BG66536B1 - Quinoline derivatives as antibacterial means - Google Patents

Abstract

The present invention relates to the use of quinoline compounds for the production of a medicament for the treatment of bacterial infections and more specifically for the treatment of infection, caused by resistant starains, and include therapeutically nontoxic forms of the possible acid addition salts. The quinoline compounds are the compounds with formula I and II, their pharmaceutical acceptable acid or basic addition salt or their N-oxide form, as follows: compounds with the formula I wherein the substitutions have the following meaning: R1 is Br, H, phenyl, R2 is OСH3, SCH3; R3 is @@, phenyl, 3-fluorophenyl; R6 е Н, Cl; compounds with formula II, обща формула ІІ, wherein the substitutions have the following meaning: R3 is 2,4-difluorophenyl, phenyl and L is NH(CH2CH3), NH(CH2CH3)(CH2phenyl), NH(CH3), 1-imidazolyl.

Description

The present invention relates to the use of quinoline derivatives for the manufacture of a medicament for the treatment of a bacterial infection.

BACKGROUND OF THE INVENTION

Resistance to older and cheaper antibiotic agents has suddenly become a problem. Some important examples include penicillin-resistant herbicides, vancomycin-resistant enterococci, methicillin-resistant, antioxidant, and polyresistant salmonella.

The effects of antibiotic resistance are serious. Infections caused by resistant germs do not respond to treatment, leading to prolonged illness and a higher risk of death. Failure to treat also leads to long periods of infection that increase the number of infected people moving into society, thereby exposing the general population to the risk of contracting resistant strains. Hospitals are a critical component in the worldwide problem of antimicrobial resistance. The combination of highly susceptible patients, the intensive and prolonged use of antimicrobials and cross-contamination lead to infections with highly resistant bacterial pathogens.

Self-medication with antimicrobials and other agents is a major contributing factor to resistance. Self-medicated antimicrobials may be unnecessary, often under-dosed, or may not contain the required amount of medicine.

Another major problem is the patient's disagreement with the recommended treatment. Patients forget to take the medicine, interrupt treatment when they feel better or cannot afford the full course, thus creating the ideal environment for the germs to adapt rather than be destroyed.

Due to the emergence of multiple antibiotic resistance, doctors are facing infections for which there is no effective therapy. The morbidity, mortality and financial costs of such infections require increased care for healthcare systems around the world.

Therefore, there is a great need for new compounds for the treatment of bacterial infections, and more specifically for the treatment of infections caused by resistant strains.

US 2004/011436 discloses substituted quinoline derivatives having activity against Musoaspace, in particular against Musoaspecific and 15g15. One particular compound of these substituted quinoline derivatives is described in 8ceps (2005), 307,223-227.

The quinoline derivatives described in HUO 2004/011436 have been found to have activity against bacteria other than Musoacase.

EP 1 901 743, incorporated herein by reference in its entirety, describes the use of compounds for the manufacture of a medicament for the treatment of a bacterial infection other than mycobacterial infection, which are of general formula (I)

their pharmaceutically acceptable acid or base addition salt, their stereochemically isomeric form or their о-oxide form, where: K? is hydrogen, halogen, polyhaloC 1-6 alkyl, C 1-6 alkyl, Ar or H ₁ ; "P" is an integer equal to 1 or 2; And ² is C 1-6 alkyloxy, C 1-6 alkyloxyC 1-6 alkyloxy or C 1-6 alkylthio; K ³ is Ar, No! or not! ¹ ; K ⁶ is hydrogen, halogen, polyhalo S ¹ H. alkyl, C ^ alkyl, C _1h. alkyloxy, C1-6alkylthio; or two adjacent radicals K ⁶ taken together form a divalent radical of formula -CH = CH-CH = CH-; "D" is an integer equal to 1 or 2.

The compound is other than (alpha8, betaK) 6-bromo-alpha- [2- (dimethylamino) ethyl] -2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolinethanol, its pharmaceutically acceptable acid or base addition salt or its о-oxide form

66536 ΒΙ

SUMMARY OF THE INVENTION

The present invention relates to compounds of general formula I,

their pharmaceutically acceptable acid or base addition salt or Ν-oxide form thereof, wherein the substituents have the following meanings:

To ¹ K ² K ³ To ^b Stereochemistry Br OCH3 f N. (A) Br OCH3 phenyl N. (B2) N. OCH3 phenyl N. (IN) phenyl OCH3 phenyl N. (IN) Br 5CH3 phenyl N. (A) Br OCH3 3-fluorophenyl N. (A2) Br OCH3 phenyl C1 (B2)

as (A) or (B) means that the compound is a mixture of two enantiomers and (A) is isolated first and (B) second;

(A2) and (B2) mean that the compound is an enantiomer and represent a second fraction isolated from (A) and (B) respectively.

The present invention also relates to compounds of general formula II

their pharmaceutically acceptable acid or base addition salt or Ν-oxide form thereof, wherein the substituents have the following meanings:

66536 ΒΙ

K ³ B Stereochemistry 2,4-difluorophenyl W (CH ₂ CH 3) (A) 2,4-difluorophenyl M (CH ₂ CH 3) (CH ₂ phenyl) (IN) phenyl IN (CH3) (IN) phenyl 1-imidazolyl (IN)

as (A) or (B) means that the compound is a mixture of two enantiomers and (A) is isolated first and (B) second.

An embodiment of the present invention is the use of the compounds of claim 1 for the manufacture of a medicament for treating a bacterial infection other than a mycobacterial infection, said compounds being compounds of formula I,

a pharmaceutically acceptable acid or base addition salt or Ν-oxide form thereof.

In another preferred embodiment of the compounds of claim 2, they are used to produce a medicament for treating a bacterial infection other than a mycobacterial infection, said compounds being compounds of formula II

an acid salt with an acid or base or a Ν-oxide form thereof.

The present invention also relates to a method for treating a bacterial infection in a mammal, namely a warm-blooded mammal and most specifically a human, comprising administering to the mammal an effective amount of a compound of the invention.

The lines coming out of the substituents in the ring systems mean that the bond can be at any suitable ring atom.

When two adjacent K ⁶ radicals are taken together to form a divalent radical of formula -CH = CH-CH = CH-, it means that the two adjacent K ⁶ radicals form together with the phenyl ring to which they are attached naphthyl.

Salts of compounds of formulas (I) and (II) for therapeutic use are those in which the amphoteric ion is pharmaceutically acceptable. However, salts of acids and bases that are pharmaceutically unacceptable may also be used, for example in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are within the scope of the present invention.

The pharmaceutically acceptable addition salts, as mentioned hereinafter, are intended to include the therapeutically active non-toxic forms of the acid addition salts which the compounds of formulas (I) and (II) can form. The latter can be conveniently obtained by treating the basic form with suitable acids, such as inorganic acids, for example, hydrohalic acids, for example hydrochloric, hydrobromic5

65 66536 to others; sulfuric acid; nitric acid; phosphoric acid, etc .; or organic acids, for example, acetic, propane, hydroxyacetic, 2-hydroxypropane, 2-oxopropane, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3-propane-tricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoene,

4-amino-2-hydroxybenzoic acid and the like. Conversely, when treated with bases, the salt can be converted to the free basic form.

