WO2003020709A1 - Derives 1,2-oxazine-3-one utilises comme agents antibacteriens - Google Patents

Derives 1,2-oxazine-3-one utilises comme agents antibacteriens Download PDF

Info

Publication number
WO2003020709A1
WO2003020709A1 PCT/US2001/027261 US0127261W WO03020709A1 WO 2003020709 A1 WO2003020709 A1 WO 2003020709A1 US 0127261 W US0127261 W US 0127261W WO 03020709 A1 WO03020709 A1 WO 03020709A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
oxazinone
hydrogen
oxazinone compound
moiety
Prior art date
Application number
PCT/US2001/027261
Other languages
English (en)
Inventor
Saul Wolfe
Christiana Akuche
Stephen Ro
Original Assignee
Simon Fraser University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Simon Fraser University filed Critical Simon Fraser University
Priority to PCT/US2001/027261 priority Critical patent/WO2003020709A1/fr
Publication of WO2003020709A1 publication Critical patent/WO2003020709A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/02—1,2-Oxazines; Hydrogenated 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • PBPs penicillin-binding proteins
  • Glycopeptide transpeptidase is an example of a PBP present in many bacteria.
  • PBPs are serine peptidases, which have a conserved Ser-X-X-Lys sequence at the active site.
  • the ⁇ -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:
  • 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).
  • the wall is weakened, becomes permeable to water, and the bacterial cell swells, bursts, and dies.
  • PBPs and ⁇ -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.
  • k 2 » k 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.
  • k 2 ⁇ k 3 i.e., the formation and hydrolysis of the acyl enzyme proceed at comparable rates).
  • antibiotics 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 ⁇ -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.
  • 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).
  • 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.
  • 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.
  • the invention pertains, at least in part, to oxazinone compounds of the formula
  • R is an amino acid side chain mimicking moiety
  • R 2 , R 4 , R 5 , R 6 , R 8 and R 9 are each independently selected substituting moieties;
  • R 7 is hydrogen, or a prodrug moiety, and pharmaceutically acceptable salts thereof, provided that R 2 is not hydroxy when R 4 , R 5 , and R 6 are each hydrogen, and R 1 is hydrogen or methyl; and provided that R 2 is not methoxy when R 4 , R 5 , and R 6 are each hydrogen.
  • the invention also includes oxazinone compounds of the formula (II):
  • R 2 is alkoxy, OH, NH 2 or NHCOR 3 ;
  • R 3 is a antibacterial substituent
  • R 4 is H or lower alkyl
  • R 5 is H, OH, NH or NHCOR 3 or the oxygen of a carbonyl group when taken together with R 6 ;
  • R 6 is H, OH, NH 2 or NHCOR , and pharmaceutically acceptable salts thereof, provided that R 2 is not hydroxy when R 4 , R 5 , and R 6 are each hydrogen, and R 1 is hydrogen or methyl; and provided that R 2 is not methoxy when R 1 , R 4 , R 5 , and R 6 are each hydrogen.
  • 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).
  • the invention also includes pharmaceutical compositions, which comprise an effective amount of an oxazinone compound of formula (I) and a pharmaceutically acceptable carrier.
  • 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):
  • R is an amino acid side chain mimicking moiety
  • R 2 , R 4 , R 5 , R 6 , R 8 and R 9 are each independently selected substituting moieties;
  • R 7 is hydrogen, or a prodrug moiety
  • L is a leaving group
  • P and P are protecting groups, and acceptable salts thereof.
  • the invention pertains, at least in part to oxazinone compounds of the formula (I):
  • R 1 is an amino acid side chain mimicking moiety
  • R 2 , R 4 , R 5 , R 6 , R 8 and R 9 are each independently selected substituting moieties;
  • R 7 is hydrogen, or a prodrug moiety, and pharmaceutically acceptable salts thereof, provided that R 2 is not hydroxy when R 4 , R 5 , and R 6 are each hydrogen, and R 1 is hydrogen or methyl; and provided that R 2 is not methoxy when R 4 , R 5 , and R 6 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 ⁇ -lactam carbonyl group
  • the hydrogen of the oxazinone hydroxyl group corresponds to the N-H hydrogen of the acylamino side chain of penicillin
  • the carboxyl group of the carboxy ethyl substituent of (D) corresponds to the C3-carboxyl group of penicillin.
  • amino acid side chain mimicking moiety (“R 1 ”) 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.
  • the "amino acid side chain mimicking moiety” allows the oxazinone to interact with the active site of a penicillin recognizing enzyme.
  • amino acid side chain moieties include the side chains of natural and unnatural D- and L- amino acids.
  • 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).
  • the amino acid side chain mimicking moiety is the side chain of alanine (e.g., methyl).
  • 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.).
  • alkyl amino acid side chain mimicking moieties include straight chain, branched and cyclic alkyl groups.
  • 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.
