Application of 4-(pyrrolidine-1-yl)quinoline compounds for elimination of clinically latent microorganisms

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry and medicine and deals with novel 4-(pyrrolidine-1-yl)quinoline compounds, a method of their obtaining and application for treatment of bacterial or fungal infection.

EFFECT: invention provides extension of arsenal of means for fighting "latent" bacteria.

17 cl, 3 dwg, 1 tbl, 47 ex

 

The present invention relates to the use of compounds based on the ring system is 4-(pyrrolidin-1-yl)quinoline for the destruction of clinically latent microorganisms. The invention additionally relates to the use of such compounds for the treatment of microbial infections, as well as, among other things, certain of the compounds as such.

In this description of the invention it is not necessary to describe or discuss previously published document to confirm that the document is part of the prior art or is a well-known technology.

Before the introduction of antibiotics for patients suffering from acute bacterial infections (such as tuberculosis or pneumonia), had a high risk of fatal outcome. For example, the tuberculosis mortality rate was about 50%.

Despite the fact that the introduction of antibacterial agents in the 1940s and 1950s, the years are rapidly changing this situation, the bacteria responded gradually acquired resistance to commonly used antibiotics. Today, in all countries there are bacteria that are resistant to antibiotics. In fact, in the USA, more than 70% of bacteria that cause hospital-acquired infections are resistant to at least one of the main antimicrobial agents, which are generally used for infection control (seeNature Reviews, rug Discovery 1, 895-910 (2002)).

One of the ways to solve the growing problem of resistant bacteria is the development of new classes of antimicrobial agents. However, prior to the introduction in 2000 of linezolid more than 37 years in the market has not been presented a new class of antibiotics. Moreover, even the development of new classes of antibiotics provides only a temporary solution, and in fact, already there are reports about the resistance of some bacteria to linezolid (seeLancet357, 1179 (2001andLancet358, 207-208 (2001)).

It is clear that for a more promising solution to the problem of bacterial resistance requires alternative approaches. One such alternative is to minimize, to the extent possible, potential, which gives bacteria the opportunity to develop resistance to important antibiotics.

Thus, strategies that can be adopted include limiting the use of antibiotics to treat infections without exacerbation, as well as control over what antibiotics given to animals for growth promotion.

However, for a more effective solution to the problem it is necessary to understand the actual mechanisms by which bacteria develop resistance to antibiotic agents. This requires, first, an analysis of how existing at the present is the third day of antibiotic agents kill bacteria.

Antimicrobial agents aimed at important components of the metabolism of bacteria. For example, β-lactams (e.g., penicillins and cephalosporins) inhibit cell wall synthesis, while other agents inhibit a number of targets, such as DNA gyrase (quinolones), and protein synthesis (e.g., macrolides, aminoglycosides, tetracyclines and oxazolidinone). The range of organisms against which it is effective antimicrobial agents varies depending on which organisms depend essentially on stage(th) metabolism, which is(s) inhibits(ut)SJ. In addition, the influence of bacteria can vary from mere inhibition of growth (i.e. bacteriostatic effect, as is illustrated by the agents, such as tetracycline) to complete destruction (i.e. bactericidal effect, as seen on the example of penicillin).

Bacteria appeared on Earth more than 3 million years ago, and at that time it was required to answer a huge number of stress-free environment. Perhaps it is not surprising that bacteria have developed a seemingly inexhaustible number of mechanisms by which they can respond to metabolic stress created for them antibiotic agents. Indeed, the mechanisms by which bacteria can create resistance include different strategies as inactivation medicines modifications the Oia website exposure modification of the permeability of the cell wall, overproduce target enzyme and bypass inhibited stages.

However, it was shown that the rate of emergence of resistance to a particular agent can vary widely depending on factors such as the mechanism of action of the agent, is there a way of destroying agent dependent on time or concentration effective against the bacteria population and the magnitude and duration of available serum concentration.

It has been suggested (see article in the journalScience264, 388-393 (1994)), which is the most prone to developing resistance to agents that target a single enzyme (e.g., rifampicin). In addition, the longer near-optimal levels of antimicrobial agent are in contact with bacteria, the more likely the emergence of resistance.

Moreover, it is now known that many bacterial infections include subpopulations of bacteria thatphenotypicresistant to antimicrobial agents (see, for example:J. Antimicrob. Chemother. 4, 395-404 (1988);J. Med. Environ. 38, 197-202 (1993);J. Bacteriol. 182, 1794-1801 (2000); ibid 182, 6358-6365 (2000); ibid 183, 6746-6751 (2001);FEMS Environ. Lett. 202, 59-65 (2001); andTrends in Microbiology13, 34-40 (2005)). Find several types of such phenotypic resistant bacteria, including persistent bacteria, the bacteria is in the stationary phase, as well as being thicker biofilms. However, each of these types is characterized by its low rate of growth (compared with bacteria in the log phase under the same conditions). Also frequent differences of such bacteria are depleted of nutrients and the high density of cells.

Despite resistance to antimicrobial agents in the state of their slow growth, phenotypic resistant bacteria are different fromgenotypicresistant the fact that they restore their sensitivity to antimicrobial agents when returning to a state of rapid growth (for example, when nutrients become more available to them).

The phenotypic resistant bacteria in infection leads to prolonged courses of antimicrobial agents containing multiple doses. This is because sustainable slowly breeding bacteria create a pool of "latent" organisms that can move to a state of rapid growth when conditions allow (resulting essentially re-initiation of infection). Multiple doses over time are struggling with this problem through the gradual destruction of the "latent" bacteria that are transferred to the "active" form.

However, the struggle with the "latent" bacteria by applying long is ursov antimicrobial creates its own problems. Then there a long lasting effect on bacteria suboptimal concentrations of antimicrobial agent can lead to the emergence of genotypic resistant bacteria, which then can multiply rapidly even in the presence of high concentrations of antimicrobial drug.

Prolonged courses of antimicrobial drugs is more likely to promote the emergence of genotypic resistance than shorter courses on the basis that non-breeding bacteria will be prone to survival and, interestingly, may have an enhanced ability to mutate to resistance (see, for example,Proc. Natl. Acad. Sci. USA92, 11736-11740 (1995);J. Bacteriol. 179, 6688-6691 (1997); andAntimicrob. Agents Chemother. 44, 1771-1777 (2000)). For example, dividingE. colicontinuously mutates to a state of resistance to ciprofloxacin during the seven days of exposure to this agent. Thus, the "latent" bacteria may constitute one of the sources of genotypic resistant bacteria.

In light of this, a new approach to counter the problem of bacterial resistance may be the selection and development of antimicrobial agents on the basis of their ability to destroy the "latent" microorganisms. Products such agents would, among other things, to reduce chemotherapy regimens in the treatment of microbial infections, so is nija frequency, in microorganisms occurs genotypic resistance.

Some compounds containing the skeleton of 4-(pyrrolidin-1-yl)quinoline, are described in WO 92/17452; WO 98/05644; WO 02/094789; and WO 2006/070284. In none of these documents describes that compounds based on 4-(pyrrolidin-1-yl)quinoline ring system destroyclinically latentthe microorganisms.

Additional compounds containing the skeleton of 4-(pyrrolidin-1-yl)quinoline, are described in US 2006/217377 and WO 2006/071875. In these documents describes compounds based on 4-(pyrrolidin-1-yl)quinoline ring system for use only as inhibitors of voltage gated (potassium or sodium) ion channels or as antagonists of the chemokine receptors.

In articleYao Xue Xue Bao827-834 (1982) mentioned activity against malaria parasites of some 6-substituted compounds (2,4-dipyrrole-1-yl) hintline.

To date, the inventors have unexpectedly found that certain 4-(pyrrolidin-1-yl)quinoline can be used to kill clinically latent microorganisms.

According to the first aspect of the invention features the use of the compounds of formula I or its pharmaceutically acceptable derivative to obtain drugs for destruction clinically latent microorganisms, where the connection is a group of formula I is represented by the structure

where

E represents CH or N;

R1represents one to four substituents in pyrrolidinium ring, and each Deputy independently represents a group-X-R4A;

X represents

(a) a simple link,

(b) -O - or

(c) -N (R4b)-;

R4Aand R4bindependently represent

(a) H,

(b) (C1-12alkyl, C3-12cycloalkyl,3-12cycloalkenyl (these latter three groups are optionally substituted by one or more substituents selected from halogen, nitrogen, CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil,3-8cycloalkyl (the latter three groups are optionally substituted by one or more substituents selected from HE, =O, halogen, C1-4the alkyl and C1-4alkoxy), or SIG5A, S(O)nR5b, S(O)2N(R5c)(R5d), N(R5e)S(O)2R5fN(R5g)(R5h), B1-C(O)-B2-R5i, aryl and Het1and those With3-12cycloalkyl or4-12cycloalkenyl groups may additionally be substituted by =O),

(C) aryl or

(d) Het2;

R2is

H,

(b) (C1-12alkyl, C2-12alkenyl,2-12quinil,3-12cycloalkyl,4-12cycloalkenyl, these latter five groups are optionally substituted by one the or more substituents, selected from halogen, nitrogen, CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil,3-8cycloalkyl (the latter three groups are optionally substituted by one or more substituents selected from HE, =O, halogen, C1-4the alkyl and C1-4alkoxy), or SIG6A, S(O)pR6b, S(O)2N(R6c)(R6d), N(R6e)S(O)2R6fN(R6g)(R6h), B3-C(O)-B4-R6i, aryl and Het3and those With3-12cycloalkyl or4-12cycloalkenyl groups may additionally be substituted by =O),

(C) aryl or

(d) Het4;

R3represents H or from one to four substituents on the condensed benzene ring, selected from

(a) halogen,

(b) CN,

(c)1-12of alkyl, C2-12alkenyl,2-12the quinil,3-12cycloalkyl,4-12cycloalkenyl, these latter five groups are optionally substituted by one or more substituents selected from halogen, nitrogen, CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil,3-8cycloalkyl (the latter three groups are optionally substituted by one or more substituents selected from HE, =O, halogen, C1-4the alkyl and C1-4alkoxy), or SIG7a, S(O)qR7b, S(O)2N(R7c)(R7d), N(R7e)S(O)2R7fN(R7g)(R7h), B -C(O)-B6-R7i, aryl and Het5and those With3-12cycloalkyl or4-12cycloalkenyl groups may additionally be substituted by =O),

(d) OR8a,

(e) S(O)rR8b,

(f) S(O)2N(R8c)(R8d),

(g) N(R8e)S(O)2R8f,

(h) N(R8g)(R8h),

(i) B7-C(O)-B8-R8i,

(j) aryl or

(k) Het6;

R5A-R5i, R6A-R6i, R7a-R7iand R8A-R8iindependently represent in each case,

(a) H,

(b) (C1-10alkyl, C2-10alkenyl,2-10quinil (the latter three groups are optionally substituted by one or more substituents selected from halogen, HE1-6alkoxy, aryl and Het7),

(C)3-10cycloalkyl,4-10cycloalkenyl (the latter two groups are optionally substituted by one or more substituents selected from halogen, HE, =O,1-6of alkyl, C1-6alkoxy, aryl and Het8),

(d) aryl or

(e) Het9,

provided that R5b, R6b, R7bor R8bdifferent from N, if n, p, q or r, respectively take the values 1 or 2;

each aryl independently represents a C6-10carbocyclic aromatic group, which may contain one or two rings and may be substituted by one or more will replace the guides and selected from the

(a) halogen,

(b) CN,

(c)1-12of alkyl, C2-12alkenyl,2-12the quinil,3-12cycloalkyl,4-12cycloalkenyl, these latter five groups are optionally substituted by one or more substituents selected from halogen, nitrogen, CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil,3-8cycloalkyl (the latter three groups are optionally substituted by one or more substituents selected from HE, =O, halogen, C1-4the alkyl and C1-4alkoxy), or SIG9a, S(O)tR9b, S(O)2N(R9c)(R9d), N(R9e)S(O)2R9fN(R9g)(R9h), B9-C(O)-B10-R9i, phenyl, naphthyl (the latter two groups are optionally substituted by one or more substituents selected from HE, halogen, C1-4the alkyl and C1-4alkoxy) and Het10and those With3-12cycloalkyl or4-12cycloalkenyl groups may additionally be substituted by =O),

(d) OR10a,

(e) S(O)uR10b,

(f) S(O)2N(R10c)(R10d),

(g) N(R10e)S(O)2R10f,

(h) N(R10g)(R10h),

(i) B11-C(O)-B12-R10i,

(j) phenyl (the latter group is optionally substituted by one or more substituents selected from HE, halogen, C1-4the alkyl and C1-4alkoxy), or

(k) Het11;

R9a-R9iand R10A-R10iindependently represent in each case,

(a) H,

(b) (C1-12alkyl, C2-12alkenyl,2-12quinil,3-12cycloalkyl,4-12cycloalkenyl (these latter five groups are optionally substituted by one or more substituents selected from halogen, HE1-6of alkyl, C3-12cycloalkyl,4-12cycloalkenyl (the latter two groups are optionally substituted by one or more substituents selected from HE, =O, halogen, C1-4the alkyl and C1-4alkoxy), C1-6alkoxy, NH2N(H)-C1-6of alkyl, N(C1-6alkyl)2, phenyl (the latter group is optionally substituted by one or more substituents selected from HE, halogen, C1-4the alkyl and C1-4alkoxy) and Het12and those With3-12cycloalkyl or4-12cycloalkenyl groups may additionally be substituted by =O),

(C) phenyl (the latter group is optionally substituted by one or more substituents selected from HE, CN, halogen, C1-6the alkyl and C1-6alkoxy), or

(e) Het13,

provided that R9bor R10bdifferent from N, if t or u, respectively take the values 1 or 2;

Het1- Het13independently represent 4-14-membered heterocyclic group containing one or a few is to heteroatoms, selected from oxygen, nitrogen and/or sulfur, these heterocyclic groups may contain one, two or three rings and may be substituted by one or more substituents selected from the

(a) halogen,

(b) CN,

(c)1-12of alkyl, C2-12alkenyl,2-12the quinil,3-12cycloalkyl,4-12cycloalkenyl, these latter five groups are optionally substituted by one or more substituents selected from halogen, nitrogen, CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil,3-8cycloalkyl (the latter three groups are optionally substituted by one or more substituents selected from HE, =O, halogen, C1-4the alkyl and C1-4alkoxy), or SIG11a, S(O)vR11b, S(O)2N(R11c)(R11d), N(R11e)S(O)2R11fN(R11g)(R11h), B13-C(O)-B14-R11i, phenyl, naphthyl (the latter two groups are optionally substituted by one or more substituents selected from HE, halogen, C1-4the alkyl and C1-4alkoxy) and Hetandand those With3-12cycloalkyl or4-12cycloalkenyl groups may additionally be substituted by =O,

(d) OR12a,

(e) =O,

(f) S(O)wR12b,

(g) S(O)2N(R12c)( R12d),

(h) N(R12e)S(O)2R12f,

(i) N(R12g)(R12h),

(j) B15-C(O)-B16-R12i ,

(k) phenyl (the latter group is optionally substituted by one or more substituents selected from HE, halogen, C1-4the alkyl and C1-4alkoxy), or

(l) Hetb;

R11a-R11iand R12A-R12iindependently represent in each case,

(a) H,

(b) (C1-12alkyl, C2-12alkenyl,2-12quinil,3-12cycloalkyl,4-12cycloalkenyl (these latter five groups are optionally substituted by one or more substituents selected from halogen, HE1-6of alkyl, C3-12cycloalkyl,4-12cycloalkenyl (the latter two groups are optionally substituted by one or more substituents selected from HE, =O, halogen, C1-4the alkyl and C1-4alkoxy), C1-6alkoxy, phenyl (the latter group is optionally substituted by one or more substituents selected from HE, halogen, C1-4the alkyl and C1-4alkoxy) and Hetwithand those With3-12cycloalkyl or4-12cycloalkenyl groups may additionally be substituted by =O),

(C) phenyl (the latter group is optionally substituted by one or more substituents selected from HE, halogen, C1-4the alkyl and C1-4alkoxy), or

(e) Hetd,

provided that R11bor R12bdifferent from N, if v or w, respectively, taking the value of 1 is 2;

B1- B16independently represent a simple bond, O, S, NH or N(R13);

n, p, q, r, s, t, u, v and w independently take values 0, 1 or 2;

R13is

(a)1-6alkyl,

(b) phenyl (the latter group is optionally substituted by one or more substituents selected from HE, halogen, C1-4the alkyl and C1-4alkoxy),

(C)3-7cycloalkyl (the latter group is optionally substituted by one or more substituents selected from HE, =O, halogen, C1-4the alkyl and C1-4alkoxy), or

(e) Hete;

Hetand- Heteindependently represent a 5-or 6-membered heterocyclic group containing one to four heteroatoms selected from oxygen, nitrogen and/or sulfur, these heterocyclic group may be substituted by one or more substituents selected from halogen, =O and C1-6of alkyl; and

unless otherwise specified

(i) alkyl, Alchemilla, Alchemilla, cycloalkyl and cycloalkenyl group, and the alkyl part of alkoxygroup can be substituted by one or more halogen atoms, and

(ii) cycloalkyl and cycloalkenyl groups can contain one or two rings and may additionally represent a ring condensed with one or two benzene rings.

In order to avoid uncertainty is nasty, each Deputy-X-R4Ajoins pyrrolidinyl ring through the fragment X.

When used in this document, the term"pharmaceutically acceptable derivative"understand:

(a) pharmaceutically acceptable salts either with acids or bases (for example, an acid additive salt) and/or

(b) solvate (e.g. hydrate)

To acid additive salts that may be mentioned include carboxylate salts (e.g., salts of formate, acetate, triptorelin, propionate, isobutyrate, heptanoate, decanoate, capret, kaprilat, stearate, acrylate, caproate, propionate, ascorbate, citrate, glucuronate, glutamate, glycolate, α-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate,about-acetoxybenzoic, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacina, fumarate, malate, maleate, hydroxymet, hippurate, phthalate or terephthalate), salt halide (for example, salts of chloride, bromide or iodide), salt sulfonates (for example, salts bansilalpet, methyl-, bromine - or chlorobenzenesulfonate, xylenesulfonate, methanesulfonate, aconsultant, propanesulfonate, hydroxyethanesulfonic, 1 - or 2-naphthalenesulfonate or 1.5-naphthalenedisulfonate) or salt sulfa is, persulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogen phosphate, metaphosphate, pyrophosphate or nitrate and the like.

Under the term"pharmaceutically acceptable derivative"also see:

(a)1-4alkyl Quaternary ammonium salts; or

(b)N-oxides

or two tertiary atomsNthe ring system is 4-(pyrrolidin-1-yl)quinoline, or tertiary atomNthat may be present in any of the substituents R1, R2and R3.

For the avoidance of doubt, the definitions of aryl, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl and alkoxygroup above apply, unless otherwise stated, whenever the use of such terms in this document. In addition, one or two benzene ring which may be condensed with cycloalkenyl groups can bear one or more substituents, as defined in the relevant cycloalkyl group.

Under the term"halogen"used in this document, understand, chlorine, bromine and iodine.

Heterocyclic (Het1-Het13and Hetand-Hete) group by nature can be fully saturated, partially unsaturated, fully aromatic or partially aromatic. To heterocyclic (Het1-Het13and Hetand-Hete) groups is m, which may be mentioned are 1-azabicyclo[2.2.2] octenyl, benzimidazolyl, benzo[c]isoxazolidine, benzisoxazole, benzodioxane, benzodioxepine, benzodioxolyl, benzofuranyl, benzofurazanyl, benzomorphans, 2,1,3-benzoxadiazole, benzoxazolinone, benzoxazolyl, benzimidazolyl, benzo[e]pyrimidine, 2,1,3-benzothiadiazole, benzothiazolyl, benzothiazyl, benzotriazolyl, bromanil, bromanil, indolinyl, 2,3-dehydrobenzperidol, 2,3-dihydrobenzo [b] furanyl, 1,3-dihydrobenzo[c]furanyl, 1,3-dihydro-2,1-benzisoxazole, 2,3-dihydropyrrolo[2,3-b]pyridinyl, dioxane, furanyl, hexahydropyridine, hydantoinyl, imidazolyl, imidazo [1,2-and]pyridinyl, imidazo[2,3-b]thiazolyl, indolyl, ethenolysis, isoxazolidine, isoxazolyl, maleimido, morpholinyl, oil[1,2-b]furanyl, oxadiazolyl, 1,2 - or 1,3-oxazinyl, oxazolyl, phthalazine, piperazinil, piperidinyl, purinol, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[5,1-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolyl, hintline, chinoline, sulfolane, 3-sulfolene, 4,5,6,7-tetrahydroindazole, 4,5,6,7-tetrahydropyrazolo, 5,6,7,8-tetrahydrobenzo[e]pyrimidine, tetrahydrofuranyl, tetrahydropyranyl, 3,4,5,6-tetrahydropyridine is l, 1,2,3,4-tetrahydropyrimidines, 3,4,5,6-tetrahydropyrimidine, thiadiazolyl, diazolidinyl, thiazolyl, thienyl, thieno[5,1-c]pyridinyl, thiochroman, thiazolyl, 1,3,4-thiazolo[2,3-b]pyrimidinyl, xantener and the like.

The Vice-Het2that can be specified include benzimidazolyl (for example, the benzimidazole-2-yl), piperidinyl (for example, piperidine-4-yl), pyridinyl (e.g. pyridin-3-yl) and pyrrolidinyl (for example, pyrrolidin-3-yl).

The Vice-Het6that can be specified include morpholinyl (for example, morpholine-4-yl), piperidinyl (for example, piperidine-4-yl) or, in particular, pyrrolidinyl (for example, 1-pyrrolidin-2-one).

The Vice-Het7that can be specified include isoxazolyl (e.g., isoxazol-3-yl), and pyridinyl (e.g. pyridin-3-yl).

The Vice-Het9that can be specified include piperidinyl (for example, piperidine-1-yl) or, in particular, furanyl (e.g., furan-2-yl), imidazolyl (for example, imidazol-5-yl), isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl or isoxazol-5-yl), pyrazinyl (for example, pyrazin-2-yl), pyrazolyl (e.g. pyrazole-3-yl or pyrazole-4-yl), pyridazinyl (for example, pyridazin-4-yl) or pyridinyl (e.g. pyridin-2-yl or pyridin-3-yl).

The Vice-Het11that can be specified include piperazinil (for example, piperazin-yl), piperidinyl (for example, piperidine-1-yl), and pyridinyl (e.g. pyridin-3-yl).

The Vice-Het13that can be specified is pyridinyl (e.g. pyridin-3-yl).

When used in this document, the term"microorganisms"understand:

(a) fungi (defined below); and in particular

(b) bacteria (defined below).

In this document the terms"microbial", "antimicrobial"and"antimicrobe"should be interpreted in accordance with the definition of"microorganisms". For example, the term"microbial"understand fungal or, in particular, bacterial.

When used in this document, the term"clinically latent"understand the micro-organisms that are viable, but non-cultivated (for example, bacteria that cannot be detected with standard techniques of cultivation, but which are defined and counted using techniques such as counting when breeding environment, microscopy, or techniques of molecular biology, such as polymerase chain reaction).

Under the term"clinically latent"also understand the microorganisms that are tolerant phenotype, for example microorganisms, which are:

(a) sensitive (for example, in log-phase) to biostatics (e.g., bacteriostatic) effects obsip inatech antimicrobial agents (i.e. microorganisms, for which the minimum inhibitory concentration (MIC) common antimicrobial agents essentially does not change); but

(b) have a significantly reduced susceptibility to destruction, induced drug (e.g., microorganisms, for which any data conventional antimicrobial agent, the ratio of the minimum microbicide concentration (for example, minimum bactericidal concentration, MBC to MIC takes the values 10 or more).

In relation to paragraph (a) above,"effectively immutable"refers to the MIC values that are in the range from 50 to 200% (for example, from 90 to 110%) value specified in the standard microorganism and interest to common antimicrobial agent conditions.

For the avoidance of doubt, the term"clinically latent"eliminates the microorganisms that genotypic resistant to conventional antimicrobial agents (i.e. organisms that are genetically different from sensitive to antimicrobial agents members of the same genus and have a high MIC (for example, in log-phase) for one or more conventional antimicrobial agents compared with those sensitive to antimicrobial drugs by microorganisms).

The term"clinically latent"includes the microorganisms, which

(i) metabolically active; but

(ii) have a growth rate that is below the threshold of development of infectious diseases.

Specialists in this field will understand that the term "the developmental threshold of infectious diseases" I understand the threshold growth rate, below which symptoms of an infectious disease (patient infected with an appropriate microorganism) are missing.

In respect of paragraph (i) above, the metabolic activity of latent microorganisms can be defined in several ways, known to specialists in this field, for example by measuring the levels of mRNA in the microorganisms or by determining the rate of absorption of them uridine. In this regard, the term"clinically latent"additionally understand the microorganisms, which in comparison with the same quantity of microorganisms able logarithmic phase of growth (in vitroorin vivo) have reduced, but still significant levels:

(I) mRNA (for example, from 0.0001 to 50%, such as from 1 to 30, 5 to 25, or 10 to 20% of the mRNA level); and/or

(II) absorption uridine (for example, [3H] uridine) (for example, from 0.0005 to 50%, such as from 1 to 40, 15 to 35, or from 20 to 30% absorption rate of [3H] uridine.

When used in this document, the term"generally accepted(e) antimicrobial(the) agent(s)" understand:

(a) conventional antifungal agents; and especially

(b) conventional antibacterial agents,

where each of paragraphs (a) and (b) is defined below.

When used in this document, the term"generally accepted(e) antimicrobial(s) agent(s)"understand bactericidal and bacteriostatic agents which are known from the prior art (i.e. the agents that were selected and developed based on the values of their MIC - specifically, their ability to inhibit the growth of bacteria). In regard to a specific conventional antibacterial agents that may be mentioned include any one or more agents from the following list.

(a) β-lactams, including:

(i) the penicillins, such as

(I) benzylpenicillin, procaine benzylpenicillin, phenoxymethylpenicillin, methicillin, propicillin, ampicillin, ciclacillin, hetacillin, 6-aminopenicillanic acid, penicillin acid, sulfon penitsillanovoy acid (sulbactam), penicillin G, penicillin V, phenethicillin, phenoxymethylpenicillin acid, azlotillin, carbenicillin, cloxacillin,

D-(-)-penicillamine, dicloxacillin, nafcillin and oxacillin,

(II) penicillins resistant to penicillinase (for example, Flucloxacillin),

(III) penicillins a wide spectrum (for example, ampicillin, amoxicillin, Metamucil is in and bacampicillin),

(IV) protivopoltavlenie penicillins (for example, carboxypenicillins, such as tikarcillin or ureidopenicillin, such as piperacillin),

(V) mecillinam (for example, pivmecillinam) or

(VI) a combination of any two or more of the agents listed in paragraphs c (I) to (V) above, or a combination of any of the agents listed in paragraphs c (I) to (V) above, with the inhibitor of β-lactamase, such as tazobactam or, in particular, clavulanic acid (which is not necessarily in the form of a metal salt, for example in the form of salts with alkali metal such as sodium or especially potassium);

(ii) cephalosporins such as cefaclor, cephalo-Smoking, cephalexin, cefcapene, cefcapene pivoxil, cefdinir, cefditoren, cefditoren pivoxil, cefixime, Cefotaxime, cefpirome, cefpodoxime, cefpodoxime proxetil, cefprozil, cefradine, ceftazidime, cefteram, cefteram pivoxil, Ceftriaxone, cefuroxime, cefuroxime aksetil, tsefaloridin cefacetrile, cefamandole, cephaloglycin, ceftobiprole, PPI-0903 (TAK-599), 7-aminocephalosporanic acid, 7-aminodesacetoxycephalosporanic acid, cefamandole, Cefazolin, cefmetazole, cefoperazone, cefsulodin, cephalosporin C (zinc salt), cefalotin, cephapirin; and

(iii) other β-lactams, such as carbapenems (e.g., aztreonam), carbapenems (e.g. imipenem (optional in combination with an inhibitor of the enzyme by the EC, such as cilastatin, Meropenem, ertapenem, doripenem (S-4661) and RO4908463 (CS-023)), Panama (for example, faropenem) and 1-oxa-β-lactam (e.g., moxalactam).

(b) the Tetracyclines, such as tetracycline, demeclocycline, doxycycline, lymecycline, minocycline, oxytetracycline, chlortetracycline, meclocycline and metatsiklina and glycylcycline (for example, tigecyclin).

(c) the Aminoglycosides, such as amikacin, gentamicin, netilmicin, neomycin, streptomycin, tobramycin, amantadin, butirosin, butirosin And, daunorubicin, dibekacin, dihydrostreptomycin, G 418, hygromycin In, kanamycin B, kanamycin, terramycin, paromomycin, ribostamycin, sizomitsin, spectinomycin, streptozocin and thiostrepton.

(d) (i) Macrolides, such as azithromycin, clarithromycin, erythromycin, roxithromycin, spiramycin, amphotericine In (for example, amphotericin b), bafilomycin (for example, bafilomycin A1), brefeldin (for example, brefeldin A), concanamycins (for example, concanamycins A), filipin complex, jozamitsin, mepartricin, midecamycin, nonactin, nystatin, oleandomitsin, oligomycin (for example, oligomycin And, oligomycin In and oligomycin), pimaricin, rifampicin, rifamycin, rapamicin, tylosin, virginiamycin and fosfomicin.

