QUINOLINE ANTIBACTERIAL COMPOUNDS AND METHODS OF USE THEREOF

Abstract: Methods, compounds and compositions are provided for inhibiting the growth of pathogenic microbes <i>in vitro</i> and of treatment of pathogenic bacterial infections <i>in vivo</i> using novel antibacterial quinoline compounds.

Description: QUINOLINE ANTIBACTERIAL COMPOUNDS AND METHODS OF USE THEREOF Field ofthe Invention The present invention relates to new 7-substituted amino-6-fluoro-l,4-dihydro-4- oxo-quinoline-3 -carboxylic acids and pharmaceutically acceptable salts thereof or esters having a solubility enhancing moiety in the 1- and/or 7-positions or prodrugs thereof, compositions of the new compounds together with pharmaceutically acceptable carriers, and uses of the new compounds in the treatment of bacterial infections. Background ofthe Invention The increasing need for broad-spectrum antibacterial agents with improved resistance profiles has prompted renewed interest in fluoroquinolones and their derivatives to meet this urgent need. Fluoroquinolones are potent antibacterial agents that kill bacteria by trapping DNA gyrase and DNA topoisomerase IN on chromosomes as quinolone-enzyme-DΝA complexes. Since the introduction of nalidixic acid in 1963, numerous analogues of this 4-quinolone antibiotic have been synthesized. In the 1980's quinolones containing fluorine atoms were introduced and proved to be significantly more potent in vitro and displayed broader antibacterial activity as compared to nalidixic acid. The efficacy of a pharmacological compound is predicated on efficient transport to its target site. This has been demonstrated for lung infections using drug administration by inhalation to deliver antibacterial agents directly to the area of infection. Thus, new fluoroquinolones with improved antibacterial properties and physical characteristics and particularly such compounds that allow for inhalation delivery are needed and must be developed as soon as possible. Summary ofthe Invention New l,4-dihydro-6-fluoro-4-oxo-quinoline-3 -carboxylic acids or esters thereof are provided ofthe formula (I): wherein R is hydrogen or a phosphate group having the formula: wherein R 2 and R are each independently hydrogen or -(CH^ n -R^ wherein R 4 is phenyl, aminodialkylamino, heterocyclo or lower alkyl, and n is 1-6; Ri is hydrogen, lower alkyl or a carboxy-protecting group; A is selected from the group -C-R 5 , -N and-CH-O-R 6 wherein R 5 is hydrogen or halo and R 6 is lower alkyl; Z is an amino group having the formula: -N wherein R 7 is hydrogen or lower alkyl, and R 8 is lower alkyl, -NH 2 , mono-(C 1 -C 4 ) alkylamino or di-(C 1 -C ) alkylamino, or Z is a substituted or unsubstituted aromatic heterocyclic ring, or an aliphatic heterocyclic ring ofthe formula: wherein R 9 is -NH, CH 2 =N-OCH 3 , or (CH 2 ) n NRπ, wherein R π is hydrogen, loweralkyl, loweralkoxy, hydroxy loweralkyl, aminoloweralkyl, oximinoether, iminoamine, alkylcarboxylic acid or ester, alkylsulphate, alkylphosphate and n is 0, 1 or 2; and Ri Q is hydrogen, amino, or aminoalkyl; provided that when R is hydrogen, Z is a substituted or unsubstituted aromatic or aliphatic heterocyclic ring; and the pharmaceutically acceptable salts, esters and prodrugs thereof. Brief Description ofthe Drawings The foregoing aspects and many ofthe attendant advantages of this invention will become more readily appreciated as the same become better understood by reference to the following detailed description, when taken in conjunction with the accompanying drawings, wherein: FIGURE 1 is a schematic representation of alternative synthesis pathways of compounds ofthe invention; FIGURE 2 is a schematic representation of further synthesis pathways of compounds ofthe invention; FIGURE 3 is a schematic representation of alternative synthesis pathway of compounds ofthe invention; FIGURE 4 is a graphical representation showing the solubility ofthe prodrug l,4-dihydro-6-fluoro-7-(4-methyl-l-piperazinyl)-4-oxoquinoline-l-[4-O-(phosphoric