  • amino acid side chain mimicking moieties include alkenyl, alkynyl, carbonyl, aralkyl or aryl moieties.
  • aryl moieties include substituted and unsubstituted phenyl and substituted and unsubstituted heteroaryl.
  • substituting moiety includes moieties which can be placed at any one of R 2 , R 4 , R 5 , R , R 8 , or R 9 of the oxazinone compound without prohibitively detrimentally affecting the ability of the oxazinone to perform its intended function.
  • substituting moieties include alkyl, hydrogen, alkenyl, alkynyl, aryl, hydroxyl, amino, protected hydroxyl, protected amino, thiol, halogen, NHCOR 3 , etc. and other substituents which are not detrimental to the antibacterial activity of the oxazinone compound.
  • substituting moieties include carbonyl and thiocarbonyl groups (e.g., R 2 and R 4 or R 5 and R 6 taken together are the oxygen of a carbonyl group or the sulfur of a thiocarbonyl group).
  • R and R include hydrogen and lower alkyl (e.g., methyl, ethyl, propyl, butyl).
  • R include protected hydroxyl, hydroxyl, alkoxy, hydrogen, etc.
  • R 4 and R 6 include hydrogen and lower alkyl.
  • R 5 include amino, NHCOR , hydroxy, methoxy, etc. In a particular embodiment, both of R 8 and R 9 are hydrogen.
  • 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.
  • 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.
  • R 7 is hydrogen.
  • antibacterial substituent 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.
  • R 2 groups include, but are not limited to, NR 3 +, SR +, NH 3 +, NO , SO R, CN, SO 2 Ar, COOH, F, Cl, Br, I, OAr, COOR, OR, COR, SH, SR, NHCOR 3 , and OH, wherein R is an alkyl, alkenyl, alkynyl, or aryl moiety.
  • R 2 is capable of hydrogen bonding.
  • groups capable of hydrogen bonding include, but are not limited to, OR, SH, SR, OH, F, COOR, NH 2 , etc.
  • R is halogen, e.g., fluorine.
  • R 2 groups include hydroxy (e.g., OH) and alkoxy (e.g., OR). Examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, etc.
  • R and R taken together are the oxygen of a carbonyl group or the sulfur of a thiocarbonyl group.
  • R is amino or NHCOR , wherein R is an antibacterial substituent (e.g., substituted or unsubstituted benzyl).
  • R 5 is hydroxyl or halogen (e.g., fluorine).
  • R 5 and R 6 taken together are the oxygen of a carbonyl group or the sulfur of a thiocarbonyl group.
  • the oxazinone compound of the invention has one of the following stereochemistries:
  • R is an amino acid side chain mimicking moiety
  • R 2 is alkoxy, OH, NH 2 or NHCOR 3 ;
  • R 3 is a antibacterial substituent;
  • R 4 is H or lower alkyl;
  • R 5 is H, OH, NH 2 or NHCOR 3 or the oxygen of a carbonyl group when taken together with R 6 ;
  • R 6 is H, OH, NH or NHCOR 3 , and pharmaceutically acceptable salts thereof, provided that R 2 is not hydroxy when R 4 , R 5 , and R 6 are each hydrogen, and R 1 is hydrogen or methyl; and provided that R 2 is not methoxy when R 1 , R 4 , R 5 , and R 6 are each hydrogen.
  • the compounds of formula II comprise compounds wherein R is hydrogen or the side chain of alanine.
  • the oxazinone compounds also include compounds wherein R 2 is OH.
  • Compounds of formula II wherein R 4 , R 5 , and R 6 are each independently hydrogen are also included.
  • the compound of formula II is 2-[2-substituted carboxyethyl]-5-hydroxy-l,2-oxazin-3-one.
  • the invention pertains to oxazinones wherein R 5 and R 6 taken together comprise the oxygen of a carbonyl group.
  • the invention includes compounds wherein R 2 is OH, and Ri, R t , R 5 and R 6 are hydrogen and the compound has S- or R- configuration at C5.
  • the invention includes compounds wherein Ri is methyl,
  • R is OH, R 4 R 5 and Re are each hydrogen with the S-configuration at both Cl ' and C5.
  • Ri is methyl
  • R 2 is OH
  • Rt R 5 and R 6 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.
  • 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):
  • R 1 is an amino acid side chain mimicking moiety
  • R 2 , R 4 , R 5 , R 6 , R and R 9 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.
  • 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.
  • mammals e.g. primates (e.g., monkeys, gorillas, chimpanzees, and, advantageously, humans
  • reptiles or fish.
  • the subject is suffering from the bacterial associated disorder at the time of administering the oxazinone compound of the invention.
  • administering includes routes of administration which allow the oxazinone compound to perform its intended function.
  • routes of administration 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.
  • 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.
  • 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.
  • bacterial associated state includes states characterized by the presence of gram-positive pathogens, for example Staphylococci, Enterococci, Streptococci and mycobacteria.
  • the bacterial associated state is associated with a bacterial strain which is resistant to conventional antibiotics.
  • bacterial strains include methicillin resistant staphylococcus (MRSA), methicillin resistant coagulase negative staphylococci (MRCNS), penicillin resistant streptococcus pneumoniae and multiply resistant Enterococcus faecium.
  • the oxazinone compound is administered in combination with a supplementary compound.