(ii) Ketolide, such as telithromycin and cethromycin (ABT-773).

(iii) Lincosamine, such as lincomycin.

(e) Clindamycin and clindamycin 2-phosphate.

(f) is anicole, such as chloramphenicol and thiamphenicol.

(g) Steroids, such as positieve acid (optionally in the form of a metal salt, for example in the form of a salt with an alkaline metal such as sodium).

(h) Glycopeptides, such as vancomycin, teicoplanin, bleomycin, bleomycin, ristomycin, proof-of-concept, dalbavancin and oritavancin.

(i) Oxazolidinone, such as linezolid and AZD2563.

(j) Streptogramin, such as inupristin, dalfopristin or a combination thereof.

(k) (i) Peptides, such as the polymyxins (e.g., colistin and polymyxin B), lysostaphin, garamycin, aktinomitinov (e.g., actinomycin C and actinomycin D), Aktionen, 7-aminooctanoic D, antimycin a, antipain, bacitracin, cyclosporine a, economizing, gramicidines (for example, gramicidin a and gramicidin), myxothiazol, lowlands, paracelsian, valinomycin and viomycin.

(ii) Lipopetides, such as daptomycin.

(iii) Lipoglycopeptide, such as ramoplanin.

(l) Sulfonamides such as sulfamethoxazole, sulfadiazine, sulfoxidation, sulfathiazole (the latter two agents are not necessarily in the form of a metal salt, for example in the form of a salt with an alkaline metal such as sodium), succinylsulfathiazole sulfadimetoksin, sulfaguanidine, sulfamethazine, sulfamonometoksin, sulfanilamide and sulfasalazin.

(m) Trimethoprim, optionally in combination with a sulfonamide, such as with lipomatosis (for example, the combination of co-trimoxazole).

(n) TB drugs such as isoniazid, rifampicin, rifabutin, pyrazinamide, ethambutol, streptomycin, amikacin, capreomycin, kanamycin, quinolones (e.g., such as in paragraph (q) below),pair-aminosalicylic acid, cycloserine, and ethionamide.

(o) Leprosy drugs, such as Dapsone, rifampicin and clofazimine.

(p) (i) Nitroimidazoles, such as metronidazole and tinidazole.

(ii) Nitrofurans, such as nitrofurantoin.

(q) Quinolones, such as nalidixic acid, norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, Gatifloxacin, gemifloxacin, garenoxacin, DX-619, WCK 771 (S-(-)-nadifloxacin arginine salt), 8-hinolinol, enoxacin, enrofloxacin, flanagin, lomefloxacin, oxolinic acid and pipemidinova acid.

(r) Derivatives of amino acids, such as azaserine, bestatin, D-cycloserine, 1,10-phenanthrolin, 6-diazo-5-oxo-L-norleucine and L-alanyl-L-1-aminoethylphosphonic acid.

(s) Aureolae acid, such as chromomycin A3, mithramycin and mitomycin C.

(t) Benzophenone, such as herbimycin A.

(u) Coumarin-glycosides, such as novobiocin.

(v) Derivatives of diphenyl ether, such as irgasan.

(w) Apiprotocolsupport, such as gliotoxin fromGliocladium fimbriatum.

(x) Derivatives of W the situations acids, such as cerulenin.

(y) Glucosamine, such as 1-methoxymandelic, 1-deoxynojirimycin andN-methyl-1-deoxynojirimycin.

(z) indole Derivatives, such as staurosporin.

(aa) Diaminopyrimidine, such as iclaprim (AR-100).

(ab) Macrolactam, such as ascomycin.

(ac) Taxaide, such as paclitaxel.

(ad) Statins, such as mevastatin.

(ae) Politologie acid such as (+)-usnic acid.

(af) Polyethers, such as lasalocid And, ionomycin And, monensin, nigericin and salinomycin.

(ag) Derived pikolinos acid, such as fusaria acid.

(ah) Peptidyl-nucleosides, such as blasticidin S, nikkomycin, nourseothricin and puromycin.

(ai) Nucleosides, such as adenine 9-β-D-arabinofuranoside, 5-azacytidine, korditsepin, formazin And, tubercidin and tunicamycin.

(aj) Pleuromutilin, such as GSK-565154, GSK-275833, tiamulin.

(ak) Inhibitors peptide deformylase, such as L415 (NVP PDF-713) and BB 83698.

(al) Antibacterial agents for the skin, such as fucidin, benzamycin, clindamycin, erythromycin, tetracycline, sulfadiazine, chlortetracycline, metronidazole, mupirocin, framycetin, gramicidin, neomycin sulfate, polymyxins (e.g., polymyxin b), and gentamicin.

(am) other agents, such as methenamine (hexamine), doxorubicin, piericidin And, stigmatella, acticin, anysome is in, apramycin, kumaresan A1, L(+)-lactic acid, cytochalasin (for example, cytochalasin and cytochalasin D), emetine and ionomycin.

Specific conventional antibacterial agents that may be mentioned include the agents listed in paragraphs (a) through (q) above, such as:

-Cellini listed in paragraph (a)(i) above (for example, amoxicillin, ampicillin, dentists or, especially, co-Amoxiclav (amoxicillin));

cephalosporins listed in paragraph (a)(ii) above (for example, cefuroxime, cefaclor or cephalexin);

carbapenems listed in paragraph (a)(iii) above (for example, ertapenem);

tetracyclines listed in paragraph (b) above (e.g., doxycycline or minocycline);

macrolides listed in paragraph (d)(i) above (e.g., clarithromycin, erythromycin, roxithromycin or, especially, azithromycin);

ketolide listed in paragraph (d)(ii) above (for example, telithromycin);

oxazolidinone listed in paragraph (i) above (for example, linezolid);

the lipopetides listed in paragraph (k)(ii) above (for example, daptomycin);

trimethoprim and the combination of them (e.g. co-trimoxazole)listed in paragraph (m) above;

nitrofurans listed in paragraph (b) above (e.g., nitrofurantoin); and

quinolones listed in paragraph (q) above (e.g., norfloxacin, ciprofloxacin, ofloxacin, or is particularly, levofloxacin or moxifloxacin).

When used in this document, the term"generally accepted(e) antifungal(e) agent(s)"understand fungicidal and fungistatic agents, which are known from the prior art (i.e. the agents that were selected and developed based on the values of their MIC - i.e. their ability to inhibit the growth of fungi). In regard to specific antifungal agents that may be mentioned include any one or more agents from the following list.

(a) azole antifungal drugs, such as imidazoles (e.g. clotrimazole, econazole, fenticonazole, ketoconazole, miconazole, sulconazole and tioconazole) or triazoles (e.g., fluconazole, Itraconazole and voriconazole);

(b) a polyene antifungal drugs such as amphotericin b and nystatin;

(c) other antifungal agents such as griseofulvin, caspofungin or flucytosine, the last two agents are optionally used in combination;

(d) allylamine antifungals such as terbinafine.

The options for the implementation of the compounds of formula I which may be mentioned are such variants where:

(1) R1represents one to four substituents (for example, two Deputy or, in particular, one Deputy), at least on the nome of which R 4Aand/or R4bdifferent from N;

(2) R4ais

(a)1-12alkyl, C3-12cycloalkyl,3-12cycloalkenyl (these last three groups substituted by aryl or the group Het1and optionally additionally substituted by one or more substituents selected from halogen, nitrogen, CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil,3-8cycloalkyl (the latter three groups are optionally substituted by one or more substituents selected from HE, =O, halogen, C1-4the alkyl and C1-4alkoxy), or SIG5A, S(O)nR5b, S(O)2N(R5c)(R5d), N(R5e)S(O)2R5fN(R5g)(R5h), B1-C(O)-B2-R5i, aryl and Het1and those With3-12cycloalkyl or4-12cycloalkenyl groups may additionally be substituted by =O),

(c) aryl or

(d) Het2;

(3) R2differs from N.

Additional options for the implementation of the compounds of formula I that may be mentioned include such options

where:

(1) R1represents two Deputy or, in particular, one Deputy on pyrrolidinium ring, and each Deputy independently represents a group-S-R4A;

(2) X represents a simple bond, -O - or-N(H)- (for example, a simple bond or-N(H)-);

(3) R4athe stand is made by a

(a)1-8alkyl (for example, C1-6or1-4alkyl, such as methyl) or (C4-6cycloalkyl, this alkyl or cycloalkyl group optionally substituted by one or more substituents selected from halogen, nitrogen, CN, C1-2of alkyl, C4-6cycloalkyl (the latter group is optionally substituted by one or more substituents selected from =O, halogen, methyl and methoxy), or SIG5A, phenyl, naphthyl (the latter two groups are optionally substituted by one or more (e.g. one to four) substituents selected from halogen, CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil or3-6cycloalkyl, OR10A, S(O)2R10band-C(O)R10ior

(b) phenyl or naphthyl (the latter two groups are optionally substituted by one or more (e.g. one to four) substituents selected from halogen, CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil or3-6cycloalkyl, OR10A, S(O)2R10band-C(O)R10i);

(4) R2represents a

(a) H,

(b) (C1-8alkyl (for example, C1-6alkyl, such as1-4alkyl or, particularly, methyl), C2-8alkenyl,2-8quinil,3-6cycloalkyl, the latter four groups are optionally substituted by one or more substituents, vibrancies halogen, methyl and methoxy;

(5) R3represents H or from one to four (for example, two or, particularly one) substituents on the condensed benzene ring (for example, from one to four substituents, including at least one substituent in position 6 of the quinoline or khinazolinov ring system selected from the

(a) halogen,

(b) CN,

(C)1-6of alkyl, C2-6alkenyl,2-6the quinil,4-6cycloalkyl, the latter four groups are optionally substituted by one or more substituents selected from halogen, nitrogen, CN, C1-3of alkyl, C2-3alkenyl,2-3the quinil,4-6cycloalkyl, OR7aN(H)S(O)2R7fN(N)(R7h), -C(O)R7i, aryl and Het5,

(d) OR8a,

(e) S(O)2R8b,

(f) S(O)2N(R8c)(R8d),

(g) N(R8e)S(O)2R8f,

(h) N(R8g)(R8h),

(i) -C(O)R8i, -N(R13)C(O)R8i, OC(O)R8iC(O)N(H)R8iC(O)OR8i,

(j) aryl or

(k) Het6;

(6) R5Arepresents in each case,

(a)1-6alkyl, C2-6alkenyl,2-6quinil (the latter three groups are optionally substituted by one or more substituents selected from halogen, C1-2alkoxy, phenyl and naphthyl, the latter two groups are optionally substituted by one or more (such as the er, from one to four substituents selected from halogen, CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil or3-6cycloalkyl, or SIG10A, S(O)2R10band-C(O)R10i),

(b) (C3-6cycloalkyl (the latter group is optionally substituted by one or more substituents selected from halogen, =O, methyl, methoxy and phenyl),

(C) phenyl or naphthyl (the latter two groups are optionally substituted by one or more (e.g. one to four) substituents selected from halogen, CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil or3-6cycloalkyl, or SIG10A, S(O)2R10band-C(O)R10i);

(7) R7a-R7iand R8A-R8iindependently represent in each case,

(a) H,

(b) (C1-6alkyl, C2-6alkenyl,2-6quinil (the latter three groups are optionally substituted by one or more substituents selected from halogen, HE, methoxy, aryl and Het7),

(C)4-6cycloalkyl (the latter group is optionally substituted by one or more substituents selected from halogen, HE, =O, methyl, methoxy, aryl and Het8),

(d) aryl or

(e) Het9,

provided that R7bor R8bdifferent from N, if q or r, respectively take the values 1 or 2;

(8) R10A, R10band R10i independently represent in each case,

(a)1-6alkyl, C2-6alkenyl,2-6quinil,4-6cycloalkyl (the latter four groups are optionally substituted by one or more substituents selected from halogen, methyl and methoxy) or

(C) phenyl (the latter group is optionally substituted by one or more substituents selected from CN, halogen, C1-2alkiline and C1-2alkoxy);

(9) Het6is a 4-7-membered aromatic, partially unsaturated or, in particular, a fully saturated heterocyclic group containing one nitrogen atom (which may form the attachment point for the group Het6the remainder of the molecule), and optionally one or two additional heteroatoms, selected from oxygen, nitrogen and/or sulfur, this heterocyclic group may be substituted by one or more substituents selected from halogen, methyl, methoxy and =On;

(10) Het7-Het9independently represent a 5-10-membered aromatic heterocyclic group containing one or more (e.g., from one to three heteroatoms selected from oxygen, nitrogen and/or sulfur, these heterocyclic groups may contain one or two rings and may be substituted by one or more (e.g. one or two) substituents selected from the

(b) CN,

(c)1-8the alkyl (for example, C1-6of alkyl, such as1-4alkyl or, particularly, methyl), C2-8alkenyl,2-8the quinil,4-6cycloalkyl, the latter four groups are optionally substituted by one or more substituents selected from halogen, methyl and methoxy,

(d) OR12a,

(i) N(H)( R12h),

(j) -C(O)R12i, -N(H)C(O)R12i, -OC(O)R12i, -C(O)N(H)R12i, -C(O)OR12i,

(k) phenyl (the latter group is optionally substituted by one or more substituents selected from HE, halogen, methyl and methoxy) or

(l) Hetb;

(11) R12A, R12hand R12iindependently represent in each case H1-2alkyl or phenyl (the latter group is optionally substituted by one or more substituents selected from HE, halogen, methyl and methoxy);

(12) R13represents a C1-3alkyl (e.g. methyl) or, in particular, H;

(13) Hetbrepresents 5 - or 6-membered aromatic heterocycle containing one to three heteroatoms selected from nitrogen and oxygen, this heterocyclic group optionally substituted by the substituents in the amount of from one to three, selected from halogen and methyl;

(14) unless otherwise specified, alkyl, Alchemilla, Alchemilla, cycloalkyl and cycloalkenyl group, and ALK is supplemented flax part of alkoxygroup not replaced;

(15) unless otherwise stated, cycloalkyl groups contain one or (if there is a sufficient number of atoms With two rings and optional ring condensed with a benzene ring (so to form a group, such as, for example, 1,2,3,4-tetrahydronaphthyl or, in particular, indanyl).

Additional options for the implementation of the compounds of formula I that may be mentioned include options where:

(1) E represents CH;

(2) R1represents one Deputy-X-R4Aon pyrrolidinium ring (e.g., a Deputy on the 3 position of the ring);

(3) X represents a simple bond or-N(H)-;

(4) R4Ais

(a)1-2alkyl (such as methyl), this alkyl group is substituted by one or more substituents selected from phenyl (the latter group is optionally substituted by one or more (e.g. two or, particularly one) substituents selected from halogen (e.g. chlorine), CN, C1-3the alkyl and or SIG10A), or

(b) phenyl (the latter group is optionally substituted by one or more (e.g. two or, particularly one) substituents selected from halogen (e.g. chlorine), CN, C1-3the alkyl and or SIG10A);

(5) R2represents a C1-2alkyl, such as methyl;

(6) R3represents on the one to four substituents on the condensed benzene ring, including at least one substituent in position 6 of the quinoline or khinazolinov ring system, where each Deputy independently selected from

(a) halogen (e.g. chlorine),

(b) or SIG8A,

(C) N(H)S(O)2R8f,

(d) N(H)( R8h),

(e) -N(H)C(O)R8iC(O)N(H)R8ior

(f) Het6;

(7) R8a-R8iindependently represent in each case,

(a)1-4alkyl (e.g. methyl or ethyl), optionally substituted phenyl (the latter group is optionally substituted by one or more substituents selected from halogen, CN, C1-2of alkyl, methoxy, ethoxy and S(O)2-(C1-2the alkyl)) or Het7,

(b) phenyl (the latter group is optionally substituted by one or more substituents selected from halogen, CN, C1-2of alkyl, methoxy, ethoxy and S(O)2-(C1-2the alkyl)) or

(e) Het9;

(8) R10Arepresents a C1-4alkyl (e.g. methyl);

(9) Het6represents 5 - or 6-membered completely saturated heterocyclic group containing one nitrogen atom (the atom forms the point of connection of the group Het6the remainder of the molecule) and optionally one additional heteroatom selected from oxygen and nitrogen, this heterocyclic group may be substituted by one or more substituents selected and is halogen, bromide and =On;

(10) Het7-Het9independently represent a 5 - or 6-membered aromatic heterocyclic groups containing from one to three (e.g. one or two) heteroatoms selected from oxygen, nitrogen and/or sulfur (for example, selected from oxygen and/or nitrogen), these heterocyclic groups may be substituted by one or more (e.g. one or two) substituents selected from halogen, CN and C1-2the alkyl (e.g. methyl).

In certain embodiments of the invention the compound of formula I is a compound of formula Ia,

where R1Arepresents-X-R4A;

R1brepresents H or one or two substituent on pyrrolidinium ring, and each Deputy independently represents a group-S-R4A;

and E, X, R2, R3and R4Adefined in this document previously.

Later in this document under the compounds of the formula I, unless the context otherwise provided, see the compounds of formula Ia. On the contrary, when referring to a specific variants of implementation of the compounds of formula Ia these implementation options apply equally, as appropriate, to compounds of formula I.

The options for the implementation of the compounds of formula Ia, which can be specified are variations which you in which the structural fragment

located in:

(a) R-configuration for an atom is attached to R1A; or

(b) S-configuration for an atom is attached to R1A.

Additional options for the implementation of the compounds of formula Ia, which can be specified are options where:

(1) E represents CH;

(2) R1brepresents N;

(3) -X-R4Arepresents a

(a) phenyl (the latter group is optionally substituted by one or more (e.g. two or, particularly one) substituents selected from halogen (e.g. chlorine) and methoxy),

(b) CH2-phenyl (the phenyl part of this group optionally substituted by one or more (e.g. two or, particularly one) substituents selected from halogen (e.g. chlorine) and methoxy, but in a particular embodiment, not replaced) or

(C) NH-phenyl (the phenyl part of this group optionally substituted by one or more (e.g. two or, particularly one) substituents selected from halogen (e.g. chlorine) and methoxy, but in a particular embodiment, not replaced);

(4) R2represents methyl;

(5) R3represents one or two substituent (for example, one Deputy) on the condensed benzene Kohl is e, including at least one substituent in position 6 of the quinoline or khinazolinov ring system, where each Deputy independently selected from halogen (e.g. chlorine), or SIG8AN(H)S(O)2R8fN(H)(R8h), -N(H)C(O)R8ior Het6(for example, every Deputy independently selected from or SIG8AN(H)(R8h), -N(H)C(O)R8ior Het6);

(6) R8Arepresents a

(a) phenyl, optionally substituted with substituents in the amount of from one to three (e.g. one Deputy, such as one Deputy for 2 - or especially 4-position)selected from halogen, CN, methyl, methoxy and S(O)2CH3(for example, selected from methoxy and S(O)2CH3),

(b) (C1-2alkyl, substituted phenyl, the latter group is optionally substituted by substituents in the amount of from one to three (e.g. one Deputy, such as one Deputy for 2 - or especially 4-position)selected from halogen, CN, methyl, methoxy and S(O)2CH3(for example, selected from methoxy and S(O)2CH3or

(C)1-2alkyl, substituted heterocyclic group Het7;

(7) R8frepresents phenyl, optionally substituted with substituents in the amount of from one to three (e.g. one Deputy, such as one Deputy in the 2 - or, especially, 4 position), using the data from halogen, CN, methyl, methoxy and S(O)2CH3;

(8) R8hrepresents a C1-2alkyl (e.g. methyl), substituted by phenyl, the latter group is optionally substituted by substituents in the amount of from one to three (e.g. one Deputy, such as one Deputy in the 2 - or, especially, 4-position)selected from halogen, CN, methyl, methoxy and S(O)2CH3(for example, selected from CN and methoxy);

(6) R8irepresents a

(a) phenyl, optionally substituted with substituents in the amount of from one to three (e.g. one Deputy, such as one Deputy in the 2 - or, especially, 4-position)selected from halogen, CN, methyl, methoxy and S(O)2CH3(for example, selected from chlorine, methyl and methoxy),

(b) (C1-3alkyl (e.g. methyl or ethyl), substituted by phenyl, the latter group is optionally substituted by substituents in the amount of from one to three (e.g. one Deputy, such as one Deputy in the 2 - or, especially, 4-position)selected from halogen, CN, methyl, methoxy and S(O)2CH3(for example, selected from chlorine, methyl and methoxy),

(C)1-2alkyl, substituted heterocyclic group Het7or

(d) Het9;

(9) Het6is pyrrolidin-1-yl, substituted by substituents in the amount of from one to three (e.g. one replacement is the Titel, such as the only Deputy in the 2nd position)selected from halogen, methyl, and =O (for example, Deputy =O);

(10) Het7and Het9independently represent a 5 - or 6-membered aromatic heterocyclic groups containing from one to three (e.g. one or two) heteroatoms selected from oxygen and/or nitrogen, these heterocyclic groups may be substituted by one or more (e.g. one or two) substituents selected from halogen and methyl (for example, substituted by two or, particularly, one methyl group).

Specific substituents R1Athat may be specified in connection with the compounds of formula Ia include phenyl, 4-methoxyphenyl, 4-chlorophenyl, benzyl, phenylamino.

Specific substituents R3(for example, in the form of a single substituent in position 6 of the quinoline or khinazolinov ring system), which may be specified in connection with the compounds of formula Ia include:

chlorine;

phenoxy;

benzyloxy; 4 methanesulfonanilide; 4 methoxybenzyloxy;

2 venlafaxi;

5-methylisoxazol-3-ylethoxy;

benzylamino; (4-cyanobenzyl)amino; (4-methoxybenzyl)amino;

phenylcarbonylamino; (4-chlorophenyl)carbylamine; (4-methoxyphenyl)carbylamine; (2-were)carbylamine;

phenylethylenediamine; (4-chlorophenyl)methylcobalamine; (4-IU is oxyphenyl)methylcobalamine;

furan-2-ylcarbonyl;

3-methyl-3H-imidazol-4-ylcarbonyl;

5-methyl-isoxazol-3-ylcarbonyl; 3,5-dimethylisoxazol-4-ylcarbonyl;

2 phenylethylenediamine;

pyrazin-2-ylcarbonyl;

5-methyl-1H-pyrazole-3-ylcarbonyl; 1H-pyrazole-4-ylcarbonyl;

pyridazin-4-ylcarbonyl;

pyridine-2-ylcarbonyl; pyridine-3-ylcarbonyl;

2-(3-methyl-isoxazol-5-yl) methylcobalamine;

benzosulfimide; and

2-oxopyrrolidin-1-yl.

Variants of the invention that may be mentioned include the cases in which the compound of formula I is a compound of examples 1 to 39 below, such as:

2-methyl-6-penetrate-4-(3-phenylpyrrolidine-1-yl)quinoline;

4-(3-benzylpyrrolidine-1-yl)-2-methyl-6-phenoxyphenol;

4-[3-(4-methoxyphenyl)pyrrolidin-1-yl]-2-methyl-6-phenoxybenzamine hydrochloride;

[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide 5-methyl-1H-pyrazole-3-carboxylic acid; or

N-[4-(3-benzylpyrrolidine-1-yl)-2-methylinosine-6-yl]benzamide

or their pharmaceutically acceptable derivative.

Additional variants of the invention that may be mentioned include the cases in which the compound of formula I is a compound of formula Ia, where the connection is inR-configuration for an atom, to which also is denen R 1Aand choose from:

(i) 4-((R)-3-benzylpyrrolidine-1-yl)-2-methyl-6-phenoxybenzamine;

(ii) 4-[(R)-3-(4-methoxyphenyl)pyrrolidin-1-yl]-2-methyl-6-phenoxybenzamine;

(iii) [2-methyl-4-((R)-3-phenyl-pyrrolidin-1-yl)-quinoline-6-yl]amide 5-methyl-1H-pyrazole-3-carboxylic acid; and

(iv) N-[4-((R)-3-benzylpyrrolidine-1-yl)-2-methylinosine-6-yl] benzamide,

or their pharmaceutically acceptable derivative.

Typical compounds which may be mentioned in this respect include the compounds (i) and (iv) above and their pharmaceutically acceptable derivatives.

Other additional variants of the invention that may be mentioned include the cases in which the compound of formula I is a compound of formula Ia, where the connection is inS-configuration for an atom is attached to R1Aand choose from:

(I) 4-((S)-3-benzylpyrrolidine-1-yl)-2-methyl-6-phenoxybenzamine;

(II) 4-[(S)-3-(4-methoxyphenyl)pyrrolidin-1-yl]-2-methyl-6-phenoxybenzamine;

(III) [2-methyl-4-((S)-3-phenyl-pyrrolidin-1-yl)-quinoline-6-yl]amide 5-methyl-1H-pyrazole-3-carboxylic acid; and

(IV) N-[4-((S)-3-benzylpyrrolidine-1-yl)-2-methylinosine-6-yl] benzamide,

or their pharmaceutically acceptable derivative.

Typical compounds which may be mentioned in this respect include the compounds (I) and (V) above and their pharmaceutically acceptable derivatives.

Drug specified in the first aspect of the invention may be used in the method of medical treatment. Thus, according to the second aspect of the invention is invited to:

(i) a method for killing clinically latent microorganisms in a mammal infected with such latent microorganisms, which includes an introduction to the specified mammal microbicide effective amount of the compounds of formula I, as defined herein before; and

(ii) a compound of formula I, as defined herein before, for use in killing clinically latent microorganisms in a mammal infected with such latent microorganisms.

Moreover, the compound of the formula I can be used to kill clinically latent microorganisms. Thus, according to a third aspect of the invention features the use of the compounds of formula I, as defined herein before, for the destruction of clinically latent microorganisms. In one embodiment, the implementation of the application on this aspect of the invention is the use ofex vivo.

In addition to the destruction of clinically latent microorganisms the inventors have discovered that compounds of the formula I capable of destroying microorganisms a large number of different phenotypes on the tea microorganisms in the growth phase.

In this respect, the fourth, fifth, sixth and seventh aspects of the invention are available, respectively:

(a) the use of the compounds of formula I, as defined herein before, to obtain drugs for treatment or prevention of microbial infection;

(b) a method of treatment or prophylaxis of a microbial infection in a mammal, comprising an introduction to the specified mammal antimicrobe effective amount of the compounds of formula I, as defined herein before;

(c) application (for example, useex vivo) the compounds of formula I for the destruction of microorganisms;

(d) compound of formula I, as defined herein before, for use in treating or preventing microbial infections in a mammal.

For the avoidance of doubt, the term"treatment"used in this document, understand therapeutic and/or prophylactic treatment.

As indicated above, the application on the third and sixth aspects of the invention may constitute the use ofex vivosuch as the use of the compounds of formula I, as defined in this document earlier:

(a) as a sterilizing agent; or

(b) as preservative.

In turn, the compounds of formula I can be used in the methods of sterilization or preservation, such as:

(i) method of sterilizing an object comprising applying to the specified object of the compounds of formula I, as defined herein before; or

(ii) method of conservation of inorganic or preferably organic material, including contactaction, combining or mixing of this material with the compound of the formula I defined in this document previously.

In the manner described in paragraph (i) above, the object is preferably different from a human or animal. In addition, materials that can be preserved according to the method described in paragraph (ii) above, include polymers, lubricants, paints, fibres, leather, paper, food, water and aqueous mixtures and solutions.

When using for the destruction of clinically latent microorganisms or for the treatment of microbial infections of the compounds of formula I can be used either independently (i.e. in individual microbicide or antimicrobial agents) or in combination with any one or more conventional antimicrobial agents described above.

In addition, when used as a sterilizing agent compounds of formula I can be used either alone or in combination with conventional sterilizing agent. Under the term"common female sterilization is the overall agent" used in this document, see alcohols (for example, industrial methylated spirits or ethanol), sodium chloride, thymol, chlorhexidine, cationic surfactants (for example, cetrimide), iodine (optional in combination with povidone), phenols (e.g., triclosan), oxidants (e.g. hydrogen peroxide, potassium permanganate or sodium hypochlorite) and any one or more conventional antimicrobial agents described above.

Thus, on the eighth and ninth aspects of the invention features, respectively:

(a) a combination product containing

(A) compound of formula I, as defined herein above, and

(C) conventional antimicrobial agent, as defined herein above,

where each of the components (a) and (b) is in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and

(b) a composition comprising a compound of formula I, as defined herein above, and the conventional sterilizing agent, as defined herein above, or its salt and/or MES.

Combination product according to the eighth aspect of the invention provides an introduction of the component (A) in combination with component (b) and may, therefore, be located either in separate compositions in which at least one of these compositions contains to the ponent (a) and at least one contains a component (C), or may be presented (i.e. be written in the form of a combined preparation (i.e. presented as a single composition, comprising component (a) and component (C)).

Thus, there are:

(1) a pharmaceutical composition comprising a compound of formula I, as defined herein above, and a conventional antimicrobial agent, as defined herein above, or its pharmaceutically acceptable derivative in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier (this song later in this document referred to as "combined preparation"); and

(2) a set, parts of which contain components:

(I) a pharmaceutical composition comprising a compound of formula I, as defined herein above, in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and

(II) a pharmaceutical composition comprising conventional antimicrobial agent, as defined herein above, or its pharmaceutically acceptable derivative in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier,

each of the components (I) and (II) are offered in a form that is suitable for administration in conjunction with another.

