hydrogen bond is in position adjacent to the position of joining to the ring, where the specified ring And optionally substituted with the substituents defined above.

In accordance with another variant of the invention, ring a of formula I is a 6-membered heteroaryl ring containing 1-3 nitrogen atom, provided that on the specified ring nitrogen atom in the position adjacent to the position of joining to the ring, where the specified ring And optionally substituted with the substituents defined above.

In some embodiments of the invention the ring And formula I is selected from rings a, b, c, d, e, f, g, h, i, j, k, l, m, p, q, r, s, t, v, w, x, y, z, aa, bb, cc, dd, and where each ring And optionally substituted with the substituents defined above.

In other embodiments of the invention the ring And formula I is selected from rings a, f, 1, s, w, y, and z, where each ring And optionally substituted with the substituents defined above.

If the ring a of formula I is a bicyclic heteroaryl ring, the preferred bicyclic ring systems And are isothiazol, the benzimidazole, benzoxazole and quinoline.

In accordance with one variant of the invention the substituents in the ring a of formula I, when present, are substituents selected from oxo, N(R')2With(O)N(R')2, CO2R', halogen, N(R')SO2R', C(O)R', OR' or R'. In accordance with another variant of the invention the substituents R' in the ring And formula I are methyl, ethyl, propyl, piperazinil, piperidinyl or morpholinyl, where these groups R' is optionally substituted by R°N R°)2or or°.

In accordance with one variant of the invention the group R1formula I is an optionally substituted phenyl.

In accordance with another variant of the invention the group R1formula I is an optionally substituted 5-membered heteroaryl ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In accordance with another variant of the invention the group R1formula I is an optionally substituted 5-membered heteroaryl ring containing 1-3 nitrogen atom.

In yet another embodiment, the present invention relates to a compound of formula I, where R1represents an optionally substituted 6-membered heteroaryl ring containing 1-2 nitrogen atom.

In some embodiments of the invention the group R1formula I is chosen from optionally substituted phenyl, or 5-6-membered heteroaryl ring, containing 1-2 nitrogen atom. In other embodiments of the invention the group R1formula I is selected from optionally substituted of pyrid-2-ilen, pyrid-3-ilen, pyrid-4-ilen, Spiridonovka, pyrimidine-2-ilen, pyrimidine-4-ilen, pyrimidine-5-ilen, pyrimidine-6-ilen, imidazol-1-ilen, imidazol-2-ilen, imidazol-4-ilen, or imidazol-5-ilen rings. In accordance with another variant of the invention the group R1formula I is an optionally substituted ring selected from pyrid-3-yl, pyrid-4-yl, pyridone, pyrimidine-5-yl or imidazol-1-yl.

In some embodiments of the invention, the substituents of group R1formula I, when present, is selected from halogen, oxo, -(T)y-Ar, R', CO2R', OR', N(R')2, SR', C(O)N(R')2, NR'r C(O)R', SO2R', SO2N(R')2or NR'r SO2R'. In accordance with other variants of the invention, the substituents of group R1formula I, when present, is selected from oxo, fluorine, chlorine, N(CH3)2, NHCH2CH3, NH-cyclopropyl, NH2, NHC(O)CH3With(O)NH-cyclopropyl, methyl, ethyl, tert-butyl, isobutyl, cyclopropyl, isopropyl, CH2-phenyl, CH2-pyridin-3-yl, HE, co3The co2CH3The co2-phenyl, co2-pyridin-3-yl, CH2-piperidinyl, CH2-cyclopropyl or CH2CH2The CH 3.

In accordance with one variant of the invention, R1substituted -(T)y-Ar, where T is a straight or branched C1-3alkylidenes a circuit in which one methylene link T optionally replaced by-O-, -NH - or-S-. In accordance with another embodiment of the invention T is a straight or branched C1-3alkylidenes a circuit in which one methylene link T replaced by-O-, -NH - or-S-. In yet another embodiment, the present invention relates to a compound of formula I, where R1substituted -(T)y-Ar, and Ar is an optionally substituted 5-6-membered saturated ring containing 1-2 heteroatoms independently selected from oxygen, nitrogen or sulfur. In accordance with another variant of the invention, the group Ar of formula I is an optionally substituted 5-membered heteroaryl ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. In accordance with another variant of the invention, the group Ar of formula I is an optionally substituted 6-membered heteroaryl ring containing 1-3 nitrogen atom. In another embodiment, its implementation of the present invention relates to a compound of formula I where Ar represents optionally substituted phenyl.

If the group R1formula I is substituted by -(T) y-Ar, examples of the substituents on Ar are halogen, OR', R', CO2R', SO2R', oxo, and C(O)R'.

In accordance with one embodiments of the invention if two Deputy located in adjacent positions R1formula I and, taken together, form an optionally substituted ring fused with R1then these rings are 5-6-membered saturated, partially unsaturated, or aryl ring containing 0-2 heteroatoms independently selected from nitrogen atom, oxygen or sulfur. In accordance with another embodiment of the invention the specified ring fused with R1selected from 5-membered saturated ring containing two oxygen atom or 6-membered saturated ring containing two atoms of oxygen. Examples of the substituents are in the specified ring fused with R1is halogen, such as fluorine.

In one embodiment, the present invention relates to a compound of formula I, where R2selected from methyl, ethyl, isopropyl or cyclopropyl. In accordance with another variant of the invention R2represents methyl or ethyl. In accordance with another variant of the invention R2formula I is ethyl.

In one of its variants the present invention relates to a compound of formula I, where Z is the battle NH.

In another embodiment, the present invention relates to a compound of formula I, where Z represents O.

Compounds of the present invention comprise the genus of compounds described in PCT/US 01/48855. However, the applicants had been suddenly and accidentally discovered that the presence of a ring As defined above, leads to increased level of inhibition Girassol activity and Topo IV activity and increased antimicrobial activity.

In one of its variants the present invention relates to the compound of formula II

or its pharmaceutically acceptable salt, where Z, R2and ring As defined above, and imidazole ring optionally substituted at the 4-position by a group S(O)N(R')2and/or substituted in the 2-position by a group R'. In accordance with this, in another embodiment, the present invention relates to the compound of formula II-a:

or its pharmaceutically acceptable salt, where Z, R2, R' and ring As defined above.

In other embodiments, R2and the ring And formula II-a have the values described above for formula I.

In other embodiments, the groups R' of formula II-a is selected from hydrogen or C1-4aliphatic group.

In one of its variants the present invention relates to the compound of formula II or II-a, where Z is Soboh the NH.

In another embodiment, the present invention relates to the compound of formula II or II-a, where Z represents O.

In another embodiment, the present invention relates to the compound of formula III:

or its pharmaceutically acceptable salt, where Z, R2and ring As defined above, and Spiridonova ring is substituted by 0-2 groups independently selected from -(CH2)y-Ar, halogen, oxo, R', CO2R', OR', N(R')2, SR', C(O)N(R')2, NR'r C(O)R', SO2R', SO2N(R')2or NR'r SO2R'.

In other embodiments, R2and the ring And formula III have the values described above for formula I.

In other embodiments, the substituents in Spiridonova ring of formula III have the same values as the preferred substituents R1formula I.

In one of its variants the present invention relates to the compound of formula III where Z represents NH.

In another embodiment, the present invention relates to the compound of formula III where Z represents O.

In another embodiment, the present invention relates to the compound of formula III-a:

or its pharmaceutically acceptable salt, where Z, R', R2and ring As defined above.

In other embodiments, the groups R2formula III-a have the meanings described above for the groups R 2formula I.

In other embodiments, ring a of formula III-a has the values described above for rings And formula I.

In some embodiments, the substituents R' in Spiridonova ring of formula III-a is selected from hydrogen or C1-4aliphatic group, where R' is optionally substituted phenyl or pyridium. In other embodiments of the invention, the substituents R' in Spiridonova ring of formula III-a is selected from methyl, ethyl, tert-butyl, isobutyl, cyclopropyl, isopropyl, CH2-phenyl, CH2-pyridin-3-yl, CH2-piperidinyl, CH2-cyclopropyl or CH2CH2Och3.

In one of its variants the present invention relates to the compound of formula III-a, where Z represents NH.

In another embodiment, the present invention relates to the compound of formula III-a, where Z represents O.

In another embodiment, the present invention relates to the compound of formula IV

or its pharmaceutically acceptable salt, where y, Z, T, Ar, R2and ring As defined above.

In other embodiments, ring a and group R2formula IV have the meanings described above for ring a and group R2the above formula I.

In one embodiment of the invention, the group Ar of formula IV is an optionally substituted 5-6-membered saturated ring containing 1-2 is heteroatom, independently selected from oxygen, nitrogen or sulfur.

In another embodiment of the invention, the group Ar of formula IV represents an optionally substituted 5-membered heteroaryl ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In another embodiment of the invention, the group Ar of formula IV is an optionally substituted 6-membered heteroaryl ring containing 1-3 nitrogen atom.

In yet another embodiment, the present invention relates to the compound of formula IV, where Ar represents optionally substituted phenyl.

In yet another embodiment, the present invention relates to the compound of formula IV where Z represents NH.

Examples of the substituents in the group Ar of formula IV are halogen, OR', R', CO2R', SO2R', oxo, and C(O)R'.

In another embodiment, the present invention relates to the compound of formula IV where Z represents O.

In another embodiment, the present invention relates to the compound of formula V

or its pharmaceutically acceptable salt, where y, Z, R2and R1defined above.

In other embodiments, the groups R1and R2formula V have the meanings described above for groups of R1and R2the above formula I.

In one of its variants present invention relative to the tsya to the compound of formula V, where Z represents NH.

Examples of the substituents in the group Ar of formula IV are halogen, OR', R', CO2R', SO2R', oxo, and C(O)R'.

In another embodiment, the present invention relates to the compound of formula V where Z represents O.

In another embodiment, the present invention relates to the compound of formula VI

or its pharmaceutically acceptable salt, where y, Z, T, Ar and R2defined above.

In other embodiments, the group R2formula IV has the values described above for group R2the above formula I.

In one embodiment of the invention, the group Ar of formula VI is an optionally substituted 5-6-membered saturated ring containing 1-2 heteroatoms independently selected from oxygen, nitrogen or sulfur.

In another embodiment of the invention, the group Ar of formula VI represents an optionally substituted 5-membered heteroaryl ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In another embodiment of the invention, the group Ar of formula VI represents an optionally substituted 6-membered heteroaryl ring containing 1-3 nitrogen atom.

In yet another embodiment, the present invention relates to the compound of formula VI, where Ar represents optionally substituted phenyl.

Even one who m his version, the present invention relates to the compound of formula VI, where Z represents NH.

Examples of the substituents in the group Ar of formula VI are halogen, OR', R', CO2R', SO2R', oxo, and C(O)R'.

In another embodiment, the present invention relates to the compound of formula VI where Z represents O.

Examples of structures of formula I are given below in table 2.

Table 2

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Compounds of the present invention can be obtained by common methods, usually used by experts to obtain analogous compounds, as illustrated by the following General schemes I, II, III and IV and in the following examples.

Scheme I

In the above scheme I illustrates the General method to obtain an N'-alkyl-N-cyanoacetyl (3)used to obtain the compounds of the present invention, where Z represents NH. In stage (a) cyanamide (2) process alkylsulfonates in aqueous sodium hydroxide solution, and after acidification get the connection 3. Each specialist is clear that different isocyanates may be subjected to reaction under the conditions illustrated in scheme I, to produce different N'-alkyl-N-cyanoacetyl.

Scheme II

Reagents and conditions: (a) perborate sodium, SPLA, 55°With; (b) ring A, NaH, THF; (C) NH3, Meon,EtOH, 80°With; (d) R1-In(OH)2Pd(PPh3)4, NaHCO3H2O, THF, 70°With; (e) H2Pd/C, EtAc; (f) 3, H2SO4, 95°With; (g) 2-methyl-2-thiopseudourea, R2-chloroformiate.

In the above scheme II illustrates the overall method of obtaining benzimidazole compounds of the present invention, where Z represents NH or O. Bromaniline (4) is treated with perborate sodium and acetic acid getting definitiomedicine (5). Compound 5 is treated by interaction with the ring And in the presence of sodium hydride to obtain burilovo connection 6. The remaining fluorine atom of compound 6 is replaced by an amino group by reacting with ammonia, resulting in a gain aminosidine (7). Then, in stage (d), 2-nitro-5-bromaniline (7) is subjected to a reaction between arylboronic acid in the presence of palladium, resulting in a gain treeline connection (8). The nitrogroup connection 8 restore getting diaminododecane, which is treated with N'-alkyl-N-cyanoacetyl (3) to give the benzimidazole compounds of the formula I, where Z represents NH (9).

Alternatively, the intermediate compound 8 can be used to obtain the compounds of formula I, where Z represents O. After recovery to diaminododecane compound 8 is treated with 2-me is Il-2-thiopseudourea and R 2-chloroformiate getting connection 10 by the method described L.I. Kruse et al., J. Med. Chem. 1989, 32, 409-417. For every person it is clear that the reaction represented above in scheme II, carried out using different groups of R1and rings And the present invention.

In an alternative method of intermediate compound 8 is treated with either N,N-diethylcarbamoyl-2-methyl-2-thiopseudourea, or N,N-diethylamido-2-methyl-2-thiopseudourea, resulting in a receive connection 10 and 9 respectively. Synthesis of N,N-diethylcarbamoyl-2-methyl-2-thiopseudourea and N,N-diethylamido-2-methyl-2-thiopseudourea described in the following examples.

Scheme III

Reagents and conditions: (a) Pd(dppf)Cl2/KOAc, DMSO, 80°and (b) Cu(OAc)2/pyridine, DMF.

In the above scheme III illustrates a General method of preparing compounds of formula II-a, basically as described Kiyomori, A., Marcoux J.F.; Buchwald, S.I., Tetrahedron letters, vol. 40 (1999) 2657-2660. Compound 7 is treated with ether complex DIBORANE acid in the presence of Pd(dppf)/potassium acetate in DMSO at 80°obtaining an intermediate compound (11). Compound 11 is treated with 4-C(O)N(R')2-imidazole in the presence of copper acetate, resulting receive a 4-C(O)N(R')2-imidazol-1-ilen connection 12. The compound of formula II-a is produced from compound 12, as described in scheme, in stages (e), (f) and (g).

Although 4-C(O)N(R')2-imidazole is used only as an example, however, each expert it is clear that in substitution reactions at the stage (C) can be used by different groups of R1in the result that can be obtained for various compounds of the present invention. In General, boronate intermediate compound 11 can be treated with different R1-halides or R1-triflate using methods well known in the art, resulting in a gain of the intermediate 12', described below. Using methods described herein and methods known in the art, compounds 12' can be used to obtain compounds 9 and 10 of the present invention, as described above in scheme II.

Scheme IV

Reagents and conditions: (a); (b) NH4HE/dioxane, boiling under reflux; (C) Pd(PPh3)4/THF, boiling under reflux; and (d) Na2CO3/DMF, the heat.

In scheme IV illustrates an alternative method of preparing compounds of formula II-A. The connection 13 is subjected to nitration to obtain compound 14. Compound 14 is treated with ammonium hydroxide to obtain amino compounds 15. The bromine atom of compound 15 replaced by quenching the TCA reagent BrZn-ring And in the presence of Pd(PPh 3)4in THF to obtain compound 16. The connection handle 16 4-C(O)N(R')2-imidazole in the presence of sodium carbonate to obtain 4-C(O)N(R')2-imidazol-1-ilen connection 18. Then get the compound of formula II-a of the connection 18, as described in stages (e), (f) and (g) of scheme II.

For every person it is obvious that various compounds of the present invention can be obtained by the General methods described in schemes I, II, III and IV, by methods known in the art, and methods of synthesis described in the following examples.

Compounds of the present invention are powerful inhibitors of gyrase and Topo IV, as determined using an enzymatic assay. It was also shown that these compounds possess antimicrobial activity by analysis of antimicrobial sensitivity. The potency of the compound used in this invention as an inhibitor of gyrase or Topo IV, can be analyzedin vitro,in vivoor in cell lines by methods known in the art. Detailed description of the conditions used in enzymatic analysis and analysis on antimicrobial sensitivity is given in the following examples.

In another embodiment, the present invention relates to compositions containing the compound of the present invention or the pharmacist who Cesky acceptable salt and a pharmaceutically acceptable carrier, adjuvant or excipient. The number of compounds in the compositions of the present invention should be effective for program inhibition of gyrase and Topo IV or program for reducing the number of bacteria in a biological sample or in a patient. The composition of the present invention are preferably for administration to a patient in need of such introduction. Most preferably, the composition of the present invention was prepared with the purpose of oral administration to a patient.

Used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts; material obtained from a mammal by biopsy, or its extracts; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts.

Inhibition Girassol activity and/or Topo IV activity in the biological sample can be used for various purposes known in the art. Such purposes include, but are not limited to, blood transfusion, organ transplantation, storage of biological samples and biological tests.

Used herein, the term "patient" means an animal, preferably a mammal, and most preferably human.

The term "pharmaceutically acceptable carrier, adjuvant elenapanther" means a non-toxic carrier, adjuvant or excipient that does not adversely affect the pharmacological activity of the compound, in combination with which it is used. Pharmaceutically acceptable carriers, adjuvants or excipients that may be used in the compositions of the present invention, include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as albumin human serum, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as Protamine sulfate, dinatriumfosfaatti, potassium phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, substances based on cellulose, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, copolymers of polyethylene and polyoxypropylene, polyethylene glycol and lanolin.

Used herein, the term "detective inhibition" means a measurable change in Girassol or Topo IV activity in the sample containing the specified composition and girazu or Topo IV, compared with the sample containing girazu or Topo IV in the absence of a specified composition.

Used herein, the term "measurable reduction to the number of bacteria" means a measurable change in the number of bacteria in the sample, containing the specified composition, compared with the sample containing only bacteria.

The term "pharmaceutically acceptable salt" means any non-toxic salt of the compound of the present invention, which, after its introduction the recipient is capable of providing, directly or indirectly, the delivery of the compounds of the present invention, or a metabolite or residue possessing inhibitory activity. Used herein, the term "metabolite or residue having inhibitory activity" means that the specified metabolite or residue are also inhibitors of gyrase and/or Topo IV.

Pharmaceutically acceptable salts of the compounds of the present invention are salts derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid additive salts are the acetate, adipate, alginate, aspartate, benzoate, bansilalpet, bisulfate, butyrate, citrate, comfort, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulphate, aconsultant, formate, fumarate, glucoheptonate, glycyrrhizinate, glycolate, incomplete sulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpro is peanut, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate. Other acids, such as oxalic acid, although are not pharmaceutically acceptable may be used to produce salts useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid additive salts.

Salts derived from appropriate bases are alkali metal salts (e.g. sodium and potassium), salts of alkaline earth metals (e.g. magnesium), ammonium salts and N+(C1-4alkyl)4-salt. The present invention also considers the quaternization of any basic nitrogen-containing groups of the compounds described herein. As a result of such quaternization can be derived products, soluble or dispersible in water or in oil.

Compositions of the present invention can be administered orally, parenterally, by inhalation, topically, rectally, intranasally, transbukkalno, vaginally or via an implanted depot drug. Used herein, the term "parenteral" refers to subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, nutrigrain, intrathecal, intrahepatic, and intracranial injection or infusion, and is also the injection or injections into the affected area. These compositions are preferably administered orally, intraperitoneally or intravenously. Sterile forms of the compositions of the present invention for injection can be an aqueous or oily suspension. These suspensions can be prepared by methods known in the art, using suitable dispersing or wetting agents and suspendida agents. A sterile preparation for injection may also be a sterile solution or suspension for injection in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol. Specified acceptable carriers and solvents that can be used are water, ringer's solution and isotonic sodium chloride solution. In addition, as a solvent or suspendida environment typically used sterile fatty oil.

For this purpose, can be used any soft fatty oils, including synthetic mono - or diglycerides. Fatty acids such as oleic acid or its glyceride derivatives, can be used in preparations for injection, because they are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, and in particular, their polyoxyethylene derivatives. These oil solutions is whether the suspension may also contain a diluent based on long-chain alcohol or dispersing agent, such as carboxymethyl cellulose or similar dispergiruyushchie agents commonly used for the preparation of pharmaceutically acceptable dosage forms including emulsions and suspensions. For the preparation of the drug is also commonly used, and other surfactants, such as twins, spiny and other emulsifying substances or substances that increase the bioavailability, which are usually used for the preparation of pharmaceutically acceptable solid substances, liquids or other medicines.

Pharmaceutically acceptable compositions of the present invention can be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral administration are typically used by carriers are lactose and corn starch. Usually also add the oil, such as magnesium stearate. For oral administration of the dosage form capsule suitable diluents are lactose and dried corn starch. If, for oral administration, you must use a water suspension, the active ingredient is combined with emulsifying and suspendresume agents. If necessary, can be also added some pods stitely, fragrances or dyes.

Alternatively, the pharmaceutically acceptable compositions of the present invention can be introduced in the form of suppositories for rectal administration. They can be obtained by mixing the specified agent with a suitable non-irritating excipient which is solid at room temperature, but liquid at the rectal temperature and therefore it is melted in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

Pharmaceutically acceptable compositions of the present invention can also be introduced locally, especially in the case when the object of processing are areas or organs readily available for local use, including eye, skin, or the lower parts of the intestinal tract. Suitable drugs for local application can be easily prepared for delivery in each of these areas or organs.

Local injection into the lower parts of the intestinal tract can be carried out using a rectal preparation, suppository (see above) or by using a suitable enema. Can also be used plasters for percutaneous local application.

For local application pharmaceutically acceptable compositions can be prepared in the form of a suitable ointment, which contains Asa active component, suspended or dissolved in one or in multiple media. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin oil, white petrolatum, propylene glycol, polyoxyethylene and polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions may be prepared in the form of a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, servicemonitor, Polysorbate 60, wax-based atilovykh esters, Cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic application of pharmaceutically acceptable compositions can be prepared in the form of micronized suspensions in isotonic sterile saline solution with adjusted pH, or preferably, as solutions in isotonic sterile saline solution with adjusted pH, in the presence or in the absence of a preservative, such as chloride benzylamine. Alternatively, for ophthalmic applications pharmaceutically acceptable compositions could the t to be prepared in the form of ointment, such as vaseline.

Pharmaceutically acceptable compositions of the present invention can be also introduced by intranasal aerosol or inhalation. Such compositions be made by methods well known in the art for the preparation of pharmaceutical products, and they can be obtained as solutions in saline, using benzyl alcohol or other suitable preservatives, stimulants absorption to enhance bioavailability, fluorocarbons, and/or other standard solubilizing or dispersing agents.

