MXPA97003543A - Antibacterials of oxazine biciclica yoxazolidinona tiaz - Google Patents

Abstract

The present invention relates to a compound of structural formula I: or a pharmaceutically acceptable salt thereof, wherein: X is (a) O, (b) S, (c) SO, (d) SO 2; R 1 is independently H, F, Cl or OMe, R 2 is (a) hydrogen, (b) C 1 -C 8 alkyl optionally substituted, (c) C 3 -C 6 cycloalkyl, (d) amino, (e) C 1 -C 8 alkylamino, ( f) C 1 -C 8 dialkylamino, (g) C 1 -C 8 alkoxy, a is from 0 to 3, b is from 0 to 2, c is from 0 to 2, (b and c can not be both O); 0 to 2, and e is from 0 to 2 (d and e can not be both

Description

ANTIBACTERIALS OF OXAZINE BICICLICA AND OXAZOLIDINONA TIAZINA BACKGROUND OF THE INVENTION The present invention describes novel and useful phenyloxazolidinone compounds that have either a pyrrolidinyl or azetidylin moiety. The compounds are useful antimicrobial agents effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as staphylococci, streptococci and enterococci, resistant to multiple drugs, as well as to anaerobic organisms, such as the bateroid species spp. , and clostridia spp. , and acid resistant organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Micobacterium spp. i Description of the Information The compounds of the present invention are related by their structure to the phenyloxazolidinone ring with the compounds described in the publications mentioned below, except that the compounds of the present invention have a multiple substituted pyrrolidinyl or azetidinyl moiety. The compounds of the present invention are unique and have a useful antibacterial activity. U.S. Patent Application PCT / US94 / 08904 discloses oxazolidinone antibacterial compounds having either morpholine or thiomorpholine substituents.

US Patent Application PCT / US93 / 03570 describes oxazolidinones containing a portion of substituted diazine and their uses as antimicrobials. U.S. Patent Application PCT / US92 / 08267 discloses oxazolidinones with aryl and substituted phenyl heteroaryl, useful as antibacterial agents. US Patent Application PCT / US89 / 03548 discloses the 5-indolinyl-5β-amidomethyl-oxazolidinones, 3-phenyl (substituted fused anyl) -5β-amidomenyloxazolidinones, and 3-substituted phenyl-substituted nitrogen) -5β-amidomethyl-oxazolidinones, which are useful as agents antibacterials Other references describing various oxazolidinones include U.S. Patent 4,801, 600; 4,921, 869. The article by W.A. Gregory and Associates, in J. Med. Chem., 32, Pags. 1673-1681, (1989); the article by W.A. Gregory and associates, in J. Med. Che., 33, Pags. 2569-2578, (1990); the article by C. Wang, and Associates, in Tetrahedron, 45, Pags. 1323-1326, (1989); and Brittelli's article, in J. Med. Chem., 35, Pags. 1 156, (1992). European Patent Publication 352,781, describes phenyl oxazolidinones with phenyl and substituted pyridyl. European Patent Publication 316,594, describes oxazolidinones with substituted styryls. European Patent Publication 312,000, describes phenyl oxazolidinones, with phenyl, methyl and substituted pyridinylmethyl.

SUMMARY OF THE INVENTION In one aspect, the present invention is a compound of Structural Formula I: Formula I The most preferred compounds, a subset of those described by structural Formula I, are represented by Structural Formula II Formula II or the pharmaceutically acceptable salts thereof wherein: X is (a) O, (b) S, (c) SO, (d) SO 2; R1 is independently H, F, Cl or OMe; R2 is (a) hydrogen, (b) Ci-Cg alkyl optionally substituted with one O more of the following: F, Cl, hydroxyl, Ci-Cg alkoxy, Cl-Cg acyloxy, (c) C- cycloalkyl Cg, (d) amino, (e) Ci-Cg alkylamino, (f) dialkylamino of Cj-Cg (g) Ci-Cg alkoxy; a is from 0 to 3; b is from O to 2; c is from 0 to 2 (b and c can not be both 0); d is from O to 2; and e is from O to 2 (d and e can not be both O). In another aspect, the present invention is directly focused on a method for the treatment of microbial infections in humans or other warm-blooded animals by means of administering to a patient, in need of such treatment, an effective amount of a compound of the invention. Formula I or II, as described above. The compound can be administered in a pharmaceutical composition either by the oral, parenteral or topical route. Preferably the compound is administered in an amount of from about 0. 1 to about 100 mg / kg body weight / day, more preferably, from 3.0 to 50 mg / kg body weight / day.

DETAILED DESCRIPTION OF THE INVENTION The present invention describes substituted oxazinyl-bicyclic or new thiazinylphenyloxazolidinones of structural Formula I and II as described above. The compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, particularly gram-positive aerobic bacteria, including staphylococci and streptococci resistant to multiple drugs, as well as to anaerobic organisms such as bacteroides and clostridia species, and bacteria. acid resistant such as Mycobacterium tuberculosis and other mycobacterial species. The term "Alkyl" means chains of carbon atoms having a designated amount of carbon atoms, which may be either straight or branched chain. The term "Alkoxy" means, the designated amount of carbon atoms, adhered to an oxygen former, in groups such as methoxy (-OCH 3), ethyloxy, butyloxy, etc. , and the isomeric forms thereof. The term "Acyloxy" means, the designated amount of carbon atoms to form an organic acid where the OH group has been removed, such as acetyl, CO-CH3; Benzoyl, CO-C6H5. The term "Cycloalkyl" means the designated amount of carbon atoms that form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. , and the isomeric forms thereof. The term "Amino" means an NH2- "alkylamino" is where one of the hydrogen positions is replaced by an alkyl and "dialkylamino" is where both hydrogens are replaced by an alkyl group. The term "pharmaceutically acceptable salts" means the acid addition salts, which can be prepared by any of the means recognized in the art. Generally, the acid addition salts include hydrochloride, hydrobromide, hydrobromide, iodohydrate, sulfate, phosphate, acetate, propionate, lactate, malate, succinate, tartrate, cyclohexanesulfamates, methanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, fumarates and other pharmaceutically acceptable counterions for the amines.

