Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to organic chemistry, medicinal chemistry, biochemistry and medicine.
• it relates to prodrugs of a cephalosporin antibiotic wherein the prodrugs are substantially more water soluble than the parent antibiotic which, among other benefits, aids parenteral administration.
• the prodrugs convert readily under physiological conditions to provide the parent antibiotic.
• Cephalosporins occurs primarily by three mechanisms: (a) the development of ⁇ -lactamases, which cleave ⁇ -lactam rings thereby deactivating the antibiotic; (b) changes in cell wall composition resulting in decreased penetration by the antibiotic; and, (c) changes in penicillin-binding proteins (PBPs) resulting in reduced binding of the PBPs with ⁇ -lactams, the binding being essential to the inhibition of cell-wall biosynthesis by ⁇ -Iactams.
• PBPs penicillin-binding proteins
• Examples of bacteria whose resistant is due to poor PBP binding are methicillin- resistant Staphylococcus aureus (“MRSA”) and the Enterococci.
• MRSA MRSA resistance in MRSA is due to the presence of high levels of an altered PBP, PBP2a, which has been shown to bind very poorly to ⁇ -lactams. Attempts to circumvent this mechanism of resistance has led to the discovery of a host of new antibacterial compounds.
• a class of compounds which have demonstrated activity against ⁇ -lactam, in particular, cephalosporin resistant, bacteria is the 7-acylamino-3-heteroarylthio- 3-cephem carboxylic acids, described in U.S. Patent No. 6,025,352, which is likewise incorporated by reference, includign any drawings, as if fully set forth herein.
• a particularly active compound is (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2- (hydroxyimino)acetamido]-3- ⁇ 3-(2-aminoethylthiomethyl]-pyrid-4-ylthio ⁇ -3-cephem- 4-carboxylic acid (1 ):
• the present invention relates to prodrugs of 1 that exhibit surprising water solubility and which are readily bioconverted in vivo to the parent compound.
• the present invention relates to compounds having the chemical structure:
• R' 1 is selected from the group consisting of hydrogen and -C(O)CH(NH 2 )CH 3 and, R' 2 is selected from the group consisting of hydrogen and an acyl group that is cleaved by an enzyme found in mammals.
• the present invention relates to the above compound wherein: R' 2 is selected from the group consisting of hydrogen, -C(0)-R 88 , -C(O)-OR 89 ,
• R' 3 is selected from the group consisting of hydrogen, -C(O)-OR 89 , and
• alk 4 is selected from the group consisting of hydrogen, and optionally substituted alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, phenyl, -COOH, -C(O)-OR 89 , -C(0)NH 2 , ⁇ — NH
• R 89 is selected from the group consisting of benzhydryl, f-butyl, allyl, p-nitrobenzyl, benzyl, p- or o-nitrobenzyl, 2,2,2-trichloroethyl, cinnamyl, 2-chloroallyl, f-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, trimethylsilyl, f-butyldimethylsilyl, ⁇ -(trimethylsilyl)ethyl, 4- or 2-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, methoxymethyl, and 3,3-dimethylallyl.
• R' 3 is selected from the group consisting of hydrogen, methyl, and -C(0)CH(NH 2 )CH 3 .
• alk 4 is selected from the group consisting of hydrogen, -CH 3 , -CH(CH 3 ) 2) -CH 2 OH, -CH 2 NH 2) -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 COOH, -CH 2 CH 2 COOH, -CH 2 -C(O)NH 2 , -CH 2 CH 2 -
• Another aspect of this invention is a compound selected from the group consisting of:
• a still further aspect of this invention is a compound selected from the group consisting of:
• an aspect of this invention is the compound (7R)-7-[(Z)-2-(2- amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3- ⁇ 3-[2-N-(L)- aspartylaminoethylthiomethyl]pyrid-4-ylthio ⁇ -3-cephem-4-carboxylic acid:
• this invention relates to a pharmaceutically acceptable salt of any of the compounds of this invention.
