WO2003020709A1 - 1,2-oxazin-3-one derivatives as antibacterial agents - Google Patents

Abstract

The invention relates to novel oxazinones, methods of synthesizing the compounds, and the use of the compounds as antibacterial agents.

Description

l , 2 -0XAZIN-3-0NE DERIVATIVES AS ANTIBACTERIAL AGENTS

Background of the Invention Many antibiotics act by interfering with the biosynthesis of bacterial cell walls

(Strominger et al J. Bio. Chem. 234:3263 (1959)). The completion of bacterial cell wall synthesis is mediated by enzymes termed penicillin-binding proteins (PBPs) which cross-link different peptidoglycan chains. In particular, PBPs link the penultimate D- Ala residue of a peptidoglycan terminating in a N-acyl-D-Ala-D-Ala moiety to the terminal amino group of a lysine residue of another peptidoglycan chain. Glycopeptide transpeptidase is an example of a PBP present in many bacteria.

Most known PBPs are serine peptidases, which have a conserved Ser-X-X-Lys sequence at the active site. The β-lactam family of antibiotics, whose members include penicillins and cephalosporins, inhibit PBPs by forming a covalent bond with the hydroxyl group to produce an acyl-enzyme as shown in Scheme 1 below:

SCHEME 1

The enzyme is then, unable to carry out the final step in the biosynthesis of the bacterial cell wall (Ghuysen, J.-M., Annu. Rev. Microbio. (1991) 45:37-67). As a result the wall is weakened, becomes permeable to water, and the bacterial cell swells, bursts, and dies.

The simplest kinetic description of the reaction between a bacterial enzyme (Enz) and a β-lactam antibiotic is given in Scheme 2 below:

SCHEME 2

In addition to the PBP's, many bacteria also produce a second type of penicillin- recognizing enzyme, known as a β-lactamase. PBPs and β-lactamase enzymes exhibit the same kinetics as set forth in Scheme 1 above, but with different rate constants. This difference in rate constants has important consequences. In the case of PBP's, k₂ » k₃ (i.e., the formation of the acyl-enzyme is much faster than its hydrolysis). The result is that the enzyme is inhibited, and antibacterial activity may be observed. In the case of a β-lactamase, k₂~k₃ (i.e., the formation and hydrolysis of the acyl enzyme proceed at comparable rates). These kinetics lead to regeneration of the enzyme, and inactivation of the antibiotic as a result of the net hydrolysis of the β-lactam bond in the deacylation step. The latter sequence of reactions comprises the principle mechanism of bacterial resistance to β-lactam antibiotics. Useful antibacterial activity is generally considered to require k₂/kι>1000M^"'sec^"1 and k₃<l x 10^"4sec^"'.

Resistance to antibiotics is a problem of much current concern. Alternatives to existing antibiotics are invaluable when bacteria develop immunity to these drugs or when patients are allergic (approximately 5% of the population is allergic to penicillin). Because of the relatively low cost and relative safety of the β-lactam family of antibiotics, and because many details of their mechanism of action and the mechanism of bacterial resistance are understood, one approach to the problem of resistance is to design new classes of compounds that will complex to and react with a penicillin recognizing enzyme, and be stable to the hydrolysis step. In order to be effective, the antibacterial agent should have the ability to react irreversibly with the active site serine residue of the enzyme.

The crystal structures of β-lactamases from B. licheniformis, S. aureus and E. coli (RTEM) suggest a chemical basis for resistance to β-lactam antibiotics. Apart from the conserved Ser-X-X-Lys active site sequence, these β-lactamases have a conserved Glul66 which participates in the hydrolysis of the acyl-enzyme. It appears that the acylated hydroxyl group of the active site serine and the carboxyl group of Glu 166, together with a water molecule, are involved in the hydrolysis step. The water molecule and the carboxyl group act in concert and this interaction is the source of bacterial resistance to β-lactam antibiotics. Drug design must therefore include a process for the removal or inactivation of this water molecule.

Numerous β-lactam compounds have been developed in the past which are structural analogues of penicillin and can complex to and react with penicillin recognizing enzymes. Like penicillin, such antibiotics are presumed to be conformationally constrained analogues of an N-acyl-D-Ala-D-Ala peptidoglycan moiety, the O=C-N β-lactam bond serving as a bioisostere of the D-Ala-D-Ala peptide bond. Effective antibacterial activity also requires a properly positioned carboxyl group or equivalent and a hydrogen bonding hydroxyl or acylamino group. A computer implemented molecular modeling technique for identifying compounds which are likely to bind to the PBP active site and, thus, are likely to exhibit antibacterial activity has been developed (U.S. Patent No. 5,552,543).

Some oxazinones having possible biological activity are known in the prior art Khomutov et al. synthesized tetrahydro-l,2-oxazin-3-one (Chem. Abs. 13754a, 1962) and 4-benzamidotetrahydro-l,2-oxazin-3-one (Chem. Abs. 58, 13944b, 1963). The latter compound is also known as N-benzoyl-cyclocanaline. According to Khomutov, cyclocanaline is known to inhibit glutamate-aspartate transaminase and exhibits activity against tuberculosis bacilli. The structure of cyclocanaline is shown in formula (A) below.

Frankel et al. reported the synthesis of DL-cyclocanaline (4-amino-tetrahydro- l,2-oxazin-3-one) hydrochloride from canaline dihydrochloride in 1969 (J. Chem. Soc. (C) 174601749, 1969) and recognized that DL-cyclocanaline is a higher homologue of the antibiotic cycloserine.

Summary of Invention The invention pertains, at least in part, to oxazinone compounds of the formula

(I):

wherein

R is an amino acid side chain mimicking moiety;

R² _, R⁴, R⁵, R⁶, R⁸ and R⁹ are each independently selected substituting moieties;

R⁷ is hydrogen, or a prodrug moiety, and pharmaceutically acceptable salts thereof, provided that R² is not hydroxy when R⁴, R⁵, and R⁶ are each hydrogen, and R¹ is hydrogen or methyl; and provided that R₂ is not methoxy when

R⁴, R⁵, and R⁶ are each hydrogen.

In a further embodiment, the invention also includes oxazinone compounds of the formula (II):

wherein:

R , ι i •s an amino acid side chain mimicking moiety;

R² is alkoxy, OH, NH₂ or NHCOR₃;

R³ is a antibacterial substituent;

R⁴ is H or lower alkyl;

R⁵ is H, OH, NH or NHCOR₃ or the oxygen of a carbonyl group when taken together with R⁶;

R⁶ is H, OH, NH₂ or NHCOR , and pharmaceutically acceptable salts thereof, provided that R² is not hydroxy when R⁴, R⁵, and R⁶ are each hydrogen, and R¹ is hydrogen or methyl; and provided that R₂ is not methoxy when R¹, R⁴, R⁵, and R⁶ are each hydrogen.

In another embodiment, the invention pertains, at least in part, to methods for treating a bacterial associated state in a subject. The method includes administering to the subject an effective amount of an oxazinone compound of formula (I).

