Antimicrobial quinolone derivatives and use of the same to treat bacterial infections

ES 2 256 331 T3

DESCRIPTION

Antimicrobial quinoline derivatives and their use to treat bacterial infections.

Field of the invention

The present invention relates to oxazolidinone substituted quinolone derivatives and their use as broad-spectrum antimicrobial agents effective against a number of gram-positive and gram-negative human and veterinary pathogens.

Background of the invention

Increased resistance of bacteria to existing antibacterial agents is a major clinical problem.

Derivatives of 7-substituted quinolonecarboxylic acid, represented by the general formula (II), in which Y is CR⁵ or N, and R¹ to R⁵ They include a wide variety of substituents, are well known as antifungal and antibacterial agents, and as synthetic intermediates of related compounds. The 7-substituted derivatives of compound (II) include the antibacterials cinoxacin (US Patent No. 3,669,965); ciprofloxacin (US Patent Nos. 4,563,459 and 4,620,007); ofloxacin (US Patent No. 4,382,892); and levofloxacin (US Patent Nos. 4,985,557, 5,053,407, and 5,142,046).

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Oxazolidinones having a general structural formula (III) are also a well-known class of orally active, synthetic antibacterial agents. The bibliography contains numerous references to oxazolidinones (III), in which R¹ to R³ they include a wide variety of substituents. Oxazolidinones having one or two substituents on the phenyl ring are described in US Patent Nos. 4,705,799; 5,523,403; and 5,654,435, for example. Oxazolidinones (III) include the antibacterial agent named DuP 721, see J. Med. Chem., 32, 1673 (1989).

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Oxazolidinones (III) having an arylbenzene substituent on the oxazolidinone ring are described in US Patent Nos. 4,948,801 and 5,130,316. The 3 - [(fused-substituted di- or ring) phenyl] -2-oxazolidinones are described in US Patent Nos. 4,977,173; 4,921,869; 4,801,600; and 5,164,510. European patent applications 0 697 412; 0 694 544; 0 694 543; and 0 693 491, and International Patent Publication No. WO 93/09103, describe 5- to 9-membered substituted aryl- and heteroaryl-phenyl oxazolidinones as antibacterial agents. US Patent No. 5,254,577 describes aminomethyloxoxazolidinyl arylbenzene derivatives as antibacterial agents. Other references describing oxazolidinones include US Patent Nos. 4,801,600 and 4,921,869. Some of the pyridine-substituted phenyloxazolidinone derivatives described in the above patents are effective against gram-positive bacteria, such as Staphylococcus aureus and Streptococcus pneumoniae. However, oxazolidinones are not active against gram-negative bacteria, such as Escherichia coli, Klebsiella, Proteus, and Seratia marcenses. Furthermore, oxazolidinones cannot be administered in the form of a solution for injection because their free amino forms are poorly soluble. Antibacterial oxazolidines are described in European patent application 0 390 215.

ES 2 256 331 T3

Summary of the invention

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or one of its pharmaceutically acceptable salts; where L is a bond or -NR⁸(CR⁹2)₂NR⁸-;

R¹ is selected from H, Ci-C alkyl₄, C cycloalkyl₃-C₅, Ci-C haloalkyl₄ and halophenyl; Y

R² selected from H, alkyl, C alkoxy₁-C₂, halo and haloalkoxy; or

R¹ and R² taken together they form an optionally substituted 5- or 6-membered heteroalkyl or heteroaryl ring;

R³ is H or F;

R⁶ selected from H, methyl, hydroxy, and halo;

each R⁶ is independently H or C alkyl₁-C₄, or the R groups⁸ taken together to form an optionally substituted 4- to 9-membered heteroalkyl or heteroaryl ring;

each R⁹ is independently H or C1-C4 alkyl, or the R groups⁹ are taken together to form a 4- to 9-membered heterocyclic or heterobicyclic ring optionally substituted with C1-C alkyl₂, haloalkyl, or methoximino;

R¹¹ is selected from H, C1-C7 alkyl, C3-C5 cycloalkyl, hydroxymethyl, haloalkyl, CH2SMe, N (R¹²) 2, C1-C4 alkoxy or aryloxy; Y

R¹² is C alkyl₁-C₄.

Another aspect of the present invention is a pharmaceutical composition containing a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient.

A further aspect of the present invention is the use of a compound of the invention for the manufacture of a medicament for the treatment of a microbial infection in a warm-blooded animal.

Detailed description of the preferred embodiments

As used herein, the terms and phrases have the meanings and definitions known in the art. Some of the most commonly used phrases are described in more detail below.

"Alkyl" refers to a cyclic, straight, or branched chain chemical group containing only carbon and hydrogen atoms, for example methyl, pentyl, and adamantyl. Alkyl groups can be unsubstituted or substituted with one or more substituents, for example halogen, alkoxy, acyloxy, amino, hydroxy, mercapto, carboxyl, benzyloxy, phenyl, and benzyl. Alkyl groups can be saturated or unsaturated (for example, containing alkenyl or alkynyl subunits), in one or more positions. Normally, alkyl groups contain 1 to 12 carbon atoms, for example 1 to 10, or 1 to 8 carbon atoms.

"Heteroalkyl" refers to a branched, straight or cyclic chain chemical group containing carbon, hydrogen, and at least one heteroatom. Heteroalkyl includes bicyclic compounds. The heteroatom is usually nitrogen, oxygen, or sulfur. Heteroalkyl groups can be unsubstituted or substituted with one or more substituents, for example halogen, alkoxy, acyloxy, amino, hydroxy, mercapto, carboxyl, benzyloxy, phenyl, and benzyl. When the heteroalkyl group contains a nitrogen atom, the nitrogen atom can be primary, secondary, tertiary, or quaternary, or it can be in various forms, such as an amide or a sulfonamide. Heteroalky groups3

ES 2 256 331 T3 may contain one or more unsaturated subunits (eg, alkenyl or alkynyl). Typically, heteroalkyl groups contain about 1 to 12 carbon atoms, for example about 1 to 8, or about 1 to 4 carbon atoms.

"Heteroaryl" refers to a monovalent aromatic group that has a single ring (eg, pyridyl or furyl) or multiple fused rings (eg, indolicinyl or benzothienyl) containing carbon atoms and having at least one heteroatom within the ring. . The heteroatom is preferably nitrogen, oxygen or sulfur. Heteroaryl groups can be optionally unsubstituted or substituted with amino, hydroxy, alkyl, heteroalkyl, alkoxy, halo, mercapto, and other substituents. In one embodiment, the heteroaryl group is substituted pyridyl.

The term "halo" or "halogen" is defined herein to include fluorine, bromine, chlorine, and iodine.

The term "haloalkyl" is defined herein as an alkyl group substituted with one or more halo substituents, any of fluorine, chlorine, bromine, iodine, or combinations thereof.

The terms "alkoxy" and "aryloxy" are defined as -OR, where R is alkyl or aryl, respectively.