The compounds of formulas (I) and (I) containing acidic protons can be converted to their therapeutically active non-toxic metal or amine addition salts by treatment with suitable organic or inorganic bases. Suitable basic salts include, for example, ammonium salts, alkali and alkaline earth metal salts, for example lithium, sodium, potassium, magnesium, calcium salts, etc., salts with organic bases, such as primary, secondary and tertiary aliphatic and aromatic amines such as methylamines ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyrrolidine, pyrrolidine, quinclidine zoquinoline, benzathine, Ν-methyl-O-glucamine, 2-amino-2- (hydroxymethyl) -1,3-propanediol, hydrobaminin salts, and salts with amino acids, such as arginine, lysine and the like. Conversely, salts can be converted to free acids by acid treatment.

The term addition salt also includes the hydrate and solvate addition forms which the compounds of formulas (I) and (I) may form. Examples of such forms are, for example, hydrates, alcoholates, and the like.

The Ν-oxide forms of the present compounds include the compounds of formulas (I) and (I), wherein one or more tertiary nitrogen atoms are oxidized to the so-called Ν-oxide.

The compounds of formulas (I) and (II) can be converted to the corresponding Ν-oxide forms by known methods of converting trivalent nitrogen to its о-oxide form.

Said N-oxidation reactions are generally carried out by reacting the starting material of formulas (I) and (II) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali and alkaline earth metal peroxides, for example sodium peroxide, potassium peroxide; suitable organic peroxides may include peroxy acids, such as benzenecarboperoxy acid or halogen-substituted benzenecarboperoxy acid, for example 3-chlorobenzene-carboperoxy acid, peroxoalkanoic acids, for example peroxoacetic acid, alkyl hydroperoxides, for example tert-butyroxy. Suitable solvents are, for example, water, lower alcohols, for example ethanol, etc., hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.

It can be appreciated that some of the compounds of formulas (I) and (II), and their о-oxides or addition salts, may contain one or more chiral centers and exist as stereochemical isomeric forms.

The term "stereochemical isomeric forms", as used hereinafter, means all the possible stereoisomeric forms which the compounds of formulas (I) and (I) may have, and their о-oxides, addition salts or physiologically functional derivatives. Unless otherwise mentioned or indicated, the chemical name of the compounds means the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. In particular, stereogenic centers may have a K- or 8-configuration; the substituents on divalent cyclic (partially) saturated radicals may have either a cis or trans configuration. Compounds containing double bonds may have E (entergenic) or Ζ (tosamine) stereochemistry at said double bond. The terms cis, trans, K, 8, E and Ζ are known to those skilled in the art.

It is envisaged to encompass the stereochemical isomeric forms of the compounds of formulas (I) and (I) within the scope of the invention.

Following the commonly accepted CA8-Nomen6

66536 B1 cluster (CA3 = Ceppsa1 Abz1gas1z Sepsis) when two stereogenic centers of a known molecular configuration are involved in the molecule, the K. or 8 parameter is specified (based on CaBp-1p§o1c1-sequence rule of Rhei§) for the chiral center with the smallest reference center number. The configuration of the second stereogenic center is indicated using relative parameters [K. *, K *] or [K. *, 8 *], where K * is always specified as the reference center and [K. *, K *] means centers with the same chirality, and [K * 8 *] means centers with different chirality. For example, if the chiral center with the smallest number in the molecule has 8 configurations and the second center is K., the stereo parameter will be defined as 8- [K *, 8 *]. If "alpha" and "beta" are used: the position of the highest priority substituent on the asymmetric carbon atom in the ring system having the smallest number in the ring is preferably always in the "alpha" position relative to the median plane determined by the ring system. The position of the highest priority substituent on the other asymmetric carbon atom in the ring system relative to the position of the highest priority substituent on the reference atom is referred to as "alpha" if it is on the same side of the median plane as defined by the ring system, or as a "beta" if it is on the other side of the median plane defined by the ring system.

When a particular stereoisomeric form is indicated, it means that said form is practically free, i.e. it is mixed with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, further preferably less than 2% and most preferably more - less than 1% of the other isomer (s). Thus, when a compound of formulas (I) and (II) is, for example, specified as (alpha3, betaK), it means that the compound is practically free of the (alpha3, betaK) isomer.

The compounds of formulas (I) and (II) can be synthesized in the form of racemic mixtures of enantiomers that can be separated from one another by known separation methods. The racemic compounds of formulas (I) and (I) can be converted to the corresponding diastereomeric salts by reaction with a suitable chiral acid. Said diastereomeric salts are subsequently separated, for example, by selective or fractional recrystallization and the enantiomers are liberated by means of bases. An alternative way of separating the enantiomeric forms of the compounds of formulas (I) and (II) involves chiral stationary phase liquid chromatography. Said pure stereochemically isomeric forms may also be prepared from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction is stereospecific. If a specific stereoisomer is sought, it is preferred that said compound be synthesized by stereospecific methods of preparation. These methods preferably use enantiomerically pure starting materials.

The invention also includes derivative compounds (commonly referred to as "precursors") of the pharmacologically active compounds of the invention that are degraded to give the compounds of the invention. Typically (but not always) precursors have lower target receptor activity than the compounds to which they are degraded. Precursors are particularly useful when the desired compound has chemical and physical properties that make its administration difficult and ineffective. For example, the desired compound may be poorly soluble, may be poorly transported through the mucosal epithelium, or may have an undesirable short plasma half-life. Further discussions on the precursors can be found in 81e11a, V. 1. βΐ а1., "Rgobgi ^ h", ϋηΐ £ Οβίϊνβϊ ZuzGetz, 1985, pp. 112-176 and ϋηΐ £ δ, 1985,29, pp. 455- 473.

The precursor forms of the pharmacologically active compounds of the invention are generally compounds of formulas (I) and (I), their pharmaceutically acceptable acid or base addition salts, their stereochemical isomeric forms, their tautomeric forms and their Ν-oxide forms having an acid group, which is esterified or amidated. Such esterified groups include the groups of formula-COOK. ^X , wherein N 1 is C 1-6 alkyl, phenyl, benzyl or one of the following groups:

66536 B1

The amidated groups include groups of the formula -ΌΟΝίνΚ ² , where K ^y is H, C _1-6 alkyl, phenyl or benzyl, and K ² is -OH, H, C 1-6 alkyl, phenyl or benzyl.

Compounds of the invention containing an amino group may be derivatized with a ketone or aldehyde, such as formaldehyde, forming a manic base. This base is hydrolyzed in aqueous solution in a first order reaction.

As used herein, the term "compounds of formulas (I) and (II)" includes their oxide forms, their addition salts or their stereochemically isomeric forms. Of particular interest are those compounds of formulas (I) and (I) which are stereochemically pure.

Also of interest is the use of the compounds of formulas (I) and (I) for the manufacture of a medicament for the treatment of infection by gram-positive and / or gram-negative bacteria.

Another embodiment of interest is the use of the compounds of formulas (I) and (II) for the manufacture of a medicament for the treatment of infection by a gram-positive bacterium.