• Another aspect of this invention is a composition for use in the treatment of a bacterial infection in a patient comprising one or more compounds of this invention.
• a still further aspect of this invention is a composition comprising a compound of this invention and a pharmaceutically acceptable carrier or excipient.
• An aspect of this invention is a composition for use in the treatment of a bacterial infection in a human being comprising one or more compounds of this invention
• composition for use in treatment of a bacterial infection in a human being further comprises a pharmaceutically acceptable carrier or excipient.
• a pharmaceutically acceptable carrier or excipient an aspect of this invention is that the above compositions are useful in the treatment of a ⁇ -lactam antibiotic resistant bacterial infection.
• the ⁇ -lactam antibiotic resistant bacterial infection is a methicillin, ampicillin or vancomycin resistant bacterial infection in another aspect of this invention.
• the bacterial infection is caused by a Staphylococcus or Entercoccus species bacteria in a further aspect of this invention.
• Staphylococcus or Enterococcus species are resistant to some, or all, other ⁇ -lactam antibiotics in a still further aspect of this invention.
• the resistant Staphylococcus species is S. aureus Col (Meth R )(bla-), S. aureus 76 (Meth R ) (bla+), S. aureus ATCC 29213, S. Aureus ATCC 25913, S. Aureus ATCC 32432 or S. Aureus ColBA in another aspect of this invention.
• the resistant Enterococcus species is E. fsecium ATCC 35667 or E. fsecalis ATCC 29212 in an aspect of this invention.
• a composition for use in the prophylactic treatment of a patient for the prevention of a bacterial infection is an aspect of this invention.
• Figure 1 shows the water solubility of the parent antibiotic, compound 1, in its zwitterionic form (2) compared to that of a prodrug of this invention, compound 3:
• alkyl refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups.
• the alkyl group has 1 to 20 carbon atoms (whenever a numerical range; e.g. "1-20", is stated herein, it means that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). More preferably, it is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having 1 to 4 carbon atoms.
• the alkyl group may be substituted or unsubstituted.
• Examples, without limitation, of unsubstituted alkyl groups are methyl, ethyl, t7-propyl, / ' so-propyl, ⁇ -butyl, sec-butyl, /so-butyl, fe/f-butyl, and 2-methylpentyl.
• the substituent group(s) may be, without limitation, one or more independently selected from the group consisting of halo, hydroxy, cyano, nitro, lower alkoxy, carboxy, carbonyl, alkylcarbonyl, alkoxycarbonyl, mercapto, alkylthio, amino, amido, isothioureido, amidino, guanidino, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, optionally substituted 6- member heteroaryl having from 1 to 3 nitrogen atoms in the ring, optionally substituted 5-member heteroaryl having from 1 to 3 heteroatoms in the ring selected from the group consisting of nitrogen, oxygen and sulfur, and optionally substituted 5- or 6-member heteroalicyclic group having from 1 to 3 heteroatoms in the ring selected from the group consisting of nitrogen, oxygen and sulfur.
• substituted alkyl groups include trifluoromethyl, 3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl, carboxy methyl, 4-cyanobutyl, 2-guanidinoethyl and 3-N,N'-dimethylisothiouroniumpropyl.
• a “cycloalkyl” group refers to a 3 to 8 member all-carbon monocyclic ring, an all-carbon 5-member/6-member or 6-memberr ⁇ -member fused bicyclic ring or a multicyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system) group wherein one or more of the rings may contain one or more double bonds but none of the rings has a completely conjugated pi-electron system.
• cycloalkyl groups examples, without limitation, are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane and, cycloheptatriene.
• a cycloalkyl group may be substituted or unsubstituted.
• the substituent group(s) may be, without limitation, one or more independently selected from the group consisting of halo, hydroxy, alkoxy, mercapto, alkylthio, cyano, nitro, optionally substituted aryl, optionally substituted aryloxy, mercapto, alkylthio, optionally substituted arylthio, amino, amido, carboxy, carbonyl, alkylcarbonyl, alkoxycarbonyl, optionally substituted 6- member heteroaryl having from 1 to 3 nitrogen atoms in the ring, optionally substituted 5-member heteroaryl having from 1 to 3 heteroatoms in the ring selected from the group consisting of nitrogen, oxygen and sulfur, and optionally substituted 5- or 6-member heteroalicyclic group having from 1 to 3 heteroatoms in the ring selected from the group consisting of nitrogen, oxygen and sulfur.