The term "hydroxy" is defined as -OH.

"Biologically active compounds" or "bioactive compounds" refer to the present quinolone derivatives that exhibit biological activity. For example, a biologically active compound can inhibit the interaction between an enzyme or a receptor and their respective endogenous substrate (s) or ligand (s), or inhibit the cell growth of a microorganism, by at least about 15% at a concentration in solution of 10³ molar or lower (ie, has inhibitory activity). For example, a biologically active compound can inhibit such processes at solution concentrations of 10⁴ M or less, preferably 10 ⁵ M or less, and more preferably 10 ⁶ M or lower.

The compounds of the present invention are effective antimicrobial agents against a number of human and veterinary pathogens, including gram-positive, gram-negative, and anaerobic bacteria, and in the treatment of microbial infections in mammals. The present compounds can also be used as cytotoxic anticancer compounds.

Furthermore, it is preferred that the compounds of formula (I) are optically pure enantiomers with the S-configuration at the carbon in position 5 of the oxazolidinone ring.

Preferred compounds of the present invention are those of Examples 1 to 3.

The substituted quinolone derivatives of the present invention can be prepared by the following general synthetic schemes.

Scheme 1 illustrates a general procedure for the synthesis of the 7-oxazolidinon-, isoxazolin-, and isoxazolinone-substituted quinolone compounds (B) of the present invention. Scheme 2 illustrates specific synthesis examples of the oxazolidinon-substituted quinolone compounds (3 and 6) of the present invention.

Scheme 1

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ES 2 256 331 T3

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In Scheme 1, a suitably substituted quinolone is used as the starting material, preferably containing a leaving group (LG) at position 7 (compound A), such as a fluorine, chlorine, or triflate derivative. Specific examples of such compounds are illustrated by compounds (1), (4), and (5). Compounds (1), (4), and (5) are readily available from a number of commercial sources or, alternatively, are known in the chemical literature or can be readily prepared by one skilled in the art. 7-Chloro-1-cyclopropyl-6-fluoro-4oxohydroquinoline-3-carboxylic acid (1) is commercially available from Acros Organics, and its synthesis is described in German patents DE 3,142,854, DE 3,248,505 and DE 3,248 .507. 1-Cyclopropyl-6,7-difluoro-4-oxo-3-quinolinecarboxylic acid is commercially available from Louston International, and its synthesis is described in German Patent DE 3,248,507. 9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H- [1,4] oxacino [2,3,4-d] quinoline-6-carboxylic acid is commercially available from Maybridge Chemical Company and its synthesis are described in Japanese patents JP 57,088,182 and JP 58,072,589 and EP 47,005. 9-Chloro-10-fluoro-3-methyl-7-oxo-2,3-dihydro-7H [1,4] oxacino [2,3,4λ] quinoline-6-carboxylic acid is commercially available from Zhejiang Hengdian Imp . &amp; Exp. Co., Ltd. and its synthesis is described in Chem. Pharm. Bull., 32,4907-13 (1984) and in EP 206,283.

In one embodiment, the suitably substituted quinolone (1), (4), or (5) is treated with an oxazolidinone substituted with a sufficiently nucleophilic linking group, L, such that the subsequent nucleophilic substitution reaction provides, in a reaction sequence in a single reactor, the corresponding crude oxazolidinon (I) substituted quinolone.

The L group on oxazolidinone can be introduced by standard synthetic procedures from commercially available reagents as described hereinafter. For example, when quinolone (1), (4), or (5) is treated with 5- (S) -aminomethyl-3- (3-fluoro-4-piperazinophenyl) oxazolidin-2-one in N-methylpyrrolin- 2-one (NMP) and N-methylmorpholine (NMM), the corresponding crude (3) or (6) oxazolidinone-substituted quinolone is formed in moderate to high yield.

Compounds (3) and (6) can then be purified following chromatographic techniques well known in the art.

Alternatively, Scheme 3 summarizes a representative procedure for the preparation of compounds in which a carbon-carbon bond connects the quinolone fragment to a phenyloxazolidinone subunit. Quinolone triflates 7a, b, (Kiely et al., J. Heterocyclic Chem., 1991, 28, 1581-1585), are reacted with boronic acid 8 in the presence of 1,2-dimethoxyethane, aqueous dibasic potassium phosphate and a suitable palladium catalyst, such as bis (triphenylphosphine) bichloride. palladium or palladium tetrakis (triphenylphosphine), and at a suitable temperature, pre5

ES 2 256 331 T3 frequently at reflux temperature, to generate the respective coupled products 9a, b. It will be apparent to one skilled in the art that compounds 9a, b are both antimicrobial compounds and synthetic intermediates. For example, the tert-butoxycarbonyl (BOC) moiety of 9a, b can be removed with, for example, trifluoroacetic acid to give an amino intermediate which can be further developed, for example acylated, using the conditions described below. Additionally, the ester moiety of 10 or one of its subsequent acylated derivatives can be hydrolyzed under acidic or basic conditions to give the corresponding carboxylic acid 11. Furthermore, when R¹ = Bn, hydrogenolysis in the presence of a suitable catalyst, such as palladium on carbon, also gives the corresponding carboxylic acid 11.

Scheme 3

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The compounds of the present invention contain at least one chiral center. It is apparent to one skilled in the art that when a chiral center is present, the compound can exist as one of two possible optical isomers ((R) and (S) enantiomers) or a racemic mixture of both. The two individual enantiomers (R) and (S), as well as their mixtures, are within the scope of the invention. In the event that a second chiral center is present in the oxazolidinon-substituted quinolones (I) of the invention, the resulting diastereoisomers, in racemic and enantiomerically enriched forms, are also within the scope of the compounds (I) of the invention.

The preferred compounds of the present invention are optically pure enantiomers having the (S) configuration at C⁵ of the oxazolidinone ring, because, for example, S-ofloxacin has a potency 10 to 100 times higher than R-ofloxacin. However, racemic mixtures are also useful, but a larger amount of racemic material may be required to produce the same effect as the pure S-enantiomer.

If desired, the mixture of enantiomers is resolved by means known to those skilled in the art. The optically pure material can be obtained by resolution of the racemic mixture by HPLC using a chiral phase, such as a Chiralpack AD column as described in Examples 4 and 6 for compounds 15 and 17 and shown in Scheme 2. Alternatively, resolution of the racemic mixture can also be accomplished by selective crystallization from a salt form using procedures known to those skilled in the art. See, for example, "Optical Remixture Procedures for Chemical Compounds, Vol. 1; Amines and Related Compounds ”, Paul Newman, Optical Remixture Information Center, Manhattan College, Riverdale, NY, 10471, 1978. For example, treatment of the R, S-aminomethyl mixture (25) with a suitable optically active acid, such as (+) - tartaric acid, or alternatively (-) - tartaric acid, gives a mixture of diastereomeric salts, which can be separate by fractional crystallization to give a salt containing one of the enantiomers of the racemic mixture. Other suitable optically active acids include (-) - dibenzoyltartaric acid, (+) - camphoric acid, (+) - and (-) - malic acid, and (+) camphor-10-sulfonic acid. By reacting the diasteromeric salt with a base, the optically pure free amino compound (25) is obtained.