Another embodiment of interest is the use of the compounds of formulas (I) and (II) for the manufacture of a medicament for the treatment of a gram-negative bacterial infection.

Also of interest is the use of the compounds of formulas (I) and (II) for the manufacture of a medicament for the treatment of bacterial infection, wherein the compounds of formulas (I) and (I) have ΙΟ, θ <15 p1 / ml against at least one bacteria, especially gram-positive bacterium, preferably -C ^ <10 p1 / T 1, more preferably 1C _ZD <5 p 1 / T1; the value of IC ₉₀ is determined as described below.

The compounds of formulas (I) and (I) can be prepared according to the methods described in 2004/011436 incorporated herein by reference.

In general, the compounds of the invention can be prepared by a series of steps, each of which is known to one of ordinary skill in the art.

In particular, the compounds of formulas (I) and (II) can be prepared by reacting an intermediate of formula (II) with an intermediate of formula (III) according to the following reaction scheme (1):

Scheme 1

using VIl in a mixture of diisopropylamine and tetrahydrofuran, wherein all substituents are defined as in formulas (I) and (II). The reaction rate can be increased by 50 with stirring. It is appropriate to carry out the reaction at a temperature in the range of -20 to -70 ° C.

The starting materials and intermediates8

66536 B1 of formulas (II) and (III) are compounds that are either commercially available or can be prepared according to conventional conventional reaction procedures. For example, intermediates of formula (II-a) can be prepared according to the following reaction scheme (2):

Scheme 2

IIIa) where all substituents are defined as in formulas (I) and (II). Reaction scheme (2) includes step (a) in which a suitably substituted aniline is reacted with the corresponding acyl chloride, such as 3-phenylpropionyl chloride, 3-fluorobenzene-propionyl chloride 35 or p-chlorobenzene-propionyl chloride, in the presence of three bases of a suitable base , and a suitable inert reaction solvent such as methylene chloride or ethylenedichloride. The reaction is suitably carried out at a temperature ranging between room temperature and the tempera- ture ^υ the boiling point of the solvent. In the next step (b), the adduct obtained in step (a) is reacted with phosphoryl chloride (POCl ₃ ) in the presence of Ν, Ν-dimethylformamide (formulation of UP5gp1g-Naask, followed by cyclization). It is appropriate to carry out the reaction at a temperature in the range between room temperature and the reflux temperature of the solvent. In the next step (c), a specific K ² -group is introduced, where K ^{2 is} for example a C 1-6 alkyloxy or alkylthio radical, by reacting the intermediate obtained in step (b) with a compound H-C 1 -C 6 alkyl where X is 8 or O.

Intermediates of formula (11-b) can be prepared according to the following reaction scheme (3), wherein in the first step (a) substituted indole-2,3-dione is reacted with substituted 3-phenylpropionaldehyde in the presence of a suitable base as sodium hydroxide (reaction of ΡίϊΙζΐηββι ·) and then in the next step (b) the carboxylic acid compound is decarboxylated at high temperature in the presence of a suitable inert solvent such as diphenylether.

66536 ΒΙ

Scheme 3

It is apparent that in the previous and subsequent reactions, the reaction products can be isolated from the reaction medium and, if necessary, further purified according to methods known in the art, such as extraction, crystallization and chromatography. Furthermore, it is clear that reaction products which exist in more than one enantiomeric form can be isolated from their mixture by known methods, in particular preparative 3θ chromatography, for example as preparative HPLC. Typically, compounds of formulas (I) and (II) are separated into their isomeric forms.

The intermediates of formula (III) are compounds which are either commercially available or can be prepared according to conventional reaction products known in the art. For example, intermediates of formula (III-a) in which K ³ is Ar, substituted by 5 substituents K. ¹⁰ , wherein each K. ¹⁰ is independently selected from the group of hydroxy, halogen, cyano, nitro, amino, mono- or di (Cl _6alkyl) amino, C _1-6 alkyl, polyhalo-C ^ alkyl, _m alkyloxy, polyhaloC _1-6 alkyloxy, carboxyl, C _m alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono- or di (C , (alkyl) aminocarbonyl and 8 is an integer equal to 0, 1,2 or 3 can be obtained according to the following reaction scheme (4):

Scheme 4

(W-a)

Reaction scheme (4) includes step (a), in which suitably substituted Ar, in particular suitably substituted phenyl, is reacted with RpheiBcChay with the corresponding acyl chloride, such as 3-chloropropionyl chloride or 4-chlorobutyryl chloride, in the presence of a suitable 50 Lewis acid. such as A1S1 ₃ ReS1 ₃

3CCl ₄ , TClCl ₄ or Ζη Cl ₂ and a suitable inert reaction solvent such as methylene chloride or ethylenedichloride. It is appropriate to carry out the reaction at a temperature in the range between room temperature and the reflux temperature of the solvent. In the next step (b), an amino group (-ΝΚ ₄ Κ ₅ ) is introduced by reacting

66536 B1 intermediate obtained in step (a) with primary or secondary amine.

Typically, bacterial pathogens are classified as either gram-positive or gram-negative pathogens. Antibiotic compounds active against both Gram-positive and Gram-negative pathogens are considered to have a broad spectrum of action. The compounds of the present invention are referred to as gram-positive and / or gram-negative bacterial pathogens. In particular, the present compounds are active against at least one gram-positive bacterium, preferably several gram-positive bacteria, more preferably one or more gram-positive bacteria and / or one or more gram-negative bacteria.

The present compounds have bactericidal or bacteriostatic activity.

Examples of gram-positive and gram-negative aerobic and anaerobic bacteria, including staphylococci, such as 8. aigeesis; enterococci, for example E. GaesaN3; streptococci, e.g. bacilli, e.g. B1z1epa, for example, pep1a toposoepez; NaetorPiz, for example, N. tiiepga; MogaheNa, for example M. Ca2a2b2aH3; Reisysutopas, for example Reisisutopas aegis; and Essepsia, such as E. coI. Gram-positive pathogens, such as staphylococci, enterococci, and streptococci, are particularly important because they develop resistant strains that once emerged are difficult to treat and difficult to eradicate in a hospital setting, for example. Examples of such strains are methicillin-resistant BSarbosusosis aigeiz (MK.8A), methicillin-coagulase-resistant staphylococci (ΜΚΌΝδ), penicillin-resistant Beryusosus rpeitosha, and polyresistant ESS.

The compounds of the present invention may also show activity against resistant bacterial strains.

The compounds of the present invention are particularly active for 81-mucous-succulent, including resistant 81-mucous-succulent, such as, for example, methicillin-resistant 8-mucous-succulent (MK.8A) and Bierus succinic suckers.

In particular, the compounds of the present invention are active in those bacteria whose vitality depends on the proper functioning of ΡΙΡΟ ATP synthase. Without being bound by any theory, the activity of the present compounds is believed to lie in the inhibition of ΡΙΡΟ ATP synthase, in particular in the inhibition of the PO complex of ΡΙΡΟ ATP synthase, more particularly in the inhibition of the subunit with the РО ATP synthase complex , which results in the destruction of the bacteria by depleting the cellular ATP levels of the bacteria.