Preferably X is S. The substituents R 1 are preferably fluorine both and, more preferably, fluorine and hydrogen. The substituent R ^ is preferably hydrogen, methyl, dichloromethyl, hydroxymethyl or methoxy. More preferably R2 is hydrogen, methoxy or methyl. It is still more preferred that the R2 substituent be methyl. The preferred absolute configuration of the C-5 position of the oxazolidinone ring of the compounds claimed in the present invention is as represented by the structures of Formulas I and II. This absolute configuration is called (S), under the Cahn-Ingold-Prelog nomenclature system. This is the (S) enantiomer, which is pharmacologically active. The racemic mixture is also useful and for the same purpose as the pure (S) enantiomer; the difference is that double the racemic material should be used to produce the same antibacterial effect. Those skilled in the art will appreciate that when an additional chiral center (s) is present in the bicyclic oxazine or thiazine fragment of the compounds of structural Formula I and II, then, diastereomers are possible. These diastereomers, in the racemic and enantiomerically enriched forms, are also within the scope of the compounds of Formula I and II of the present invention. Preferred compounds of the present invention are: (S) -N - [[3- [3-fluoro-4 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2. 1] heptan-5-yl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (Example 1); (S) -N - [[3- [3-fluoro-4 - [(lS, 4S), -2-thia-5-azabicyclo [2.2. 1] heptan-5-yl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (Example 2); (S) -N - [[3- [3-fluoro-4- [l S, 4S) -2-thia-2,2-dioxo-5-azabicyclo [2.2. l] heptan-5-yl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (Example 3); (S) -N - [[3- [3-fluoro-4- (tetrahydro-H-thieno [3,4-c] pyrrol-5- (3H) -yl) phenyl] -2-oxo-5- oxazolidinyl] methyl] acetamide (Example 4); (S) -N - [[3- [3-fluoro-4- (tetrahydro-H-thieno (3,4-c] pyrrol-5- (3H) -yl) phenyl] -2-oxo-5 -oxazolidinyl] methyl] acetamide, oxide-S (Example 5); (S) -N - [[3- [3-fluoro-4- (tetrahydro-H-thieno [3,4-c] pyrrol-5- (3H) -yl) phenyl] -2-oxo-5- oxazolidinyl] methyl] acetamide, dioxide-S, S (Example 6); cis- (S) -N - [[3- [3-fluoro-4- [3-oxa-7-azabicyclo [3.3.0] octane-7-yl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] acetamide (Example 7); (S) -N - [[3- [3-fluoro-4 - [(1 R, 4R) -2-thia-5-azabicyclo [2.2. 1] heptane-5-yl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide; (S) -N - [[3- [3-fluoro-4- (2-thia-6-azabicyclo [3.2.0] heptan-6-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide; (S) -N - [[3- [3-fluoro-4- (3-thia-6-azabicyclo [3.2.0] heptane-6-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide; (S) -N - [[3- [3-fluoro-4 (3-thia-7-azabicyclo [3-3- l] nonan-7-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide; (S) -N - [[3- [3-fluoro-4- (3-thia-9-azabicyclo [3-3- l] nonan-9-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl ] acetamide; (S) -N - [[3- [3-fluoro-4- (2-thia-6-azabicyclo [3.2.1] octan-6-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide; (S) -N - [(3- [3-fluoro-4- (2-thia-6-azabicynic [3.3.1] nonan-6-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide; (S) -N - [[3- [3-fluoro-4- (7-thia-3-azabicyclo [4.2.1] nonan-3-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide; (S) -N - [[3- [3-fluoro-4- (9-thia-3-azabicyl [3.3.1] nonan-3-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl ] acetamide; (S) -N - [[3- [3-fluoro-4- (3-oxa-6-azabicyclo [3.2.0] heptan-6-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide; (S) -N - [[3- [3-fluoro-4- (6-oxa-3-azabicyclo [3.,1.1] heptan-3-yl) phenyl] -2-oxo-5 -oxazolidinyl] methyl] acetamide; (S) -N - [[3- [3-fluoro-4- (3-oxa-7-azabicyclo [3.3.1] nonan-7-yl) phenyl] -2-oxo- 5-oxazolidinyl] methyl] acetamide; (S) -N - [[3- [3-fluoro-4- (3-oxa-9-azabicyclo [3.3.1] nonan-9-yl) phenyl] -2-oxo -5-oxazolidinyl] methyl] acetamide; (S) -N - ([3- [3-fluoro-4- (9-oxa-3-azabicyclo (3.3.1.1] nonan-3-yl) phenyl] -2 -oxo-5-oxazolidinyl] methyl] acetamide; (S) -N - [[3- [3-fluoro-4- (2-oxa-5-azabicyclo [2.2.2] octan-5-yl) -phenyl] -2-oxo-5-oxazolidinyl) methyl] acetamide; (S) -N - [[3- [3-fluoro-4- (2-oxa- 5-azabicyclo [3.2. 1] octan-6-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (S) -N - [[3- [3-fluoro-4- (3-oxo-7-azabicyclo [4.2. 0] octan-7-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide; (S) -N - [[3- [3-fluoro-4- (3-oxa-8-azabicyclo (3.2.1] octan-8-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide; (S) -N - [[3- [3-fluoro-4- (6-oxa-2-azabicyclo [3-2- l] octan-2-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide; (S) -N - [[3- [3-fluoro-4- (8-oxa-3-azabicyclo [3.2.1] octan-3-yl) phenyl] -2-oxo-5-oxazolidinyl ] methyl] acetamide; and (S) -N - [[3- (3-fluoro-4 - [(1 F, 4R) -2-oxa-5-azabicyclo (2.2.1) he? tan-5-iIo ] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide.

The most preferred compounds are: (S) -N - [[3- [3-fluoro-4 - [(1S, 4S) -2-thia-5-azabicyclo [2.2. 1] heptan-5-yl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (Example 2). (S) -N - [[3- [3-fluoro-4- (tetrahydro-H-thieno [3,4-c]? Irrol-5 (3H) -yl) phenyl] -2-oxo-5- oxazolidinyl] methyl] acetamide (Example 4). (S) -N - [[3- [3-fluoro-4- (tetrahydro-H-thieno [3,4-c] pyrrol-5- (3H) -yl) phenyl] -2-oxo-5- oxazolidinyl] methyl] acetamide, dioxide-S, S (Example 6).