Component (I) is a thus, the component (A) in a mixture with a pharmaceutically PR is acceptable adjuvant, diluent or carrier. Similarly, component (II) is component (B) in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

According to the tenth aspect of the invention proposes a method of creating a set defined above, comprising bringing the component (I)defined above, in Association with a component (II), as defined above, thus placing the two components suitable for the introduction, together with each other.

Under the coercion of the two components "in Association" with each other, the authors understand that the components (I) and (II) the set can be:

(i) proposed as separate compositions (i.e. independently from each other), which are later brought together for use in combination with each other in combination therapy; or

(ii) packaged and presented together as separate components of "combination packaging" for use in combination with each other in combination therapy.

Therefore, further provides a kit, which contains:

(1) one of the components (I) and (II)as defined herein; together with

(2) guidance on the application of this component with the other component of the two possible.

To ensure re-dosing the set described in this document may contain more than one composition includes the right amount of/dose of component (A), and/or more than one composition including an appropriate quantity/dose of component (B). If there is more than one composition (containing different active connection), such compositions may be the same or may differ in terms of the dose of the component (A) or component (C), chemical composition and/or physical form.

Combination product according to the eighth aspect of the invention can be used to kill clinically latent microorganisms and/or treatment of microbial infection. Thus, in additional aspects of the invention include:

(i) the combined product according to the eighth aspect of the invention to obtain drugs for destruction clinically latent microorganisms;

(ii) a method for killing clinically latent microorganisms in a mammal infected with such latent microorganisms, including the introduction of a given mammal microbicide effective amount of a combined product according to the eighth aspect of the invention;

(iii) a combination product according to the eighth aspect of the invention for use in killing clinically latent microorganisms in a mammal infected with such latent microorganisms;

(iv) the combined product according to the eighth aspect and the gaining to obtain drugs for treatment or prevention of microbial infection;

(v) a method of treatment or prophylaxis of a microbial infection in a mammal, comprising an introduction to the specified mammal antimicrobe effective amount of a combined product according to the eighth aspect of the invention; and

(vi) a combination product according to the eighth aspect of the invention for use in treating or preventing microbial infections in a mammal.

Method (v) above creates an advantage in that the number of common antimicrobial agent needed to treat the microbial infection is reduced compared with the number required in the absence of the compounds of formula I.

When used in this document under the terms"bacteria"(and their derivatives, such as"bacterial infection") understand the organisms (or infections due to organisms) the following classes and specific types:

Gram-positive cocci, such as

staphylococci (e.g.,Staph. aureus, Staph. epidermidis, Staph. saprophytics, Staph. auricularis, Staph. capitis capitis, Staph. c. ureolyticus, Staph. caprae, Staph. cohnii cohnii, Staph. c. urealyticus, Staph. equorum, Staph. gallinarυm, Staph. haemolyticus, Staph. hominis hominis, Staph. h. novobiosepticius, Staph. hyicus, Staph. intermedius, Staph. lugdunensis, Staph. pasteuri, Staph. saccharolyticus, Staph. schleiferi schleiferi, Staph. s. coagulans, Staph. sciuri, Staph. simulans, Staph. wameri and Staph. xylosusand

Streptococcus (for example,

beta-hemolytic pyogenic streptococci (such asbeta-haemolytic, pyogenic streptococci (the hat as Strept. agalactiae, Strept. canis, Strept. dysgalactiae dysgalactiae, Strept. dysgalactiae equisimilis, Strept. equi equi, Strept. equi zooepidemicus, Strept. iniae, Strept. porcinus and Strept. pyogenes),

microaerophile pyogenic streptococci (Streptococcus “milleri”, such asStrept. anginosus, Strept. constellatus constellatus, Strept. constellatus pharyngidis and Strept. intermedius),

streptococci in the oral cavity groups “mitis” (alpha-hemolytic - Streptococcus “viridans”, such asStrept. mitis, Strept. oralis, Strept. sanguinis, Strept. cristatus, Strept. gordonii and Strept. parasanguinis),“salivarius” (non-haemolytic, such asStrept. salivariusandStrept. vestibularisand “mutans” (streptococci surfaces of the teeth, such asStrept. criceti,Strept. mutans,Strept. rattiandStrept. sobrinus),

Strept. acidominimus, Strept. bovis, Strept. faecalis, Strept. equinus, Strept. pneumoniae and Strept. suis,

or streptococci, alternate classified as streptococci groups A, B, C, D, E, G, L, P, U or V);

Gram-negative cocci such asNeisseria gonorrhoeae, Neisseria meningitidis, Neisseria cinerea, Neisseria elongate, Neisseria flavescens, Neisseria lactamica, Neisseria mucosa, Neisseria sicca, Neisseria subflavaandNeisseria weaveri;

Bacillaceae, such asBacillus anthracis, Bacillus subtilis, Bacillus thuringiensis, Bacillus stearothermophilus and Bacillus cereus;

Enterobacteriaceae, such as

Escherichia coli

Enterobacter (e.g.,Enterobacter aerogenes, Enterobacter agglomeransandEnterobacter cloacae)

Citrobacter (such asCitrob. freundiiandCitrob. divernis),

Hafnia (for example,Hafnia alvei),

Erwinia (for example,Erwinia persicinus),

Morganella morganii,

Salmonella (Salmonella entericaandSalmonella typhi),

Shigella (for example, Shigella dysenteriae, Shigella flexneri, Shigella boydiiandShigella sonnei),

Klebsiella (e.g.,Klebs. pneumoniae, Klebs. oxytoca, Klebs. ornitholytica, Klebs. planticola, Klebs. ozaenae, Klebs. ternigena, Klebs. granulomatis (Calymmatobacterium granulomatis)andKlebs. minoscleromatis),

Proteus (for example,Pr. mirabilis, Pr. rettgeriandPr. vulgaris),

Providencia (for example,Providencia alcalifaciens, Providencia rettgeriandProvidencia stuartii),

Serratia (e.g., Serratia marcescens and Serratia liquifaciens), and

Yersinia (for example,Yersinia enterocolitica, Yersinia pestisandYersinia pseudotuberculosis) ;

Enterococci (for example,Enterococcus avium, Enterococcus casseliflavus, Enterococcus cecorum, Enterococcus dispar, Enterococcus durans, Enterococcus faecalis, Enterococcus faecium, Enterococcus flavescens, Enterococcus gallinarum, Enterococcus hirae, Enterococcus malodoratus, Enterococcus mundtii, Enterococcus pseudoavium, Enterococcus raffinosusandEnterococcus solitarius);

Helicobacter (e.g.,Helicobacter pylori, Helicobacter cinaediandHelicobacter fennelliae);

Acinetobacter (for example,A. baumanii, A. calcoaceticus, A. haemolyticus, A. johnsonii, A. junii, A. IwoffiandA. radioresistens);

Pseudomonas (for example,Ps. aeruginosa, Ps. maltophilia (Stenotrophomonas maltophilia), Ps. alcaligenes, Ps. chlororaphis, Ps. fluorescens, Ps. luteola. Ps. mendocina, Ps. monteilii, Ps. oryzihabitans, Ps. pertocinogena, Ps. pseudalcaligenes, Ps. putidaandPs. stutzeri);

Bacteriodes fragilis;

Peptococcus (for example,Peptococcus niger);

Peptostreptococcus;

Clostridium (for example,C. perfringens, C. difficile, C. botulinum, C. tetani, C. absonum, C. argentinense, C. baratii, C. bifermentans, C. beijerinckii, C. butyricum, C. cadaveris, C. carnis, C. celatum, C. clostridioforme, C. cochlearium, C. cocleatum, C. fallax, C. ghonii, C. glycolicum, C. haemolyticum, C. hastiforme, C. histolyticum, C. indolis, C. innocuum, C. irregulare, C. leptum, C. limosum, C. malenominatum, C. novyi, C. oroticum, C. paraputrificum, C. piliforme, C putrefasciens, C. ramosum, C. septicum, C. sordelii, C. sphenoides, C. sporogenes, C. subterminale, C. symbiosumandC. tertium);

Mycoplasma (for example,M. pneumoniae, M. hominis, M. genitaliumandM. urealyticum);

Mycobacteria (e.g.,Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium fortuitum, Mycobacterium marinum, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium leprae, Mycobacterium smegmitis, Mycobacterium africanum, Mycobacterium alvei, Mycobacterium asiaticum, Mycobacterium avium, Mycobacterium bohemicum, Mycobacterium bovis, Mycobacterium branderi, Mycobacterium brumae, Mycobacterium celatum, Mycobacterium chubense, Mycobacterium confluentis, Mycobacterium conspicuum, Mycobacterium cookii, Mycobacterium flavescens, Mycobacterium gadium, Mycobacterium gastri, Mycobacterium genavense, Mycobacterium gordonae, Mycobacterium goodii, Mycobacterium haemophilum, Mycobacterium hassicum, intracellular Mycobacterium, Mycobacterium interjectum, Mycobacterium heidelberense, Mycobacterium lentiflavum, Mycobacterium malmoense, Mycobacterium microgenicum, Mycobacterium microti, Mycobacterium mucogenicum, Mycobacterium neoaurum, Mycobacterium nonchromogenicum, Mycobacterium peregrinum, Mycobacterium phlei, Mycobacterium scrofulaceum, Mycobacterium shimoidei, Mycobacterium simiae, Mycobacterium szulgai, Mycobacterium terrae, Mycobacterium thermoresistabile, Mycobacterium triplex, Mycobacterium triviale, Mycobacterium tusciae, Mycobacteriumulcerans, Mycobacterium vaccae, Mycobacterium wolinskyi and Mycobacterium xenopi);

Haemophilus (for example,Haemophilus influenzae, Haemophilus ducreyi, Haemophilus aegyptius, Haemophilus parainfluenzae, Haemophilus haemolyticusandHaemophilus parahaemolyticus);

Actinobacillus (for example,Actinobacillus actinomycetemcomitans, Actinobacillus equuli, Actinobacillus hominis, Actinobacillus lignieresii, Actinobacillus suisandActinobacillus ureae);

Actinomyces (e.g.,Actinomyces israelii);

Propionibacteria (for example,Propionibacterium acnes);

Brucella (e.g.,Brucella abortus, Brucella canis, Brucella melintensisandBrucella suis);

Campylobacter (for example,Campylobacter ejuni, Campylobacter coli, Campylobacter lariandCampylobacter fetus);

Listeria monocytogenes;

Vibrio (for example,Vibrio cholerae and Vibrio parahaemolyticus, Vibrio alginolyticus, Vibrio carchariae, Vibrio fluvialis, Vibrio furnissii, Vibrio hollisae, Vibrio metschnikovii, Vibrio mimicusandVibrio vulnificus);

Erysipelothrix rhusopathiae;

Corynebacteriaceae (for example,Corynebacterium diphtheriae, Corynebacterium jeikeiumandCorynebacterium urealyticum);

Spirochaetaceae, such asBorrelia (e.g., Borrelia recurrentis, Borrelia burgdorferi, Borrelia afzelii, Borrelia andersonii, Borrelia bissettii, Borrelia garinii, Borrelia japonica, Borrelia lusitaniae, Borrelia tanukii, Borrelia turdi, Borrelia valaisiana, Borrelia caucasica, Borrelia crocidurae, Borrelia duttoni, Borrelia graingeri, Borrelia hermsii, Borrelia hispanica, Borrelia latyschewii, Borrelia mazzottii, Borrelia parkeri, Borrelia persica, Borrelia turicataeandBorrelia venezuelensis)andTreponema (Treponema pallidum ssp. pallidum, Treponema pallidum ssp. endemicum, Treponema pallidum ssp. pertenueandTreponema carateum);

Pasteurella (for example,Pasteurella aerogenes, Pasteurella bettyae, Pasteurella canis, Pasteurella dagmatis, Pasteurella gallinarum, Pasteurella haemolytica, Pasteurella multocida multocida, Pasteurella multocida gallicida, Pasteurella multocida septica, Pasteurella pneumotropicaandPasteurella stomatis);

Bordetella (for example,Bordetella bronchiseptica, Bordetella hinzii, Bordetella holmseii, Bordetella parapertussis, Bordetella pertussisandBordetella trematum);

Nocardiaceae, such as Nocardia (for example,Nocardia asteroidesandNocardia brasiliensis);

Rickettsia (e.g., Ricksettsii or Coxiella burnetii);

Legionella (for example,Legionella anisa, Legionella birminghamensis, Legionalla bozemanii, Legionalla cincinnatiensis, Legionalla dumoffii, Legionalla feeleii, Legionalla gormanii, Legionalla hackeliae, Legionalla israelensis, Legionalla jordanis, Legionalla lansingensis, Legionalla longbeachae, Legionalla maceachernii, Legionalla micdadei, Legionalla oakridgensis, Legionalla pnumophila, Legionalla sainthelensi, Legionalla tucsonensisandLegionalla wadsworthii);

Moraxella catarrhalis;

Stenotrophomonas maltophilia;

Burkholderia cepacia;

Francisella tularensis;

Gardnerella (for example,Gardneralla vaginalisandGardneralla mobiluncus);

Streptobacillus moniliformis;

Flavobacteriaceae, such as Capnocytophaga (for example,Capnocytophaga canimorsυs, Capnocytophaga cynodegmi, Capnocytophaga gingivalis, Capnocytophaga granulosa, Capnocytophaga haemolytica, Capnocytophaga ochraceaandCapnocytophaga sputigena);

Bartonella (Bartonella bacilliformis, Bartonella clarridgeiae, Bartonella elizabethae, Bartonella henselae, Bartonella quintanaandBartonella vinsonii arupensis);

Leptospira (for example,Leptospira biflexa, Leptospira borgpetersenii, Leptospira inadai, Leptospira interrogans, Leptospira kirschneri, Leptospira noguchii, Leptospira santarosaiandLeptospira weilii);

Spirillium (for example,Spirillum minus);

Bacteroides (for example,Bacteroides caccae, Bacteroides capillosus, Bacteroides coagulans, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides forsythus, Bacteroides fragilis, Bacteroides merdae, Bacteroides ovatus, Bacteroides putredinis, Bacteroides pyogenes, Bacteroides splanchinicus, Bacteroides stercoris, Bacteroides tectus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides ureolyticusandBacteroides vulgatus);

Prevotella (for example,Prevotella bivia, Prevotella buccae, Prevotella corporis, Prevotella dentalis (Mitsuokella dentalis), Prevotella denticola, Prevotella disiens, Prevotella enoeca, Prevotella heparinolytica, Prevotella intermedia, Prevotella loeschii, Prevotella melaninogenica, Prevotella nigrescens, Prevotella oralis, Prevotella oris, Prevotella oulora, Prevotella tannerae, Prevotella venoralis and Prevotella zoogleoformans);

Porphyromonas (for example,Porphyromonas asaccharolytica, Porphyromonas cangingivalis, Porphyromonas canons, Porphyromonas cansulci, Porphyromonas catoniae, Porphyromonas circumdentaria, Porphyromonas crevioricanis, Porphyromonas endodontalis, Porphyromonas gingivalis, Porphyomonas gingivicanis, Porphyromonas leviiandPorphyromonas macacae);

Fusobacterium (for example,F. gonadiaformans, F. mortiferum, F. naviforme, F. necrogenes, F. necrophorum necrophorum, F. necrophorum fundiliforme, F. nucleatum nucleatum, F. nucleatum fusiforme, F. nucleatum polymorphum, F. nucleatum vincentii, F. periodonticum, F. russii, F. ulceransandF. varium);

Chlamydia (for example,Chlamydia trachomatis);

Chlamydophila (for example, Chlamydophila abortus (Chlamydia psittaci), Chlamydophila pneumoniae {Chlamydia pneumoniae)andChlamydophila psittaci (Chlamydia psittaci));

Leuconostoc (for example,Leuconostoc citreum, Leuconostoc cremoris, Leuconostoc dextranicum, Leuconostoc lactis, Leuconostoc mesenteroidesandLeuconostoc pseudomesenteroides) ;

Gemella (for example,Gemella bergeri, Gemella haemolysans, Gemella morbillorumandGemella sanguinis); and

Ureaplasma (for example,Ureaplasma parvumandUreaplasma urealyticum).

In one of the embodiments of the invention, the term"bacteria"understand any of the above classes or specific types of organisms, exceptShigella(for example,Shigella flexneriorSalmonella(for example,Salmonella typhi).

When used in this document under the terms"mushrooms"(and their derivatives, such as"fungal infection") understand the organisms or infections caused by organisms) the following classes and specific types:

Absidia (e.g.,Absidia corymbifera);

Ajellomyces (for example,Ajellomyces capsulatusandAjellomyces dermatitidis);

Arthroderma (for example,Arthroderma benhamiae, Arthroderma fulvum, Arthroderma gypseum, Arthroderma incurvatum, Arthroderma otaeandArthroderma vanbreuseghemii);

Aspergillus (e.g.,Aspergillus flavus, Aspergillus fumigatus, Aspergllus niger andAspergillus terreus);

Blastomyces (for example,Blastomyces dermatitidis);

Candida (e.g.,Candida albicans, Candida glabrata, Candida guillierinondii, Candida krusei, Candida parapsilosis, Candida is tropical, Candida pelliculosaandCandida lusitaniae);

Cladophialophora (for example,Cladophialophora carrionii);

Coccidioides (for example,Coccidioides immitis);

Cryptococcus (e.g.,Cryptococcus neoformans);

Cunninghamella (for example,Cunninghamella sp.)

Epidermophyton (for example,Epidermophyton floccosum);

Exophiala (for example,Exophiala dermatitidis);

Filobasidiella (for example,Filobasidiella neoformans);

Fonsecaea (for example,Fonsecaea pedrosoi);

Fusarium (for example,Fusarium solaniandFusarium oxysporum);

Geotrichum (for example,Geotrichum candidum);

Histoplasma (for example,Histoplasma capsulatum);

Hortaea (for example,Hortaea wemeckii);

Issatchenkia (for example,Issatchenkia orientalis);

Madurella (for example,Madurella grisae);

Malassezia (otherwise known asPityrosporum) (for example,Malassezia furfur, Malassezia globosa, Malassezia obtusa, Malassezia pachydermatis, Malassezia resthcta, Malassezia slooffiae, Malassezia sympodialis, Malassezia dermatis, Malassezia nanaandMalassezia yamatoensis);

Microsporum (for example,Microsporum canis, Microsporum fulvum, Microsporum gypseum, Microsporum audouiniiandMicrosporum ferrugineum);

Mucor (e.g.,Mucor circinelloides);

Agent (for example,Nectha haematococca);

Paecilomyces (for example,Paecilomyces variotii);

Paracoccidioides (for example,Paracoccidioides brasiliensis);

Penicillium (for example,Penicillium mameffei);

Pichia (e.g.,Pichia anomalaandPichia guilliermondii yeast);

Pneumocystis (e.g.,Pneumocystis jiroveci (Pneumocystis carinii));

Pseudalleschria (for example, Pseudallescheha boydii);

Rhizopus (for example,Rhizopus oryzaeandRhizopus oligosporus);

Rhodotorula (for example,Rhodotorula rubra);

Scedosporium (for example,Scedosporium apiospermum);

Schizophyllum (for example,Schizophyllum commune);

Sporothrix (for example,Sporothrix schenckii);

Trichophyton (e.g.,Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton verrucosum, Trichophyton violaceum, Trichophyton schoenleinii, Trichophyton tonsurans, Trichophyton concentricum, Trichophyton gourvilii, Trichophyton interdigitale, Trichophyton megninii, Trichophyton soudanense); and

Trichosporon (for example,Trichosporon asahii, Trichosporon cutaneum, Trichosporon inkinandTrichosporon mucoides).

Thus, the compounds of formula I or combination products containing the compounds of formula I can be used for the destruction of any of the above bacterial or fungal organisms (clinically latent or otherwise).

Specific bacteria which can be mentioned in this respect include:

(i) staphylococci, such asStaph. aureus(either methicillin-sensitive (i.e. MSSA)or methicillin-resistant (i.e. MRSA)),Staph. epidermidis,Staphylococcus haemolyticus,Staphylococcus hominisandStaphylococcus lugdunensis);

(ii) streptococci, such asStrept. agalactiae,Strept. pyogenes;Strept. pneumoniaeand Streptococcus group C);

(iii) Bacillaceae, such asBacillus anthracisor, especially,Bacillus cereus;

(iv) enterobacteria, such asEscherichia coli, Klebsiella (e.g.,Klebs. pneumoniaeandKlebs. oxytoca) and Proteus (for example,Pr. mirabilis, Pr. rettgeriandPr. vulgaris);

(v)Haemophilus influenzae;

(vi) enterococci, such asEnterococcus faecalis, Enterococcus faecium,Enterococcus gallinarumandEnterococcus casseliflavus;

(vii) mycobacteria, such asMycobacterium tuberculosis;

(viii) propionibacteria, such asPropionibacterium acnes;

(ix) Corynebacterium, such asCorynebacterium jeikeium;

(x)Stenotrophomonas maltophilia; and

(xi) Mycoplasma, such asM. pneumoniae.

Some bacteria that can be specified include the bacteria in paragraphs (i), (ii) and (viii) above.

To specific fungi, which can also be specified in this regard include:

(I) Aspergillus (e.g.,Aspergillus fumigatus; Aspergillus niger, Aspergillus flavusorAspergillus terreus);

(II) Candida (e.g.,Candida albicans, Candida tropicalis, Candida parapsilosis, Candida glabrataorCandida lusitaniae);

(III)Cryptococcus neoformans;

(IV)Histoplasma capsulatum;

(V)Pneumocystis jiroveci;

(VI)Issatchenkia orientalis;

(VII)Rhizopus oligosporus;

(VIII)Fusarium oxysporum;

(IX) Microsporum (for example,Microsporum audouinii, Microsporum ferrugineumorMicrosporum canis);

(X)Epidermophyton floccosum;

(XI) Malassezia (for example,Malassezia furfur); b

(XII) Trichophyton (e.g.,Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton verrucosum, Trichophyton violaceum, Trichophyton schoenleinii, Trichophyton tonsurans, Trichophyton concentricum, Trichophyton gourvilii, Trichophyton interdigitale, Trichophyton megninii, Trichophyton soudanense (such as Trichophyton violaceum, Trichophyton mentagrophytesor, especially,Trichophyton rubrum)).

Some mushrooms that can be specified, otnosiatsia in paragraphs (I), (II), (X), (XI) and (XII) above.

Specific bacterial or fungal infections, which can be specified in connection with

(i) applying on the first or fourth aspect of the invention,

(ii) a method according to the second or sixth aspect of the invention,

(iii) the compound for use according to the second or seventh aspect of izobreteniya, and

(iv) described above applications, ways or combined with products to use, including the combination product according to the eighth aspect of the invention (i.e. the use of (i) or (iv) above, the method (ii) or (v) above or a combination product for use (iii) or (vi) above)

are infectious diseases caused by

Staph. aureus(either methicillin-sensitive (i.e. MSSA)or methicillin-resistant (i.e. MRSA)) andStaph. epidermidis,

streptococci, such asStrept. agalactiaeandStrept. pyogenes,

Bacillaceae, such asBacillus anthracisor, especially,Bacillus cereus,

the enterobacteria, such asEscherichia coli, Klebsiella (e.g.,Klebs. pneumoniaeandKlebs. oxytoca) and Proteus (for example,Pr. mirabilis, Pr. rettgeriandPr. vulgaris),

Haemophilus influenzae,

the enterococci, such asEnterococcus faecalisandEnterococcus faecium,

mycobacteria, such asMycobacterium tuberculosis,

propionibacteria, such asPropionibacterium acnesor

mushrooms, such asAspergillus fumigatus, Candida albicans, Cryptococcus neoformans, Histoplasma capsulatum Pneumocystis jiroveci, Epidermophyton floccosum, Malassezia(for example,Malassezia furfuror, especially,Trichophyton(for example,Trichophyton violaceum, Trichophyton mentagrophytesor, especially,Trichophyton rubrum).

In this regard, for the particular conditions under which the compounds of formula I or combination products containing the compounds of formula I, can be used to treat include tuberculosis (e.g., tuberculosis, nulegacy tuberculosis (such as tuberculosis of the lymph nodes, genitourinary tuberculosis, tuberculosis of bones and joints, tuberculous meningitis and miliary tuberculosis), anthrax, abscesses, acne vulgaris, acne rosacea, rosacea (including erythematotelangiectatic rosacea, papulopustular rosacea, hematozoa rosacea and ocular rosacea), actinomycosis, bacillary dysentery, bacterial conjunctivitis, bacterial keratitis, botulism, Buruli ulcer, infectious diseases of bones and joints, bronchitis (acute or chronic), brucellosis, burn wounds, fever cat scratch, cellulitis, folliculitis (including Jacuzzi folliculitis), chancroid, cholangitis, cholecystitis, cutaneous diphtheria, cystic fibrosis, cystitis, diffuse panbronchiolitis, diphtheria, dental caries, diseases of the upper respiratory tract, empyema, endocarditis, endometritis, enteric fever, enteritis, epididymitis, epiglottitis, erysipelas, erysipeloid, Erie is unwinding diameter, ectima, proboda ectima, eye infections, boils, gardnerelly vaginitis, infectious diseases of the gastrointestinal tract (gastroenteritis), genital infections, gingivitis, gonorrhea, inguinal granuloma, haverhills fever, atopic eczema with staphylococcal carriage, infectious eczema, infected burn wounds infected scratches, infected skin wounds, infections after surgical intervention on the teeth, infectious diseases of the oral cavity infections associated with prostheses, intra-abdominal abscesses, Legionnaires disease, leprosy, leptospirosis, listeriosis, liver abscesses, Lyme disease, venereal lymphogranuloma, mastitis, mastoiditis, meningitis and infectious diseases of the nervous system, mycetoma, Nocardia (for example, madorsky foot), nonspecific urethritis, ophthalmia (for example, ophthalmia neonatorum), osteomyelitis, otitis media (for example, external otitis and otitis media), orchitis, pancreatitis, paronychia, pelvioperitonit, peritonitis, peritonitis with appendicitis, pharyngitis, cellulitis, pint, plague, pleural effusion, pneumonia, infections of surgical wounds, postoperative gas gangrene, prostatitis, pseudomembranous colitis, psittacosis, emphysema, pyelonephritis, pyoderma (e.g., impetigo, furunculosis, carbuncles, staphylococcal toxic the epidermis of the capacity necrolysis, surgical scarlet fever, perianal streptococcal disease, syndrome streptococcal toxic shock, punctuate keratosis, axillary triominos, infections of the external ear canal syndrome green nails, spirochaetes, necrotizing fasciitis, mycobacterial infections of the skin (such as lupus ordinary, scrofuloderma, warty tuberculosis, tuberculin, erythema nodosum, indurativnyy erythema, cutaneous manifestations tuberculocides leprosy or lepromatous leprosy, leprosy erythema nodosum, cutaneous infectious diseases caused byM. kansasii, M. malmoense, M. szulgai, M. simiae, M. gordonae, M. haemophilum, M. avium, M. intracellulare, M. chelonae (includingM. abscessus)orM. fortuitum, granuloma swimmers (or aquarium), lymphadenitis and Buruli ulcer (Bairnsdale ulcer, ulcer of Sirles, ulcer to Kacarevo or ulcer Toro)), q fever, a disease from the bite of a rat, retikulez, disease Ritter, salmonellosis, salpingitis, septic arthritis, septic infections, septicemia, sinusitis, skin infections (e.g., granuloma of the skin), syphilis, systemic infections, tonsillitis, toxic shock syndrome, trachoma, tularemia, typhoid, typhus (e.g., epidemic typhus, rat typhus, Japanese river fever and epidemic cerebrospinal meningitis), urethritis, wound infections, tropical yaws, aspergillosis, candidiasis (for example, roaringly candidiasis, vaginal candidiasis or balanitis), cryptococcosis, favus, histoplasmosis, intertriginoznoy dermatitis, motorbikes, tinea corporis (for example, trichophytosis smooth skin, ringworm of the crotch cruris, tinea of the feet and the tinea of the nails, onychomycosis, pityriasis versicolor, trichophytosis and sporotrichosis.

Additional conditions that may be specified in this regard are infectious diseases caused by MSSA, MRSA,Staph. epidermidis, Strept. agalactiae, Strept. pyogenes, Escherichia coli, Klebs. pneumoniae, Klebs. oxytoca, Pr. mirabilis, Pr. rettgeri, Pr. vulgaris, Haemophilus influenzae, Enterococcus faecalisorEnterococcus faecium.

Specific compounds of formula I which may be specified in connection with the above-described aspects of the invention include the compounds of examples 1 to 43 (for example, from 1 to 39) below.

The use of some compounds of formula I in medicine, including the compounds of formula I (and Ia), as defined herein before, is new according to the inventors.

For the avoidance of doubt, this document under the compounds of formulas I understand all options for the implementation described above in connection with compounds of formulas I and Ia.