When it is said so far or further that the compounds can treat a bacterial infection, it is meant that the compounds can treat the infection from one or more bacterial strains.

When a bacterial infection is so far or hereafter said to be different from a mycobacterial infection, it is meant that the bacterial infection is different from an infection by one or more mycobacteria.

The exact dosage and frequency of administration of the present compounds, as known to one skilled in the art, depends on the particular compound of formula (I) used, the exact condition being treated, the severity of the condition being treated, the age, the weight, sex, diet, time of administration, and general physical condition of the individual patient, the route of administration, and other medicines the patient may take. Furthermore, it is clear that the effective daily amount may be reduced or increased depending on the response of the individual being treated and / or at the discretion of the physician prescribing the compounds of the present invention.

The compound of the present invention may be administered in a pharmaceutically acceptable form, optionally in a pharmaceutically acceptable carrier. The compounds and compositions containing the compounds can be administered topically, locally or systemically. Systemic administration includes any method of administration of a compound to body tissues, for example, intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal and oral administration. The specific dosage of antibacterial medium administered11

66536 B1 as well as the duration of treatment may be specified if necessary.

Bacterial infections that can be treated with the present compounds include, for example, central nervous system infections, external ear infections, middle ear infections such as acute medial otitis, cranial sinus infections, eye infections, oral infections such as infections of the teeth, gums and mucous membranes, infections of the upper respiratory tract, infections of the lower respiratory tract, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, infections of the skin minutes and skin structures, bacterial endocarditis, burns, antibacterial prophylaxis of surgical and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients.

Due to the fact that the compounds of formulas (I) and (I) are active against gram-positive and / or gram-negative bacteria, the present compounds can be combined with other antibacterial agents to effectively combat bacterial infections.

Therefore, the present invention also relates to a combination of (a) a compound of formulas (I) and (I) and (b), one or more other antibacterial agents, provided that these one or more other antibacterial agents are other than antimycobacterial agents funds.

The present invention also relates to a combination of (a) a compound of formulas (I) and (II) and (b), one or more other antibacterial agents, provided that these one or more other antibacterial agents are other than antimycobacterial agents, for use as a medicine.

The present invention also includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as an active ingredient a therapeutically effective amount of (a) a compound of formulas (I) or (II) and (b) one or more other antibacterial agents, provided that these one or more other antibacterial agents are other than antimycobacterial agents.

The present invention also relates to the use of a combination or pharmaceutical composition as defined above for the treatment of a bacterial infection.

For its administration, the present pharmaceutical composition may be in various pharmaceutical forms. Suitable compositions may be cited for all compositions used for systemically administered drugs. For the preparation of the pharmaceutical compositions of this invention, an effective amount of the individual compounds, optionally in the form of an addition salt, as the active ingredient mixed in a homogeneous mixture is a pharmaceutically acceptable carrier, which carrier may have a wide variety of forms depending on the desired preparation . These pharmaceutical compositions are desirably in unit dosage form, suitable in particular for oral administration or parenteral injection. For example, in the preparation of compositions in oral dosage form, any conventional pharmaceutical medium, such as water, glycols, oils, alcohols, and the like, may be used in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrants and the like - in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most preferred oral unit dosage form, naturally using solid pharmaceutical carriers. For parenteral compositions, the carrier typically contains sterile water, at least for the most part, but other ingredients may be included, for example, to aid solubility. For example, injectable solutions may be prepared in which the carrier includes saline, glucose solution or a mixture of saline and glucose solution. For example, injectable suspensions may be prepared, in which case appropriate liquid carriers, suspending agents and the like may be used. Also included are solid preparations that can be converted to liquid shortly before use.

Depending on the route of administration, the pharmaceutical composition preferably contains from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight. of the active components and of

66536 B1 to 99.95% by weight, more preferably from 30 to 99.9% by weight from a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

The weight / weight ratios of the compound of formulas (I) or (II) and (b), the other antibacterial agent (s) when given in combination, can be determined by one of ordinary skill in the art. Said ratio and exact dosage and frequency of administration, as known to one of ordinary skill in the art, depend on the exact condition being treated, the severity of the condition being treated, the age, weight, sex, diet, time of administration, and the general physical condition of the individual patient, the route of administration, and other medicines the patient may take. Furthermore, it is clear that the effective daily amount may be reduced or increased depending on the response of the individual being treated and / or at the discretion of the physician prescribing the compounds of the present invention.

The compounds of formulas (I) and (I) and these one or more other antibacterial agents may be combined in a single preparation or formulated in separate preparations so as to be administered simultaneously, separately or sequentially. Thus, the present invention also relates to a product containing (a) a compound of formula (I) and (b), one or more antibacterial agents, provided that these one or more antibacterial agents are other than antimycobacterial agents, in the form of combination preparation for simultaneous, separate or sequential administration in the treatment of bacterial infection.

The pharmaceutical composition may further comprise a variety of other known ingredients, for example, a lubricant, a stabilizing agent, a buffering agent, an emulsifying agent, a viscosity regulating agent, a surfactant, a preservative, a flavoring agent or a colorant.

It is particularly advisable to formulate the above pharmaceutical compositions in unit dosage form for easy administration and uniform dosage. A unit dosage form as used herein refers to physical discrete units suitable as unit dosages, each unit containing a predetermined amount of active ingredient, calculated to give the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including graphite or film-coated tablets), capsules, pills, powders, patches, suppositories, injectable solutions or suspensions and other similar and separate multiples thereof. The daily dose of the compound of the invention naturally varies with the compound used, the route of administration, the desired treatment and the bacterial disease indicated.

Other antibacterial agents that can be combined with the compounds of formulas (I) and (I) are the antibacterial agents known in the art. These other antibacterial agents include antibiotics of the beta-lactam group such as natural penicillins, semi-synthetic penicillins, natural cephalosporins, semi-synthetic cephalosporins, cephamycin, 1-oxacephemes, clavulanic acids, penemes, carbapenems, nocardicins; tetracyclines, anhydrotetracyclines, anthracyclines; aminoglycosides; nucleosides such as N-nucleosides, C-nucleosides, carbocyclic nucleosides, blasticidin 8; macrolides such as 12-membered ring macrolides, 14-membered ring macrolides, 16-membered ring macrolides; ansamycin; peptides such as bleomycin, gramicidins, polymyxins, bacitracins, large-ring eptide antibiotics containing lactone bonds, actinomycin, amphomycin, capreomycin, dystamycin, enduracidin, mycamycin, neocarcinostatin, stendomycin, viomycin, viomycin; cycloheximide; cycloserine; variotin; sarcomycin A; novobiocin; griseofulvin; chloramphenicol; mitomycin; fumagiline; monensins; pyrrolitrin; phosphomycin; fusidic acid; O- (p-hydroxyphenyl) glycine; N-phenylglycine; united.