The pharmaceutical compositions of the present invention can be prepared by means of the combination of the compounds of Formula I or II of the present invention, with a solid or liquid pharmaceutically acceptable carrier, optionally, with pharmaceutically acceptable adjuvants and excipients, employing standard techniques. and conventional. The solid form compositions include powders, tablets, dispersible granules, capsules, lozenges and suppositories. A solid carrier may be at least one substance which may also have a function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, linker, tablet disintegrating agent, and encapsulating agent. Inert solid carriers include, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like. The compositions in liquid form include solutions, suspensions and emulsions. For example, solutions of the compounds of the present invention, dissolved in water and a mixture of propylene glycol-water and polyethylene glycol-water systems, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and agents, can be produced. thickeners. Preferably, the pharmaceutical composition is produced employing conventional techniques in unit dosage forms, which contain an appropriate or effective amount of the active component, that is, the compound of Formula I according to the present invention. The amount of active component, which is the compound of Formula I or II, according to the present invention, in the pharmaceutical composition and the unit dosage form thereof, may vary or be adjusted broadly depending on the particular application , the potency of the particular compound, the desired concentration. Generally, the amount of active component will be in the range of from 0.5% to 90% by weight of the composition. In the therapeutic use for treatment, or to combat bacterial infections in warm-blooded animals, the compounds or pharmaceutical compositions thereof, can be administered orally and / or parentally in a dosage to obtain and maintain a concentration, that is, an amount, or level, of the active component in the blood of the animal under treatment, which may be effective in combating the bacteria. Generally, said amount effective to combat the bacteria of the dosage of the active component may be in the range of from about 0. 1 to about 100, more preferably from about 3.0 to about 50 mg / kg of body weight. day. It should be understood that the dosages may vary depending on the requirements of the patient, the severity of the bacterial infection being treated, and the particular compound being used. Also, it should be understood that the initial dose administered may be increased beyond the upper level, in order to quickly achieve the level in the desired blood, or the initial dose may be smaller than optimal and the daily dosage may be be progressively increased during the course of treatment, depending on the particular situation. If desired, the daily dose can also be divided into multiple doses of application, for example, two to four times a day. The compounds of Formula I or II, according to the present invention, are administered parentally, for example, by injection, for example, by intravenous injection or by other routes of parenteral administration. Pharmaceutical compositions for parenteral administration, will generally contain a pharmaceutically acceptable amount of compound according to Formula I or II, in the form of a soluble salt (Acid addition salt or base salt), dissolved in a pharmaceutically acceptable liquid carrier, such as, for example, water for injection and a regulator for providing a properly regulated isotonic solution, for example having a pH of about 3 to 7. Suitable regulating agents include, for example, trisodium orthophosphate, sodium bicarbonate, citrate of sodium, N-methylglucamine, L (+) lysine, and L (+) arginine, to mention only a few of the representative regulatory agents. The compound according to Formula I will generally be dissolved in the carrier or vehicle in an amount sufficient to produce a pharmaceutically acceptable concentration, within the range of from about 1 mg / ml to about 400 mg / ml of solution. The resulting liquid pharmaceutical composition will be administered so that the effective dosage amount can be obtained to combat the aforementioned bacteria. The preferred method for the preparation of the oxazolidinones of Formula I and II in the enantiomerically pure form, is illustrated in Graphs I through IV. As shown in Figure I, bicyclic oxazines and thiazines (commercially available or known in the literature), such as (1S, 4S) -2-oxa-5-azabicyclo [2.2. 1] heptane (X-0) and (l S, 4S) -2-thia-5-azabicyclo [2.2. The heptane (X = S) of the structure of compound 1, are reactivated with a functionalized nitrobenzene of compound 2 (Y-halogen or trifluoromethanesulfonate) in the presence of a suitable base such as N, N-diisopropylethylamino and in a suitable solvent such as acetonitrile, tetrahydrofuran (THF), or ethyl acetate at a temperature from room temperature to the reflux temperature to produce the adducts of compound 3. When X-O, the nitro group of compound 3, is then reduced by hydrogenation catalytic in the presence of a suitable catalyst, such as 10% palladium on carbon or Raney W-2 nickel, and in a suitable solvent such as ethyl acetate, tetrahydrofuran, aqueous tetrahydrofuran, methanol and mixtures thereof, to produce the Anilines of compound 4. In the case where X-S, the nitro group of compound 3, can be reduced by the action of sodium hydrosulfite in aqueous tetrahydrofuran, from room temperature to 55qC to produce the anilines of the compound 4. Alternatively, the reduction of the nitro group of the compound 3 (X = S) can be carried out by catalytic hydrogenation in the presence of a suitable catalyst, such as a platinum on sulfide carbon or nickel Raney W-2, and in a suitable solvent system, for example, aqueous tetrahydrofuran. The latter conditions are especially useful for the reaction mixture to be simply filtered through Celite ® or the like, to remove the catalyst and filtrate containing the aniline of compound 4, which is used directly in the next step: For this purpose , the anilines of compound 4 are converted into their benzylic carbamate derivatives (R-3 and CH2PI1) or methyl (R-3 «CH3 of compound 5, using standard Schotten-Baumann conditions or other variations known to those skilled in the art. The urethanes of compound 5 are then deprotonated with a suitable base, such as butyllithium-n, lithium diisopropylamide, or bis (trimethylsilyl) lithium amide, in a suitable solvent such as tetrahydrofuran or N, N-dimethylformamide and at a temperature suitable as in the range of -78 ° C to -60 ° C to produce the lithiated intermediate, which is then treated with butyrate (-) - (R) -glycidyl available on the market. environment, then produces the 5- (hydroxymethyl) oxazolidinones of compound 6, in the enantiomerically enriched form. Compound 6 is then converted to the corresponding mesylate of compound 7 (R ^ = methanesulfonyl) or aryl sulfonate of compound 7 (R4 = ArS02, for example p-toluenesulfonyl) by the action of for example, methanesulfonyl chloride / pyridine or methanesulfonyl chloride / triethylamino / dichloromethane or p-toluenesulfonyl chloride / pyridine. As illustrated in Figure II, the sulfonate derivative resulting from compound 7 is then reactivated with an azide source, such as sodium or potassium azide in an aprotic solvent such as N, N-dimethylformamide (DMF), ol- methyl-2-pyrrolidinone, optionally in the presence of a catalyst such as 18-crown-6, at a temperature between 50 and 90 ° C to produce the azide of compound 8. The azide is then reduced by hydrogenation with palladium on carbon or a platinum catalyst, in a suitable solvent, such as ethyl acetate or methanol, to produce the corresponding amine of compound 9. Alternatively, and preferably in the case where X = S, the azide can be reduced by treatment with a compound of trivalent phosphorus, such as triphenylphosphine in a suitable solvent such as tetrahydrofuran, followed by the addition of water. Alternatively, the mesylate or aryl sulfonate group of the compoundscan be displaced with potassium phalimide in acetonitrile at reflux temperature to produce the intermediate phthalimide of compound 10. The phthalimide of compound 10 is then deprotected by treatment with aqueous methyl amine in refluxing ethanol to produce the amine of compound 9. in another alternative, the mesylate of compound 7 is reactivated with ammonium hydride in hot isopropanol and isopropanol / tetrahydrofuran, preferably in a sealed reaction vessel, to directly produce the amine of compound 9. The amine of compound 9, then is acylated by reactions known to those skilled in the art, to produce oxazolidinones of structure 1 1. For example, the amine can be reactivated with an acid chloride or anhydride in a basic solvent, such as pyridine at a temperature within the range of -30 to 30 ° C to produce the acylated compound 1 1 (R2 = optionally substituted alkyl). Those skilled in the art will appreciate that other acyl groups within the scope of the present invention can be readily attached to the amine of compound 9, by means of standard acylation techniques, for example those described by J. March, in "Advanced Organic Chemistry. ", 4a. edition; John Wiley 8B Sons: New York, 1992; p. 417 to 425, to provide additional examples of compound 1 1. The compounds of structure 1 1, represent examples of bicyclic oxazine antibacterial agents and substituted thiazine oxazolidinones of Formula II, which are subject of the present invention. As shown in Figure III, the oxazolidinones of compound 11 are themselves examples of antibacterial agents of Formula II, and can be further elaborated to formulate further additional compounds of Formula II. Specifically, compound 1 1 (X = S) can be oxidized to the corresponding sulfoxide (s) 12 (X = • SO) with sodium metaperiodate in a mixture of water and methanol. Those skilled in the art will appreciate that both endo and exo sulfoxides are possible, and both isomeric forms, as well as mixtures thereof, are within the scope of the present invention. In addition, compounds 1 1 and 12 can be oxidized to corresponding sulfones of compound 13 (X-SO 2) by treatment with 4-methylmorpholine N-oxide and osmium catalytic tetraoxide in aqueous acetone. Those skilled in the art will appreciate that alternative conditions are known for the oxidation of compound 1 1 (X = S) to obtain compound 12 or 13, for example those described by J. March, in "Advanced Organic Chemistry", 4 edition; John Wiley ds Sons: New York, 1992; p. 1201 to 1202. As shown in Figure IV, the synthesis of compounds incorporating a thienopyrrolidine begins with the reduction of the diester of compound 14 to the diol of compound 15, using lithium aluminum hydride as a reducing agent. Compound 15 is then converted to the bis-mesylate of compound 16 by reaction with methanesulfonyl chloride and a trialkylamine base. Cycling compound 16 to the thienopyrrolidine of compound 17 is carried out by the reaction with sodium sulfide, and compound 17 is debenzylated to thienopyrrole of compound 18 by reaction with hydrogen in the presence of a suitable catalyst such as palladium on carbon. The compound of Example 4 is then prepared from compound 18 following the procedures outlined in Figures I and II (but substituting compound 18 for compound 1). The compounds of Examples 5 and 6 are prepared by oxidation of the compound of Example 4, using the same procedures as illustrated in Figure III.

The antimicrobial activity was tested in vivo, using a Murine Assay procedure. Groups of female mice were injected intraperitoneally with bacteria, which were applied only before use and suspended in a brain heart infusion with a 4% Brewer's fungus UC9213 (Staphylococcus aureus), brain ear infusion (Streptococcus species). The treatment of six levels per drug was administered in 1 hour and 5 hours after infection, either orally or subcutaneously. Survival was observed daily for 6 days. The ED50 values based on the mortality proportions were calculated using probit analysis. The compounds of the present invention were compared against a well-known antimicrobial (Vancomycin) as a control. The data are illustrated in Table 1.