A compound of formula (I), or one of its prodrugs or its physiologically acceptable salts or solvates can be administered as the compound alone or as a pharmaceutical composition containing either entity.

The pharmaceutical compositions of the present invention can be prepared by mixing a compound of formula (I) with a pharmaceutically acceptable solid or liquid carrier, and, optionally, with pharmaceutically acceptable adjuvants and excipients employing common and conventional techniques. Compositions in solid form

ES 2 256 331 T3 include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier can be at least one substance that can further act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, disaggregating agent for tablets, and encapsulating agent. Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, a low melting point wax, coconut butter, and the like. Compositions in liquid form include solutions, suspensions, and emulsions. For example, the compounds of the present invention can be dissolved in water, water-propylene glycol, or water-polyethylene glycol, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents. The oxazolidinone-, isoxazolin-, and isoxazolinone-substituted quinolones (I) can be used alone, or in conjunction with other antibacterial agents and / or non-antibacterial agents, as is known to those skilled in the art.

Pharmaceutically acceptable refers to those properties and / or substances that are acceptable from a pharmacological or toxicological point of view and from a physical or chemical point of view with respect to composition, formulation, stability, patient acceptance and bioavailability. Pharmaceutically acceptable hydrates means hydrates useful for the administration of the compounds of this invention, and suitable hydrates include compounds complexed with at least one molecule of water.

"Pharmaceutically acceptable salts" means salts useful for the administration of the compounds of the present invention. Suitable salts include acid addition salts when a basic group is present, as is the preferred piperazinyl group. Acid addition salts include those prepared from mineral acids, for example, hydrochloric, hydrobromic, hydroiodic, sulf , phosphoric, and the like, organic sulfonic acids, eg, methanesulfonic, 2-hydroxyethylsulfonates, organic carboxylic acids, for example , amino acids and carbohydrate acids, eg, gluconic, galacturonic, acetates, propionates, lactates, maleates, malates, succinates, tartrates, citric acid, fumarates, and the like. These salts can be in hydrated form.

"Pharmaceutically acceptable prodrugs" means prodrugs useful for the administration of the compounds of this invention. Suitable prodrugs include acid derivatives, eg, amides, esters, eg, methyl esters, ethyl esters, and the like. Those skilled in the art will also appreciate that the N-oxides of the nitrogens of the oxazolidinon-substituted quinolones (I) are included within the scope of the invention. These prodrugs can also be in hydrated form.

Compounds and pharmaceutical compositions suitable for use in the present invention include those in which the active ingredient is administered in an effective amount to achieve its intended purpose. More specifically, a "therapeutically effective amount" means an amount effective to prevent the development of, or alleviate existing symptoms of the treated subject. Determination of effective amounts is within the capabilities of those skilled in the art, especially in view of the detailed description provided herein.

A "therapeutically effective dose" refers to that amount of compound that results in the achievement of the desired effect. The toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, for the determination of LD.₅₀ (the lethal dose for 50% of the population) and the ED₅₀ (the lethal dose for 50% of the population). The relationship between the toxic and therapeutic effects of the dose is the therapeutic index, which is expressed as the relationship between the LD₅₀ and of₅₀. Compounds exhibiting high therapeutic indices are preferred. The data obtained from such data can be used in formulating a range of dosage for use in humans. The dosage of such compounds preferably falls within a range of circulating concentrations that includes ED.₅₀ with little or no toxicity. The dosage can vary within this range depending on the dosage form used, and the route of administration used.

Humans and other mammals, eg, cattle, horses, sheep, pigs, dogs, and cats, can be treated with the oxazolidinon-substituted quinolones (I) of the present invention. The quinolones (I) of the present invention can be administered in forms and dosages similar to those of the known antibacterial agents described above. In therapeutic use to treat, or combat, bacterial infections in humans and warm-blooded animals, the compounds of formula (I), or their pharmaceutical compositions, are administered by conventional techniques, such as orally in solid and liquid dosage forms and / or parenterally (iv, im, sc), in a unit dosage form to obtain and maintain a concentration, that is, an amount, or a plasma level of the active component in the animal undergoing treatment that is antibacterially effective or appropriate.

Generally, the amount of compound (I) in a pharmaceutical composition is from about 0.5% to about 90% by weight. An antibacterially effective dosage of compound (I) is from about 0.1 to about 100 mg / kg of body weight / day, more preferably from about 3 to about 50 mg / kg of body weight / day. The amount of the oxazolidinon-substituted quinolone compounds of formula (I) in the pharmaceutical composition, their exact unit dosage form to be administered, the frequency of administration, and the route of administration will vary, and can be widely adjusted depending on a series of factors known to those skilled in the art, including the particular mode of administration, the particular compound used, the potency of the particular compound, the desired concentration, the age, weight, sex, and general physical condition and requirements of the patient, the nature and severity of the bacterial infection treated, and the like,

ES 2 256 331 T3 as is known to the practitioner who treats infectious diseases. Furthermore, it should be understood that the initial dosage administered may be increased above the above upper level to rapidly achieve the desired plasma level, or the initial dosage may be less than optimal and the daily dosage may be progressively increased over the course of the procedure. treatment depending on the particular situation. Usual pharmaceutical dosage forms suitable for parenteral (mixture, suspension in oil) and oral (tablet, capsule, syrup, suspension, etc.) administration are known to those skilled in the art.

The compounds of the present invention can be administered by any suitable route, for example, by oral, topical, buccal, inhalation, sublingual, rectal, vaginal, transurethral, ​​nasal, percutaneous, i.e., transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, and intracoronary). Parenteral administration can be carried out using a needle and syringe, or using an elevated pressure technique, such as POWDERJECT ™.

If the compounds or pharmaceutical compositions of the present invention are administered parenterally, that is, by injection, for example by intravenous injection or by other parenteral routes of administration, it is generally in the form of a soluble salt (acid addition salt or basic salt ) of the compound according to formula (I) in a pharmaceutically acceptable amount dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water for injection; and a buffer to provide a suitable buffered isotonic solution, eg, with a pH of from about 3.5 to about 6.

Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L (+) - lysine and L (+) - arginine. A compound of formula (I) is generally dissolved in the vehicle in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about 1 to about 400 mg / ml of solution. The resulting liquid pharmaceutical composition is administered in such a way that the aforementioned antibacterially effective dosage amount is obtained.

For use in humans, a compound of formula (I) can be administered alone, but is generally administered in admixture with a pharmaceutical carrier selected considering the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use according to the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliary agents that facilitate the processing of compounds of formula (I) into preparations that can be used. pharmaceutically.