In yet another embodiment, the invention also includes pharmaceutical compositions, which comprise an effective amount of an oxazinone compound of formula (I) and a pharmaceutically acceptable carrier. In another embodiment, the invention also pertains, at least in part, to methods of synthesizing oxazinone compounds. The method includes contacting an amino acid compound with a butanoic acid compound under conditions such that cyclization occurs and the oxazinone compound of formula (I) is formed. The amino acid compound is of the formula (III):

The butanoic acid compound

and the oxazinone compound

wherein

R is an amino acid side chain mimicking moiety;

R² _, R⁴, R⁵, R⁶, R⁸ and R⁹ are each independently selected substituting moieties;

R⁷ is hydrogen, or a prodrug moiety,

L is a leaving group; and

P and P are protecting groups, and acceptable salts thereof.

Detailed Description of the Invention In one embodiment, the invention pertains, at least in part to oxazinone compounds of the formula (I):

wherein R¹ is an amino acid side chain mimicking moiety;

R², R⁴, R⁵, R⁶, R⁸ and R⁹ are each independently selected substituting moieties;

R⁷ is hydrogen, or a prodrug moiety, and pharmaceutically acceptable salts thereof, provided that R² is not hydroxy when R⁴, R⁵, and R⁶ are each hydrogen, and R¹ is hydrogen or methyl; and provided that R₂ is not methoxy when

R⁴, R⁵, and R⁶ are each hydrogen.

The oxazinone compounds of the invention, such as compounds of formula I, were designed using the computer-implemented molecular modeling technique described in United States Patent No. 5,552,543. The structural relationship between the N-acyl-D-Ala-D-Ala peptidoglycan moiety, penicillin and the oxazinone compounds of the invention are illustrated by formulae (B) - (D) below, the bold lines highlighting the structural similarities.

Both the (C) and D) compounds are considered to be conformationally constrained analogues of the peptidoglycan moiety (which explains their ability to bind specifically to the active site of bacterial enzymes linking peptidoglycan chains). The oxazinone carbonyl group corresponds to the penicillin β-lactam carbonyl group; the hydrogen of the oxazinone hydroxyl group corresponds to the N-H hydrogen of the acylamino side chain of penicillin; and the carboxyl group of the carboxy ethyl substituent of (D) corresponds to the C3-carboxyl group of penicillin.

The language "amino acid side chain mimicking moiety" ("R¹") includes moieties that are amino acid side chains or mimic amino acid side chains and which allow the oxazinone (e.g., a compound of formula I) to perform its intended function by, e.g., mimicking the structure or function of an amino acid side chain. For example, the "amino acid side chain mimicking moiety" allows the oxazinone to interact with the active site of a penicillin recognizing enzyme. Examples of amino acid side chain moieties include the side chains of natural and unnatural D- and L- amino acids. For example, the amino acid side chain mimicking moiety may be the side chain of a neutral amino acid (e.g., glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, or methionine), a polar amino acid (e.g., serine, threonine, cysteine, tyrosine, asparagine, or glutamine), or a charged amino acid (e.g., aspartic acid, glutamic acid, lysine, arginine, or histidine). In an embodiment, the amino acid side chain mimicking moiety is the side chain of alanine (e.g., methyl).

In another embodiment, the amino acid side chain mimicking moiety is substituted or unsubstituted alkyl, e.g., lower alkyl. The side chain mimicking moiety may be substituted with any substituent that allows it to perform its intended function (e.g., when present in the oxazinone, it should allow the oxazinone to interact with penicillin recognizing enzyme, etc.). Examples of alkyl amino acid side chain mimicking moieties include straight chain, branched and cyclic alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, i-propyl, n-propyl, i-butyl, n-butyl, t-butyl, pentyl, cyclopentyl, cyclohexyl, or hexyl. Other examples of amino acid side chain mimicking moieties include alkenyl, alkynyl, carbonyl, aralkyl or aryl moieties. Examples of aryl moieties include substituted and unsubstituted phenyl and substituted and unsubstituted heteroaryl. The term "substituting moiety" includes moieties which can be placed at any one of R², R⁴, R⁵, R , R⁸, or R⁹ of the oxazinone compound without prohibitively detrimentally affecting the ability of the oxazinone to perform its intended function. Examples of substituting moieties include alkyl, hydrogen, alkenyl, alkynyl, aryl, hydroxyl, amino, protected hydroxyl, protected amino, thiol, halogen, NHCOR³, etc. and other substituents which are not detrimental to the antibacterial activity of the oxazinone compound. Other examples of substituting moieties include carbonyl and thiocarbonyl groups (e.g., R² and R⁴ or R⁵ and R⁶ taken together are the oxygen of a carbonyl group or the sulfur of a thiocarbonyl group).

Examples of R and R include hydrogen and lower alkyl (e.g., methyl, ethyl, propyl, butyl). Examples of R include protected hydroxyl, hydroxyl, alkoxy, hydrogen, etc. Examples of R⁴ and R⁶ include hydrogen and lower alkyl. Examples of R⁵ include amino, NHCOR , hydroxy, methoxy, etc. In a particular embodiment, both of R⁸ and R⁹ are hydrogen.

The language "prodrug moiety" includes moieties which can be cleaved in vivo to yield an active drug (see, e.g., R.B. Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action", Academic Press, Chp. 8). Prodrugs can be used to alter the biodistribution or the pharmacokinetics for a particular compound. Examples of prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl moieties, lower alkenyl moieties, di-lower alkyl-amino lower-alkyl moieties (e.g., dimethylaminoethyl), acylamino lower alkyl moieties (e.g., acetoxymethyl), acyloxy lower alkyl moieties (e.g., pivaloyloxymethyl), aryl moieties (e.g., phenyl), aryl-lower alkyl (e.g., benzyl), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl moieties, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxy amides. Also included are groups which may not need to be removed to yield an active drug.

In another embodiment, R⁷ is hydrogen. The term "antibacterial substituent" ("R ") includes such substituents such as, for example, those described in U.S. 4,013,653, U.S. 4,775,670; and U.S. 4,822,788, as substituents which enhance the antibacterial activity of cephalosporin or penicillin. Each of these patents is incorporated herein by reference in their entirety. Examples of substituents include substituted and unsubstituted arylalkyls, such as benzyl. In a further embodiment, R is electron withdrawing. Examples of electron withdrawing R² groups include, but are not limited to, NR₃+, SR +, NH₃+, NO , SO R, CN, SO₂Ar, COOH, F, Cl, Br, I, OAr, COOR, OR, COR, SH, SR, NHCOR³, and OH, wherein R is an alkyl, alkenyl, alkynyl, or aryl moiety.

In another embodiment, R² is capable of hydrogen bonding. Examples of groups capable of hydrogen bonding, include, but are not limited to, OR, SH, SR, OH, F, COOR, NH₂, etc.

In a further embodiment, R is halogen, e.g., fluorine. Other potentially advantageous R² groups include hydroxy (e.g., OH) and alkoxy (e.g., OR). Examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, etc. In a further embodiment, R and R taken together are the oxygen of a carbonyl group or the sulfur of a thiocarbonyl group.

In a further embodiment, R is amino or NHCOR , wherein R is an antibacterial substituent (e.g., substituted or unsubstituted benzyl). In another embodiment, R⁵ is hydroxyl or halogen (e.g., fluorine). In another further embodiment, R⁵ and R⁶ taken together are the oxygen of a carbonyl group or the sulfur of a thiocarbonyl group.