In this regard, in an additional aspect, the invention features a compound of formula Ib for use in medicine, where the compounds of formula Ib have the same definition as the compounds of formula I defined in this document is the earlier, except that:

R4Arepresents a

(a)1-12alkyl, C3-12cycloalkyl,3-12cycloalkenyl (these last three groups are substituted by aryl or the group Het1and optionally additionally substituted by one or more substituents selected from halogen, nitrogen, CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil,3-8cycloalkyl (the latter three groups are optionally substituted by one or more substituents selected from HE, =O, halogen, C1-4the alkyl and C1-4alkoxy), or SIG5A, S(O)nR5b, S(O)2N(R5c)(R5d), N(R5e)S(O)2R5fN(R5g)(R5h), B1-C(O)-B2-R5i, aryl and Het1and those With3-12cycloalkyl or4-12cycloalkenyl groups may additionally be substituted by =O),

(C) aryl or

(d) Het2,

and provided that:

(a) if E represents CH, R3differs from one or more (e.g. one or two) substituents, which include one Deputy or SIG8Ain position 7 of the ring system quinoline; and

(b) if E is a N and R2represents N. R1differs from the Deputy-O-R4Ain position 3 pyrolidine ring, where R4Arepresents aryl or Het2.

To link the m formula Ib, which may be mentioned include compounds where:

(i) R3differs from one or more (e.g. one or two) substituents, which include one Deputy or SIG8Ain position 7 of the quinoline ring system;

(ii) R1different from (for example, if R2represents H) Deputy-O-R4Ain position 3 pyrolidine ring (for example, the Deputy-O-R4Ain which R4Arepresents aryl or Het2);

(iii) R2differs from aryl or Het4if E represents N; and/or

(iv) R1differs from piperazine-1-Il.

To the use of compounds of the formula Ib in medicine is their use as pharmaceuticals. The invention therefore additionally relates to the use of compounds of formula Ib as pharmaceuticals.

According to the authors of the invention the compounds of formula Ib are essentially new. Thus, according to another additional aspect of the invention features a compound of formula Ib.

When used in this document, the term "compounds of examples 1 through 43 below" refer to compounds of these examples are listed in the headings, namely:

(1) 6-chloro-2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline;

(2) 6-benzyloxy-2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline;

(3) 2-methyl--(3-phenylpyrrolidine-1-yl)-6-(pyridine-3-ylethoxy) quinoline;

(4) 6-(4-methysulfonylmethane)-2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline;

(5) 6-(4-methoxybenzyloxy)-2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline;

(6) 2-methyl-6-penetrate-4-(3-phenylpyrrolidine-1-yl)quinoline;

(7) 2-methyl-6-(5-methylisoxazol-3-ylethoxy)-4-(3-phenylpyrrolidine-1-yl)quinoline;

(8) 4-(3-benzylpyrrolidine-1-yl)-2-methyl-6-phenoxyphenol;

(9) 4[3-(4-methoxyphenyl)pyrrolidin-1-yl]-2-methyl-6-phenoxyphenol;

(10) 4[3-(4-chlorophenyl)pyrrolidin-1-yl]-2-methyl-6-phenoxyphenol;

(11) [1-(2-methyl-6-phenoxyphenol-4-yl)pyrrolidin-3-yl] phenylamine;

(12) N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl] benzamide;

(13) N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]-2-phenylacetamide;

(14) 4-chloro-N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl] benzamide;

(15) 4-methoxy-N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl] benzamide;

(16) 2-methyl-N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl] benzamide;

(17) [2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide of pyrazin-2-carboxylic acid;

(18) [2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide of 1H-pyrazole-4-carboxylic acid;

(19) [2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide, furan-2-carboxylic acid;

(20) N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl] nicotinamide;

(21) [2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide of 3-methyl-3H-imidazole-4-carboxylic acid;

(22) [2-methyl-4-(3-phenylpyrrole the n-1-yl)quinoline-6-yl]amide 5-methyl-1H-pyrazole-3-carboxylic acid;

(23) [2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide of pyridazin-4-carboxylic acid;

(24) 2-(4-methoxyphenyl)-N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]ndimethylacetamide;

(25) 2-(4-chlorophenyl)-N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]ndimethylacetamide;

(26) [2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide of 3,5-dimethyl-isoxazol-4-carboxylic acid;

(27) 2-(3-methyl-isoxazol-5-yl)- N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]ndimethylacetamide;

(28) N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl] benzosulfimide;

(29) benzyl-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl] amine;

(30) (RorS-) benzyl-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amine;

(31) (SorR-)benzyl-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amine;

(32) (4-methoxybenzyl)-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amine;

(33) 4-{[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-ylamino]methyl}benzonitrile;

(34) 1-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl] pyrrolidin-2-he;

(35) N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]-3-phenylpropionamide;

(36) [2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide 5-methylisoxazol-3-carboxylic acid;

(37) [2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide pyridine-2-carboxylic acid;

(38) N-[4-(3-benzylpyrrolidine-1-yl)-2-methylinosine-6-yl] benzamide;

(39) 2-methyl-6-phenoxy-4-(3-phenylpyrrolidine-1-yl)quinoline;

(40(a) 4-(( RorS)-3-benzylpyrrolidine-1-yl)-2-methyl-6-phenoxyphenol;

(40(b)) 4-((SorR)-3-benzylpyrrolidine-1-yl)-2-methyl-6-phenoxyphenol;

(41(a)) 4-[(RorS)-3-(4-methoxyphenyl)pyrrolidin-1-yl]-2-methyl-6-phenoxyphenol;

(41(b)) 4-[(SorR)-3-(4-methoxyphenyl)pyrrolidin-1-yl]-2-methyl-6-phenoxyphenol;

(42(a)) [2-methyl-4-((RorS)-3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide 5-methyl-1H-pyrazole-3-carboxylic acid;

(42(b)) [2-methyl-4-((SorR)-3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide 5-methyl-1H-pyrazole-3-carboxylic acid;

(43(a)) N-[4-((RorS)-3-benzylpyrrolidine-1-yl)-2-methylinosine-6-yl]benzamide;

(43(b)) N-[4-((SorR)-3-benzylpyrrolidine-1-yl)-2-methylinosine-6-yl]benzamide

and their pharmaceutically acceptable salt and/or solvate.

In addition, possessing activity against fungi and bacteria, the compounds of formula I (for example, the compounds of formula Ia or Ib) may also have activity against other organisms such as protozoa. Therefore, additional aspects of the invention is invited to:

(i) the use of the compounds of formula I, Ia or Ib, as defined herein before, to obtain drugs for treatment or prevention of a disease caused by protozoa;

(ii) a method of treatment or prevention of a disease caused by protozoa, mammal, vklyuchayuthie specified mammal an effective amount of the compounds of formula I, Ia or Ib, as defined herein before;

(iii) a compound of formula I, Ia or Ib, for use in the treatment or prevention of a disease caused by protozoa;

(iv) application (for example, useex vivo) the compounds of formula I, Ia or Ib to destroy protozoa.

On these aspects of the invention the compound of formula I, Ia or Ib may be a compound in which R2different from Het4(for example, pyrrolidin-1-yl), if E is a n

When used for treatment or prevention of a disease caused by protozoa, the compounds of formula I, Ia or Ib may be present in the mixture, as described below (i.e. to be included in the pharmaceutical composition or pharmaceutical composition for topical application containing a compound of formula I, Ia or Ib in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier).

When used in this document under the terms"simple"(and its derivatives, such as"the disease is caused by protozoa") understand the organisms (or infectious diseases caused by organisms) the following classes and specific types:

Leishmania(for example,Leishmania donovanii);

Plasmodium spp.;

Trypanosoma spp.;

Giardia lamblia;

coccidia (for example,Cryptosporidium parvum, Isospora belli);

Toxoplasma(for example,oxoplasma gondii);

Balantidium coli;

amoeba (for example,Entamoebasuch asEntamoeba histolytica, Entamoeba coli, Entamoeba hartmanniandEntamoeba polecki); and

Microsporidia(for example,Enterocylozoon bieneusi, Encephalitozoon hellem, Encephalitozoon cuniculiandSeptata intestinalis).

To the specific conditions under which the compounds of formula I, Ia or Ib can be used to treat include leishmaniasis, malaria, trypanosomiasis, toxoplasmosis, giardiasis, balantidiasis, amebiasis (amebic dysentery), cryptosporidiosis, isosporiasis and microsporidiosis.

The compounds of formula I (including compounds of formula Ia or Ib) can be obtained in accordance with methods known to experts in this field, for example, as described herein below.

Thus, according to an additional aspect of the invention proposes a method of obtaining compounds of formula I (for example, the compounds of formula Ia or Ib), which includes:

(a) interactions of the compounds of formula II,

where L1constitutes a suitable remove the group (for example, halogen, such as chlorine), and E, R2and R3defined herein before, with a compound of formula III,

where R1defined herein before, for example under conditions known to specialists in this field, such as interaction at elevated temperatures (for example from 70 to 250°C. for example, achieved by heating in a microwave oven) and optionally at elevated pressure (i.e. above 1 atmosphere) in the presence of a suitable organic solvent, such as2-4allenglish (for example, ethylene glycol or mono - or di - C1-4alkyl ester With2-4alkalophiles (for example, ethoxyethanol) and optionally in the presence of a suitable base (for example, the compound of formula II can interact with the compound of the formula III, taken in an amount of 1 to 3 equivalents (for example, from 2 to 2.5 equivalents) at elevated temperature (e.g., above 180°C., such as from 200 to 240°C), where the reaction mixture is optionally heated using microwaves in the presence of a suitable solvent, boiling at high temperatures (for example, ethoxyethanol));

(b) for compounds of formula I, where E represents CH, interaction of the compounds of formula IV

where R2and R3defined herein before, with a compound of formula III, as defined herein before, for example under conditions known to specialists in this field, such as ambient temperature or elevated temperature (for example, from 40 to 200°C) in the presence of cilleruelo agent (for example, hexamethyldisilazane) and optionally in the presence of a suitable katal is congestion (for example, ammonium salts such as ammonium sulfate);

(C) for compounds of formula I, where R3represents or includes the Deputy-N(H)C(O)R8ithe condensation of the corresponding compounds of formula I, where R3represents or includes the Deputy-NH2with the compound of the formula V,

where L2represents the group that you want (such as HE, halogen (such as chlorine or bromine) or-C(O)R8iand R8idefined herein before, for example under conditions known to specialists in this field (such as: (i) if L2HE is a in the presence of a coupling agent (for example, oxalicacid in DMF; EDC; DCC; HBTU; HATU; PyBOP; or TBTU, these last six optional agents can be used together with a catalyst such as HOBt, HOAt, or HOSu), a suitable base (e.g. pyridine, DMAP, TEA, 2,4,6-collidine or DIPEA) and a suitable organic solvent (such as DCM, MeCN, EtOAc or DMF); or (ii) if L2represents a halogen or OS(O)R8iin the presence of a suitable base (e.g. pyridine, DMAP, TEA, 2,4,6-collidine or DIPEA) and a suitable organic solvent (such as DCM, MeCN, EtOAc or DMF));

(d) for compounds of formula I, where R3represents or includes the Deputy-N(H)S(O)2R8fthe condensation of the corresponding connection is ormula I, where R3represents or includes the Deputy-NH2with a compound of formula VI,

where L3represents a group to delete (for example, halogen (such as chlorine) or OS(O)2R8fand R8fdefined herein before, for example under conditions known to specialists in this field, such as the presence of a suitable solvent (such as DCM) and a suitable base (e.g. pyridine);

(e) for compounds of formula I, where R3represents or includes the Deputy-N(H)R8hwhere R8hoptionally substituted C1-10the alkyl, the interaction of the corresponding compounds of formula I, where R3represents or includes the Deputy-NH2with a compound of formula VII,

where R8h1represents H or C1-9alkyl, the latter group is optionally substituted as defined above in relation to R8hin the presence of a suitable reducing agent (for example, cyanoborohydride sodium or triacetoxyborohydride sodium), for example under conditions known to specialists in this field, such as ambient temperature, in the presence of catalytic amounts of carboxylic acids (for example, C2-4alanovoy acid, such as acetic acid) and a suitable process is Italia (for example, 1,2-dichloroethane);

(f) for compounds of formula I, where R3represents or includes a Deputy OR8awhere R8aoptionally substituted C1-10the alkyl, condensation of the corresponding compounds of formula I, where R3represents or includes the Deputy-OH, with a compound of formula VIII

where R8a1represents a C1-10alkyl group which is optionally substituted as defined above in relation to R8Aand L3defined herein before, for example under conditions known to specialists in this field, such as ambient temperature or elevated temperature (for example, 120°C), where the reaction mixture is optionally heated using microwaves in the presence of a base (e.g. alkali metal hydride such as sodium hydride or carbonate of an alkali metal such as cesium carbonate) and a suitable solvent (such as DMF); or

(g) for compounds of formula I, where R1is a or-N(H)-R4Awhere R4Arepresents aryl, interaction of the compounds of formula IX,

where E, R2and R3defined herein before, with a compound of formula X

where RArepresents aryl, and L3the aryl is defined herein before, in the presence of cross-linking of palladium catalyst (for example,Tris(dibenzylideneacetone) diplodia), for example under conditions known to specialists in this field, such as increased temperature (for example, 150°C), where the reaction mixture is optionally heated using microwaves in the presence of a suitable phosphine (for example, 2-dicyclohexylphosphino-2'-dimethylaminophenyl), a suitable base (for example,tert-butoxide sodium) and an organic solvent (e.g. toluene).

The compounds of formula II, where L1is a halogen, can be obtained by interaction of the corresponding compounds of formula IV, as defined herein before, with a suitable halogenation reagent (for example, phosphorus oxychloride), for example under conditions known to specialists in this field, such as ambient temperature or elevated temperature (for example, from 100 to 120°C), optionally in the presence of a suitable organic solvent (e.g. toluene or xylene).

The compounds of formula II, where R3is a Deputy-NH2can be obtained by reduction of the corresponding compounds of formula II, where R3is a Deputy-NR2for example, catalytic hydrogenation in the presence of a suitable catalyst is a (such as Pd/C, Pt2O or Raney Nickel) under conditions known to specialists in this field, such as the ambient temperature in the presence of a suitable organic solvent (e.g. ethanol).

The compounds of formula II, where R3is a Deputy-NR2can be obtained according to or by analogy with the procedures known to specialists in this field (for example, described inJ. Chem. Soc. 1367 (1949)), such as the interaction of the corresponding compounds of formula II, where R3represents H, with a suitable nitration agent (for example, a mixture of nitric and sulphuric acids), for example under conditions known to specialists in this field, such as ambient temperature or elevated temperature (for example, from 50 to 75°C).

The compounds of formula III, where R1represents a single substituent in position 3 pyrolidine ring, can be obtained by methods known to experts in this field (e.g., according to or by analogy with the appropriate methods described in:J. Org. Chem.55, 270 (1990);Synthesis1023 (1991);J. Am. Chem. Soc. 124 (2002);J. Org. Chem.64, 4273 (1999);Synlett2092 (2002);Med. Chem. Res. 7, 76 (1997); orJ. Org. Chem.60, 4743 (1995); or one of the following methods.

(i) the Recovery of the corresponding compounds of formula XI

where R1the limit in this document earlier, in the presence of a suitable reducing agent (e.g. lithium aluminium hydride), for example under conditions known to specialists in this field, such as ambient temperature or elevated temperature (for example, from 50 to 75°C), in the presence of a suitable organic solvent (e.g. tetrahydrofuran).

(ii) the Interaction of the corresponding compounds of formula XII

where L3and R1defined herein before, with ammonia or a compound of formula XIII

where Randrepresents a suitable protective group (for example, -CH2Ph or HE), for example under conditions known to specialists in this field, such as ambient temperature or elevated temperature (for example, from 50 to 65°C), in the presence of a suitable organic solvent (e.g. tetrahydrofuran) and a suitable base (e.g. base Hunga or 4-dimethylaminopyridine), followed (if necessary) removing the protective group Randin conditions known to specialists in this field (for example, by catalytic hydrogenation, using as catalyst Pd/C, for example, at ambient temperature or elevated temperature (for example, from 50 to 65°C) in the presence of a suitable organic solvent, is such as ethanol or methanol).

The compounds of formula IV can be obtained by the coupling of compounds of formula XIV,

where R3defined herein before, with a compound of formula XV

where Rbrepresents a C1-4alkyl (such as ethyl), in the presence of acid (e.g., polyphosphoric acid), for example under conditions known to specialists in this field, such as ambient temperature or elevated temperature (for example, from 90 to 105°C) in the presence of a suitable organic solvent (e.g. dioxane).

The compounds of formula IV alternative can be obtained by cyclization of the compounds of formula XVI, or compounds of formula XVII

where R2and R3defined herein before, for example under conditions known to specialists in this field, such as increased temperature (for example, from 70 to 250°C., for example, by heating in a microwave oven) in the presence of a suitable solvent (for example, dichlorobenzene or diphenyl ether).

The compounds of formula XI can be obtained by interaction of the corresponding compounds of formula XVIII,

where Rwithrepresents halogen, HE or1-9alkoxy, with a compound of formula XIII, in certain given the th document previously for example, under conditions known to specialists in this field. For example, if Rwithis a HE, the reaction can be carried out in the presence of a suitable binding reagent, and optionally in the presence of a suitable base, a suitable solvent and/or catalyst (e.g., hydrate 1-hydroxybenzotriazole). Alternatively, if Rwithrepresents a halogen (e.g. chlorine), the reaction can be carried out, for example, when the ambient temperature (or below) in the presence of a suitable base and/or a suitable solvent.

With regard to the reaction between the compounds of formulas XIII to XVIII and suitable binding agents include, for example:

1,1'-carbonyldiimidazole;N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (or its hydrochloride);N,N'-disuccinimidyl carbonate; benzotriazol-1-yloxytris (dimethylamino)phosphonium hexaflurophosphate; 2-(1N-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate; benzotriazol-1-yloxytris-pyrrolidinone hexaphosphate; bromo-Tris-pyrrolidinone hexaphosphate; 2-(1N-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate; 1-cyclohexylcarbodiimide-3-propylacetate polystyrene;About-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaphosphate; andAbout-benzotriazol-1-the l- N,N,N',N'-tetramethylurea tetrafluoroborate.

In addition, suitable bases include, for example, sodium hydride, sodium bicarbonate, potassium carbonate, pyridine, triethylamine, dimethylaminopyridine, Diisopropylamine, sodium hydroxide,tert-piperonyl potassium and/or diisopropylamide lithium. Also suitable solvents that may be mentioned include tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, triptoreline, dioxane or triethylamine.

The compounds of formula XII, where L3is a OS(O)2R8fcan be obtained:

the recovery of the corresponding compounds of formula XVIII, where Rwithrepresents a C1-9alkoxy in the presence of a suitable reducing agent (e.g. lithium aluminium hydride or diisobutylaluminium hydride), for example under conditions known to specialists in this field, such as ambient temperature or elevated temperature (for example, from 50 to 70°C) in the presence of a suitable organic solvent (e.g. tetrahydrofuran); followed

interaction diol obtained with the compound of the formula XIX

where L3and R8fdefined herein before, for example under conditions known to specialists in this field, such as tempera is ur environment or low temperature (for example, from 0 to 5°C) in the presence of a suitable organic solvent (e.g. tetrahydrofuran or dichloromethane) and a suitable base (e.g. triethylamine or 4-dimethylaminopyridine).

The compounds of formula XVI can be obtained by interaction of the corresponding compounds of formula XIV, as defined herein before, with a compound of formula XV as defined herein before, for example under conditions known to specialists in this field, such as ambient temperature or elevated temperature (for example, from 100 to 120°C), optionally in the presence of a solvent.

The compounds of formula XVII can be obtained according to or by analogy with the procedures known to specialists in this field (for example, described in the journalSynthesis482 (1987)), such as the interaction of the corresponding compounds of formula XIV, as defined herein before, with a compound of formula XX,

where L4constitutes a suitable remove the group (for example, ethylthio) and R2defined herein before, for example under conditions known to specialists in this field, such as ambient temperature or elevated temperature (for example, from 100 to 120°C), optionally in the presence of a suitable solvent.

The compounds of formula XVIII, the de R 1represents-CH2aryl and Rwithrepresents a C1-9alkoxy, can be prepared by the interaction of the corresponding compounds of formula XXI,

where RC1represents a C1-9alkoxy, with a compound of formula XXII,

where aryl is defined in this document, for example under conditions known to specialists in this field, such as ambient temperature or elevated temperature (for example, from 60 to 80°C) in the presence of a suitable base (for example,tert-BuOK) and an appropriate organic solvent (for example,tert-butanol) and subsequent reduction of the obtained intermediate product alkenyl, for example, by catalytic hydrogenation under conditions known to specialists in this field, such as ambient temperature or elevated temperature (for example, from 50 to 65°C) in the presence of a catalyst (such as Pd/C) and a suitable organic solvent (e.g. ethanol or methanol).

The compounds of formula XVIII, where R1represents-CH2aryl and RwithHE is a, can be obtained by interaction of the corresponding compounds of formula XXIII

where each Rdindependently represents a C1-9/sub> alkyl, with a compound of formula XIV,

where aryl and L3defined herein before, for example under conditions known to specialists in this field, such as ambient temperature or elevated temperature (for example, from 40 to 120°C) in the presence of a suitable base (e.g., K2CO3, NaOH, NaH, triethylamine or 4-dimethylaminopyridine) and a suitable organic solvent (such as DMF, tetrahydrofuran, dichloromethane or ethanol), followed by hydrolysis of the three ester groups (i.e., the transformation of each Rdin N) and monocarboxylate, for example under conditions known to specialists in this field, such as increased temperature (for example, from 50 to 65°C) in the presence of a suitable aqueous acid (such as sulfuric or hydrochloric acid) and a suitable organic solvent (e.g. ethanol or methanol).

The compounds of formula XVIII, where Rwithrepresents a C1-9alkoxy, can be prepared by the interaction of the compounds of formula XV,

where Rddefined herein before, with a compound of formula XXVI,

where R1and halogen are defined in this document, for example under conditions known to specialists in this field, such the AK ambient temperature or elevated temperature (for example, from 60 to 120°C) in the presence of a suitable catalyst based on palladium for a combination of Hake and a suitable organic solvent (e.g. dimethylformamide, toluene, acetonitrile or tetrahydrofuran, and optionally in the presence of a suitable base (e.g., K2CO3Ag2CO3, NAOAc or triethylamine) and/or socializaton (for example,n-Bu4NBr or Nal) with subsequent catalytic hydrogenomonas obtained intermediate product alkenyl, for example under conditions known to specialists in this field, such as ambient temperature or elevated temperature (for example, from 50 to 65°C) in the presence of a suitable catalyst gidrogenizirovanii (for example, Pd/C, [(R)- or (S)-DIPAMP]or RhCl [(R)- or (S)-BINAP]Ru(OAc)2) and a suitable organic solvent (e.g. ethanol or methanol).

The catalyst based on palladium for a combination of Hake may contain a source of palladium (0) (for example, Pd(OAc)2Pd(OCOCF3)2(PPh3)2Pd(dba)2Pd(PPh3)4) and optionally a suitable ligand for coordination of palladium (e.g., PPh3,P(Oi-Pr)3or three-(about-tolyl)phosphine).

Compounds of formulas II, III, IV, V, VI, VII, VIII, IX, X, XII, XIII, XIV, XV, XIX, XX, XXI, XXII, XXIII, XXIV, XXV and XXVI are either commercially available, known from the literature or can the be obtained by analogy with the methods, described in this document, or accepted procedures for the synthesis according to standard methods from readily available starting materials using appropriate reagents and conditions for reaction.

The substituents on the alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl and heterocyclic groups in the compounds of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV and XXVI can be entered and/or mutually transformed into each other using techniques well known to specialists in this field, by standard mutual transformations of functional groups in accordance with standard techniques, from readily available starting materials using appropriate reagents and conditions for reaction. For example, benzyloxy may be converted into hydroxy, etc.

The compounds of formula I can be isolated from their reaction mixtures using conventional techniques. For example, the compounds of formula I can be isolated by transformation in acid (e.g. hydrochloric acid) salt (for example, by adding acid to the crude product) and then recrystallization of the salt from a suitable solvent (e.g. methanol or, especially, ethanol). Alternatively, to obtain pure acid salts of the compounds of formula I salt can be easily washed or suspended in presets the Wii is such a suitable solvent.

According to the present invention to pharmaceutically acceptable derivatives of compounds of formula I are also "protected derivatives of compounds of formula I and/or compounds that act as prodrugs.

The compounds of formula I may be tautomerism. The invention covers all tautomeric forms and mixtures thereof.

The compounds of formula I can also contain one or more asymmetric carbon atoms and therefore they may be optical and/or diastereoisomerism. Diastereoisomer can be separated using conventional techniques such as chromatography. A large number of stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional techniques, such as HPLC. Alternatively, the desired optical isomers may be created by the interaction of the appropriate optically active starting materials in conditions that will not cause racemization or epimerization, or derivatization (for example, with the homochiral acid followed by separation of the diastereomeric derivatives generally accepted methods (e.g., fractionated crystallization, HPLC, chromatography on silica gel). The invention encompasses all stereoisomers.

Specialists in this field will understand that the methods described herein above and the dal is, you may want to protect the functional groups of intermediate compounds with protective groups.

To functional groups, which it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protective groups for hydroxy include optionally substituted and/or unsaturated alkyl groups (e.g. methyl, allyl, benzyl ortert-butyl), trialkylsilyl or diarylethylene group (for example,tert-butyldimethylsilyl,tert-butyldiphenylsilyl or trimethylsilyl), and tetrahydropyranyl. Suitable protective groups for carboxylic acids include1-6alkyl or benzylamine. Suitable protective groups for amino includetert-butyloxycarbonyl and benzyloxycarbonyl.

Protect and unprotect functional groups can occur before or after the condensation or before or after any other reaction in the above schema.

The protective group may be removed in accordance with techniques which are well known to specialists in this field, and as described in this document below.

The person skilled in the art will understand that alternative of obtaining compounds of the formula I and in some cases a more appropriate way of individual stages of the method specified in this document can be implemented in other the order and/or the individual reactions may be carried out on the great stage of the whole path (i.e. the substituents can be added and/or chemical transformations carried out on the basis of other intermediate products than those specified in this document earlier in connection with a particular reaction). It can reject or confirm the necessity of protective groups.

The nature of the chemistry involved will be dictated by the need and type protective groups, as well as the sequence of synthesis implementation.

The use of protective groups described in the books “Protective Groups in Organic Chemistry”, edited by J. W. F. McOmie, Plenum Press (1973) and ' Protective Groups in Organic Synthesis”, 3eedition, T. W. Greene &P. G. M. Wutz, Wiley-Interscience (1999).

Protected derivatives of compounds of formula I can be converted chemically into compounds according to the invention using standard techniques unprotect (for example, gidrogenizirovanii). Professionals should also be understood that certain compounds of formula I can also be referred to as a "protected derivatives" other compounds of formula I.

Professionals in this field should also be understood that certain compounds of formula I can be used as intermediates in the synthesis of other compounds of formula I.

When used in the above method of treatment of compounds of formula I (for example, the compounds of formula Ia or Ib) can be a mixture of DL is the introduction of the patient. In this regard, according to another additional aspect of the invention features a pharmaceutical composition including a compound of formula I (for example, the compounds of formula Ia or, especially, Ib), in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

The above drugs, combination products, and pharmaceutical compositions (components) can be obtained according to methods known to experts in this field, for example by mixing the compounds of formula I, Ia or Ib with excipients or excipients.

When mixed with excipients compounds of formula I, Ia or Ib may be present in the above-mentioned drugs, combination products, and pharmaceutical compositions (or their components) at a concentration of from 0.1 to 99.5% (for example, from 0.5 to 95%) of the masses. from all of the mixture.

When administered to patients with any of the above drugs, combination products, and pharmaceutical compositions (components) of the compound of formula I, Ia or Ib, as a rule, must be administered orally, by any parenteral way or by inhalation.

When applied to animals, the compounds of formula I, Ia or Ib can also be introduced by the inclusion of compounds of formula I, Ia or Ib in food or drinking water.

One of the prefer is lnyh ways of administration of the compounds according to the invention is oral.

Suitable daily doses of the compounds according to the invention in the prophylactic and/or therapeutic treatment of mammals (e.g. humans) include, for example, a dose of 0.001-100 mg/kg body weight by oral administration and 0.001-50 mg/kg body weight at parenteral administration.

In a specific embodiment of the invention compounds of formula I, Ia or Ib are applied topically. Thus, according to the invention is invited to:

(I) a pharmaceutical composition for topical application containing a compound of formula I, Ia or Ib in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier;

(II) a combination product for topical application, containing

(A) compound of formula I, Ia or Ib, as defined herein before, and

(C) conventional antimicrobial agent, as defined herein before,

where each of the components (a) and (b) are in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

When used in this document, the term "local" understand composition adapted for application to a body surface (e.g., skin or mucous membranes). To mucous membranes, which can be mentioned in this respect include the mucosa of the vagina, penis, urethra, bladder, anus, oral cavity (including the mucosa of the cheeks, me is who the sky, under the surface of the tongue and floor of the mouth, nose, pharynx (including the mucosa of the pharynx, larynx, trachea and esophagus), bronchi, lungs, eyes and ear.

In relation to paragraph (II) above, the combined product provides an introduction of the component (A) with component (B), and may thus be presented either as separate compositions for topical application, in which at least one of the compositions contains a component (a) and at least one contains a component (C), or may be presented (i.e. it must be a mixture) in the form of a combined preparation for local application (i.e. to be presented in the form of a single composition for topical application comprising component (A) and the component (C)).