Certain antibiotics that may be combined with the present compounds with

66536 ΒΙ formulas (I) and (II) are, for example, benzylpenicillin (potassium, procaine, benzatin), phenoxymethylpenicillin (potassium), pheneticillin potassium, propicillin, carbenzylin (disodium, phenyl sodium, indanyl sodium), sulbenicillin, ticitricinitricin cloxin, cloxin, cloxin, cloxin Adin, cephapirin sodium, cephalothin sodium, cephacetrile sodium, cefsulodin sodium, cephaloridine, cefatrizine, cefoperazone sodium, cefamandole, vefotiam hydrochloride, cefazolin sodium, ceftizoxime sodium, cefotaxime sodium, cefmenoxime hydrochloride, cefuroxime, ceftriaxone sodium, ceftazidime, cefoxitin, cefmetazole, cefotetan , latamoxef, clavulanic acid, imipenem, aztreonam, tetracycline, chlortetracycline hydrochloride, demethylchlorotetracycline, oxytetracycline, metacyclin, doxycycline, rolleritracycline, minocycline, daunorubicin hydrochloride ksorubitsin, aclarubicin, kanamitsinsulfat, bekanamitsin, tobramycin, gentamycin sulfate, dibekacin, amikacin, mikronomitsin, ribostamycin, neomycine sulphate, paromomitsinsulfat, streptomycin sulfate, dihydrostreptomycin, streptomycin, destomitsin A, hygromycin B, apramycin, sisomicin, netilmitsinsulfat, spectinomycin hydrochloride, astromitsinsulfat, validamycin, kasugamycin , polyoxin, blasticidin 8, erythromycin, erythromycinestolate, oleandomycin phosphate, tracetyloleandomycin, kitamycin, zhosomycin, spiramycin, tylosin, ivermectin, midecamycin, bleomycin sulfate, pemicinsulfate, gramicin, pesticide, pearl, pearl, pearl , trichomycin, mitramycin, lincomycin, clindamycin, hydrochloride, clindamycin palmitate, flavophospholipol, cycloserine, pecilocin, griseofulvin, chloramphenicol, chloramphenicol palmitate, mitomycin C, pyrrolitrin, fosfomincin acid, bicosamycin, thiamulin, sicanin.

Examples of carrying out the invention

Tables 1 and 2 list compounds of formulas (I) and (II) according to the present invention.

Some compounds have not been experimentally determined by the absolute stereochemical configuration of the stereogenic carbon atom (s). In these cases, the stereochemical isomeric form, which is isolated first, is referred to as "A" and the second as "B" without further citing the actual stereochemical configuration. However, said "A" and "B" isomeric forms can be unambiguously characterized by one of ordinary skill in the art, using methods known in the art, such as X-ray diffraction.

If "A" and "B" are stereoisomeric mixtures, they can be further separated, whereby the corresponding isolated first fractions are denoted by "A 1" and "B 1" respectively, and the second by "A2" respectively. ", 32" without further citing the actual stereochemical configuration. However, said "A1, A2" and "B1, B2" isomeric forms can be unambiguously characterized by one of ordinary skill in the art, using methods known in the art, for example, by X-ray diffraction.

The present compounds are numbered in accordance with the compounds of 2004/011436 and can be prepared according to the methods described in 2004/011436. "Etc. No. ”in the tables below refers to the example numbers in ΨΟ 2004/011436, indicating according to which method the compounds can be prepared.

The additional compounds are indicated by letters.

Compounds A, B and C were prepared according to the methods described in λΥΟ 2004/011436. The following diagram shows the synthesis of compounds A, B and C. Examples Nos. A8, A9, B12 and B13 correspond to the methods of ν / Ο 2004/011436.

66536 B1

Compound C, which is a diastereoisomer (B), is isolated from the diastereoisomer mixture as follows:

The residue (5.4) obtained according to the procedure of B12 was purified by column chromatography on silica gel (eluent: ΟΗ ^ Ι / 25 cyclohexane: 60/40). Two fractions were collected and the solvent was evaporated. The second fraction was crystallized from diisopropyl ether to give 0.83 g of compound C (diastereoisomer B) (yield: 13%). 30

Compound A, which is the diastereoisomer (B), and compound B, which is the diastereoisomer (A), are isolated from the mixture of diastereoisomers as follows: The residue (1.7 §) obtained according to the procedure of Example B13 is purified by silica gel column chromatography. (eluent: CH ₂ Cl ₂ / CH ₃ OH / MH ₄ OH; 98/2 / 0.1). Two fractions were collected and the solvent was evaporated. The fractions were recrystallized individually in diisopropyl ether to give 0.31 § of compound B (diastereoisomer A) (yield: 27%) and 0.52 § of compound A (diastereoisomer B) (yield: 45%).

Compound ϋ was prepared according to the methods described in US 2004/011436. The diagram below shows the course of compound synthesis ϋ. Examples Nos. A9, B12 and B13 correspond to the methods of ν / Ο 2004/011436.

66536 B1

Compound ϋ, which is the diastereoisomer (B), is isolated from the mixture of diastereoisomers as follows:

The residue (1.2 §) obtained according to the procedure of Example B13 was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / CH ₃ OH / LH ₄ OH; 95/5 / 0.5). Two fractions were collected and the solvent was evaporated. The second fraction was crystallized from diisopropyl ether to give 0.08 g of compound ϋ (diastereoisomer B) (yield: 10%).

Compounds E and P were prepared by separating compound 4 (diastereoisomer B) from DUO 2004/011436 into its enantiomers by the following method: The final compound 4 (2.5 §) was separated into its enantiomers by column chromatography (eluent: hexane / ethanol 99.95 / 0.05; column: DOWNLOAD SO). Two pure fractions were collected and the solvents were evaporated. Yield: 0.5 § of compound E (enantiomer B1) (melting point 180 ° C) and 0.12 § of compound P (enantiomer B2) (melting point 175 ° C).

Compound O was prepared as follows:

Mixture of compound 115 (prepared according to B15 of AATO 2004/011436) (0.00028 mol), pyridine 3-boric acid 1,3-propanediol cyclic ester (0.00055 mol), Pd [P (Pb ₃ )] ₄ (0.00003 mol) and Ia ₂ CO ₃ 2M (0.0011 mol) in dimethoxyethane (4 ml) was stirred at 90 ° C for 1.5 b, then poured into H ₂ O and extracted with

CH ₂ C1 ₂ . The organic layer was separated, dried (M§80 ₄ ), filtered and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / CH ₃ OH 95/5; 5 µm). The pure fractions were collected and the solvent was evaporated. Yield: 0.09 § of compound O (60%) (mp 201 ° C).

Compound H was prepared as follows:

Mixture of compound 15 (prepared according to B7 of 2004/011436) (0.0009 pg), 2-furanboric acid (0.0018 mp), Pd [P (Pb ₃ )] ₄ (0.00009 mp) and No. ₂ CO ₃ 2M (0.0036 mole) ) in dimethoxyethane (10 ml) was stirred at 90 ° C for 6 b, then poured into H ₂ O and extracted with CH ₂ Cl ₂ . The organic layer was separated, dried (M§8O _4), filtered and the solvent evaporated. The residue (0.57 §) was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / CH ₃ OH / 1H ₄ OH 99/1 / 0.1; 10 µm). The pure fractions were collected and the solvent was evaporated, yielding a 0.23 оста residue.

The fraction was recrystallized from diisopropyl ether / acetonitrile. The precipitate was filtered off and dried. Yield: 0.071 § of compound H (15%) (mp 215 ° C).