In a further embodiment, the oxazinone compound of the invention has one of the following stereochemistries:

In a further e (II):

wherein: R is an amino acid side chain mimicking moiety;

R² is alkoxy, OH, NH₂ or NHCOR₃; R³ is a antibacterial substituent; R⁴ is H or lower alkyl;

R⁵ is H, OH, NH₂ or NHCOR₃ or the oxygen of a carbonyl group when taken together with R⁶;

R⁶ is H, OH, NH or NHCOR₃, and pharmaceutically acceptable salts thereof, provided that R² is not hydroxy when R⁴, R⁵, and R⁶ are each hydrogen, and R¹ is hydrogen or methyl; and provided that R₂ is not methoxy when R¹, R⁴, R⁵, and R⁶ are each hydrogen. In a further embodiment, the compounds of formula II comprise compounds wherein R is hydrogen or the side chain of alanine. The oxazinone compounds also include compounds wherein R² is OH. Compounds of formula II wherein R⁴, R⁵, and R⁶ are each independently hydrogen are also included.

In a further embodiment, the compound of formula II is 2-[2-substituted carboxyethyl]-5-hydroxy-l,2-oxazin-3-one.

In one embodiment, the invention pertains to oxazinones wherein R₅ and R₆ taken together comprise the oxygen of a carbonyl group. In another embodiment, the invention includes compounds wherein R₂ is OH, and Ri, R_t, R₅ and R₆ are hydrogen and the compound has S- or R- configuration at C5. In another embodiment, the invention includes compounds wherein Ri is methyl,

R is OH, R₄ R₅ and Re are each hydrogen with the S-configuration at both Cl ' and C5. Ri is methyl, R₂ is OH, Rt, R₅ and R₆ are hydrogen, and which has either the R- configuration at both Cl ' and C5, the S-configuration at Cl ' and the R-configuration at cs, or the R-configuration at Cl ' and the S-configuration at C5. Examples of compounds of the invention include, but are not limited to, 2-carboxymethyl-5-hydroxy- l,2-oxazin-3-one, 2-[2-carboxypropyl]-5-hydroxy-l,2-oxazin-3-one, and 2-[2- substituted carboxyethyl]-5-hydroxy-l ,2-oxazin-3-one.

In another embodiment, the invention pertains to a method for treating a bacterial associated state in a subject. The method includes administering to said subject an effective amount of an oxazinone compound of formula (I):

wherein

R¹ is an amino acid side chain mimicking moiety;

R², R⁴, R⁵, R⁶, R and R⁹ are each independently selected substituting moieties; R is hydrogen, or a prodrug moiety, and pharmaceutically acceptable salts thereof. The term "treating" includes curing as well as ameliorating at least one symptom of the state, disease or disorder.

The term "subject" includes organisms capable of suffering from an bacterial associated state, such as mammals (e.g. primates (e.g., monkeys, gorillas, chimpanzees, and, advantageously, humans), goats, cattle, horses, sheep, dogs, cats, mice, rabbits, pigs, dolphins, ferrets, squirrels), reptiles, or fish. In a further embodiment, the subject is suffering from the bacterial associated disorder at the time of administering the oxazinone compound of the invention.

The term "administering" includes routes of administration which allow the oxazinone compound to perform its intended function. Examples of routes of administration which can be used include parental injection (e.g., subcutaneous, intravenous, and intramuscular), intraperitoneal injection, oral, inhalation, and transdermal. The injection can be bolus injections or can be continuous infusion. Depending on the route of administration, the oxazinone compound can be coated with or disposed in a selected material to protect it from natural conditions which may detrimentally effect its ability to perform its intended function. The oxazinone compound can be administered alone, with a pharmaceutically acceptable carrier, or in combination with a supplementary compound, e.g., an antibiotic, e.g., penicillin or cephalosporin. The oxazinone compound can be administered prior to the onset of an bacterial associated state, or after the onset of a bacterial associated state. The oxazinone compound also can be administered as a prodrug which is converted to another (e.g., active) form in vivo. The term "bacterial associated state" includes states characterized by the presence of gram-positive pathogens, for example Staphylococci, Enterococci, Streptococci and mycobacteria. In a further embodiment, the bacterial associated state is associated with a bacterial strain which is resistant to conventional antibiotics. Examples of such strains include methicillin resistant staphylococcus (MRSA), methicillin resistant coagulase negative staphylococci (MRCNS), penicillin resistant streptococcus pneumoniae and multiply resistant Enterococcus faecium.

In a further embodiment, the oxazinone compound of the invention is administered in combination with a pharmaceutically acceptable carrier.

In another further embodiment, the oxazinone compound is administered in combination with a supplementary compound. Examples of supplementary compounds include antibiotics such a penicillin, methicillin, cephalosphorin, vancomycin, etc.

The term "in combination with" a supplementary compound is intended to include simultaneous administration of the oxazinone compound and the supplementary compound, administration of the oxazinone compound first, followed by the supplementary compound, and administration of the supplementary compound first, followed by the oxazinone compound second. Any of the therapeutically useful compound known in the art for treating a particular bacterial associated state can be used in the methods of the invention. In yet another embodiment, the invention includes pharmaceutical compositions comprising an e

wherein

R , ι is an amino acid side chain mimicking moiety;

RR²² _,, RR⁴⁴,, RR⁵⁵,, RR⁶⁶,, RR⁸ aanndd RR⁹⁹ aarree eeaacchh iinnddeeppeennddeennttllyy sseelected substituting moieties;

R I ⁷ is hydrogen, or a prodrug moiety, and pharmaceutically acceptable salts thereof. In a further embodiment, the pharmaceutical composition of the invention includes a pharmaceutically acceptable carrier and/or a supplementary agent, e.g., an antibiotic. In further embodiment, the effective amount of the oxazinone compound is effective to treat a bacterial infection of a subject, e.g., a human.

In a further embodiment, the invention also includes a method of synthesizing an oxazinone compound. The method includes contacting an amino acid compound with a butanoic acid compound under appropriate conditions such that cyclization occurs, such that an oxazinone compound is formed, wherein said amino acid compound is of the

the butanoic acid compound i

and the oxazinone compound

wherein

R is an amino acid side chain mimicking moiety;

R² _, R⁴, R⁵, R⁶, R⁸ and R⁹ are each independently selected substituting moieties;

R⁷ is hydrogen, or a prodrug moiety,

L is a leaving group; and

P and P are protecting groups, and acceptable salts thereof.

The term "leaving group" or "L" include groups which present in the butanoic acid compound result in the formation of the oxazinone compound in acceptable yields. Examples of leaving groups include halogens such as bromine, although other groups compatible to the chemistry of the cyclization reaction may also be substituted for the bromine.

The language "protecting group" includes groups which can be used to protect the carboxylic acid functionality during synthesis of the oxazinone compound. Any protecting moiety known in the art and compatible with the other functionality of the oxazinones, the starting materials, and the intermediates may be used. Examples of protecting moieties include esters, groups known to those of skill in the art, and those described in Greene, Protective Groups in Organic Synthesis, Wiley, New York (1981), incorporated herein by reference. The term "appropriate conditions " includes the conditions necessary for the condensing agent and the cyclization agent to form the desired oxazinone compound. The appropriate conditions may comprise reagents, solvent, atmosphere composition, time, pressure, catalysts, and other variables known to those of skill in the art that may effect the outcome and yield of a chemical reaction. The appropriate conditions may be altered during the synthesis of an oxazinone such that a multistep synthesis can be performed. For example, for the synthesis of certain oxazinone compounds of the invention, it may be necessary to perform multistep syntheses after or before the cyclization to yield the desired oxazinone of the invention. For example, the appropriate conditions may comprise several reaction conditions (optionally with purification of the intermediates) and intermediates. Examples of other reagents which may be used to transform the aminoxy compound into a particular desired oxazinone of the invention include protecting agents, deprotecting agents, oxidation agents, etc.