These pharmaceutical compositions can be prepared in a conventional manner, for example, by mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing procedures. The appropriate formulation depends on the chosen route of administration. When a therapeutically effective amount of a compound of the present invention is administered orally, the composition is usually in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the composition may additionally contain a solid carrier, such as gelatin or an adjuvant. The tablet, capsule, and powder contain from about 5% to about 95% of the compound of the present invention, and preferably from about 25% to about 90% of the compound of the present invention. When administered in liquid form, a liquid vehicle such as water, petroleum, or oils of animal or vegetable origin can be added. The liquid form of the composition may additionally contain physiological saline, dextrose or other solutions of saccharides, or glycols. When administered in liquid form, the composition contains from about 0.5% to about 90% by weight of a compound of the present invention, and preferably from about 1% to about 50% of a compound of the present invention.

When a therapeutically effective amount of a compound of the present invention is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, with respect to pH, isotonicity, stability, and the like, is within the skill of the art. A preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains, in addition to a compound of the present invention, an isotonic vehicle.

For oral administration, the compounds can be easily formulated by combining a compound of formula (I) with pharmaceutically acceptable carriers well known in the art. Such carriers allow the present compounds to be formulated into tablets, pills, lozenges, capsules, liquids, gels, syrups, mixtures, suspensions, and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by adding a compound of formula (I) to a solid carrier, optionally grinding the resulting mixture, and processing the mixture into granules, after adding suitable auxiliary agents, if desired, to obtain tablets or dragee nuclei. Suitable excipients include, for example, cellulose fillers and preparations. If desired, disaggregating agents can be added.

For administration by inhalation, the compounds of the present invention may be administered in the form of an aerosol spray presentation in pressurized containers or in a nebulizer, with the use of a suitable propellant. In the case of a pressurized aerosol, the dosage unit can be determined by supplying a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin, for use in

ES 2 256 331 T3 An inhaler or insufflator may be formulated containing a powdered mixture of the compound and a suitable powdered base such as lactose or starch.

The compounds can be formulated for parenteral administration by injection, eg, by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage forms, for example, in ampoules or in multidose containers, with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble forms. Additionally, suspensions of the active compounds can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds and allow the preparation of highly concentrated solutions. Alternatively, a composition of the present invention may be in powdered form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, prior to use.

The compounds of the present invention can also be formulated into rectal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases. In addition to the formulations previously described, the compounds can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example, in the form of an emulsion in an acceptable oil) or with ion exchange resins, or in the form of poorly soluble derivatives, for example, as a salt. slightly soluble.

For topical administration, the present compounds can be applied neat, for example, when the compound is a liquid. However, it is desirable to administer the compounds to the skin as compositions in combination with a dermatologically acceptable carrier, which can be a solid, a semi-solid, or a liquid. Useful solid carriers include, but are not limited to, finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like. Useful liquid carriers include, but are not limited to, water, alcohols, glycols, and water-alcohol / glycol mixtures in which the present compounds can be dissolved or dispersed to effective levels, optionally with the aid of a surfactant. Adjuvants, such as fragrances and additional antimicrobial agents, can be added to optimize properties for a given use. The resulting liquid compositions can be applied topically via absorbent pads, can be used to impregnate bandages and other dressings, or can be sprayed onto the affected area using aerosol or pump type sprays.

For veterinary use, a compound of formula (I) or a non-toxic salt thereof is administered in the form of a suitably acceptable formulation in accordance with normal veterinary practice. The veterinarian can easily determine the most appropriate dosage regimen and route of administration for a particular animal.

General procedures and definitions

The reagents were purchased from commercial sources and used without further purification. All temperatures are in degrees Celsius. When solvent pairs are used, the ratios of the solvents used are in volume / volume (v / v). When using the solubility of a solid in a solvent, the ratio of solid to solvent is weight / volume (w / v). Reactions with moisture-sensitive reagents were carried out under a nitrogen atmosphere. The concentration of the solutions was carried out by rotary evaporation under reduced pressure. Brine refers to a saturated aqueous sodium chloride mixture. High performance liquid chromatography (HPLC) analysis and purification were performed using a Beckman System Gold®; detection at 220 nm. Analytical HPLC was performed on a YMC 5 micron C18 (4.6 mm x 50 mm) reversed phase (RP) column (gradient from 100% 0.1% aqueous trifluoroacetic acid (TFA) to 100% 0.1% TFA in acetonitrile (MeCN) for 6 minutes, flow rate 2.0 ml / min). Preparative thin layer chromatography (TLC) was performed using EM 60 F silica gel (SG) plates (20 x 20.2 mm thick)₂₅₄. NMR refers to nuclear magnetic resonance spectroscopy. MRI¹H refers to proton nuclear magnetic resonance spectroscopy with chemical shifts reported in ppm downfield from tetramethylsilane. Mass spectrum (MS) refers to mass spectrometry expressed in the form of units of m / e or mass / charge and was obtained using the electron impact (EI) technique. The [M + H] + refers to the positive ion of a precursor plus a hydrogen atom. The retention time (R_t) is in minutes and refers to x. IR refers to infrared spectroscopy. FTIR refers to Fourier transform IR.

The following abbreviations are used in the following examples: millimole (mmol), milliliter (ml), potassium carbonate (K₂CO₃), ethyl acetate (EtOAc), DMSO (dimethylsulfoxide), magnesium sulfate (MgSO₄), sodium bicarbonate (NaHCO3), and ethyl alcohol (EtOH).

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Examples

The following examples describe how to prepare the various compounds and / or carry out the various procedures of the invention, and are to be construed as illustrative only, and not as limitations in any way on the preceding description. Those skilled in the art will recognize appropriate variations of procedures, both for reagents and for reaction conditions and techniques.

General procedure for the synthesis of quinolon-oxazolidinones linked to quinolon-7-yl and related analogs

A mixture of an oxazolidinone attached to an appropriate nucleophile, or an oxazolidinone precursor such as an amino alcohol (1-2 mmol) was stirred with an appropriate 7-substituted quinolone (preferably the 7-fluorine, 7-chloro, or 7- -triflate) (1 mmol) in N-methylpyrrolidin-2-one (NMP) (2 ml), N-methylmorpholine (NMM) (0.4 ml) and optionally, DMSO, as an additional cosolvent, at 110-130 ° C for 24-96 h (preferably, 24-48 h (hours) and 96 h for the reactions with 7-fluoro and 7-chloroquinolones, respectively). The mixture was cooled to room temperature, and most of the solvent was removed in vacuo. The residue was triturated with water (7 ml), precipitated, filtered, washed with excess water, THF (ca. 4 x 15 ml), ether, and dried in vacuo. Optionally, the resulting intermediate amino alcohol derivative was purified by crystallization from an appropriate solvent (eg, MeOH) or by silica gel column chromatography (eluent: dichloromethane-MeOH). The amino alcohol (1 mmol) was dissolved in an aprotic organic solvent (eg tetrahydrofuran (THF) or NMP) (2-5 ml), and carbonyldiimidazole (1.1 mmol) was added. Optionally an organic base (eg imidazole) (1.1 mmol) was added. The mixture was stirred at 2040 ° C for 1-3 h. The solvent was removed in vacuo, and the crude product was purified by crystallization from an appropriate solvent (eg, MeOH) or by silica gel column chromatography (eluent: dichloromethane-MeOH). Optionally, the carboxylic function is esterified under standard alcohol coupling conditions (eg, polyethylene glycol with diethyl cyanophosphate, 4-dimethylaminopyridine in NMP at 20-40 ° C for 4-8 h) to give an ester-derived prodrug.