• alkenyl refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond.
• alkynyl refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
• aryl group refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted.
• the substituting group(s) may be, without limitation, one or more independently selected from the group consisting of alkyl, (halo) 3 C-, halo, hydroxy, alkoxy, mercapto, alkylthio, cyano, nitro, amino, amido, carboxy, carbonyl, alkylcarbonyl, alkoxycarbonyl, optionally substituted 6- member heteroaryl having from 1 to 3 nitrogen atoms in the ring, optionally substituted 5-member heteroaryl having from 1 to 3 heteroatoms in the ring selected from the group consisting of nitrogen, oxygen and sulfur, and optionally substituted 5- or 6-member heteroalicyclic group having from 1 to 3 heteroatoms in the ring selected from the group consisting of nitrogen, oxygen and sulfur.
• substituted aryl groups are biphenyl, iodobiphenyl, methoxybiphenyl, anthryl, bromophenyl, iodophenyl, chlorophenyl, hydroxyphenyl, methoxyphenyl, formylphenyl, acetylphenyl, trifluoromethylthiophenyl, trifluoromethoxyphenyl, alkylthiophenyl, trialkylammoniumphenyl, amidophenyl, thiazolylphenyl, oxazolyl phenyl, imidazolylphenyl, imidazolylmethylphenyl, cyanophenyl, pyridylphenyl, pyrrolylphenyl, pyrazolylphenyl, triazolylphenyl and tetrazolylphenyl.
• heteroaryl group refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur and, in addition, having a conjugated pi-electron system.
• heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine and carbazole.
• a heteroaryl group may be substituted or unsubstituted.
• the substituted group(s) may be, without limitation, one or more independently selected from the group consisting of alkyl, (halo) 3 C-, halo, hydroxy, lower alkoxy, mercapto, alkylthio, arylthio, cyano, nitro, amino, amido, carboxy, carbonyl, alkylcarbonyl and alkoxycarbonyl.
• substituted heteroaryl groups are, without limitation, 2-aminothiazol-4-yl, 2-amino-5- chIorothiazol-4-yl, 5-amino-1 ,2,4-thiadiazol-3-yl, 2,3-dioxopiperazinyl, 4-alkylpiperazinyl, 2-iodo-3-dibenzfuranyl and 3-hydroxy-4-dibenzthienyl.
• heteroalicyclic group refers to a monocyclic or fused ring group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur.
• the rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system.
• the heteroalicyclic ring may be substituted or unsubstituted.
• the substituting group(s) may be, without limitation, one or more independently selected from the group consisting of alkyl, (halo) 3 C-, halo, hydroxy, alkoxy, mercapto, alkylthio, cyano, nitro, amino, amido, carboxy, carbonyl, alkylcarbonyl and alkoxycarbonyl.
• a "hydroxy” group refers to an -OH group.
• alkoxy refers to both an -O-(unsubstituted alkyl) and an -O- (unsubstituted cycloalkyl) group.
• aryloxy refers to both an -O-aryl and an -O-heteroaryl group, as defined herein.
• a “mercapto” group refers to an -SH group.
• alkylthio refers to both an (unsubstituted alkyl)S- and an (unsubstituted cycloalkyl)S- group.
• arylthio refers to both an -S(aryl) and an -S(heteroaryl group), as defined herein.
• halo refers to fluorine, chlorine, bromine or iodine.
• a “cyano” group refers to a -C ⁇ N group.
• a “nitro” group refers to a -NO 2 group.
• amino refers to an NRR' group wherein R and R' are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heteroalicyclic.
• An “amido” group refers to a -C(O)NRR', wherein R and R' have the above meaning.