The term "condensing agent" includes chemical entities which promote the chemical coupling of the amino acid compound and the butanoic acid compound. One example of a condensing agent is dicyclohexylcarbodiimide.

The term "cyclization agent" includes agents which promote the formation of the oxazinone ring. Examples of cyclization agents include, but are not limited to, bases, such as organic amines.

In a further embodiment, the oxazinone is synthesized by the condensation of a carboxyl-protected N-hydroxy alpha-amino acid with a 3-hydroxy- protected-4-bromobutanoic acid, cyclization of the resulting doubly protected N- hydroxy-N-acylated alpha amino acid, and removal of the protecting groups. In yet a further embodiment, the carboxyl-protecting group is t-butyl, the hydroxyl-protecting group is 2-tetrahydropyranyl, the condensing agent is dicyclohexylcarbodiimide, the cyclization is performed with an organic amine, and the removal of the protecting groups is performed with trifluoroacetic acid. As set forth in the following examples, two oxazinones exhibiting antibacterial activity have been synthesized and chemically characterized, namely 2- carboxymethyl-5-hydroxy-l,2-oxazin-3-one and 2-[2-substituted carboxyethyl]-5- hydroxy-l,2-oxazin-3-one. These compounds are chemically stable, can be synthesized easily in large quantities from inexpensive and readily available starting materials, and exhibit antibacterial activity.

The chemical syntheses of 2-carboxymethyl-5-hydroxy-l,2-oxazin-3-one and 2-[2-substituted carboxyethyl]-5-hydroxy-l,2-oxazin-3-one are summarized in Scheme 3.

SCHEME 3

Briefly, a carboxyl-protected N-hydroxyamino acid is condensed with a 3- hydroxyprotected-4-bromobutanoic acid to form a doubly protected N-hydroxy N- acylamino acid. In Example 1 below, the carboxyl-protected N-hydroxy amino acid is t- butyl N-hydroxyglycine. In Example 2 below, the carboxyl-protected N-hydroxy amino acid is t-butyl N-hydroxyalanine. The doubly protected N-hydroxy N-acylamino acid is cyclized with an organic base to yield a doubly protected l,2-oxazin-3-one. The protecting groups are then removed to provide an antibacterial agent. In a preferred embodiment, the carboxyl and hydroxyl protection are, respectively, t-butyl and 2- tetrahydropyranyl, the condensing agent is dicyclo-hexylcarbodiimide, the cyclizing agent is diazabicycloundecene, and the deprotecting agent is trifluoroacetic acid. Other methods of synthesizing the oxazinone compounds of the invention are described in U.S. Provisional Patent Application 60/310,103, and U.S. Provisional Patent Application Serial No. 60/XXX,XXX, entitled "Methods for Synthesizing Oxazinones," filed on August 29, 2001, both of which are incorporated herein by reference.

The term "alkyl" includes saturated aliphatic groups, including straight- chain alkyl groups (e.g. , methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (e.g., isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. The term alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkyl has 6 or fewer carbon atoms in its backbone (e.g, Cι-C for straight chain, C₃-C for branched chain), and more preferably 4 or fewer. Likewise, preferred cycloalkyls have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure. The term Cι-C₆ includes alkyl groups containing 1 to 6 carbon atoms. Moreover, the term alkyl includes both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxy carbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Cycloalkyls can be further substituted, e.g., with the substituents described above. An "alkylaryl" or an "arylalkyl" moiety is an alkyl substituted with an aryl (e.g, phenylmethyl (benzyl)). The term "alkyl" also includes the side chains of natural and unnatural amino acids.

The term "aryl" includes groups, including 5- and 6-membered single- ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, the term "aryl" includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzthiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, diazapurine, or indolizine. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles", "heterocycles," "heteroaryls" or "heteroaromatics". The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfliydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifiuoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g., tetralin). The term "alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.

For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups

(cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups. The term alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-Cg for straight chain, C3-C6 for branched chain). Likewise, cycloalkenyl groups may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure. The term C₂-C₆ includes alkenyl groups containing 2 to 6 carbon atoms. Moreover, the term alkenyl includes both "unsubstituted alkenyls" and

"substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfliydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

The term "alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.

For example, the term "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups. The term alkynyl further includes alkynyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-Cg for straight chain, C3-C5 for branched chain). The term C -C₆ includes alkynyl groups containing 2 to 6 carbon atoms.

Moreover, the term alkynyl includes both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including, e.g., alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfliydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to five carbon atoms in its backbone structure. "Lower alkenyl" and "lower alkynyl" have chain lengths of, for example, 2-5 carbon atoms. The term "acyl" includes compounds and moieties which contain the acyl radical (CH₃CO-) or a carbonyl group. The term "substituted acyl" includes acyl groups where one or more of the hydrogen atoms are replaced by, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonylj alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfliydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

The term "acylamino" includes structures wherein an acyl moiety is bonded to an amino group. For example, the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups. The term "aroyl" includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthylcarboxy, etc.

The terms "alkoxy alkyl", "alkylaminoalkyl" and "thioalkoxyalkyl" include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.

The term "alkoxy" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfliydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc.

The term "amine" or "amino" includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom. The term "alkylamino" includes groups and compounds wherein the nitrogen is bound to at least one additional alkyl group. The term "dialkylamino" includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups. The term "arylamino" and "diarylamino" include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively. The term "alkylarylamino," "alkylaminoaryl" or "arylaminoalkyl" refers to an amino group which is bound to at least one alkyl group and at least one aryl group. The term "alkylaminoalkyl" refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group.

The term "amide" or "aminocarboxy" includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group. The term includes "alkylaminocarboxy" groups which include alkyl, alkenyl, or alkynyl groups bound to an amino group bound to a carboxy group. It includes arylaminocarboxy groups which include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group. The terms "alkylaminocarboxy," "alkenylaminocarboxy," "alkynylaminocarboxy," and "arylaminocarboxy" include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties, respectively, are bound to a nitrogen atom which is in turn bound to the carbon of a carbonyl group.

The term "carbonyl" or "carboxy" includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom. Examples of moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc. The term "thiocarbonyl" or "thiocarboxy" includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.

The term "ether" includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms. For example, the term includes "alkoxyalkyl" which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group. The term "ester" includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group. The term "ester" includes alkoxycarbony groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynyl groups are as defined above.

The term "thioether" includes compounds and moieties which contain a sulfur atom bonded to two different carbon or hetero atoms. Examples of thioethers include, but are not limited to alkylthioalkyls, alkylthioalkenyls, and alkylthioalkynyls. The term "alkylthioalkyls" include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group. Similarly, the term

"alkylthioalkenyls" and alkylthioalkynyls" refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.