More preferably, the pharmaceutically acceptable compositions of the present invention are prepared for oral administration.

In monotherapy for the prevention and treatment of bacterial infections caused by bacteria, such asStreptococcus pneumoniae,Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Klebsiella pneumoniae,Enterobacter sps., Proteus sps., Pseudomonas aeruginosa, E. coli, Serratia marcesens, Staphylococcus aureus, coagulasepositive staphylococci,Haemophilus influenzae,Bacillus anthracis,Mycoplasma pneumoniae,Moraxella catarralis, chlamydia pneumoniae, Legionella pneumophila, Mycobacterium tuberculosis, Staphylococcus epidermidisorHelicobacter pylorican be used dose levels of active ingredient comprising from 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 is, and most preferably from about 1 to 50 mg/kg of body weight per day.

The pharmaceutical compositions of the present invention is usually administered about 1-5 times a day or, alternatively, by continuous infusion. Or, alternatively, compositions of the present invention can be introduced in the form of the drug for pulsating perfusion. This introduction can be used for the treatment of chronic or acute infections. The amount of active ingredient that may be combined with materials native to prepare a single dosage form may vary depending on the particular host being treated and the particular route of administration. A typical preparation contains from about 5% to about 95% active compound (wt./wt.). Preferably, such preparations contain from about 20% to about 80% active compound.

If the composition of the present invention contain a combination of compounds of formula I and one or more therapeutic or prophylactic agents, the compound and the additional agent should both available in doses, comprising about 10-80% of the doses usually introduced when alone.

After improvement of the condition of the patient, if necessary, can be entered maintenance dose of a compound, composition or combination nastojasih the invention. Then, depending on the symptoms, the dose or frequency of doses, or both can be reduced to the level at which there is such an improvement, and if the symptoms are attenuated to the desired level, then the treatment should be discontinued. However, some patients may require periodic treatment for a long period of time after the occurrence of any of recurrence or symptoms.

For every person it is obvious that you may need the introduction of a lower or higher doses than the doses above. Specific schemes of doses and treatment for any particular patient depends on various factors, including the activity of specific connections in use, the age, body weight, General health, sex, diet, time of administration, rate of excretion, used a combination of drugs, the severity and course of the disease and the susceptibility of the patient to the disease, and are appointed by the treating physician.

Depending on the specific condition or disease susceptible to treatment or prevention, in the composition of the present invention may also include additional therapeutic agents that are normally administered to treat or prevent this condition. Under used here, the concept of the "additional therapeutic agent, which is usually administered for the treatment or prevention of a specific disease or condition" is usually taken to mean "products suitable for treatment of the specified disease or condition". Such means include, but are not limited to, antibiotic, anti-inflammatory agent, an inhibitor of metalloprotease matrix, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, an anticancer agent, an antiviral agent, a cytokine, a growth factor, an immunomodulator, a prostaglandin, a connection that prevents hyperproliferative vessels, or the agent that increases the susceptibility of bacterial organisms to antibiotics.

Tools that increase the susceptibility of bacterial organisms to antibiotics, are known. For example, in U.S. patent No. 5523288, in U.S. patent No. 5783561 and in U.S. patent No. 6140306 described methods using bactericidal proteins/proteins, improves the penetration of microorganisms (BPI), in order to increase the sensitivity of gram-positive and gram-negative bacteria to antibiotics. A way of improving the permeability of the outer membrane of bacterial microorganisms described Vaara M., Microbiological reviews (1992) pp. 395-411, and the sensitivity of gram-negative bacteria described Tsubery, H., et al., J. Med. Chem. (2000), pp. 3085-3092.

In another embodiment, the present invented the e relates to a method of treating a bacterial infection or reduce its severity, the patient, where the method involves the step of introducing the indicated patient a composition of the present invention.

In another embodiment, the present invention relates to a method of inhibiting gyrase in a biological sample.

In another embodiment, the present invention relates to a method of inhibiting Topo IV in a biological sample.

In another embodiment, the present invention relates to a method for reducing the number of bacteria in a biological sample.

In another embodiment, the present invention relates to a method for reducing the number of bacteria in a biological sample, where the specified method also involves the step of contacting the specified biological sample with an agent that increases the susceptibility of bacterial organisms to antibiotics.

Pharmaceutical compositions and methods of the present invention can be effective mainly for bacterial infectionsin vivo. Examples of bacterial pathogens, against which can be applied to the compositions and methods of the present invention, include, but are not limited to, the following microorganisms:Streptococcus pneumoniae,Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Klebsiella pneumoniae,Enterobacter sps., Proteus sps., Pseudomonas aeruginosa, E. coli, Serratia marcesens, Staphylococcus aureuscoagulase-negative staphylococci,Hamophilus infuenzae ,Bacillus anthracis,Mycoplasma pneumoniae,Moraxella catarralis, H. influenzae, Chlamydia pneumoniae, Legionella pneumophila, Mycobacterium tuberculosis, Helicobacter pyloriandStaphylococcus epidermidis.

Therefore, these compositions and methods can be used for the destruction of hospital or nanotribology infections or to reduce the degree of progression, severity or complications of these infections. Examples of nosocomial infections include, but are not limited to, urinary tract infections, respiratory infections, such as pneumonia, infection, made during surgery, and blood infection (also known as bacteremia). Examples nanotribology infections include, but are not limited to, urinary tract infections, pneumonia, prostatitis, skin infections and soft tissue infections, abdominal infections, and infections that cause patients neutropenia accompanied by fever.

The term "pharmaceutically effective amount" means an amount effective to treat or reduce the level of bacterial infection in the patient. The term "prophylactically effective amount" means an amount effective to prevent or significantly reduce the level of bacterial infections in a patient.

Compounds of the present invention can be used in the standard ways of dealing with bacterial infects the s in vivoand treatment of diseases or reducing the progression or severity of complications caused by these bacteria. Such methods of treatment, dose and necessary conditions can be selected by the expert from the existing known methods and technologies.

For example, the compound of the present invention may be combined with a pharmaceutically acceptable adjuvant for administration to a patient suffering from a bacterial infection or bacterial disease, pharmaceutically acceptable way in a quantity effective to reduce the severity of such infections or diseases.

Alternatively, compounds of the present invention can be used in the compositions and methods of treatment or prevention of bacterial infection or disease in individuals over long periods of time. These compounds may be used in such compositions, either individually or together with other compounds of the present invention the method, which is typically used when using a standard enzyme inhibitors in pharmaceutical compositions. For example, the compound of the present invention may be combined with pharmaceutically acceptable adjuvants commonly used in vaccines, and put in prophylactically effective amounts to preduprezhdayushchie bacterial infections or diseases in the individual over a long period of time.

To enhance the effect of therapy or prevention of various bacterial infections, the compounds of formula I can also be put together with other antibiotics. If the compounds of the present invention is administered in combination with other therapeutic means, they can be administered to the patient sequentially or simultaneously. Alternatively, the pharmaceutically or prophylactically acceptable compositions of the present invention include a combination of compounds of formula I and another therapeutic or prophylactic agent.

The above-described additional therapeutic agent can be introduced separately as part of a scheme of multiple doses of the composition containing the inhibitor. Alternatively, these means may constitute part of a single dosage form, mixed with the inhibitor in a single composition.

For a better understanding of the present invention presents the following examples. These examples are only for illustrative purposes and should not be construed as limiting the scope of the present invention.

EXAMPLES

Example 1

5-bromo-1,3-debtor-2-nitrobenzene:To a suspension tetrahydrate sodium perborate (1.04 g, 5 mmol) in acetic acid (20 ml), stir at 55°C, for 1 hour was added dropwise a solution of 4-bromo-2,6-diptiranjan in the UKS the Noah acid (10 ml). After stirring at 55°C for a further 3 hours the solution was cooled to room temperature and filtered. The filtrate is poured into ice and twice were extracted with ethyl acetate. The combined organic extracts are then washed 5×100 ml portions of water and saturated salt solution, dried (MgSO4) and concentrated in vacuum. The obtained residue was purified column chromatography on silica gel, elwira a mixture of ethyl acetate:hexane (1:20), resulting in a received 780 mg specified in the title compound as a brownish-yellow solid.1H-NMR (CDCl3) δ: to 7.32 (dt, 2H).

Example 2

1-(5-bromo-3-fluoro-2-nitrophenyl)-1H-pyrazole:To a suspension of sodium hydride (44 mg, 1.1 mmol, 60% oil dispersion) in THF (4 ml), stir at 0°C, was added a solution of pyrazole (72 mg, 1.05 mmol) in THF (1 ml). The resulting mixture was stirred at 0°C for 5 minutes and the solution was added 5-bromo-1,3-debtor-2-nitrobenzene (238 mg, 1 mmol) in THF (1 ml). The mixture was stirred at room temperature for 1 hour and then the reaction mixture was extinguished with water (1 ml) and distributed between water (20 ml) and ethyl acetate (50 ml). The organic layer was washed with a saturated solution of salt, dried (MgSO4) and concentrated in vacuum. The residue was purified column chromatography on silica gel, elwira a mixture of ethyl acetate:g is Xan (1:6), as a result, we received 240 mg (86%) specified in the connection header.1H-NMR (CDCl3) δ: 6,55 (t, 1H), 7,45 (d, 1H), 7,60 (s, 1H), 7,80 (m, 2H). MS (M+1) 287, (M+1+2) 289.

Example 3

5-bromo-2-nitro-3-pyrazole-1-yl-phenylamine:To a solution of 1-(5-bromo-3-fluoro-2-nitrophenyl)-1H-pyrazole (240 mg, 0.84 mmol) in ethanol (3 ml) was added ammonia (3 ml, 2 N. in methanol). The resulting mixture was heated in a sealed tube at 80°C for 16 hours and then concentrated in vacuum. The residue was purified column chromatography on silica gel, elwira a mixture of ethyl acetate:hexane (1:3), resulting in a received 250 mg (86%) indicated in the title compound as a yellow solid.1H-NMR (CDCl3) δ: 5,20 (Sirs, 2H), 6,50 (t, 2H), 6,9 (d, 1H), and 7.1 (d, 1H), 7.7 (d, 1H), and 7.8 (d, 1H). MS (M+1) 283, (M+1+2) 285.

Example 4

2-nitro-3-pyrazole-1-yl-5-pyridin-3-yl-phenylamine:To a solution of 5-bromo-2-nitro-3-pyrazole-1-yl-phenylamine (200 mg, 0.71 mmol) in THF (8 ml), was added 3-pyridylmethylamine (157 mg), (tetranitroaniline)palladium (0) (84 mg) and sodium carbonate (1.1 ml, 2.2 mmol of 2 M aqueous solution). The resulting mixture was stirred at 70°during the night, and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with water (50 ml) and saturated salt solution (50 ml), then dried (MgSO4) and concentrated vacuume. The obtained residue was purified column chromatography on silica gel, elwira gradient mixture of ethyl acetate:hexane(1:3, 1:2, 1:0, 2:1, 4:1, 8:1), as a result, we obtained 120 mg (60%) indicated in the title compound as a yellow solid.1H-NMR (DMSO-d6) δ: 6,45 (Sirs, 2H), 6,55 (t, 1H), and 7.1 (s, 1H), 7,25 (s, 1H), 7,55 (m, 1H), and 7.7 (s, 1H), 8,1 (dt, 1H), 8.3 (l, 1H), and 8.7 (d, 1H), 8,9 (s, 1H).

Example 5

1-ethyl-3-(7-pyrazole-1-yl-5-pyridin-3-yl-1H-benzoimidazol-1-yl)urea (I-2):A suspension of 2-nitro-3-pyrazole-1-yl-5-pyridin-3-yl-phenylamine (120 mg, 0.40 mmol) and 10% palladium on coal (12 mg) in ethyl acetate (10 ml) were placed in hydrogenator Parra under hydrogen pressure of 45 psi. The mixture was stirred for 16 hours, filtered and the filtrate was concentrated in vacuum. The obtained residue was diluted with H2SO4(1.6 ml or 1 BC) was added N'-ethyl-N-tenomodulin (0.8 ml of 1 M). The mixture was heated at 95°C for 4 hours and then concentrated in vacuum. The residue was purified preparative HPLC to obtain 75 mg specified in the connection header in the form of bis-TEA-salt, which was then converted into the free base, resulting in the received specified in the header of the connection.1H-NMR (DMSO-d6) δ: 1,1 (t, 3H), 3,2 (m, 2H), 7,0 (m, 1H), and 7.3 (d, 1H), 7.5 (m, 1H), 7,55 (s, 1H), 8.0 a (d, 1H), 8,55 (DD, 1H), cent to 8.85 (s, 1H), 10,1 (s, 1H), 12,0 (s, 1H). 1C/VS: single peak, (M+1) 348,23, (M-1) 346,18.

Example 6

<> N'-ethyl-N-Cinemotion:To a solution of sodium hydroxide (1.5 M aqueous solution, 50 ml, 75,02 mmol) at 20°With dropwise within 10 minutes was added cyanamide (8.5 g, 202,25 mmol), and then utilizationa (4 ml, 50,56 mmol). After stirring for 30 minutes was added sodium hydroxide (3 M, 25 ml, 75,02 mmol) and utilizationa (4 ml, 50,56 mmol). The resulting solution was kept at least 30 minutes, and then immediately used without highlighting.

Example 7

4-(pyridin-3-yl)-2-nitroaniline:To a solution of 4-bromo-2-nitroaniline (4.8 g, 22 mmol) in DME (100 ml) was added to a complex of 1,3-propanediylbis cyclic ether pyridine-3-Bronevoy acid (4 g, 24 mmol), sodium bicarbonate (45 ml, 1 M) and tetrakis(triphenylphosphine)palladium (of 0.05 EQ.). The resulting mixture was heated at 90°C for 8 hours and then cooled to room temperature. The solids were collected, washed with water, 5% EtOAc in hexane and dried to obtain specified in the title compound (5 g).1H-NMR (CDCl3) δ: 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), 6,25 (Sirs, 2H).

Example 8

2-bromo-6-nitro-4-pyridin-3-yl-phenylamine:To a solution of 4-(pyridin-3-yl)-2-nitroaniline (1.3 g, 9 mmol) in SPLA (25 ml) was added bromine (1,58 g, 9.9 mmol) in SPLA (5 ml). The resulting mixture was stirred at room temperature for 1 hour and then the reaction was suppressed in ice-cold water. Solid ve is esta collected, washed with water and dried. Then the solid in EtOAc washed with NaOH (2 BC; 20 ml), water and saturated salt solution and concentrated in vacuum. The concentrate was purified by chromatography [silica gel, ethyl acetate:hexane (1:1)] and has been mentioned in the title compound (0.8 g).1H-NMR (CDCl3) δ: 8,83 (d, 1H), 8,55 (m, 1H), to 8.41 (d, 1H), 8,15 (d, 1H), of 7.96 (m, 1H), 7,41 (m, 1H), 6,80 (Sirs, 2H). MS (M+1) 294.

Example 9

2-nitro-6-pyridin-2-yl-4-pyridin-3-yl-phenylamine:A mixture of 2-bromo-6-nitro-4-pyridin-3-yl-phenylamine (100 mg, 1 EQ.), bromide 2-pyridylthio (6 EQ.) and tetrakis(triphenylphosphine)palladium (0.1 EQ.) in THF (10 ml) was heated at 100°C for 18 hours. The reaction extinguished with water (2 ml). The product was extracted with EtOAc (20×3). Then the combined organic layer was concentrated in vacuum and the residue was purified by chromatography (silica gel, EtOAc), the result of which has been specified in the title compound (75 mg) as a yellow solid. (M+1) 293.

Example 10

3-pyridin-2-yl-5-pyridin-3-yl-benzene-1,2-diamine:To a solution of 2-nitro-6-pyridin-2-yl-4-pyridin-3-yl-phenylamine (75 mg, 0.26 mmol) in ethyl acetate (20 ml) was added 10% palladium on coal (50 mg). The resulting suspension was placed in hydrogenator Parra under hydrogen pressure of 40 psi and stirred at room temperature for one hour. The catalyst was removed by filtration and the filtrate conc the Wali in vacuum, the result has been specified in the title compound (50 mg, 0,19 mmol).

Example 11

1-ethyl-3-(7-pyridin-2-yl-5-pyridin-3-yl-1H-benzoimidazol-2-yl)urea (I-31):To a solution of 3-pyridin-2-yl-5-pyridin-3-yl-benzene-1,2-diamine (50 mg, 0,19 mmol) and sulfuric acid (from 0.76 ml, 1 N.) in water (1 ml) was added N'-ethyl-N-tenomodulin (0,76 ml, 1 M). Then was added dropwise sulfuric acid in a quantity sufficient to bring the pH to 3. The resulting mixture was heated at 100°C for 8 hours. Then the reaction mixture was cooled to room temperature. The solids were collected, washed with water and dried. The solids were purified by chromatography (silica gel, EtOAc, then 10% of the Meon in EtOAc) and received the connection 5 (27 mg).1H-NMR (CDCl3) δ: of 8.92 (d, 1H), 8,80 (m, 1H), charged 8.52 (m, 1H), 8.30 to (m, 1H), 8,21 (d, 1H), 8,04 (s, 1H), 7,94 (m, 1H), of 7.75 (s, 1H), 7,56 (d, 1H), 7,37 (m, 2H), 3,36 (square, 2H), 1,24 (t, 3H). (M+1) 359.

Example 12

2,2-dimethyl-N-(2-pyrimidine-2-yl-phenyl)propionamide:A 5-liter flask was loaded above Bronevoy acid tetrahydrate (281,4 grams, 960 mmol), 2-chloropyrimidine (100 g, 874 mmol), NaHCO3(146,8 grams, 1,746 mol) and Pd(PPh3)4(10.0 grams, 8,72 mmol). Then added water (1 l) and dimethoxyethane (1 l), and the mixture was slowly heated to 83°C (internal temperature) for 1 hour with the top of the agitator. Through , 2 hours all solids were dissolved. The reaction mixture was left for 8 hours for mixing. The mixture was cooled to room temperature and was stirred over night, which formed a thick precipitate. The crude mixture was diluted with water (2 l) and stirred for another 2 hours, and then the mixture was filtered and the solids then washed with water, 0.1 G. of NaOH and again with water. Then, the solids were dried in high vacuum at 50°C obtaining specified in the connection header (˜233 grams) in the form of a brownish-yellow powder.

Example 13

N-(4-bromo-2-pyrimidine-2-yl-phenyl)-2,2-dimethyl-propionamide:To a suspension of 2,2-dimethyl-N-(2-pyrimidine-2-ylphenyl)propionamide (˜117 grams, 437 mmol) in acetic acid (1 l) at room temperature for 1 hour was added bromine (67 ml, 1,31 mol) in solution in 100 ml of acetic acid. The heterogeneous mixture was stirred at room temperature for 5 hours, which formed a thick precipitate. The mixture is then poured into ice, diluted 1 N. Na2S2O3(2 l) and stirred for 1 hour. The solids were filtered, resuspendable in water (2 l)was stirred for 1 hour, and then filtered and again washed with water. The obtained solid was dried by suction to dryness at 50°resuspendable in SPLA (1 l) and within 20 minutes was treated with a solution of bromine (22 ml, 430 mmol) in acetic acid (20 ml). The obtained heterogeneous mixture was stirred for 5 hours, and then extinguished and processed as described above. The obtained solids were dried in vacuum at 50°obtaining specified in the connection header (165 grams) in the form of a brownish-yellow powder.

Example 14

N-(4-bromo-2-nitro-6-pyrimidine-2-yl-phenyl)-2,2-dimethyl-propionamide:To a suspension of N-(4-bromo-2-pyrimidine-2-ylphenyl)-2,2-dimethylpropanamide (32.6 g, 97.5 mmol) in TFA (400 ml) at 5°C for 30 minutes was added 90% nitric acid (70 ml of 1.46 mmol). Then the mixture was heated to room temperature and stirred 2 hours. The crude reaction mixture (already homogeneous) poured into ice to obtain a pasty mass. After that, the mixture was diluted with water to a volume of about 2 l, was treated with 500 ml of methanol and was intensively stirred for 12 hours. The obtained solids were filtered, abundantly washed with water, and then dried in vacuum at 50°C obtaining specified in the title compound (29.9 g, yield 81%) as a brownish-yellow powder.

Example 15

4-bromo-2-nitro-6-pyrimidine-2-yl-phenylamine:A suspension of N-(4-bromo-2-nitro-6-pyrimidine-2-yl-phenyl)-2,2-dimethylpropanamide (29.9 grams of 78.8 mmol) in concentrated HCl(200 ml) was boiled under reflux for 8 hours. Partially homogeneous crude reaction mixture was cooled to room temperature, diluted with water (500 ml) and the precipitate was stirred for 1 hour. Then the solids were filtered, washed with water and dried in vacuum at 50°C, resulting in the received specified in the title compound (21.1 g, yield 91%) as an orange powder.

Example 16

2-nitro-6-pyrimidine-2-yl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenylamine:A mixture of 4-bromo-2-nitro-6-pyrimidine-2-yl-phenylamine (1,82 g, 6.2 mmol), bis(pinacolato)Debora (3,144 g, 12.4 mmol), PdCl2dppf2(453 mg, 0.6 mmol) and Kaas (3.03 g, 31 mmol) in dioxane (60 ml) was heated at 105°C for 2.5 hours. The reaction mixture was filtered and washed with dichloromethane. The combined filtrates were concentrated in vacuo and to the residue was added water (100 ml). After extraction with dichloromethane (3×50 ml), drying and concentration was obtained a residue, which was washed with a mixture of ether and hexane and got mentioned in the title compound (2,07 g, 98%).

Example 17

N-[2-(3-herperidin-2-yl)phenyl]-2,2-dimethylpropanamide:A 3-liter flask was loaded above Bronevoy acid tetrahydrate (of 92.1 g, 314 mmol), chlorpheneramine (37.6 g, 286 mmol), NaHCO3(48.0 grams, 572 mmol) and PdPPh 3)4(3.3 grams, of 2.86 mmol). Then added water (300 ml) and dimethoxyethane (300 ml) and the mixture was slowly heated to 83°C (internal temperature) for 1 hour with the top of the agitator. Through ˜2 hours all solids were dissolved. The reaction mixture was left for 10 hours for mixing. The mixture was cooled to room temperature and was stirred overnight, resulting in a thick resin. The crude mixture was diluted with water (2 l) and stirred for another 2 hours. After that, the mixture was left without stirring until, while on the bottom of the flask were not deposited resin. The liquid phase was removed in vacuo, then was replaced with 0.1 G. of NaOH and stirred for 15 minutes. The resin was left to settle and the liquid was removed under vacuum. After that, the resin in the same way three times washed with water and then in acetone solution was transferred into odnogolosy flask. The mixture was concentrated in vacuum and five times was subjected to azeotropic distillation with ethyl acetate.