acid)phenyl]-3-carboxylic acid (PA2808, Examples 11 and 21), in the form of its sodium, potassium and ammonium salts, and of the sodium salt of l,4-dihydro-6- fluoro-7-(4-methyl- 1 -piperazinyl)-4-oxoquinoline- 1 -4-oxyphenyl-3 -carboxylic acid (PA2789, the phenol drug analog of prodrug PA2808) at various pH levels, as described in Example 34; FIGURE 5 is a graphical representation showing the stability of the sodium, potassium and ammonium salts of PA2808, as described in Example 34; FIGURE 6 is a graphical representation showing perfusate concentrations of PA2808 and PA 2789 versus time in the isolated perfused rat lung model described in Example 32; FIGURE 7 is a graphical representation showing the density of salts of PA2808 as described in Example 34; FIGURE 8 is a graphical representation showing the viscosity of salts of PA2808 as described in Example 34; FIGURE 9 is a graphical representation showing the osmolality of salts of PA2808 as described in Example 34; FIGURE 10 is a graphical representation showing the particle size (MMD) of salts of PA2808 as described in Example 34; FIGURE 11 is a graphical representation showing the output of salts of PA2808 from a LC Star Jet Nebulizer as described in Example 34; and FIGURE 12 is a graphical representation showing the percentage of particles in the 1-5 μm range of salts of PA2808 from a LC Star Jet Nebulizer as described in Example 34; Detailed Description ofthe Preferred Embodiment In accordance with one aspect of the present invention, new l,4-dihydro-6- fluoro-4-oxo-quinoline-3 -carboxylic acids or esters thereof are provided of the formula (I): wherein R is hydrogen or a phosphate group having the formula: O II --- p v Λ / n oR 2 OR 3 wherein R 2 and R 3 are each independently hydrogen or wherein R 4 is phenyl, aminodialkylamino, heterocyclo or lower alkyl, and n is 1-6; Ri is hydrogen, lower alkyl or a carboxy-protecting group; A is selected from the group -C-R 5 , -N and-CH-O-R 6 wherein R 5 is hydrogen or halo and R 6 is lower alkyl; Z is an amino group having the formula: - wherein R 7 is hydrogen or lower alkyl, and R 8 is lower alkyl, -NH 2 , mono-(C 1 -C 4 ) alkylamino or di-(d-C 4 ) alkylamino, or Z is a substituted or unsubstituted aromatic heterocyclic ring, or an aliphatic heterocyclic ring ofthe formula: wherein R 9 is -NH, CH2=N-OCH 3 , or (CH 2 ) n Rπ, wherein Rπ is hydrogen, loweralkyl, loweralkoxy, hydroxy loweralkyl, aminoloweralkyl, oximinoether, iminoamine, alkylcarboxylic acid or ester, alkylsulphate, alkylphosphate and n is 0, 1 or 2; and R 10 is hydrogen, amino, or aminoalkyl; provided that when R is hydrogen, Z is a substituted or unsubstituted aromatic or aliphatic heterocyclic ring; and the pharmaceutically acceptable salts, esters and prodrugs thereof. Aliphatic heterocyclic rings may be substituted with an amine group having the formula: , R 11 — N R 12 wherein Rπ and R 12 are each independently hydrogen, loweralkyl; hydroxy loweralkyl, alkanoyl, alkanoylamido and amino loweralkyl. In other aspects, the present invention provides pharmaceutical compositions comprising at least one compound of formula I together with a pharmaceutically acceptable carrier suitable for administration to a human or animal subject, either alone or together with other antibacterial or antifungal agents. In another aspect, the present invention provides methods of treating human or animal subjects suffering from a pathogenic microbial infection. Thus, the present invention provides a method of treating a human or animal subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a quinoline compound of formula (I), above, either alone or in combination with other antibacterial or antifungal agents. When Z is a heterocyclic ring, representative aromatic heterocyclic groups include, for example, substituted or unsubstituted pyridyl, pyrazinyl, thiozoyl, furyl, and thienyl, and representative aliphatic heterocyclic groups include, for example, substituted or unsubstituted piperazinyl groups, piperidinyl groups, pyrrolpdinyl groups and morpholino groups. As used herein "loweralkyl" includes both substituted or unsubstituted straight or branched chain alkyl groups having from 1 to 6 carbon atoms. Representative loweralkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl and the like. Representative of halo-substituted and hydroxy-substituted loweralkyl include chloromethyl, chloroethyl, hydroxyethyl, etc. As used herein, the term "halogen" refers to chloro, bromo, fluoro and iodo groups. As used herein, the term "alkanoyl" refers to O wherein R 13 is loweralkyl. As used herein, the term "alkanoylamido" refers to O R 14 NH- wherein R 14 is loweralkyl. As used herein, the term "alkylcarboxylic acid or ester" refers to O — R 15 OR 16 wherein R 15 is loweralkyl and R 16 is hydrogen or loweralkyl. As used herein, the term "alkylsulphate" refers to wherein Rπ is lower alkyl. As used herein, the term "alkylphosphate" refers to O -R 18 -0-P-OH O wherein R 18 is lower alkyl. The term "heterocycle" as used herein refers to an aromatic ring system composed of 5 or 6 atoms selected from the heteroatoms nitrogen, oxygen, and sulfur. The heterocycle maybe composed of one or more heteroatoms that are either directly connected such as pyrazole or connected through carbon such as pyrimidine. Heterocycles can be substituted or unsubstituted with one, two or three substituents independently selected from amino, alkylamino, halogen, alkyl acylamino, loweralkyl, aryl, and alkoxy. The term "substituted heterocycle" or "heterocyclic group" or heterocycle as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from nitrogen, oxygen, and sulfur or a 5- or 6-membered ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, or sulfur; wherein the 5-membered ring has 0-2 double bounds and the 6-membered ring has 0-3 double bounds; wherein the nitrogen and sulfur atom maybe optionally oxidized; wherein the nitrogen and sulfur heteroatoms maybe optionally quarternized; and including any bicyclic group in which any ofthe above heterocyclic rings is fused to a benzene ring or another 5- or 6-membered heterocyclic ring independently defined above. Heterocyclics in which nitrogen is the heteroatom are preferred. Fully saturated heterocyclics are also preferred. Preferred heterocycles include: diazapinyl, pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazoyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, N-methyl piperazinyl, azetidinyl, N-methylazetidinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, triazolyl and benzothienyl. Heterocyclics can be unsubstituted or monosubstituted or disubstituted with substituents independently selected from hydroxy, halo, oxo (C=O), alkylimino (RN=, wherein R is a lower alkyl or alkoxy group), amino, alkylamino, dialkylamino, acylaminoalkyl, alkoxy, thioalkoxy, polyalkoxy, loweralkyl, cycloalkyl or haloalkyl. The most preferred heterocyclics include imidazolyl, pyridyl, piperazinyl, azetidinyl, thiazolyl, triazolyl benzimidazolyl, benzothiazolyl, and benzoxazolyl. As used herein, the term "carboxy-protecting group" refers to a carbonyl group which has been esterified with one of the commonly used carboxylic acid protecting ester groups employed to block or protect the carboxylic acid function while reactions involving other functional sites of the compound are carried out. In addition, a carboxy protecting group can be attached to a solid support whereby the compound remains connected to the solid support as the carboxylate until cleaved by hydrolytic methods to release the corresponding free acid. Representative carboxy- protecting groups include, for example, loweralkyl esters, secondary amides and the like. As used herein, the term "pharmaceutically acceptable salts" refers to the nontoxic acid or alkaline earth metal salts of the compounds of Formula I. These salts can be prepared in situ during the final isolation and purification of the compounds