The term "hydroxy" or "hydroxyl" includes groups with an -OH or -O^". The term "halogen" includes fluorine, bromine, chlorine, iodine. The term "perhalogenated" generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.

The terms "polycyclyl" or "polycyclic radical" refer to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g. , the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the poly cycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, arylalkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfliydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety.

The term "heteroatom" includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus. It will be noted that the structure of some of the compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof. The invention also pertains to pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention and, optionally, a pharmaceutically acceptable carrier.

The language "pharmaceutically acceptable carrier" includes substances capable of being coadministered with the compound(s) of the invention, and which allow both to perform their intended function. Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc. The pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds of the invention. The compounds of the invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of the compounds of the invention that are basic in nature are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and palmoate [i.e., 1,1'- methylene-bis-(2-hydroxy-3-naphthoate)] salts. Although such salts must be pharmaceutically acceptable for administration to a subject, e.g. , a mammal, it is often desirable in practice to initially isolate a compound of the invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The preparation of other compounds of the invention not specifically described in the foregoing experimental section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art.

The compounds of the invention that are acidic in nature are capable of forming a wide variety of base salts. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of the invention that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmaceutically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g. , calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines. The pharmaceutically acceptable base addition salts of compounds of the invention that are acidic in nature may be formed with pharmaceutically acceptable cations by conventional methods. Thus, these salts may be readily prepared by treating the compound of the invention with an aqueous solution of the desired pharmaceutically acceptable cation and evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, a lower alkyl alcohol solution of the compound of the invention may be mixed with an alkoxide of the desired metal and the solution subsequently evaporated to dryness.

The compounds of the invention and pharmaceutically acceptable salts thereof can be administered via either the oral, parenteral or topical routes. In general, these compounds are most desirably administered in effective dosages, depending upon the weight and condition of the subject being treated and the particular route of administration chosen. Variations may occur depending upon the species of the subject being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out.

The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the routes previously mentioned, and the administration may be carried out in single or multiple doses. For example, the novel therapeutic agents of this invention can be administered advantageously in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically- effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.

For parenteral administration (including intraperitoneal, subcutaneous, intravenous, intradermal or intramuscular injection), solutions of a therapeutic compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. For parenteral application, examples of suitable preparations include solutions, preferably oily or aqueous solutions as well as suspensions, emulsions, or implants, including suppositories. Therapeutic compounds may be formulated in sterile form in multiple or single dose formats such as being dispersed in a fluid carrier such as sterile physiological saline or 5% saline dextrose solutions commonly used with injectables. Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin. Examples of methods of topical administration include transdermal, buccal or sublingual application. For topical applications, therapeutic compounds can be suitably admixed in a pharmacologically inert topical carrier such as a gel, an ointment, a lotion or a cream. Such topical carriers include water, glycerol, alcohol, propylene glycol, fatty alcohols, triglycerides, fatty acid esters, or mineral oils. Other possible topical carriers are liquid petrolatum, isopropylpalmitate, polyethylene glycol, ethanol 95%, polyoxyethylene monolauriate 5% in water, sodium lauryl sulfate 5% in water, and the like. In addition, materials such as anti-oxidants, humectants, viscosity stabilizers and the like also may be added if desired.

For enteral application, particularly suitable are tablets, dragees or capsules having talc and/or carbohydrate carrier binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch. A syrup, elixir or the like can be used wherein a sweetened vehicle is employed. Sustained release compositions can be formulated including those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc. In addition to treatment of human subjects, the therapeutic methods of the invention also will have significant veterinary applications, e.g. for treatment of livestock such as cattle, sheep, goats, cows, swine and the like; poultry such as chickens, ducks, geese, turkeys and the like; horses; and pets such as dogs and cats. Also, the compounds of the invention may be used to treat non-animal subjects, such as plants. It will be appreciated that the actual preferred amounts of active compounds used in a given therapy will vary according to the specific compound being utilized, the particular compositions formulated, the mode of application, the particular site of administration, etc. Optimal administration rates for a given protocol of administration can be readily ascertained by those skilled in the art using conventional dosage determination tests conducted with regard to the foregoing guidelines.

In a further embodiment, the compounds of the invention do not include 2- [2- carboxyethyl]-5-hydroxy-l,2-oxazin-3-one (e.g., a compound of formula (I) wherein R₂ is OH, R₄, R₅, and R₆ are each hydrogen, and Ri is methyl); 2-carboxymethyl-5- hydroxy-l,2-oxazin-3-one (e.g., a compound of formula (I) wherein R is OH, R_t, R₅, and R₆ are each hydrogen, and Ri is hydrogen); nor 2-carboxymethyl-5-methoxy-l ,2- oxazin-3-one (e.g., a compound of formula (I) wherein R₂ is MeO, R₄, R₅, and R are each hydrogen, and Ri is hydrogen). In a further embodiment, the compounds of the invention do not include those compounds described in Stephen Ro, Studies Related to the Synthesis, Biosynthesis, and Mechanisms of Action of β-Lactam Compounds (1998), Ph.D. Thesis, Simon Fraser University nor C.I. Akuche, A Novel Antibacterial Agent by Design: 2-Carboxymethyl-5-Hydroxy-l,2-Oxazin-3-one, (1997), M.S. Thesis, Simon Fraser University; both of which are hereby incorporated herein by reference. The invention is further illustrated by the following examples, which should not be construed as further limiting.

Example 1: 2-CARBOXYMETHYL-5-HYDROXY-1,2-OXAZIN-3-ONE Step 1. Benzyl γ-Bromoacetoacetate. Diketene (500 μL, 545 mg, 6.5 mmoles) was dissolved, under nitrogen, in dichloromethane (2 mL), cooled to -25°C, and treated dropwise with a solution of bromine (333 μL, 1.02 g, 6.5 mmoles) in dichloromethane (2 mL). After the addition was complete, the solution was stirred at -25°C for 15 min, and benzyl alcohol (700 μL, 732 mg, 6.8 mmoles) was added dropwise. Stirring was continued for 15 min, and the solution was warmed to room temperature and evaporated. The residue was dissolved in diethyl ether (20 mL), washed successively with saturated sodium bicarbonate (2 x 20 mL), water (20 mL) and saturated sodium chloride (20 mL), dried over anhydrous magnesium sulfate and evaporated to give benzyl γ- bromoacetoacetate as a pale yellow oil (1.70 g, 97%). 1HMR (CDCI₃, δ): 7.36 (5H, m), 5.19 (2H, s), 4.02 (2H, s), 3.75 (2H, s). IR (neat); 3033, 1734, 1654 cm^"1. Mass spectrum (Cl, m/z): 271, 273 (M+l, M+3), Calcd. for C,ιHι>BrO₃: C48.69; H 4.05. Found: C 48:55; H 3.94.