Example 18

N-[4-bromo-2-(3-herperidin-2-yl)phenyl]-2,2-dimethyl-propionamide:To a suspension of N-[2-(3-herperidin-2-yl)phenyl]-2,2-dimethylpropanamide (˜77 mmol) in acetic acid (300 ml) for 1 hour at room temperature was added bromine (12 ml, 228 mol) in solution in 50 ml of acetic acid. The heterogeneous mixture was stirred the ri room temperature for 5 hours, resulting form a thick sludge. The mixture is then poured into ice, diluted 1 N. Na2S2O3(500 ml) and was stirred for 1 hour. The solids were filtered, resuspendable in water (2 l)was stirred for 1 hour, and then filtered and again washed with water. The obtained solid was dried by suction to dryness at 50°, resuspendable in SPLA (1 l) and within 20 minutes was treated with a solution of bromine (4 ml, 76 mmol) in acetic acid (20 ml). The obtained heterogeneous mixture was stirred for 5 hours, and then extinguished and processed as described above. The obtained solids were dried in vacuum at 50°C obtaining specified in the title compound (19.1 g, 72%) as a brownish-yellow powder.

Example 19

N-[4-bromo-2-(3-herperidin-2-yl)-6-nitrophenyl]-2,2-dimethyl-propionamide:To a suspension of N-[4-bromo-2-(3-herperidin-2-yl)phenyl]-2,2-dimethylpropanamide (6.45 g, 18.4 mmol) in TFA (100 ml) and TFAA (25,5 ml, 183,6 mmol) at 0°With added TEA solution (30 ml) of 90% fuming nitric acid (2,46 ml, with 55.1 mmol) for 45 minutes. Then the mixture was stirred at 0°With only 4 hours. The crude reaction mixture (already homogeneous) poured into ice to obtain a pasty mass. After that, the mixture was diluted with water to the total volume 500 ml) was treated with 50 ml of methane is and was intensively stirred for 12 hours. The obtained solids were filtered, abundantly washed with water, and then dried in vacuum at 50°obtaining specified in the title compound (6.1 g, yield 82%) as a brownish-yellow powder.

Example 20

2-(3,5-differenl)pyrimidine:A solution of diperbarui acid (5.4 g, to 34.1 mmol) and 2-chloropyrimidine (3.0 g, to 26.2 mmol) in ethanol (50 ml) was treated with Na2CO3(3.6 g, to 34.1 mmol) and Pd(PPh3)4(1.5 g, of 1.31 mmol), and then boiled under reflux for 3 days. The resulting mixture was diluted in EtOAc, was added silica gel and the suspension was stirred at room temperature for 3 hours. Then the crude mixture was filtered through a layer of silica gel with EtOAc, concentrated in vacuo and subjected to flash chromatography (silica gel, gradient hexane/EtOAc, 19/1-14/1-9/1-7/1), resulting in the received specified in the header connection (1,38 g, 27%) as a white solid.1H-NMR (DMSO-d6, 500 MHz): 8,95 (d, 2H), 7,98 (m, 2H), EUR 7.57 (DD, 1H), of 7.48 (m, 1H).

Example 21

2-(3,5-debtor-2-nitrophenyl)pyrimidine:To a solution of 2-(3,5-differenl)pyrimidine (1.2 g, 6,24 mmol) in N2SO4(3 ml) at room temperature for 10 seconds, the syringe was added 90% NHO3(0,375 ml, 9,37 mmol). The resulting mixture was stirred at the room for the Noah temperature for 1 hour, and then poured into ice. The obtained heterogeneous mixture was diluted with water, was heated to room temperature and filtered. The solids were washed with water and dried in vacuum to obtain specified in the connection header (1,53 g, 100%) as a brownish-yellow solid.1H-NMR (DMSO-d6, 500 MHz): of 8.92 (d, 2H), 8,67 (m, 1H), 7,94 (m, 1H), 7,65 (DD, 1H).

Example 22

5-fluoro-2-nitro-3-pyrimidine-2-yl-phenylamine:To a solution of 2-(3,5-debtor-2-nitrophenyl)pyrimidine (1.5 g, 6,32 mmol) in dioxane (10 ml) at room temperature was added BuNH2(6.6 ml, 63,24 mmol). The mixture was heated to 100°in a sealed tube for 10 hours. Then the mixture was cooled to room temperature, poured into water and the solids were stirred for 1 hour. The mixture was filtered and the solids washed with water up until the filtrate became clear. After that, the crude product was diluted in Meon, was added 6 N. HCl and the resulting mixture was boiled under reflux for 3 hours. The reaction mixture was cooled to room temperature and poured into ice. The obtained heterogeneous mixture was heated to room temperature, filtered, the solids washed with water up until the filtrate became transparent, and dried under vacuum, resulting in the floor which were specified in the header connection (1,33 g, 90%) as an orange powder.1H-NMR (DMSO-d6, 500 MHz): 8,87 (d, 2H), 7,52 (DD, 1H), was 7.08 (DD, 1H), 6,86 (DD, 1H), 6,60 (s, 2H).

Example 23

Cyclopropylamino 1-(3-amino-4-nitro-5-pyrimidine-2-ylphenyl)-1H-imidazole-4-carboxylic acid:To a mixture of 5-fluoro-2-nitro-3-pyrimidine-2-yl-phenylamine (650 mg, 2.77 mmol) in DMF (5 ml) was added compound 17 (545 mg, 3.6 mmol) and Na2CO3(381 mg, of 3.60 mmol) at room temperature. The resulting mixture was heated to 125°C for 6 hours and then cooled to room temperature. The resulting mixture was diluted with water and the yellow precipitate was stirred for 1 hour. The crude reaction mixture was filtered and the solids washed with water up until the filtrate became clear. Then the washed solids were dried in vacuum and got mentioned in the title compound (960 mg, 95%) as a yellow powder.1H-NMR (DMSO-d6, 500 MHz): 8,91 (d, 1H), 8,42 (s, 1H), 8,29 (s, 1H), 8,08 (d, 1H), 7,52 (DD, 1H), was 7.36 (d, 1H), 7,29 (d, 1H), 6,59 (s, 2H), 2,89 (m, 2H), 0,072 (m, 2H), 0.64 in (m, 2H).

Example 24

N,N-diethylcarbamoyl-2-methyl-2-thiopseudourea:To a mixture of sulfate of 2-methyl-2-thiopseudourea (22,8 g, or 81.9 mmol) in methylene chloride (200 ml) was added triethylamine (34,5 ml 245,7 mmol) and ethylchloride (20,65 g, 245 mmol). After stirring over night the mixture is washed with water and saturated salt solution, and then was dried over sodium sulfate, filtered and concentrated in vacuum to obtain caustic oil, which was subjected to flash chromatography (10% ethyl acetate/hexane), the result of which has been specified in the header connection (16,68 g, yield of 86.9%) as a colourless oil, which was aterials when defending.1H-NMR (500 MHz, CDCl3) δ: 1,3 (square, 6N), is 2.41 (s, 3H), 4,22 (m, 4H).

Example 25

N,N-diethylamido-2-methyl-2-thiopseudourea:To a mixture of sulfate of 2-methyl-2-thiopseudourea (2.0 g, 7,18 mmol) in water (3 ml) was added utilizationa (1,137 ml, 14,37 mmol)and then was added dropwise 6 N. NaOH to achieve a stable pH 8. After incubation for 1 hour at pH 8 biphasic solution was diluted with aqueous saturated sodium bicarbonate and was extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with saturated salt solution and dried over sodium sulfate, and then filtered and concentrated in vacuum to obtain specified in the connection header in the form of caustic oil (1.54 g, 92.7%of). TLC (50% ethyl acetate/methylene chloride) and1H-NMR suggested that this product was a mixture of mono - and diarylpyrimidine.1H-NMR (500 MHz, CDCl3) δ: of 1.18 (m, 2, 6N), 2,31 and 2.41 (2s, 3H), of 3.28 (m, 4H).

Example 26

Complex ethyl ester [5-(4-cyclopropanecarbonyl-imidazol-1-yl)-7-pyrimidine-2-yl-1H-benzoimidazol-2-yl]carbamino acid:To a solution of cyclopropylamine 1-(3-amino-4-nitro-5-pyrimidine-2-ylphenyl)-1H-imidazole-4-carboxylic acid (65 mg, 0,178 mmol) in Meon (10 ml) was added Nickel catalyst of the Raney (2 drops of water suspended solids, catalytic amount) and the resulting suspension was placed for 2 hours in an atmosphere of H2under pressure 45 psi (Parr shaker). The resulting mixture was filtered, concentrated, diluted with 3 ml of buffer with pH=3,5 (obtained from 1 M H2SO4with the addition of NaOAc in a quantity sufficient to bring the pH to 3.5) and was treated with N,N-diethylcarbamoyl-2-methyl-2-thiopseudourea (0,267 ml, 1 M solution of N,N-diethylcarbamoyl-2-methyl-2-thiopseudourea in dioxane) at room temperature. The resulting mixture was boiled under reflux for 5 hours to obtain a heterogeneous suspension. The reaction mixture was cooled to room temperature, diluted with water and added NH4HE is in a quantity sufficient to bring the pH to ˜6,0. Then the solids were filtered and then washed with water, water/methanol 2/1, EtOAc and finally with hexane. The obtained solids suspended in the Meon, was added 2 equivalents methanesulfonic acid and concentrated in vacuum to obtain indicated the data in the connection header (75, 70%) in the form of not-quite-white solid.1H-NMR (DMSO-d6, 500 MHz): 9.28 are (s, 1H), remaining 9.08 (d, 1H), 8,8-7,4 (very broad s, 4H), 8,67 (s, 1H), 8,53 (s, 1H), 8,46 (d, 1H), with 8.05 (d, 1H), to 7.59 (DD, 1H), 4,33 (square, 2H), 2,88 (m, 1H), 2,35 (C, 6N), of 1.34 (t, 3H), 0.76 to (m, 2H), 0,61 (m, 2H).

Example 27

The authors of the present invention were obtained and other compounds of formula I by methods essentially the same methods described in schemes I-IV, in examples 1-26 and known methods. The characteristic data of these compounds are systematized in the following table 3, and these data include data LC/MS (observed) and1H-NMR.

Data1H-NMR systematized in the following table 3, where1H-NMR spectra were obtained at 500 MHz in deuterated DMSO, if it is not specifically mentioned, and it was found that they correspond to the expected structure. The numbers of the compounds correspond to the numbers of the compounds listed in table 2.