Example 1

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Preparation of 7- [4 - [(5- (S) -acetamidomethyloxazolidin-2-on-3-yl) -2-fluorophenyl] piperazin-1-yl] -3-carboxy-1-cyclopropyl-6-fluoro-1 , 4-dihydroquinolin-4-one (Compound 3)

Compound 3 was prepared from 5- (S) -aminomethyl-3- (3-fluoro-4-piperazinophenyl) oxazolidin-2-one (0.372 g, 1.1 mmol) and 3-carboxy-1-cyclopropyl- 7-Chloro-6-fluoro-1,4-dihydroquinolin-4-one (0.282 g, 1 mmol) according to the General Procedure for the Synthesis of Quinolin-7-yl Linked Oxazolidinones. The reaction was carried out at 120 ° C for 96 h. Yield: 0.36 g (62%).

MS (m / z): 582 [M + H] +. R_t: 4.6 min.

Example 2

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Preparation of 10- [4 - [(5- (S) -acetamidomethyloxazolidin-2-on-3-yl) -2-fluorophenyl] piperazin-1-yl] -6-carboxy-9-fluoro2,3-dihydro-3 -methyl-7-oxo-7H-pyrido [1,2,3-de] -1,4-benzoxazine (Compound 6)

Compound 6 was prepared from 5- (S) -aminomethyl-3- (3-fluoro-4-piperazinophenyl) oxazolidin-2-one (0.372 g, 1.1 mmol) and 9,10-difluoro-2 acid , 3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de] -1,4-benzoxazine-6-carboxylic acid (0.281 g, 1 mmol) according to the General Procedure for the Synthesis of oxazolidinones linked to quinolin-7-yl. The reaction was carried out at 110 ° C for 24 h. Yield: 0.444 g (74%).

MS (m / z): 598 [M + H]⁺. Rt: 4.5 min. Separation of the enantiomers by chiral HPLC gives the isomer with the preferred (S) configuration.

ES 2 256 331 T3

Example 3

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Preparation of 7- [4 - {(5S) -5 - [(acetylamino) methyl] 2-oxo-1,3-oxazolidin-3-yl} -2-fluorophenyl} -1-cyclopropyl-6-fluoro-4 acid -oxo-1,4-dihydro-3-quinolinecarboxylic (Compound 11)

Benzyl 1-cyclopropyl-6-fluoro-4-oxo-7 {[(trifluoromethyl) -sulfonyl] oxy} -1,4-dihydro-3-uinolinecarboxylate (Compound 7a)

A suspension of 1-cyclopropyl-6-fluoro-4-oxo-7-hydroxy-1,4-dihydro-3-quinolinecarboxylate (1.51 g, 5.75 mol), prepared as described in Kiely, JS; Laborde, E .; Lesheshki, LE; Busch, RA, J. Heterocyclic Chem. 1991, 28, 1581-1585, in dry pyridine (15 ml) cooled to 0 ° C and treated by syringe with trifluoromethanesulfonic anhydride (2.5 ml, 14.86 mol) . The resulting homogeneous amber solution was slowly warmed to room temperature and stirred for 24 hours. Benzyl alcohol (20 ml, 193.3 mol) was added, and the reaction was stirred at room temperature for 2 hours. After pouring the solution into 100 ml of water, the aqueous phase was extracted (3x) with CH₂Cl₂. The combined organic phases were dried (Na₂SW₄), filtered and evaporated. The crude product was chromatographed on a 40 g Biotage column. The column was conditioned and loaded with CH₂Cl₂ and eluted with 850 ml of CH₂Cl₂ and 800 ml of MeOH / CH₂Cl₂ at 5%. Fractions 7-13 (A) and Fractions 27-28 (B) (~ 45 ml sections) were combined and evaporated, but neither was pure. The impure fraction A contained benzyl alcohol, which was removed in a stream of nitrogen. The resulting solids were triturated with EtOAc, filtered and dried (lab vacuum, 55 ° C, 1 hour) to give Compound 7a as a white solid (36A) weighing 99.0 mg (3.5%). Another 67 mg of 7a was obtained from the filtrate. The impure fraction B was recrystallized from MeOH / CH₂Cl₂ and EtOAc. The solids (36B) were collected by suction filtration (lab vacuum, 55 ° C, 1 hour) to give Compound 7a as an off-white solid weighing 285 mg (10%). Another 235 mg of Compound 7a were obtained from the mother liquids. The ES-MS for these products did not provide useful information.

NMR (DMSO-de, TMS): δ 8.54 (s, 1H), 8.30 (d, J = 8 Hz, 1H), 8.04 (d, J = 12 Hz, 1H), 7, 49 (m, 2H), 7.427.33 (m, 3H), 5.29 (s, 2H), 3.69 (m, 1H), 1.26 (m, 2H), 1.11 (m, 2H ). MRI¹H of 36B was identical to that of 36A. TLC (from 36A and 36b): R_F = 0.67 (5% EtOAc / MeOH); UV visualization.

Preparation of tert-butyl [(5S) -3- (4-borono-3-fluorophenyl) -2-oxo-1,3-oxazlidin-5-yl] methylcarbamate (Compound 8) (4-bromo-3-fluorophenyl ) 2-methylpropyl carbamate