Compounds I and II were prepared according to the methods described in US 2004/011436. The following diagram shows the course of synthesis of compound 1. Examples Nos. A10 and B1 correspond to the methods of US 2004/011436.

Intermediate)

66536 B1

A mixture of commercially available 5-acetyl-1,2-dihydroacenaphthylene (0.0407 mol) and dimethylamine hydrochloride (0.0858 mol) in paraformaldehyde (37% in water, 4 ml), HCl-BrOH (1 ml) and ethanol (100 ml) was stirred and refluxed. for 48 b. The solvent was evaporated. The residue was mixed with H ₂ O / HCl 3Ν / ΟΗ ₂ Ο1 ₂ . The aqueous layer was basified and extracted with CH ₂ Cl ₂ . The organic layer was separated, dried (M§ZO _4), filtered and the solvent evaporated. The residue was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ CH ₃ OH / MH ₄ OH 95/5 / 0.2; 15-40 ppm). The pure fractions were collected and the solvent was evaporated. Yield: 4.9 § of intermediate b (48%).

n-ViP 1.6M (0.0102 mol) was added dropwise at -20 ° C to a solution of diisopropylamine (0.0091 mol) in tetrahydrofuran (15 ml) in a flow of на ₂ . The mixture was stirred at -20 ° C for 20 hours then cooled to -70 ° C. A solution of intermediate 3 (0.0091 mol) in tetrahydrofuran (10 ml) was added dropwise. The mixture was stirred at -70 ° C for 2 b. A solution of intermediate b (0.01 ml) in tetrahydrofuran (20 ml) was added dropwise. The mixture was stirred at -70 ° C for 3 H, poured into ice water and extracted with EtOAc. The organic layer was separated, dried (M§80 ₄ ), filtered and the solvent was evaporated. The residue (6.5 §) was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH / 1H ₄ OH 99/1 / 0.2; 15-40 ppm). Two fractions were collected and the solvent was evaporated. Yield: 0.96 § P1.0.72 § P2. P1 was recrystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 0.87 § of compound b (17%).

66536 ΒΙ

Table 1:

With No Etc. No a ' a ² a ³ a ⁶ Stereochemistry, etc. 41 ΒΙ N. OCH3 phenyl N. (IN); 160 ° C 206 Q7 Br OCH3 1-naphthyl R. (B); 213 ° C 31 B1 With! OCH3 phenyl N. (IN); 181 ° C 26 B1 phenyl OCH3 phenyl N. (A); 174 ° C 27 B1 phenyl OCH3 phenyl N. (IN); 192 ° C 32 ΒΙ Br OCH3 phenyl N. (A); 208 ° C 33 B1 Br OCH3 phenyl N. (IN); 196 ° C 109 Q9 Br OCH3 3-fluorophenyl N. (A2); 156 ° C 39 Q9 Br OCH3 3-fluorophenyl N. (IN); 207 ° C 36 B1 Br OCH3 phenyl C1 (A); 197 ° C 14 Q7 Br OCH3 1-naphthyl n (A); 210 ° C 15 Q7 Br OCH3 1-naphthyl n (IN); 244 ° C 46 Q7 Br OCH3 2-naphthyl n (IN); 162 ° C 4 B1 Br OCH3 phenyl n (IN); 190 ° C 174 Q9 F-. OCH3 3-fluorophenyl n (A); 159 ° C 24 B1 Br OCH3 3-thienyl n (A); 162 ° C 5 B2 Br OCH ₂ CH3 phenyl n (A); 162 ° C 38 Q9 Br OCH3 3-fluorophenyl n (A); 198 ° C

66536 B1

ΐ 69 B1 Br OCH3 2-fluorophenyl N. (A); butter 70 B1 Br OCH3 2-fluorophenyl N. (IN); butter 16 B1 Br OCH3 4-chlorophenyl N. (A); 200 ° C 17 B1 Br OCH3 4-chlorophenyl N. (IN); 190 ° C 67 Q8 Br OCH3 2,5-difluorophenyl N. (A); 60 ° C 116 Q15 Br OCH3 3.5-d difluorophenyl N. (IN); 224 ° C 159 Q8 Br OCH3 2,5-difluorophenyl n (A1); 208 ° C 160 Q8 Br OCH3 2,5-difluorophenyl n (A2); 167 ° C 113 B14 Br OCH3 2,3-difluorophenyl n (A); 128 ° C 196 Q15 Br OCH3 3,4-difluorophenyl N. (IN); 184 ° C 76 B1 Br OCH3 CO N. (IN); 130 ° C 84 B1 phenyl Axis, 1-naphthyl N. (A); 248 ° C 45 Q7 Br OCH3 2-naphthyl N. (A); 262 ° C 77 B1 Br OCH3 'CO N. (A); 202 ° C 78 B1 Br OCH3 co n (IN); 202 ° C 165 Q9 Br 3-fluorophenyl n (IN); butter 72 B1 Br OCH3 1-naphthyl CH3 (IN); 178 ° C 212 Q7 OCH3 1-naphthyl N. (IN); 220 ° C 163 Q7 Br OCH3 6-methoxy-2-naphthyl n (IN); 206 ° C 73 B1 Br OCH3 1-naphthyl C1 (B); 174 ° C 201 B1 Br OCH3 N. (A); 214 ° C 30 31 C1 OCH3 phenyl n (A); 170 ° C 21 B1 Br OCH3 2-thioyl n (IN); 176 ° C 25 B1 Br OCH3 3-thienyl n (IN); 160 ° C 20 B1 Br OCH3 2-thienyl n (A); 96 ° C 6 B2 Br OCH ₂ CH3 phenyl n (IN); 74 ° C

66536 B1

108 Q9 Br OCH3 3-fluorophenyl N. (A1); 160 ° C 37 ΒΙ Br OCH3 phenyl C1 (B); 221 ° C 13 Q7 Br OCH3 1-naphthyl N. (A2); 120 ° C 130 Q7 Br SNS, 5-bromo-2-naphthyl N. (IN); 220 ° C p 3-Pyridyl OCH3 3,5-difluorophenyl n (A); 201 ° C n 2-furanyl OCH3 1-naphthyl n (IN); 215 ° C I Br OCH3 f N. (A); > 260 ° C R. B1 Br OCH3 phenyl n (B2); 175 ° C Well B1 Br OCH3 phenyl n (B1); 180 ° C

Table 2:

With No Etc. No B Stereochemistry, etc. 50 B1 phenyl 1-imidazolyl (IN); 230 ° C 137 Q7 2-naphthyl 4-methylpyrazinyl (IN); 232 ° C 154 Q7 6-bromo-2-naphthyl 4-methylpiperazinyl (IN); 254 ° C 49 B1 phenyl 1-imidazolyl (A); 216 ° C 136 Q7 2-naphthyl 4-methylpyrazinyl (A); 188 ° C 48 B1 phenyl 1-piperidinyl (IN); 210 ° C 55 B1 phenyl thiomorpholinyl (A); butter 171 Q7 2-naphthyl 1-pyrrolidinyl (B); 218 ° C 129 B1 2-naphthyl 1-piperidinyl (B); 212 ° C 149 Q7 1-naphthyl 4-methylpyrazinyl (IN); 232 ° C