• a “carboxy” group refers to a -CO(0)H group.
• a “carbonyl” group refers to a -C(O)H group.
• acyl refers to a -C(O)R group, in which R is hydrogen or alkyl as defined above, such as formyl, acetyl, propionyl, or butyryl.
• alkylcarbonyl refers to a -C(0)(alkyl) group.
• alkoxycarbonyl refers to an -C(0)(0-alkyl) group.
• a “trialkylsilyl” groups refers to an RR'R"Si- group, where R, R' and R" are alkyl as defined above.
• a “trialkylammonium” group refers to a [RR'R"N-] + , where R, R' and R" are alkyl as defined above.
• method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from those manners, means, techniques and procedures known to practitioners of the chemical, pharmaceutical, biological, biochemical and medical arts.
• a “pharmaceutical composition” refers to a mixture of one or more of the compounds described herein, or physiologically acceptable salts thereof, with other chemical components, such as physiologically acceptable carriers and excipients.
• the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
• a pharmaceutically acceptable salt refers to any of the compounds of this invention in its cationic or anionic form together with an appropriate counterion.
• a compound of this invention may exist as a singly or a doubly charged species, in the latter instance it will form a salt with two counterions, which may be the same or different.
• Preferred pharmaceutically acceptable salts include (1) inorganic salts such as sodium, potassium, chloride, bromide, iodide, nitrate, phosphate or sulfate; (2) carboxylate salts such as acetate, trifluoroacetate, propionate, butyrate, maleate, or fumarate; (3) alkylsulfonat.es such as methanesulfonate, ethanesulfonate, 2-hydroxyethylsulfonate, n-propylsulfonate or isopropylsulfonate; and (4) hydroxycarboxylates such as lactate, malate, and citrate.
• inorganic salts such as sodium, potassium, chloride, bromide, iodide, nitrate, phosphate or sulfate
• carboxylate salts such as acetate, trifluoroacetate, propionate, butyrate, maleate, or fumarate
• Salts in which a compound of this invention is the cationic species are prepared by reacting the compound with an organic or inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
• an organic or inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
• the acid used provides the anionic counterion.
• Salts in which a compound herein is the anionic species of the pair are prepared by reacting any one of the compounds of the invention with an organic or inorganic base, such as benzathene, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procain, and the hydroxide, alkoxide, carbonate, bicarbonate, sulfate, bisulfate, amide, alkylamide, or the dialkylamide salts of lithium, sodium, potassium, magnesium, calcium, aluminum, and zinc.
• the base supplies the cation.
• a "prodrug” refers to an compound which is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug.
• prodrug may, for instance, be bioavailable by oral administration whereas the parent drug is not.
• the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
• An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water solubility is beneficial.
• a further example of a prodrug might be a single amino acid or a short polypeptide, for example, without limitation, a 2 - 10 amino acid polypeptide, bonded through a terminal amino group to a carboxy group of a compound or through a carboxy group of the amino acid to an amino group of a compound, as is the case with the compounds of this invention.
• the compound thus formed is then converted in vivo to release the active molecule.
• a “physiologically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
• An “excipient” refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
• in vitro refers to procedures performed in an artificial environment such as, e.g., without limitation, a test tube or a petri dish containing a culture medium.
• In vivo refers to procedures performed in a living organism such as, without limitation, a mouse, rat, dog, cat, rabbit, cow, pig, horse or a human.
• a "bacterial infection” refers to the establishment of a sufficient population of a pathogenic bacteria in a patient to have a deleterious effect on the health and well-being of the patient and/or to give rise to discernable symptoms associated with the particular bacteria.
• the terms “prevent”, “preventing” and “prevention” refer to a method for barring an organism from acquiring a bacterial infection in the first place.
• the terms “treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a bacterial infection and/or its attendant symptoms.
• administer refers to the delivery of a compound, or salt thereof, or a pharmaceutical composition containing a compound or salt thereof to an organism for the purpose of treating or preventing a bacterial infection.
• a patient refers to any living entity capable of being infected by bacteria.