Table 3< / br>
Characterization data for selected compounds of the formula
Connection # I-M-1 (observed)M+1 (observed)1H-NMR
16347,2349,21,1 (t, 3H), 3,2 (square, 2H), 6,8 (t, 1H), 7.5 (m, 1H), and 7.7 (s, 1H), and 7.9 (s, 1H)and 8.1 (d, 1H), and 8.3 (s, 1H), and 8.6 (d, 1H), 8,9 (s, 1H), and 9.6 (s, 1H), 10,3 (C, 1)
20360,3362,3(CD3OD): 8,89 (DD, 1H), 8,51 (DD, 1H), 8,42-8,29 (Sirs, 1H), 8,18 (DDD, 1H), 7,94-to 7.77 (Sirs, 1H), 7,63 (Sirs), 7,58 (Sirs, 1H), 7,53 (DD, 1H), 3,32 (square, 2H), of 2.21 (s, 3H), of 1.23 (t, 3H)
24391,3to 393.3of 1.13 (t, 3H)and 1.3 (t, 3H), 3,24 (square, 2H), 3,37 (square, 2H), 7,82 (s, 1H), 7,82 (s, 1H), of 7.96 (t, 1H), 8,19 (s, 1H), 8,56 (s, 1H), to 8.62 (d, 1H), 8,82 (d, 1H), 9.15, with (s, 1H), 11,02 (s, 1H)
42390,3392,2of 1.13 (t, 3H), of 2.45 (s, 3H), 3,23 (square, 2H), 3.46 in (s, 3H), return of 6.58 (m, 4H), 7,78 (m, 3H), 9,11 (s, 1H), 10,51 (s, 1H), 12,18 (s, 1H)
43--to 1.15 (t, 3H), of 3.25 (m, 2H), 3,35 (s, 3H), 4,6 (s, 2H), and 7.4 (Sirs, 1H), 7,55 (s, 1H), 7,8 (m, 1H), 8.0 a (d, 1H), with 8.05 (d, 1H), and 8.6 (m, 1H), 8,7 (m, 1H), and 9.2 (s, 1H), 10,4 (Sirs, 1H)
49--of 1.3 (t, 3H), 4,3 (square, 2H), 6,65 (t, 1H), of 7.75 (d, 1H), a 7.85 (DD, 1H), and 7.9 (s, 1H), with 8.05 (d, 1H), and 8.5 (d, 1H), up 8.75 (DD, 1H), and 9.1 (s, 1H), 11,7 (Sirs, 1H)
50377,2379,1of 1.23 (t, 3H), 2,89 (s, 3H), 3,36 (square, 2H), to 7.93 (d, 1H), 8,16 (d, 1H), compared to 8.26 (d, 1H), with 8.33 (d, 1H), 8,86 (d, 1H), 8,97 (d, 1H), of 9.30 (d, 1H)
51--1,1 (t, 3H), 1,25 (t, 3H), 3,25 (square, 2H), 3,37 (s, 3H), 4,05 (square, 2H), 6,6 (m, 4H), of 7.65 (s, 1H), 7,9 (m, 2H), 9,1 (Sirs, 1H), 10,2 (Sirs, 1H), 11.8 in (Sirs, 1H)
54--0,5 (m, 2H), 0,8 (m, 2H), and 2.7 (m, 1H), 6,4 (Sirs, 1H), 6,7 (m, 1H), of 7.75 (s, 1H), 7,8 (m, 1H), a 7.85 (s, 1H), with 8.05 (m, 1H), 8,5 (W is D.C, 1H), and 8.7 (m, 1H), 9,05 (s, 1H), 9.15, with (s, 1H), 10,2 (Sirs, 1H)
55--to 1.15 (t, 3H), of 3.25 (m, 2H), 7,25 (m, 1H), 7.5 (Sirs, 1H), and 7.7 (m, 1H), a 7.85 (s, 1H), and 8.3 (s, 1H), and 8.4 (m, 1H), 8,7 (m, 2H), cent to 8.85 (s, 1H), and 9.1 (s, 1H), 9,15 (DD, 1H), 10,5 (Sirs, 1H)
57377,1to 379.2the remaining 9.08 (d, 1H), 8,48 (Sirs, 1H), 8,13 (d, 1H), 7,95 (d, 1H), 7,88 (s, 1H), 7,25 (d, 1H), 6.75 in (d, 1H), only 6.64 (s, 1H), 6,62 (DD, 1H), 6,4-5,7 (Sirs, 2H), 5,69 (square, 2H), 3,48 (s, 3H), of 1.48 (t, 3H)
61--1,13 (n, 3H), of 2.38 (s, 3H), 3,24 (square, 2H) are 5.36 (s, 2H), of 6.71 (m, 2H), 6,83 (s, 1H), 7,18 (d, 2H), 7,28 (m, 1H), 7,38 (m, 2H), 7,76 (s, 1H), 7,92 (s, 2H), 8,30 (s, 1H), remaining 9.08 (s, 1H), 11,50 (s, 1H)
62404,3406,312,15, 11,81 (s, 1H), 10,34, of 9.99 (s, 1H), 9,13, 8,99 (s, 1H), 7,99-7,81 (m, 3H), 7,68 (s, 1H), 7,30-6,59 (m, 4H), 5,09 (m, 1H), 3,23 (t, 2H), of 1.33 (d, 6H), of 1.13 (t, 3H)
63--to 1.15 (t, 3H), of 2.44 (s, 3H), 3,25 (square, 2H) 5,44 (s, 2H), 6,70 (m, 3H), 7,40 (d, 1H), 7,49 (t, 1H), of 7.75 (s, 1H), a 7.85 (m, 1H), 7,97 (s, 2H), 8,12 (s, 1H), at 8.60 (d, 1H), which is 9.09 (s, 1H), 11,21 (s, 1H)
64--1,2 (t, 3H), 2,2 (m, 2H), 3,3 (m, 2H), 3,65 (m, 2H), 4,1 (t, 2H), of 7.75 (s, 1H), to 7.84 (s, 1H), 7,87 (s, 1H), 7,8 (m, 1H), 8,5 (m, 1H), 8,65 (m, 1H), and 9.0 (s, 1H)
65423,1425,1(MeOH-d4and CDCl3): 8,30-a 7.85 (m, 4H), 6,78 (s, 1H), return of 6.58 (s, 1H), 3,60 (s, 3H), 3,37 (square, 2H), 2,80 (s, 3H), 1,25 (t, 3H)
67--to 1.15 (t,6H), 3,45 (square, 4H), 6,7 (s, 1H), and 7.7 (m, 2H), and 7.9 (s, 1H)and 8.1 (s, 1H), and 8.4 (m, 1H), 8,7 (m, 1H), 9,1 (m, 2H), 10,6 (Sirs, 1H)
68453,2to 455.212,17, 11.81 (s, 1H), 10,35, of 9.99 (s, 1H), 9,13, of 9.00 (s, 1H), charged 8.52 (s, 1H), 7,99-of 7.69 (m, 5H), 7,32-7,27 (m, 2H), 6,93-6,59 (m, 4H), 5,23 (s, 2H), 3,22 (square, 2H), 1,13 (t, 3H)
69407,3409,2(MeOH-d4, HCl salt): to 8.62 (s, 1H), of 7.96-to 7.93 (m, 2H), to 7.59 (s, 1H), to 6.67 (s, 1H), of 5.81 (s, 1H), 3,45, 3,39 (s, 3H), 3,36 (square, 2H), 3,28, 3,20 (s, 3H), of 1.23 (t, 3H)
70--to 1.15 (t, 3H), of 1.35 (t, 3H), 3,25 (square, 2H), 4,3 (square, 2H), 7,1 (Sirs, 1H), a 7.85 (s, 1H), with 8.05 (m, 1H), and 8.2 (s, 1H), and 8.3 (s, 1H), 8,8 (m, 1H), cent to 8.85 (d, 1H), 9,25 (s, 1H), 9,65 (s, 1H), 10,7 (Sirs, 1H)
71416,2418,20,84 (m, 2H), 1.14 in (m, 5H), to 2.55 (s, 3H), 2.91 in (m, 1H), 3,26 (square, 2H), 6,59 (s, 1H), 6,65 (s, 1H), 6,69 (s, 1H), 7,65 (s, 1H), 7,81 (m, 1H), of 7.97 (s, 1H), 8,07 (s, 1H), 9,07 (s, 1H), 11,59 (s, 1H)
72--1,1 (t, 3H), 3,2 (square, 2H), 7,1 (Sirs, 1H), and 7.8 (s, 1H), 8.0 a (m, 1H), and 8.2 (s, 1H), of 8.25 (s, 1H), 8,7 (m, 1H), 8,8 (m, 1H), and 9.2 (s, 1H), and 9.6 (s, 1H), 10,7 (Sirs, 1H)
73USD 448,2450,2(CD3OD): 1.18 to 1.26 in (m, 9H), with 3.27 (s, 3H), 3,36 (square, 2H), is 4.21 (s, 2H), 6,65 of 6.68 (m, 1H), 6.90 to-6,94 (m, 1H), 6,98-7,01 (m, 1H), 7,78-to 7.84 (m, 2H), 7,93-of 7.96 (m, 1H), 8,09-8,11 (m, 1H), total of 8.74-8,76 (m, 1H)
74434,3436,3(CD3OD): 1,21-of 1.27 (m, 9H), 3,36 (square, 2H), 4,17 (s, 2H), 6,65 of 6.68 (m, 1H), 6,95-6,99 (m, 1H), 7,00-7,03 (m, 1H), 7,79-of 7.82 (m, 1H), 7,89 (d, H), 7,94-of 7.96 (m, 1H), 8,09-8,11 (m, 1H), 8,73-8,76 (m, 1H)
75--1,1 (t, 3H), 3,0 (Sirs, 3H), of 3.25 (m, 5H), 7,0 (Sirs, 1H), to 7.75 (m, 2H), with 8.05 (s, 1H), 8,15 (s, 1H), 8,45 (m, 1H), 8,7 (m, 1H), and 9.1 (s, 1H), and 9.4 (s, 1H), 10,4 (Sirs, 1H)
77448,3450,2(CD3OD): δ to 1.24 (t, 3H), of 1.27 (d, 3H), of 1.47 (d, 3H), 3,36 (square, 2H), 3,37 (s, 3H), to 3.58-to 3.67 (m, 1H), to 5.21 is 5.28 (m, 1H), 6,68-of 6.71 (m, 1H), 7,80 (d, 1H), a 7.85 (s, 1H), 7.95 is-to 7.99 (m, 2H), of 8.27 (s, 1H), scored 8.38 (d, 1H), 8,78-8,82 (m, 1H)
78448,3450,3(CD3OD): δ to 1.24 (t, 3H), of 1.31 (d, 3H)and 1.51 (d, 3H), 3,38 (square, 2H), 3,42 (s, 3H), 3,66-to 3.73 (m, 1H), 5,44-the 5.51 (m, 1H), 6,68-of 6.71 (m, 1H), 7,94 (d, 1H), of 7.96-7,98 (m, 1H), 8,03 (s, 1H), 8,07 (s, 1H), 8,32 (s, 1H), 8,43 (d, 1H), 8,81-8,86 (m, 1H)
79434,3436,2(CD3OD): δ to 1.24 (t, 3H), of 1.32 (d, 3H), of 1.50 (d, 3H), 3,37 (square, 2H), 3,93-was 4.02 (m, 1H), 5,14-5,22 (m, 1H), 6,67-of 6.71 (m, 1H), of 7.90 (d, 1H), 7.95 is-7,98 (m, 1H), 8,02 (s, 1H), 8,04 (s, 1H), 8,32 (s, 1H), to 8.41 (d, 1H), 8,81 cent to 8.85 (m, 1H)
82428,2430,19,0 (m, 1H), and 8.6 (d, 1H), and 8.4 (m, 1H), 8,1-8,2 (m, 2H), 8,0 (m, 1H), 7,8 (m, 1H), 7.5 (m, 2H), and 6.6 (s, 1H), 4,8 (s, 1H), to 2.55 (s, 3H), of 3.25 (m, 2H), 2,1 (s, 3H), 1,1 (t, 3H)
83417,1419,1br11.01 (Sirs, 1H), 9,10 (d, 1H), of 8.37 (s, 1H), 8,19 (s, 1H), of 7.97 (s, 1H), 7,78 (Sirs, 1H), 7,58 (m, 1H), was 7.08 (s, 1H), of 6.68 (m, 1H), 3,88 (DD, 2H), 3,22 (DQC., 2H), 2,99 (DD, 2H), 1.91 a (DDD, 2H), of 1.85 (DDD, 2H), 1,11 (t, 3H)
84377,2to 379.2(MeOD-d 3): 8,72 (Sirs, 1H), 8,58 (s, 1H), 8,40 (s, 1H), 8,19 (s, 1H), 7,95 (s, 1H), 7,14 (s, 1H), of 6.68 (s, 1H), 3,60 (s, 3H), 3,21 (square, 2H), 1,24 (t, 3H)
85430,2432,2(MeOD-d3, Sol): 8,64 (d, 1H), 8,14 (s, 1H), 8,00 (s, 1H), of 7.97 (d, 1H), to 7.64 (s, 1H), 6,66 (DD, 1H), 6,51 (s, 1H), with 3.89 (s, 3H), of 3.48 (s, 3H), 3,37 (square, 2H), 1,24 (t, 3H)
87360,1362,1MeOD-d3, of 1.24 (t, 3H), 2,42 (s, 3H), 3,38 (square, 2H), 6.87 in (s, 1H), 7,94 (s, 1H), 8,15 (m, 2H), cent to 8.85 (d, 1H), 8,98 (d, 1H), of 9.30 (s, 1H)
883883909,27 (s, 2H), 9,20 (s, 1H), of 8.27 (s, 1H), 8,10 (m, 1H), 7,94 (s, H), 7,92 (d, 1H), 6,95 (d, 1H), 4,10 (s, 3H), of 3.25 (m, 2H), 1,11 (t, 3H)
89386,9389,2(CD3OD): 8,92-of 6.96 (m, 9ArH), to 3.99 (s, 3H), 3,36 (square, 2H), 1,24 (t, 3H)
90457,1459,2-
91429,2431,2(CD3OD): 8,97 (s, 1H), 8,89 (d, 1H), 8,49 (d, 1H), of 8.37 (m, 2H), by 8.22 (DDD, 1H), to 7.93 (d, 1H), to 7.64 (DD, 1H), 3,38 (square, 2H), 2.91 in (m, 1H), 1,25 (t, H)to 0.88 (m, 2H), 0.67 and (m, 2H)
92360,13362,19to 1.15 (t, 3H), of 3.25 (m, 2H), 3,9 (s, 3H), 7,15 (m, 1H), 7,65 (m, 1H), and 7.8 (s, 1H), and 8.0 (s, 1H), and 8.2 (m, 1H), 8,3 (m, 1H), 8,65 (m, 1H), 9,0 (m, 2H), 10,3 (Sirs, 1H)
93371373of 1.12 (t,3H), of 3.25 (m, 2H), 4.2V (Sirs, 2H), 7,02-7,25 (m, 1H), 7.5 (m, 1H), 7,81 (m, 1H), 8,08 (t, 1H), they were 8.22 (m, 1H), 8,61-8,48 (m, 2H), and 8.4 (d, 1H), 8,46 (s, 1H)
94 430432to 0.92 (d, 6H), of 1.12 (m, 3H), of 2.23 (m, 1H), and 2.83 (d, 2H), 3,35 (m, 2H), 7.5 (m, 1H), to 7.61 (Sirs, 1H), 7,89 (s, 1H), 8,1 (m, 1H), and 8.4 (s, 1H), 8,58 (m, 1H), 8,78 (Sirs, 1H), 8.3 (l, 1H)
95431,03433,2(CD3OD): 1,2 (7, 3H), 3,3 (square, 2H), and 3.8 (m, 2H), 4,6 (m, 2H), and 7.4 (m, 1H), 7,8 (m, 1H), and 8.0 (s, 1H), 8,3 (m, 2H), 8,5 (m, 1H), 8,7 (m, 2H), and 9.1 (s, 1H)
96507,2509,2(CD3OD): 8,9 (d, 1H), 8,55 (d, 1H), and 8.4 (s, 1H), 8,3 (m, 1H), and 8.0 (s, 1H), and 7.7 (m, 1H), and 7.3 (t, 1H), 7,0 (s, 2H), 6,85 (d, 1H), 6,7 (d, 2H), and 5.5 (s, 2H), and 3.7 (s, 3H), 3,3 (square, 2H), and 2.5 (s, 3H), of 1.25 (t, 3H)
97401403and 9.1 (s, 1H), and 8.6 (d, 2H), 8,3 (m, 1H), and 8.1 (s, 1H), and 7.9 (s, 1H), and 7.8 (s, 1H) 7.5 (m, 1H), 7,0 (d, 1H), 4,3 (m, 2H), 3,3 (m, 2H), 1,4 (t, 3H), 1,1 (t, 3H)
98497,03499,18of 1.16 (t, 3H), 3,25 (square, 2H) of 4.44 (d, 2H) 7,17 (t, 2H) 7,38 (m, 2H), 7,53 (t, 1H) 7,79 (m, 1H), 7,87 (s, 1H), 8,10 (t, 1H), 8,32 (s, 1H), 8,51 (s, 1H), to 8.57 (d, 1H), 8,77 (s, 1H), 8,82 (d, 1H) to 8.94 (t, 1H), 11,10 (Sirs, 1H)
99432434-
100418,25420,151,1 (t, 3H), 3,2 (m, 2H), 3,95 (s, 3H), 4,1 (s, 2H), 7,2 (Sirs, 1H), 7,25 (Sirs, 1H), and 7.9 (s, 1H), and 8.2 (m, 1H), of 8.25 (s, 1H), and 8.7 (d, 1H), 9,05 (s, 2H), 10,4 (Sirs, 1H)
1014314338,65 (d, 1H), 8,28 (s, 1H), 8,24 (s, 1H), 7,98 (d, 1H), 7,78 (d, 1H), 7,38 (m, 1H), 6,93 (s, 1H), 6.89 in (DD, 1H), 4,51 (square, 2H), 3,63 (s, 3H), 3,35 (square, 2H), 1.55V (t, 3H), 1,22 (t, 3H)
102/td> 3753778,86 (d, 1H), 8,69 (m, 1H), charged 8.52 (d, 1H), 8,16 (m, 2H), 7,79 (m, 2H), 7,56 (m, 1H), 7,50 (m, 1H), 3,55 (m, 2H), of 1.23 (t, 3H)
103430432,18,87 (Sirs, 1H), 8,81 (d, 1H), 8,66 (Sirs, 1H), 8,49 (s, 1H), 8,39 (Sirs, 1H), of 8.25 (d, 1H), 8,09 (DDD, 1H), 7,87 (d, 1H), 7,52 (DD, 1H), 5,3 (very Sirs, 5H), 4,29 (square, 2H), 2,85 (m, 1H), 1,31 (t, 3H), 0,72 (m, 2H), 0,63 (m)
104417,19419,141,1 (t, 3H), 3,2 (square, 2H), 3.45 points (s, 3H), 4,1 (s, 3H), 6,7 (DD, 1H), 6,85 (d, 1H), 7,15 (Sirs, 1H), 7,35 (Sirs, 1H), and 7.8 (d, 1H), 7,95 (s, 1H), and 8.2 (s, 1H), 8.4V (Sirs, 1H), and 8.7 (d, 1H), 10,5 (Sirs, 1H)
1054064088,97 (Sirs, 2H), at 8.60 (d, 1H), 7,99 (Sirs, 1H), of 7.96 (m, 1H), 7,81 (Sirs, 1H), EUR 7.57 (m, 1H), 3,98 (s, 3H), of 3.25 (m, 2H), 1,11 (t, 3H)
106508,2510,21,1 (t, 3H), and 2.4 (s, 3H), 3,2 (square, 2H), 4,1 (s, 3H), 5,4 (s, 2H), 6,65 (s, 1H), 6.75 in (s, 1H), 7,15 (Sirs, 1H), and 7.3 (m, 2H), 7,35 (m, 1H), 7,8 (m, 1H), 7,95 (s, 1H), of 8.25 (s, 1H), 8,35 (Sirs, 1H), 8,5 (m, 1H), up 8.75 (m, 1H), 10,5 (Sirs, 1H)
107495,2497,2of 8.8 (m, 1H), and 8.2 (m, 1H), and 7.9 (s, 1H), 7,8 (m, 1H), and 7.4 (m, 2H), 7,35 (d, 2H), 7,25 (d, 2H), 6,7-6,8 (m, 2H), 5,3 (2, 2H), 4,0 (m, 1H), 3,4 (kV, 2H), and 2.4 (s, 3H), 1,1 (t, 3H)
1084174199,12 (Sirs, 1H), at 8.60 (d, 1H), 8,39 (m, 1H), at 8.36 (s, 1H), of 8.25 (s, 1H), 7,89 (s, 1H), of 7.70 (DD, 1H), 7,41 (m, 1H), 4,13 (s, 3H), 3,98 (s, 3H), 3,26 (m, 2H)and 1.15 (t, 3H)
109385,3360,1(CD 3OD): being 9.61 (d, 1H), which 9.22 (d, 1H), 8,83-8,79 (m, 3H), 8,65 (d, 1H), of 8.47 (d, 1H), 8,02 (DD, 1H), 8,00 (s, 1H), 3,37 (square, 2H), 1,24 (t, 3H)
110388,3390,2(CDCl3): 14,05 (Sirs, 1H), 12,85 (Sirs, 1H), of 8.37 (t, 1H), of 7.97 (d, 1H), 7,88 (d, 1H), 7,79-7,74 (m, 2H), 7,63 (DD, 1H), 7,46 (d, 1H), 6,62 (DD, 1H), 5,75 (Sirs, 1H), 3.45 points is 3.40 (m, 2H), 1.27mm (t, 3H)
111492,3494,1to 10.3 (s, 1H), 8,9 (d, 1H), and 8.6 (m, 1H), and 8.5 (d, 1H), and 8.2 (s, 1H), with 8.05 (t, 1H), 7,8-7,9 (m, 2H), 7.5 (m, 2H), and 7.4 (d, 1H), and 7.3 (m, 1H), 6,7 (s, 1H), and 6.6 (s, 1H), 3,3 (square, 2H), and 1.9 (d, 3H), 1.1 to 1.2 (t, 3H)
112475,2477,2to 10.62 (s, 1H), total of 8.74 (d, 1H), 8,65 (s, 1H), 8,40 (s, 1H), 8,28 (s, 1H), 8,23 (s, 1H), 7,87 (s, 1H), 7,43 (s, 1H), 7,32 (m, 2H), 5,52-to 4.41 (Sirs, 3H), 4,10 (s, 3H), 3,24 (dt, 2H), of 1.41 (s, 9H), of 1.13 (t, 3H)
113494,2496,2(CD3OD): 9,06 (s, 1H), 8,93 (d, 1H), 8,71 (d, 1H), and 8.50 (m, 2H), 8,39 (s, 1H), 8,00 (s, 1H), 7,87 (DD, 1H), 7,42 (d, 2H), 7,35 (DD, 2H), 7,25 (DD, 1H), 5,27 (square, 1H), to 4.41 (square, 2H), of 1.62 (d, 3H), of 1.42 (t, 3H)
114370,2372,212,09 and 12,74 (s, 1H), of 10.25 and 9,94 (s, 1H), 9,12 and to 8.94 (s, 1H), 8,35 return of 6.58 (m, 9H), 3,24 (m, 2H), 1,13 (t, 3H)
115442,1444,3(CD3OD): 8,65 (d, 1H), 7,94 (s, 1H), to $ 7.91 (d, 1H), 7,72 (d, 2H), 7,66 (s, 1H), 7,40 (d, 2H), 6,63 (DD, 1H), to 4.52 (s, 2H), 3,40 (t, 2H), 3,35 (square, 2H), 2,47 (t, 2H), 2,09-2,03 (m, 2H), 1,24 (t, 3H)
116382384-
117415 4179,17 (Sirs, 1H), and 9.0 (m, 1H), 8,98 (d, 1H), 8,72 (d, 1H), 8,55 (m, 1H), scored 8.38 (s, 1H), 7,94 (s, 1H), 7,86 (d, 1H), 7,79 (m, 1H), of 3.97 (s, 3H), of 3.27 (m, 2H)and 1.15 (t, 3H)
118401403-
119403,3405,2(CD3OD): 8,78 (s, 1H), 8,67 (d, 1H), of 8.37 (d, 1H), 8,24 (d, 1H), they were 8.22 (s, 1H), 8,04 (d, 1H), to $ 7.91 (s, 1H), to 7.67 (DD, 1H), 7,40 (DD, 1H), 4,22 (s, 3H), 3,34 (square, 2H), of 1.23 (t, 3H)
120434,32436,231,1 (t, 3H), and 2.8 (s, 6H), 3,2 (m, 2H), 3,4 (s, 3H), 4,6 (s, 2H), and 6.6 (d, 1H), 6,8 (s, 1H), 7,2 (Sirs, 1H), and 7.6 (s, 1H), and 7.8 (d, 1H), and 7.9 (s, 1H), 7,95 (s, 1H), 10.0 g (Sirs, 1H), 10,2 (Sirs, 1H)
121414416(CD3OD): 9,40 (Sirs, 1H), 9,07 (d, 1H), 8,98 (d, 1H), 8,91 (d, 1H), 8,80 (s, 1H), at 8.60 (s, 1H), 8,24 (DD, 1H), 8,11 (d, 1H), to 7.84 (DD, 1H), 3,35 (m, 2H), 3,01 (s, 3H), 1,25 (t, 3H)
122415417-
123435,28437,26of 1.3 (t, 3H), and 2.8 (s, 6H), 3,5 (s, 3H), 4.2V (square, 2H), 4,6 (s, 2H), and 6.6 (DD, 1H), 6,7 (s, 1H), and 7.7 (s, 1H), and 7.8 (d, 1H), 8.0 a (m, 2H), 10,1 (Sirs, 1H), 11,7 (Sirs, 1H)
124431,2433,29.28 are (s, 1H), remaining 9.08 (d, 1H), 8,8-7,4 (very Sirs, 4H), 8,67 (s, 1H), 8,53 (s, 1H), 8,46 (d, 1H), with 8.05 (d, 1H), to 7.59 (DD, 1H), 4,33 (square, 2H), 2,88 (m, 1H), 2,35 (s, 6H), of 1.34 (t, 3H), 0.76 to (m, 2H), and 0.61 (m, 2H)
125447,4-9,10 (s, 1H), at 8.60 (d, 1H), of 8.47 (m, 2H), 7,95 (s, 1H), 7,83 (s, 1H), 7,12 (d, 1H), 5,2-3,6 (SIRM, 7H), and 2.6 (m, 1H), of 1.30 (t, 3H), 0.75 in (m, 2H), 0.64 in (m, 2H)
126439,2441,2(CDCl3): 13,89 (Sirs, 1H), 12,89 (Sirs, 1H), 8,28 (d, 1H), of 8.25 (d, 1H), of 7.96 (d, 1H), 7,74 (s, 1H), 7,69-the 7.43 (m, 6H), 7,40 (s, 1H), only 6.64 (DD, 1H), 6,11 (Sirs, 1H), 3.46 in is 3.40 (m, 2H), 1.27mm (t, 3H)
127418,2420,2(CD3OD): 9,72 (d, 1H), 8,87 (d, 1H), 8,82 (d, 1H), 8,11 (d, 1H), of 8.09 (d, 1H), a 7.85 (d, 1H), 7,39 (d, 1H), was 7.36 (d, 1H), 4,43 (square, 2H), 3,35 (square, 2H), of 1.44 (t, 3H), of 1.24 (t, 3H)
128449,8452,1(CD3OD): of 9.21 (d, 1H), 8,83 (DDD, 1H), 8,81 (DD, 1H), 8,68 (d, 1H), compared to 8.26 (d, 1H), 8,18 (d, 1H), 8,07 (DD, 1H), with 8.05 (d, 1H), 7,50 (DD, 1H), 3,36 (square, 2H), 3,34 (s, 3H), of 1.23 (t, 3H)
129--9,31 (s, 1H), remaining 9.08 (d, 2H), 8,63 (s, 1H), 8,43 (d, 1H), 8,02 (d, 1H), 7,89 (s, 1H), EUR 7.57 (t, 1H), 8,8-6,6 (very Sirs, 4H), or 4.31 (square, 2H), 2,32 (s, 6H), of 1.42 (s, 9H), of 1.33 (t, 3H)
130495,4497,29,07 (d, 2H), 8,73 (d, 1H), 8,56 (s, 1H), 8,44 (d, 1H), 8,03 (d, 1H), EUR 7.57 (t, 3H), 7,44 (d, 2H), was 7.36 (DD, 2H), 7,26 (DD, 1H), 6,95-5,90 (very Sirs, 5H), 5,18 (dt, 1H), 4,32 (square, 2H), 2,32 (s, 6H), of 1.53 (d, 3H), of 1.33 (t, 3H)
131432434(CD3OD): a 1.08 (d, 6H), USD 1.43 (t, 3H), 2,33 (m, 1H), 2.91 in (d, 2H), 4,45 (square, 2H), 7,53 (t, 1H), 8,08 (s, 1H), 8,79 (s, 1H), to 8.94 (s, 1H), 9,05 (d, 2H), and 9.5 (s, 1H)
132514,23516,238,84 (d, 1H), 8,81-8,83 (m, 1H), 8,35 (s, 1H), of 8.06 (DD, 1H), of 7.90 (DD, 1H), 7,80 (d, 1H), 6,80 (Sirs, 1H), 6,70 (d, 1H), 4,30 (square, 2H), 3,42-of 3.54 (m,4H), of 3.48 (s, 3H), 3,12-3,17 (m, 4H), of 2.81 (d, 3H), of 1.32 (t, 3H) ppm
133501,33503,26-
134521,6523,2(CD3OD): 8,82 (s, 1H), 8,46 (d, 1H), 8.30 to (s, 1H), 8,13 (DD, 1H), of 7.90 (s, 1H), 7,55 (DD, 1H), 7,28 (DD, 1H), 6,86-6,77 (m, 4H), 6,74 (s, 1H), of 3.77 (s, 3H), 3,36 (square, 2H), 2,41 (Sirs, 3H), of 1.97 (d, 3H), 1,24 (t, 3H)
135470,3472,5(CD3OD): cent to 8.85 (Sirs, 1H), 8,45 (d, 1H), 8.34 per (DD, 1H), compared to 8.26 (DD, 1H), 8,13 (DDD, 1H), of 7.96 (DD, 1H), 7,56 (DD, 1H), 7,43 (DD, 1H), 7.29 trend and then 7.20 (s, 1H), 5,49 (m, 1H), 3,66 is 3.25 (m, 4H), 3,38 (square, 2H), equal to 2.94 (2s, 3H), 2,52 (m, 1H), of 2.38 (m, 1H), 2,15 (m, 1H)