  • supplementary compounds include antibiotics such a penicillin, methicillin, cephalosphorin, vancomycin, etc.
  • a supplementary compound 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.
  • the invention includes pharmaceutical compositions comprising an e
  • R , ⁇ is an amino acid side chain mimicking moiety
  • R I 7 is hydrogen, or a prodrug moiety, and pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition of the invention includes a pharmaceutically acceptable carrier and/or a supplementary agent, e.g., an antibiotic.
  • the effective amount of the oxazinone compound is effective to treat a bacterial infection of a subject, e.g., a human.
  • 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
  • R is an amino acid side chain mimicking moiety
  • R 2 , R 4 , R 5 , R 6 , R 8 and R 9 are each independently selected substituting moieties;
  • R 7 is hydrogen, or a prodrug moiety
  • L is a leaving group
  • P and P are protecting groups, and acceptable salts thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • condensing agent includes chemical entities which promote the chemical coupling of the amino acid compound and the butanoic acid compound.
  • a condensing agent is dicyclohexylcarbodiimide.
  • 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.
  • 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.
  • 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
  • the removal of the protecting groups is performed with trifluoroacetic acid.
  • 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.
  • 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.
  • the carboxyl-protected N-hydroxy amino acid is t- butyl N-hydroxyglycine.
  • 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.
  • the carboxyl and hydroxyl protection are, respectively, t-butyl and 2- tetrahydropyranyl
  • the condensing agent is dicyclo-hexylcarbodiimide
  • the cyclizing agent is diazabicycloundecene
  • the deprotecting agent is trifluoroacetic acid.
  • 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.
  • straight- chain alkyl groups e.g. , methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, oc
  • alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkyl has 6 or fewer carbon atoms in its backbone (e.g, C ⁇ -C for straight chain, C 3 -C for branched chain), and more preferably 4 or fewer.
  • preferred cycloalkyls have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
  • C ⁇ -C 6 includes alkyl groups containing 1 to 6 carbon atoms.
  • 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.
  • 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, s
  • 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.
  • 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.
  • 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.
  • 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
  • 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).
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • 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
  • alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • 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).
  • 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.
  • C 2 -C 6 includes alkenyl groups containing 2 to 6 carbon atoms.
  • alkenyl includes both "unsubstituted alkenyls" and
  • substituted alkenyls refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • 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, carb
  • alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • 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.
  • alkynyl further includes alkynyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • 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 -C 6 includes alkynyl groups containing 2 to 6 carbon atoms.
  • 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.
  • 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
  • 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.
  • acyl includes compounds and moieties which contain the acyl radical (CH 3 CO-) or a carbonyl group.
  • 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, sulf
  • acylamino includes structures wherein an acyl moiety is bonded to an amino group.
  • the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
  • aroyl includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthylcarboxy, etc.
  • alkoxy alkyl includes 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.
  • alkoxy includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom.
  • alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups.
  • 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, thiocar
  • amine or “amino” includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom.
  • alkylamino includes groups and compounds wherein the nitrogen is bound to at least one additional alkyl group.
  • dialkylamino includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups.
  • arylamino and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively.
  • alkylarylamino alkylaminoaryl or “arylaminoalkyl” refers to an amino group which is bound to at least one alkyl group and at least one aryl group.
  • alkylaminoalkyl refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group.