To compositions for topical application, which can be used to treat disorders of the skin or mucous membranes (for example, membranes, achievable finger, such as membranes of the mouth, vagina, cervix, anus and rectum), include creams, ointments, lotions, sprays, gels and sterile aqueous solutions or suspensions. Essentially, to compositions for topical application include compositions where the active(s) ingredient(s) dissolved(s) or dispersed(s) in dermatological carrier known in this field (e.g., aqueous or non-aqueous gels, ointments, emulsions, water-in-oil or the aslo-in-water). Such carriers may include water, aqueous buffer solutions, non-aqueous solvents (such as ethanol, isopropanol, benzyl alcohol, 2-(2-ethoxyethoxy) ethanol, propylene glycol, propylene glycol monolaurate, glycoluril or glycerin); oils (e.g. mineral oil such as liquid paraffin, natural or synthetic triglycerides, such as MiglyolTMor silicone oils such as Dimethicone). Depending, among other things, on the nature of the composition, and intended for her use and place of drawing used dermatological carrier may contain one or more components (for example, if the composition is a water-based gel, the components are added to the water), selected from the following list:

solubilizers agent or solvent (for example, β-cyclodextrin, such as hydroxypropyl β-cyclodextrin, or alcohol or polyhydric alcohol, such as ethanol, propylene glycol or glycerol);

thickener (e.g., hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose or carbomer);

geleobrazuyuschie agent (for example, a copolymer of polyoxyethylene-polyoxypropylene);

a preservative (e.g. benzyl alcohol, benzalkonium chloride, chlorhexidine, chlorbutol, benzoate, potassium sorbate or EDTA or its salts); and

pH sauterelle(e) agent(s (a(s) as a mixture of monopotassium phosphate and secondary hydrogen phosphate, or a mixture of citric acid and the secondary acid phosphate).

The amount of compounds of formulas I, Ia or Ib used in compositions for topical application or combined products will depend, among other things, on the specific nature of the composition or combination product, and planned to use them. In any case, the person skilled in the art will be able to identify common and simple ways number of compounds of formulas I, Ia or Ib, which can be used. Typically, however, the compound of formula I, Ia or Ib must be in the composition for local application or a combined product in an amount of from 0.01 to 25 wt%. (for example, from 0.1 to 10 wt. -%, such as from 0.1 to 5 wt%. or, in particular, from 0.5 to 3% of the mass. (for example, 2% or 1%)from the composition or product.

Specific compositions for topical application, which can be specified are those compositions which contain a compound of the formula I (for example, in amounts of from 0.5 to 3%, such as 2% or 1% of the mass.) and:

(a) water;

(b) one or more polar non-aqueous solvent (e.g. alcohol or polyhydric alcohol, such as ethanol, propylene glycol and/or glycerol);

(c) a preservative (e.g. benzyl alcohol);

(d) a thickener (e.g., hydroxyethyl cellulose); and optional

(e) pH sauterelle(e) agent(s) ((s) as a mixture of monopotassium salts is of Osvita and secondary hydrogen phosphate).

In particular the compositions and depending, inter alia, on the amount of the compounds of formula I are present (as a rule, to solubilize compounds needed more compounds of formula I, more polar non-aqueous solvents):

(i) the water may be present in an amount of from 55 to 75% (for example, from 60 to 72.5%) mass.;

(ii) one or more polar non-aqueous solvents can (together) be in the amount of from 15 to 40% (for example, from 24 to 35%) mass.;

(iii) glycerol, if used, may be present in an amount of 5 to 25% (for example, from 15 to 20%) mass.;

(iv) ethanol, if used, may be present in an amount of from 3 to 10% (for example, from 5 to 8%) mass.;

(v) propylene glycol, if used, may be present in an amount of from 2 to 15% (for example, from 4 to 6%) mass.;

(vi) the preservative may be present in amounts of from 0.1 to 3% (e.g. about 1%) of the masses.;

(vii) the thickener may be present in an amount of from 1 to 5% (for example, about 2 wt. -%).

More specific compositions for local application pH sauterelle(e) agent(s) to be used and dissolved in the water component of the composition may(gut) to provide a pH in the range from 5 to 7 (e.g., pH about 5.5).

Methods of obtaining pharmaceutical compositions for topical application such as creams, ointments, elk the us, sprays and sterile aqueous solutions or suspensions, are well known in this field. Suitable methods of obtaining pharmaceutical compositions for topical application are described, for example, in WO 95/10999, US 6974585, WO 2006/048747, as well as in the documents cited in any of these sources.

Pharmaceutical compositions for local application and combination products according to the present invention can be used for treating a number of disorders of the skin or mucous membranes, such as infectious diseases of the skin or mucous membranes (for example, infectious diseases of the mucous membrane of the nose, armpit, groin, perineum, rectum, skin dermatitis, skin ulcers and plots the introduction of medical equipment such as needles, intravenous catheters and tubes for tracheostomy or feeding)caused by any bacteria, fungi described in this document (for example, all organisms are staphylococci, streptococci, mycobacteria, or Pseudomonas, specified in this document before, such asS. aureus(for example, methicillin-resistantS. aureus(MRSA))).

To specific conditions, caused by a bacterial infection that can be treated with pharmaceutical compositions for local application and combination products of the present invention also is related condition, associated with skin and mucous membranes described in this document, as well as: acne vulgaris; acne rosacea; rosacea (including erythematotelangiectatic rosacea, papulopustular rosacea, hematozoa rosacea and ocular rosacea), erysipelas, eritrazma, ectima, proboda ectima, impetigo; paronychia; cellulite; folliculitis (including Jacuzzi folliculitis, furunculosis; carbuncles; staphylococcal toxic epidermal necrolysis, surgical scarlet fever, perianal streptococcal disease, streptococcal toxic shock syndrome, punctuate keratosis, axillary triominos, pyoderma; infections of the external ear canal syndrome green nails, spirochaetes, necrotizing fasciitis, mycobacterial infections of the skin (such as lupus ordinary, scrofuloderma, warty tuberculosis, tuberculin, erythema nodosum, indurativnyy erythema, cutaneous manifestations tuberculocides leprosy or lepromatous leprosy, leprosy erythema nodosum, cutaneous infectious diseases caused byM. kansasii, M. malmoense, M. szulgai, M. simiae, M. gordonae, M. haemophilum, M. avium, M. intracellulare, M. chelonae (includingM. abscessus)orM. fortuitum, granuloma swimmers (or aquarium), lymphadenitis and Buruli ulcer (Bairnsdale ulcer, ulcer of Sirles, ulcer to Kacarevo or ulcer Toro)); intertrigo; atopic eczema with the staphylococcal noitalls the PTO; and infectious eczema, burn wounds, scratches and skin wounds.

To a specific condition caused by a fungal infection that can be treated with pharmaceutical compositions for local application and combination products of the present invention also include conditions associated with skin and mucous membranes described in this document, as well as: candidiasis (e.g., oropharyngeal candidiasis, vaginal candidiasis or balanitis), sporotrichosis; tinea corporis (e.g., tinea of the feet, groin tinea, ringworm, tinea of the nails or trichophytosis smooth skin); pityriasis versicolor; and infectious diseases caused by fungiTrichophyton, Microsporum, EpidermophytonorPityrosporum ovale(Malassezia furfur).

In addition to the above, the composition for local application and combination products according to the present invention can be used for effective cleaning (for example, preventive cleansing):

(a) Staphylococcus (e.g., MRSA);

(b) propionibacteria, such asPropionibacterium acnes; or

(c) fungi (such asCandida albicans, Cryptococcus neoformans, Histoplasma capsulatum, Epidermophyton floccosum, Malassezia(for example,Malassezia furfuror, especially,Trichophyton(for example,Trichophyton violaceum, Trichophyton mentagrophytesor, especially,Trichophyton rubrum),

with skin or mucous membranes of a patient in need of such cleansing.

<> In the case of staphylococci purification can be effective, particularly with the skin (e.g., before surgery, or administration of medical equipment such as needles, intravenous catheters and tubes for tracheostomy or feeding), nose (for example, nostrils), RAS or atopic eczema (atopic dermatitis).

Thus, according to an additional aspect of the invention features a method of treating any condition and infectious diseases, mentioned above, with regard to compositions for topical application or effective purification from microorganisms described above, comprising the administration to a patient in need, an effective amount of the composition for local use, as defined herein before, and / or the combination product, as defined herein before.

Similarly, a composition for topical application, as defined herein before, or a combination product for local use, as defined herein before, for use in the treatment of any condition and infectious diseases, mentioned above, with regard to compositions for topical application or in the efficient purification from microorganisms described above.

Microorganisms destroyed by applying the composition for local the applications or combined product can be clinically latent. Thus, the invention also encompasses a method for killing clinically latent microorganisms in a mammal infected with such latent microorganisms, including the introduction of a given mammal microbicide effective amount of a composition for topical application according to the first aspect of the invention, or a combination product according to the second aspect of the invention.

When used to treat microbial infections of the compounds of formula I, Ia or Ib, administered either alone or in combination with conventional antimicrobial agent, preferably used in fewer doses than required to treat the same microbial infection using only conventional antimicrobial agents (e.g., less than 7, 6, 5, 4 or 3 doses 2 doses or, in particular, 1 dose).

In this respect, another aspect of the invention relates to a method of reducing the dose of conventional antimicrobial agent needed to treat a microbial infection, comprising co-administration of compounds of formula I, Ia or Ib.

Compounds of formula I, Ia or Ib are an advantage because they can be use to kill clinically latent microorganisms. In addition, in the treatment of microbial infections of the compounds of formula I, Ia or Ib may have more is the added advantage, they allow to reduce time of treatment (either alone or in combination with conventional antimicrobial agent), thus increasing patient compliance with a treatment regimen (for example, through the need to obtain a smaller dose of antimicrobial agents) and/or minimizing the risk of subpopulations of microorganisms that are (genetically) resistant to common antimicrobial agents.

In addition, the compounds according to the invention may have the advantage that they can be more effective, less toxic, to have a broader range of activity, be stronger, to create fewer side effects or have other used pharmacological properties compared to the compounds known from the prior art.

Biological tests

The test procedures that can be used to determine biological (e.g., bactericidal or antibacterial) activity of the compounds of formula I, Ia or Ib include procedures known to specialists in this area to determine:

(a) bactericidal activity against bacteria in stationary phase or "persistent" (i.e."clinically latent"bacteria); and

(b) antibacterial activity against bacteria in the log phase.

In about the wearing of paragraph (b) above, the methods for determining the activity against bacteria in the log phase is determined under standard conditions (i.e. conditions that are known to specialists in this field, such as the conditions described in WO 2005/014585, the description of this document is reproduced in this document as a reference) minimum inhibitory concentration (MIC) or minimum bactericidal concentration (“MBC”) test connection.

In relation to paragraph (a) above, to methods for determining the activity against the clinically latent bacteria applies the definition in condition, well-known experts in this field (such as the conditions described in articleNature Reviews, Drug Discovery1, 895-910 (2002)described in this document by reference) minimum bactericidal concentration against bacteria in stationary phase ("MSC") or minimum bactericidal concentration against dormant bacteria ("MDC") of the test compounds. The following describes specific examples of such methods.

The Protocol for pyogenic bacteria

Bacterial strains

The following table presents the strains used for screening.

tr>
Staphylococcus aureus(Oxford)GramThe control strain
Escherichia coliK12GramThe control strain
Enterococcus,GramClinical isolate
PseudomonasGramClinical isolate
Methicillin-resistantS. aureus(MRSA)GramClinical isolate
Klebsiella aerogrenesGramClinical isolate
E. coliGramClinical isolate
Streptococcus pneumoniaeGramThe control strain
Streptococcus group a Streptococcus pyogenesGramThe control strain
Streptococcus group B (Streptococcus agalactiae)GramThe control strain
Streptococcus viridansGramThe control strain
Haemophilus influenzaeGramThe control strain
Coagulasenegativeaureus(CNS)GramThe control strain
Propionibacterium acnesGramThe control strain (NCTC 737)

The growth of bacteria

Bacteria (except for streptococci andH. InfluenzaeandP. cnes) were grown in 10 ml of nutrient broth No. 2 (production company Oxoid)) over night at 37°C with continuous shaking at 120 rpm Streptococcus spp. andH. influenzaewere grown overnight in broth Todd-Hewitt (production company Sigma) without shaking.P. acneswere grown overnight in 10 ml of nutrient broth without shaking. Night culture was diluted (1000 times) in 100 ml of medium for growth and then incubated with shaking or without it for 10 days. The viability of bacteria was assessed by counting colony forming units (CFU) with an interval of 2 hours in the first 24 hours and at intervals of 12-24 hours later. From serial 10-fold dilutions of experimentalresults to plates with nutrient agar (production company Oxoid) and a Cup with blood agar (production company Oxoid) in three repetitions were added to the samples in the amount of 100 µl. After incubation cups at 37°C for 24 hours counted the number of colony-forming units (CFU). The number of CFUP. acneswas evaluated after incubation cups under anaerobic conditions for 48 hours.

Culture in log phase: The preceding night culture was diluted (1000 times) environment isoenzymes. The culture is then incubated at 37°C, shaking for 1-2 hours, until the value of log CFU 6, except for streptococci,H. InfluenzaeandP. cnes, which were incubated at 37°C, without shaking. These cultures served as cultures in log phase.

Culture in stationary phase: Culture, incubated for more than 24 hours, are in stationary phase. For screening drug use 5-6 day culture in stationary phase, as shown in figure 1 (segments between two arrows). The culture was diluted with phosphate-buffered saline solution to a value of log 6, these cultures were used for incubation with the test compounds.

Measurement of bactericidal activity against cultures in log phase

Different concentrations of each test compound were incubated with the cultures in log phase in 96-well tablets during different periods of time(2, 4, 6, 12, 24 hours). Bactericidal activity was then assessed using spectrophotometry (using spot reader) is received cultures, as well as the number of CFU as described above.

Measurement of bactericidal activity against cultures in stationary phase

Different concentrations of each test compound were incubated with the cultures in stationary phase (5-6 days of culture) in 96-well tablets within 24 or 48 hours. Bactericidal activity was then determined by the number of CFU obtained cultures as described above.

Measurement of bactericidal activity against persistent bacteria

To the 5-6-day cultures in stationary phase was added to the antibiotic (e.g. gentamicin) to a final concentration of 50 to 100 mcg/ml within 24 hours. After 24 hours exposure to the antibiotic, the cells washed 3 times with phosphate-buffered saline (PBS) and then resuspended in PBS. Viable bacterial cells used as persistent bacteria. Viability assessed by counting CFU. Persistent bacteria is then used in the measurement of bactericidal activity of the test compounds.

Different concentrations of each test compound were incubated with a suspension of (persistent) cells in 96-well tablets during different time periods (24 and 48 hours). Bactericidal activity was then determined by counting CFU cultures obtained as described above.

The Protocol forM. tuberculosis

Cultivation of M. tuberculosis

M. tuberculosisH37Rv was grown in 10 ml of medium Middlebrook 7H9 broth suspensions containing 0.05% Tween 80, supplemented with 10% ADC without failure for up to 100 days. To obtain uniformly dispersed cultures to experimental exposure concentrations in the cultures were divided, mixing culture on the vortex in the presence of glass beads 2 mm in size (the production company Philip Harris Scientific, Staffordshire, UK) for 2 minutes with subsequent destruction by ultrasound in water ultrasonic bath (firm output Branson Ultrasonic B.V.) for 5 minutes. The number of viableM. tuberculosisin the cultures was determined by counting colony forming units (CFU) on agar Middlebrook 7H11. In the medium Middlebrook 7H9 broth suspensions, supplemented with 0.05% of about. Tween 80, but without the ADC, perform a series of 10-fold dilutions of the cultures. Then into segments of size one third cups with agar in two repetitions were added to 100 ál of the samples. The cups were incubated in plastic bags for 3 weeks at 37°C.

Measurement of bactericidal activity against cultures in log phase

Different concentrations of each test compound were incubated with the cultures in log phase (4-day culture) for different time periods (4, 8, 16, 24 days). Bactericidal activity was then determined by counting CFU cultures obtained as described above.

Measuring bactericidal Akti is particular about cultures in stationary phase and persistent bacteria

Model 1 - Culture in stationary phase. Different concentrations of each test compound were incubated with a 100-day cultures, treated with ultrasound, each concentration for individual culture volume of 10 ml After incubation for 5 days was determined by the number of viable CFU, inocula a couple of cups with medium N 10-multiples of serial dilutions of the obtained cultures in a volume of 100 μl.

Model 2 - persistent bacteria, selected using rifampicin. To each culture from a number of 100-day-old cultures, treated with ultrasound, added rifampicin (100 mg/l), these cultures are then incubated for 5 days. After the first day of incubation on plates inoculated with culture, the colonies could not be obtained. After washing twice with PBS by centrifugation to generate a volume of 10 ml was added fresh (and not containing rifampicin) Wednesday N, and the test compound was added in the same concentrations as in model 1. After additional incubation for 7 days was determined by the number of CFU, inocula 1 ml from each container to the Cup with the environment N. These cups are then incubated for 2 weeks and very small colonies were counted and noted. After an additional 2 weeks of incubation to the posted colonies added any additional unlabeled to onii (i.e. colonies that grew slowly). Control studies showed that after about 4 days of incubation cultures without rifampicin counting on the Cup begin to appear colony subculture.

Model 3. The procedure is similar to model 2, but only with different concentrations of the test compounds were added to the 100-day culture on the third day after treatment with rifampicin. At the end of the 7-day incubation period (4 days with candidate drugs plus rifampicin) all cultures were washed, replacing the medium containing the test compounds and then incubated for an additional 7 days before determining the number of CFU.

The Protocol forCandida albicans

Used clinical isolateCandida albicans. The strain was grown in 10 ml of potato-dextrose nutrient medium (production company Sigma-Aldrich) at 24°C with continuous shaking at 120 rpm for 24 hours. Then 1 ml of culture was inoculable in 100 ml of fresh medium, which was incubated under the same conditions for 6 days.

Culture in log phase: The preceding 24-hour culture was diluted (100-fold) potato-glucose culture medium. The culture is then incubated at 24°C with shaking for 20-24 hours, they served as cultures in log phase. Culture in log phase were diluted with fresh, nutritious, Sedogo values of log CFU 6, they were used to test activity of compounds.

Culture in stationary phase: For screening drugs used 5-6 day culture in stationary phase. Culture in stationary phase were diluted with phosphate-buffered saline to a value of log CFU 6, these cultures were used to evaluate the activity of the test compounds.

Measuring activity against cultures in log phase

Different concentrations of each test compound were incubated with the cultures in log phase in 96-well tablets during different periods of time(2, 4, 6, 12, 24 hours). The activity of the drug was then estimated using spectrophotometry (using spot reader) obtained cultures, as well as by the number of CFU as described above.

Measuring activity against cultures in stationary phase

Different concentrations of each test compound were incubated with the cultures in stationary phase (5-6 days of culture) in 96-well tablets within 24 or 48 hours. The activity was then determined by receiving the number of CFU obtained cultures as described above.

The model on the skin (local)

In addition to testing against bacteria in stationary and log phasein vitro, the compounds of formula I, Ia or Ib can also be tested in a large number of models ofin vivoincluding the model, well-known experts in this field. For example, for determining the activity of compounds against bacteria in or on the skin to protocols that may be offered include the protocols described in the journalAntimicrobial Agents and Chemotherapy49(8), 3435-41 (2005), as well as the following.

Superficial skin bacterial model mice (intact skin)

The ICR mice or BALB/c mice aged 6-8 weeks were obtained from the firm Harlan UK. Mice were anesthesia intra-abdominal injection of 200 μl of a solution of ketamine hydrochloride/xylazine. The hair on the back of the mouse was removed using electric clippers. The area of skin the size of 2 cm2(2 cm × 1 cm) were marked with a marker. To estimate the number of bacteria on the skin marked area of the skin 3 times and cleaned using disposable swab. The bacteria on the swab rubbed the Cup with blood agar (production company OxoidTM).

Used bacterial or yeast culture in log phase or stationary phase. The culture was concentrated by centrifugation to obtain from 109up to 1010CFU/ml of Cell sediment resuspendable using nutrient broth or PBS and glycerol (50%). 15-20 µl of cell suspension was added to the skin (2 cm2), as a result when the skin 106-7SOME. The skin was left to dry for about 15 minutes the Solution tested is connected to the I at various concentrations were applied to the skin area during different periods of time.

The number of bacteria or yeast on the skin was evaluated according to the following: after the mouse umertvlâl, the skin is marked on the plot were cut and added to a test tube with a volume of 2 ml containing 1 ml of water and glass beads (1 mm). Skin homogenized using reciprocating shutter apparatus (production company Hybaid Ltd, UK) for 45 seconds (setting speed of 6.5) or mixing on a vortex for 1 minute Remaining of the test compound was removed by washing 3 times with water or PBS (with precipitation of the test compound in a buffer system for cleaning used water). Counting was carried out after SOME series of 10-fold dilution of the homogenates. One third cups with blood agar (production company OxoidTMin binary recurrence was added to the samples in the amount of 100 µl. Then after incubation of bacterial cups at 37°C for 24 hours or yeast cups at 24°C for 48 hours were counting colony-forming units (CFU)using aCoLye (count colonies).

Infectious model of the skin surface mouse infection model with striping stripes)

The ICR mice or BALB/c mice aged 6-8 weeks were obtained from the firm Harlan UK. Mice were anesthesia intra-abdominal injection of 200 μl of a solution of ketamine hydrochloride/xylazine. The fur of the mice on the back was removed with electric cars for Reiki. The area of skin the size of 2 cm2stripped strips, using indicator tape for autoclaves. The skin is consistently stripped 10 times. After this procedure, the skin is visibly damaged and was characterized by redness and Shine, but without the constant bleeding. To reduce long-term pain syndrome during the period of anesthesia and every 12 hours up to 3 days were given buprenorphine. After Stripping skin bacterial infection is initiated by applying to the affected skin area 10 μl of bacterial cell suspension containing 107cells from overnight culture or culture in stationary phase. At 0 hours and 4 hours after infection, 3 mice were scored to assess the number of CFU on the skin. After 24 hours, the solutions of the test compounds at various concentrations were applied to the skin for various periods of time. The experiments were completed within 18 h after the last local processing.

The number of bacteria RAS were evaluated according to the following: after euthanasia of the mouse wounds about the size of 2 cm2cut out and added to a test tube with a volume of 2 ml containing 1 ml of water and glass beads (1 mm). Skin homogenized using reciprocating shutter apparatus (production company Hybaid Ltd, UK) for 45 seconds (setting speed of 6.5). The remaining test connection is dalali by washing 3 times with water. Counting was carried out after SOME series of 10-fold dilution of the homogenates. One third cups with blood agar (OxoidTMin binary recurrence was added to the samples in the amount of 100 µl. After incubation cups at 37°C for 24 hours counted the number of colony-forming units (CFU)using aCoLye (count colonies).

The invention is illustrated by, but is not limited to the following examples and figures, which represent data relating inter alia to the biological studies described above.

In the figure 1illustrates the impact NT onStaphylococcus aureusin stationary phase on the infected skin of a mouse. Connection NT was introduced in the form of a solution in water, solubilizing 10% of the mass. hydroxypropyl β-cyclodextrin.

In the figure 2illustrates the impact NT onStaphylococcus aureusin stationary phase on the intact skin of the mouse. Connection NT was introduced in the form of a solution in water, solubilizing 10% of the mass. hydroxypropyl β-cyclodextrin.

In the figure 3illustrates the impact NT onCandida albicansin stationary phase on the intact skin of the mouse. Connection NT was introduced in the form of a solution in water, solubilizing 10% of the mass. hydroxypropyl β-cyclodextrin.

Characters

NT: 4-(3-benzylpyrrolidine-1-yl)-2-methyl-6-phenoxyphenol

C: control (without treatment)

With+CD: control group, printing handling the data (by means of local application) solvent system, used for dissolving NT (i.e. aqueous solution of 10% of the mass. hydroxypropyl β-cyclodextrin).

EXAMPLES

The basic experimental procedures

Range1H NMR were recorded at ambient temperature using either a spectrometer Varian Unity Inova (400 MHz)or a spectrometer Bruker Advance DRX (400 MHz), both equipped with a probe of a triple resonance 5 mm Chemical shifts are expressed in ppm relative to tetramethylsilane. We used the following abbreviations: s = singlet, d = doublet, DD = double doublet, t = triplet, square = Quartet, m = multiplet.

Experiments on high-performance liquid chromatography - mass spectrometry (LCMS) to determine retention times and ions depending on the mass, was performed using the following methods:

Method: the Experiments were carried out on the spectrometer Micromass Platform LCT with ionization elektrorazpredelenie and registration of positive ions and detection at a single wavelength UV 254 nm, using a column Higgins Clipeus C18 100×3.0 mm with a particle size of 5 microns and a flow rate of 1 ml/min. The initial solvent system consisted of water at a concentration of 95%, containing 0.1% formic acid (solvent A)and acetonitrile at a concentration of 5%, containing 0.1% formic acid (solvent B), within the first minute, followed by a gradient up to 5% of the RA is the solvent a and 95% solvent b over the next 14 minutes. The final solvent system was left unchanged for an additional 5 minutes.

Method: the Experiments were performed on a quadrupole spectrometer Micromass Platform ZQ with ionization elektrorazpredelenie and registration of positive ions and detection at a single wavelength UV 254 nm, using a column Higgins Clipeus C18 100×3.0 mm with a particle size of 5 microns and a flow rate of 1 ml/min. The initial solvent system consisted of solvent And at a concentration of 95% and a solvent In a concentration of 5% within the first minute, followed by a gradient up to 5% solvent a and 95% solvent b over the next 14 minutes. The final solvent system was left unchanged for an additional 5 minutes.

Microwave experiments were carried out using either the synthesizer ersonal Chemistry Smith SynthesizerTMor mrys OptimizerTMusing single-mode resonator and dynamic field setting, both give the reproducibility and control. Can be obtained temperature of 40-250°C, and can be reached pressure up to 20 bar.

Preparative HPLC was carried out using column Genesis C18size h,6 mm with a particle size of 7 microns, elwira at 10 ml/min with a gradient of water/MeCN (+0.1% of formic acid or 0.1% triperoxonane acid). The fractions containing the desired product were concentrated. Sometimes the connection is then turned in hydrochloric salt processing 1M hydrochloric acid, followed by evaporation.

Preparative chiral HPLC was carried out, unless otherwise stated, using a column Chiralpak IA size h,6 mm, particle size 5 microns, elwira at 18 ml/min with a mixture of diethylamine (0.1%) and ethanol (7%) in heptane.

Receive

Getting 1

6-benzyloxy-4-chloro-2-methylinosine

(i)complex ethyl ester of 3-(4-benzyloxyaniline)but-2-ene acid

4-benzyloxyaniline (10 g) and ethylacetoacetate (6,9 g) was heated at 120°C for 3 hours. The residue was purified by chromatography on silica gel, elwira a mixture of dichloromethane and pentane. The desired fractions were concentrated, and the sample evaporated to obtain specified in paragraph (i) of the compound (7.8 g).

1H NMR (D6-DMSO) δ 10,2 (s, 1H), 7.5 to to 7.3 (m, 7H), 7,2 (d, 2H), 7,0 (d, 2H), and 5.2 (s, 1H), 4,1 (square, 2H), 1.8 m (s, 3H), 1,4 (t, 3H)

(ii)6-benzyloxy-4-hydroxy-2-methylinosine

Complex ethyl ester of 3-(4-benzyloxyaniline)but-2-ene acid (3.1 g; see stage (i) above) in dichlorobenzene (12 ml) was heated in a microwave oven at 220°C for 45 minutes. The reaction mixture was diluted with pentane and the precipitate was filtered, washed with pentane and dried to obtain 6-benzyloxy-4-hydroxy-2-methylinosine.

1H NMR (D6-DMSO) δ of 7.6 (s, 1H), 7.5 to to 7.3 (m, 8H), 5,7 (s, 1H), and 5.2 (s, 2H), 2,3 (s, 3H)

(iii)6-benzyloxy-4-chloro-2-methylinosine

6-benzyloxy-4-hydroxy-2-methylinosine (2.6 g; see stage (ii)above) in phosphorus oxychloride (40 ml) was heated at the boil under reflux for 3.5 hours. The mixture was then carefully added to the system ice/water and was added solid sodium carbonate until the solution pH to 8.0. The mixture was extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The obtained solid phase was poroshkovo diethyl ether to obtain the connection specified in the header (6.4 g) as a white solid phase.

1H NMR (Dl3) δ 8,0 (d, 1H), 7,5 to 7.4 (m, 8H), and 5.2 (s, 2H), and 2.7 (s, 3H)

Getting 2

4-chloro-2-methyl-6-(pyridine-3-ylethoxy)quinoline

4-chloro-6-iodine-2-methylinosine (0,61 g; see obtaining 6(ii) below), 3-pyridylcarbinol (0.26 g), copper iodide (I) (0,038 g), cesium carbonate (0,78 g), 1,10-phenanthroline (0,072 g) in toluene (3 ml) was heated in a microwave oven at 160°C for 40 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel, elwira mixture of methanol and dichloromethane. Evaporation of the desired fractions led to the connection specified in the header, in the form of a pale pink solid phase.