136521,3523,3(CD3OD): 8,81 (d, 1H), 8,43 (d, 1H), of 8.27 (s, 1H), 8,11 (DDD, 1H), 7,88 (s, 1H), 7,54 (DD, 1H), 7,28 (DD, 1H), 6.87 in (d, 1H), at 6.84 (d, 1H), for 6.81 (s, 1H), 4,42 (square, 2H), of 3.78 (s, 3H), 2,50 (Sirs, 3H), from 2.00 (d, 3H), of 1.41 (t, 3H)
137is 522.6524,2(CD3OD): 8,90 (d, 1H), 8,81 (d, 1H), 8,49 (DD, 1H), to 8.41 (s, 1H), of 8.06 (s, 1H), to 7.84 (DD, 1H), 7,29 (DD, 1H), 6,99 (Sirs, 1H), 6,92 (s, 1H), 6.87 in (d, 1H), at 6.84 (d, 1H), for 6.81 (s, 1H), 4,42 (square, 2H), of 3.78 (s, 3H), 2,50 (Sirs, 3H), from 2.00 (d, 3H), of 1.41 (t, 3H)
1385255271,2 (t, 3H), 1.5 a (d, 3H), of 3.73 (s, 3H), 4,3 (square, 2H), 5,13 (m, 1H), 6,8 (d, 1H), 7,0 (m, 2H), 7,24 (t, 1H), 7,53 (t, 1H), to 7.93 (s, 1H), 8,24 (s, 1H), 8,32 (m, 2H), and 8.4 (s, 1H), remaining 9.08 (s, 1H), to 11.79 (Sirs, 1H), 12,18 (s, 1H)
139522,5524,2(CD3OD): 8,86 (d, 1H), total of 8.74 (d, 1H), to 8.41 (DD, 1H), 8,35 (s, 1H, to 7.99 (s, 1H), 7,78 (DD, 1H), 7,28 (DD, 1H), 6,85 (d, 1H), 6,83 (d, 1H), 6,80 (s, 2H), 6,76 (s, 1H), to 4.41 (square, 2H), of 3.77 (s, 3H), 2,41 (Sirs, 3H), of 1.97 (d, 3H), of 1.41 (t, 3H)
140499501-
141425,3428,2(CD3OD): 8,8 (d, 1H), 8,35 (d, 1H), and 8.2 (s, 1H), 8,1 (t, 1H), and 8.0 (s, 1H), 7,9 (d, 1H), and 7.8 (s, 1H), 7,65 is 7.7 (DD, 1H), 7.5 (t, 1H), 7,49 (d, 1H), 4,6 (s, 2H), 4,45 (s, 1H), 3,4 (square, 2H), 3,2 (s, 3H), 3.15 in (s, 1H), 1,2 (t, 3H)
142426,3428,2(CD3OD): 8,8 (d, 1H), and 8.6 (d, 1H), 8,3 (m, 2H), and 8.1 (s, 1H), 8.0 a (d, 1H), and 7.9 (s, 1H), 7.7 (d, 1H), 4,6 (s, 2H), 4,45 (s, 1H), 4.4 to 4.5 (square, 2H), and 3.3 (s, 3H), 3.15 in (s, 1H), 1,4 (t, 3H)
143498500-
144497499(CD3OD): to 1.42 (t, 3H), of 1.84 (d, 3H), 4,49 (square, 2H), to 6.43 (square, 1H), 7,58 (t, 1H), 8,03 (t, 1H), 8,08 (s, 1H), 8,23 (d, 1H), 8,67 (t, 1H), 8,73 (s, 1H), 8,39 (d, 2H), 8,88 (d, 2H), 9,06 (s, 2H)
145457459(CD3OD): 1,4 (t, 3H), 3,48 (d, 4H), to 3.99 (s, 4H), to 4.41 (s, 2H), 7.7 (d, 1H), 8,07 (s, 1H) 8,05 (m, 3H), 8,73 (s, 1H), 8,9 (s, 1H), 9,12 (s, 1H)
146-502,21(CD3OD): 8,89 (s, 1H), 8,49 (d, 1H), 8,45 (s, 1H), they were 8.22 (d, 1H), 8,11 (d, 1H), of 8.06 (s, 1H), 7,47 (shirt, 1H), was 7.36 (Sirs, 1H), 3,91 (s, 3H), 3,68-3,89 (SIRM, 8H), 3,38 (square, 2H), 1,25 (t, 3H) ppm
147-487,2(CD3OD): 8,99 (s, 1H), 8,54 (d, 1H), 8,46 (s, 1H), 8,27 (d, 1H), 8,01 (s, 1H), 7,85 (Sirs, H), 6,97 (Sirs, 1H), 6,91 (Sirs, 1H), 4,47 (square, 2H), 3,66 at 3.69 (m, 5H), 3,59-3,62 (m, 2H), 2,01-to 2.06 (m, 2H), 1,96 is 2.00 (m, 2H), USD 1.43 (t, 3H) ppm
148375377(CD3OD): 9,02 (t, 2H), 8,98 (s, 2H), 8,82 (d, 1H), with 8.05 (d, 1H), 7,54 (t, 1H), 4,48 (square, 2H), of 1.44 (t, 3H)
149-486,22(CD3OD): 8,98 (s, 1H), 8,44 (m, 1H), scored 8.38 (Sirs, 1H), 8,19 (shirt, 1H), 8,02 (Sirs, 1H), 7,98 (Sirs, 1H), 7,15 (Sirs, 1H), 7,13 (Sirs, 1H), 3,79 (Sirs, 3H), to 3.67 (m, 2H), 3,61 (m, 2H), 3,37 (square, 2H), 2.05 is (m, 2H), 2,00 (m, 2H), of 1.25 (t, 3H)
150494,3496,2(CD3OD): 9,0 (d, 2H), and 8.8 (s, 1H), and 8.6 (d, 1H), and 8.2 (t, 1H), 7,95 (s, 1H), and 7.8 (d, 1H), 7,65 (t, 1H), 7.5 (t, 1H), 6,9 (s, 1H), and 6.6 (s, 1H), 6,1 (m, 1H), 4,4 (square, 2H), and 2.7 (s, 3H), of 2.05 (d, 3H)that 1.4 (t, 3H)
151493,4495,2(CD3OD): 8,95 (d, 2H), and 8.6 (s, 1H), and 8.5 (d, 1H), 8,1 (t, 1H), and 7.8 (s, 1H), 7.7 (d, 1H), 7.5 (t, 1H), and 7.4 (t, 1H), 6,8 (s, 1H), and 6.6 (s, 1H), 6,0 (m, 1H), 3,35 (square, 2H), and 2.6 (s, 3H), 2.0 (d, 3H), and 1.2 (t, 3H)
152-462,21(CD3OD): 8,90 (d, 1H), 8,81 (d, 1H), 8,49 (m, 1H), 8,39 (d, 1H), 8,04 (d, 1H), a 7.85 (m, 1H), 7,02 (Sirs, 1H), 6.90 to (d, 1H), 4,82 (m, 1H, under the peak of water), 4,42 (square, 2H), 4,29 (m, 1H), and 3.72 (m, 1H), 3,35 (s, 3H), 2,65 & 2,90 (s, 3H), 1
153504,3506,312,14 (s, 1H), 11.11 (with, 1H), 9,59 (s, 1H), remaining 9.08 (d, 2H), scored 8.38 (s, 1H), with 8.33 (d, 1H), they were 8.22 (s, 1H), 7,95 (d, 1H), 7,56 (DD, 1H), 4,32 (square, 2H), 4,12 (Sirs, 4H), 3,62 (Sirs, 4H), 2,46 (Sirs, 2H), 1,31 (DD, 2H), 1,22 (t, 3H)
154 474,3476,310,31 (s, 1H), which is 9.09 (d, 2H), 8,79 (s, 1H), 8,44(s, 1H), 8,42 (s, 1H), 8,00 (s, 1H), 7,68 (t, 2H), 7,7-6,6 (Sirs, 3H), 4,32 (square, 2H), 3,55 (m, 4H), of 3.12 (m, 4H), of 2.34 (s, 6H), of 1.32(t, 3H)
155479,3481,2of 1.33 (t, 3H) a 2.36 (s, 3H) 4,35 (square, 2H) ceiling of 5.60 (s, 2H) 6,84 (s, 1H) to 6.88 (s, 1H) to 7.68 (t, 1H), 7,81 (d, 2H) to 7.99 (s, 1H) compared to 8.26 (t, 1H) 8,35 (s, 1H), 8,78 (d, 1H), 8,89 (d, 3H) 11,75 (Sirs, 2H)
156-461,22(CD3OD): 8,83 (m, 1H), 8,44 (d, 1H), of 8.25 (d, 1H), 8,12 (m, 1H), 7,88 (d, 1H), 7,54 (m, 1H), 6,70 (s, 1H), of 6.68 (s, 1H), and 4.68 (m, 1H), 4,32 (m, 1H), 3,70 (m, 1H), 3,38 (square, 2H), 3,35 (s, 3H), of 2.56 (s, 3H), to 1.60 (d, 3H), of 1.24 (t, 3H) ppm
157486,3488,3(CD3OD): to 1.37 (t, 3H), of 1.57 (m, 4H), and 2.27 (m, 1H), 2,82 (s, 3H), 3,41 (t, 2H), 3.96 points (d, 2H), 4,29 (d, 2H), 4,43 (square, 2H), 7,27 (s, 1H), 7,50 (s, 1H), of 7.90 (t, 1H), 8,17 (s,1H), 8,55 (s, 1H), 8,659 (t, 1H), of 8.95 (d, 1H), which is 9.09 (d, 1H)
158474,3476,3(CD3OD): a 1.08 (d, 6H), of 1.42 (t, 3H), was 2.76 (s, 3H), of 3.57 (m, 1H), 2,82 (t, 2H), 4,42 (m, 4H), 6,98 (s, 1H), 7,05 (s, 1H), 7,86 (t, 1H), of 8.09 (s, 1H), to 8.41 (s, 1H), 8,51 (t, 1H), 8,82 (d, 1H), 8,91 (d, 1H)
159458460(CD3OD): USD 1.43 (t, 3H), 3,48 (Sirs, 24H), 3,99 (Sirs, 4H), 4,48 (1, 2H), 4,63 (s, 2H), 7,55 (t, 1H), 7,71 (d, 1H), and 8.1 (s, 1H), with 8.33 (d, 1H), 8,9 (1H), 9,03 (d, 2H), 9,13 (s, 1H)
160457459(CD3OD): to 1.35 (t, 3H), 3,3-3,5 (m, 6H), 3,99 (Sirs, 4H), to 4.62 (s, 2H), 7,52 (t, 1H), 7.7 (d, 1H), 8,08 (s, 1H), 8,32 (d, 1H), 8,88 (s, 1H), 9,05 (d, 2H), and 9.1 (s, 1H)
161446,28USD 448,21,2 (t, 3H), 3,2 (m, 2H), 3,3 (Sirs, 4H), 3,9 (Sirs, 4H), 4,7 (s, 2H), and 7.7 (s, 1H), 7,8 (Sirs, 1H), 7,95 (m, 1H), and 8.1 (s, 1H), of 8.25 (s, 1H), 8,7 (m, 1H), 8,8 (m, 1H), and 9.2 (s, 1H), 10,6 (Sirs, 1H)
162550,3552,312,32 (s, 1H), 11,18 (s, 1H), remaining 9.08 (d, 2H), to 8.62 (s, 1H), 8,39 (s, 1H), of 8.37 (s, 1H), 7,98 (s, 1H), 7.62mm (m, 2H), 7,58 (DD, 1H), of 7.48 (m, 3H), from 6.4 to 5.9 (Sirs, 3H), of 4.38 (s, 2H), 4,33 (square, 2H), 3,42 (m, 4H), 3.15 in (m, 4H), of 1.35 (t, 3H)
163501,3503,3(CD3OD): 9,1 (d, 1H), 8,8 (t, 1H), and 8.5 (d, 1H), and 8.4 (s, 1H), and 8.3 (s, 1H), and 8.2 (t, 1H), and 7.7 (s, 1H), and 7.5 (s, 1H), and 4.8 (t, 2H), 4,4 (square, 2H), 4,1 (d, 2H), 3,9 (t, 2H, in), 3.75 (d, 2H), and 3.7 (t, 2H), 3,4 (m, 2H), 3,3 (s, 2H), 2,85 (s, 3H), 2,0 (s, 5H), and 1.4 (t, 3H)
164500,4502,3(CD3OD): is 8.75 (d, 1H), 8.3 (l, 1H), and 8.2 (s, 1H), 8.0 to with 8.05 (t, 1H), and 7.8 (s, 1H), 7.5 (t, 1H), 6,8 (s, 1H), 6,7 (s, 1H), 4,5-4,6 (t, 2H), 4.0 (with shirts, 4H), 3,5-3,6 (t, 4H), 3,4 (square, 2H), 3,3 (t, 2H), of 2.6 (s, 3H), 1,2-1,3 (t, 3H)
165474476(CD3OD): 9,04 (d, 1H), 8,71 (d, 1H), 8.34 per (d, 1H), 8,23 (DD, 1H), 7,94 (d, 1H), to 7.84 (m, 1H), 7,65 (d, 1H), EUR 7.57 (m, 1H), 4,56 (s, 2H), 3,98 (t, 4H), of 3.45 (t, 4H), 3,37 (square, 2H), 1,24 (t, 3H)
166475477(CD3OD): 9,07 (d, 1H), 8,72 (d, 1H), 8,49 (d, 1H), 8,28 (DD, 1H), 8,04 (d, 1H), 7,92 (m, 1H), 7,69 (d, 1H), 7,63 (m, 1H), 4,63 (s, 2H), 4,47 (square, 2H), 3,99 (m, 4H), 3,44 (m, 4H), USD 1.43 (t, 3H)
167522,3524,4(CD3OD): to 8.94 (d, 2H), 8,65 (s,1H), the 7.85 (s, 1H), 7,44 (DD, 1H), 7,27 (DD, 1H), at 6.84 (d, 2H), 6,80 (s, 1H), 6,70 (s, 1H), only 6.64 (s, 1H), of 3.77 (s, 3H), 3,36 (square, 2H), 2,39 (Sirs, 3H), 1,96 (d, 3H), of 1.24 (t, 3H)
168-474,3(CD3OD): a 1.45 (t, 3H), of 1.80 (d, 3H), 2,69 (m, 2H), 3,50 (m, 2H), 3,97 (m, 4H), 4,49 (square, 2H), 4.72 in (m, 1H), 7,55 (t, 1H), 7,71 (d, 1H)and 1.15 (s, 1H), with 8.33 (d, 1H), 8,91 (s, 1H), remaining 9.08 (d, 2H), 9,17 (s, 1H)
169445,44447,24of 1.3 (t, 3H), 2,9 (Sirs, 6H), 3,6 (Sirs, 2H), 4,3 (square, 2H), 4,6 (m, 2H), and 7.1 (m, 1H), 7,6 (m, 1H), and 7.9 (s, 1H), and 8.2 (m, 1H), of 8.25 (s, 1H), 8,3 (m, 1H), and 8.6 (d, 1H), and 8.7 (d, 1H), and 9.1 (s, 1H), 9,7 (Sirs, 1H)
170444,43446,221,2 (t, 3H), 2,9 (Sirs, 6H), of 3.25 (m, 2H), 3,6 (Sirs, 2H), 4,6 (m, 2H), and 7.1 (m, 1H), and 7.4 (Sirs, 1H), 7,6 (m, 1H), and 7.9 (s, 1H), 8,1 (Sirs, 1H), and 8.2 (s, 1H), 8,3 (m, 1H), and 8.6 (d, 1H), and 8.7 (d, 1H), 9,1 (s, 1H), 9,8 (Sirs, 1H), 10,5 (Sirs, 1H)
171460,2462,2(CD3OD): of 8.95 (d, 1H), 8,86 (d, 1H), 8,57 (dt, 1H), 8,46 (d, 1H), 8,17 (d, 1H), to 7.93 (t, 1H), 7.62mm (Sirs 1H), 7,33 (d, 1H), 5,14 (m, 1H), 4,42 (square, 2H), 4.26 deaths (m, 1H, in), 3.75 (DD, 1H), on 3.36 (s, 3H), of 2.81 (s, 3H), of 1.42 (d, 3H), of 1.30 (t, 3H) ppm
172485487(CD3OD): 1,45-of 1.12 (m, 3H), and 1.9 (m, 1H), 2,1 (m, 2H), 2,32 (m, 1H), 3,5-3,3 (m, 5H), and 3.7 (m, 4H), 3,99 (Sirs, 1H), 4,4 (square, 2H), 4,57 (shirt, 1H), 7,58 (d, 1H), and 7.8 (t, 1H), 8,03 (s, 1H), 8,32 (d, 1H), 8,42 (m, 2H), up 8.75 (d, 1H), 8,88 (s, 1H), and 9.1 (s, 1H)
173484486(CD3OD): to 1.15 (t, 3H), 1,4 (t, 3H), to 3.02 (s, 2H), 3,6 (m, 2H), 3,68 (m, 2H), 3,95 (s, 2H), 4,4 (m, 2H), br4.61(s, 2H), and 7.8 (m, 2H), 8,08 (s, 1H), 8,48 (m, 3H), 8,78 (d, 1H), 8,9 (d, 1H), 9,17 (s, 1H)
174503,2505,2(CDCl3): to 8.94 (d, 1H), 8,87 (d, 1H), 8,15 (d, 1H), 8,11 (d, 2H), 7,95 (DDD, 1H), of 7.90 (s, 1H), of 7.70 (d, 1H), 7,42 (DD, 1H), amounts to 4.76 (s, 2H), 4,46 (square, 2H), 3,82 (t, 4H), to 3.64 (t, 4H), 3,40 (s, 6H), of 1.45 (t, 3H)
175593,4595,310,85 (s, 1H), 8,84 (s, 1H), 8,72 (s, 1H), 8,58 (d, 1H), charged 8.52 (s, 1H), 8.30 to (d, 1H), 8,08 (s, 1H), 7,92 (l, aH), 7,44 (d, 2H), 7,34 (DD, 2H), 7,24 (t, 1H), 6,05-4,9 (Sirs), to 5.21 (DQC., 1H), 4,78 (d, 2H), or 4.31 (square, 2H), to 3.58 (d, 2H), 3,52
176543.5 nm545,311,76 (s, 1H), 9,59 (s, 1H), 8,89 (d, 1H), 8,78 (s, 1H), 8,65 (s, 1H), 8,40 (s, 1H), with 8.05 (d, 1H), 7,9-6,2 (Sirs, 2H), 4,87 (d, 2H), 4,32 (square, 2H), 3.96 points (DD, 2H), 3,68 (DD, 2H), to 3.58 (m, 4H), 3,20 (m, 2H), to 2.94 (d, 3H), of 1.98 (m, 2H), 1,88
177542,5to 544.311,12 (s, 1H), 10,84 (s, 1H), remaining 9.08 (s, 1H), 8,87 (d, 1H), 8,66 (s, 1H), to 8.41 (s, 1H), 8,01 (s, 1H), of 7.96 (d, 1H), 7,58 (s, 1H), 6,3-4,6 (Sirs, 6H), 4,82 (d, 2H), 3.96 points (DD, 2H), to 3.58 (m, 6H), 3,26 (m, 2H), 3.15 in (m, 2H), 2,84 (d, 3H), 1,96
178470,4472,39,05 (d, 2H), 8,54 (s, 1H), 7,89 (s, 1H), 8,01 (s, 1H), 7,78 (d, 1H), 7,55 (t, 1H), 7,05 (d, 1H), 5,5-4,2 (Sirs, 1H), 4,33 (square, 2H), 3,50 (DD, 2H), 3,36 (DD, 2H), 3,12 (s, 3H), 2,85 (s, 3H), of 1.33 (t, 3H),
179415,4417,3(CD3OD): 9,54 (d, 1H), of 9.21 (m, 1H), 9.15, with (s, 1H), 8,97 (d, 1H), of 8.92 (d, 1H), 8,83 (d, 1H), 8,28 (DD, 1H), to 8.20 (d, 1H), 7,69 (m, 1H), to 4.62 (s, 2H), 4,48 (square, 2H), 3.00 and (s, 6H), of 1.44 (t, 3H) ppm
18044,4 416,3(CD3OD): 9,54 (d, 1H), which 9.22 (m, 1H), 9,05 (s, 1H), 8,97 (d, 1H), 8,93 (d, 1H), 8,79 (d, 1H), 8,28 (DD, 1H), 8,17 (d, 1H), 7.62mm (m, 1H), 4,59 (s, 2H), 3,39 (square, 2H), 2,99 (s, 6H), 1,25 (t,3H) ppm
181513515(CD3OD): 9,14 (d, 1H), 9,06 (d, 1H), cent to 8.85 (t, 1H), 8,67 (t, 1H), 8,46 (d, 1H), of 8.37 (d, 1H), 8,11 (m, 1H), of 7.97 (d, 1H), 7,55 (m, 1H), 4,07 (Sirs, 2H), 3,88 (t, 4H), 3,71 (Sirs, 2H), 3,48 (t, 4H), 3,36 (square, 2H), of 1.24 (t, 3H)
182477,4479,37of 0.9 (d, 6H), 1,3 (t, 3H), 2,1 (m, 1H), 2,9 (s, 6H), of 3.75 (d, 2H), 4,3 (square, 2H), 4,6 (s, 2H), 6,6 (dt, 1H), 6,7 (d, 1H), and 7.7 (s, 1H), and 7.8 (d, 1H), 7,95 (s, 1H), 8,010,2 (Sirs, 1H), (s, 1H)
183476,42478,41of 0.9 (d, 6H), 1,1 (t, 3H), 2,1 (m, 1H), 2,9 (s, 6H), 3,2 (m, 2H), and 3.8 (d, 2H), 4,6 (s, 2H), 6,6 (dt, 1H), 6,7 (d, 1H), and 7.3 (Sirs, 1H), and 7.7 (s, 1H), and 7.8 (d, 1H), 7,95 (s, 1H), and 8.0 (s, 1H), 10,2 (Sirs, 1H)
184514516-
185470,4472,2(CD3OD): a 1.25 (t, 3H), of 1.78 (d, 3H), 3,30 (m, 2H), 3,35 (square, 2H), 3,50 (m, 2H), 3,93 (m, 4H), 4,73 (square, 1H), 7,72 (t, 1H), 7,45 (d, 1H), 8,01 (s, 1H), 8,27 (t, 1H), 8,35 (m, 2H), charged 8.52 (d, 1H), 8,91 (d, 1H), 9,18 (s, 1H)
186498,4500,3(CD3OD): to 1.16 (m,3H), 1.26 in (m, 6H), of 1.80 (d, 3H), 2,82 (t, 2H), 3,20 (d, 1H), 3,35 (square, 2H), and 3.72 (d, 1H), 3,91 (m, 1H), Android 4.04 (m, 1H), 4,68 (square, 1H), 7,65 (t, 1H), 7,71 (d, 1H), 8,01 (s, 1H), they were 8.22 (t, 1H), 8,35 (m, 2H), 8,49 (d, 1H), 8,89 (d, 1H), 9,18 (s, 1H)
187499,5501,3 (CD3OD): to 1.16 (m, 3H), of 1.29 (d, 3H), of 1.41 (t, 3H), 1,79 (d, 3H), 2,82 (t, 2H), 3,20 (d, 1H), 3,74 (d, 1H), 3,92 (m, 1H), Android 4.04 (m, 1H), 4,43 (square, 2H), 4,69 (square, 1H), of 7.70 (d, 1H), 7,87 (t, 1H), 8,11 (s, 1H), 8,35 (d, 1H), 8,46 (m, 2H), up 8.75 (d, 1H), of 8.92 (d, 1H), 9,34 (s, 1H)
188486488(CD3OD): 8,91 (m, 1H), 8,65 (m, 1H), of 8.47 (m, 1H), 8,31 (m, 2H), 8,29 (m, 1H), of 7.96 (m, 1H), 7,73 (m, 1H), 7,19 (m, 1H), 4,08 (m, 2H), 3,90 (m, 2H), and 3.72 (m, 4H), 3,66 (m, 4H), 3,37 (m, 2H), 1,24 (t, 3H)
189487489(CD3OD): 8,89 (d, 1H), 8,69 (d, 1H), 8,61 (d, 1H), to 8.41 (t, 1H), 8,32 (d, 1H), to 8.20 (DD, 1H), 7,95 (d, 1H), 7,78 (t, 1H), 7,10 (d, 1H), 4,42 (square, 2H), 4.09 to (m, 2H), 3,86 (m, 2H), 3,70 (m, 4H), to 3.33 (m, 4H), of 1.24 (t, 3H)
190388,38390,191,2 (t, 3H), 3,3 (m, 2H), 3,5 (s, 3H), and 6.6 (DD, 1H), 6,7 (d, 1H), and 7.6 (t, 1H), and 7.8 (d, 1H), 7,95 (Sirs, 1H), and 8.0 (s, 1H), and 8.6 (s, 1H), 9,05 (d, 2H)
191359,3361,2-
192KZT 446.4448,3-
193474,2476,4(CD3OD): 9,14 (s, 1H), remaining 9.08 (d, 2H), 8,91 (s, 1H), 8,39 (d, 1H), 8,14 (s, 1H), 7,78 (s, 1H), 7,55 (DD, 1H), 4.72 in (s, 2H), 4,48 (square, 2H), 3,81 (t, 2H), of 3.56 (t, 2 H), 3.46 in (square, 2H), 3,41 (s, 3H), of 1.44 (t, 3H), was 1.43 (t, 3H)
194486,1488,1(CDCl3): 12,31 (Sirs, 1H), of 8.95 (s, 1H), 8,93 (d, 2H), 8,58 (s, 1H), with 8.05 (s, 1H), 8,01 (d, 1H), 7,50 (d, 1H), 7,24 (DD, 1H), 4,46 (square, 2H), 3,78 (m, 2H), and 3.72 (s, 2H), 2,78 (d, 2H), 1,91 (DD, 2H), of 1.41 (t, 3H), of 1.17 (d, 6H)
195/td> --11,5 (Sirs, 1H), 9,19 (Sirs, 1H), 8,97 (s, 1H), 8,88 (d, 1H), 8,45 (m, 1H), 8,40 (s, 1H), 7,98 (d, 1H), to 7.77 (d, 1H), 7,60 (d, 1H), 4,57 (s, 2H), 4,47 (shirt, 2H), 4,32 (square, 2H), 3,90 (SIRM, 4H), 3,32 (Sirs, 4H), 2,80 (d, 6H), 1,34
197460,2462,2(CD3OD and CDCl3): 8,98 (d, 2H), cent to 8.85 (d, 1H), at 8.60 (d, 1H), 8,16 (DD, 1H), 7,86 (d, 1H), to 7.67 (d, 1H), 7,40 (DD, 1H), 4,37 (square, 2H), 3,81 (s, 2H), 3,60 (t, 2H), 3,37 (s, 3H), 2,74 (t, 2H), of 2.38 (s, 3H), of 1.41 (t, 3H)
198459,3461,2(CD3OD): 8,95 (d, 2H), 8,83 (s, 1H), 8,54 (s, 1H), 8,15 (d, 1H), 7,82 (s, 1H), 7,65 (d, 1H), 7,39 (DD, 1H), 3,79 (s, 2H)and 3.59 (t, 2H), 3,36 (square, 2H), 3,35 (s, 3H), of 2.72 (t, 2H), a 2.36 (s, 3H), of 1.24 (t, 3H)
199488490-
200487489-
201488490-
202487489-
2034894919,06 (m, 4H), and 8.50 (d, 1H), 7,98 (d, 1H), 7,54 (t, 1H), 4,79 (t, 2H), or 4.31 (square, 2H), 4,01 (m, 2H), 3,79 (m, 2H), to 3.67 (m, 2H), of 3.56 (m, 2H), 3,25 (m, 2H), 1,33 (t, 3H)
204488490(CD3OD): 9,02 (m, 4H), up 8.75 (s, 1H), of 7.97 (d, 1H), 7,52 (m, 1H), 4,88 (m, 2H), 3.75 to to 3.73 (m, 10H), to 3.35 (m, 2H), 1,25 (t, 3H)
205400,1402,1of 1.31 (t, 3H), 2,70 (s, 3H), 4,32 (square, 2H), 7,55 (t, 1H), 8,00 (s, 1H), of 8.09 (d, 1H), 8,14 (t, 1H) 8,39 (s, 1H), 8,44 (d, 1H), to 8.70 (d, 1H), 8,81 (d, 1H), 9,19 (s, 1H)
206458,1460(CD3OD): 9,41 (d, 2H), of 8.92 (m, 1H), 8,80 (d, 1H), 8,48 (m, 2H), 8,10 (Sirs, 1H), to 7.84 (m, 1H), amounts to 4.76 (s, 2H peak water), 4,42 (square, 2H), 4,11 (SIRM, 2H), 3,95 (SIRM, 2H), 3,71 (SIRM, 2H), 3.45 points (SIRM, 2H), of 1.42 (t, 3H) ppm
207457,2459,1(CD3OD): was 9.33 (s, 2H), 8,89 (d, 1H), 8,53 (d, 1H), 8,44 (d, 1H), to 8.20 (m, 1H), 8,04 (d, 1H), 7,63 (m, 1H), amounts to 4.76 (s, 2H, peak water)4,12 (SIRM, 2H), 3,94 (SIRM, 2H), 3,71 (SIRM, 2H), 3,44 (SIRM, 2H), 3,39 (square, 2H), 1,25 (t, 3H) ppm
208391393-
209441,1443(CD3OD): USD 1.43 (t, 3H), 4,50 (s, 2H), 4,89 (s, 2H), 7,55 (t, 1H), 8,10 (d, 1H), to 8.20 (s, 1H), 8,87 (d, 1H), 9,01 (s, 1H), 9,10 (d, 2H), of 9.30 (s, 1H)
210472,4474,2(CD3OD): a 9.25 (s, 1H), 9,02 (d, 2H), 8,87 (d, 1H), 8,65 (d, 1H), 8,18 (s, 1H), 8,08 (d, 1H), 7,54 (DD, 1H), 4,88 (s, 2H), 4,49 (square, 2H), 4,27 (Sirs, 1H), 3,68 (m, 4H), 3,40 (s, 3H), 2,32 (m, 2H), 1,45 (t, 3H)
211471,2473,1(CD3OD): 9,16 (s, 1H), 8,98 (d, 2H), 8,76 (d, 1H), 8,48 (d, 1H), with 8.05 (s, 1H), to $ 7.91 (d, 1H), 7,50 (DD, 1H), to 4.81 (s, 2H), 4,27 (Sirs, 1H), 3,69 (m, 4H), 3,40 (s, 3H), 3,38 (square, 2H), 2,32 (m, 2H), 1.26 in (t, 3H)
212485,2487,3(CD3OD): 9,16 (s, 1H), 9,03 (d, 2H), 8,87 (s, 1H), and 8.50 (d, 1H), 8,14 (s, 1H), 7,92 (d, 1H), 7,54 (DD, 1H), and 4.75 (s, 2H), 4,49 (square, 2H), 4,06 (s, 2H), 3,74 (Sirs, 4H), 3,06 (s, 3H), 1,45 t, 3H)
213484,2486,2(CD3OD): 9,16 (s, 1H), 9,01 (d, 2H), 8,78 (s, 1H), charged 8.52 (d, 1H), 8,07 (s, 1H), of 7.96 (d, 1H), 7,52 (DD, 1H), of 4.77 (s, 2H), 4,07 (s, 2H), 3,75 (Sirs, 4H), 3,38 (square, 2H), 3,06 (s, 3H), of 1.26 (t, 3H)
214350,1to 12.28 (Sirs, 1H), 11,77 (Sirs, 1H), 9,73 (s, 1H), remaining 9.08 (d, 2H), 8,49 (d, 1H), of 8.37 (m, 1H), 8,08 (d, 1H), 7,94 (m, 1H), to 7.59 (t, 1H), 4,32 (square, 2H), 2,30 (s, 3H), of 1.32 (t, 3H)
215502,4504,1(CD3OD): 9,17 (s, 1H), 9,02 (d, 2H), cent to 8.85 (s, 1H), 8,48 (d, 1H), 8,15 (s, 1H), of 7.90 (d, 1H), 7,53 (DD, 1H), 4,81 (d, 1H), 4,77 (d, 1H), 4,48 (square, 2H), 4,18 (Sirs, 2H, in), 3.75 (m, 4H), 3,47 (s, 6H), of 1.45 (t, 3H)
216347,2349,1to 12.28 (Sirs, 1H), 10,22 (Sirs, 1H), at 9.53 (s, 1H), remaining 9.08 (d, 2H), to 8.41 (d, 1H), 8,29 (m, 1H), 7,98 (d, 1H), 7,83 (m, 1H), EUR 7.57 (t, 1H), 7,22 (m, 1H), 3,26 (DQC., 2H), 2,31 (s, 3H)and 1.15 (t, 3H)
217501,4503,1(CD3OD): to 9.15 (s, 1H), 9,03 (d, 2H), cent to 8.85 (s, 1H), 8,43 (d, 1H), 8,10 (s, 1H), 7,83 (d, 1H), 7,53 (DD, 1H), 4,78 (d, 1H), 4,74 (d, 1H), 4,18 (Sirs, 2H), 3,74 (m, 4H), 3,47 (s, 6H), 3,38 (square, 2H), 1.26 in (t, 3H)
218456458(CD3OD): 1,24 (t, 3H), 3,38 (m, 2H), 3,57 (Sirs, 4H), 3,99 (Sirs, 4H), 4,63 (s, 2H), 7,68 (m, 1H), 7,73 (m, 1H), 8,02 (s, 1H), 8,24 (t, 1H), 8,48 (m, 1H), 8,49 (d, 1H), 8,9 (d, 1H), 9,13 (s, 1H)
219--12,25 (s, 1H), 11,75 (s, 1H), being 9.61 (d, 1H), 9,07 (d, 2H), to 8.45 (s, 1H), 8,11 (s, 1H), 8,02 (d, 1H), to 7.59 (t, 1H), or 4.31 (square, 2H), of 2.38 (s, 3H), 2,29 (who, 3H), of 1.32 (t, 3H)
220502,3504,2(CD3OD): 9,10 (d, 1H), 9,05 (d, 2H), 8,91 (d, 1H), 8,32 (DD, 1H), 8,11 (d, 1H), 7,69 (d, 1H), 7,55 (DD, 1H), 4,73 (d, 1H), 4,69 (d, 1H), 4,49 (square, 2H), 4,17 (Sirs, 2H), 3,70 (m, 4H), 3.46 in (s, 6H), of 1.44 (t, 3H)
221501,3503,2(CD3OD): a 9.09 (s, 1H), 9,05 (d, 2H), 8,86 (s, 1H), 8,29 (d, 1H), of 8.09 (s, 1H), to 7.67 (d, 1H), 7,54 (DD, 1H), 4.72 in (d, 1H), 4,67 (d, 1H), 4,17 (Sirs, 2H), 3,71 (m, 4H), 3,47 (s, 6H), 3,39 (square, 2H), 1.26 in (t, 3H)
222-559(CDCl3): 12,29 (Sirs, 1H), to 8.94 (s, 1H), to 8.94 (d, 2H), at 8.60 (s, 1H), 8,04 (s, 1H), 8,02 (d, 1H), 7,50 (d, 1H), 7,25 (DD, 1H), 4,46 (square, 2H, in), 3.75 (s, 2H), 3,50 (m, 4H), of 2.51 (m, 4H), of 1.47 (s, 9H), of 1.41 (t, 3H)
223513,2515,141,1 (d, 6H), 1,3 (t, 3H), 3,5 (m, 4H), 3,7 (Sirs, 2H), 4,3 (square, 2H), 4,5 (Sirs, 2H)and 4.65 (m, 1H), 7.5 (t, 1H), 7.7 (d, 1H), 8.0 a (d, 1H), 8,3 (DD, 1H), and 8.5 (d, 1H), and 9.0 (d, 2H), 9,05 (d, 1H)
224457,207459,207(CD3OD): 9,54 (s, 1H), 9.28 are (s, 1H), which 9.22 (d, 1H), 8,97 (d, 1H), 8,93 (d, 1H), cent to 8.85 (Sirs, 1H), 8,27 (t, 1H), 8,20 (Sirs, 1H), 7,71 (d, 1H), 4,63 (s, 2H), 4,48 (square, 2H), 4,05 (Sirs, 4H), 3,44 (SIRM, 4H), of 1.44 (t, 3H) ppm
225472,2474,49(CD3OD): 9,0 (d, 1H), 8,95 (m, 1H), and 8.6 (s, 1H), 8,5 (s, 1H), and 8.4 (s, 1H), and 8.3 (s, 1H), and 7.9 (s, 1H), 7,55 (m, 1H), and 4.5 (s, 2H), 3,9 (s, 2H),3,4 (square, 2H), 3.0 a (s, 6H)and 1.3 (t, 3H)
226562,3564,2(CD3OD): 9,0 (d, 1H), 8,9 (m, 1H), and 8.6 (s, 1H), 8, 5C, 1H), and 8.3 (s, 1H), of 8.25 (s, 1H), and 7.9 (s, 1H), 7,55 (m, 1H), 7.3 to 7.4 (m, 5H), and 5.2 (s, 2H), and 4.5 (s, 2H), 4,0 (s, 2H), 3,4 (square, 2H), 3.0 a (s, 6H)and 1.3 (t, 3H)
227389391-
228457,3459,1-
229456,3458,1-
230433,3435,1-
231487489(CD3OD): of 9.30 (s, 2H), 9,04 (d, 2H), 8,89 (d, 1H), 8,11 (d, 1H), 7,54 (t, 1H), 4,46 (square, 2H), was 4.02 (m, 2H)and 3.59 (m, 2H), 2,89 (m, 2H), 1,44 (t, 2H), 1,13 (t, 3H) ppm
232456,3458,3(CD3OD): which 9.22 (s, 1H), 9,05 (d, 2H), of 8.92 (s, 1H), 8,78 (d, 1H), 8,17 (s, 1H), 8,08 (d, 1H), 7,54 (DD, 1H), 4,42 (s, 2H), 3,52 (m, 4H), 3,39 (square, 4H), of 3.28 (m, 4H), of 1.26 (t, 3H)
233-459,1(CD3OD): which 9.22 (s, 1H), 9,06 (d, 2H), 8,96 (s, 1H), 8,77 (d, 1H), they were 8.22 (s, 1H), 8,07 (d, 1H), 7,56 (DD, 1H), 4,49 (square, 2H), 4,42 (s, 2H), 3,52 (m, 4H), 3,29 (m, 4H), of 1.45 (t, 3H)
234-537(CD3OD): which 9.22 (s, 1H), 9,04 (d, 2H), of 8.90 (s, 1H), 8,54 (d, 1H), 8,16 (s, 1H), to 7.99 (d, 1H), 7,54 (DD, 1H), 4,78 (s, 2H), 4,49 (square, 2H), 3,69, and 3,63 (m, 8H), of 3.00 (s, 3H), of 1.45 (t, 3H)
235534,2536,1(CD3OD): 9,20 (s, 1H), 9,02 (d, 2H), 8,82 (s, 1H), charged 8.52 (d, 1H), of 8.09 (s, 1H), 7,98 (d, 1H), 7,52 (DD, 1H), 4,78 (s, 2H), 3,69, and 3,62 (m, 8H), 3,39 (square, 2H), 3.00 and (s, 3H), 1,25 (t, 3H)
236496,4 498,3(CD3OD): 9.28 are (s, 1H), 9,06 (Sirs, 2H), 8,96 (s, 1H), cent to 8.85 (Sirs, 1H), 8,24 (s, 1H), 8,15 (Sirs, 1H), 7,56 (Sirs, 1H), 4,49 (square, 2H), 4,42 (s, 2H), of 3.73 (Sirs, 4H), 3,35 (Sirs, 4H), 3,01 (Sirs, 1H), 1,45 (t, 3H), 1,20 (Sirs, 2H), 1,00 (Sirs, 2H)
237496,4498,3(CDCl3) 11,82 (Sirs, 1H), 8,88 (s, 1H), 8,71 (Sirs, 2H), 8,48 (s, 1H), 7,89 (d, 1H), 7,79 (s, 1H), 7,42 (d, 1H), 7,05 (Sirs, 1H), 3,71 (s, 2H), 3.46 in (square, 2H), 2,70, and to 2.55 (m, 8H), of 1.28 (t, 3H), 0,45-0,41 (m, 4H)
238447,2449to 12.35 (s, 1H), 9,07 (d, 2H), 8,82 (s, 1H), to 8.41 (d, 1H), 8,13 (s, 1H), 7,95 (d, 1H), EUR 7.57 (t, 1H), 6,7-5,2 (Sirs, 4H), to 4.38 (s, 2H), 4,32 (square, 2H), 3,92 (shirt, 4H), 3,32 (shirt, 4H), of 1.33 (t, 3H)
239490,1492,2(CD3OD): of 9.21 (s, 1H), 9,05 (d, 2H), of 8.92 (s, 1H), 8,54 (d, 1H), 8,17 (s, 1H), of 7.97 (d, 1H), 7,55 (DD, 1H), 4,78 (s, 2H), 4,49 (square, 2H), 4,01 (sird, 2H), 3,74 (shirt, 2H), 3.43 points (sird, 2H), 3.27 to (shirt, 2H), 1,45 (t, 3H)
240471,3473(CD3OD): 9.28 are (s, 1H), 9,05 (Sirs, 2H), 8,96 (s, 1H), 8,89 (s, 1H), of 8.25 (s, 1H), 8,17 (s, 1H), 7,55 (Sirs, 1H), 4,49 (square, 2H), 4,39 (s, 2H), 3,64-3,13 (m, 8H), of 3.00 (s, 3H), of 1.45 (t, 3H)
241-531,01of 1.3 (t, 3H), of 1.55 (d, 3H), 3,3 (Sirs, 4H), 3,9 (Sirs, 4H), 4.0 (with square, 1H), 4,35 (square, 2H), 4,6 (s, 2H), and 7.6 (DD, 1H), and 7.8 (d, 1H), and 8.0 (s, 1H), and 8.4 (d, 1H), 8,42 (s, 1H), and 8.7 (s, 1H), and 8.8 (d, 1H), 9,15 (s, 1H), 11...2 (Sirs, 1H)
242486,-2488,1(CD3OD): was 9.33 (s, 2H), of 8.92 (d, 1H), 8,7 (d, 1H), of 8.47 (m, 2H), of 8.09 (d, 1H), to 7.84 (m, 1H), 4,42 (square, 2H), of 4.05 (m, 2H), to 3.67 (m, 2H), 3,39 (m, 2H, under the peak of water)to 3.00 (m, 2H), of 1.42 (t, 3H), of 1.28 (d, 6H) ppm
243488,2490,05of 1.3 (t, 3H), 3,2 (m, 2H), 3,5 (m, 2H), and 3.7 (m, 2H), 3,9 (m, 2H), 4,0 (m, 2H), 4,3 (square, 2H), and 4.8 (m, 2H), 7,6 (7,1H)and 8.1 (d, 1H), 8,2 (Sirs, 1H), and 8.6 (d, 1H), 8,65 (d, 1H), and 8.8 (d, 1H), 9,05 (d, 2H), 11,6 (Sirs, 1H), 12.7mm (Sirs, 1H)
244457,21459,09of 1.35 (t, 3H), 2,8 (Sirs, 3H), 3,2 (m, 2H), 3,4 (m, 2H), 3,55 (m, 2H), 4,3 (m, 2H), 4,35 (square, 2H), and 7.6 (t, 1H)and 8.1 (d, 1H), 8.3 (Sirs, 1H), 8,55 (d, 1H), and 8.6 (d, 1H), and 8.7 (d, 1H), 9,05 (d, 2H), and 11.2 (Sirs, 1H), 12,4 (Sirs, 1H)
245529,2531,1(CD3OD): the remaining 9.08 (d, 1H), 9,01 (d, 2H), 8,82 (d, 1H), 8.30 to (d, 1H), 8,04 (d, 1H), 7,68 (d, 1H), 7,51 (DD, 1H), 4,63 (s, 2H), 4,47 (square, 2H), 4,22 (s, 2H), 3,91 (Sirs, 4H), 3,49 (Sirs, 4H), 3.43 points (s, 3H), of 1.44 (t, 3H)
246555,3557,1(CD3OD): 9,23 (s, 1H), 9,04 (d, 2H), of 8.90 (s, 1H), 8,56 (d, 1H), 8,17 (s, 1H), 8,00 (d, 1H), 7,55 (DD, 1H), of 4.77 (s, 2H), 4,49 (square, 2H), 4,12-a-3.84 (m, 6H), 3,57 (Sirs, 4H), 3,48 (Sirs, 1H), 2,18 (m, 2H), of 1.97 (m, 2H), a 1.45 (t, 3H)
247485,1487(CD3OD): 9,34 (s, 2H), 8,93 (d, 1H), 8,80 (d, 1H), 8,48 (m, 2H), 8,10 (d, 1H), a 7.85 (t, 1H), 4,88 (s, 2H), of 4.44 (square, 2H), is 4.21 (s, 2H), 3,86 (m, 2H), 3,79 (m, 2H), to 3.09 (s, 3H), of 1.42 (t, 3H) ppm
248458,15460,02of 1.23 (t, 3H), 3,17 (m, 4H), of 3.65 (m, 4H), 4,34 (square, 2H), of 4.77 (s, 2H), EUR 7.57 (t, 1H), 8,11 (s, 1H), 8,61 (s, 1H), 9,06 (d, 2H), 9,39 (s, 2H), 9,87 (Sirs, 2H)/td>
249472,3474(CD3OD): 9,17 (s, 1H), 9,04 (d, 2H), of 8.92 (s, 1H), 8,45 (d, 1H), 8,15 (s, 1H), 7,87 (d, 1H), 7,55 (DD, 1H), and 4.68 (s, 2H), 4,69 (square, 2H), 4,11 (DD, 1H), was 4.02-3,95 (m, 2H), only 3.57 (m, 2H), 3,03 (DD, 1H), 1,44 (t, 3H), 1.26 in (d, 3H)
250499,2501,3(CD3OD): a 9.25 (s, 1H), 9,06 (d, 2H), 8,97 (s, 1H), 8,84 (d, 1H), 8,23 (s, 1H), 8,12 (d, 1H), 7,56 (DD, 1H), 4,49 (square, 2H), 4,37 (s, 2H), 3,65-of 3.12 (m, 9H), 1,46 was 1.43 (m, 9H)
251514,9517(CD3OD): 9,27 (s, 1H), 9,05 (d, 2H), of 8.95 (s, 1H), 8,86 (d, 1H), of 8.25 (s, 1H), 8,16 (d, 1H), 7,56 (DD, 1H), 4,49 (square, 2H), 4,46 (s, 2H), 3,81-3,50 (m, 12H), 3,44 (s, 3H), of 1.45 (t, 3H)
252527,2529(CD3OD): 9,06 (s, 1H), 8,97 (d, 2H), 8,76 (s, 1H), 8,28 (d, 1H), 8,00 (s, 1H), 7,69 (d, 1H), 7,49 (DD, 1H)and 4.65 (s, 2H), 4,45 (square, 2H), 3,99 (Sirs, 4H), 3,49 (Sirs, 4H), 2,99 (hept., 1H), the 1.44 (t, 3H), 1.14 in (d, 6H)
253502504(CD3OD): the remaining 9.08 (d, 2H), 8,73 (s, 1H), 8,51 (s, 1H), scored 8.38 (DD, 1H), 8,07 (d, 1H), 7,92 (m, 1H), to 7.77 (d, 1H), to 7.64 (m, 1H), 4,67 (s, 2H), 4,48 (square, 2H), 4,01 (s, 2H), the 3.65 (m, 4H), 3,06 (m, 2H), USD 1.43 (t, 2H), of 1.13 (t, 3H) ppm
254454,17456,0214,52 (s, 1H), which 9.22 (s, 2H), 9,05 (d, 2H), 8,56 (d, 1H), 8,04 (d, 1H), 7,74 (s, 1H), 7.62mm (s, 1H), 7,55 (t, 1H), 6,8-5,6 (Sirs), 5,79 (s, 2H), 4,33 (square, 2H), 2,62 (s, 3H), of 1.33 (t, 3H)
255530,17532,031,1 (d, 6H), of 1.35 (t, 3H), 2,3 (s, 6H), 3,5 (m, 2H), 3,6 (m, 2H), 3,9 (s, 2H), 4,3 (square, 2H), 4,6 (s, 2H)and 4.65 (m, 1H),7.7 (d, 1H), and 7.9 (s, 1H), 8.0 a (dt, 1H), and 8.3 (s, 1H), and 8.4 (DD, 1H), and 8.8 (d, 1H), cent to 8.85 (m, 1H), and 9.1 (s, 1H)
256486,23488,05of 1.3 (d, 6H), of 1.35 (t, 3H), 3,1 (m, 2H), 3,5 (m, 1H), 3,6 (m, 4H), 4,3 (square, 2H), and 4.8 (m, 2H), and 7.6 (t, 1H), and 7.9 (s, 1H), 8,5 (s, 1H), 8,9 (s, 2H), 9,05 (d, 1H), 10,5 (Sirs, 1H)
257499,2501,1(CD3OD): 9,34 (s, 2H), 8,93 (m, 1H), 8,81 (d, 1H), 8,49 (m, 2H), 8,11 (d, 1H), a 7.85 (t, 1H), to 4.87 (s, 2H), 4,42 (square, 2H), 4,11 (Sirs, 2H), a 3.87 (SIRM, 4H), 3,71 (m, 3H), of 1.48 (d, 6H), of 1.42 (t, 3H) ppm
258571,3573,1(CDCl3) was 12.75 (Sirs, 1H), 12,29 (s, 1H), to 8.94 (d, 2H), of 8.92 (s, 1H), at 8.60 (s, 1H), with 8.05 (s, 1H), 8,04 (d, 1H), to 7.59 (d, 1H), 7,25 (DD, 1H), 4,46 (square, 2H), 4,23 (Sirs, 1H), 3,86 (d, 1H), 3,80 (d, 1H), 3,65 (d, 1H), 3,19 (DDD, 1H), 2,86 (d, 1H), 2,66 (d, 1H)
259-473(CD3OD): 9,24 (s, 1H), 9,04 (d, 2H), to 8.94 (s, 1H), 8,81 (d, 1H), they were 8.22 (s, 1H), 8,11 (d, 1H), 7,55 (DD, 1H), 4,49 (square, 2H), 4,42 (s, 2H), of 3.77-2,89 (m, 7H), of 1.45 (t, 3H), of 1.41 (d, 3H)
259485,3487,3(CD3OD): 9,24 (s, 1H), 9,06 (d, 2H), 8,96 (s, 1H), 8,83 (d, 1H), 8,23 (s, 1H), 8,11 (d, 1H), 7,56 (DD, 1H), 4,49 (square, 2H), 4,39 (s, 2H), 3,76 (m, 2H), 3,40 (d, 2H), 2,80 (d, 2H), 1,45 (t, 3H), of 1.40 (d, 6H)
261485,2487(CD3OD): 9,23 (s, 1H), 9,06 (d, 2H), 8,97 (s, 1H), 8,82 (d, 1H), 8,24 (s, 1H), 8,13 (d, 1H), 7,56 (DD, 1H), 4,74 (d, 2H), 4,49 (square, 2H), 4.25 in (d, 1H), 3,80 of 2.92 (m, 6H), of 1.45 (t, 3H), of 1.36 (d, 6H)
262513,2515(CD 3OD): 9,10 (s, 1H), 9,02 (d, 2H), cent to 8.85 (s, 1H), 8,31 (d, 1H), of 8.06 (s, 1H), 7,68 (d, 1H), 7,52 (DD, 1H), to 4.62 (s, 2H), 4,46 (square, 2H), 3,92-and 3.16 (m, 8H), 2,48 (square, 2H), to 1.86 (m, 2H), of 1.44 (t, 3H), 1.14 in (t, 3H)
263-557,3(CD3OD): 9,11 (s, 1H), 9,03 (d, 2H), cent to 8.85 (s, 1H), 8,32 (d, 1H), 8,07 (s, 1H), 7,69 (d, 1H), 7,52 (DD, 1H), 4,63 (s, 2H), 4,47 (square, 2H), 3,99-with 3.79 (m, 8H), 3,50 is-3.45 (m, 5H), of 2.15 (m, 2H), of 1.44 (t, 3H)
264-501,1(CD3OD): 9,10 (s, 1H), 9,03 (d, 2H), cent to 8.85 (s, 1H), to 8.62 (d, 1H), 8,08 (s, 1H), 7,94 (d, 1H), 7,52 (DD, 1H), 4,46 (square, 2H), 4,12 (s, 2H), 3.46 in-a 3.01 (m, 10H), of 1.80 (m, 2H), USD 1.43 (t, 3H), was 1.04 (t, 3H)
265-531,1(CD3OD): of 9.21 (s, 1H), 8,96 (d, 2H), 8,82 (s, 1H), 8,59 (d, 1H), 8,12 (s, 1H), of 8.06 (d, 1H), of 7.48 (DD, 1H), and 4.75 (s, 2H), 4,42 (square, 2H), 4,12 (square, 2H), 3,83 (Sirs, 4H), 3,47 (Sirs, 4H), to 1.38 (t, 3H), of 1.23 (t, 3H)
266543,2545(CD3OD): was 9.33 (s, 1H), 8,99 (d, 2H), 8,83 (s, 1H), 8,79 (Sirs, 1H), 8,18 (s, 1H), 7,54 (Sirs, 1H), is 4.93 (m, 1H), 4,89 (s, 2H), 4,49 (square, 2H), 3,90 (Sirs, 4H), 3,57 (Sirs, 4H), of 1.45 (t, 3H), of 1.29 (d, 6H)
267516518-
268557,3559,2(CD3OD): the remaining 9.08 (s, 1H), 8,969 (d, 2H), 8,78 (s, 1H), 8,29 (d, 1H), 8,01 (s, 1H), to 7.67 (d, 1H), 7,49 (DD, 1H), to 4.62 (s, 2H), 4,45 (square, 2H), 3,93 (d, 2H), 3,85 (Sirs, 4H), 3.46 in (Sirs, 4H), to 1.96 (m, 1H), USD 1.43 (t, 3H), and 0.98 (d, 6H)
269553,3555,1(CD3OD): to 9.15 (s, 1H), 9,05 (d, 2H), 8,91 (s, 1H), 839 (d, 1H), 8,14 (s, 1H), 7,79 (d, 1H), 7,55 (DD, 1H), 4,71 (square, 2H), and 4.68 (s, 2H), 4,49 (square, 2H), 3,88 (Sirs, 4H), 3,49 (Sirs, 4H), 1,82 (t, 3H), of 1.44 (t, 3H)
270557,3559,2(CD3OD): 9,11 (s, 1H), 9,03 (d, 2H), 8,84 (s, 1H), 8,31 (d, 1H), with 8.05 (s, 1H), 7,68 (d, 1H), 7,52 (DD, 1H), 4,63 (s, 2H), 4,46 (square, 2H), 3.96 points (Sirs, 4H), 3,52 (Sirs, 2H), 3,44 (Sirs, 2H), 2,71 (t, 2H), 2,65 (t, 2H)that was 1.43 (t, 3H)
271573,2575,2(CD3OD): 9,12 (s, 1H), 9,05 (d, 2H), 8,86 (s, 1H), 8,32 (d, 1H), 8,07 (s, 1H), 7,68 (d, 1H), 7,53 (DD, 1H), 4,63 (s, 2H), 4,46 (square, 2H), 4,37 (s, 2H), is 4.21 (s, 2H), 3,98 (Sirs, 4H), 3,52 (Sirs, 2H), 3,47 (Sirs, 2H), the 1.44 (t, 3H)
272500,23502,05to 1.21 (m, 9H), 3,17 (s, 1H), 3,61 (m, 8H), 4,32 (square, 2H)and 4.65 (s, 2H), 7,56 (t, 1H), 8,10 (s, 1H), 8,58 (s, 1H), 9,07 (d, 2H), of 9.30 (s, 2H)
2734764789,29 (s, 2H), 8,66 (s, 1H), 8,02 (s, 1H), 7,95 (m, 2H), to 7.59 (m, 1H), amounts to 4.76 (s, 2H), 4,30 (m, 2H), 3,94-3,68 (m, 4H), 3,50-3,17 (m, 4H), of 1.30 (t, 3H)
274417,14199,1 (s, 2H), and 9.0 (s, 2H), and 8.4 (s, 1H), and 7.8 (s, 1H), 7.5 (t, 1H), 4,1-4,2 (square, 2H), and 3.7 (s, 2H), 2,3 (s, 6H)and 1.3 (t, 3H)
275466468-
276445,1447of 1.33 (t, 3H), of 2.06 (m, 1H), and 2.26 (m, 1H), 3,88 (m, 4H), 4,33 (square, 2H), to 5.85 (m, 1H), 6,97 (d, 1H), 7,55 (t, 1H), to $ 7.91 (s, 1H), 8,08 (d, 1H), charged 8.52 (m, 2H), 9,05 (d, 2H), to 12.44 (Sirs, 1H)
277475,1477of 1.3 (t, 3H), 2,3 (s, 6H) 3,35 (m, 4H), a 3.9 (m, 4H), 4,3 (square, 2H), 4,6 (s, 2H), 7.7 (d, 1H), and 7.9 (s, 1H), 8.0 a (dt, 1H), and 8.3 (s, 1H), 8,35 (DD, 1H), up 8.75 (d, 1H), 8,8 (Sirs, 1H), and 9.1 (d, 1H), 10,4 (Sirs, 1H)
278502,1504of 1.3 (t, 3H), 3,2 (s, 3H), 3,4 (Sirs, 4H), 3,7 (Sirs, 4H), 3,8 (Sirs, 2H), 4,3 (square, 2H), 4,8 (Sirs, 2H), 7,55 (t, 1H), 8.0 a (d, 1H), and 8.5 (d, 1H), and 9.0 (s, 2H), 9,05 (d, 2H), 11,8 (Sirs, 1H), 12,6 (Sirs, 1H)
279525,2527-
280567,2569(CD3OD): 9,11 (s, 1H), 9,03 (d, 2H), 8,83 (s, 1H), with 8.33 (d, 1H), of 8.06 (s, 1H), 7,68 (d, 1H), 7,52 (DD, 1H), 4,63 (s, 2H), 4,46 (square, 2H), 3,94 (m, 4H), 3,59 (square, 2H), 3,47 (m, 4H), of 1.44 (t, 3H)
281458,15459,989,11 (Sirs, 2H), which is 9.09 (s, 1H), 8,82 (d, 1H), 8,78 (Sirs, 1H), 8,64 (d, 1H), 8,28 (s, 1H), 8,10 (DD, 1H), 7,88 (s, 1H), 7,52 (DD, 1H), 5,38 (m, 1H), 5,5-4,2 (Sirs, 4H), 4,32 (square, 2H), 3.45 points (m, 1H), 3,37 (m, 1H), of 3.12 (m, 2H), 2.05 is (M, 1
282514,2516of 10.05 (m, 1H), 9,24 (m, 1H), 9.15, with (d, 2H), 8,82 (d, 1H), 8,67 (d, 1H), 8,31 (s, 1H), 8,12 (m, 1H), of 7.90 (s, 1H), 7,53 (m, 1H), 5,52 (m, 1H), 4,32 (square, 2H), 3,78 (m, 1H),3,55-is 2.88 (m, 4H), 2,12 (m, 1H), 2,02 (m, 1H), of 1.88 (m, 1H), 1,33 (t
283519,15521,02of 1.3 (t, 3H), 2,35 (s, 12H), and 2.8 (s, 3H), 3,0-3,7 (Sirs, 10H), 4,3 (square, 2H), 4,7 (Sirs, 2H), 7,6 (m, 1H), and 7.9 (s, 1H), 7,95 (m, 2H), 8,65 (m, 1H), and 9.0 (s, 2H)
290487,1489-
291-490-
292482,1484-
293483484,9-
294460,11461,96to 1.15 (t, 3H), 2,3 (s, 9H), of 3.25 (m, 2H), 3,5 (m, 4H), and 3.8 (m, 4H), 7.5 (Sirs, 1H), 7,6 (m, 1H), 7,95 (m, 1H), and 8.0 (s, 1H), 8,1 (m, 1H), and 8.2 (m, 1H), and 8.4 (d, 1H), and 8.6 (s, 1H), and 8.7 (d, 1H), 10,3 (Sirs, 1H)
295--(CD3OD): 9,13 (d, 1H), 9,05 (d, 2H), of 8.92 (d, 1H), of 8.37 (m, 1H), 8,13 (d, 1H), of 7.75 (dt, 1H), 7,55 (t, 1H), 4,70 (s, 2H), 4,49 (square, 2H), 3,62 (m, 4H), 2,47 (m, 4H), of 1.44 (t, 3H) ppm