66536 B1

166 Q7 6-bromo-2-naphthyl 1-piperidinyl 1 1 (B); 218 ° C 151 Q7 3-Bromo-1-naphthyl 4-methylpiperazinyl (A); 178 ° C 53 B1 phenyl 1- (1,2,4-triazolyl) (A); 180 ° C 47 B1 phenyl 1-piperidinyl (A); 190 ° C 51 B1 phenyl 1- (4-methyl) piperazinyl (A); 150 ° C 170 Q7 2-naphthyl 1-pyrrolidinyl (A); 238 ° C 128 B1 2-naphthyl 1-piperidinyl (A); 254 ° C 145 Q7 1-naphthyl 1-piperidinyl (A); 212 ° C 139 Q7 2-naphthyl morpholinyl (A); 258 ° C 140 Q7 2-naphthyl morpholinyl (B); 214 ° C 155 Q7 6-bromo-2-naphthyl 1-piperidinyl (A); 224 ° C A B13 2,4-difluorophenyl BH (CH ₂ CH,) (IN) IN B13 2,4-difluorophenyl MH (CH ₂ CH ₃ ) (A) P B12 2,4-difluorophenyl M (CH ₂ CH ₁ ) (CH ₂ phenyl) (IN) ϋ B13 phenyl B1H (CH ₃ ) (IN); 197 ° C 209 Q7 2-naphthyl (IN); 198 ° C 58 Q6 phenyl · < 0 (A); 208 ° C 11 Q6 phenyl 1 \ 0 (IN); 208 ° C

66536 ΒΙ

Analytical methods

The mass of some compounds was recorded by bcmc (liquid chromatography by mass spectrometry). The method used is described below. The data are summarized in Table 3.

LBM8 method

The BCHM3 assay was performed (positive ionization ionization, scanning from 100 to 900 ati) on a Kgotazy C18 column (1µggs1pt, Mopsisop, RI; 5 µm, 4.6 x 150 mm) with a flow rate of 1 ml / ml. Two mobile phases (mobile phase A: 30% 6.5 mM ammonium acetate + 40% acetonitrile + 30% formic acid (2 ml / l) were used; mobile phase B: 100% acetonitrile) to achieve a 100% A gradient over 1 wt to 100% B for 4 wt, 100% B for 5 wt to 100% A for 3 wt and re-equilibration with 100% A for 2 wt.

Table 3; Bcmz - initial peak

Compound Νο Bcm5 start peak (MH ⁺ ) A 541 IN 541 P 631

Pharmacological examples

Preparation of bacterial suspensions for sensitivity testing:

The bacteria used in this study were cultured in flasks containing 100 ml of MieNeg-Ηΐηίοη broth (VesTop ENSWHP - Cat. No. 275730) in sterile deionized water with shaking at 37 ° C overnight. Stock solutions (0.5 ml / tube) were stored at -70 ° C until used. The bacteria were titrated in microtiter plates to determine TCO ₅₀ , where TCO ₅₀ represents the dilution, which gives an increase in bacterial growth in 50% of the inoculated cultures.

Typically for susceptibility testing using the level of inoculation of about 100TSGO _5O.

Antibacterial susceptibility test: determination of 1C ₉₀

Analysis in microtiter plates Flat-bottomed sterile 96-well plastic microtiter plates are filled with 180 ppg of sterile deionized water, with the addition of 0.25% BSA. Subsequently, stock solutions (7.8 x final test concentration) of the compounds in a volume of 45 ppm were added to column 2 and sterile five-fold dilutions (45 ppg1 in 180 ppg1) were made directly into the microtiter plates of column 2 to reach column 11. To each the plaque included untreated control samples with (column 1) and without (column 12) inoculum. Depending on the type of bacteria, rows A to H, except column 12, were added approximately 10 to 60 Cpi per well of bacterial inoculum (100 TCO ₅₀ ) in a volume of 100 ppgo1 in 2.8x MieNeg-ηηοοη broth. The same volume of inoculum broth was added in rows A to H of column 12. The cultures were incubated at 37 ° C for 24 b in a normal atmosphere (incubator with open air valve and constant ventilation). At the end of incubation, one day after inoculation, the bacterial growth fluorometrically was quantified. For this purpose, 3 b after inoculation, resorcinol (0.6 mg / ml) in a volume of 20 psi was added to each well and the plates incubated overnight. The change in color from blue to pink indicates bacterial growth. Fluorescence was counted with a computer-controlled fluorometer (SuJyog Vuezagb) at an excitation wavelength of 530 nm and an emission wavelength of 590 nm. The percent inhibition of growth achieved with the compounds was calculated by standard methods. IC ₉₀ (expressed in ppg / ml) was defined as a 90% bacterial growth inhibition concentration. The results are shown in Table 4.

Agar dilution method The values of M1C ₉₀ (the minimum concentration to obtain 99% inhibition of bacterial growth) can be determined by carrying out the standard agar dilution method according to ICCI3 * standards, in which the medium used consists of MieNeg- Ηΐηίοη.

♦ Institute for Clinical Laboratory Standards. 2005. Dilution Methods Tests for

66536 B1 Antimicrobial susceptibility to aerobic bacteria: approved standard - sixth edition.

Destruction time analysis The bactericidal or bacteriostatic activity of the compounds can be determined by the time of destruction using the broth microarray method *. In the destruction time analysis θ of 31arNu1ososize aigeesis and methicillin-resistant 8. aigeise (MK.8A), the starting inoculum of 8. aigeise and MK.8A is 10 ⁶ CPi / t1 in Mie11e broth Ηίηίοη. The antibacterial compounds were used at a concentration of 0.1 to 10 times the concentration of M1C (i.e., 1C90 as determined in the microtiter plate assay). Wells that do not receive an antibacterial agent are controls for the growth of the crop. Plates containing the microorganism and the test compounds were incubated at 37 ° C. After 0.4,24 and 48 b incubation, the samples were separated to determine the viable bacterial counts by serial dilution (10 ¹ to 10 ' ⁶ ) 25 in sterile PB8 and placing (200 ppgo1) on MieNeg agar Ηίηίοη. The plates were incubated at 37 ° C for 24 b and the number of colonies was determined. Destruction curves can be plotted by plotting §10 CPI per µl versus time. The bactericidal effect is usually defined as a 3-1ο§ _1θ decrease in the _CPI number of _rp1 relative to the untreated inoculum. The potential effect of drug delivery was eliminated by serial dilutions and colony counts at the highest dilution used.

♦ gigepko, oe e1 a1. ΓΟη νϊίΓΟ бу Ш з з з-----100592 б и--100766, ηονεί ίο попо пепо попо Appbs. AEpGz Sietoizeg. 40, 839-845 (1996).