To a solution of 500 g (4.50 mol) of 3-fluoroaniline and 2 L of CH₂Cl₂ A solution of 473 g (3.42 mol, 0.76 equiv.) of K was added to a 12 L round bottom flask.₂CO₃ in 2 L of water. Isobutyl chloroformate (663 g, 4.86 mol, 1.08 equiv.) Was added with stirring through an addition funnel for 3 h to allow heating of the isotherm and keep the mixture under gentle reflux. The gas evolved vigorously near the end of the addition. The organic phase was sampled for gC analysis 1 hr after the addition was complete; less than 0.5% 3-fluoroaniline remained. The mixture was quenched by the addition of 72 ml of concentrated NH4OH. After stirring for 15 minutes, the pH of the mixture was neutralized by the addition of 120 ml of concentrated aqueous HCl. The phases were separated and the aqueous phase was extracted with 1.5 L of CH₂Cl₂. 987 g (3.45 mol, 0.77 equiv.) Of 1,3-dibromo-5,5-dimethylhydantoin and 2.5 L of water were added to the combined organic phases. The mixture was allowed to reach an isotherm at 39 ° C and was kept at that temperature by gentle heating for 2 hours. The reaction was estimated to be complete by HPLC analysis of the organic phase. The mixture was cooled to 32 ° C by the addition of 500 g of ice, and solids not soluble in any liquid phase (mainly hydantoins and partially brominated hydantoins) were removed by filtration. The filtered phases were separated, extracting the aqueous phase with 500 ml of CH2Cl2. The combined organic phases were added with rapid stirring to a solution of 410 g of Na₂SW₃ in 3 L of water. The phases were separated, extracting the aqueous phase with 3400 ml of CH₂Cl₂. The combined organic extracts were distilled on a rotary evaporator and replaced with heptane, maintaining a constant volume. The resulting thick suspension was cooled to 4 ° C for 2.5 h. The solids were collected by filtration, washed with heptane (2 x 750 ml) and air dried to give 1097 g (84%) of 2-methylpropyl (4-bromo-3-fluorophenyl) carbamate as a solid. white crystalline.

(5R) -3- (4-bromo-3-fluorophenyl) -5- (hydroxymethyl) -1,3-oxazolidin-2-one

A solution of 1056 g (3.64 mol) of 2-methylpropyl (4-bromo-3-fluorophenyl) carbamate in 6.65 L of THF cooled to -15 ° C in a 22 L round bottom flask was A solution of 428 g (4.55 mol, 1.25 equiv.) of lithium t-amylate was added to it over 10 minutes through an addition funnel, maintaining -15 ° C to -12 ° C. Separating the 5 L flask, a solution of 438 g (4.37 mol, 1.20 equiv.) Of (S) -3-chloro-1,2-propanediol in 1.75 L of THF was

ES 2 256 331 T3 cooled to -25 ° C and treated with a 20% solution of t-BuOK in THF (2645 ml, 4.29 mol, 1.18 equiv.) For 25 min, resulting in a suspension thick, but agitable. This was allowed to warm to 10 ° C for 75 min and then poured into a 22 L flask containing the carbamate solution. The resulting suspension was allowed to warm from -7 ° C to 7 ° C over 1.5 h, monitoring the progress of the reaction by HPLC. After completion (~ 2.5% each of the remaining 2-methylpropyl (4-bromo-3-fluorophenyl) carbamate and excess addition product) an inactivating solution composed of 1.05 L of AcOH and 3 , 5 L of water. The phases separated. The aqueous phase was re-extracted with 1 L THF, and the combined organic phases were washed with brine. Volatile compounds were removed, giving white solids moistened with acetic acid. This material was suspended in 1.6 L of EtOAc. Hexane (4 L) was added over 1 hr. The resulting suspension was cooled to 2 ° C for 1 h and filtered, yielding 916 g (87%) of (5R) -3- (4-bromo-3-fluorophenyl) -5- (hydroxymethyl) -1,3-oxazolidine -2-one in the form of coarse white crystals: TLC R_F = 0.008 (50% EtOAc / hexane); HPLC R_t = 2.55 min; mp 114-121 ° C; [to]_D = + 52.2 ° C = 1, MeOH;

NMR ¹H (DMSO) δ 7.49 (m, 2H), 7.15 (d, 1H, J = 8.5 Hz), 5.30 (bs, 1H), 4.54 (m, 1H), 3, 89 (t, 1H, J = 8.6 Hz), 3.67 (m, 1H), 3.50 (dd, 1H, J = 3.0, 11.8 Hz), 3.39 (dd, 1H , 3.8, 11.8 Hz);

NMR ¹³C (DMSO) δ 158.1 (s, Jcf = 241 Hz), 154.2 (s), 139.7 (s, Jcf = 10 Hz), 133.3 (d), 114.9 (d), 105.9 (d, Jcf = 29 Hz), 100.9 (s, Jcf = 21 Hz), 73.3 (d), 61.5 (t), 45.9 (t); Anal. calc. for C1 „H₉BrFNO3: C, 41.40; H, 3.13; N, 4.83; Br, 27.55; found: C, 41.11; H, 3.06; N, 4.83; Br, 26.97.

[(5R) -3- (4-bromo-3-fluorophenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl 3-nitrobenzenesulfonate

To a suspension of 907 g (3.13 mol) of (5R) -3- (4-bromo-3-fluorophenyl) -5- (hydroxymethyl) -1,3-oxazolidin-2-one in 4.5 L of CH₂Cl₂ 654 ml (4.69 mmol, 1.50 equiv.) of triethylamine was added to a 22 L round bottom flask. The mixture was cooled to 0 ° C, and a solution of 832 g (34.75 mol, 1.20 equiv.) Of m-nitrobenzenesulfonyl chloride in 2 L of CH2Cl2 was added, keeping the temperature below 6 ° C . The mixture was sampled for HPLC, and an additional 55 g of solid m-nitrobenzenesulfonyl chloride was added to complete the reaction. Hydrochloric acid (1 M, 4.5 L) was added to the suspension. The solids were collected by filtration and washed with water. The filtrate phases were separated, and the aqueous phase was extracted with 2 x 500 ml of CH2Cl2. The combined organic phases were concentrated and combined with the previously isolated solids, 2 L of CH2Cl2 and 2 L of methanol. This suspension was distilled on a rotary evaporator, keeping the volume at ~ 5 L by adding methanol. The solids were collected by filtration, washed with 1 L of MeOH, and air dried to give 1415 g (95%) of [(5R) -3- (4-bromo-3-fluorophenyl) - 3-nitrobenzenesulfonate. 2-oxo-1,3-oxazolidin-5-yl] methyl: TLC R_F = 0.15 (50% EtOAc / hexanes); HPLC R_t = 5.68 min; mp 153-156 ° C; [to]_D = -76.6 ° C c = 1, MeOH / CH₂Cl₂;

NMR ¹H (DMSO) δ 8.77 (d, 1H, J = 8.2 Hz), 8.71 (s, 1H), 8.52 (d, 1H, 7.9 Hz), 8.14 (t, 1H, J = 8.1 Hz), 7.85 (t, 1H, J = 8.5 Hz), 7.73 (dd, 1H, J = 2.3, 11.4 Hz), 7.40 ( d, 1H, J = 8.9 Hz), 5.12 (m, 1H), 4.68 (m, 2H), 4.28 (t, 1H, J = 9.4 Hz), 3.89 ( m, 1H);

NMR ¹³C (DMSO) δ 157.3 (s, Jcf = 242 Hz), 152.4 (s), 147.2 (s), 138.3 (s, Jcf = 10 Hz), 135.4 (s), 132.7 (d), 132.6 (d), 131.1 (d), 128.2 (d), 121.7 (d) 114.2 (d), 105.3 (d, Jcf = 29 Hz), 100.6 (s, Jcf = 20 Hz), 70.4 (t), 69.0, (d), 44.8 (t); Anal. calc. for CMnBrF ^ OvS: C, 40.44; H, 2.55; N, 5.89; Br, 16.81; found: C, 40.22; H, 2.45; N, 5.86; Br, 16.60.