• a “patient” refers to a mammal such as a dog, cat, horse, cow, pig, rabbit, goat or sheep. Most particularly, a patient herein refers to a human being.
• a therapeutically effective amount refers to that amount of a compound being administered that will relieve, to some extent, one or more of the symptoms of the disorder being treated.
• a therapeutically effective amount refers to that amount of a compound that (1 ) reduces, preferably eliminates, the population of the bacteria in the patient's body, (2) inhibits (that is, slows to some extent, preferably stops) proliferation of the bacteria, (3) inhibits to some extent (that is, slows to some extent, preferably stops) spread of the infection caused by the bacteria, and/or, (4) relieves to some extent (preferably, eliminates) one or more symptoms associated with the bacterial infection.
• prophylactically effective amount refers to that amount of a compound that (1) maintains a reduced level of a population of a bacteria; (2) maintains the level of inhibition of proliferation of the bacteria; (3) maintains the level of inhibition of spread of the infection and/or (4) maintains the level of relief of one or more symptoms associated with the baterial infection, achieved by the adminstration of a therapeutically effective amount of the compound.
• beta-lactam resistant bacteria refers to bacteria against which a beta-lactam antibiotic has a minimum inhibitory concentration (MIC) of greater than 32 ⁇ g/mL.
• Compound 1 is synthesized using well-known organic chemistry reactions and procedures from readily available materials. Texts such as, without limitation, March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure (McGraw-Hill, latest edition); Larock, Comprehensive Organic Transformations (VCH Publishers, latest edition); Greene and Wuts, Protective Groups in Organic Synthesis (John Wiley & Sons, latest edition) and G.I. Georg, The Organic Chemistsry of ⁇ -Lactams (VCH Publishers, latest edition) provide ample direction for the synthesis of 1. A method for the preparation of 1 can also be found in U.S. Patent No. 6,025,352, which is incorporated, including any drawings, as if fully set forth herein. The following is representative of that synthesis:
• the methanesulfonate salt was prepared by suspending the zwitterionic product in water (15 mL) followed by addition of methanesulfonic acid (1.0 M in water, 0.98 eq) and acetonitrile (5 mL). After evaporation of the resulting solution to dryness, the residue was dissolved in water (30 mL) and centrifuged to remove insoluble material, and the supernatant was lyophilized to give the title compound (274 mg, 44%).
• Prodrugs of 1 which are the subject of this invention, can also be prepared by standard organic synthetic procedures found in the above-referenced texts. The following are examples of such preparations.
• the syntheses shown are not to be construed as limiting the scope of this invention in any manner whatsoever. That is, other prodrugs and other approaches to sythesizing them will become apparent to those skilled in the art based on the disclosures herein; all such prodrugs and syntheses are within the scope of this invention. 1.
• reaction mixture was thoroughly washed with water and dried over anhydrous sodium sulfate.
• the mixture was subjected to column chromatography on silica gel (eluting with 2:1 hexane/ethyl acetate, followed by 1 :3) to afford the desired coupling product as an oily solid (107 mg).
• Standard deprotection trifluoroacetic acid, dichloromethane, triethylsilane was conducted, and the title product was precipitated by addition of diethyl ether. The precipitate was filtered, washed thoroughly with diethyl ether and dried to afford the title compound (48 mg).
• the fractions containing pure product (800 mL) were combined, the acetonitrile was removed by evaporation under reduced pressure, and the aqueous solution of the product was desalted by loading it onto a column containing HP20 resin and washing thoroughly with water.
• the product was eluted with 20% aqueous acetonitrile, and the fractions containing pure desalted product were concentrated under reduced pressure to remove the acetonitrile.
• the remaining water was removed from the resulting cloudy solution by lyophilization.
• the lyophilized material was redissolved in water and the cloudy solution was adjusted to pH 6.1 with addition of sodium bicarbonate solution.
• the resulting clear solution was lyophilized to yield the pure title product as a pale yellow solid (3.99 g.).