  • 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.
  • 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.
  • alkylaminocarboxy 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.
  • carbonyl or “carboxy” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom.
  • moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
  • thiocarbonyl or “thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
  • ether includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms.
  • alkoxyalkyl which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group.
  • esteer 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.
  • esteer includes alkoxycarbony groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.
  • the alkyl, alkenyl, or alkynyl groups are as defined above.
  • 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.
  • alkylthioalkyls include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group.
  • 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.
  • hydroxy or "hydroxyl” includes groups with an -OH or -O " .
  • halogen includes fluorine, bromine, chlorine, iodine.
  • perhalogenated generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.
  • 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
  • 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.
  • 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.
  • 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.
  • 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
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • oral pharmaceutical compositions can be suitably sweetened and/or flavored.
  • 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.
  • 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.
  • 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.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • 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.
  • preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • 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.
  • 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.
  • 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.
  • therapeutic compounds can be suitably admixed in a pharmacologically inert topical carrier such as a gel, an ointment, a lotion or a cream.
  • 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.
  • materials such as anti-oxidants, humectants, viscosity stabilizers and the like also may be added if desired.
  • tablets, dragees or capsules having talc and/or carbohydrate carrier binder or the like are particularly suitable, 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.
  • the therapeutic methods of the invention also will have significant veterinary applications, e.g.
  • 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.
  • 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 R 2 is OH, R 4 , R 5 , and R 6 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 , R 5 , and R 6 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 R 2 is MeO, R 4 , R 5 , and R are each hydrogen, and Ri is hydrogen).
  • 2- [2- carboxyethyl]-5-hydroxy-l,2-oxazin-3-one e.g., a compound of formula (I) wherein R 2 is OH, R 4 ,
  • 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 ⁇ -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 ⁇ -Bromoacetoacetate. Diketene (500 ⁇ L, 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 ⁇ L, 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 ⁇ L, 732 mg, 6.8 mmoles) was added dropwise.
  • 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.
  • 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 ⁇ L, 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.
  • 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%).
  • Mass spectrum (Cl, m/z): 267, 269 (M+l, M+3).
  • 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 ⁇ L, 10.2 mg, 0.10 mmol) was added.
  • the solution was left, under nitrogen, for 1 h, and diazabicycloundecene (DBU) (7 ⁇ L, 0.047 mmol) was added followed, after 2 h, by an additional 5.0 ⁇ L (0.33 mmol) of DBU.
  • DBU diazabicycloundecene
  • 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 ⁇ L), after an additional 20 min (500 ⁇ L), and after an additional 30 min (300 ⁇ L). After an additional 55 min, the solvent was removed.
  • 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 ⁇ L) 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).
  • 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.
  • 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)
  • dichloromethane 3 mL
  • dicyclohexylcarbodiimide 41 mg, 0.20 mmole
  • 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 ⁇ L), 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.
  • Example 3 Bioassay of the Product of Example 1
  • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouvelles oxyzinones, des techniques de synthèse de ces composés et l'utilisation de ces composés comme agents antibactériens.
PCT/US2001/027261 2001-08-30 2001-08-30 Derives 1,2-oxazine-3-one utilises comme agents antibacteriens WO2003020709A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/US2001/027261 WO2003020709A1 (fr) 2001-08-30 2001-08-30 Derives 1,2-oxazine-3-one utilises comme agents antibacteriens