Step 2. Benzyl-3-Hydroxy-4-Bromobutanoate. The product of step 1 (500 mg, 1.84 mmoles) was dissolved in a mixture of tetrahydrofuran (9 mL) and methanol (1 mL), the solution was cooled in an ice-bath, and sodium borohydride (72 mg, 1.90 mmoles) was added in one portion. Stirring was continued in the ice-bath for 15 min, and ethyl acetate (50 mL) and M hydrochloric acid (1.5 mL) were added. The aqueous layer was separated, extracted with ethyl acetate (20 mL), and the combined organic layers were washed with saturated sodium bicarbonate (40 mL), dried over anhydrous magnesium sulfate and evaporated to give benzyl 3-hydroxy-4-bromobutanoate (433 mg, 86%). 'HMR (CDC1₃, δ): 7.36 (5H, s), 5.17 (2H, s), 4.26 (1H, m), 3.50 (1H, dd, 5.0, 10.5 Hz), 3.47 (1H, dd, 5.6, 10.5 Hz), 3.06 (1H, d, 5.1 Hz), 2.72 (1H, dd, 5.0, 16.6 Hz), 2.69 (1H, dd, 7.3, 16.6 Hz). IR (neat): 3443, 3064, 1731, 1624 cm^"1. Mass spectrum (CI,m/z): 273, 275 (M+l, M+3). Calcd. for C_πHι₃BrO₃ 0.5H₂O: C 53.75; H 5.88. Found: C 53.65; H 5.60.

Step 3. Benzyl 3-[2-tetrahydropyranyloxy]-4-Bromobutanoate. The product of step 2 (845 mg, 3.09 mmoles) dissolved in dichloromethane (10 mL), and dihydropyran (300 μL, 277 mg, 3.29 mmole) and p-toluenesulfonic acid monohydrate (3 crystals) were added. The solution was stirred at room temperature for 1.5 h. Diethyl ether (40 mL) was then added, and the solution was washed with saturated sodium bicarbonate (2 x 40 mL), dried over anhydrous sodium sulfate, and evaporated. Purification by column chromatography using ethyl acetate-hexanes (3:7) gave benzyl 3-[2- tetrahydropyranyloxy]-4-bromobuta-noate (1.07 g, 97%) as a 1 :1 mixture of diastereisomers. IR (neat): 3033, 1737 cm-1. Mass spectrum (Cl, m/z): 357, 3539 (M+l, m+3). Calcd. for Cι₆H₂₁BrO₄: C 53.75; H 5.88. Found: C 53.65; H 5.60.

Step 4. 3-[2-Tetrahydropyranyloxy]-4-Bromobutanoic Acid. The product of Step 3 (73 mg, 0.20 mmole) was dissolved in tetrahydrofuran (3 mL) and 10% palladium on charcoal (65 mg) was added. The mixture was flushed thrice with nitrogen, thrice with hydrogen, and then stirred under hydrogen for 45 min. The mixture was filtered through Celite, the Celite was rinsed with ethyl acetate (10 mL), and the combined filtrates were evaporated to give 3-[2-tetrahydropyranyloxy]-4-bromobutanoic acid as a colourless oil, 54 mg (98%). IR (neat): 1715 cm^"1. Mass spectrum (Cl, m/z): 267, 269 (M+l, M+3).

Step 5. t-Butyl N-Hydroxyglycine. Z-Benzaldoxime (5.64 g, 46.61 mmol) and t-butyl bromoacetate (7.58 mL, 10 g, 51.27 mmol) were added successively to a solution of sodium (1.07 g, 0.047 g-atom) in a 2-propanol (120 mL). The suspension was stirred for 2 h and then poured into water (100 mL). Extraction with dichloromethane, followed by drying over anhydrous magnesium sulfate and concentration gave a residue which was chromatographed on silica gel. Elution with 60% ethyl acetate-hexanes gave t-butyl N- benzylideneglycine N-oxide.

The t-butyl N-benzylideneglycine N-oxide (1.3 g, 5.53 mmol) was added to a stirred suspension of sodium methoxide (0.418 g, 7.74 mmol) and hydroxylamine hydrochloride (0.538 g, 7.74 mmol) in methanol (6 mL). The mixture was stirred at 50°C until the solid dissolved, and the solvent was then removed. The residue was treated with dichloromethane, filtered and concentrated. The residue was chromatographed on silica gel. Elution with 60% ethyl acetate-hexanes gave t-butyl N- hydroxyglycine. Calculated for C₆H_nNO₂: C, 48.98; H, 8.84; N, 9.52. Found: C, 48.13; H, 8.65: N, 9.44.

Step 6. The product of Step 5 (85 mg, 0.32 mmol) was dissolved, under nitrogen, in methylene chloride (3 mL), the solution was cooled in an ice-bath, stirred, and dicyclohexylcarbodiimide (70 mg, 0.34 mmol) was added, followed by a solution of the product of Step 4 (46.8 mg, 0.32 mmol) in methylene chloride (3 mL). The cloudy mixture was stirred for 5 min in the ice-bath and was then allowed to warm to room temperature. After 12 h, ether (20 mL) was added, the mixture was filtered, and the filtrate was evaporated. The residue was chromatographed on silica gel. Elution with 30:70 ethyl acetate :hexane gave the compound shown in Scheme 3 at page 9, lines 27 - 30, R=H.

Step 7. Protected 2-Carboxymethyl-5-Hydroxy-l,2-Oxazin-3-One. The product of Step 6 (37 mg, 0.093 mmol) was dissolved in methylene chloride (2 mL), and triethylamine (14 μL, 10.2 mg, 0.10 mmol) was added. The solution was left, under nitrogen, for 1 h, and diazabicycloundecene (DBU) (7 μL, 0.047 mmol) was added followed, after 2 h, by an additional 5.0 μL (0.33 mmol) of DBU. Stirring was continued under nitrogen for 3.2 h, and the reaction mixture was then diluted with methylene chloride (10 mL), washed with water (10 mL), dried over anhydrous sodium sulfate and evaporated. Chromatography on silica gel and elution with 45:55 ethyl acetate :hexanes gave the product as a mixture of two diastereomers. 'Hmr (CDC1₃, δ): 4.66 (1H, m, one isomer), 4.41 (1H, m, second isomer), 4.32-4.45 (2H, m, both isomers), 3.83 (1H, m, one isomer), 2.94-2.62 (2H, both isomers), 1.8 (2H, m), 1.7 (2H, m), 1.55 (2H, m), 1.47 (9H, s).

Step 8. 2-Carboxymethyl-5-Hydroxy-l,2-Oxazin-3-one. The product of Step 7 (11 mg, 0.35 mmol) was dissolved, under nitrogen, in methylene chloride (1 mL), the solution was cooled in an ice-bath, and trifluoroacetic acid (3 mL) was added. Additional trifluoroacetic acid was added after 15 min (3 μL), after an additional 20 min (500 μL), and after an additional 30 min (300 μL). After an additional 55 min, the solvent was removed. The product was redissolved in trifluoroacetic acid (500 μL), evaporated after 30 min, and the residue was shaken with ethyl acetate (2 mL), water (1 mL) and sodium bicarbonate (3 mg). The aqueous phase was separated, washed with ethyl acetate, and lyophilized to give RS-2-carboxymethyl-5-hydroxy-l,2-oxazin-3-one as the sodium salt. Ηmr (D₂O, δ): 4.49 (1H, m), 4.29 (1H, dd, 12.1, 4.6 Hz), 4.28 (1H, d, 18.2 Hz), 4.15 (1H, d, 18.2 Hz), 4.02 (1H, ddd, 12.1, 3.2, 0.8 Hz), 2.92 (1H, dd, 16.8, 5.9 Hz), 2.52 (1H, ddd, 16.8, 3.2 Hz). The proton nmr spectrum of this compound is shown in Figure 3. Figure 4 suggests that the 5S enantiomer exhibits a slightly better fit to a model of the penicillin receptor than the 5R enantiomer.