1H NMR (Dl3) δ of 8.7 (s, 1H), and 8.6 (d, 1H), 7,9 (d, 1H), and 7.8 (d, 1H), and 7.5 (s, 1H), and 7.4 (d, 1H), and 7.3 (m, 2H), 5,3 (s, 2H), and 2.7 (s, 3H)

Getting 3

4-chloro-2-methyl-6-phenoxyphenol

(i)4-hydroxy-2-methyl-6-phenoxyphenol

A named connection was received, use the procedures I, similar to that described in paragraph Obtaining 6(i) below, but using 4-fenoxedilom instead of 4-itanyone.

1H NMR (D6-DMSO) δ 7.5 (d, 1H), and 7.4 (m, 5H), 7,2 (t, 1H), and 7.1 (d, 2H), 2,3 (s, 3H)

(ii)4-chloro-2-methyl-6-phenoxyphenol

The connection specified in the header, obtained using procedures similar to those described in paragraph Obtain 1((iii) above but using 4-hydroxy-2-methyl-6-phenoxyphenol (see stage (i) above) instead of 6-benzyloxy-4-hydroxy-2-methylinosine.

1H NMR (Dl3) δ 8,0 (d, 1H), and 7.6 (s, 1H), 7.5 (d, 1H), and 7.4 (m, 3H), 7,2 (t, 1H), and 7.1 (d, 2H), and 2.7 (s, 3H)

Getting 4

Benzyl-(4-chloro-2-methylinosine-6-yl)amine

(i)N-(4-hydroxy-2-methylinosine-6-yl)ndimethylacetamide

The named compound was obtained using procedures similar to those described in paragraph Obtaining 6(i) below, but using 4-aminoacetanilide instead of 4-itanyone.

1H NMR (D6-DMSO) δ 10,2 (s, 1H), and 8.2 (s, 1H), and 7.8 (d, 1H), and 7.4 (d, 1H), and 5.8 (s, 1H), 3,4 (s, 3H), 2,3 (s, 3H)

(ii)6-amino-4-chlorhydrin

N-(4-hydroxy-2-methylinosine-6-yl)ndimethylacetamide (0.05 g; see stage (i) above)in methanol (2 ml) and 5 n hydrochloric acid (6 ml) was heated at the boil under reflux for 90 minutes. The reaction mixture is evaporated and the residue was dissolved in ethyl acetate and sodium carbonate solution. The organic phase is washed with water, dried (Na2SO4), filtered and concentrated, obtaining mentioned which paragraph (ii) compound as a pale yellow solid phase.

1H NMR (D6-DMSO) δ 7.7 (d, 1H), and 7.4 (s, 1H), 7,2 (d, 1H), 7,0 (s, 1H), and 5.8 (s, 2H), and 2.5 (s, 3H)

(iii)Benzyl-(4-chloro-2-methylinosine-6-yl)amine

6-amino-4-chlorhydrin (0.1 g; see stage (ii) above), benzaldehyde (by 0.055 g) and triacetoxyborohydride sodium (0,22 g) in 1,2-dichloroethane was stirred over night. The mixture was diluted with dichloromethane and washed with water, then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel, elwira a mixture of ethyl acetate and pentane. The desired fractions were concentrated, and the sample is evaporated to the dry state, receiving the connection specified in the header, in the form of oil.

1H NMR (Dl3) δ of 7.8 (d, 1H), 7.5 to about 7.2 (m, 6H), 7,2 (d, 1H), and 7.1 (s, 1H), and 4.5 (s, 2H), and 2.6 (s, 3H)

Getting 5

N-(4-chloro-2-methylinosine-6-yl)benzamid

(i)N-(4-hydroxy-2-methylinosine-6-yl)benzamid

The named compound was obtained using procedures similar to those described in paragraph Obtaining 6 (i) below, but using N-(4-AMINOPHENYL) benzamide instead of 4-itanyone.

(ii)N-(4-chloro-2-methylinosine-6-yl)benzamid

The connection specified in the header, obtained using procedures similar to those described in paragraph Obtaining 1 (iii) above but using N-(4-hydroxy-2-methylinosine-6-yl)benzamide (see stage (i) above) instead of 6-benzyloxy-4-hydroxy-2-methylinosine.

1H NMR (D6-DMSO) δ is 10.6 (s, 1H), 8,7 (1H), of 8.2 (d, 1H), 8,0-7,5 (m, 5H), 5,6 (s, 1H), and 2.6 (s, 3H)

Getting 6

1-(4-chloro-2-methylinosine-6-yl)pyrrolidin-2-he

(i)4-hydroxy-6-iodine-2-methylinosine

4-stanlin (25 g), ethylacetoacetate (17.8 g) and polyphosphoric acid (112,5 g) in dioxane (500 ml) was heated at boiling under reflux for 20 hours. The reaction mixture was diluted with water (2 l) was added solid sodium carbonate until then, until the solution pH reached a value of 10.0. The precipitate was isolated by filtration, washed with water and dried under vacuum. Poroshkovaya with simple ether resulted in the receipt of the indicated compounds (10 g) as a white solid phase.

1H NMR (Dl3) δ of 8.3 (s, 1H), and 7.8 (d, 1H), and 7.3 (d, 1H), 5,9 (s, 1H), 2,3 (s, 3H)

(ii)4-chloro-6-iodine-2-methylinosine

4-hydroxy-6-iodine-2-methylinosine (10 g; see stage (i) above) in phosphorus oxychloride (70 ml) was heated at 80°C for 1 hour. The reaction mixture was then carefully added to the system ice/water and was added solid sodium carbonate until then, until the solution pH reached a value of 8.0. The mixture was extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The obtained solid phase was poroshkovo diethyl ether, obtaining a named connection (6.4 g) as a solid phase are white in color.

1H NMR (Dl3) δ of 8.5 (s, 1H), 8.0 a (d, 1H), 7.7 (d, 1H), and 7.4 (s, 1H), and 2.7 (s, 3H)

(iii)1-(4-chloro-2-etelginen-6-yl)pyrrolidin-2-he

4-chloro-6-iodine-2-methylinosine (0,61 g; see stage (ii) above). 2 pyrrolidine (0.24 g), copper iodide (I) (0,038 g), potassium phosphate (0.5 g) and N,N'-dimethylethylenediamine (0.035 g) in dimethylformamide (3 ml) was heated in a microwave oven at 100°C for 1 hour. The reaction mixture was diluted 1 N. sodium hydroxide and was extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel, elwira a mixture of dichloromethane and methanol. The desired fractions were concentrated and the sample is evaporated to the dry state. Poroshkovaya of simple ether resulted in the receipt of the connection specified in the header, in the form of a white powder (0.2 g).

1H NMR (Dl3) δ and 8.4 (d, 1H), and 8.1 (s, 1H), 8.0 a (d, 1H), and 7.4 (s, 1H), 4,0 (t, 2H), and 2.7 (s, 3H), and 2.6 (t, 2H), 2,3 (square, 2H)

Getting 7

2-methyl-6-nitro-4-(3-phenylpyrrolidine-1-yl)quinoline

4-chloro-2-methyl-6-nitroquinoline (0.2 g), 3-phenylpyrrolidine (0.14 g) and diisopropylethylamine (0,27 ml) in 2-ethoxyethanol (4 ml) was heated in a microwave oven to 200°C for 15 minutes. The reaction mixture was diluted with water and was extracted with dichloromethane, washed with water, dried (Na2SO4), filtered and evaporated, receiving a yellow oil. The residue was purified by chromatography on silica gel, elwira a mixture of dichloromethane and ethanol and ammonia (200:8:1). The desired fractions were concentrated, produces the connection, specified in the header, in the form of an orange oil.

1H NMR (Dl3) δ of 9.3 (s, 1H), and 8.4 (d, 1H), and 8.0 (s, 1H), between 7.4 and 7.3 (m, 5H), 6,5 (s, 1H), 4,2-3,5 (m, 5H), and 2.7 (s, 3H), and 2.6 (m, 1H), 2,4 (m, 1H)

Examples

Example 1

6-chloro-2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline

4,6-dichloro-2-methylinosine (0.1 g) and 3-phenylpyrrolidine (0.15 g) in 2-ethoxyethanol (1.5 ml) was heated in a microwave oven at 240°C for 10 minutes. The mixture was diluted with water and extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel, elwira mixture of methanol and dichloromethane. Evaporation of the desired fractions resulted in the receipt of the connection specified in the header, in the form of a solid phase white.

1H NMR (Dl3) δ 8,1 (s, 1H), and 7.8 (d, 1H), 7.5 (d, 1H), and 7.4 (t, 2H), and 7.3 (m, 3H), of 6.4 (s, 1H), 4,0 (t, 1H), 3,9 (m, 1H), and 3.8 (m, 2H), 3,5 (m, 1H), and 2.6 (s, 3H), 2,4 (m, 1H), 2,3 (m, 1H)

LCMS (method A)retention time of 7.90 min; (M+N+) 323

Example 2

6-benzyloxy-2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline

The named compound was obtained using procedures similar to those described in example 1 above but using 6-benzyloxy-4-chloro-2-methylinosine (see Getting 1 above) instead of 4,6-dichloro-2-methylinosine.

1H NMR (Dl3) δ 8,0 (m, 1H), and 7.5 (s, 1H), and 7.4 to 7.2 (m, 11H), to 6.4 (s, 1H), 5,1 (s, 2H), 3,9 (t, 1H), and 3.8 (m, 1H), 3,7 (m, 2H), 3,5 (m, 1H), and 2.6 (s, 3H), 2,4 (m, 1H), 2,2 (m, 1H)

LCMS (SPO is about 7), the retention time of 8.9 minutes; M+= 396 (M+N+)

Example 3

2-methyl-4-(3-phenylpyrrolidine-1-yl)-6-(pyridine-3-ylethoxy) quinoline hydrochloride

The free base was obtained using procedures similar to those described in example 1 above but using 4-chloro-2-methyl-6-(pyridine-3-ylethoxy)quinoline (see Getting 2 above) instead of 4,6-dichloro-2-methylinosine. The connection specified in the header (corresponding cleaners containing hydrochloride salt) was obtained by treatment of the free base with hydrochloric acid, followed by evaporation of solvent.

1H NMR (D6-DMSO) δ 14,0 (s, 1H), and 8.8 (s, 1H), and 8.6 (s, 1H)and 8.1 (d, 1H), 8.0 a (d, 1H), and 7.9 (s, 1H), 7.7 (d, 1H), 7.5 (m, 1H), and 7.4 (m, 4H), and 7.3 (m, 1H), 6,7 (s, 1H), 5,4 (s, 2H), 4,3 (t, 1H), 4,1 (m, 2H,), a 3.9 (t, 1H), 3,6 (m, 1H), and 2.6 (s, 3H), 2,4 (m, 1H), 2,2 (m, 1H)

LCMS (method B), the retention time of 6.13 minutes (M+H+) 396

Example 4

6-(4-methysulfonylmethane)-2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline

2-Methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-ol (0.05 g; see example 42 below), 1-methyl bromide-4-methanesulfonate (0.08 g), cesium carbonate (0.1 g) in DMF (2 ml) was heated in a microwave oven at 120°C for 15 minutes. The reaction mixture was diluted with water and was extracted with dichloromethane, washed with water, dried (MgSO4), filtered and evaporated to obtain oil. The residue was purified by chromatography on silica gel, elwira a mixture of dichloromethane and methane is La. Evaporation of the desired fractions resulted in the receipt of the connection specified in the header, in the form of a pale yellow solid phase.

1H NMR (Dl3) δ 8.0 to about 7.8 (m, 3H), and 7.6 (d, 2H), and 7.5 (s, 1H), and 7.4 to 7.2 (m, 6H), 6,5 (s, 1H), and 5.2 (d, 2H), 3,9-3,6 (m, 4H), 3,5 (m, 1H), and 3.0 (s, 3H), and 2.6 (s, 3H), 2,4 (m, 1H), 2,2 (m, 1H)

LCMS (method A)retention time to 7.77 min (M+N+) 473

Example 5

6-(4-methoxybenzyloxy)-2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline

2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-ol (0.05 g; see example 42 below) was stirred with sodium hydride (60% dispersion in mineral oil; 0.035 g) in DMF (2 ml) for 15 minutes, after which was added 4-methoxybenzylamine (0.12 g). After 18 hours the reaction mixture was diluted with water and was extracted with dichloromethane, washed with water, dried (MgSO4), filtered and evaporated to obtain a brown oil. The residue was purified by chromatography on silica gel, elwira a mixture of dichloromethane and methanol. Evaporation of the desired fractions resulted in the receipt of the connection specified in the header, in the form of a cream solid phase.

1H NMR (Dl3) δ 8,6 (d, 1H), and 7.6 (s, 1H), and 7.4 to 7.2 (m, 8H), 6,8 (d, 2H), 6,2 (s, 1H), 5,1 (d, 2H), 4,1 (t, 1H), 3,9 (m, 2H), and 3.8 (t, 1H), and 3.7 (s, 3H), 3,6 (m, 1H), and 2.8 (s, 3H), 2,5 (m, 1H), 2,3 (m, 1H)

LCMS (method A)retention time 8,82 minutes (M+H+) 425

Example 6

2-methyl-6-penetrate-4-(3-phenylpyrrolidine-1-yl)quinoline hydrochloride

It is the initial basis of the received using procedures similar to those described in example 5 above, but using (2-bromacil)benzene instead of 4-methoxybenzylamine. The connection specified in the header (corresponding cleaners containing hydrochloride salt) was obtained by treatment of the free base with HCl (aq.) in methanol, followed by evaporation of solvent.

1H NMR (D6-DMSO) δ 13,8 (s, 1H), 7,9 (d, 1H), and 7.8 (s, 1H), and 7.6 (d, 1H), and 7.4 to 7.2 (m, 10H), 6,7 (s, 1H), 4,4 (t, 2H), 4,4-to 3.8 (m, 4H), 3,6 (m, 1H), 3,1 (t, 2H), and 2.6 (s, 3H), 2,5 (m, 1H), 2,2 (m, 1H)

LCMS (method A)retention time of 9.1 minutes (M+H+) 409

Example 7

2-methyl-6-(5-methylisoxazol-3-ylethoxy)-4-(3-phenylpyrrolidine-1-yl)quinoline hydrochloride

The free base was obtained using procedures similar to those described in example 5 above, but using 3-methyl bromide-5-methylisoxazol instead of 4-methoxybenzyl bromide. The connection specified in the header (corresponding cleaners containing hydrochloride salt) was obtained by treatment of the free base with HCl (aq.) in methanol, followed by evaporation of solvent.

1H NMR (D6-DMSO) δ 14,1 (s, 1H), 8.0 a (d, 1H), and 7.9 (s, 1H), 7.7 (d, 1H), and 7.4 (m, 4H), and 7.3 (t, 1H), 6,7 (s, 1H), 6,4 (s, 1H), 5,4 (s, 2H), 4,4-3,9 (m, 4H), 3,6 (m, 1H), and 2.6 (s, 3H), 2,5 (m, 1H), 2.4GHz (with, 3H), 2,2 (m, 1H)

LCMS (method A)retention time of 8.0 minutes (M+H+) 400

Example 8

4-(3-benzylpyrrolidine-1-yl)-2-methyl-6-phenoxybenzamine hydrochloride

4-chloro-2-methyl-6-phenoxyphenol (0.2 g; with whom. Getting 3 above) and 3-benzylpyrrolidine (0.3 g) in 2-ethoxyethanol (4 ml) was heated in a microwave oven to 200°C for 20 minutes. The mixture was diluted 1 N. sodium hydroxide and was extracted with ethyl acetate, dried (MgSO4), filtered and evaporated. The residue was purified preparative HPLC, the desired fractions were combined and evaporated to obtain a clear oil, which was acidified with concentrated hydrochloric acid and then evaporated. Poroshkovaya simple ether resulted in the receipt of the connection specified in the header, in the form of a white powder.

1H NMR (D6-DMSO) δ 14,3 (s, 1H)and 8.1 (d, 1H), and 7.9 (s, 1H), 7.7 (d, 1H), 7.5 (t, 2H), and 7.3 (t, 2H), 7,2 (m, 4H), and 7.1 (d, 2H), and 6.6 (s, 1H), and 3.8 (m, 3H), 3,5 (m, 1H), 2,8-2,5 (m, 6H), 2.0 (m, 1H), 1,7 (m, 1H)

LCMS (method A)retention time 9,02 minutes (M+H+) 395

In an alternative obtain 4-chloro-2-methyl-6-phenoxyphenol (1 EQ.) and 3-benzylpyrrolidine (1 EQ.) was heated in nitrogen atmosphere up to 150-170°C in the presence of from 3 to 4 equivalents of 2,4,6-trimethylpyridine. The result was obtained 4-(3-benzylpyrrolidine-1-yl)-2-methyl-6-phenoxyphenol in the form of free base.

Example 9

4-[3-(4-methoxyphenyl)pyrrolidin-1-yl]-2-methyl-6-phenoxybenzamine hydrochloride

The connection specified in the header, obtained using procedures similar to those described in example 8 above but using 3-(4-methoxyphenyl)pyrrolidin instead of 3-benzylpyrrolidine.

sup> 1H NMR (D6-DMSO) δ 14,1 (s, 1H)and 8.1 (d, 1H), and 7.9 (s, 1H), 7.7 (d, 1H), and 7.4 (t, 2H), and 7.3 (d, 2H), 7,2 (t, 1H), and 7.1 (d, 2H), 6,9 (d, 2H), 6,7 (s, 1H), 4,2 (m, 1H), 3,9 (m, 2H), and 3.8 (m, 4H), 3,5 (m, 1H), and 2.6 (s, 3H), 2,4 (m, 1H), 2,1 (m, 1H)

LCMS (method B); retention time of 8.2 minutes (M+H+) 411

Example 10

4-[3-(4-chlorophenyl)pyrrolidin-1-yl]-2-methyl-6-phenoxybenzamine hydrochloride

The named compound was obtained using procedures similar to those described in example 8 above but using 3-(4-chlorophenyl)pyrrolidin instead of 3-benzylpyrrolidine.

1H NMR (D6-DMSO) δ 14,2 (s, 1H)and 8.1 (d, 1H), and 7.9 (s, 1H), 7.7 (d, 1H), and 7.4 (m, 6H), 7,2 (t, 1H), and 7.1 (d, 2H), 6,7 (s, 1H), 4,2 (m, 1H), 3,9 (m, 2H), and 3.8 (m, 1H), 3,5 (m, 1H), and 2.6 (s, 3H), 2,4 (m, 1H), 2,1 (m, 1H)

LCMS (method B); retention time of 8.9 minutes (M+H+) 416

Example 11

[1-(2-methyl-6-phenoxyphenol-4-yl)pyrrolidin-3-yl]phenylamine

1-(2-methyl-6-phenoxyphenol-4-yl)pyrrolidin-3-ylamine (0,107 g; see example 43 below), brobinson (0,058 g), 2-dicyclohexylphosphino-2'-dimethylaminophenyl (0,023 g),Tris(dibenzylideneacetone)dipalladium (0.03 g),tert-piperonyl sodium (0,044 g) and toluene (3 ml) was heated in a microwave oven at 150°C for 20 minutes. The reaction mixture was diluted with water and was extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated to obtain a brown oil. The residue was purified by chromatography on silica gel, elwira a mixture of dichloromethane and the of ethanol. Evaporation of the desired fractions were resulted after powdering simple ester compounds specified in the header, in the form of a white solid phase.

1H NMR (Dl3) δ of 7.8 (d, 1H), and 7.7 (s, 1H), and 7.4 to 7.2 (m, 3H), 7,2 (t, 2H), and 7.1 (t, 1H), 7,0 (d, 2H), 6,8 (t, 1H), and 6.6 (d, 2H), 6,4 (s, 1H), 4,2 (m, 1H), 3,9 (square, 1H), and 3.8 (m, 1H), 3,6 (m, 1H), 3,4 (m, 1H), and 2.6 (s, 3H), 2,3 (m, 1H), 2,1 (m, 1H)

LCMS (method A); the retention time of 8.4 minutes (M+H+) 396

Example 12

N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]benzamide hydrochloride

2-methyl-6-amino-4-(3-phenylpyrrolidine-1-yl)quinoline (0.07 g; see example 45 below), benzoyl chloride (0.035 g) and Diisopropylamine (0,065 g) was stirred in dichloromethane (3 ml). The reaction mixture was diluted 1 N. sodium hydroxide and was extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated to obtain a brown oil. The residue was purified by chromatography on silica gel, elwira a mixture of dichloromethane and methanol. The desired fractions were concentrated, and then added hydrochloric acid and the sample is evaporated to the dry state. Poroshkovaya simple ether resulted in the receipt of the connection specified in the header, in the form of a solid phase white (0.03 g).

1H NMR (D6-DMSO) δ 13,95 (s, 1H), and 10.8 (s, 1H), and 9.1 (s, 1H), 8.3 (l, 1H), 8.0 a (m, 3H), 7,6 (m, 3H), of 7.4 (m, 4H), and 7.3 (t, 1H), 6,8 (s, 1H), 3,8-4,4 (m, 4H), and 3.7 (m, 1H), and 2.6 (s, 3H), 2,1 (m, 1H)

LCMS (method B); time odergivaniya,75 minutes (M+H +) 408

Example 13

N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]-2-phenylacetamide

The named compound was obtained using procedures similar to those described in example 12 above, but using phenylacetylene instead of benzoyl chloride. In addition, the final product was not made in cleaners containing hydrochloride salt.

1H NMR (Dl3) δ of 8.95 (s, 1H), and 7.8 (d, 1H), 7,2-7,5 (m, 11H), and 7.1 (d, 1H), 6,4 (s, 1H), 4,0 (m, 2H), 3,9 (m, 1H), and 3.8 (s, 2H), and 3.7 (m, 1H), 3,5 (m, 1H), and 2.6 (s, 3H), 2,5 (m, 1H), 2,1 (m, 1H)

LCMS (method A)retention time 8,32 minutes (M+H+) 422

Example 14

4-chloro-N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl] benzamide hydrochloride

The named compound was obtained using procedures similar to those described in example 12 above, but using 4-chlorobenzylchloride instead of benzoyl chloride.

1H NMR (D6-DMSO) δ is 10.6 (s, 1H), and 9.1 (s, 1H), 8.3 (l, 1H)and 8.1 (d, 2H), 7,9 (d, 1H), and 7.6 (d, 2H), and 7.4 (m, 4H), and 7.3 (t, 1H), 6,7 (s, 1H), 4,4 (m, 1H), 4,1 (m, 2H), 4,0 (t, 1H), 3,7 (m, 1H), and 2.6 (s, 3H), 2,5 (m, 1H), 2,2 (m, 1H)

LCMS (method B); retention time of 8.50 min (M+N+) 442

Example 15

4-methoxy-N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl] benzamide

The named compound was obtained using procedures similar to those described in example 12 above, but using 4-methoxybenzophenone instead of benzoyl chloride. The final product was isolated as free base.

1H NMR (D6-DMSO) in order to 10.6 (s, 1H), and 8.8 (s, 1H), 8.0 a (m, 3H), 7.7 (d, 1H), and 7.4 (m, 4H), and 7.3 (t, 1H), and 7.1 (d, 2H), 6,5 (s, 1H), 4,0 (m, 2H), 3,9 (s, 3H), and 3.7 (m, 2H), 3,5 (m, 1H), 2,3 (s, 3H), 2,4 (m, 1H), 2,2 (m, 1H)

LCMS (method A)retention time 8.30 minutes (M+H+) 438

Example 16

2-methyl-N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl] benzamide

The named compound was obtained using procedures similar to those described in example 12 above, but using 2-methylbenzylamine instead of benzoyl chloride. The final product was isolated as free base.

1H NMR (D6-DMSO) δ of 10.5 (s, 1H), 8.0 a (d, 1H), 7.7 (d, 1H), 7.5 (d, 1H), and 7.4 to 7.2 (m, 9H), 6,5 (s, 1H), 3,9 (m, 2H), and 3.8 (m, 2H), 3,5 (m, 1H), and 2.6 (s, 3H), 2,3 (m, 4H), 2,2 (m, 1H)

LCMS (method B); retention time 8,14 minutes (M+H+) 422

Example 17

[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide of pyrazin-2-carboxylic acid hydrochloride

2-methyl-6-amino-4-(3-phenylpyrrolidine-1-yl)quinoline (0.07 g; see example 45 below), 2-pyrazinecarboxamide acid (0.037 g), HATU (0,113 g) and Diisopropylamine (0,116 g) was stirred in N,N-dimethylformamide (4 ml) for 15 hours. The reaction mixture was diluted 1 N. sodium hydroxide and was extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated to obtain a brown oil. The residue was purified by chromatography on silica gel, elwira a mixture of dichloromethane and methanol. The desired fractions were concentrated, and then added sour salt is at and the sample evaporated to the dry state. Poroshkovaya simple ether resulted in the receipt of the connection specified in the header, in the form of a solid phase white (0,045 g).

1H NMR (D6-DMSO) δ 11,0 (s, 1H), and 9.4 (s, 1H), 8,95 (m, 2H), 8,9 (s, 1H)and 8.1 (d, 1H), 7.7 (d, 1H), and 7.4 (m, 4H), and 7.3 (t, 1H), 6,5 (s, 1H), 4,0 (m, 2H), and 3.8 (m, 2H), 3,6 (m, 1H), 2,5 (s, 3H), 2,4 (m, 1H), 2,1 (m, 1H)

LCMS (method A)retention time 7,39 minutes (M+H+) 410

Example 18

[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide of 1H-pyrazole-4-carboxylic acid hydrochloride

The named compound was obtained using procedures similar to those described in example 17 above, but using 4-pyrazolylborate acid instead of 2-pyrazinecarboxamide acid.

1H NMR (D6-DMSO) δ 13,8 (s, 1H), 10,3 (s, 1H), and 9.2 (s, 1H), and 8.3 (s, 1H), and 8.2 (d, 1H), 7,9 (d, 1H), and 7.4 (m, 4H), and 7.3 (t, 1H), and 6.6 (s, 1H), 4,4 (m, 1H), 4,2 (m, 2H), 4,0 (m, 2H), 3,6 (m, 1H), and 2.6 (s, 3H), 2,5 (m, 1H), 2,2 (m, 1H)

LCMS (method B); retention time 6.40 min (M+N+) 398

Example 19

[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide, furan-2-carboxylic acid hydrochloride

The named compound was obtained using procedures similar to those described in example 17 above, but using 2-frankenboob acid instead of 2-pyrazinecarboxamide acid.

1H NMR (D6-DMSO) δ of 13.7 (s, 1H), 10,6 (s, 1H), and 9.2 (s, 1H), 8,5 (s, 1H), and 8.2 (d, 1H), 7,9 (d, 1H), and 7.8 (s, 1H), and 7.4 (m, 4H), and 7.3 (t, 1H), and 7.1 (s, 1H), 6,7 (s, 1H), 4,4-to 3.8 (m, 4H), and 3.7 (m, 1H), 2,6 (, 3H), 2,5 (m, 1H), 2,2 (m, 1H)

LCMS (method A); time is derivare of 7.64 minutes (M+H +) 398

Example 20

N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl] nicotinamide hydrochloride

The named compound was obtained using procedures similar to those described in example 17 above, but using nicotinic acid instead of 2-pyrazinecarboxamide acid.

1H NMR (D6-DMSO) δ 14,0 (s, 1H), 11,1 (s, 1H), and 9.3 (s, 1H), and 9.2 (s, 1H), and 8.8 (d, 1H), and 8.5 (d, 1H), 8.3 (l, 1H), 8.0 a (d, 1H), and 7.7 (m, 1H), and 7.4 (m, 4H), and 7.3 (t, 1H), 6,8 (s, 1H), 4,4-to 3.8 (m, 4H), 2,6 (, 3H), 2,5 (m, 1H), 2,2 (m, 1H)

LCMS (method B); retention time 6,74 minutes (M+H+) 409

Example 21

[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide of 3-methyl-3H-imidazole-4-carboxylic acid hydrochloride

The named compound was obtained using procedures similar to those described in example 17 above, but using 1-methyl-5-imidazolinone acid instead of 2-pyrazinecarboxamide acid.

1H NMR (D6-DMSO) δ 13,8 (s, 1H), and 10.5 (s, 1H), and 9.0 (s, 1H), and 8.2 (d, 1H), and 7.8 (m, 3H), 7,5 to 7.4 (m, 4H), to 7.4 (t, 1H), and 6.6 (s, 1H), 4,4-to 3.8 (m, 4H), and 3.8 (s, 3H), 3,6 (m, 1H), and 2.6 (s, 3H), 2,5 (m, 1H), 2,2 (m, 1H)

LCMS (method B); retention time 5,63 minutes (M+H+) 412

Example 22

[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide 5-methyl-1H-pyrazole-3-carboxylic acid hydrochloride

The named compound was obtained using procedures similar to those described in example 17 above, but using 5-methyl-3-pyrazolinone acid instead of 2-pyrazinecarboxamide acid

1H NMR (D6-DMSO) δ 13,8 (s, 1H), 10,6 (s, 1H), and 9.1 (s, 1H), and 8.4 (d, 1H), 7,9 (d, 1H), 7,5 to 7.4 (m, 4H), and 7.3 (t, 1H), 6,7 (s, 1H), and 6.6 (s, 1H), 4,4-3,4 (m, 5H), and 2.6 (s, 3H), 2,5 (m, 1H), 2,3 (m, 4H)

LCMS (method B); retention time 7,19 minutes (M+H+) 412

Example 23

[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide of pyridazin-4-carboxylic acid hydrochloride

The named compound was obtained using procedures similar to those described in example 17 above, but using pyridazin-4-carboxylic acid instead of 2-pyrazinecarboxamide acid.