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2001/027261 WO2003020709A1 (fr) 2001-08-30 2001-08-30 Derives 1,2-oxazine-3-one utilises comme agents antibacteriens

Publications (1)

Publication Number Publication Date
WO2003020709A1 true WO2003020709A1 (fr) 2003-03-13

Family

ID=21742809

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2001/027261 WO2003020709A1 (fr) 2001-08-30 2001-08-30 Derives 1,2-oxazine-3-one utilises comme agents antibacteriens

Country Status (1)

Country Link
WO (1) WO2003020709A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5552543A (en) * 1988-12-14 1996-09-03 Simon Fraser University Six-membered hetero "N" compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5552543A (en) * 1988-12-14 1996-09-03 Simon Fraser University Six-membered hetero "N" compounds

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
K. TABEI ET AL: "Reaction of gamma-bromoacetoacetyl bromide with N-phenylhydroxylamine derivatives: synthesis of 1,2-oxazine derivatives", CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 27, no. 8, 1979, pages 1842 - 1846, XP002193587 *
M. FRANKEL ET AL: "DL-Cyclocanaline (Cyclohomoserine) and related compounds", JOURNAL OF THE CHEMICAL SOCIETY, SECTION C: ORGANIC CHEMISTRY, 1969, LETCHWORTH GB, pages 1746 - 1749, XP002193586 *

Similar Documents

Publication Publication Date Title
ES2271070T3 (es) Compuestos de minociclina 9-sustituidos.
US8119622B2 (en) 7-phenyl-substituted tetracycline compounds
US7893282B2 (en) 7-substituted fused ring tetracycline compounds
US7521437B2 (en) 7-phenyl-substituted tetracycline compounds
KR101027625B1 (ko) 7-치환 테트라사이클린 화합물
JP2004502750A (ja) ７、８および９−置換テトラサイクリン化合物
JP2005506291A (ja) ７，９−置換テトラサイクリン化合物
US4942183A (en) Aminomethyl oxooxazolidinyl aroylbenzene derivatives useful as antibacterial agents
WO2001098259A1 (fr) Composes de tetracycline 7-phenyl-substituee
US20030232820A1 (en) Method for synthesizing oxazinones
US20050124612A1 (en) Oxazinones and methods for their use and synthesis
WO2003020709A1 (fr) Derives 1,2-oxazine-3-one utilises comme agents antibacteriens
HRP20030092A2 (en) 13-substituted methacycline compounds
JP2005535637A (ja) 抗菌剤としてのグリコロイル置換オキサゾリジノン誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PH PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BY BZ CA CH CN CO CR CU CZ DE DM DZ EC EE ES FI GB GD GE GH HR HU ID IL IN IS JP KE KG KP KR LC LK LR LS LT LU LV MA MD MG MN MW MX MZ NO NZ PH PL PT RO SD SE SG SI SK SL TJ TM TR TT TZ UG US UZ VN YU ZA

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ UG ZW AM AZ BY KG KZ MD TJ TM AT BE CH CY DE DK ES FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP