MXPA00004528A - Oxazolidinone derivatives and pharmaceutical compositions - Google Patents

Abstract

A compound of Formula (I) or a pharmaceutically acceptable salt thereof, which is antimicrobial agents, effective against various human and veterinary pathogens, including gram positive aerobic organisms, gram negative organisms, and anaerobic organisms.

Description

DERIVATIVES OF OXAZOLIDINONE AND PHARMACEUTICAL COMPOSITIONS BACKGROUND OF THE INVENTION The present invention relates to novel oxazolidinone compounds or their pharmaceutically acceptable salts, and pharmaceutical agents containing them as active ingredients for preventing or treating infectious diseases. The compounds are single oxazolidinones having a hexahydro-1,4-diazepin-5-one substituent. More specifically, the novel oxazolidinone compounds of the present invention relate to useful antimicrobial agents effective against various human and veterinary pathogens, including gram-positive aerobic organisms such as staphylococci and streptococci, resistant to gram-negative organisms, and for example H. influenzae and M. catar rhalis, as well as anaerobic organisms such as, for example, bacteroides and clostridia species, and acid-resistant organisms such as for example Mycobacterium tuberculosis and Mycobacterium avium.

EXPOSURE OF THE INFORMATION International Publication No. 97/27188 discloses piperazin-3-one analogues which are homologs of the invention. International Publication No. 093/23384 discloses oxazolidinones containing a substituted diazine (piperazine) entity and its uses as antimicrobials. International Publication No. WO93 / 09103 discloses. substituted aryl and heteroaryl phenyl-oxazolidinones useful as antimicrobials. International Publication No. O90 / 02744 discloses 5'-indolinyl-5-amidomet-iloxa-zolidinones, 3- (substituted-fused ring) phenyl-5-amidomet-yl-oxazolidinones, and 3- (t -titue with nitrogen) -phenyl-5-a gone ethyloxazolidinones that are useful as antibacterial agents. Other references disclose various oxazolidinones which include U.S. Patents 5,547,950, 4,801,600, J. Med. Chem., 32 1673- (1989) J, Med. Chem, _ 33 - ^ J- 2569-7 (1990); Tetrahedron, 45, 1323-26 (1989); and ^ J_. Med. Chem., 35, 1156 (1992).

European Patent Publication 352,781 discloses phenyl and pyridyl substituted phenyloxazolidinones. European Patent Publication 316,594 discloses 3-thyloxazolidinones. European Patent Publication 312,000 discloses phenyloxazolidinones substituted with phenylmethyl and pyridylmethyl.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides an oxazolidinone derivative represented by the general structural Formula I or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof wherein: R is H, C2-β alkenyl, C2-1 alkynyl C1-6 alkyl or C-e alkyl substituted with one or two of the following: F, Cl, CF3, -OH, C alco _ alkoxy, -CH2C (= 0) C? _ Alkyl, -OC (= 0) N (R4) 2, C ?4 S (0) n alkyl, (where n is 0 -CN, carboxy, alkoxycarbonyl of -C? ~ 4, -C (= 0) N (R4) 2, -N (R) S02alkyl of C? -, -N (R4) C (= 0) C-alkyl? _, -N (R 4) C (= 0) N (R 4) 2, -N (R 4) C (= 0) C 1 alkoxy, aryl, or Het; aryl is phenyl, optionally substituted with one or two of the following: a) F, b) Cl, c) Br, d) -CF 3, e) CN, f) C 1 -3 alkoxy, or g) C 1 -3 alkylthio; Het is a 5- or 6-membered heteroaromatic portion having from 1 to 3 N, O or S atoms, optionally substituted with the following: a) F, b) Cl, c) C 3 alkoxy, d) alkylthio from C? _3, oe) CN; i and R2 are independently H, F, or Cl; R3 is a) C6_6 alkyl, optionally substituted with one to three F atoms or one to two Cl atoms, b) C6_6 alkoxy, c) amino, d) C6_6 alkylamino, and ) dialkylamino of C? _6) cycloalkyl of C3_s, g) alkylthio of C? _6, or -N (CH2) mh) \ - "(where it is O, 1, 2, 3 or 4; Rz is a) H, or b) C? _3 alkyl; Y X is O or S The present invention also provides an antimicrobial agent or pharmaceutical composition containing the oxazolidinone compound or a pharmaceutically acceptable salt thereof as an active ingredient. The antimicrobial agent containing the active ingredient of the present invention can be used for the treatment or prevention of infectious diseases.

DETAILED DESCRIPTION OF THE INVENTION The compounds of Formula I, as are structurally stated in the foregoing, are useful antimicrobials. Typically, as explained further below, the compounds may be administered .co or antibacterial agents "in a dose variation from about 0.1 to 100 mg / kg or preferably from about 3.0 to about 50 mg / kg of body weight per day. In the structural formula shown above, the carbon content of various hydrocarbon-containing entities is indicated by a prefix designating the minimum and maximum number of carbon atoms in the entity, ie, the prefix Ci-C- , defines the number of carbon atoms present from the integer "i" to the integer "j" inclusive.The term "C? -61 'alkyl, as used herein, refers to an alkyl group having one to six carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl and their isomeric forms; preferably methyl, ethyl, propyl and their isomeric forms: The term "C2_6 alkenyl" refers to at least one double bond of the alkenyl group having from two to six carbon atoms such as, for example, vinyl, 1-propenyl , 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentepyl, 1-hexenyl and its isomeric forms, preferably an alkenyl group which tj.ene of 2 to 6 carbon atoms, and more preferably an alkenyl group having 2 to 4 carbon atoms.

The term "C2-7 alkynyl" refers to at least one triple bond of the alkynyl group having from two to seven carbon atoms such as, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl and its isomeric forms . The term "Ci-g alkylamino" refers to an alkyl group having one to six carbon atoms attached to an amino entity. The term "? -β-dialkylamino" refers to two alkyl groups having from one to six carbon atoms attached to an amino entity. The term "C 1-4 alkoxy" refers to an alkyl group having one to four carbon atoms attached to an oxygen atom of the hydroxyl group such as, for example, methoxy, ethoxy, propoxy, butoxy and its isomeric forms , preferably, an alkoxy group having 1 to 2 carbon atoms. The term "Cilt _6 alkylthio" refers to an alkyl group having one to six carbon atoms attached to the thio entity such as, for example, methylthio, ethylthio, propylthio and its isomeric forms, preferably an alkylthio group which has 1 to 2 carbon atoms.

The term "C3_6 cycloalkyl" refers to three to six carbon atoms that form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and their isomeric forms. The term "aryl" refers to a phenyl entity optionally substituted with one or two F, Cl, Br, -CF3, -CN, -C1-3 alkoxy, or -C3 -3alkylthio; The term "Het" refers to a 5 or 6 member heteroaromatic entity having one to three atoms selected from the group consisting of O, N or S atoms such as, for example, furapo, thiophene, pyrrole, pyrazole, triazoles, oxazole, thiazole, isothiazole, oxadiazoles, oxathiazole, pyridine, pyridazine, pyrimidine, pyrazine, piperazine and triazine all of which may optionally be substituted with a substituent selected from the group consisting of F, Cl, C1-.3 alkoxy, C1-3 alkylthio or CN. The compounds of the present invention can be converted to their salts according to conventional methods. "Pharmaceutically acceptable salts" means acid addition salts useful for administering the compounds of this invention and these include hydrochloride, hydrobromide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, succinate, tartrate, citrate, 2-hydroxyethyl sulfonate, fumarate and the like when a basic group is present. These salts may be in hydrated form. Some of the compounds of this invention can form metal salts such as, for example, sodium salts, potassium, calcium and magnesium and these are encompassed by the term "pharmaceutically acceptable salts". Due to the C-5 configuration of the oxazolidinone ring of the compounds as represented in the structure of Formula I, the compounds of this invention can exist in geometric, optical and other isomeric forms and this invention encompasses any of these isomers . It is believed that the racemic mixture and the enantiomers are all useful as an antibacterial. Despite this, the preferred absolute configuration in. C-5 of the oxazolidinone ring of the compounds is as represented in the structure of Formula I. This absolute configuration is referred to as (S) according to the Cahn-Ingold-Prelog nomenclature system. It is believed that a majority of the pharmacological activity resides in this (S) -enantiomer to produce the antibacterial effect.

The compounds of Formula I can be prepared as shown in Scheme I, where P represents an alcohol protecting group such as, for example, benzyl or tert-butyldimethylsilyl. Structure 2 of this scheme is prepared according to the methods outlined in Example 1, Steps 1 and 2. In Scheme I, the alcohols of 2 are protected as benzylethers. In a suitable procedure for this reaction, a solution of alcohol 2 in a solvent such as Et20 or THF is allowed to react first with sodium hydride at 0-25 ° C and then with benzyl bromide and tetrabutylammonium iodide at 0 ° C. -25 ° C to provide the structure 3. The ethylene ketal of 3 can then be removed with an acid catalyst such as, for example, p-toluenesulfonic acid in acetone (as described in Example 1, Step 2) to provide the structure 5, where P is benzyl. Alternatively, the ketal of 2 can be removed, the resulting structure 4 is allowed to react with tert-butyldylamino-ylsilyl chloride and imidazole in DMF or tert-butyldimethylsilyl chloride and triethylamine in methylene chloride to provide structure 5 where the protecting group of alcohol (P) is tert-butyldimethylsilyl. Ketone 5 is allowed to react with hydroxylamine hydrochloride and sodium acetate in methanol-methylene chloride to provide oxime 6 (see Example 1, Step 3). The Beckmann rearrangement of structure 6 is carried out with p-toluenesulfonyl chloride and sodium carbonate in aqueous acetone at 20-40 ° C to provide structure 7. For the compounds of Formula I, where R is not hydrogen, the compounds 7 can be alkylated with R'Y where Y is Br, I, CH3S03 or p-CH3PhS03 and R 'is an appropriate alkyl substituent. In a method for this alkylation, the compounds of structure 7 are allowed to react with sodium hydride and R'Y in a solvent such as DMF at 0-25 ° C to provide 8. Alternatively, structure 7 can be reacted with R Y, potassium hydroxide and tetrabutylammonium bromide in THF or acetonitrile at 20-50 ° C to provide 8. Deprotection of alcohols 7 or 8 provides structure 9. When P is a benzyl ether, it can be carried out by hydrogenolysis with hydrogen and a palladium catalyst in ethanol or with ammonium formate and a palladium catalyst in methanol at 10-30 ° C. The protective group tert-butyldimethylsilyl can be removed under arid conditions or with fluoride ion. This deprotection can be carried out, for example, with trifluoroacetic acid in methylene chloride at 25 ° C or with tetrabutylammonium fluoride in THF at 25 ° C to provide the alcohol 9. The conversion of the alcohol 9 to the amine 11 can be carried out as described in Example 1, Step 1. Alternatively, the reaction of 9 with n-nor trobenzenesulfonyl chloride and triethylamine chloride in methylene at 5-25 ° C will provide the m-nitrobenzenesulfonate 10 which is it will react with ammonium hydroxide in THF or acetonitrile-isopropanol at 30-60 ° C to provide the amine 11. Reaction of compound 11 with acyl halides, anhydrides, isocyanates, isothiocyanates or dithioesters provides the compounds of Formula I. - The compounds of Formula I, wherein R is hydrogen and X is oxygen, are conveniently prepared by allowing the compounds 12 to react with p-toluenesulfonyl chloride and sodium carbonate in aqueous acetone at 20-40 ° C (see Example 1, Step 4).

Scheme I H OH cxx R2? v - ,, or- CH, Ph 3 The compounds of the invention are useful for the treatment of microbial infections in humans and other warm-blooded animals by either parenteral, oral, or topical administration. The term "treatment", in the sense in which it is used herein, means the partial or total loss of symptoms in a patient suffering from a disease; the term "prevention", in the sense in which it is used herein, means to partially or totally avoid the symptoms in a patient suffering from a disease, according to a medical diagnosis, you may suffer from the disease or a related condition unless preventive measures are taken. The pharmaceutical compositions of this invention can be prepared by combining the compounds of Formula I of this invention with a pharmaceutically acceptable solid or liquid carrier and, optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques. Compositions in solid form include powders, tablets, dispersible granules, capsules and suppositories. A solid carrier can be at least one substance that can also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, 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 waxes, cocoa butter, and the like. The compositions in liquid form include solutions, suspensions and emulsions. For example, solutions of the compounds of this invention dissolved in water and systems of aqueous propylene glycol and aqueous polyethylene glycol can be provided, optionally containing conventional coloring agents, flavoring agents, stabilizers and thickening agents. Preferably, the pharmaceutical composition is made by employing conventional techniques in unit dosage form containing effective amounts of the active component, ie, the compound of Formula I according to this invention. The amount of the active component, i.e., the compound of Formula I, in the pharmaceutical composition and the unit dosage form thereof can be varied or adjusted widely depending on the particular application method, the potency of the particular compound and the concentration desired. In general, the amount of the active component will vary between 0.5% to 90% by weight of the composition. In therapeutic use for treating or combating bacterial infections in humans and other animals that have been diagnosed with bacterial infections, the compounds or pharmaceutical compositions thereof can be administered orally, parenterally and / or topically at a dose for obtaining and maintaining a concentration, i.e., an amount, or blood level of the active component in the animal to which the treatment will be administered which will be antibacterially effective. In general, this antibacterially effective amount of active agent dose will vary in the range of from about 0.1 to about 100 mg / kg, more preferably from about 3.0 to about 50 mg / kg of body weight / day. It should be understood that the doses may vary depending on the requirements of the patient, the severity of the bacterial infection that will be treated, and the particular compound that will be used. Also, it should be understood that the initial dose administered can be increased beyond the previous upper level to quickly achieve the desired blood level or dose, initial can be lowered from the optimum and the daily dose can be progressively increased during the course of the treatment depending on the particular situation. If desired, the daily dose can also be divided into multiple doses for administration, for example, two to four times a day. The compounds of Formula I are administered parenterally, i.e., by injection, for example, by intravenous injection or by other parenteral routes of administration. Pharmaceutical compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compound according to Formula I as a soluble salt (acid addition salt or base salts) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water for injection and an isotonic solution properly cushioned, for example, which has a pH of about 3.5-6. Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L (+) -lysin and L (+) - arginine, to name a few. The compounds according to Formula I will generally be dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about 1 mg / ml to about 400 mg / ml. The resulting liquid pharmaceutical composition will be administered to obtain the antibacterially effective amount mentioned in the above dosages. The compounds of Formula I, according to this invention, are advantageously administered orally in solid and liquid dosage forms. As a topical treatment, an effective amount of a compound of Formula I is mixed in a pharmaceutically acceptable gel or cream carrier that can be applied to the skin of the patient in the treatment area. The preparation of these creams and gels is well known in the art and may include penetration enhancers. The compounds of this invention are useful antimicrobial agents, effective against various human and veterinary pathogens, including gram-positive aerobic organisms such as st aphyl oco cci and strep to cocci of multiple resistance, gram-negative organisms such as for example H. influenzae and M. catar rhal is, as well as anaerobic organisms such as, for example, bacteroid and clostridia species, and acid resistant organisms such as for example Mycobacterium tuberculosis and Mycobacterium avium. To illustrate more fully the nature of the invention and the manner of practicing it, the following experimental examples are presented, although they should not be taken as limitations.

EXAMPLE 1 Preparation of (S) -N- [[3- [3-fluoro-4- (1,2,3,4,6,7-hexahydro-5-oxo-l, 4-diazepin-1-yl) phenyl] -2 -oxo-5-oxazolidinyl] ethyl] -acetamide Step 1: Preparation of (S) -N- [3- (3-fluoro-4-piperidin-1-yl-enyl) -2 -oxo-oxazolidin-5-ylmethyl) -acetamide: Diisopropylethylamine (15.7 ml) is added and 3,4-difluoronitrobenzene (5.0 ml) successively to a solution of ethyl acetate (70 ml) of piperidine (5.77 g) and the mixture is stirred at room temperature for 2 days. Water is added to the reaction solution and the ethyl acetate layer which separates is washed with water and brine, dried over anhydrous sodium sulfate. The solvent is evaporated to produce a nitro compound (10.1 g) in 100% yield. Palladium on carbon (10%, 1.0 g) is added to a solution of ethyl acetate (101 ml) of the nitro compound (10.1 g) and the mixture is stirred at room temperature for 4 hours under a hydrogen atmosphere. The palladium on carbon is removed by filtration and the filtrate is concentrated under vacuum to provide an amine (8.75 g, 100%). Sodium hydrogen carbonate (5.0 g) and benzyloxycarbonyl chloride (8.4 ml) are added successively to a solution of tetrahydrofuran (THF) (100 ml) of the amine (8.75 g), and the mixture is stirred at room temperature for 14 hours . Water is added to the reaction solution and the separating THF layer is washed with water and brine, dried over anhydrous sodium sulfate. The solvent is evaporated and the residue is purified by silica gel column chromatography (solvent: ethyl acetate / hexane / chloroform = 1/6/4) to yield a benzyl carbamate (14.5 g) in a yield of 98%. %. Butyl lithium (1.6M hexane solution: 5.2 ml) is added to a THF solution (24 ml) of the benzyl carbamate (2.75 g) at -78 ° C and the mixture is stirred for 5 minutes. At the same temperature, - (R) - (-) - glycidylbutyrate (1.25 ml) is added to the stirred solution and the mixture is stirred for 14 hours while the temperature is slowly increased to room temperature. Water is added to the reaction solution and the separating THF layer is washed with water and brine, dried over anhydrous sodium sulfate. The solvent is evaporated and the residue is purified by silica gel column chromatography (solvent: ethyl acetate / hexane = 3/1) to yield an alcohol (2.20 g) in an 89% yield. Tosyl chloride (2.85 g) is added to a solution of pyridine (8 ml) of the alcohol (_2.20 g) and the mixture is stirred at room temperature for 6 hours. Water (32 ml) is added to the reaction solution and the mixture is stirred for 1 hour. The resulting precipitate is collected by filtration and washed with water, followed by drying under vacuum at room temperature to produce a tosylate (3.28 g) in 98% yield. Azide (3.80 g) is added to a solution of dimethylformamide (DMF) (23 ml) of tosylate (3.28 g) at room temperature and the mixture is stirred at 65 ° C for 5.5 hours. After the reaction mixture is cooled to room temperature, water is added and the mixture is extracted with ethyl acetate; The organic layer is concentrated under vacuum. The resulting residue is dissolved in ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate. The solvent is evaporated and the residue is purified by silica gel column chromatography (solvent: ethyl acetate / hexane = 1/1) to yield an azide (2.20 g) in 94% yield. Acetic anhydride (0.65 ml) and pyridine (1.0 ml) are added to a solution of ethyl acetate (19 ml) of the azide (2.20 g) at room temperature; After the addition of palladium on carbon (10%, 0.22 g), the mixture is stirred at room temperature for 6 hours under 1 atm atmosphere of hydrogen. The palladium on carbon is removed by filtration and the filtrate is washed with water and brine, dried over anhydrous sodium sulfate. The solvent is evaporated and the residue is purified by silica gel column chromatography (solvent: acetone / hexane = 1/1) to produce the title compound.

Step 2: Preparation of (S) -N-. { 3- [3-fluoro-4- (4-oxo-piperidin-1-yl) -phenyl] -2 -oxo-oxazolidin-5-ylmethyl} -acetamide. Using a commercially available 1, -dioxo-8 -aza-spiro [4.5] decane, the (S) -N- is synthesized. { 3- [- (1, 4-dioxa-8-aza-spiro [4.5] dec-8-yl) -3-fluoro-phenyl] -2-oxo-oxazolidin-5-ylmethyl} -acetamide by the same method as in Step 1. To a solution of acetone (70 ml) of this compound (3.79 g), water (20 ml) and p-toluenesulfonic acid monohydrate (3.66 g) are added successively and the mixture is added. it is heated under reflux for 3 hours. After the reaction mixture is cooled to room temperature, the acetone is distilled off and the aqueous layer is neutralized with triethylamine. The solution is extracted with methylene chloride and the organic layer is washed with brine, dried over anhydrous sodium sulfate. The solvent is evaporated and the residue is purified by silica gel column chromatography (solvent: chloroform / methanol = 50 / 1-25 / 1) to yield the title compound.

Step 3: Preparation of (S) -N-. { 3- [3-fl-4- (4-hydroxyimino-piperidin-1-yl) -phenyl] -2-oxo-oxazolidin-5-ylmethyl} -acetamide. Sodium acetate (517 mg) and hydroxylamine hydrochloride (219 mg) are successively added to a solution of meth anol-methylene chloride (10-10 ml) of 1.00 g of the product of Step 2, and the mixture is stirred at room temperature for 2 days. The solvent is evaporated and the residue is dissolved in methanol, followed by the addition of a silica gel (8 g). The methanol is evaporated and the residue is purified by silica gel column chromatography (solvent: chlorofor or / methanol = 50 / 1-25 / 1) to yield the title compound.

Step 4: Preparation of (S) -N- [[3- [3-Fluoro-4- (1,2,3,4,6,7-hexahydro-5-oxo-l, 4-diazepin-1-yl ) phenyl] -2 -oxo-5-oxazolidinyl] methyl] -acetamide. A stirred mixture of the product compound of Step 3 (0.200 g, 0.549 mmol) in acetone (5.3 L), under nitrogen, is treated first with 5% aqueous sodium carbonate (5.3 mL) and then, dropwise during 3 minutes with a solution of p-toluenesulfonyl chloride (0.16 g, 0.82 mmol) in acetone (2.7 mL). Initially this mixture is a two-phase solution; however, after approximately 25 minutes, it becomes a precipitate. It is kept at room temperature (23 ° C) for 4 hours and filtered. The filtrate is concentrated under reduced pressure to remove the acetone and the aqueous residue is extracted with CH2C12. The extract is dried (MgSO4) and concentrated to provide a small amount of the product without purification. The majority of the product is in the aqueous layer which is concentrated in vacuum. The residue is combined with the unpurified product from the CH2C12 extract and chromatographed on silica gel with mixtures of MeOH-NH OH-CH2C12 which is continued with 3-5% MeOH and 0.3-0.5% NH4OH. . The product is crystallized from MeOH-EtOAc to provide the title compound. p. F. 140-146 ° C. MS m / z (relative intensity) 364 (M +, 96.1), 320 (100), 306 (6.7), 294 (10.9), 236 (41.8); HRMS calculated for C? 7H2? FN404; 364.1547 (M +); found 364.1545; XH NMR '[300 MHz, (CD3) 2SO] d 1.81 (s, 3H), 2.57 (m, 2H), 3.07 (m, 4H), 3.24 (m, 2H), 3.38 (t, 2H) 3.67 (d , d, 1H), 4.06 (t, 1H), 4.68 (m, 1H), 7.08 (t, 1H), 7.13 (d, d, 1H), 7.45 (d, d, 1H), 7.65 (t, 1H) ), 8.21 (t, 1H).

EXAMPLE 2: Preparation of (S) -N- [[3- [3-fluoro-4- (1,2,3,4,6,7-hexahydro-5-oxo-l, 4-diazepin-1-yl phenyl] -2 -oxo-5-oxazolidinyl] methyl] - ioace amide Step 1: Preparation of (S) - [3- [3-fl-4- (1,2,3,4,6,7-hexahydro-S-oxo-l, 4-diazepin-1-yl) - phenyl] -2 -oxo-5-oxazolidinyl] methyl t-tr-butyldimethylsilylether. A stirred solution of 10.6 g (0.03 mole) of (S) - [3- [4- (1,4-dioxo-8 -azaespiro [4.5] dec-8-yl) -3-fluorophenyl] -2 -oxo- 5-oxazolidinyl] methanol, the intermediate of formula 2 (Scheme 1) for the preparation of (S) -N-. { 3- [3-fluoro-4 - (4-oxopiperidin-1-yl) phenyl] -2-oxooxazolidin-5-ylmethyl} -acetamide (Example 1, Step 2), in acetone (230 mL) is treated with water (65 mL) and p-toluenesulfonic acid monohydrate (11.4 g, 0.06 moles), brought to reflux under nitrogen for 5 hours and maintained at room temperature (24 ° C) for 161 hours. Then concentrate in vacuo to remove the acetone. The aqueous residue is neutralized with sodium bicarbonate and extracted with ethyl acetate.; the extract is washed with saturated sodium bicarbonate, water and dilute sodium chloride, dried (Na2SO4) and concentrated to provide the ketone; a compound of formula 4 (Scheme 1). A stirred solution of the ketone and triethylamine (12.5 mL, 0.09 mol) in methylene chloride (100 mL) is treated with tert-butyldimethylsilyl chloride (6.03 g, 0.04 mol) and kept under nitrogen at room temperature for 23 hours. Additional tert-butyldimethylsilyl chloride (3.0 g) is added and the mixture is kept at room temperature for an additional 20 hours Additional triethylamine (3.0 mL) and tert-butyldimethylsilyl chloride (3.0 g) are added again. the mixture is kept at room temperature for 4 days, diluted with methylene chloride, washed with water and dilute sodium chloride, dried (Na2SO) and concentrated by chromatography of the residue on silica gel. of acetone-heptane containing 20-30% acetone provides 7.72 g of the tert-butyldimethylsilylether (TBDMS), a compound of the formula 5 (Scheme 1) where P is TBDMS.A stirred solution of the TBDMS ether (7.27 g, 17.2 mmol) in methanol (150 mL) is treated dropwise drop with a solution of hydroxylamine hydrochloride (1.44 g, 0.021 mol) and sodium acetate (1.72 g, 0.021 mol) in water (15 mL) and kept at room temperature for 20 hours. The mixture is concentrated under reduced pressure. A solution of the residue, a white solid, in methylene chloride is washed with water and dilute sodium chloride, dried (Na2SO4) and concentrated to provide 7.25 g of the oxime, a compound of the formula 6 (Scheme 1). A stirred solution of the oxime in acetone (165 mL), under nitrogen, is treated with 5% aqueous sodium carbonate (1755 mL) and then dropwise for 20 minutes with a solution of p-chloride. toluenesulfonyl (4.92 g, 0.0258 mol) in acetone (80 mL) The mixture is kept at room temperature for 18 hours and then concentrated under reduced pressure.A solution of the residue in methyl chloride, log is washed with water and chloride Dilute sodium, dry (Na2SO4) and concentrate The chromatography of the residue on silica gel with 3% methanol-0.3% ammonium hydroxide-methylene chloride provides 5.98 g of the title compound.

Step 2: Preparation of (S) - [[3- [3- luoro-4- (1,2,3,4,6,7-hexahydro-5-oxo-l, 4-diazepin-1-yl) phenyl) ] -2 -oxo-5-oxazolidinyl] methyl] -amine. A stirred mixture, cooled with ice, of the product of Example 2, Step 1 (0.22 g 0.50 mmol) in tetrahydrofuran (THF, 15 mL), under nitrogen, is treated dropwise for 2 minutes, with a 1M solution of fluoride. t etrabut ilamonio in TRF (1.5 mL). The mixture is kept in the ice bath for 10 minutes and at room temperature (24 ° C) for 1 hour and 25 minutes, diluted with ethyl acetate, washed with water and brine, dried (Na 2 SO) and concentrated. Chromatography of the residue on silica gel, with mixtures of methanol-methylene chloride containing 3-6% methanol provides 0.15 g of the alcohol, a compound of the formula 9 (Scheme 1) where R is hydrogen: MS (ES) m / z 324 (M + H +). A stirred suspension of the alcohol (0.15 g, 0.46 mmol) in methylene chloride (15 L) and THF (8 mL), under nitrogen, is treated with triethylamine (0.5 mL, 1.4 mmol) and then in portions for 1 minute at room temperature. environment, with 0.14 g (0.56 mmoles) of m-nit robencensul fonilo chloride. The mixture is stirred for 90 minutes, mixed with additional methylene chloride (10 mL) to provide a solution and maintained at room temperature for 1 hour. It is then kept for several days at -11 ° C, diluted with methylene chloride, washed with saturated sodium bicarbonate, water and brine, dried (Na2SO4) and concentrated to provide 0.21 g of the m-nitrobencenesulfonate, a compound of formula 10 (Scheme 1). A stirred mixture of m-nitrobenzenesulfonate (0.21 g, 0.44 mmol), acetonitrile (10 mL), 2-propanol (10 mL) and 29% ammonium hydroxide (10 L) is heated to 45-50 ° C under a condenser of acetone in Dry Ice for 4.5 hours and kept at room temperature for 18 hours. Additional ammonium hydroxide is added (5 L) and the mixture is heated at 45-50 ° C for 4.5 hours, maintained at room temperature for 1 hour, treated with 5 mL of ammonium hydroxide and maintained at room temperature for 18 hours. It is then concentrated to provide a yellow solid which is chromatographed on silica gel with mixtures of methylene chloride methanol containing 5-7.5% methanol followed by 8% methanol-0.2% ammonium hydroxide -chloride. of methylene to provide the title product.

Step 3: Preparation of (S) -N- [[3- [3-fl-4- (1,2,3,4,6,7-hexahydro-5-oxo-l, 4-d azepin-1 -yl) phenyl] -2 -oxo-5-oxazolidinyl] methyl] -t-oacetamide. A stirred solution of 0.12 g of the product from Example 2, Step 2 and 0.40 mL of triethylamine in a mixture of methylene chloride (10 mL) and methanol (10 mL), under nitrogen, is treated with ethyl dithioacetate (0.05 mL) and it is maintained at room temperature for 145 hours. Additional 0.05 mL portions of ethyl dithioacetate are added after 24, 31 and 49 hours; additional triethylamine (1.0 mL) is also added after 49 hours. The mixture is concentrated to a small volume, diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and concentrated. Chromatography of the residue on silica gel with 3.5% methanol-methylene chloride provides 0.061 g of the title product. 1 H NMR [300 MHz, (CD 3) 2 SO] d 2.42 (s, 3 H), 2.56 (, 2 H), 3.07 (m, 4 H), 3.24 (m, 2 H), 3.76 (dd, 1 H), 3.87 (m, 2H), 4.11 (t, 1H), 4.91 (, 1H), 7.12 (m, 2H), 7.46 (dd, 1H), 7.67 (broad s, 1H), 10.35 (broad s, 1H).

EXAMPLE 3: Preparation of (S) -N- [[3- [3-fluoro-4 - (1,2,3,4,6,7-hexahydro-4-methyl-5-oxo-l, 4-diazepin -1-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -acetamide Step 1: Preparation of (S) - [[3- [3-fluoro-4- (1,2,3,4,6,7-hexahydro-4-methyl-5-oxo-l, 4-diazepin-1 -yl) phenyl] -2-oxo-5-oxazolidinyl] -methyl] amide. A mixture of 0.63 g (1.4 mmol) of the product of Example 2, Step 2, methyl iodide (0.093 mL) and THF (40 mL) is added dropwise over 12 minutes, under nitrogen, to a stirred mixture of powdered potassium hydroxide (0.12 g) and tet rabutyl ammonium bromide (0.096 g) in THF (10 L) and maintained at room temperature for 20 hours. It is then diluted with ethyl acetate, washed with water and brine, dried (MgSO) and concentrated. Chromatography of the residue on silica gel with mixtures of acetone-methylene chloride containing 10-40% acetone gives 0.46 g (71%) of the methylated product, a compound of formula 8 (Scheme 1) where R ' It is methyl. A stirred, ice-cooled mixture of this product (0.17 g, 0.38 mmol) and THF (12 mL), under nitrogen, is treated dropwise with a 1M solution of tetrabutylammonium fluoride in THF (1.2 mL). It is kept in the ice bath for 15 minutes and at room temperature for 3 hours, mixed with ice water and extracted with ethyl acetate. The extract is washed with water and brine, dried (MgSO) and concentrated to rovide 0.15 g of the alcohol, a compound of the formula 9 (Scheme 1). An ice-cooled, stirred solution of the alcohol (0.52 g, 1.5 mmol) and triethylamine (0.60 mL) in methylene chloride (45 mL) is treated portionwise for 5 minutes with m-nitrobenzenesulfonyl chloride (0.42 g). The mixture is kept in the ice bath for 15 minutes and at room temperature for 3 hours, diluted with methylene chloride, washed with saturated sodium bicarbonate, water and brine, dried (MgSO4) and concentrated to provide the -nitrobenzenesulfonate, a compound of formula 10 (Scheme 1). A stirred mixture of this product, acetonitrile (35 mL), 2-propanol (35 mL) and concentrated ammonium hydroxide (35 mL) is maintained at 45-50 ° C under a Dry Ice-acetone condenser for 4.5 hours and at room temperature. environment for 20 hours. Additional ammonium hydroxide (6 mL) is added and the mixture is maintained at 45-50 ° C for 5.5 hours and at room temperature for 18 hours. The mixture is then concentrated under reduced pressure to remove the organic solvents and the aqueous residue is extracted first with ethyl acetate and then with methylene chloride. The extracts are washed with water and brine, dried (MgSO4) and concentrated. Chromatography of the residue on silica gel with mixtures of methanol-methylene chloride containing 7.5-10% methanol gives the title compound. * Step 2: Preparation of (S) -N- [[3- [3-fluoro-4- (1,2,3,4,6,7-hexahydro-4-methyl-5-oxo-l, 4-diazepin -1-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide. A stirred, ice-cooled mixture of 0.10 g (0.30 mmol) of the product from Example 3, Step 1, and pyridine (1.74 mL), under nitrogen, is treated dropwise with acetic anhydride (0.57 mL, 6. 04 mmoles) and kept in the bath with ice for 15 minutes and at room temperature during 3. 5 hours. Then he concentrates in a vacuum; The residue is mixed with ice water and saturated sodium bicarbonate and extracted with ethyl acetate. The extract is washed with water and brine, dried (MgSO) and concentrated. Crystallization of the residue from ethyl acetate and io-methanol provides 0.053 g of the title compound. p. F. 203-204 ° C. MS (ES) m / z 379 (M + H +), 401 (M + Na +). Analysis calculated for C? 8H23Fl ^ 04: C, 57.13; N, 14.81. Found C, 57.05; H, 6.23; N, 14.85.

EXAMPLE 4 Preparation of (S) -N- [[3- [3- Luoro-4- (1,2,3,4,6,7-hexahydro-4-methyl-5-oxo-l, 4- diazepin- 1-yl) phenyl] -2-oxo-5-oxazolidinyl] -methyl] -thioacetamide A stirred, ice cooled solution of 0.18"g (0.535 mmol) of the product of Example 3, Step 1 and triethylamine (0.21 mL) in _THF (8 mL) and methylene chloride (10 mL) is treated with a dithioacetate solution. of ethyl (0.074 mL, 0.6T4 ~ mmoTL) in THF (2 mL) The mixture is kept at room temperature for 20 hours, treated with an ethyl dithioacetate drop and maintained at room temperature for 7 hours. Then it is concentrated under a stream of nitrogen. The residue is mixed with methylene chloride, washed with saturated sodium bicarbonate, water and brine, dried (Na 2 SO) and concentrated. Chromatography of the residue on silica gel with mixtures of methanol-methylene chloride containing 2-4% methanol and crystallization of the product from ethyl acetate provide 0. 13 g of the title compound. p. F. 157-158 ° C. Analysis calculated for C? 8H23FN403S: C, J 54.81; H, 5.88; N, 14.20. Found: C, 54.83; H, . 93; "N, 14.11.