TABLE I In vivo activity against S. Aureus UC® 92 13 Those skilled in the art will appreciate that the synthetic procedures described are solely representative in nature, and that the use of the alternative bicyclic oxazines and thiazines known in the patent and the open literature allows the preparation of additional examples of Structural Formula I.

EXAMPLE 1: (Si-N-ff3-f4-f (lS.4Si-2-oxa-5-azabicyclo1.2.2Hheptan-5-ylol-3-fluorophenyl-2-oxo-5-oxazolidinyl-methylketamide Step 1: 4 - [(lS.4S) -2-oxa-5-azabicyclo [2.2.1 | heptan-5-yl] -3-fluoronitrobenzene A mixture of hydrochloride (lS, 4S) -2-oxa-5-azabicyl [2.2 Commercially available ljheptane (0.200 g, 1.47 mmol), dipotassium hydrogen phosphate (1.030 g, 5.90 mmol) and 3,4-difluoronitrobenzene (0.194 mL, 1.77 mmol) in dimethyl sulfoxide (6 mL) was stirred at room temperature under N atmosphere TLC analysis (5% MeOH / CDCl 3) after 3 hours revealed that the starting nitrobenzene was consumed The reaction mixture was diluted with H 2 O and (60 mL) and extracted with CHCl 3 The combined organic extracts were washed with H 2 O and brine, dried over Na 2 S 4, filtered and concentrated under reduced pressure to yield a yellow solid, chromatography on silica gel (60 g), eluting with a gradient of 0 2% MeOH / CHC13, produced, after s of the appropriate concentration of fractions, 0.314 g (90%) of the titled compound in the form of a yellow solid with melting point 106.5-108 ° C and MS (EI) 238 (M +).

Step 2: N- (carbobenzyloxy) -4 - [(lS, 4S) -2-oxa-5-azabicyclo [2.2. l.jheptan-5-yl) -3-fluoroaniline A solution of 4 - [(lS, 4S) -2-oxa-5-azabicyclo [2.2. l] heptan-5-yl] -3-fluoronitrobenzene (0.160 g, 0.672 mmol) in 3: 1 THF / H2? (4 mL), was treated with acetic acid (0.115 mL) and then palladium / 10% carbon ( 0.020 g) under a stream of N2- The atmosphere was replaced with H (balloon) by evacuation and repeated filling and the mixture was stirred at room temperature. After 2 hours, TLC analysis (6% CH3CH / CHCl3), revealed that the reduction was complete. The reaction mixture was filtered through Celite (^), and filtered immediately, placed under an N2 atmosphere and treated with K2CO3 (0.464 g, 3.36 mmol), followed by benzyl chloroformate (0.117 mL, 0.864 mmol). TLC analysis (6% CH3CN / CHCl3), after 0.5 hours revealed that the reaction was complete. The reaction mixture was concentrated under reduced pressure and subjected to chromatography on silica gel (20 g), eluting with a gradient of 1-5% CH3CN / CHCl3. Concentration of the appropriate fractions yielded 0.226 g (98%) of the title compound in the form of a white solid with a melting point of 120-121 ° C and MS (EI) 342 (M +).

Step 3:, Rl-f3-f4-f (lS.4S) -2-oxa-5-azabicicof2.2.11heptan-5-yl] -3-fluorophenyl-2-oxo-5-o-azolidinyl-methanol A solution of N- (carbobenzyloxy) -4 - [(lS, 4S) -2-oxa-5-azabicyclo [2.2. 1] heptan-5-yloxy-3-fluoroaniline (0.169 g, 0.494 mmol) in dry THF (2 mL) was cooled to -78 ° C under an N 2 atmosphere and then treated with n-butyllithium ( 0.312 mL of a 1.6M hexane solution, 0.499 mmol). After stirring for 10 minutes at the temperature of -78 ° C, the reaction mixture was treated with butyrate (R) -glycidyl (0.070 mL, 0.499 mmol).

When the addition was complete, the cooling bath was removed and the mixture was allowed to settle to room temperature overnight, during which time a white discolored precipitate appeared. TLC analysis (5% MeOH / CHCl3) revealed that the reaction was complete. The reaction mixture was treated with 5 drops of saturated aqueous NH 4 Cl, which caused the reaction mixture to form a homogeneous solution. The reaction mixture was concentrated under reduced pressure to obtain a faded white solid. Chromatography on silica gel, eluting with a gradient of 1 -5% MeOH / CHCl 3, produced, after concentration of the appropriate fractions, 0. 1 16 g (84%) of the title compound in the form of a white solid. with melting point 138-140 ° C and MS (EI) 308 (M +). In addition, 0.018 g (10%) of a second component, identified as the butyrate ester of the compound titrated by H-NMR analysis, was obtained in the form of an amber oil.

Step 4: ÍR) -f [3-f4 -fí l S.4S) -2-oxa-5-azabiciclof2.2. 1 l-he-tan-5-yl-3-fluorophenyl] -2-oxo-5-oxazolidyl] methyl) -methanesulfonate A solution of (R) - [3- [4- l S, 4S) -2-oxa-5 -azabiciclo [2.2. l] heptan-5-yl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl-methanol (0.765 g, 2.48 mmol) in CH2Cl2 (30 mL) was cooled to a temperature of 0 ° C under an N2 atmosphere, and treated with Et 3 N (0.518 mL, 3.73 mmol), followed by methanesulfonyl chloride (0.202 mL, 2.61 mmol). TLC analysis (5% MeOH / CHCl3), after 0.5 hours revealed that the reaction was complete. The reaction mixture was washed with H2O and brine, dried over Na2S4, filtered and concentrated in vacuo to yield 0.992 g (100%) of the title compound in the form of a brown solid. The analytical sample was prepared by recrystallization from 5% CH2Cl2 / i-PrOH. This sample had a melting point of 124.5 at 126 ° C and MS (EI) 386 (M +).

Step 5:, R) -ff3-í4-ypS.4S) -2-oxa-5-azabiciclof2.2.11heptan-5-ylol-3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl azide A solution of (R) - [[3- [4 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2. l) heptane-5-yl] -3-fluorophenyl} -2-oxo-5-oxazolidinyl] methyl] methanesulfonate (0.869 g, 2.25 mmol) in dry DMF (10 mL), was treated with solid Na 3 (0.732 g, 11.3 mmol) at room temperature under N. The mixture was then heated to the temperature of 65 ° C, and the progress of the reaction was monitored by TLC analysis. After 7.5 hours at this temperature, TLC analysis (5% MeOH / CHCl3) revealed that the reaction was complete. The reaction mixture was diluted with EtOAc (100 mL), washed with H2O (3 x 15 mL) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield 0.692 g (92%) of the titled compound in the form of a solid brown color. An analytical sample was prepared by recrystallization from 1: 1 EtOA / hexane in the form of a colorless white solid with a melting point of 101 ° C to 102.5 ° C and MS (EI) 333 (M +).