Example 2: 2-[2-CARBOXYPROPYL]-5-HYDROXY-1,2-OXAZIN-3-ONE

Step 1. t-Butyl 2-Bromopropionate. Isobutylene (2.4 g, 42.8 mmoles) was condensed into a pressure bottle at -15°C. Dioxane (6 mL) and 2-bromopropionic acid (3.5 mL, 38.9 mmoles) were added and the mixture was stirred for 5 min, warmed to -10°C, and concentrated sulfuric acid (250 μL) was added. The bottle was scaled, the reaction mixture was stirred overnight at room temperature, and the bottle was then opened and the contents poured into dichloromethane (50 mL). The solution was washed with 20% potassium carbonate (50 mL), water (50 mL), dried over anhydrous magnesium sulfate and evaporated to give t-butyl bromopropionate (2.17 g, 27%). 1H NMR (CDC1₃, δ): 4.31 (IH, q, 7.1 Hz), 1.81 (3H, d, 7.1 Hz), 1.52 (9H, s).

Step 2. t-Butyl N-Benzylidenealanine N-Oxide. Z-Benzaldoxime (580 mg, 4.79 mmoles) and t-butyl 2-bromopropionate (VI- 18) (980 mg), 4.69 mmoles) were added successively to a solution of sodium hydride (200 mg, of a 60% dispersion in mineral oil, 5.00 mmoles) in 2-propanol (20mL). The suspension was stirred at room temperature for 3 h, and then poured into water and extracted with ethyl acetate (2 x 20 mL). The organic extract was dried over anhydrous magnesium sulfate and evaporated to give a white coloured solid. Trituration with anhydrous diethyl ether (8 mL) afforded the product (464 mg, 40%), m.p. 115-117°C. 1HMR (CDC1₃, δ): 8.26-8.23 (2H, m, Ar + HC=N⁺), 7.43-7.41 (4H, m, Ar), 4.65 (IH, q, 7.0 Hz, α-CH), 1.73 (3Η, d, 7.0 Hz, CH₃), 1.47 (9Η, s, CO₂C(CH₃)₃). IR (KRr): 1736, 1582 cm^"1. Mass spectrum (Cl, m/z): 250 (M+l). Calcd. for Cι₄Η19N<O₃: C 67.45; H 7.68; N 5.62. Found: C 67.10; H 7.59; N 5.90.

Step 3. t-Butyl N-Hydroxyalanine. The product of step 2 (460 mg, 185 mmoles) was added to a stirred suspension of sodium methoxide (141 mg, 2.61 mmoles) and hydroxylamine hydrochloride (182 mg, 2.62 mmoles) in dry methanol (5.5 8.69. Found: C 51.98; H 9.30; N 8.55.

Step 4. Coupling of3-[2-Tetrahydropyranyloxy]-4-Bromobutanoic Acid with t-Butyl N- hydroxyalanine. The 3-12-tetrahydropyranyloxyl-4-bromobutanoic acid (54 mg, 0.20 mmole (as prepared in Example 1 above, step 4)) was dissolved in dichloromethane (3 mL), the solution was cooled in an ice-bath, stirred, and dicyclohexylcarbodiimide (41 mg, 0.20 mmole) was added, followed by a solution of the ester t-Butyl N- hydroxyalanine in dichloromethane (2 mL). The mixture was stirred in the ice-bath for 5 min, the ice-bath was then removed, and stirring was continued for 3 h. The mixture was filtered, and the filtrate was evaporated. The residue was chromatographed on silica gel. Elution with ethyl acetate-hexanes (2:3) gave the compound shown in Scheme 3 at page 9, lines 27 - 30, R=CH₃ (74 mg, 54%). IR (CH₂CI₂): 3432, 1736, 1657 cm^"1. Mass spectrum (Cl, m/z): 410, 412 (M+l, M+3). Step 5. t-Butyl 2-[2-Carboxypropyl]-5-[2-Tetrahydropyranyloxy]-l,2-Oxazin-3-one. The product of Step 4 (36 mg, 0.088 mmole) was dissolved in dichloromethane (10 mL), cooled in an ice-bath, and l,8-diazobicyclo[5.4.0]undec-7-one (15μL, 0.1 mmole) was added. The solvent was removed after 1 h. The residue was dissolved in ethyl acetate (25 mL) and the solution was washed with water (2 x 25 mL), dried over anhydrous magnesium sulfate and evaporated to the protected oxazinone t-butyl 2- [2- carboxypropyl]-5-[2-tetrahydropyranyloxy]-l,2-oxazin-3-one (25 mg, 85%). IR (CH₂C1₂): 1736, 1678 cm^"1. Mass spectrum (Cl, m/z): 330 (M+l). HRMS-CI calcd. for Cι₆H₂₇NO₆: 330.1917 (M+l). Found: 330.1916.

Step 6. The product of Step 5 (10.1 mg, 0.031 mmol) was dissolved in dichloromethane, the solution was cooled in an ice-bath, and trifluoroacetic acid (1 mL^', 13.0 mmoles) was added. The solution was stirred for 30 min, and the solvent was then removed. The residue was dissolved in trifluoroacetic acid (500 μL), and the solution was stirred at room temperature for 15 min and evaporated. The residue was shaken with ethyl acetate (3 mL) and a solution of sodium bicarbonate (2.8 mg) in water (2mL). The aqueous phase was lyophilized to give the sodium salt of 2-[2-carboxypropyl]-5-hydroxy-l,2- oxazin-3-one as an approximately 1 :1 mixture of RR/SS and RS/SR diastereomers. 'HMR (D₂O, δ): 4.89 (lh, q, 7.3 hZ, α-CH, one isomer), 4.88 (1Η, q 7.3 Ηz, α-CH, second isomer), 4.72-4.69 (2Η, m, H5, both isomers), 4.54 (IH, d, 10.5 Hz, H6, one isomer), 4.53 (IH, d, 10.5 Hz, H6, second isomer), 4.35 (2H, d, 10.5 Hz, H6, both isomers), 2.97 (IH, d, 18.3 Hz, H4, one isomer), 2.95 (IH, d, 18.3 Hz, H4, second isomer), 2.51 (2H, m, 18.3 Hz, H4, both isomers), 1.45 (3H, d, 7.3 Hz, CO₂C(CH₃)₃, one isomer), 1.42 (3Η, d, 7.3 Hz, CO C(CH₃)₃, second isomer). Mass spectrum (Cl, m/z, for the acid VI- la): 190 (M+l), 172 (M+l-Η₂O) HRMS-CI calcd. for C₇H₁₂NO₅: 190.0716 (Ml). Found: 190.0712.

Example 3: Bioassay of the Product of Example 1

Samples were applied to filter discs in the amounts indicated. The discs were applied to agar plates seeded with Micrococcus luteus, and the plates were incubated overnight at 37°C. The results are summarized in Table 1.

Table 1

Example 4: Bioassay of the Product of Example 2

Samples were assayed as in Example 3, with the results summarized in Table 2.