EXAMPLE 5 MIC Test Method The MIC in vi t ro of the test compounds are determined by a standard agar dilution method. A concentrated drug solution of each analog is prepared in the preferred solvent, typically DMSO: H20 (1: 3). Double serial dilutions of each sample were made using aliquots of 1.0 ml of sterile distilled water. To each aliquot of 1.0 ml of drug, 9 ml of molten Mueller Hinton agar medium is added. The drug-supplemented agar is mixed, emptied into 15 x 100 mm petri dishes, and allowed to solidify and dry before inoculation. The vials or vials of each of the test organisms are kept frozen in the vapor phase of a liquid nitrogen freezer. The test cultures are allowed to grow overnight at 35 ° C in the medium suitable for the organism. Colonies are harvested with a sterile swab and cell suspensions are prepared in Trypticase Soy Broth (TBS) to equalize the turbidity of a 0.5 McFarland standard. A dilution of 1:20 of each suspension in TBS is made. The plates containing the drug-supplemented agar are inoculated with a 0.001 ml drop of the cell suspension using a Steers replicator, providing approximately 104 to 105 cells per spot. The plates are incubated overnight at 35 ° C. After incubation of the Minimum Inhibitory Co-concentration (MIC μg / ml), the lowest concentration of the drug that inhibits the visible growth of the organisms is read and recorded. The data is shown in Table I.

TABLE I a) S. aureus, culture 9213 b) S. epidermidis, culture 12084 c) E. faecalis, culture 9217 d) S. pueumoniae, culture 9912 e) H. influenzae, culture 30063 f) _. taste rhalis, crop 30610

Claims (10)

1. CLAIMS A compound of Formula I or a pharmaceutically acceptable salt thereof wherein: R is H, C2_6 alkenyl, C2_7 alkynyl, C6_6 alkyl or C3_6 alkyl substituted with one or two of the following: a) F, b ) Cl, c) CF 3, d) -OH, e) C 1 alkoxy, f) -CH 2 C (= 0) C 1 alkyl, g) -0C (= 0) N (R 4) 2, h) alkyl of C? _4 S (0) n, (where n is 0, 1 or 2) i) -CN, j) carboxy, k) alkoxycarbonyl of -C? _, 1) -C (= 0) N ( R4) 2, m) -N (R4) S02alkyl of C? _4, n) -N (R4) C (= 0) alkyl of C? _, O) -N (R4) C (= 0) N (R4) ) 2, p) -N (R) C (= 0) C 1 -4 alkoxy, q) aryl, or) Het; aryl is phenyl, optionally substituted with one or two of the following: a) F, b) Cl, c) Br, d) -CF 3, e) CN, f) C 1 alkoxy, or g) C 1-3 alkylthio; Het is a 5- or 6-membered heteroaromatic portion having from 1 to 3 N, O or S atoms, optionally substituted with the following: a) F, b) Cl, c) C 3 alkoxy, d) alkylthio of C? _3, or CN; Ri and R2 are independently a) H, b) F, or c) Cl; R. is a) C? _6 alkyl, optionally substituted with one to three F atoms or one to two Cl atoms, b)? -s alkoxy, c) amino, d) C? -6 alkylamino, and ) dialkylamino of C? _g) C3-6 cycloalkyl, g) C1-6 alkylthio, or h) (where m is 0, 1, 2, 3 6 R < is a) H, or b) C? _3 alkyl; Y X is O or S.
2. 2. A compound according to claim 1, wherein X is 0.
3. 3. A compound according to claim 1, wherein X is S.
4. 4. A compound according to claim 1, wherein R is H.
5. 5. A compound according to claim 1, wherein R is C? _4 alkyl.
6. 6. A compound according to claim 1, wherein R 3 is C 1 - alkyl, optionally substituted with one to three of F or one to two of Cl.
7. 7. The compound according to claim 1, wherein Formula I is the S-enantomer.
8. 8. A compound according to claim 1 which is (a) (S) -N - [[3- [3-fluoro-4- (1, 2,3,4,6,7-hexahydro-5-oxo-1, 4 -diazepin-1-yl) phenyl] -2 -oxo-5-oxazolidinyl] methyl] acetamide (b) (S) -N - [[3- [3-fluoro-4- (1, 2,3,4, 6,7-hexahydro-5-oxo-1,4-diazepin-1-yl) phenyl] -2 -oxo-5-oxazolidinyl] methyl] thioacetamide (c) (S) -N - [[3- [3- fluoro-4- (1, 2,3,4,6,7-hexahydro-4-methy1-5 -oxo-1,4-diazepin-1-yl) phenyl] -2-oxo-5-oxazolidinyl] met il ] acetamide, or (d) (S) -N - [[3- [3-fluoro-4- (1, 2,3,4,6,7-hexahydro-4-methyl-5-oxo-1, 4-diazepin-l-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide
9. 9. A method for treating microbial infections in a human being comprising administering to a patient in need thereof an effective amount of a compound of Formula I as shown in claim 1.
10. 10. A pharmaceutical composition comprising a compound of Formula I as shown in claim 1 and a pharmaceutically acceptable carrier.