Step 6: (S) -N- [f3-f4-i (lS, 4S) -2-oxa-5-azabiciclof2.2. 11heptan-5-ylol-3-flurofeniIl-2-oxo-5-oxazolidinil | metillacetamide A solution of (R) - [[3- [4 - [(l S, 4S) -2-oxa-5-azabicyclo [2.2 . l] heptan-5-yl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl] azide (0.652 g, 1.96 mmol) in MeOH (20 mL) and CH2Cl2, was treated with 10% palladium / carbon (0.095 g), under a stream of N2. The atmosphere was then replaced with H2 (balloon) by evacuation and repeated filling and the mixture was stirred at room temperature under H2. After 3 hours, TLC analysis (5% MeOH / CHCl 3), revealed that the reduction was complete. The reaction mixture was filtered through Celite (R), and the filtrate concentrated under reduced pressure. The crude oxazolidinin 5- (aminomethyl), was dissolved in CH2Cl2 (20 mL) and treated with pyridine (0.190 mL), 2.35 mmol) and then acetic anhydride (0.222 mL, 2.35 mmol). After 0.5 hours, TLC analysis (5% MeOH / CHCL3) indicated that the acetylation was complete. The reaction mixture was washed with H2O and brine, dried over Na2S4, filtered and concentrated in vacuo to yield a faded white solid. Chromatography on silica gel (70 g), eluting with a gradient of 1-3% MeOH / CHCb, produced, after concentration of the appropriate fractions, 0.517 g (76%) of the oxazolidinone antibacterial agent titrated in the form of a white solid, with a melting point of 60 ° C to 65 ° C and MS (EI) 349 (M +).

EXAMPLE 2:, S? -N- [r3-f3-fluoro-4-fp S.4S) -2-thia-5-azabiciclof2.2. 11heptan-5-yloxy-phenyl-2-oxo-5-oxazolidinyl] methyl] acetamide Step 1: 4-f (l S.4Sl-2-thia-5-azabicyclo [2.2.1 l-heptan-5-yl] -3- fluoronitrobenzene A mixture of (1S, 4S) -2-thia-5-azabicyclo [2.2. 1) heptane (0.500 g, 3.30 mmol) available on the market, diisopropylethylamine (1.434 mL, 8.24 mmol) and 3,4-difluoronitrobenzene (0.437 mL, 3.96 mmol), in dry acetonitrile (15 mL), was heated to reflux temperature under an N2 atmosphere for one hour and then cooled to room temperature overnight. The reaction mixture was concentrated under reduced pressure to produce a yellow syrup. Chromatography on silica gel (50 g), eluting with chloroform, produced, after concentration of the appropriate fractions, 0.700 g (84%) of the titled compound in the form of a yellow solid with a melting point of 97 °. C at 98 ° C and MS (EI) 254 (M +).

Step 2: N-Icarbobenzyloxy) -4- (1S, 4S) -2-thia-5-azabiciclof 2.2. 1 lheptan-5-yl1-3-fluoroaniline A solution of 4- [(l S, 4S) -2-thia-5-azabicyclo [2.2. 1 jheptan-5-yl] -3-fluoronitrobenzene (1.64 g, 6.46 mmol) in 20% H2O / THF (50 mL), was treated with platinum on sulfide carbon (0.200 g), under a stream of N2 - La atmosphere was replaced with H2 (balloon) by evacuation and repeated filling. After 12 hours, the TLC analysis revealed that a significant amount of starting material still remained. The reaction mixture was transferred to a Parr apparatus and stirred under a 45 psi H2 pressure. TLC analysis after 2 hours indicated that some of the starting material still remained. The reaction mixture was filtered through CeliteÍR! and the filtrate, which contains a mixture of the desired intermediate aniline and the starting nitrobenzene derivative, was cooled to the temperature of 0 ° C and treated with NaHC 3 (2. 170 g, 25.8 mmol), and chloroformate. benzyl (1.02 mL, 7.10 mmol). After 0.5 hours, the reaction mixture was concentrated under reduced pressure to obtain a yellow / green syrup. This material was dissolved in CHC13, washed with H2O and brine, dried over Na2S4, filtered and concentrated in vacuo. Filtration through a plug of silica gel, eluting with 20 to 30% EtOA / hexane, produced, after concentration of the appropriate fractions, a mixture of the starting nitrobenzene derivative and the titled compound. This material was collected in 20% H2O / THF (50 mL) and treated with Raney W-2 nickel (ca 0.400 g). The reaction mixture was stirred in a Parr apparatus, under 45 psi H2 pressure. After 3 hours the reaction mixture was filtered through Celite (R), and the filtrate was cooled to 0 ° C and treated with NaHC 3 (2.00 g, 23.8 mmol), followed by benzyl chloroformate ( 0.600 mL, 4. 19 mmol). After 0.5 hours, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to chromatography on silica gel (125 g), eluting with 10 to 20% EtOA / hexane, to produce, after concentration of the suitable fractions, 2.20 g (95%) of the title compound in the form of a yellow solid with melting point of 9 1 ° C to 93 ° C and MS (EI) 358 (M +).

Step 3: fR) -í3-f4-f (l S .4S) -2-thia-5-azabicycloi2.2. 11-heptane-5-yl-3-fluorophenyl) -2-oxo-5-oxazolidinyl) methanol A solution of N- (carbobenzyloxy) -4- (1S, 4S) -2-thia-5-azabicyclo [2.2. l) heptan-5-yl] -3-fluoroaniline (0.359 g, 1.00 mmol) in dry THF (4 mL), under N2, was cooled to -78 ° C and then treated with n-butyl-lithium (0.633 mL of a hexane solution of 1.6 M, 1.01 mmol). The reaction mixture was stirred at -78 ° C for 15 minutes and then treated with butyrate (R) -glycidyl (0.151 mL, 1.00 mmol). When the addition was complete, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature overnight. TLC analysis (5% MeOH / CHCl3), indicated that the reaction was complete, but that a small amount of the butyrate ester of the titled compound was present. The addition of 5 drops of a 25% by weight MeOH / OMe NA solution by weight, followed by stirring for 20 minutes at room temperature, was effective to convert this intermediate to the titled compound. The reaction mixture was treated with NH 4 Cl (10 drops) and then concentrated in vacuo to yield a crude product. Chromatography on silica gel (50 g), eluting with 1 to 3% MeOH / CHCl 3, produced after concentration of the appropriate fractions, 0. 132 g (4 1%) of the titled compound in the form of an oil . Trituration with EtOAc produced a precipitate, which was isolated and dried in vacuo to yield a faded white solid with a melting point of 156 ° C to 157 ° C and MS (EI) 324 (M +) Step 4: IR, - f (3- [4-fflS.4S) -2- thia-5-azabiciclof 2.2.1 lheptan-5-ylol-3-fluorophenyl] -2-0X0-5-oxazolidinyl] methyl] sulphonate A solution of (R) - [3- [4 - [(lS, 4S) -2-thia-5-azabicyclo [2.2. l] heptan-5-yl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methanol (1.68 g 5.19 mmol) in dry CH2Cl2 (100 mL) under N2, was cooled to the temperature of 0 ° C and treated with Et 3 N (0.793 mL, 5.70 mmol), followed by methanesulfonyl chloride (0.442 mL, 5.70 mmol). After 0.5 hours at this temperature, the reaction appeared to be complete according to TLC analysis (5% MeOH / CHCl3). The mixture was washed with H2O, saturated aqueous NaHC3 and brine, dried over a2SO4, filtered and concentrated in vacuo to yield 1.65 g (79%) of the title compound in the form of a white solid with a melting point of 139 ° C. at 142 ° C and MS (EI) 402 (M +).