1H NMR (D6-DMSO) δ 13,8 (s, 1H), and 11.4 (s, 1H), and 9.7 (s, 1H), and 9.5 (s, 1H), and 9.2 (s, 1H), and 8.4 (d, 1H), and 8.2 (s, 1H), 8.0 a (d, 1H), 7,5 to 7.4 (m, 4H), and 7.3 (t, 1H), 6,8 (s, 1H), 4,4-to 3.8 (m, 4H), 3,6 (m, 1H), 2,6 (s, 3H), 2,2 (m, 1H)

LCMS (method B); retention time of 6.52 minutes (M+H+) 410

Example 24

2-(4-methoxyphenyl)-N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]ndimethylacetamide

The named compound was obtained using procedures similar to those described in example 17 above, but using 4-methoxyphenylalanine acid instead of 2-pyrazinecarboxamide acid.

1H NMR (Dl3) δ of 10.4 (s, 1H), and 8.8 (s, 1H), 7,6 (m, 3H), of 7.4 to 7.2 (m, 6H), 6,8 (d, 2H), 6,5 (s, 1H), 3,9 (m, 2H), 3,7 (m, 5H), 3,5 (m, 3H), and 2.6 (s, 3H), 2,5 (m, 1H), 2,1 (m, 1H)

LCMS (method A)retention time 8.15 minutes (M+H+) 452

Example 25

2-(4-chlorophenyl)-N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]ndimethylacetamide

The named compound was obtained using procedure is s, similar to that described in example 17 above, but using 4-chlorophenylalanine acid instead of 2-pyrazinecarboxamide acid.

1H NMR (Dl3) δ of 10.4 (s, 1H), and 8.7 (s, 1H), and 7.7 (s, 2H), between 7.4 and 7.3 (m, 8H), and 7.3 (t, 1H), 6,5 (s, 1H), 3,9 (m, 2H), and 3.7 (m, 4H), 3,5 (m, 1H), and 2.6 (s, 3H), 2,4 (m, 1H), 2,1 (m, 1H)

LCMS (method A)retention time 8,73 minutes (M+H+) 456

Example 26

[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide of 3,5-dimethylisoxazol-4-carboxylic acid hydrochloride

The named compound was obtained using procedures similar to those described in example 17 above, but using 3,5-dimethylisoxazol-4-carboxylic acid instead of 2-pyrazinecarboxamide acid.

1H NMR (D6-DMSO) δ 13,5 (s, 1H), and 10.5 (s, 1H), and 9.0 (s, 1H)and 8.1 (d, 1H), and 7.8 (d, 1H), between 7.4 and 7.3 (m, 4H), and 7.3 (t, 1H), 6,7 (s, 1H), 4,3 (m, 1H), 4,1 (m, 2H), 3,9 (m, 1H), 3,6 (m, 1H), and 2.6 (s, 3H), 2,5 (, 3H), and 2.4 (s, 3H), 2,3 (m, 1H)

LCMS (method B); retention time 7,42 minutes (M+H+) 427

Example 27

2-(3-methylisoxazol-5-yl)-N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]ndimethylacetamide hydrochloride

The named compound was obtained using procedures similar to those described in example 17 above, but using 3-methyl-5-isoxazolone acid instead of 2-pyrazinecarboxamide acid.

1H NMR (D6-DMSO) δ of 13.7 (s, 1H), up 10.9 (s, 1H), and 9.0 (s, 1H)and 8.1 (d, 1H), 7,9 (d, 1H), between 7.4 and 7.3 (m, 4H), and 7.3 (t, 1H), 6,7 (s, 1H), and 6.3 (s, 1H), 4,3 (m, 1H), 4,1 (m, 2H), 4,0 (s, 2H), 3,9 (m, 1H), 3,6 (m, 1H), and 2.6 (s, 3H), 2,2 (m, 4H)

LCMS (method A); BP is me holding 7,30 minutes (M+H +) 427

Example 28

N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl] benzosulfimide hydrochloride

2-methyl-6-amino-4-(3-phenylpyrrolidine-1-yl)quinoline (0.07 g; see example 45 below), benzosulphochloride level (0.041 g) and pyridine (0.04 g) was stirred in dichloromethane (4 ml). The reaction mixture was diluted 1 N. sodium hydroxide and was extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated to obtain a brown oil. The residue was purified by chromatography on silica gel, elwira a mixture of dichloromethane and methanol. The desired fractions were concentrated, was added hydrochloric acid and the sample is evaporated to the dry state. Poroshkovaya simple ether resulted in the receipt of the connection specified in the header, in the form of a solid phase white (0.035 g).

1H NMR (D6-DMSO) δ of 10.5 (s, 1H), and 7.8 (s, 1H), 7.7 (d, 2H), and 7.6 (d, 1H), 7.5 (t, 1H), between 7.4 and 7.3 (m, 9H), 6,5 (s, 1H), 3,8-3,4 (m, 5H), and 2.4 (s, 3H), 2,4 (m, 1H), 2,1 (m, 1H)

LCMS (method B); retention time 7,53 minutes (M+H+) 444

Example 29

Benzyl-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amine

Benzyl-(4-chloro-2-methylinosine-6-yl)amine (0,041 g; see Getting 4 above) and 3-phenylpyrrolidine 2-ethoxyethanol (1 ml) was heated in a microwave oven to 240°C for 10 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate, washed with water, dried (MgSO4), filter the Ali and evaporated. The residue was purified by chromatography on silica gel, elwira a mixture of dichloromethane and methanol. The desired fractions were concentrated, and the sample is evaporated to the dry state. Poroshkovaya simple ether resulted in the receipt of the connection specified in the header.

1H NMR (Dl3) δ of 7.8 (d, 1H), and 7.4 to 7.2 (m, 11H), and 7.1 (d, 1H), 7,0 (s, 1H), 6,4 (s, 1H), 4,4 (s, 2H), and 3.7 (t, 1H), 3,6-3,3 (m, 4H), and 2.6 (s, 3H), 2,3 (m, 1H), 2,1 (m, 1H)

LCMS (method A)retention time of 8.9 minutes (M+H+) 394

Example 30

(RorS-)benzyl-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amine

Benzyl-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amine (see Example 29 above) was purified chiral HPLC, elwira gradient solution of acetonitrile/water containing 0.1% formic acid. Named the title compound of example 30 was loirevalley with the first column. The solvent was removed from the respective samples to obtain the separated enantiomer in the form of a yellow powder.

1H NMR (Dl3) δ of 7.8 (d, 1H), and 7.4 to 7.2 (m, 11H), and 7.1 (d, 1H), 7,0 (s, 1H), 6,4 (s, 1H), 4,4 (s, 2H), and 3.7 (t, 1H), 3,6-3,3 (m, 4H), and 2.6 (s, 3H), 2,3 (m, 1H), 2,1 (m, 1H)

LCMS (method A); the retention time of 8.6 minutes (M+H+) 394

Example 31

(SorR-)benzyl-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amine

The named compound of example 31 was obtained according to the procedure described in example 30 above, and this compound was loirevalley with a column is which. The solvent was removed from the respective samples to obtain the separated enantiomer in the form of a yellow powder.

1H NMR (Dl3) δ is 7.9 (d, 1H), and 7.4 to 7.2 (m, 11H), and 7.1 (d, 1H), 7,0 (s, 1H), 6,4 (s, 1H), 4,4 (s, 2H), and 3.7 (t, 1H), 3,6-3,3 (m, 4H), and 2.6 (s, 3H), 2,3 (m, 1H), 2,1 (m, 1H)

LCMS (method A)retention time of 8.8 minutes (M+H+) 394

Example 32

(4-methoxybenzyl)-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amine

2-Methyl-6-amino-4-(3-phenylpyrrolidine-1-yl)quinoline (0.08 g; see example 45 below), 4-methoxybenzaldehyde (0,071 g), triacetoxyborohydride sodium (0,165 g) and acetic acid (0.05 ml) in 1,2-dichloroethane (5 ml) was heated at boiling under reflux for 4 hours. The reaction mixture was diluted 1 N. sodium hydroxide and was extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel, elwira a mixture of dichloromethane and methanol. The desired fractions were concentrated, and the sample is evaporated to the dry state. Poroshkovaya with simple ether resulted in the receipt of the connection specified in the header, in the form of a white powder (0.01 g).

1H NMR (Dl3) δ of 7.8 (d, 1H), and 7.4 to 7.2 (m, 7H), and 7.1 (d, 2H), 6,8 (d, 2H), 6,4 (s, 1H), 4,4 (s, 2H), and 3.8 (m, 1H), and 3.7 (s, 3H), 3,7-3,4 (m, 4H), and 2.6 (s, 3H), 2,3 (m, 1H), 2,1 (m, 1H)

LCMS (method B); retention time 8,42 minutes (M+H+) 424

Example 33

4-{[2-methyl-4-(3-phenylpyrrolidine-1-yl)hee the Olin-6-ylamino] methyl}benzonitrile

The named compound was obtained using procedures similar to those described in example 32 above, but using 4-cyanobenzaldehyde instead of 2-pyrazinecarboxamide acid.

1H NMR (D6-DMSO) δ a 7.6-7.5 (m, 4H), to 7.4 (t, 2H), 7,3 to 7.2 (m, 3H), and 7.1 (d, 1H), 6,7 (s, 1H), and 6.6 (t, 1H), 6,4 (s, 1H), 4,4 (m, 2H), 3,6-3,2 (5H), and 2.4 (s, 3H), 2,2 (m, 1H), 2,1 (m, 1H)

LCMS (method A)retention time 8,23 minutes (M+H+) 419

Example 34

1-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl] pyrrolidin-2-he

A mixture of 1-(4-chloro-2-methylinosine-6-yl)pyrrolidin-2-she (0.2 g; see obtaining 6 above) and 3-phenylpyrrolidine (0,282 g) in 2-ethoxyethanol was heated in a microwave oven at 250°C for 20 minutes. The reaction mixture was diluted 1 N. sodium hydroxide and was extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. Poroshkovaya with simple ether gave the connection specified in the header, in the form of a white powder (0.08 g).

1H NMR (D6-DMSO) δ is 8.6 (s, 1H), and 7.8 (d, 1H), 7.7 (d, 1H), between 7.4 and 7.3 (m, 4H), 7,2 (t, 1H), 6,5 (s, 1H), 3,9 (m, 4H), and 3.7 (t, 2H), 3,5 (m, 1H), 2,5 (m, 1H), 2,4 (m, 1H), 2,1 (m, 1H)

LCMS (method B); retention time of 6.7 minutes (M+H+) 372

Example 35

N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]-3-phenylpropionamide

The named compound was obtained using procedures similar to those described in example 12 above, but using 3-phenylpropionylamino instead of benzoyl chloride. Horse the hydrated product was isolated as free base.

1H NMR (D6-DMSO) δ of 10.4 (s, 1H), 10,1 (s, 1H), and 8.7 (s, 1H), and 7.7 (s, 2H), and 7.4 to 7.1 (m, 9H), 6,5 (s, 1H), 3,9 (m, 1H), 3,7 (m, 2H), 3,5 (m, 1H), and 2.8 (t, 2H), and 2.6 (t, 2H), and 2.5 (s, 3H), 2,4 (m, 1H), 2,2 (m, 1H)

LCMS (method B); retention time 8,18 minutes (M+H+) 436

Example 36

[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide 5-methylisoxazol-3-carboxylic acid

The named compound was obtained using procedures similar to those described in example 17 above, but using 5-methyl-3-isoxazolidinone acid instead of 2-pyrazinecarboxamide acid. The final product was isolated as free base.

1H NMR (D6-DMSO) δ is 10.7 (s, 1H), and 8.8 (s, 1H), 8.0 a (d, 1H), 7.7 (d, 1H), 7.5 to to 7.3 (m, 4H), and 7.3 (m, 1H), 6,7 (s, 1H), 6,5 (s, 1H), 3,9 (m, 2H), and 3.7 (t, 2H), 3,5 (m, 1H), 2,5 (m, 6H), 2,4 (m, 1H), 2,2 (m, 1H)

LCMS (method A)retention time of 7.90 minutes (M+H+) 413

Example 37

[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide pyridine-2-carboxylic acid hydrochloride

The named compound was obtained using procedures similar to those described in example 17 above, but using pyridine-2-carboxylic acid instead of 2-pyrazinecarboxamide acid.

1H NMR (D6-DMSO) δ 14,0 (s, 1H), and 11.3 (s, 1H), and 9.2 (s, 1H), 8,9 (d, 1H), and 8.5 (d, 1H), and 8.2 (d, 1H), 8,1 (t, 1H), 8.0 a (d, 1H), and 7.7 (m, 1H), 7,5 to 7.4 (m, 4H), and 7.3 (t, 1H), 6,7 (s, 1H), 4,4-4,0 (m, 4H), 3,6 (m, 1H), and 2.6 (s, 3H), 2,2 (m, 1H)

LCMS (method A)retention time of 7.95 minute (M+N+) 409

Example 38

N-[4-(3-benzylpyrrolidine the-1-yl)-2-methylinosine-6-yl]benzamide

The named compound was obtained using procedures similar to those described in example 1 above but using N-(4-chloro-2-methylinosine-6-yl)benzamide (see getting 5 above) instead of 4,6-dichloro-2-methylinosine and 3-benzylpyrrolidine instead of 3-phenylpyrrolidine.

1H NMR (D6-DMSO) δ of 10.5 (s, 1H), 8,9 (s, 1H), 8.0 a (m, 2H), 7,9 (d, 1H), 7.7 (d, 1H), 7,5 to 7.4 (m, 3H), and 7.3 (m, 4H), 7,2 (m, 1H), 6,4 (s, 1H), and 3.8 (m, 3H), 3,5 (t, 1H), 2,8 (m, 2H), 2,5 (m, 1H), 2.4GHz (with, 3H), 2,1 (m, 1H), 1,7 (m, 1H)

LCMS (method B); retention time 8,19 minutes (M+H+) 422

In the alternative receiving the named compound was obtained by heating N-(4-chloro-2-methylinosine-6-yl) benzamide (1 EQ.) and 3-benzylpyrrolidine (1 EQ.) together in an atmosphere of nitrogen up to 150-170°C in the presence of 3-4 equivalents of 2,4,6-trimethylpyridine.

Example 39

2-methyl-6-phenoxy-4-(3-phenylpyrrolidine-1-yl)quinoline hydrochloride

The named compound was obtained using procedures similar to those described in example 8 above but using 3-phenylpyrrolidine instead of 3-benzylpyrrolidine.

1H NMR (D6-DMSO) δ 14,0 (s, 1H), 8.0 a (d, 1H), and 7.9 (s, 1H), 7.7 (d, 1H), and 7.4 to 7.2 (m, 7H), 7,2 (t, 1H), and 7.1 (d, 2H), 6,7 (s, 1H), 4,2 (m, 1H), 3,9 (m, 2H), and 3.8 (m, 1H), 3,5 (m, 1H), and 2.7 (s, 3H), 2,5 (m, 1H), 2,1 (m, 1H)

LCMS (method B); the retention time of 8.7 minutes (M+H+) 381

Example 40

The form of the free base of the titled compound of example 8 was subjected to analytical chiral HPLC under the following conditions.

Column: ChiralpakTM IB with a particle size of 5 μm size 250×4.6 mm

Mobile phase: heptane/isopropanol/diethylamine 70/30/0,1

Flow rate: 1 ml/min

Detection: UV 250 nm

Temperature: 25°C

Using analytical HPLC revealed two main products:

(a) retention time to 7.59 minutes (49,63% of the total area under the curve); and

(b) retention time 12,94 minutes (50,30% of the total area under the curve).

Using this information, 100 mg of the free base form of the compound indicated in the heading of example 8 was subjected to preparative HPLC under the following conditions.

Column: ChiralpakTMIB 5 microns in size 250×20 mm

Mobile phase: heptane/isopropanol/diethylamine 70/30/0,1

Flow rate: 20 ml/min

Detection: UV 250 nm

Temperature: 25°C

Products, eluruumina the first and second (enantiomers) were collected separately, receiving:

(a) 40.5 mg eluruumideta first enantiomer (retention time of 7.6 minutes); and

(b) to 41.4 mg eluruumideta second enantiomer (retention time of 12.9 minutes).

(a)4-((RorS-)-3-benzylpyrrolidine-1-yl)-2-methyl-6-phenoxyphenol

Enantiomer, eluruumist first.

Analysis of this product by analytical HPLC (conditions suitable for analytical chiral HPLC, above) showed the following:

Product: retention time 7,51 minutes (99.96% of the total area under the curve).

Minor admixture: time derivan the 6,48 minutes (0,03% of the total area under the curve).

Calculated enantiomeric excess of >99.5%pure.

1H NMR spectrum identical to the racemate (see example 8 above).

(b)4-((SorR-)-3-benzylpyrrolidine-1-yl)-2-methyl-6-phenoxyphenol

Enantiomer, eluruumist first.

Analysis of this product by analytical HPLC (conditions suitable for analytical chiral HPLC, above) showed the following:

Product: retention time 12,86 minutes (99.95% of the total area under the curve);

Minor admixture: retention time 7,18 minutes (0,05% of the total area under the curve).

Calculated enantiomeric excess of >99.5%pure;

1H NMR spectrum identical to the racemate (see example 8 above).

Example 41

The form of the free base of the compound indicated in the heading of example 9 were subjected to analytical chiral HPLC under the following conditions.

Column: ChiralpakTMIA 5 microns in size 250×4.6 mm

Mobile phase: heptane/isopropanol/Ethylenediamine 70/30/0,1

Flow rate: 1 ml/min

Detection: UV 280 nm

Temperature: 25°C

Using analytical HPLC revealed two main products:

(a) retention time 8,63 minutes (50,58% of the total area under the curve); and

(b) retention time 10,42 minutes (49,42% of the total area under the curve).

Using this information, 100 mg of the free base form of the compound indicated in the heading of example 9 was subjected to preparative HPLC in the following the conditions.

Column: ChiralpakTMAD-H 5 μm size 250×30 mm

Mobile phase: heptane/isopropanol/diethylamine 70/30/0,1

Flow rate: 42,5 ml/min

Detection: UV 250 nm

Temperature: 25°C

Products, eluruumina the first and second (enantiomers) were collected separately, receiving:

(a) 50,1 mg enantiomer, eluruumideta first (the retention time of 8.6 minutes); and

(b) to 50.3 mg of enantiomer, eluruumideta second (retention time of 10.4 minutes).

(a)4-[(R- or S-)-3-(4-methoxyphenyl)pyrrolidin-1-yl]-2-methyl-6-phenoxyphenol

Enantiomer, eluruumist first.

Analysis of this product by analytical HPLC (conditions suitable for analytical chiral HPLC, above) showed the following:

Product: retention time of 8.50 minutes (100.00% of the total area under the curve).

Calculated enantiomeric excess of >99.5%pure;

1H NMR spectrum identical to the racemate (see example 9 above).

(b)4-[(SorR-)-3-(4-methoxyphenyl)pyrrolidin-1-yl]-2-methyl-6-phenoxyphenol

Enantiomer, eluruumist second.

Analysis of this product by analytical HPLC (conditions suitable for analytical chiral HPLC, above) showed the following:

Product: retention time 10,38 minutes (100.00% of the total area under the curve).

Calculated enantiomeric excess of >99.5%pure;

1H NMR spectrum identical to the racemate (see the use of the 9 above).

Example 42

The form of the free base of the compound indicated in the heading of example 22 was subjected to analytical chiral HPLC under the following conditions.

Column: ChiralpakTMIA 5 microns in size 250×4.6 mm

Mobile phase: heptane/ethanol/Ethylenediamine 70/30/0,1

Flow rate: 1 ml/min

Detection: UV 280 nm

Temperature: 25°C

Using analytical HPLC revealed two main products:

(a) retention time of 10.47 minutes (50, 20mm% of the total area under the curve); and

(b) retention time 14,15 minutes (49, 80mm% of the total area under the curve).

Using this information, 100 mg of the free base form of the compound indicated in the heading of example 22 was subjected to preparative HPLC under the following conditions.

Column: ChiralpakTMIA 5 microns in size 250×20 mm

Mobile phase: heptane/ethanol/diethylamine 80/20/0,1

Flow rate: 20 ml/min

Detection: UV 290 nm

Temperature: 25°C

Products, eluruumina the first and second (enantiomers) were collected separately, receiving:

(a) to 52.1 mg of enantiomer, eluruumideta first (retention time of 10.5 minutes); and

(b) to 44.0 mg enantiomer, eluruumideta second (retention time of 14.1 minutes).

(a)[2-methyl-4-((RorS-)-3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide 5-methyl-1H-pyrazole-3-carboxylic acid

Enantiomer, eluruumist first.

Analysis of this product by analytical HPLC (in us what the conditions, suitable for analytical chiral HPLC, above) showed the following:

Product: retention time 10,44 minutes (99.95% of the total area under the curve);

Minor admixture: retention time 14,30 minutes (0,05% of the total area under the curve).

Calculated enantiomeric excess of >99.5%pure;

1H NMR spectrum identical to the racemate (see example 22 above).

(b)[2-methyl-4-((SorR-)-3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide 5-methyl-1H-pyrazole-3-carboxylic acid

Enantiomer, eluruumist second.

Analysis of this product by analytical HPLC (conditions suitable for analytical chiral HPLC, above) showed the following:

Product: retention time 14,04 minutes (99.95% of the total area under the curve);

Minor admixture: retention time to 10.62 min (0,05% of the total area under the curve).

Calculated enantiomeric excess of >99.5%pure;

1H NMR spectrum identical to the racemate (see example 22 above).

Example 43

The connection specified in the header of example 38 was subjected to analytical chiral HPLC under the following conditions.

Column: ChiralpakTMIC 5 microns in size 250×4.6 mm

Mobile phase: heptane/isopropanol/Ethylenediamine 75/25/0,1

Flow rate: 1 ml/min

Detection: UV 280 nm

Temperature: 25°C

By analytical HPLC revealed two main products:

(a) retention time of 14.28 min is t (49,52% of the total area under the curve); and

(b) retention time 17,56 minutes (50,48% of the total area under the curve).

Using this information, 100 mg of the compound indicated in the heading of example 38 was subjected to preparative HPLC under the following conditions.

Column: ChiralpakTMIC 5 microns in size 250×50 mm

Mobile phase: heptane/isopropanol/diethylamine 75/25/0,1

Flow rate: 100 ml/min

Detection: UV 250 nm

Temperature: 25°C

Products, eluruumina the first and second (enantiomers) were collected separately, receiving:

(a) to 44.8 mg of enantiomer, eluruumideta first (retention time of 14.3 minutes); and

(b) to 43.4 mg of enantiomer, eluruumideta second (retention time of 17.6 minutes).

(a)N-[4-((RorS)-3-benzylpyrrolidine-1-yl)-2-methylinosine-6-yl]benzamide

Enantiomer, eluruumist first.

Analysis of this product by analytical HPLC (conditions suitable for analytical chiral HPLC, above) showed the following:

Product: retention time 14,16 minutes (100.00% of the total area under the curve).

Calculated enantiomeric excess of >99.5%pure;

1H NMR spectrum identical to the racemate (see example 38 above).

(b)N-[4-((SorR-)-3-benzylpyrrolidine-1-yl)-2-methylinosine-6-yl]benzamide

Enantiomer, eluruumist second.

Analysis of this product by analytical HPLC (conditions suitable for analytical chiral HPLC indicated in the above) showed the following:

Product: retention time 17,52 minutes (99.85% of the total area under the curve);

Minor admixture: retention time 14,40 minutes (0,15% of the total area under the curve).

Calculated enantiomeric excess of >99.5%pure;

1H NMR spectrum identical to the racemate (see example 38 above).

Example 44

2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-ol

6-benzyloxy-2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline (0.3 g; see example 2 above) and palladium on carbon (10%; 0.2 g) in ethanol (8 ml) was stirred in hydrogen atmosphere for 3 hours. The mixture was filtered and then concentrated to obtain the compound indicated in the title, in the form of a yellow oil which was used without further purification.

Example 45

1-(2-methyl-6-phenoxyphenol-4-yl)pyrrolidin-3-ylamine

(i)Complex tert-butyl ether [1-(2-methyl-6-phenoxyphenol-4-yl)-pyrrolidin-3-yl] carbamino acid

The named compound was obtained using procedures similar to those described in example 8 above but using 3-(tert-butyloxycarbonyl)pyrrolidin instead of 3-benzylpyrrolidine. The product was used directly in the next stage.

(ii)1-(2-methyl-6-phenoxyphenol-4-yl)pyrrolidin-3-ylamine

The product from step (i) above was treated triperoxonane acid in dichloromethane (1:1) to obtain, after evaporation of the connection specified in the zag is lowke, in the form of an orange oil which was used without further purification.

Example 46

2-methyl-6-amino-4-(3-phenylpyrrolidine-1-yl)quinoline

2-Methyl-6-nitro-4-(3-phenylpyrrolidine-1-yl)quinoline (0.29 grams; see getting 7 above) and palladium on carbon (10%; 0.2 g) in ethanol (10 ml) and dichloromethane (4 ml) was stirred in hydrogen atmosphere for 3 hours. The reaction mixture was filtered and concentrated to obtain the compound indicated in the title, in the form of a viscous yellow oil which was used without further purification.

Example 47

It was found that the compounds of examples 1 through 46 above have activity in the biological test described above. Defined biological activity included the log value destruction at 20, 10 or 5 μg/ml of test compounds above 0.5 (e.g., above 3) against bacteria in log phase, stationary phase and/or persistent bacteria speciesStaph. aureus, methicillin-resistantStaph. aureus(MRSA), coagulase-negativeStaphylococcus(CNS),Streptococcus pneumoniae,Streptococcus pyogenes, Streptococcus agalactiae, Enterococcus, E. Coli, Candida albicans, Propionibacterium acnesandMycobacterium tuberculosis.

In fact, the following compounds had a specified activity.

(a) The compound of example 6 when tested against bacteriaStaph. aureusin the stationary phase at the concentration tested is connected to the I 5 µg/ml was observed value of log destruction, equal 6,16.

(b) The compound of example 8 when tested at a concentration of test compound (10 μg/ml was observed:

(i) the value of log destruction 6,34 against bacteria methicillin-resistantStaph. aureusin stationary phase;

(ii) the value of log destruction 0,97 against bacteriaStreptococcus agalactiaein stationary phase;

(iii) the value of log destruction 3,70 againstCandida albicansin stationary phase; and

(iv) the value of log destruction 5,76 and 2.26 in relation toMycobacterium tuberculosisaccordingly, in the stationary phase and persistent.

(C) compounds of example 9 when tested against bacteriaStreptococcus pyogenesin stationary phase when the concentration of the test compound 20 µg/ml was observed value of log destruction, equal to 6.42 per.

(d) The compound of example 22 when tested at concentrations of test compounds 5 µg/ml was observed:

(i) the value of log destruction of 5.99 against coagulasenegativeStaphylococcusin stationary phase; and

(ii) the value of log destruction 3,22 against bacteriaEnterococcus,in stationary phase.

(e) a compound of example 39 when tested at a concentration of test compound (10 μg/ml was observed:

(i) the value of log destruction 7,32 against bacteriaStreptococcus pneumoniaein stationary phase;

(ii) the value of log destruction 6,80 against bacteriaE. coliK12 stationary FA is e; and

(iii) the value of log destruction 6,34 against bacteriaPropionibacterium acnesin stationary phase.

(f) both enantiomers of example 40, and both enantiomers of example 43 when tested at a concentration of test compound 20 µg/ml was observed:

(i) the value of log destruction of 6.26 against bacteriaStaph. aureusin stationary phase;

(ii) the value of log destruction 6,22 against MRSA bacteria in stationary phase; and

(iii) the value of log destruction 6,27 againstCandida albicansin stationary phase.

(g) both enantiomers of example 41, and both enantiomers of example 42 when tested at concentrations of test compounds 5 µg/ml was observed:

(i) the value of log destruction of 6.26 against bacteriaStaph. aureusin stationary phase; and

(ii) the value of log destruction 6,22 against MRSA bacteria in stationary phase.