Tert-Butyl [(5S) -3- (4-bromo-3-fluorophenyl) -2-oxo-1,3-oxazolidin-5-yl] methylcarbamate

In three fractions, the [(5R) -3- (4-bromo-3-fluorophenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl 3-nitrobenzenesulfonate (1400 g, 2.95 mol) in 15 ml / g of a mixture of NH solvents₄29% aqueous OH, MeCN, and MeOH in a ratio of 5: 2.5: 1 in an autoclave. The system was sealed and heated at 80 ° C for 3-4 h with stirring. After cooling, the mixtures were extracted three times each with CH2Cl2. The combined extracts were concentrated to give the crude amine as a solid. The solids were suspended in 8.5 L of CH2Cl2. Di-t-butyl dicarbonate (985 g, 4.42 mol, 1.5 equiv.) Was added as a solid over 15 min with vigorous gas evolution. The mixture was stirred at room temperature overnight, after which the reaction was estimated to be complete by TLC. Water (3 L) was added, and stirring was continued for 30 min. The mixture was filtered, washing the collected solids with additional CH2Cl2. The phases were separated from the filtrate. The organic phase was concentrated to a white solid, crude tert-butyl [(5S) -3- (4-bromo-3-fluorophenyl) -2-oxo-1,3-oxazolidin-5-yl] methylcarbamate. This was suspended in 3 L of EtOAc and heated to 70 ° C until dissolved. After cooling to room temperature, 3 L of hexane were added over 1 hr. The resulting suspension was cooled to 0 ° C. The solids were collected by filtration and washed with hexane to obtain 763 g of [(5S) -3- (4-bromo-3-fluorophenyl) -2-oxo-1,3-oxazolidin-5-yl] methylcarbamate of tert -butyl. A second seeding was obtained by concentrating the mother liquids to 1.2 L and cooling to 0 ° C, giving an additional 50 g (813 g total, 71%): TLC R_F = 0.31 (50% EtOAc / hexane); HPLC R_t = 5.02 min; mp 145-146 ° C; [to]_D = + 30.0 ° C c = 1, MeOH;

NMR ¹H (CDCl₃) δ 7.50 (m, 2H), 7.12 (d, 1H, 8.5 Hz), 5.04 (bs, 1H), 4.77 (m, 1H), 4.01 (t, 1H , J = 8.7 Hz), 3.84 (m, 1H), 3.53 (m, 2H), 1.40 (s, 9H);

NMR ¹³C (CDCl₃) δ 160.2 (s), 157.3 (s, Jcf = 242 Hz), 154.0 (s), 138.8 (s, Jcf = 9 Hz), 133.5 (d), 114.4 (d), 106.8 (d, J_CF = 28 Hz), 103.3 (s, J_CF = 21 Hz), 80.4 (s), 72.1 (d), 47.3 (t), 43.2 (t), 28.2 (c);

ES 2 256 331 T3

Anal. calc. for Ci₅Hi₈BrFN₂O4: C, 46.29; H, 4.66; N, 7.20; Br, 20.53; Found: C, 46.32, H, 4.57; N, 7.21, Br, 20.63.

Tert-Butyl [(5S) -3- (4-borono-3-fluorophenyl) -2-oxo-1,3-oxazolidin-5-yl] methylcarbamate (Compound 8)

To a solution of 2.00 g (5.14 mmol) of [(5S) -3- (4-bromo-3-fluorophenyl) -2-oxo-1,3-oxazolidin-5-yl] methylcarbamate of tert- butyl in 40 ml of THF was added 1.94 ml (1.49 g, 12.8 mmol, 2.50 equiv.) of N, N, N ', N'-tetramethylenediamine. The solution was cooled to -50 ° C, and 4.86 ml (5.45 mmol, 1.06 equiv.) Of a 1.12 M solution of ethyl magnesium bromide in THF was added via syringe. After 5 min, 4.06 ml (10.8 mmol, 2.10 equiv.) Of a 2.66 M solution of n-butyl lithium in hexane was added dropwise via syringe with vigorous stirring, maintaining the temperature. below 45 ° C. A thick suspension was produced, which was stirred for an additional 15 min. Trimethylborate (1.17 ml, 1.07 g, 10.3 mmol, 2.00 equiv.) Was added with a syringe. The mixture was allowed to warm to 20 ° C over 90 min. It was then poured into 25 ml of 4M hydrochloric acid and stirred for 15 min. The phases were separated and the aqueous phase was extracted with 20 ml of CH₂Cl₂ to complete removal of boronic acid. The combined organic extracts were dried (MgSO₄), filtered and concentrated to give crude Compound 8 as an oil.

7- [4 - ((5S) - {[(tert-butoxycarbonyl) amino] methyl} -2-oxo-1,3-oxazolidin-3-yl) -2-fluorophenyl] -1-cyclopropyl-6-fluoro- Benzyl 4oxo-1,4-dihydro-3-quinolinecarboxylate (Compound 9a)

A mixture of Compound 7a (369 mg, 0.76 mol) and Compound 8 (298 mg, 0.84 mol) in 1,2-dimethoxyitan (8 ml) was degassed and flushed several times with nitrogen. Palladium (II) dichlorobis (triphenylphosphine) (56.3 mg, 0.08 mol) and K₂HPO₄ 2M (0.77 ml, 1.54 mmol). The mixture was degassed and flushed several times with nitrogen and then heated at 90 ° C for 22 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure, and the residue was chromatographed on a 40 gram Biotage column. The column was conditioned with CH₂Cl₂/ EtOAc / heptane 3: 3: 4, charged with CH₂Cl₂ and eluted with 900 ml of CH₂Cl₂/ EtOAc / heptane 3: 3: 4 and 500 ml of EtOAc. Fractions 23-49 (~ 20 ml sections) were combined, evaporated and dried (high vacuum, room temperature, 1 hour) to give 257.1 mg (52%) of Compound 9a as a tan amorphous solid .

MS (ESI +) for C35H33F2N3O7 m / z 646.3 (M + H) +. NMR¹H (CDCIs, TMS); δ 8.64 (s, 1H), 8.24 (d, J = 13 Hz, 1H), 7.98 (d, J = 7 Hz, 1H), 7.71-7.61 (m, 2H) , 7.55-7.47 (m, 3H), 7.42-7.33 (m, 3H), 5.42 (s, 2H), 5.03 (m, 1H), 4.82 (m , 1H), 4.11 (m, 1H), 3.94 (m, 1H), 3.57 (m, 2H), 3.49 (m, 1H), 1.43 (s, 9H), 1 , 33 (m, 2H), 1.16 (m, 2H). TLC: R_F = 0.14 (80% EtoAc / hexane); UV viewing.