Step 5: (Sl-N-yf3-r3-fluoro-4-f (lS.4S) -2-thia-5-azabicyclo2.2.11heptan-5-yl-phenyl) -2-oxo-5-oxazolidinyl-1-methyl] acetamide A mixture of (R) - [[3- [4 - [(lS, 4S) -2-thia-5-azabicyl [2.2. l] heptan-5-yl | -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl] methanesulfonate (.156 g, 3.88 mmol), 1: 1 THF / i-PrOH (4mL) and 30% NH4OH ( 4 mL), was heated to 95 ° C in a sealed tube for 14 hours and then cooled to room temperature. TLC analysis (5% MeOH / CHCl3) revealed that the reaction was complete. The mixture was diluted with CH 2 Cl 2 (75 mL), washed with saturated aqueous NaHC 3 (15 mL) and brine (15 mL), dried over Na 2 SO 4, filtered and concentrated under reduced pressure to produce a syrup. The crude intermediate 5- (aminomethyl) oxazolidinone was dissolved in CH2Cl2 (75 mL) and treated with pyridine (0.345 mL, 4.27 mmol) and acetic anhydride (0.403 mL, 4.27 mmol) at room temperature. After 1 hour, TLC analysis (5% MeOH / CHCl3) indicated that the acetylation was complete. The reaction mixture was washed with H2O and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain an amber-colored solid. Chromatography on silica gel (125 g), eluting with 1 to 3% MeOH / CHCl 3, produced, after concentration of the appropriate fractions, 1.23 g (87%) of the oxazolidinone antibacterial agent titrated in the form of a solid with melting point of 90 ° C to 95 ° C and MS (EI) 365 (+).

EXAMPLE 3: (S) -N-((3-3 3-fluoro-4-f (lS, 4S) -2-thia-2,2-dioxo-5-azabicyclo [2.2.1 jheptan-5-yl] phenyl] - 2-oxo-5-oxazolidinyl] methyl] acetamide A solution of (S) -N - ([3- [3-fluoro-4 - [(lS, 4S) -2-thia-5-azabicyclo (2.2.1) heptan-5-yl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -acetamide (0.300 g, 0.82 mmol) in 25% H2? / acetone (16 mL) was treated at room temperature with 4-methylmorpholine -N-oxide (0.288 g, 2.47 mmol), followed by osmium tetraoxide (0.102 mL of a 2.5% by weight tert-butanol solution, 0.008 mmol) After 18 hours, TLC analysis (10% MeOH / CHCl3), revealed that the oxidation was complete.The reaction mixture was treated with saturated aHS? 3 aqueous and then extracted with CHCl3 The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. it was subjected to chromatography on silica gel (10 g), eluting with 1 to 3% MeOH / CHCL3, to produce, after the concentration of the appropriate fractions, 0.321 g (98%) of the oxazolidinone antibacterial agent titrated in the form of a white solid with a melting point of 95 ° C to 105 ° C.

EXAMPLE 4: (Sl-N-ff3-f3-fluoro-4- (tetrahydro-lH-thienyl3.4-c] pyrrol-5- (3H) -yl) phenyl] -2-oxo-oxazolidinyl] methyl] acetamide Step 1: cis-1- (Phenylmethyl) -3,4-pyrrolidinadimethanol) Dimethyl ester of (cis) -l- (Phenylmethyl) -3,4-pyrrolidinedicarboxylic acid was prepared according to the procedure described by Y. Terao et al. (Chem. Pharm. Bull., 1985, 33, pp. 2762 to 2766). To a stirred solution of this diester (12.14 g, 43.8 mmoi) in dry THF 175 L) under N2, cooled to the temperature of 0 ° C, was added a solution in the form of drops of lithium aluminum hydride (1M in THF). , 87 mL, 87 mmol) for 15 minutes. The reaction mixture was stirred at the temperature of 0 ° C for 1 hour, then at room temperature for 18 hours. The reaction mixture was cooled to a temperature of 0 ° C and quenched with the successive addition of H 2 O (3.2 mL), 5 N NaOH (3.2 mL) and H 2 O (11.7 mL). The reaction mixture became very thick and it was very difficult to stir it. The reaction mixture was diluted with ether (500 mL) and filtered through a small pad of celite. The filter was washed with ether (250 mL). The filter was washed with H2O (1 x 300 mL) and the organics were dried (MgSO4), filtered and concentrated to yield 9.3 g (41.8 mmol, 96%) of the desired diol and a coarse yellow oil. It is used without further purification. HRMS (FAB) calculated for C 13 H 19 NO 2 + H 222.1494, found 222.1490.

Step 2: cis-l- (Phenylmethyl-3,4-di (methylsulfonyloxy) methylpyrrolidine) A stirred solution of cis-1- (phenylmethyl) -3,4-pyrrolidinedimethane (9.2 g, 41.6 mmol) in CH 2 Cl 2 (240 mL) cooled to At 0 ° C, triethylamine (29 mL, 208.1 mmol) was added, followed by methanesulfonyl chloride (8.1 mL, 104.0 mmol) .The reaction mixture was stirred until the opening at 0 ° C for 15 minutes, then The reaction mixture was poured into H 2 O (240 mL) and the phases were separated, the aqueous phase was extracted with CH 2 Cl 2 (1 x 100 mL). MgSO 4), filtered and concentrated The residue was purified by flash chromatography, using ethyl acetate as eluent to yield 14.2 g (37.5 mmol, 90%) of the desired mesylate-bis, in the form of a thick yellow oil HRMS (El) calculated for C15H23NO6S2377.0967, found 377.0958.

Step 3: Hexahydro-5- (phenylmethyl) -lH-thienol [3,4-c] pyrrole To a stirred solution of cis-1- (phenylmethyl) -3,4-di (methylsulfonyloxy) methylpyrrolidine (9.2 gmmole) in DMSo dry (48 mL), anhydrous sodium sulfate (5.7 g, 73.3 mmol) was added. The dark reaction mixture was heated to the temperature of 120 ° C for 18 hours. The cooled reaction mixture was poured into ice of H2O (150 mL). The resulting mixture was extracted with ether (3 x 200 mL). The combined organics were dried over (MgSO 4), filtered and concentrated. The resulting residue was purified by flash chromatography, using ethyl acetate as eluent to yield 4.2 g (19.1 mmol, 78%) of the desired product in the form of a thick yellow oil. HRMS (El) calculated for C13H17 NS 219.1082, found 219.1080. Analysis calculated for C13H17NS: C, 71.19; H, 7.81; N, 6.39. Found: C, 70.82; H, 7.83; N, 6.35 Step 4: Hexahydro-lH-thienol hydrochloride [3,4-c] pyrrole To a solution of hexahydro-5- (phenylmethyl) -lH-thienol [3,4-cjpyrrole (1.2 g, 5.3 mmol) in CH2Cl2 (21 mL) cooled to the temperature of 0 ° C, 1-chloroethylchloroformate (1.15 mL, 10.7 mmol) was added in the form of drops by means of a syringe. The reaction mixture was stirred at the temperature of 0 ° C for 20 minutes, and then at room temperature for 90 minutes. The reaction mixture was concentrated. The resulting residue was purified by flash chromatography, using 25% ethyl acetate in hexane, as the eluent to yield 611.3 mg (2.6 mmol), 49%) of 1-chloroethylcarbamate. The column was then washed with 20% methanolic ammonium in CHC13, to yield 160.5 mg (1.24 mmol, 23%) of the desired amine in the free base form. The 1-chloroethylcarbamate (611.3 mg, 2.6 mmol) was dissolved in methanol (15 mL) and heated to reflux for 90 minutes. The cooled reaction mixture was concentrated to yield 408.0 mg (2.5 mmol), 47%) of the desired amine in the HCl salt form (based on chlorocarbamate). Melting point from 149 ° C to 151 ° C; HRMS (El) calculated for C HiiNS 129.0612, found 129.0614. Analysis calculated for C5H12CINS; C, 43.50; H, 7.30; N, 8.45; Cl: 21.39; S: 19.35. Found: C, 43.39; H, 7.23; N, 8.24; Cl: 21.08; S: 19.12.