• a prodrug of the present invention or a physiologically acceptable salt thereof can be administered as such to a patient or can be administered in pharmaceutical compositions in which the foregoing materials are mixed with suitable carriers or excipient(s).
• suitable carriers or excipient(s) suitable carriers or excipient(s).
• Suitable routes of administration may include, without limitation, oral, rectal, transmucosal, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intravitreal, intraperitoneal, intranasal, or intraocular.
• the preferred routes of administration are oral and intravenous.
• compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
• compositions may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
• physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
• Proper formulation is dependent upon the route of administration chosen; such formulations are well-known to those skilled in the art and include, without limitation, the following:
• compounds may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
• physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
• penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
• the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
• Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient.
• Pharmaceutical preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding other suitable auxiliaries, if desired, to obtain tablets or dragee cores.
• Some useful excipients are fillers such as sugars such as lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as maize starch, wheat starch, rice starch and potato starch and other materials such as gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone (PVP).
• disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid. Salts such as sodium alginate may also be used.
• Dragee cores are normally provided with suitable coatings.
• suitable coatings For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
• Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
• compositions which can be used orally include push-fit capsules made of gelatin, soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol, and the like.
• Push-fit capsules may contain the active ingredients in admixture with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate and, optionally, stabilizers.
• the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
• Stabilizers may be added in these formulations, also.
• the compounds are conveniently delivered in the form of an aerosol spray using a pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or carbon dioxide.
• a suitable propellant e.g., without limitation, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or carbon dioxide.
• the dosage unit may be controlled by providing a valve to deliver a metered amount.
• Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
• the compounds may also be formulated for parenteral administration, e.g., by bolus injection or continuous infusion.
• Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
• the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating materials such as suspending, stabilizing and/or dispersing agents.
• compositions for parenteral administration include aqueous solutions of a water soluble form, such as, without limitation, a salt, of the active compound.
• suspensions of the active compounds may be prepared in a lipophilic vehicle.
• Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes.
• Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
• the suspension may also contain suitable stabilizers and/or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
• the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
• a suitable vehicle e.g., sterile, pyrogen-free water
• the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
• compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
• a compound may be formulated for this route of administration with suitable polymeric or hydrophobic materials (for instance, in an emulsion with a pharmacologically acceptable oil), with ion exchange resins, or as a sparingly soluble derivative such as, without limitation, a sparingly soluble salt.
• the pharmaceutical compositions herein also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
• the compounds of the invention may be provided as physiologically acceptable salts wherein the claimed compound may form the negatively or the positively charged species.
• salts in which the compound forms the positively charged entity include, without limitation, quaternary ammonium salts such as the hydrochloride, sulfate, carbonate, lactate, tartrate, maleate, succinate wherein the nitrogen atom of the quaternary ammonium group is a nitrogen of the compound herein which has reacted with the appropriate acid.
• Salts in which a compound of this invention forms the negatively charged species include, without limitation, the sodium, potassium, calcium and magnesium salts formed by the reaction of a carboxylic acid group of a compound herein with an appropriate base, e.g., sodium hydroxide (NaOH), potassium hydroxide (KOH), Calcium hydroxide (Ca(OH) 2 ), etc.
• an appropriate base e.g., sodium hydroxide (NaOH), potassium hydroxide (KOH), Calcium hydroxide (Ca(OH) 2 ), etc.
• a therapeutically effective amount of a ⁇ -lactam antibiotic compound of this invention can be administered to a patient to ameliorate or eliminate a methicillin or other ⁇ -lactam, such as vancomycin or ampicillin, resistant bacterial infection.
• infections caused by resistant S. aureus species such as, without limitation, S. aureus Col (Meth R )(bla-), S. aureus 76 (Meth R ) (bla+), S. aureus ATCC 29213, S. Aureus ATCC 25913, S. Aureus ATCC 32432 and S. Aureus ColBA or resistant Enterococcus species such as E. f ⁇ cium ATCC 35667, or E.
• compositions containing a compound or compounds of the invention can be administered for prophylactic or therapeutic treatment.
• the compositions are administered to a patient already suffering from an infection, as described above, in an amount sufficient to cure or at least partially arrest the symptoms of the infection.
• An amount adequate to accomplish this is defined as "therapeutically effective amount or dose” and will depend on the severity and course of the infection, previous therapy, the patient's overall health status and response to the drugs, and the judgment of the treating physician.
• compositions containing a compound or compounds of the invention are administered to a patient who is who has previously been treated with a therapeutically effective amount of a compound to prevent recurrence of the infection, or they may be adminstered to a patient who, for one reason or another, may be susceptible to infection but is not yet infected such as the case of presurgical adminstration an antibiotics.
• a therapeutically effective amount or dose Such an amount is defined to be a "prophylactically effective amount or dose.” The precise amounts again depend on factors such as those described above.
• the proper dosage will depend on the severity and course of the infection, previous therapy, the patient's general health status, his or her response to the drugs, etc., all of which are within the knowledge, expertise and judgment of the treating physician.
• a suitable effective dose of the compound of the invention will be in the range of 0.1 to 10000 milligram (mg) per recipient per day, preferably in the range of 20 to 2000 mg per day.
• the desired dosage is preferably presented in one, two, three, four or more subdoses administered at appropriate intervals throughout the day. These subdoses can be administered as unit dosage forms, for example, containing 5 to 1000 mg, preferably 10 to 100 mg of active ingredient per unit dosage form.
• the compounds of the invention will be administered in amounts of between about 2.0 mg/kg to 250 mg/kg of patient body weight, between about one to four times per day.
• a maintenance dose may be administered if desired by the treating physician.
• the dosage, frequency, or both, can be reduced as a function of the patient's response to a level at which the improvement persists.
• treatment may be stopped although some patients may require intermittant treatment on a long-term basis should flare-ups of the symptoms reccur.
• Biological Evaluation The biological activity of compound 1 was previously reported as compound 16 in U.S. Patent No. 6,025,352, which is incorporated by reference, including any drawings, as if fully set forth herein. Thus, the biological activity of the prodrugs described herein are expected to be the same since they hydrolyze readily to the parent compound in vivo.
• the prodrugs and salts thereof described in the present invention are substantially more water soluble at or near neutral pH that the parent compound of its salts. It is this surprisingly enhanced solubility that is the focus of this invention.
• the solubility of any of the prodrugs herein can be determined using the following procedure: A small amount (5-8 mg) of a salt of a compound of this invention is weighed into a screw cap vial. Water is added to dissolve the salt at a high concentration (50-75 mg/mL). To this " solution is added small amounts (1-5 ⁇ L increments) of 0.1 N aqueous sodium hydroxide until a faint precipitate remains after mixing. The suspension is maintained at room temperature for 15 minutes with periodic vortexing.
• the zwitterion When starting with a zwitterion, the zwitterion is suspended in water and 0.1 N sodium hydroxide or 0.1 N hydrochloric acid is added to begin to dissolve the solid. The suspensions are held at room temperature for 15 minutes with frequent stirring and then are subjected to the same treatment described above (centrifugation, dilution and quantitation).
• FIG. 1 An example of the vastly greater water solubility at or near neutral pH of the compounds of this invention compared to that of 1 is shown in Figure 1.
• Fig. 1 the water solubility of 1 , in its zwitterionic form (2) is compared to that of its L-aspartyl prodrug (3):
• prodrug cleavage in serum the key to the utility of the prodrugs of this invention is their ready conversion to the parent active compound, 1 , under physiological conditions.
• the ability of a prodrug herein to revert to 1 can be evaluated using the following protocol: Fresh control human serum, fresh control rat serum, and rhesus monkey plasma (heparinized and stored frozen) are preincubated at 37 °C for 15 min in a shaking water bath. The pH of the serum or plasma is measured using test strips. Then 25 ⁇ L aliquots of a solution in water of a prodrug of this invention (2 mg/mL) are added to each matrix resulting in a final solution volumn of 1 mL.

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