List of abbreviations

ush.=wide (in relation to NMR)
d=doublet (in relation to NMR)
DCC=dicyclohexylcarbodiimide
DCE= 1,2-dichloroethane
DCM=dichloromethane
DEAD=diethylazodicarboxylate
DIPEA=diisopropylethylamine
DMAP=4-(N,N-dimethylamino)pyridine
DMF=dimethylformamide
DMSO=the sulfoxide
EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
EDTA=ethylenediaminetetraacetic acid
HATU=About(asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaphosphate
HBTU=[N,N,N',N'-tetramethyl-O(benzotriazol-1-yl) Urania hexaphosphate]
HEC=hydroxyethylcellulose
HOAt=1-hydroxy-7-asobancaria
HOBt=1-hydroxybenzotriazole
HOSu=N-hydroxysuccinimide
HPLC=high performance liquid chromatography
LC=liquid chromatography
m=multiplet (in relation to NMR)
MBC=the minimum bactericidal concentration
Me=methyl
min=minute(s)
MIC=the minimum inhibitory concentration
MS =mass spectroscopy
NMR=nuclear magnetic resonance
PyBOP=(benzotriazol-1 yloxy)triprolidine hexaphosphate
square=Quartet (in relation to NMR)
=the singlet (in relation to NMR)
t=the triplet (in relation to NMR)
TBTU=[N,N,N',N'-tetramethyl-O(benzotriazol-1-yl) Urania tetrafluoroborate]
TEA=the triethylamine

The prefixn-,Deut-,ISO-,tert- have normal values: normal, secondary,fromand tertiary.

1. The compound of formula I or its pharmaceutically acceptable salt and/or MES
,
where
R1is a group-X-R4a; where
X represents a simple bond or-NH-;
R4apresented yet a C 1-2alkyl substituted by phenyl, which is optionally substituted by one or more substituents selected from halogen, CN, C1-3the alkyl and OR10a; or phenyl, optionally substituted by one or more substituents selected from halogen, CN, C1-3the alkyl and OR10a;
R10arepresents a C1-4alkyl;
R2represents a C1-2alkyl; and
R3represents halogen, OR8aN(H)S(O)2R8fN(H)(R8h),
-N(H)C(O)R8i, Het6; where
R8arepresents a C1-4alkyl substituted by phenyl, which is optionally substituted by methoxy or SO2(C1-2by alkyl); C1-4alkyl, substituted Het7where Het7is a 5-6-membered aromatic heterocyclic group containing one or two heteroatoms selected from oxygen and nitrogen, and this heterocyclic group can be substituted C1-2by alkyl; phenyl;
R8frepresents phenyl;
R8hrepresents a C1-4alkyl substituted by phenyl, which is optionally substituted by methoxy or CN;
R8irepresents a C1-4alkyl substituted by phenyl, which is optionally substituted with halogen or methoxy; C1-4alkyl, substituted by a group Het7where Het7represents a 5-membered aromatic heterocyclics the group, containing two heteroatoms, selected from nitrogen and oxygen, which is replaced by one C1-2by alkyl; phenyl, optionally substituted with halogen, C1-2by alkyl or methoxy; or Het9where Het9is a 5-6-membered aromatic heterocyclic group containing one or two heteroatoms selected from oxygen and/or nitrogen, and this heterocyclic group may be substituted by one or two C1-2alkilani; and
Het6represents a 5-membered completely saturated heterocyclic group containing one nitrogen atom (which forms the attachment point for Het6group to the remainder of the molecule), substituted group =O.

2. The compound according to claim 1, where R1is in position 3 pyrolidine ring.

3. The compound according to claim 2, where-X-R4arepresents phenyl, CH2-phenyl, or NH-phenyl, and these phenyl groups may be substituted by one or more substituents selected from halogen and methoxy.

4. The compound according to claim 3, where-X-R4aselected from the group comprising phenyl, 4-methoxyphenyl, 4-chlorophenyl, benzyl, phenylamino.

5. The compound according to any one of the preceding paragraphs, where R2represents methyl.

6. The compound according to any one of the preceding paragraphs, where R3choose from a group including: chlorine, phenoxy, benzyloxy, 4-methanesulfonyl is siloxy, 4 methoxybenzyloxy, 2-phenylethane, 5-methylisoxazol-3-ylethoxy, benzylamino, (4-cyanobenzyl)amino, (4-methoxybenzyl)amino, phenylcarbonylamino, (4-chlorophenyl)carbylamine, (4-methoxyphenyl)carbylamine, (2-were)carbylamine, phenylethylenediamine, (4-chlorophenyl)methylcobalamine, (4-methoxyphenyl)-methylcobalamine, furan-2-ylcarbonyl, 3-methyl-3H-imidazol-4-ylcarbonyl, 5-methylisoxazol-3-ylcarbonyl; 3,5-dimethylisoxazol-4-ylcarbonyl, 2-phenylethylenediamine, pyrazin-2-ylcarbonyl, 5-methyl-1H-pyrazole-3-ylcarbonyl, 1H-pyrazole-4-ylcarbonyl, pyridin-4-ylcarbonyl, pyridine-2-ylcarbonyl, pyridine-3-ylcarbonyl, 2-(3-methylisoxazol-5-yl)methylcobalamine; benzosulfimide and 2-oxopyrrolidin-1-yl.

7. The compound according to claim 1, selected from the group including:
6-chloro-2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline;
6-benzyloxy-2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline;
2-methyl-4-(3-phenylpyrrolidine-1-yl)-6-(pyridine-3-ylethoxy)quinoline;
6-(4-methysulfonylmethane)-2-methyl-4-(3-phenylpyrrolidine-1-yl) quinoline;
6-(4-methoxybenzyloxy)-2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline;
2-methyl-6-penetrate-4-(3-phenylpyrrolidine-1-yl)quinoline;
2-methyl-6-(5-methylisoxazol-3-ylethoxy)-4-(3-phenylpyrrolidine-1-yl)quinoline;
4-(3-benzylpyrrolidine-1-yl)-2-methyl-6-phenoxyphenol;
4-[3-(4-methoxyphenyl)p is Raiden-1-yl]-2-methyl-6-phenoxyphenol;
4-[3-(4-chlorophenyl)pyrrolidin-1-yl]-2-methyl-6-phenoxyphenol;
[1-(2-methyl-6-phenoxyphenol-4-yl)pyrrolidin-3-yl]phenylamine;
N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]benzamide;
N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]-2-phenylacetamide;
4-chloro-N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]benzamide;
4-methoxy-N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]benzamide;
2-methyl-N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]benzamide;
[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide of pyrazin-2-carboxylic acid;
[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide of 1H-pyrazole-4-carboxylic acid;
[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide, furan-2-carboxylic acid;
N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]nicotinamide;
[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide of 3-methyl-3H-imidazole-4-carboxylic acid;
[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide 5-methyl-1H-pyrazole-3-carboxylic acid;
[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide of pyridazin-4-carboxylic acid;
2-(4-methoxyphenyl)-N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]ndimethylacetamide;
2-(4-chlorophenyl)-N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]ndimethylacetamide;
[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide of 3,5-dimethyl-isoxazol-4-carboxylic acid;
2-(3-methyl-isoxazol-5-yl)-N-[2-methyl-4-(3-phenylpyrrolidine-1-yl) quinoline-6-yl]ndimethylacetamide
N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]benzosulfimide;
benzyl-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amine;
(R - or S-) benzyl-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amine;
(S - or R-)benzyl-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amine;
(4-methoxybenzyl)-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amine;
4-{[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-ylamino]methyl}benzonitrile;
1-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]pyrrolidin-2-he;
N-[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]-3-phenylpropionamide;
[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide 5-methylisoxazol-3-carboxylic acid;
[2-methyl-4-(3-phenylpyrrolidine-1-yl)quinoline-6-yl]amide pyridine-2-carboxylic acid;
N-[4-(3-benzylpyrrolidine-1-yl)-2-methylinosine-6-yl]benzamide;
2-methyl-6-phenoxy-4-(3-phenylpyrrolidine-1-yl)quinoline
or their pharmaceutically acceptable salt and/or solvate.

8. The compound according to claim 1, which represents a 4-(3-benzylpyrrolidine-1-yl)-2-methyl-6-phenoxyphenol or its pharmaceutically acceptable salt and/or MES.

9. The compound according to claim 1, which represents the N-[4-(3-benzylpyrrolidine-1-yl)-2-methylinosine-6-yl]benzamide or its pharmaceutically acceptable salt and/or MES.

10. The method of obtaining the compounds of formula I according to claim 1, which includes:
(a) interactions of the compounds of formula II

where L 1represents a removable group, E represents CH, and R2and R3have the meanings defined in claim 1, with a compound of formula III

where R1matter defined in claim 1; or
(C) for compounds of formula I, where R3represents-N(H)C(O)R8ithe combination of the corresponding compounds of formula I, where R3represents-NH2with a compound of formula V

where L2represents a removable group, and R8imatter defined in claim 1; or
(d) for compounds of formula I, where R3represents-N(H)S(O)2R8fthe combination of the corresponding compounds of formula I, where R3represents-NH2with a compound of formula VI

where L3represents a removable group, and R8fhas the meanings given in claim 1.

11. Pharmaceutical composition for treatment of bacterial or fungal infection, comprising a compound according to any one of claims 1 to 9 in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

12. The pharmaceutical composition according to claim 11 for local use.

13. The compound according to any one of claims 1 to 9 for use in medicine.

14. The use of compounds according to any one of claims 1 to 9 to obtain medicines for cured the I or prevention of bacterial or fungal infection, caused by Staph. aureus, methicillin-resistant Staph. aureus (MRSA), coagulase-negative Staphylococcus (CNS), Streptococcus pneumoniae, Streptococcus pyogenes. Streptococcus agalactiae, Enterococcus, E. Coil, Candida albicans, Propionibacterium acnes and Mycobacterlum tuberculosis.

15. The use of compounds according to any one of claims 1 to 9 to obtain drugs for destruction clinically latent microorganisms selected from Staph. aureus, MRSA, CNS, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Enterococcus, E. Coli, Candida albicans, Propionibacterium acnes, and Mycobacterium tuberculosis.

16. Combination product for the treatment of bacterial or fungal infection, containing
(A) a compound according to any one of claims 1 to 9, and
(B) conventional antimicrobial agent,
where each of the components (a) and (b) is in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

17. Combination product according to clause 16, where conventional antimicrobial agent is a penicillin (optional in combination with the inhibitor of β-lactamase), cephalosporins, monobactam, carbapenem (optional in combination with the inhibitor of renal enzyme), 1-oxa-β-lactam, tetracycline, aminoglycoside, macrolide, ketolide, lincosamide, clindamycin, clindamycin 2-phosphate, fenicol, steroid, glikopeptid oxazolidinone, streptogramin (or a combination of streptogramins), polymyxin, lysostaphin, actinomycin, Aktionen, 7-aminooctanoic D, antimycin a, antipain, bazi Razin, cyclosporine a, economizing, gramicidin, myxothiazol, lowlands, paracelsian, valinomycin, viomycin, lipopeptide, sulfonamide (optional in combination with trimethoprim, trimethoprim, isoniazid, rifampicin, rifabutin, pyrazinamide, ethambutol, streptomycin, Dapsone, clofazimine, nitroimidazol, nitrofuran, hinolan, azaserine, bestatin, D-cycloserine, 1,10-phenanthrolin, 6-diazo-5-oxo-L-norleucine, L-alanyl-L-1-aminoethylphosphonic acid, aureolae acid, bethenod, coumarin-glycoside, irgasan, apiprotocolsupport, cerulenin, glucosamine, staurosporin, macrolactam, taxoid, a statin, polifenolov acid, lasalocid And, ionomycin And, monensin, nigericin, salinomycin, futaleufu acid, blasticidin S, nikkomycin, nourseothricin, puromycin, adenine 9-β-D-arabinofuranoside, 5-azacytidine, korditsepin, formazin And, tubercidin, tunicamycin, methenamine (hexamine), piericidin And, stigmatella, acticin, anisomycin, apramycin, kumaresan Al, L(+)-lactic acid, cytochalasin, emetine, ionomycin, azole antifungal, antifungal Polian, griseofulvin, caspofungin or flucytosine (the last two agents are optionally used in combination) or antifungal allylamine.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of pharmaceutics, namely represents compositions for treating nail and nail bed diseases and methods of treating nail diseases.

EFFECT: claimed compositions do not form a film when applied on the nail surface and contain a carrier, in which suspended, dispersed or emulsified are all components of the composition, a non-volatile solvent, a moistening preparation and a pharmaceutically active ingredient, soluble in the non-volatile solvent and/or in a mixture of the carrier and the non-volatile solvent, with the composition being efficient in treatment of nail or nail bed diseases.

30 cl, 2 dwg, 4 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: in a complex preparation containing a carrier representing an enterosorbent; the enterosorbent is modified by immobilising high-disperse silver - nanosilver in a concentration of 0.01 - 1.0 wt % on its surface. The enterosorbent represents activated carbon, kaolin, bentonit, or enterodesum, or monocrystalline cellulose. A modifying silver-containing solution - a nanosilver source - is silver clusters in an aqueous solution.

EFFECT: higher specific antimicrobial activity.

2 cl, 3 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and concerns a local topical composition characterised by the fact that it contains synthetic lipoic acid; 95% ethyl alcohol; 1,2-propylene glycol, polyacrylic acid (any other hydrophilic gelling agent), triethanolamine, purified water; a method for preparing the local topical composition characterised by the fact that synthetic lipoic acid is dissolved while stirring in mixed ethyl alcohol and propylene glycol; at the same time polyacrylic acid is dispersed in a specified amount of water sufficient to reduce the ratio of the ingredients up to 100 wt %, after 3-hour swelling, the prepared solution is added to synthetic lipoic acid dissolved in mixed ethyl alcohol and propylene glycol and mixed up; the prepared composition is neutralised by a triethanolamine solution to pH 5.5-6.5 and mixed to form a light-yellow transparent gel-like mass.

EFFECT: group of inventions provides high antirheumatic, anti-inflammatory and analgesic activity, as well as effective antibacterial and anti-burn action.

4 cl, 4 ex, 1 tbl, 3 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to obstetrics and gynaecology, and may be used for preconception preparation in early recurrent miscarriage caused by chronic genital inflammation or inflammatory hormonal ovarian insufficiency. That is ensured by 12 intravaginal introductions of disposable injectors with Dead sea mud gel as a therapeutic agent daily for 30 minutes within one therapeutic course upon completion of the anti-inflammatory treatment following the early miscarriage.

EFFECT: invention provides 50% higher safety and effectiveness of preconception preparation in the given group of patients.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to a composition containing encapsulated triterpenic acid: betulinic acid, ursolic acid or derivatives thereof in the form of salts and esters, or triterpene alcohol - betulin, which may be used in medicine for treating and preventing viral infections caused by DNA and RNA-containing viruses, such as influenza viruses, oncogenic viruses, herpes virus, herpes zoster virus, as well as infections caused by gram-positive and gram-negative bacteria: Staphylococcus spp., Streptococcus spp., Enterococcus spp., Shigella spp., Escherichia spp., Salmonella spp., Proteus spp., Acinetobacter spp., Citrobacter spp., Pseudomonas spp., Serratia spp., Klebsiella spp., Antracoides spp., Cryptococcus spp., pathogenic fungi of the genus Microsporum, Trichophyton, Nocardia, Aspergillus, yeast-like fungi of the genus Candida, including multiresistant strains, as well as Actinomycetes and some pathogenic protozoa: Entamoeba histolytica, Trichomonas vaginalis. The invention presents the composition containing an active ingredient presented by 0.5 wt % of betulin or 0.5 wt % of encapsulated triterpenic acid: betulinic acid, ursolic acid or derivatives thereof in the form of salts and esters and others, and carriers presented by: β-cyclodextrins, fullerene, lecithins and polymers binding to the ingredients to form ingredient-carrier complexes, and excipients.

EFFECT: higher efficacy of using the composition.

3 cl

FIELD: chemistry.

SUBSTANCE: invention relates to field of food industry, biotechnology and deals with antibacterial composition and strain of bacteriophage Escherichia coli, used for obtaining said composition. Characterised composition includes filtrate of Escherichia coli phage lysate, obtained with application of strain of bacteriophage Escherichia coli, deposited in collection of museum of microorganisms of Federal Budget Institution of Science "State Research Centre for Applied Microbiology and Biotechnology" of the Federal Service on Customers' Rights Protection and Human Well-being Surveillance (FBIS SRC AMB of Rospotrebnadzor) under number Ph 64, filtrate of Escherichia coli phage lysate, containing coli bacteriophage, filtrate of staphylococcus phage lysate, filtrate of salmonella phage lysate, filtrate of Listeria monocyctogenes phage lysate and target additives in amount 1.0÷95.0 wt % of composition weight.

EFFECT: claimed composition has required spectrum of specific activity due to inclusion of polyvalent bacteriophage and can be used in production of biologically active additives and food additives.

11 cl, 1 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmacology and medicine and concerns using a dipeptide of a general formula Tyr-Pro-X, where X - OH, NH2, OCH3, OC2H5, as an anti-inflammatory, antibacterial, wound-healing, regenerative, analgesic and burntreating agent for external application, as well as a dosage form for external application containing this dipeptide.

EFFECT: group of inventions provides preparing the effective agent for external applications with no side effects.

3 cl, 1 tbl, 22 ex

FIELD: medicine.

SUBSTANCE: composition contains the bactericidal substance Poviargol in the amount of 2.1-7.0 wt % and zosterin in the amount of 1.1-7.0 wt %.

EFFECT: synergetic action of the ingredients of the composition and promotion of the anti-inflammatory, radio protective, reparative action.

1 ex

FIELD: veterinary medicine.

SUBSTANCE: kobaktan is administered intramuscularly at a dose of 2 ml per 50 kg of body weight daily for 7 days, glutoxim is administered subcutaneously at a dose of 3 mg per 1 kg of body weight once in 2 days in an amount of 10 injections, and also 1-3 sessions of hemosorption is carried out with the interval of 24-48 hours.

EFFECT: method enables to improve the efficiency of treatment while reducing mortality due to suppression of microbial factor, neutralisation and elimination of toxins from the body, normalisation of functional disorders.

1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: what is used is a targeted transport of antibacterial drugs to an area of inflammation by a single use of an extracorporeal antibiotic therapy including the antibiogram findings. With underlying intraoperative autologous blood donation combined with hypervolemic haemodilution and neuraxial anaesthesia, the infusion is followed by an autologous blood exfusion in a volume of 5-10 ml/kg of body weight with the total volume of the infusion dominating over the volume of the autologous blood exfusion by 130-140%, with the autologous blood reinfusion following a surgical haemostasis.

EFFECT: invention reduces the postoperative inflammatory complications in high-risk groups, enables reducing a therapeutic dose and a frequency of administration of a drug, eliminating or reducing the amount of transfused blood components, avoiding an adverse effect on a foetus presented in the form of the newborn's microflora change and the appearance of antibiotic-resistant forms of pathogens.

2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of structural formula or a salt thereof, where each of Z1, Z2 and Z3 is independently selected from N and C(R9), where not more than one of Z1, Z2 and Z3 is N; each R9 is hydrogen; and is a second chemical bond between either W2 and C(R12), or W1 and C(R12); W1 is -N=, and W2(R14) is selected from -N(R14)- and -C(R14)=, such that when W1 is -N=, W2(R14) is -N(R14)- and is a second chemical bond between W1 and C(R12); R11 is selected from phenyl and a heterocycle which is selected from a saturated or aromatic 5-6-member monocyclic ring, which contains one or two or three heteroatoms selected from N, O and S, or an 8-member bicyclic ring which contains one or more heteroatoms selected from N, O and S, where R11 is optionally substituted with one or two substitutes independently selected from halogen, C1-C4 alkyl, =O, -O-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from -C1-C4alkyl; or two R13 together with a nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, optionally containing an additional heteroatom selected from NH and O, where if R13 is an alkyl, the alkyl is optionally substituted with one or more substitutes selected from -OH, fluorine, and if two R13 together with the nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, the saturated heterocycle is optionally substituted on any carbon atom with fluorine; R12 is selected from phenyl, a 4-6-member monocyclic saturated ring and a heterocycle, which is selected from an aromatic 5-6-member monocyclic ring which contains one or two heteroatoms selected from N and S, where R12 is optionally substituted with one or more substitutes independently selected from halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen, C1-C4 alkyl, C1-C4 fluorine-substituted alkyl, C1-C4 alkyl-N(R13)(R13), C1-C4 alkyl-C(O)-N(R13)(R13); and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, -NH-S(=O)2-†, where † denotes the point where X1 is bonded to R11. The invention also relates to a pharmaceutical composition having sirtuin modelling activity based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a subject suffering from or susceptible to insulin resistance, metabolic syndrome, diabetes or complications thereof.

18 cl, 2 tbl, 52 ex

FIELD: chemistry.

SUBSTANCE: invention relates to form A of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl-)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, where said form A is characterised by peak at approximately 7.9 degree, peak at approximately 11.9 degree, peak at approximately 14.4 degree and peak at approximately 15.8 degree in powder X-ray. Invention also relates to pharmaceutical composition and set based on said form A, application of form A, method of CFTR modulation.

EFFECT: obtained is novel form of quinoline derivative, which is modulator of CFTR activity.

12 cl, 3 dwg, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein R1 represents an alkoxy group or halogen; each U and V independently represents CH or N; "----" means a bond or is absent; W represents CH or N, or if "----" is absent, then W represents CH2 or NH, provided not all U, V and W represent N; A represents a bond or CH2; R2 represents H, or provided A means CH2, then it also can represent OH; each m and n are independently equal to 0 or 1; D represents CH2 or a bond; G represents a phenyl group that is single or double substituted in meta- and/or para-position(s) by substitutes specified in alkyl, C1-3alkoxy group and halogen, or G represents one of the groups G1 and G2: wherein each Z1, Z2 and Z3 represents CH; and X represents N or CH and Q represents O or S; it should be noted that provided each m and n are equal to 0, then A represents CH2; or a pharmaceutically acceptable salt of such compound. Besides, the invention refers to a pharmaceutical composition for treating a bacterial infection containing an active ingredient presented by a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert additive.

EFFECT: preparing the oxazolidine compounds applicable for preparing a drug for treating and preventing the bacterial infections.

14 cl, 8 dwg, 2 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: invention relates to antibacterial compounds of formula (I), where R1 represents alkoxygroup; U, V and W each represents CH or one of U, V and W represents N, and each other represents CH; A represents CH2 or O; G represents CH=CH-E, where E represents phenyl group, mono- or di-substituted with halogen, or G represents group of one of the formulas given below , , where Z represents CH or N, Q represents O or S and K represents O or S; or salt of such compound. In addition, invention also relates to pharmaceutical composition based on formula (I) compound for prevention or treatment of bacterial infection, as well as to application of claimed compounds for obtaining medication for prevention or treatment of bacterial infection.

EFFECT: novel compounds, which can be applied in treatment of bacterial infection, are obtained and described.

23 cl, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a pharmaceutical salt of 8-methyl-7-[5-methyl-6-(methylamino)-3-pyridinyl]-1-cyclopropyl-4-oxo-1,4-dihydro-3-quinoline carboxylic acid, characterised by that it is in form of a hydrochloride monohydrate and by solubility of at least 0.050 mg/ml water. The invention also relates to a pharmaceutical composition based on said pharmaceutical salt, use of said pharmaceutical salt and a method of treating or preventing bacterial infections based on use of said pharmaceutical salt.

EFFECT: obtaining a novel pharmaceutical salt of 8-methyl-7-[5-methyl-6-(methylamino)-3-pyridinyl]-1-cyclopropyl-4-oxo-1,4-dihydro-3-quinoline carboxylic acid, characterised by good solubility in water, which influences bioavailability of the active ingredient.

7 cl, 16 dwg, 2 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to application of compounds of formula I, where R1 represents hydrogen atom, C1-7-alkyl, C1-7-alkoxy, C1-7-alkyl, substituted with halogen atom, C1-7-alkoxy, substituted with halogen atom, halogen atom, cyano, nitro, hydroxy, C(O)O-C1-7-alkyl, S(O)2-C1-7-alkyl, C(O)OCH2-phenyl, OCH2-phenyl, tetrazol-1-yl, phenyl, possibly substituted with halogen atom, or represents phenyloxy, possibly substituted with halogen atom, or represents benzyl, possibly substituted with halogen atom, or represents benzyloxy, possibly substituted with halogen atom; in case, when n>1, R1 substituents can be similar or different; X represents -O-(CH2)2-, -O-CHR"-CH2-, -O-CH2-CHR', -O-CR"2-CH2-, -(CH2)2-CHR'-, -CHR'-(CH2)2-, -CR"2-(CH2)2-, -CH2-CHR'-CH2-, -CH2-CR"2-CH2-, -CHR"-O-CH2-, -CR"2-O-CH2-, -CF2(CH2)2-, -CR"2-CH2-, -SiR"2-(CH2)2-, -S-(CH2)2-, -S(O)2-(CH2)2-, -(CH2)4-, -CH2-O-(CH2)2-, formula (a) or (b), where m has value 0, 1, 2 or 3; R' represents C1-7-alkyl, C1-7-alkoxy or C1-7-alkyl, substituted with halogen atom; R" represents C1-7-alkyl or C1-7-alkyl, substituted with halogen atom; R2 represents hydrogen atom or C1-7-alkyl; Y represents phenyl, naphthyl, C3-6-cycloalkyl or pyridin-2- or 3-yl, pyrimidin-2-yl or quinolin-6 or 7-yl; n has value 1, 2 or 3; or pharmaceutically acceptable salt of acid attachment in manufacturing medication for treatment anxiety disorders, bipolar disorder, stress-induced disorders, psychotic disorders, schizophrenia, neurological diseases, Parkinson disease, neurodegenerative disorders, Alzheimer's disease, epilepsy and migraine. Invention also relates to compounds of formula I, where R1 represents hydrogen atom, C1-7-alkyl, C1-7-alkoxy, C1-7-alkyl, substituted with halogen atom, C1-7-alkoxy, substituted with halogen atom, halogen atom, cyano, nitro, hydroxy, C(O)O-C1-7-alkyl, S(O)2-C1-7-alkyl, C(O)OCH2-phenyl, OCH2phenyl, tetrazol-1-yl, phenyl, possibly substituted with halogen atom, or represents phenyloxy, possibly substituted with halogen atom, or represents benzyl, possibly substituted with halogen atom, or represents benzyloxy, possibly substituted with halogen atom; in case when n>1, R1 substituents can be similar or different; X represents -(CH2)2-CHR', -CHR'-(CH2)2-, -CR"2-(CH2)2-, -CH2-CHR'-CH2-, -CH2-CR"2-CH2-, -CF2(CH2)2-, formula (a), where m has value 0, 1, 2 or 3; R' represents C1-7-alkyl, C1-7-alkoxy or C1-7-alkyl, substituted with halogen atom; R" represents C1-7-alkyl or C1-7-alkyl, substituted with halogen atom; R2 represents hydrogen atom or C1-7-alkyl; Y represents phenyl, naphthyl, C3-6-cycloalkyl or pyridin-2- or 3-yl, pyrimidin-2-yl or chinolin-6 or 7-yl; n has value 1, 2 or 3; or pharmaceutically acceptable salt of acid attachment. Also claimed are methods of obtaining formula (I) compounds.

EFFECT: 4,5-dihydro-oxazol-2-ylamine derivatives for treatment of diseases, associated with biological function of receptors, associated with trace amines.

22 cl, 1 tbl, 176 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where A is a 6-member heteroaryl, having 1 nitrogen atom as a heteroatom, substituted with 2-3 substitutes such as indicated in the claim, R5 is a halogen atom, cyano or C1-C6alkyl, optionally substituted with a halogen atom; R6 is C1-C6 alkyl, optionally substituted with OH; C1-C3 alkenyl; a 5-member heteroaryl, having 2-4 heteroatoms, each independently selected from N, O or S, substituted with 0-2 substitutes such as indicated in the claim, R10 is a 5-member heteroaryl, having 2-3 heteroatoms, each selected from N, O or S, substituted with 0-2 substitutes, which are C1-C3 alkyl; R7, R8, R17 denote a hydrogen or halogen atom. The invention also relates to a pharmaceutical composition, having BK B2 receptor inhibiting activity, which contains compounds of formula (I), a method of inhibiting, a method of localising or detecting the BK B2 receptor in tissue, use of the compounds of compositions to produce a medicinal agent and methods for treatment.

EFFECT: compounds of formula (I) as BK B2 receptor inhibitors.

22 cl, 1 tbl, 54 ex

FIELD: biotechnologies.

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

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to chemical-pharmaceutical industry and presents using (-)-(3aR,4S,7aR)-4-hydroxy-4-m-tolylethinyloctahydroindole-1-carboxylic acid methyl ester for treating, preventing or arresting the development of dyskinesia caused by levodopa (L-dopa) in treating Parkinson's disease.

EFFECT: invention refers to a pharmaceutical composition, a kit and a foodstuff containing (-)-(3aR,4S,7aR)-4-hydroxy-4-m-tolylethinyloctahydroindole-1-carboxylic acid methyl ester.

5 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a therapeutic agent for treating a peripheral artery disease or a cerebrovascular accident. The declared therapeutic agent contains a combination of 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril or a salt thereof and L-carnitine or a salt thereof, or carnitine chloride.

EFFECT: invention refers to a method of treating the occlusal peripheral artery disease or cerebrovascular accident that involves administering a therapeutically effective amount of the above combination into the patient in need thereof.

10 cl, 5 dwg, 1 ex

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S)-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I): with the crystalline modification A and a drug eliciting effect against pathogenic microorganisms. The prepared crystalline modification shows stability and doesn't transform to another crystalline modification or amorphous form being even at prolonged storage.

EFFECT: improved and valuable properties of compound.

4 cl, 4 dwg, 6 ex

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