Step 5: 5-f2-Fluoro-4-nitrophenyl) -hexahydro-1H-thieno [3,4-c] pyrrole To a stirred suspension of hexahydro-5-lH-thieno hydrochloride [3,4-c] pyrrole ( 147.3 mg, 0.89 mmol), in acetonitrile (5 mL), 3,4-fluoronitrobenzene (0.11 mL, 0.98 mmol) was added, followed by diisopropylethyl amine (0.36 mL, 2.05 mmol). The homogeneous reaction mixture was heated to reflux for 18 hours. The reaction mixture was concentrated. The resulting residue was diluted with EtOAc (50 mL) and washed with saturated aqueous NH4CI (1 x 25 mL). The aqueous layer was extracted with EtOAc (1 x 30 mL). The combined organics were washed with saturated NaHC 3 (1 x 40 mL), brine (1 x 40 mL), dried over (MgSO 4), filtered and concentrated. The residue was purified by flash chromatography, using 20% EtOAc in hexane as the eluent to yield 202.5 mg (0.75 mmol, 89%) of the desired nitro compound in the form of a bright yellow solid. Melting point from 107 ° C to | 09 ° C; Analysis calculated for Ci 2 H 13 FN 2 O 2 S: C, 53.72; H, 4.88; N, 10.44; S: 11.94. Found C, 53.38; H, 5.03; N, 10.34; S: 11.89.

Step 6: 3- [3-Fluoro-4- (tetrahydro-lH-thienof3.4-clpyrrol-5í3H) -yl) phenylcarbamic acid, phenylmethyl ester To a stirred suspension of 5- (2-fluoro-4-nitrophenyl) -hexahydro -lH-thieno [3,4-c] pyrrole (1.44 g, 5.4 mmol) in ethanol (70 mL), 2 M aqueous CUSO 4 (2.9 mL) was added. This mixture was cooled to the temperature of 0 ° C and sodium borohydride (1.10 g, 26.8 mmol) was added as a portion. (Warning: Very exothermic!). The dark reaction mixture was then heated to reflux for 2 hours. The cooled reaction mixture was partitioned between EtOAc and H2 ° - The phases were separated. The aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organics were dried over (MgSO 4), filtered and concentrated. The resulting dark residue was dissolved in acetone / H 2 O (2: 1, 60 mL) This stirred solution was cooled to 0 ° C and solid NaHCO 3 (1.35 g, 16.1 mmol) was added, followed by benzylchloroformate ( 1.9 mL, 13.4 mmol) The reaction mixture was stirred at the temperature of 0 ° C for 15 minutes, then at room temperature for 2 hours.The reaction mixture was quenched by means of a careful addition of 10% aqueous NaHS04. (30 mL) The reaction mixture was poured into EtOAc (250 mL), and the phases were separated The aqueous layer was extracted with EtOAc (1 x 100 mL) The combined organic layers were dried over (MgSO 4). ), filtered and concentrated The residue was purified by flash chromatography, using 20% EtOAc in hexane, to yield 1.6 g, (4.3 mmol), 81%) of the desired carbamate: melting point 101 ° C at 102 ° C; Analysis Calculated for C20H2 1 PN2O2S: C, 64.50; H, 5.68; N, 7.52; S: 8.61. Found: C, 64.33; H, 5.56; N, 7.53; S: 8.61.

Step 7: (5R) -3-f3-Fluoro-4-phthatrahydroyl H-thienof3, 4-chloro-5- (3H) -lolfenyl-5- (hydroxymethyl) -2-oxazolidinone To a stirred solution of 3- [3-fluoro-4- (tetrahydro-1 H -thieno [3,4-c] pyrrol-5- (3H) -yl) phenylcarbamic acid, phenylmethyl ester (1.36 g, 3.6 mmol) dried over THF 814 mL ), under N2 cooled to -78 ° C, n was added. butyl lithium (1.6 M in hexane, 2.4 mL, 3.8 mmol). The reaction mixture was stirred at -78 ° C for 35 minutes and then butyrate (R) - (-) - glycidyl (0.54 L, 3.8 mmol) was added. The reaction mixture was stirred at -78 ° C for 30 minutes, then at room temperature overnight. A thick precipitate formed. The reaction mixture was quenched with saturated aqueous NH4CI, and poured into EtOAc (50 mL). The phases were separated. The organic layer was washed with saturated aqueous NaHC 3 (1 x 30 mL), brine (1 x 30 mL, dried over (MgSO 4), filtered and concentrated, the residue was purified by flash chromatography, using EtOAc. as the eluant to produce 801.6 mg (3.4 mmol, 65%) of the desired product, Melting point 165 ° C to 167 ° C, Analysis Calculated for C 16 H 19 FN 2 O 3 S: C, 56.79; H, 5.66; N, 8.28; S: 9.48. Found: C, 56.88; H, 5.74; N, 8.21; S: 9.33.

Step 8: (5R) -3- [3-Fluoro-4- (tetrahydro-lH-thieno [3,4-c] pyrrol-5 (3H) -ylphenyl] -5 - [[(methylsulfonyl) oxy] methyl] -2-oxazolidinone To a solution of (5R) -3- [3-fluoro-4- (tetrahydro-lH-thieno [3,4-c] pyrrol-5- (3H) -yl) phenyl] -5- ( hydroxymethyl) -2-oxazolidinone (656.5 mg, 1.9 mmol) in CH2Cl2 (20 mL) cooled to 0 ° C, added triethylamine (0.41 mL, 2.9 mmol) followed by methanesulfonyl chloride (0.18 mL, 2.3 mmol The reaction mixture was stirred at the temperature of 0 ° C for 15 minutes, then at room temperature for 18 hours.The reaction mixture was poured into H 2 O (20 mL) The phases were separated The aqueous layer was extracted with CH2Cl2 (1 x 50 mL) The combined organic layers were dried over (MgSO4), filtered and concentrated, the residue was triturated with ether / hexane and the solid was isolated by filtration and dried to yield 773.9 mg (1.9 mmol. 96%) of the desired mesylate, melting point 148 ° C to 150 ° C, analysis calculated for C17H21FN2O5S2: C, 49.03; H, 5.08; N, 6.73; S: 15.40. Found: C, 48.56; H, 5.12; N, 6.48; S: 15.41. Found: C, 48.46; H, 5.25; N, 6.38.

Step 9: (S) -N - [[3-3-fluoro-4- (tetrahydro-lH-thieno [3,4-c] pyrrol-5- (3H) -yl) phenyl] -2-oxo-5 -oxazolidinyl] methyl] acetamide A suspension of (5R) -3- [3-fluoro-4- (tetrahydro-lH-thienof3,4-c] pyrrol-5- (3H) -yl) phenyl] -5 - [[ (methylsulfonyl) oxy] methyl] -2-oxazolidinone (208.5 mg, 0.5 mmol) in THF (3 mL) and methanolic ammonia (3 mL), was heated in a sealed tube at the temperature of 100 ° C for 48 hours. (The reaction mixture became homogeneous to about 80 ° C). The cooled reaction mixture was concentrated and the resulting residue was dissolved in CH2Cl2 (5 mL) and cooled to 0 ° C. To this stirred suspension was added pyridine (0.12 mL, 1.5 mmol) followed by acetic anhydride (60 μL, 0.6 mmol). The homogeneous reaction mixture was stirred at the temperature of 0CC for 15 minutes, then at room temperature for 1 hour, then concentrated.

The residue was purified by means of flash chromatography, using 7% methanol in EtOAc as the eluent to produce 148.2 mg (0.4 mmol, 78%) of the desired acetamide. Melting point from 143 ° C to 144 ° C; KF-H2O: 0.52% Analysis Calculated for C 18 H 22 FN 3 O 3 S plus 0.52% H O: C, 56.68; H, 5.87; N, 1 1 .01; S: 8.40.

