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Oxazinones and methods for their use and synthesisRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered And Includes At Least Nitrogen And Oxygen As Ring Hetero Atoms (e.g., Monocyclic 1,2- And 1,3-oxazines, Etc.)Oxazinones and methods for their use and synthesis description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060069091, Oxazinones and methods for their use and synthesis. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATIONS [0001] This application is a continuation application of U.S. Ser. No. 10/411,547, filed Apr. 10, 2003, Issuing; which is a continuation application of U.S. Ser. No. 10/210,970, filed Aug. 2, 2002, Abandoned; which claims priority to U.S. Provisional Application Ser. No. 60/310,103, filed Aug. 3, 2001. The entire contents of each of these applications are hereby incorporated herein by reference in their entirety. [0002] This application is related to U.S. Pat. No. 6,399,600 B1, issued on Jun. 4, 2002, the entire contents of this patent are hereby incorporated herein by reference. BACKGROUND OF THE INVENTION [0003] Many antibiotics act by interfering with the biosynthesis of bacterial cell walls (Strominger et al. J. Biol. 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. [0004] Most known PBPs are serine peptidases, which have a conserved Ser-X-X-Lys sequence at the active site. The .beta.-lactam family of antibiotics, whose members include penicillins and cephalosporins, inhibit PBPs by forming a covalent bond with the serine hydroxyl group to produce an acyl-enzyme. The enzyme is then unable to carry out the final step in the biosynthesis of the bacterial cell wall. As a result the wall is weakened, becomes permeable to water, and the bacterial cell swells, bursts, and dies. [0005] The simplest kinetic description of the reaction between a bacterial enzyme (Enz) and a .beta.-lactam antibiotic is given in Scheme 1 below: [0006] In addition to the PBP's, many bacteria also produce a second type of penicillin-recognizing enzyme, known as a O-lactamase. PBPs and .beta.-lactamase 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, k.sub.2>>k.sub.3 (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 .beta.-lactamase, k.sub.2.apprxeq.k.sub.3 (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 .beta.-lactam bond in the deacylation step. The latter sequence of reactions comprises the principle mechanism of bacterial resistance to .beta.-lactam antibiotics. Useful antibacterial activity is generally considered to require k.sub.2/k.sub.1.gtoreq.1000 M.sup.-1 sec.sup.-1 and k.sub.3.ltoreq.1.times.10.sup.-4 sec.sup.-1. [0007] 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 .beta.-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. [0008] The crystal structures of .beta.-lactamases from B. licheniformis, S. aureus and E. coli (RTEM) suggest a chemical basis for resistance to .beta.-lactam antibiotics. Apart from the conserved Ser-X-X-Lys active site sequence, these .beta.-lactamases have a conserved Glu166 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 .beta.-lactam antibiotics. Drug design must therefore include a process for the removal or inactivation of this water molecule. [0009] Numerous .beta.-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.dbd.C--N .beta.-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. Pat. No. 5,552,543). [0010] Some oxazinones having possible biological activity are known in the prior art Khomutov et al. synthesized tetrahydro-1,2-oxazin-3-one (Chem. Abs. 13754a, 1962) and 4-benzamidotetaahydro-1,2-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. [0011] Frankel et al. reported the synthesis of DL-cyclocanaline (4-amino-tetrahydro-1,2-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 THE INVENTION [0012] The invention pertains, at least in part, to new intermediates and synthetic methods for the stereospecific synthesis of oxazinone compounds, which are useful, for example, as antibiotics. The invention also pertains to novel olefinic oxazinone compounds, methods for their synthesis, and methods of using these compounds for the synthesis of oxazinones. [0013] In one embodiment, the invention pertains to olefinic oxazinones of the formula (I): [0014] wherein: [0015] R.sub.1 is an amino acid side chain mimicking moiety; R.sub.4, R.sub.6, R.sub.8, and R.sub.9 are substituting moieties; [0016] R.sub.7 is hydrogen, a protecting moiety, or a prodrug moiety, and acceptable salts and esters thereof. [0017] The invention also pertains, at least in part, to methods for synthesizing oxazinones of the formula (II): wherein: [0018] R.sub.1 is an amino acid side chain mimicking moiety; [0019] R.sub.2 is halogen, OH, SH, NH.sub.2, NHCOR.sub.3, or an electronegative moiety; [0020] R.sub.3 is an antibacterial substituent; R.sub.4, R.sub.8 and R.sub.9 are each independently selected substituting moieties; [0021] R.sub.5 is OH, NH.sub.2, NHCOR.sub.3, or an electronegative moiety; and [0022] R.sub.6 is a substituting moiety or the oxygen of a carbonyl group when taken together with R.sub.5; [0023] R.sub.7 is hydrogen, a protecting moiety, or a prodrug moiety, and pharmaceutically acceptable salts and esters thereof. [0024] The method includes contacting an olefinic oxazinone of formula (I) with a derivatizing agent, under appropriate conditions such that an oxazinone of formula (II) is; synthesized. [0025] In another embodiment, the invention pertains in part to epoxide oxazinones of formulae (III) and (IV): [0026] R.sub.1 is an amino acid side chain mimicking moiety; [0027] R.sub.4, R.sub.6, R.sub.8 and R.sub.9 are each independently selected substituting moieties; [0028] R.sub.7 is hydrogen, a protecting moiety, or a prodrug moiety, and acceptable salts and esters thereof. [0029] In yet another embodiment, the invention pertains to methods for the synthesis of olefinic oxazinones. The method includes contacting a diolefin of formula (V) with a cyclization catalyst under appropriate conditions, such that an olefinic oxazinone of formula (I) is formed. The diolefin of formula (V) is: [0030] wherein: [0031] R.sub.1 is an amino acid side chain mimicking moiety; [0032] R.sub.4, R.sub.6, R.sub.8 and R.sub.9 are each independently selected substituting moieties; [0033] R.sub.7 is hydrogen, a protecting moiety, or a prodrug moiety, and acceptable salts and esters thereof. [0034] The invention also pertains, at least in part, to another method for the synthesis of an olefinic oxazinone of formula (I). The method includes treating an olefinic triphenyl phosphine salt with ozone under appropriate conditions, such that an olefinic oxazinone is formed. The olefinic triphenyl phosphine salt is of formula (VI) [0035] wherein: [0036] R.sub.1 is an amino acid side chain mimicking moiety; [0037] R.sub.4, R.sub.6, R.sub.8 and R.sub.9 are each independently selected substituting moieties; [0038] R.sub.7 is hydrogen, a protecting moiety, or a prodrug moiety, and pharmaceutically acceptable salts and esters thereof. [0039] 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 the invention, e.g., a compound of formula (I), (II), (III), (IV) or otherwise described herein. [0040] In yet another embodiment, the invention includes pharmaceutical compositions comprising an effective amount of a compound of the invention, e.g., a compound of formula (I), (II), (III), (IV) or otherwise described herein. Continue reading about Oxazinones and methods for their use and synthesis... Full patent description for Oxazinones and methods for their use and synthesis Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Oxazinones and methods for their use and synthesis patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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