Table 2

With reference to Tables 1 and 2, the bioassays suggest that the 2- carboxymethyl product of Example 1 (where R=H) exhibits weak antibacterial activity at least 1000 times less than that of penicillin. The 2-carboxyethyl analogue more closely resembles and is approximating the three-dimensional molecular structure of the D-Ala-D-Ala peptidoglycan skeleton and has approximately 50 times the activity of the carboxymethyl product.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope of the following claims. All patents, patent applications, and literature references cited herein are hereby expressly incorporated by reference.

Claims

1. An oxazinone compo

wherein

R¹ is an amino acid side chain mimicking moiety;

R² _, R⁴, R⁵, R⁶, R⁸ and R⁹ are each independently selected substituting moieties;

R⁷ is hydrogen, or a prodrug moiety, and pharmaceutically acceptable salts thereof, provided that R² is not hydroxy when R⁴, R⁵, and R⁶ are each hydrogen, and R¹ is hydrogen or methyl; and provided that R is not methoxy when R*_; R⁴, R⁵, and R⁶ are each hydrogen.

2. The oxazinone compound of claim 1, wherein R is alkyl.

3. The oxazinone compound of claim 2, wherein R 1 i •s methyl, ethyl, propyl or butyl.

The oxazinone compound of claim 1, wherein R is hydrogen.

5. The oxazinone compound of claim 1, wherein R is aryl.

6. The oxazinone compound of claim 1, wherein the oxazinone compound has the following stereochemistry:

7. The oxazinone compound of any one of claims 1-5, wherein R is electron withdrawing.

8. The oxazinone compound of any one of claims 1-5, wherein R² is a moiety capable of hydrogen bonding.

9. The oxazinone compound of claim 1 or 7, wherein R is halogen.

10. The oxazinone compound of claim 8, wherein R is fluorine.

11. The oxazinone compound of claim 1, wherein R 2 is alkoxy or a hydroxyl group.

12. The oxazinone compound of claim 1 , wherein R is hydrogen or lower alkyl.

13. The oxazinone compound of any one of claims 1-12, wherein said oxazinone compound has the following stereochemistry:

14. The oxazinone compound of claim 1 , wherein R² and R⁴ taken together are the oxygen of a carbonyl group.

15. The oxazinone compound of any one of claims 1-14, wherein R⁵ is amino or NHCOR , and R is an antibacterial substituent.

16. The oxazinone compound of claim 15, wherein R³ is benzyl.

17. The oxazinone compound of any one of claims 1-14, wherein R is hydroxyl.

18. The oxazinone compound of any one of claims 1-14, wherein R is halogen.

19. The oxazinone compound of claim 18, wherein said halogen is fluorine.

20. The oxazinone compound of any one of claims 1-19, wherein R⁶ is lower alkyl or hydrogen.

21. The oxazinone compound of any one of claim 1 -20, wherein said oxazinone compound has the following stereochemistry: A

22. The oxazinone compound of any one of claims 1-14, wherein R⁵ and R⁶ taken together are the oxygen of a carbonyl group.

23. The oxazinone compound of any one of claims 1-22, wherein R and R are each hydrogen.

24. The oxazinone compound of any one of claims 1-23, wherein R⁷ is a prodrug moiety.

25. The oxazinone compound of any one of claims 1-23, wherein R⁷ is hydrogen.

26. The oxazinone compound of any one of claims 1-25, wherein the stereochemistry is:

27. An ox

wherein:

R¹ is an amino acid side chain mimicking moiety;

R² is alkoxy, OH, NH₂ or NHCOR₃;

R is a antibacterial substituent;

R⁴ is H or lower alkyl;

R⁵ is H, OH, NH or NHCOR₃ or the oxygen of a carbonyl group when taken together with R°;

R > 6 is H, OH, NH₂ or NHCOR₃, and pharmaceutically acceptable salts thereof, provided that R² is not hydroxy when R⁴, R⁵, and R⁶ are each hydrogen, and R¹ is hydrogen or methyl; and provided that R₂ is not methoxy when R¹, R⁴, R⁵, and R⁶ are each hydrogen.

28. The oxazinone compound of claim 27, wherein R¹ is hydrogen.

29. The oxazinone compound of claim 27, wherein R¹ is the side chain of alanine.

30. The oxazinone compound of claim 27, wherein R is OH.

31. The oxazinone compound of claim 27, wherein R⁴ is hydrogen.

32. The oxazinone compound of claim 27, wherein R⁵ is hydrogen.

33. The oxazinone compound of claim 27, wherein R⁶ is hydrogen.

34. The compound of claim 27, wherein said compound is 2-[2-substituted carboxy ethyl] -5 -hydroxy- 1 ,2-oxazin-3 -one.

35. A method for treating a bacterial associated state in a subject, comprising administering to said subject an effective amount of an oxazinone compound, such that said bacterial associated state is treated, wherein said oxazinone compound is of formula

wherein

R is an amino acid side chain mimicking moiety;

R² _, R⁴, R⁵, R⁶, R⁸ and R⁹ are each independently selected substituting moieties; R⁷ is hydrogen, or a prodrug moiety, and pharmaceutically acceptable salts thereof.

36. The method of claim 35, wherein said compound is a compound of any one of claims 2-34.

37. The method of claim 35 or 36, wherein said subject is a mammal.

38. The method of claim 37, wherein said subject is a human.

39. The method of claim 35 or 36, wherein said oxazinone compound is administered in combination with a pharmaceutically acceptable carrier.

40. The method of claim 35, 36, or 39, wherein said oxazinone compound is administered in combination with a supplementary compound.

41. The method of claim 40, wherein said supplementary compound is an antibiotic.

42. The method of claim 41 , wherein said supplementary compound is penicillin or cephalasporin.

43. The method of any one of claims 35-42, wherein said bacterial associated state is a bacterial infection.

44. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amo

wherein

R¹ is an amino acid side chain mimicking moiety;

R² _; R⁴, R⁵, R⁶, R⁸ and R⁹ are each independently selected substituting moieties; R⁷ is hydrogen, or a prodrug moiety, and pharmaceutically acceptable salts thereof.

45. The pharmaceutical composition of claim 44, wherein said oxazinone compound is a compound of claims 2-35.

46. The pharmaceutical composition of any one of claims 44 or 45, wherein said composition further comprises a supplementary agent.

47. The pharmaceutical composition of claim 46, wherein said supplementary agent is a antibiotic.

48. The pharmaceutical composition of claim 47, wherein said antibiotic is penicillin or cephalosporin.

49. The pharmaceutical composition of claim 44, wherein said effective amount is effective to treat a bacterial infection.

50. A method of synthesizing an oxazinone compound, comprising contacting an amino acid compound with a butanoic acid compound under appropriate conditions such that cyclization occurs, such that an oxazinone compound is formed, wherein said amino acid compound is of the formula (III):

the butanoic acid

and the oxazinone compound is of the formula (I)

wherein

R is an amino acid side chain mimicking moiety;

R², R⁴, R⁵, R⁶, R⁸ and R⁹ are each independently selected substituting moieties;

R⁷ is hydrogen, or a prodrug moiety,

L is a leaving group; and

P and P are protecting groups, and acceptable salts thereof.

51. The method of claim 50, wherein said appropriate conditions comprise a condensing agent and a cyclization agent.

52. The method of claim 51, wherein said appropriate conditions comprise a condensing agent is dicyclohexylcarbodiimide.

53. The method of claim 51, wherein the cyclization agent is an organic amine.

54. The method of claim 50, wherein the leaving group is bromine.