Example 27

Analysis on the ATPase activity of gyrase

ATP-hydrolytic activity of DNA gyrase was measured by the production of ADP by pervadinti/lactate dehydrogenase with NADH oxidation. This method was described previously (Tamura & Gellert, 1990, J. Biol. Chem., 265, 21342).

The analysis of the ATPase was carried out at 30°in buffered solutions containing 100 mm Tris, pH of 7.6, 1.5 mm MgCl2, 150 mm KCl. System to link contained (final concentration) of 2.5 mm phosphoenol-pyruvate, 200 μm nicotinamide-adenindinucleotide (NADH), 1 mm DTT, 30 μg/ml pyruvate kinase and 10 μg/ml lactate-dehydrogenase. To this was added 40 nanomoles enzyme (374 kDa-subunit Gyr A2B2 fromStaphylococcus aureus) and DMSO solution of the inhibitor to a final concentration of 4% and the reaction mixture was left for 10 minutes at 30°for incubation. Then the reaction had been initiated is ovali by adding ATP to a final concentration of 0.9 mm and the rate of disappearance of NADH at 340 nm was measured for 10 minutes. Values of Kiwas calculated based on the velocity profiles, depending on the concentration.

It was found that the compounds of the present invention inhibit girazu. In some embodiments of the invention, in the above analysis, the compounds of the present invention inhibit girazu with inhibition constant Kiless than 50 nm.

Example 28

Analysis on the ATPase activity of Topo IV

The conversion of ATP to ADP by the enzyme Toro IV is caused by conversion of NADH to NAD+, and was measured by the change in optical density at 340 nm. Toro IV were incubated with the inhibitor (4% DMSO, final concentration) in buffer for 10 minutes at 30°C. the Reaction was initiated ATP and carried out continuous monitoring of the rate of reaction for 20 minutes at 30°on the flatbed reader Molecular Devices SpectraMAX. The inhibition constant, Ki, was determined by the curve of the reaction rate depending on the inhibition of [inhibitor], built by the equation Morrison for tightly binding inhibitors.

Buffer for Toro IVS. aureus:

100 mm Tris, a 7.5, 2 mm MgCl2, 200 mm To·glutamate, 2.5 mm phosphoenol-pyruvate, 0.2 mm NADH, 1 mm DTT, 4,25 μg/ml linearized DNA, 50 μg/ml BSA, 30 μg/ml pyruvate kinase and 10 μg/ml lactate-dehydrogenase (LDH).

Buffer for Toro IVE. coli:

100 7,5 mm Tris, 6 mm MgCl2, 20 mm KCl, 2.5 mm phosphoenol-pyruvate, 0.2 mm NADH, 1 DTT, the 5.25 μg/ml linearized DNA, 50 μg/ml BSA, 30 μg/ml pyruvate kinase and 10 μg/ml lactate-dehydrogenase (LDH).

It was found that the compounds of the present invention inhibit Toro IV. In some embodiments of the invention, in the above analysis, the compounds of the present invention inhibit Toro IV inhibition constant Kiless than 50 nm.

Example 29

The test sensitivity in liquid media

Compounds of the present invention also analyzed for antimicrobial activity using the test sensitivity in liquid media. Such analyses were carried out in accordance with the guidelines of the latest edition of NCClS document, supervising their application in 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), describes the basic practical methods of conducting tests of antibiotics in laboratories. In General, several discrete coloniesStaphylococcus aureus(3-7), obtained from cups fresh bar culture, transferred to the appropriate nutrient broth medium, such as EOM, in which, for the more "demanding" organisms, if necessary, were added to the appropriate components. These cultures were grown overnight to high the lotnosti, and then 1000 - or 2000-fold diluted with obtaining density inoculation 5×105and 5×106CFU/ml. Alternative, picked colonies can be incubated at 37aboutC for approximately 4-8 hours up until the turbidity of the cultures is not equal to or does not exceed 0.5 McFarland standard (approximately 1.5×108cells/ml), and then they can be diluted with obtaining the same CFU/ml as described above. In the more usual method of getting the inoculate using commercially available mechanical devices (BBL PROMPT System), in which five colonies in direct contact with the rod having at its lower end the bar groove, and then receive a suspension of bacteria in an appropriate volume of saline. This cell suspension was diluted to the appropriate cell density of the inoculum. The broth used for the testing environment consists of the EOM, which was added 50 mg/l of Ca2+and 25 mg/l of Mg2+. Then got panels for standard cultivation control of antibiotics and kept in accordance with the standards of the NCCIS M7-A5, the interval cultivation typically ranged from 128 μg/ml to 0.015 μg/ml (2-fold serial dilution). Fresh test compounds were dissolved and diluted on the day of the experiments; this usage is whether the same or similar intervals concentrations, as specified above. Test compounds and controls were divided into multilinear the plate and added the tested bacteria so that the final inoculation was approximately 5×104CFU per well, and the final volume was 100 μl. The plates were incubated at 35°C overnight (16-20 hours) and were visually evaluated for turbidity or conducted a quantitative assessment on multilauncher tablet reader. Minimum inhibitory concentration at the end point (MIC) is the lowest drug concentration at which no growth of the test microorganism (Staphylococcus aureus). The data obtained were also compared with the corresponding tabular data available in the above two publications, to ensure that the level of antibacterial activity is within the relevant limits for the standardized analysis.

It was found that in the above analysis on the MICS. aureuscompounds of the present invention have antimicrobial activity.

Although the authors of the present invention have been described various embodiments of the present invention, however, it is clear that the basic design options can be changed by other options in which to use the products and how us is Vashego of the invention.

61. The compound of the formula I:

or its pharmaceutically acceptable salt,

where W is selected from CH or CF;

X represents CH;

Z represents O or NH;

R1represents phenyl or 5-6-membered heteroaryl ring containing 1-3 nitrogen atom, where

R1substituted by 0-3 groups independently selected from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN, or C(O)N(R')2;

y is 0 or 1;

T is a straight or branched C1-4alkylidene chain, where one methylene link T optionally replaced by-O-;

each R' is independently selected from hydrogen, C1-4of alkyl, C2-4-quinil,3-7-cycloalkyl, phenyl or 5-6-membered saturated, heterocyclic ring containing 1-2 heteroatom, representing nitrogen atoms, where

R' is substituted by 0-3 groups independently selected from halogen, oxo, R°N R°)2, OR°, CO2R°, NR°C(O)R°, where

each R° is independently selected from hydrogen, C1-4of alkyl, phenyl or 5-6-membered saturated heterocyclic or heteroaryl ring containing 1-2 heteroatoms independently selected from nitrogen or oxygen, and where

two Deputy in related provisions of R1taken along the, may form a 5-7-membered saturated, or aryl ring, optionally containing 1-2 heteroatoms independently selected from nitrogen or oxygen;

Ar represents phenyl,3-7-cycloalkyl, 5-6-membered saturated heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl ring containing 1-2 nitrogen atom, where

Ar is substituted by 0-3 groups independently selected from R', oxo, CO2R', OR', halogen, SO2R' and C(O)R';

R2selected from C1-3the alkyl and C3-7-cycloalkyl; and

ring a is a 5-6-membered heteroaryl ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, provided that said ring has a hydrogen bond acceptor in the position adjacent to the position of joining to the ring, where

ring And substituted 0-3 groups independently selected from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'r C(O)R', or NR'r SO2R', where

two Deputy in the adjacent positions of the ring And, taken together, may form a 6-membered saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atom.

2. The compound according to claim 1, where the ring And selected from the following optionally substituted rings:

3. The compound according to claim 2 in which the ring a represents an optionally substituted ring selected from rings a, f, I, s, w, y, or z

,,,,,or.

4. The compound according to claim 1, where R1selected from optionally substituted phenyl, or 5-6-membered heteroaryl ring containing 1-2 nitrogen atom.

<> 5. The compound according to claim 4, where R1represents an optionally substituted ring selected from pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, pyrimidine-6-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl or imidazol-5-yl.

6. The compound according to claim 5, where R1substituted by 0-2 groups independently selected from oxo, R', OR', N(R')2, SR', or C(O)N(R')2.

7. The connection according to claim 6, where R is selected from methyl, ethyl, isopropyl or cyclopropyl.

8. The compound according to claim 1, where the specified compound is a compound of formula II-a:

or its pharmaceutically acceptable salt.

9. The compound according to claim 1, where the specified compound is a compound of formula III:

or its pharmaceutically acceptable salt, where Spiridonova ring is substituted by 0-2 groups independently selected from oxo, R', OR', N(R')2, SR', or C(O)N(R')2.

10. The connection according to claim 9, where the specified compound is a compound of formula III-a:

or its pharmaceutically acceptable salt.

11. The connection of claim 10, where R' represents hydrogen or C1-4alkyl, and where R' is optionally substituted phenyl or pyridium.

12. The compound according to claim 1, where the specified connection is the connection formula is IV:

or its pharmaceutically acceptable salt.

13. The connection section 12, where Ar is an optionally substituted 5-6-membered saturated heterocyclic ring containing 1-2 heteroatoms independently selected from oxygen, nitrogen or sulfur.

14. The connection section 12, where Ar represents an optionally substituted 5-membered heteroaryl ring containing 1-2 nitrogen atom.

15. The connection section 12, where Ar represents an optionally substituted 6-membered heteroaryl ring containing 1-2 nitrogen atom.

16. The connection section 12, where Ar represents optionally substituted phenyl.

17. The compound according to claim 1, where the specified connection is the connection of the formula V:

or its pharmaceutically acceptable salt.

18. The connection 17, where the specified compound is a compound of formula VI:

or its pharmaceutically acceptable salt.

19. The compound according to any one of p, 11, 12 or 17, where R2represents ethyl.

20. A compound selected from the group consisting of:

21. Pharmaceutical composition having the properties of an inhibitor of activity of bacterial gyrase and Topo IV, containing an effective amount of a compound according to any one of claims 1 to 20 and a pharmaceutically acceptable carrier, adjuvant or excipient.

22. Method of inhibiting Girassol activity in a biological sample, comprising the Tadeu contact specified biological sample with a composition according to item 21 or with the compound according to any one of claims 1 to 20.

23. Method of inhibiting Toro IV activity in the biological sample, comprising the stage of contact specified biological sample with a composition according to item 21 or with the compound according to any one of claims 1 to 20.