7- (4 - {(5S) -5 - {(acetylamino) methyl} -2-oxo-1,3-oxazolidin-3-yl} -2-fluorophenyl) -1-cyclopropyl-6-fluoro-4-oxo Benzyl -1,4-dihydro3-quinolinecarboxylate (Compound 10a)

A solution of Compound 9a (253 mg, 0.391 mol) in 5.2 ml of CH₂Cl₂ at 0 ° C it was treated by syringe with trifluoroacetic acid (2.6 ml, 33.7 mol). The resulting solution was stirred at 0 ° C for 30 minutes and at room temperature for 1.5 hours. After concentrating the reaction under reduced pressure, the residue was dried (high vacuum, room temperature, 2 hours) to give the trifluoroacetic acid salt as an amorphous amber solid (372 mg, above theoretical yield). The above salt was dissolved in 6.5 ml of pyridine at room temperature and treated with acetic anhydride (1.5 ml, 15.9 mol). After stirring at room temperature for 17 hours, the reaction was cooled to 0 ° C and quenched with 1.5 ml of MeOH. The reaction was stirred at 0 ° C for 10 minutes and at room temperature for 20 minutes. The solvent was removed under reduced pressure, and the crude product (863 mg) was chromatographed on a 40 gram Biotage column. The column was conditioned with EtOAc, loaded with EtOAc (plus a small amount of CH₂Cl₂) and eluted with 500 ml of EtOAc, 500 ml of MeOH / CH₂Cl₂ 2% and 500 ml of MeOH / CH₂Cl₂ at 5%. Slightly impure fractions 42-70 (~ 20 ml sections) were combined, evaporated (271 mg) and rechromatographed on an 8 gram Biotage column. The column was conditioned, loaded and eluted with MeOH / CH₂Cl₂ at 5%. Fractions 7-44 (approximately 7 ml sections) were combined, evaporated and dried (laboratory vacuum, room temperature, 16 hours) to generate 218.5 mg (95%) of Compound 10a as a beige solid.

MS (ESI +) for C32H27F2N3O6 m / z 588.2 (M + H) +. NMR¹H (CDCIs, +2 CD3OD drops, TMS): δ 8.70 (s, 1H), 8.17 (d, J = 10 Hz, 1H), 8.03 (m, 1H), 7.60 ( m, 1H), 7.50-7.46 (m, 3H), 7.41-7.31 (m, 4H), 5.41 (s, 2H), 4.83 (m, 1H), 4 , 11 (t, J = 9Hz, 1H), 3.86 (m, 1H), 3.66 (m, 2H), 3.54 (m, 1H), 2.03 (s, 3H), 1 , 36 (m, 2H), 1.18 (m, 2H). TLC: R_F = 0.28 (MeOH / CH₂Cl₂ 5%); UV visualization.

7- (4 - {(5S) -5 - [(acetylamino) methyl] -2-oxo-1,3-oxazolidin-3-yl} -2-fluorophenyl) -1-cyclopropyl-6-fluoro-4- acid oxo-1,4-dihydro-3-quinolinecarboxylic (Compound 11)

A solution of Compound 10a (215 mg, 0.365 mol) in neat ethanol was treated with 30 mg of 10% Pd / C. The mixture was placed in a hydrogenator at room temperature and 275.8 kPa (40 psi) of H₂ during 3 hours. Since TLC analysis indicated the presence of starting material, an additional 30 mg of catalyst was added and the reaction was returned to the hydrogenator at 275.8 kPa (40 psi) H₂ for 16 hours. After removing the catalyst by filtration through a Celite pad and washing the filter cake with neat ethanol, the filtrates were combined and concentrated leaving a yellowish black residue (160 mg). The residue was subjected to chromatography

ES 2 256 331 T3 on an 8 gram Biotage column. The column was conditioned, loaded and eluted with MeOH / CH₂Cl₂ 5%, but only mixed fractions were obtained. The fractions containing the desired product were combined and concentrated leaving a solid which was crystallized from EtOAc / heptane. TLC analysis of the solids (22 mg) revealed that crystallization did not improve the product. Therefore, the solids and mother liquids were dissolved in a minimal amount of MeOH / CH₂Cl₂ and loaded onto two 500 pm pre-TLC plates. After eluting with MeOH / CH₂Cl₂ at 5%, the plates were eluted a second time with MeOH / CH₂Cl₂ 5% + 0.5% AcOH. The separation was not perfect, but a clean sample of the desired band was isolated giving 21.8 mg (12%) of Compound 11 as a golden solid. This product decomposed at 120 ° C.

MS (ESI +) for C₂₅H_2yesF₂N₃OR₆ m / z 498.2 (M + H)⁺. High Resolution MS (FAB): Calculated for C₂₅H₂iF₂N₃OR₆ + H, 498.1476; found, 498.1476.

CLIHC NMR, +1 drop of CD3OD, TMS): δ 8.890 (s, 1H), 8.24 (d, J = 13 Hz, 1H), 8.16 (d, J = 8 Hz, 1H), 7.66 ( m, 1H), 7.52 (m, 1H), 7.38 (m, 1H), 4.86 (m, 1H), 4.14 (m, 1H), 3.89 (m, 1H), 3.70-3.61 (m, 3H), 2.05 (s, 3H), 1.41 (m, 2H), 1.25 (m, 2H). TLC: R_F = 0.22 (MeOH / CH₂Cl₂ 5% + 1% AcOH); UV visualization.

As shown in Table 1, the compounds of Examples 1, 2 and 3 demonstrated potent antibacterial activity.

TABLE 1

Antibacterial Activity of Selected Examples

<td rowspan="2">Ex n °</td><td colspan="6">MIC (ug / ml)</td>

<td>E. faecalis UC9217</td><td>S. aureus UC9218</td><td>S. pneumoniae UC9912</td><td>H. influenzae UC30063</td><td>M. catarrhalis UC30607</td><td>E. coli UC6674</td>

<td> 1</td><td> 0,25</td><td> 0,5</td><td> 0,125</td><td> 8</td><td> 1</td><td> 16</td>

<td> 2</td><td> 0,5</td><td> 1</td><td> 0,25</td><td> 4</td><td> 2</td><td> 16</td>

<td> 3</td><td> 8</td><td> 2</td><td> 4</td><td> 0,5</td><td> 4</td><td> 4</td>

The compounds of the invention can be used for the treatment or prevention of infectious disorders caused by a variety of bacterial organisms. Examples include gram-positive and gram-negative aerobic bacteria and anaerobic bacteria, including Staphylococci, eg, S. aureus; Enterococci, for example, E.faecalis; Streptococci, for example S. pneumoniae; Haemophilis, for example, H. influenza; Moraxella, for example, M. catarrhalis; and Escherichia, for example, E. coli. Other examples include Mycobacteria, eg, M. tuberculosis; intracellular microbes, eg, Chlamydia and Rickettsiae; and Mycoplasma, for example, M. pneumoniae.