Determination of cellular ATP levels

In order to analyze the change in total cellular concentration of ATP (using ATP 10 bioluminescent kit, KosBe), the assays were performed by growing stock solution of culture 8. aigeiz (ATCC 29213) in 100 ml of MieNeg flasks and incubating and incubating incubator for 24 b at 37 ° C (300 rpm). Οϋ 4θ5 _pt is measured and CPi / m1 is calculated. The cultures were diluted to 1 x 10 ⁶ CPi / ml (final concentration for the measurement of ATP: 1 x 10 ⁵ CPi / 100 psi1 per well) and the test compound added at a concentration of 0.1 to 10 times the concentration of M1C (ie 1C _M as determined by microtiter plate analysis). These tubes were incubated for 0, 30 and 60 mm at 300 rpm and 37 ° C. A 0.6 ml bacterial suspension of the sealed tubes was used and placed in new 2 ml ErrepNog Tubes. 0.6 µl of cell-lysis reagent (KosBeer kit) was added, vortexed at maximum speed, and incubated for 5 g at room temperature. Cool on ice. The luminometer was allowed to warm up to 30 ° C (Acep! Laser pump with an injector). One column (= 6 wells) is filled with 100 ppg of the same sample. Using the injector system, 100 µg of CO2 luciferase reagent was added to each well. Luminescence was measured at 1 h.

Table 4; 1C10 values (p§ / m1) determined by microtiter plate analysis.

1Sdo (cr / t1> With took ESO EPA EPA Hmm RAE 5M and 3ΡΝ 8ΡΥ THAT THAT THAT THAT No 43639 25922 14506 29212 49594 27853 3340 2 6305 8668 43300 25923 29213 Mayor A 10.8 1.1 10.8 10.8 12.1 50 10.5 10.5 23.6 21.0 26.5 26.5 10.5 41 17.0

66536 B1

Ρ 22.6 25.3 22.6 206 12.8 31 10.3 4.6 4.1 10.3 10.3 5.2 1.8 11.6 44 7.6 7.6 26 10.0 4.5 4.5 2.0 11.3 5.6 2.5 11.3 8.9 27 10.0 8.9 12.6 Well 12.7 11.3 7.1 10.1 10.1 5.7 5.1 12.7 32 11.7 4.6 4.6 10.4 4.6 13.1 4.6 13.1 9.3 13.1 33 10.4 11.7 4.6 2.3 11.7 10.4 5.9 2.6 5.9 13.1 109 11.7 9.3 11.7 13.1 13.1 13.1 10.4 39 10.4 4.7 10.4 11.7 5.9 1.9 13.1 10.4 137 21.2 23.8 8.4 21.2 36 24.1 4.8 5.4 4.8 3.8 2.7 0.4 4.8 14 11.1 9.9 5.0 2.5 5.0 12.4 6.2 2.8 5.6 9.9 14.0 15 24.8 24.8 5.0 2.5 12.4 12.4 6.2 2.2 5.0 46 5.0 2.8 5.0 5.6 2.8 0.6 5.6 154 10.9 27.4 27.4 27.4 13.8 24.5 4 12.7 174 10.2 175 10.2 12.8 24 10.2 5 10.4 38 10.4 69 10.4 10.4 13.1 70 10.4 13.1 49 10.5 10.5 13.3 10.5 5.9 11.8 136 10.6 10.6 10.6 19 13.4 215 10.7 P 13.6 10.8 10.8 16 13.6 17 10.8 0.5 67 10.8 13.6 116 10.8 110 10.8 13.6 111 10.8 113 10.8 13.6

66536 B1

196 10.8 IN 8.6 N. 13.6 13.6 48 10.9 10.9 10.9 13.7 13.7 76 11.0 11.0 84 11.0 11.0 7.0 11.0 45 11.1 12.4 77 11.2 14.2 78 11.2 11.2 11.2 55 0.6 165 14.3 14.3 11.3 72 9.0 14.3 11.4 226 14.3 212 11.4 171 11.6 163 14.7 73 11.8 14.8 129 11.9 15.0 11.9 149 12.2 201 12.3 12.3 12.3 12.3 P 15.9 18 13.3 13.3 0.7 165 16.9 151 15.4 15.4 30 10.3 10.3 9.2 10.3 5.2 10.3 ϋ 4.9 229 22.5 5.0 21 11.5 4.6 11.5 12.8 12.8 25 11.5 11.5 11.5 12.8 4.1 12.8 20 2.6 6 11.6 11.6 11.6 4.6 13.0 4.6 108 13.1 53 5.9 37 12.1 47 6.9 227 5.0 13 11.1 11.1 8.8 11.1 2.2 1 3.5 2.8 8.8 11.1 11.1

66536 ΒΙ

51 28.1 25.0 25.0 5.6 I 11.6 170 26.0 128 9.4 145 23.7 9.4 139 18.9 26.7 140 9.5 223 5.4 13.6 5.4 130 10.1 155 26.9 209 15.1 58 5.9 8.3 11 11.7 10.4 11.7

43δυ 43639 stands for Your Business (ATCC 43639); ESO 25922 means EssenceMass (ATCC 25922); EPA 14506 stands for EPG 25 RaesaP3 (ATCC 14506); EPA 29212 means Eyegosossis RaesaPz (ATCC 29212); LMO 49594 stands for 1lz1epa topos (oepepez (ATCC 49594); RAE 27853 means rseidotopaz aegi§toza (ATCC 27853); ruo§epz (ATCC 8668); 8TA 43300 means 81 aruosussiz aigeiz (ATSC 29213); MK.8A) (clinically isolated from the University of Apueregp) ATCC stands for American Cell Culture Type.

Claims (4)

Claims CLAIMS 1. Quinoline derivatives of general formula I are a pharmaceutically acceptable acid or base addition salt or сол-oxide form thereof, wherein the substituents have the following meanings: 66536 B1 to ¹ K ² K ³ E ⁶ Stereochemistry Br OCH3 f N. (A) Br OCH3 phenyl N. (B2) N. OCH3 phenyl N. (IN) phenyl OCH3 phenyl N. (IN) Br 5CH3 phenyl N. (A) Br OCH3 3-fluorophenyl N. (A2) Br OCH3 phenyl C1 (B2) as (A) or (B) means that the compound is a mixture of two enantiomers and (A) is isolated first and (B) second; (A2) and (B2) mean that the compound is an enantiomer and represent a second fraction isolated from (A) and (B) respectively. 2. Quinoline derivatives of general formula II are a pharmaceutically acceptable acid or base addition salt or Ν-oxide form thereof, wherein the substituents have the following meanings: K ³ B Stereochemistry 2,4-difluorophenyl RS (CH ₂ CH3) (A) 2,4-difluorophenyl (CH ₂ CH 3) (CH ₂ phenyl) (IN) phenyl IN (CH3) (IN) phenyl 1-imidazolyl (IN) 66536 B1 as (A) or (B) means that the compound is a mixture of two enantiomers and (A) is isolated first and (B) second. Use of quinoline derivatives according to claim 1 for the manufacture of a medicament for the treatment of a bacterial infection other than a mycobacterial infection, said derivatives being compounds with a soluble acid or base salt or Ν-oxide form thereof. Use of quinoline derivatives according to claim 2 for the manufacture of a medicament for the treatment of a bacterial infection other than mycobacterial infection, said derivatives being compounds of formula II their pharmaceutically acceptable addition pharmaceutically acceptable addition salt with an acid or base or their Ν -oxide form.