24. Method of inhibiting Girassol and topo IV activity in the biological sample, comprising the stage of contact specified biological sample with a composition according to item 21 or with the compound according to any one of claims 1 to 20.

25. The way to reduce the number of bacteria in the body of a mammal, comprising the stage of introduction of a given mammal a composition according to item 21 or compounds according to any one of claims 1 to 20.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to new annelated azaheterocyclic amides, including a pyrimidine fragment, with the general formula 1, method of obtaining them and their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of P13K kinase, in compounds with the general formula 1: , where: X represents an oxygen atom, sulphur atom or not necessarily substituted at the nitrogen NH group, where the substitute is selected from lower alkyls and possibly a substituted aryl; Y represents an atom of nitrogen or substituted at the carbon atom CH group, where the substitute is selected from lower alkyls; Z represents an oxygen atom; R1 represents a hydrogen atom or not necessarily substituted C1-C6alkyl, or Z represents a nitrogen atom, which is together with a carbon atom, with which it is joined, form through Z and R1 annelated imidazole cycle; R2 and R3 independently from each other represent hydrogen, not necessarily substituted with C1-C6alkyl, C3-C6cycloalkyl, not necessarily substituted with phenyl, not necessarily substituted with 6-member aza-heteroaryl, under the condition, when Y represents a nitrogen atom, or R2 and R3 independently from each other represent not necessarily substituted C1-C6alkyl, not necessarily substituted with phenyl, not necessarily substituted with 5-7-member heterocycle with 1-2 heteroatoms, selected from nitrogen and oxygen, and possibly annelated with a phenyl ring, under the condition, when Y does not necessarily represent a substituted carbon atom at the CH group, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents a substituted aminoC1-C6alkyl and not necessarily substituted 5-6-member aza-heterocycloalkyl, under the condition, when Y represents a group which is substituted at the CH atom, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents phenyl which is not necessarily substituted, pyridyl which is not necessarily substituted, pyrimidinyl which is not necessarily substituted, under the conditions, when R1 represents a substituted aminoC1-C6alkyl, substituted C2-C3hydroxyalkyl and aza-heterocycloalkyl not necessarily substituted, Y represents a group with CH substituted, and X represents an oxygen atom, sulphur, and the substitute of the above indicated substituted alkyl, phenyl, heterocycle, pyridyl, pyrimidyl are selected from groups of hydroxyl-, cyano-groups, hydrogen, lower alkyls, possibly mono- or di-substituted lower alkyl sulfamoyl, carbamoyl, C1-C6alkoxycarbonyl, amino, mono- or di-lower alkyl-amine, N-(lower alkyl), N-(phenylC1-C6alkyl)amine, phenyl, possibly substituted with a halogen atom, C1-C6alkyl, haloid-C1-C6alkyl; phenylC1-C6alkyl, saturated or non-saturated 5-6-member heterocycle containing 1-2-heteroatoms, selected from nitrogen, oxygen and sulphur, and possible condensation with a benzene ring R4 represents hydrogen or a lower alkyl.

EFFECT: obtaining new annelated aza-heterocyclic amides, including a pyrimidine fragment, with the general formula with the possibility of their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of PI3K kinase.

16 cl, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1 represents similar or different 2 groups, each of which is selected from group consisting of C1-3alkyl, or when R1 are two adjacent groups, two groups R1, taken together, can form saturated or unsaturated 5- or 6-member cyclic group, which can have 1 or 2 oxygens as heteroatom; X represents oxygen or sulphur; values of other radicals are given in invention formula.

EFFECT: increase of composition efficiency.

16 cl, 11 tbl, 31 ex

FIELD: medicine; pharmacology.

SUBSTANCE: new annelated asaheterocycles include pyrimidine fragment of general formula I in the form of free bases or pharmaceutically acceptable salts. Compounds of this invention possess properties of PI3 kinase inhibitors. In general formula I X represents oxygen atom or sulphur atom; Z represents oxygen atom, R1 represents hydrogen atom or optionally substituted C1-C6alkyl, or Z represents nitrogen atom together with bound carbon atom forming through Z and R1 optionally substituted annelated imidazoline cycle; R2 represents optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, possibly annelated with 5-6-term heterocyclyl containing heteroatoms chosen from oxygen and nitrogen, optionally substituted 5-6-term heterocyclyl containing heteroatoms chosen from nitrogen, oxygen and/or sulphur, possibly annelated with phenyl ring. Invention also concerns method of production of compounds, pharmaceutical compositions and medical products.

EFFECT: effective application for preparation of medical products for oncologic therapy.

14 cl, 3 dwg, 1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: in general formula I

R1 is phenyl or 5-6-member heterocycle, containing one N atom and/or one O atom; R2 is imidazole or annelated imidazole, selected from group, including a), b), c), d) and e); and R3 stands for hydrogen, phenyl, 2,3-dihydrobenzo[1,4]dioxin-6-yl, benzo[b]thiophen-3-yl, 3-methylbenzo[b] thiophen-2-yl, thiophen-2-yl or thiophen-2-ylmethyl, R4 is hydrogen or lower alkyl, R5 is hydrogen, lower alkyl, halogen, morpholinyl, -NR'R", piperydinyl, optionally substituted with hydroxy-group, or is pyrrolidin-1-yl; R6 is hydrogen or -(CH2)nO-lower alkyl, R7 is hydrogen, -C(O)O-lower alkyl, -C(O)-C6H4-halogen, -C(O)-C6H4-lower alkyl, -C(O)-lower alkyl, -C(O)-cycloalkyl, -C(O)-NR'R", -C(O)-(CH2)nO-lower alkyl, -S(O)2-lower alkyl, -(CH2)nO-lower alkyl, -C(O)-pyridin-4-yl, whose ring can contain as substituents lower alkyl, halogen-lower alkyl or pyrrolidin-1-ylmethyl or is -(CH2)n-C(O)-NR'R"; R'/R" independently on each other stand for hydrogen, lower alkyl or -(CH2)n-tetrahydropyran-4-yl, X is -CH2-, -NR'''- or -O-; R''' is hydrogen, -C(O)-lower alkyl, -C(O)O-lower alkyl, -C(O)-C6H4CH3 or benzyl; n is 1 or 2.

EFFECT: increase of composition and treatment method efficiency.

14 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of formula (I) as well as to synthesis procedure and application for treatment of various disorders, including inflammatory and autoimmune disorders, and disorders caused by malignant growths or by increased angiogenesis where R1-R11, t, X, Y, Z and n have values specified in the description.

EFFECT: production of macrocyclic compounds used for treatment of various disorders, including inflammatory and autoimmune disorders, and disorders caused by malignant growths or by increased angiogenesis.

41 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns new tricyclic derivatives of the formula (I) and their pharmaceutically acceptable salts, where: 1 to 3 of A1, A2, A3 and A4 are nitrogen atoms, while the rest are -CH- groups; G1 is a group selected out of -CH2-O-, -CH2-CH2-, - CH=CH-; -N(C1-C4alkyl)-CH2; G2 is a group selected out of -O-CH2-, -CH=CH-, -CH2- CH2-; R4 can be identical or different and are selected out of a group including hydrogen or halogen atoms; p are independently equal to 0, 1 or 2; Y is and optionally substituted residuum selected out of the group of alkyl, cycloalkyl, alkylaryl, alkylcycloalkylalkyl; Z is a tetrazolyl, -COOR5, -CONR5R5, NHSO2R5 or -CONHSO2R5 group, where R5 is hydrogen or optionally substituted alkyl or aryl. The invention also concerns a method of obtaining the claimed compounds.

EFFECT: possible application in treatment and prophylactics of inflammation and allergy diseases.

20 cl, 2 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the bonds consistent with the general formula (I) or the general formula (II) where: R1 = H; Z = O or S; P1 = CR5R6, P2 = CR7R8, Q = CR9R10; each of R5, R6, R7, R8, R9 and R10 denotes H; Y = CR12R13-CO, where R12, R13 is selected from C0-7-alkyl; C3-6-cycloalkyl or phenyl-C0-7-alkyl; and where the phenyl ring doesn't have to be substituted R19, specified below; in the group (X)0, X = CRI4R15, where R14 and R15 are independently selected from C0-7-alkyl, and o represents a number from zero to three; (W)n, W = O, S, C(O), S(O) or S(O)2 or NR16, where R16 denotes H, and n equals zero or one; (V)m, V = C(O), NHC(O), C(O)NH or CR17R18, where R17 and R18 denotes H, and m represents a number from zero to three, on condition that, when m is more than one, (V)m contains a maximum of one carbonyl group; U = a stable 5-7-member monocyclic or 8-11-member dicyclic ring, which is saturated or non-saturated and which has from zero to four heteroatoms selected from: , where R19 represents: C0-7-alkyl, C3-6-cycloclkyl, Ar-C0-7-alkyl, O-C0-7-aklyl, NH-C0-7-alkyl, N(C0-7-alkyl)2, O-phenyl, S-phenyl; or, as a part of CHR19 or CR19 group, R19 can represent a halogen; where Ar represents a stable 5- or 6- member monocyclic or stable 9- or 10- member dicyclic ring, which is unsaturated as determined earlier for U, and where Ar doesn't have to be substituted R19, which is of importance specified above; C0-7-alkyl represents a stable linear or a branched aliphatic carbon chain, which contains from 0 to 7 carbon atoms, which doesn't have to be substituted with one, two or three halogen atoms and doesn't have to contain one or few heteroatoms selected from O, N and S, where the heteroatom is present only when C0-7-alkyl contains as a minimum one carbon atom; C3-6-cycloalkyl relates to C0-7-alkyl, certainly higher than the additionally contained carboxyl ring, which doesn't have to be substituted with one or more halogens, selected from F, Cl, Br and I or heteroatoms, selected from N, O, S; A represents O; B, D and G are independently selected from: CR19, where R19 is as specified above or N; E represents O or S; J, L, M, R, T, T2, T3 and T4 which are independently selected from: CR19 and N, where R19 is as specified above; T5 represents N; q represents a number from one to three, determining in this way a 5-, 6- or 7- member ring or its salt, hydrate or solvate. The bonds of the general formula (I) or the general formula (II), represent cruzipain inhibitors and inhibitors of other cisteinproteases and can be used as therapeutic agents, for example, in cases of Chagas disease or for confirmation of target oriented therapeutic bonding.

EFFECT: new bonds which posses helpful biological properties have been discovered.

27 cl, 156 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the bonds consistent with the general formula (I) or the general formula (II) where: R1 = H; Z = O or S; P1 = CR5R6, P2 = CR7R8, Q = CR9R10; each of R5, R6, R7, R8, R9 and R10 denotes H; Y = CR12R13-CO, where R12, R13 is selected from C0-7-alkyl; C3-6-cycloalkyl or phenyl-C0-7-alkyl; and where the phenyl ring doesn't have to be substituted R19, specified below; in the group (X)0, X = CRI4R15, where R14 and R15 are independently selected from C0-7-alkyl, and o represents a number from zero to three; (W)n, W = O, S, C(O), S(O) or S(O)2 or NR16, where R16 denotes H, and n equals zero or one; (V)m, V = C(O), NHC(O), C(O)NH or CR17R18, where R17 and R18 denotes H, and m represents a number from zero to three, on condition that, when m is more than one, (V)m contains a maximum of one carbonyl group; U = a stable 5-7-member monocyclic or 8-11-member dicyclic ring, which is saturated or non-saturated and which has from zero to four heteroatoms selected from: , where R19 represents: C0-7-alkyl, C3-6-cycloclkyl, Ar-C0-7-alkyl, O-C0-7-aklyl, NH-C0-7-alkyl, N(C0-7-alkyl)2, O-phenyl, S-phenyl; or, as a part of CHR19 or CR19 group, R19 can represent a halogen; where Ar represents a stable 5- or 6- member monocyclic or stable 9- or 10- member dicyclic ring, which is unsaturated as determined earlier for U, and where Ar doesn't have to be substituted R19, which is of importance specified above; C0-7-alkyl represents a stable linear or a branched aliphatic carbon chain, which contains from 0 to 7 carbon atoms, which doesn't have to be substituted with one, two or three halogen atoms and doesn't have to contain one or few heteroatoms selected from O, N and S, where the heteroatom is present only when C0-7-alkyl contains as a minimum one carbon atom; C3-6-cycloalkyl relates to C0-7-alkyl, certainly higher than the additionally contained carboxyl ring, which doesn't have to be substituted with one or more halogens, selected from F, Cl, Br and I or heteroatoms, selected from N, O, S; A represents O; B, D and G are independently selected from: CR19, where R19 is as specified above or N; E represents O or S; J, L, M, R, T, T2, T3 and T4 which are independently selected from: CR19 and N, where R19 is as specified above; T5 represents N; q represents a number from one to three, determining in this way a 5-, 6- or 7- member ring or its salt, hydrate or solvate. The bonds of the general formula (I) or the general formula (II), represent cruzipain inhibitors and inhibitors of other cisteinproteases and can be used as therapeutic agents, for example, in cases of Chagas disease or for confirmation of target oriented therapeutic bonding.

EFFECT: new bonds which posses helpful biological properties have been discovered.

27 cl, 156 ex, 2 tbl

FIELD: chemistry; pharmacy.

SUBSTANCE: invention claims novel [1,2,4]triazolo[1,5-a]pyrimidine-2-ylurea derivatives of the general formula (1), or their pharmaceutically acceptable salts: [formula 1] , where Ar is optionally substituted phenyl group, dihydrobenzofuranyl or thiophenyl group. X is O. R is group of formula (2)-(6) or , where values of Cy and R4-R12 radicals are given in the claim, and medicine containing these compounds.

EFFECT: obtaining compounds with immunosuppressive or immune tolerance inducing effect, which can be applied in medicine.

14 cl, 16 tbl, 333 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new macrocyclic compounds with formula (I): (where R3, R6, R7 and R21 can be identical or different from each other, and each of them assume values given in the description), their salts used in pharmacology and their hydrate. Compounds with formula (I) are capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, and can be used as therapeutic means of treating solid malignant tumours. The invention also relates to medicinal agents based on these compounds, prevention and treatment method and use of these compounds in making preparations for preventing and treating cancerous diseases.

EFFECT: obtaining compounds, capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, which can be used as therapeutic means of treating solid malignant tumours.

35 cl, 3 tbl, 147 ex

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of pyridazin-3(2H)-one of formula (I), where R1, R2 and R4 are organic radicals described in the claim 1, R3 is cyclic group described in the claim, and R5 is phenyl or heteroaryl group described in the claim. Compounds of formula (I) inhibit phosphodiesterase 4 (PDE-4) and can be applied in treatment of various diseases or pathological states alleviated by PDE-4 inhibition, and in medicine production for treatment of aforesaid diseases. Also invention claims method of obtaining these compounds and intermediate compounds for their obtainment.

EFFECT: obtaining compounds which can be used in treatment of various diseases or pathological states and in medicine production for treatment of aforesaid diseases.

25 cl, 28 tbl, 243 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new annelated azaheterocyclic amides, including a pyrimidine fragment, with the general formula 1, method of obtaining them and their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of P13K kinase, in compounds with the general formula 1: , where: X represents an oxygen atom, sulphur atom or not necessarily substituted at the nitrogen NH group, where the substitute is selected from lower alkyls and possibly a substituted aryl; Y represents an atom of nitrogen or substituted at the carbon atom CH group, where the substitute is selected from lower alkyls; Z represents an oxygen atom; R1 represents a hydrogen atom or not necessarily substituted C1-C6alkyl, or Z represents a nitrogen atom, which is together with a carbon atom, with which it is joined, form through Z and R1 annelated imidazole cycle; R2 and R3 independently from each other represent hydrogen, not necessarily substituted with C1-C6alkyl, C3-C6cycloalkyl, not necessarily substituted with phenyl, not necessarily substituted with 6-member aza-heteroaryl, under the condition, when Y represents a nitrogen atom, or R2 and R3 independently from each other represent not necessarily substituted C1-C6alkyl, not necessarily substituted with phenyl, not necessarily substituted with 5-7-member heterocycle with 1-2 heteroatoms, selected from nitrogen and oxygen, and possibly annelated with a phenyl ring, under the condition, when Y does not necessarily represent a substituted carbon atom at the CH group, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents a substituted aminoC1-C6alkyl and not necessarily substituted 5-6-member aza-heterocycloalkyl, under the condition, when Y represents a group which is substituted at the CH atom, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents phenyl which is not necessarily substituted, pyridyl which is not necessarily substituted, pyrimidinyl which is not necessarily substituted, under the conditions, when R1 represents a substituted aminoC1-C6alkyl, substituted C2-C3hydroxyalkyl and aza-heterocycloalkyl not necessarily substituted, Y represents a group with CH substituted, and X represents an oxygen atom, sulphur, and the substitute of the above indicated substituted alkyl, phenyl, heterocycle, pyridyl, pyrimidyl are selected from groups of hydroxyl-, cyano-groups, hydrogen, lower alkyls, possibly mono- or di-substituted lower alkyl sulfamoyl, carbamoyl, C1-C6alkoxycarbonyl, amino, mono- or di-lower alkyl-amine, N-(lower alkyl), N-(phenylC1-C6alkyl)amine, phenyl, possibly substituted with a halogen atom, C1-C6alkyl, haloid-C1-C6alkyl; phenylC1-C6alkyl, saturated or non-saturated 5-6-member heterocycle containing 1-2-heteroatoms, selected from nitrogen, oxygen and sulphur, and possible condensation with a benzene ring R4 represents hydrogen or a lower alkyl.

EFFECT: obtaining new annelated aza-heterocyclic amides, including a pyrimidine fragment, with the general formula with the possibility of their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of PI3K kinase.

16 cl, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to methane sulphonate of 8-(3-pentylamino)-2-methyl-3-(2-chloro-4-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrazol[1,5-a]pyrimidine, its crystal and method of obtaining it. Methane sulphonate of 8-(3-pentylamino)-2-methyl-3-(2-chloro-4-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrazol[1,5-a]pyrimidine has excellent thermal stability. The invention also relates to pharmaceutical compositions based on the above mentioned salt and its crystal. The compositions are CRF antagonists and can be used for treating neuropsychiatric disorders or alimentary system diseases. The invention also pertains to an efficient high output new method of making the intermediate compound 1-cyano-1-(2-chloro-4-methoxyphenyl)propan-2-one from 1-bromo-2-chloro-4-methoxybenzol.

EFFECT: obtaining intermediate compound with efficient high output.

16 cl, 6 dwg, 10 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new compound - acid mesylate of 4-(4-trans-hydroxycyclohexyl) amino-2-phenyl-7H-pyrrolo [2,3d]pyrimidine and its polymorphous α and β forms. The compound has agonistic activity towards adenosine-1 receptor and can be used for making medicinal preparations for treating hypertensive diseases, congestive heart failure and renal failure.

EFFECT: obtaining a compound with better bioavailability due to high solubility and which is more stable in ambient conditions.

17 cl, 6 dwg, 6 ex

FIELD: chemistry.

SUBSTANCE: described is 4-(4'-hydroxybutyl)-6-phenyl-1,2,4-triazolo[5,1-c] [1,2,4]triazin-7-on of formula (1) possessing anti-viral activity, , which can be applied in medicine and agriculture.

EFFECT: obtaining compound which possesses antiviral activity.

1 cl, 3 ex, 1 tbl

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of diaminopyrrolo quinazoline of formula (I), which possess properties of protein tyrosine phosphatase PTP-1B inhibitors and can be used for reduction of glucose concentration in blood. In general formula (I) A stands for 5- or 6-member unsaturated or saturated hydrocarbon ring or 5- or 6-member unsaturated or saturated ring, which contains at least one heteroatom, selected from S, N or O, R1 represents hydrogen or lower alkyl; Ra represents hydrogen,

,

,

,

or lower alkyl , R1, Ra, Rb, Rc, Rd, Re, Rf are such as defined in invention formula.

EFFECT: obtaining derivatives of diaminopyrrolo quinazoline which possess properties of protein tyrosine phosphatase inhibitors.

32 cl, 5 dwg, 118 ex

FIELD: chemistry.

SUBSTANCE: this invention refers to new production method of composition of formula I where R1 represents: H; cyano; optionally unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; or -C(O)-R5, where R5 represents H; optionally unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; either OR6 or NR6R7 where each R6 and R7 independently represents H optionally unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; R2 represents H; R3 represents H or alkyl; R4 represents H, halogen or alkyl including: a) Sonogashira coupling of formula II , where X represents halogen or CF3SO2-O- with compound of formula III to produce compound of formula IV ; b) reduction of connection of formula IV to produce compound of formula V ; c) transformation of compound of formula V into compound of formula VI ; d) N,N-dimethyl-2-nitroethylenamine treatment of compound of formula VI to produce compound of formula VII ; e) reduction of connection of formula VII to produce compound of formula VIII ; f) of compound of formula VIII by Raney-nickel reduction and subsequent base ring formation into compound of formula I. Besides described is production method of 8-fluorine-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indole-6-one through key Sonogashira coupling reaction and CuI-promotor indole production.

EFFECT: new production method of compounds of formulas I effective as poly(ADP-ribose)polymerase inhibitors is developed.

8 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: sodium salt of 2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazin-7-one, dehydrate of formula (1) is obtained by interaction of salt of 3-methylthio-1,2,4-triazol-5-yl-diazonium with diethylnitromalonate in presence of base at 0-25°C in water-alcohol medium.

EFFECT: compound possesses antivirus activity and can find application in medicine.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new 7-azaindoles with general formula 1: where (a) A stands for an N-oxide group and B stands for CH, nitrogen, (b) A stands for nitrogen and B stands for an N-oxide group, or (c) A and B stand for an N-oxide group, R1 stands for (i) -C1-10-alkyl, unbranched or branched, which, if necessary, is monosubstituted with saturated mono- C3-C6carbocycle, or mono-, bi- multi-unsaturated C6-C10carbocycle. C6-10-aryl groups in turn, if necessary, can be mono- or multi-substituted with -C1-6-alkyl, -CN, -F, -CI, -Br, -I, -O-C1-6-alkyl groups. Alkyl groups in carboxylic substitutes, in turn, if necessary, can be mono- or multi-substituted with -F groups. R2 stands for hydrogen, C1-C3alkyl. R3 and R4 are identical or different, and stand for hydrogen, -F, -Cl, -Br, -I. The invention also relates to pharmaceutical salts of these 7-azaindoles.

EFFECT: compounds with general formula I exhibit phosphodiesterase 4 inhibiting activity, which allows for their use as therapeutic active substances for making medicinal agents, which suppress pulmonary neutrophilia and eosinophilia.

14 cl, 2 tbl, 7 ex

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