Found: C, 56.3 1; H, 5.90; N, 10.74; S: 8.30.

EXAMPLE 5: .S) -Nf f3-f3-fluoro-4- (tetrahydro-H-thienoyl-3,4-c] pyrrol-5- (3H) -yl) phenyl) -2-oxo-5-oxazolidinipmethyl] acetamide , S-oxide To a stirred solution of (S) -N - [(3- [3-fluoro-4- (tetrahydro-1 H -thieno [3, 4-c-] pyrrol-5- (3H) -ylphenyl) ] -2-oxo-5-oxazolidinyl] methyl] acetamide (2 16.8 mg, 0.57 mmol) in methanol (4 mL) and H2O (4 mL) cooled to the temperature of 0 ° C, sodium metaperiodate was added (134.4 mg, 0.63 mmol) The reaction mixture was stirred at the temperature of 0 ° C for 1 hour, then at room temperature for 18 hours The solid precipitation was removed by filtration The solid was washed with CHCl 3 (50 mL The filtrate was washed with H 2 O (1 x 30 mL), the aqueous layer was extracted with CHCl 3 (2 x 25 mL), the combined organic layers were dried over (MgSO 4), filtered and concentrated. by means of flash chromatography, using 7% methanol in CH2Cl2 as the eluent to produce 195.7 mg (0.5 mmol, 87%) of the desired sulfoxide. Melting point 162 ° C to 164 ° C; HRMS (El) calculated for C 18 H 22 FN 3 O 4 S 395, 1315, found 395. 1309. KF-H2O: 2.87% Analysis Calculated for C 1 gH22Ir 3O4S plus 2.87% H2O: C, 53.09; N, 10.32; S: 7.87. Found: C, 53.07; H, 6.01; N, 10.30; S: 7.87 EXAMPLE 6: (S) -Nf f3-fluoro-4- (tetrahydro-H-thienof3,4-c] pyrrol-5- (3H) -yl) phenyl-2-oxo-5-oxazolidinyl) methyl] acetamide, SS-dioxide To a stirred solution of (S) -N- [[3- [3-fluoro-4- (tetrahydro-H-thieno [3,4-c-] pyrrole-5- (3H) -yl)] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (213.9 mg, 0.56 mmol) in 25% acetone / H2? (8 mL), was added N-methylmorpholine-N-oxide (198.1 mg, 1.7 mmol) followed by osmium tetraoxide in tert-butanol (2.5% by weight) (30 μL, 0.08 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched by careful addition of saturated sodium bisulfite (8 mL). The mixture was poured into CH 2 Cl 2 (50 mL) and the phases were separated. The aqueous phase was extracted with CH2Cl2 (2 x 25 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over (MgSO 4), filtered and concentrated. The residue was purified by flash chromatography, using 7% methanol in CHCl3 as the eluent to yield 194.3 mg (0.47 mmol, 84%) of the desired sulfone. Melting point from 135 ° C to 137 ° C; HRMS (El) calculated for C? H22F 3? SS 411.1264, found 411.1263. KF-H2O: 1.10%. Analysis Calculated for C? GH22frN3? 5S plus 1.10% H2O: C, 51.96; H, 5.45 N, 10.10; S: 7.71. Found C, 51.73; H, 5.62; N, 9.96; S: 7.75.

EXAMPLE 7: cis- (S? -N-ff3-f3-fluoro-4-f3-oxa-7azabicyclo3.3.0] octan-7-yl) phenyl] -2-oxo-5-oxazolidinylmethyl] acetamide Following the general procedure of EXAMPLE 2, and without making critical variations, but substituting hexahydro-lH-furo (3,4-c) pyrrole (Miller, AD US Patent 3,975,532 1976). (2.33 g, 20.66 mmol) for (1S, 4S) -2-thia-5-azabicyclo [2.2. 1) heptane, the titled compound was obtained, with a melting point of 124 ° C to 126 ° C.

GRAPH I GRAPH II GRAPH III GRAPH IV

Claims (11)

1. R E I V I N D I C A C I O N S A compound of structural Formula I: Formula I or a pharmaceutically acceptable salt thereof, wherein: X is (a) O, (b) S, (c) SO, (d) SO2; R1 is independently H, F, Cl or OMe; R ^ is (a) hydrogen, (b) Cj-Cg alkyl optionally substituted with one or more of the following: F, Cl, hydroxyl, Ci-Cg alkoxy, Ci-C allyloxy (c) C3-C6 cycloalkyl, (d) amino, (e) Cj-Cg alkylamino, (f) Cj-Cg dialkylamino ((g) Ci-Cg alkoxy;, a is from 0 to 3; it is from 0 to 2, c is from 0 to 2 (b and c can not be both 0), d is from 0 to 2, and e is from 0 to 2 (d and e can not be both 0) 2 The compound as it is described in Claim 1, further characterized in that X is S. The compound as described in Claim 1, further characterized in that R1 is independently H or F. The compound as described in Claim 3 , further characterized by the fact that each R1 is F. The compound as described in Claim 1, further characterized in that R ^ is hydrogen, a Ci-Cg alkoxy, or a Ci-Cg alkyl, optionally substituted with one or more Cl or OH 6. The compound as described in Claim 1, further characterized in that R 2 is methyl, dichloromethyl, hydroxymethyl, or methoxy 7. The compound as described in Claim 1 ation 1, which is: (a) (S) -N - [[3- [3-fluoro-4 - [(lS, 4S) -2-oxa-5-azabicyclo [2.2.1] -heptan-5 -yl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide; (b) (S) -N - [[3- [3-fluoro-4 - [(1S, 4S) -2-thia-5-azabicyclo- [2.2. l] heptan-5-yl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide; or (c) (S) -N - [[3- [3-fluoro-4 - [(1S, 4S) -2-thia-2,2-dioxo-5-azabicyclo [2.2. l] heptan-5-yl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide. 8. The compound as described in Claim 1, further characterized in that it is in the form of the S-enantiomer. 9. The compound as described in Claim 1, further characterized in that c and b are both 1. 10. The compound as described in Claim 9, further characterized in that d and e are both 1. The compound as described in Claim 10, further characterized in that a is 0. 12. The use of a compound of Formula 1, to prepare medicaments useful in the treatment of microbial infections in a patient in need of them, by means of the administration of an effective amount of a compound of Formula I. 13. A compound of structural Formula II: Formula II or the pharmaceutically acceptable salts thereof, wherein: X is (a) O, (b) S, (c) SO, (d) SO 2; R l is independently H, F, Cl or Orne; R2 is (a) hydrogen, (b) C] -Cg alkyl optionally substituted with one or more of the following: F, Cl, hydroxyl, Cj-Cg alkoxy, Cj-Cg acyloxy (c) C3- cycloalkyl C6, (d) amino, (e) C 1 -Cg alkylamino, (f) dialkylamino of Cj-Cg (g) Ci-Cg alkoxy;, The compound as described in the claim 13, which is in the form of the S-enantiomer. 15. The use of a compound of Formula II, to prepare a medically useful for the treatment of microbial infections, in warm-blooded animals, by means of administration to a patient in need thereof, in an effective amount of a compound of Formula II. EXTRACT OF THE INVENTION Phenyloxazolidinone Compounds of Formula I Formula I or the pharmaceutically acceptable salt thereof, characterized by a bicyclic thiazine, or oxazine substituent. The compounds are useful as antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria, such as staphylococci, streptococci and in terococci resistant to multiple drugs, as well as anaerobic organisms, such as Bacteroides spp. . and Clostridia spp, and acid resistant organisms, such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.