of Formula I, or by separately reacting the base or acid functions with a suitable organic or inorganic acid or base, respectively. Representative acid salts include the hydrochloride, hydrobromide, bisulfate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, citrate, maleate, tartrate and the like. Representative alkali metals of alkaline earth metal salts include sodium, potassium, calcium, and magnesium salts. As used herein, the term "pharmaceutically acceptable ester" refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters includes formates, acetates, propionates, butyrates, acrylates and ethylsuccinates. The term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs ofthe compounds ofthe present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound ofthe above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and N. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 ofthe A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. As used herein, the term "alkoxy" refers to -O-R wherein R is lower alkyl as • defined above. Representative examples of lower alkoxy groups include methoxy, ethoxy, tert-butoxy and the like. The term "pathogenic microbes" refers to microbial organisms which do not normally reside in a human or animal host, and which are capable of causing a disease state in the host. Representative examples of pathogenic microbes include, for example, Acinetobacter Spp., Aeromona Spp., Bacteroides fi-agilis, Citrobacter Spp., Campylobacter Sp., Chlamydia trachomatis, Enterobacter Spp., Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Haemophilus influenzae, Klebsiella Spp., Legionella pneumophila, Moraxella catarhalis, Morganella Spp., Neisseria Spp., Proteus Spp., Providencia Spp., Pseudomonas aeruginosa, Salmonella Spp., Shigella Spp., Staphylococcus aureus, Coagulase-negative Staphylococcus Spp., Steptococcus pyogenes, Streptococcus pneumonia and Yersinia Spp. Preferred compounds of the invention include compounds of the formula (I) wherein Z is piperazinyl or N-methyl piperazinyl. Other preferred compounds ofthe invention include compounds ofthe formula (I) wherein A is -CF-. In representative embodiments of the invention, the compounds of the invention include, for example, benzyl l,4-dihydro-6-fluoro-7-(4-methyl-l- piperazinyl)-4-oxoquinoline-l-[4-O-(phosphoric acid dibenzyl ester)phenyl]-3- carboxylate, 1 ,4-dihydro-6-fluoro-7-(4-methyl- 1 -piperazinyl)-4-oxoquinoline- 1 -[4- O-(phosphoric acid)phenyl] -3 -carboxylic acid, ethyl l,4-dihydro-6-fTuoro-7-(4- methyl- l-piperazyl)-4-oxoquinoline-l-[4-O-(phosphoric acid monobenzyl ester)- phenyl] -3 -carboxylate, 1 ,4-dihydro-6-fluoro-7-(4-methyl- 1 -piperazyl)-4- oxoquinoline-l-[4-O-(phosphoric acid monobenzyl ester)-phenyl] -3 -carboxylic acid, ethyl 1 ,4-dihydro-6-fluoro- 1 -(4-dibenzylphosphonophenyl)-7-(4-methyl- 1 - piperazyl)-4-oxoquinoline-3 -carboxylate, 1 ,4-dihydro-6-fluoro-7-(4-methyl- 1 - piperazinyl)-4-oxoquinoline-l-[4-O-(phosphoric acid)phenyl]- 3-carboxylic acid, l,4-dihydro-6,8-difluoro-7-(4-methyl-l-piperazinyl)-4-oxoquinoline-l-[4-O- (phosphoric acid)phenyl]- 3-carboxylic acid, l,4-dihydro-6-fluoro-7-(4-methyl-l- piperazinyl)- 1 ,8-naphthyridine-4oxo- 1 -[4-O-(phosphoric acid)phenyl]- 3-carboxylic acid, 1 ,4-dihydro-6-fluoro-8-methoxy-7-(4-methyl- 1 -piperazinyl)-4-oxoquinoline- 1 - [4-O-(phosphoric acid)phenyl] -3 -carboxylic acid, . l,4-dihydro-6-fluoro-7-(l- piperazinyl)-4-oxoquinoline-l-[4-O-(phosphoric acid)phenyl]-3-carboxylic Acid, 1 ,4-dihydro-6-fluoro-7-(4-hydroxy- 1 -piperazinyl)-4-oxoquinoline- 1 -[4-O- (phosphoric acid)phenyl]- 3-carboxylic acid, l,4-dihydro-6-fluoro-7-(4-hydroxy-l- piperazinyl)-4-oxoquinoline-l-[4-O-(phosphoric acid)phenyl]- 3-carboxylic acid, 1 ,4-dihydro-6-fluoro-7-(3-amino- 1 -pyrrolidinyl)-4-oxoquinoline- 1 -[4-O-(phosphoric acid)phenyl]- 3-carboxylic acid, l,4-dihydro-6-fluoro-7-(3 -hydroxy- 1-pyrrolidinyl)- 4-oxoquinoline-l-[4-O-(phosphoric acid)phenyl]- 3-carboxylic acid and their pharmaceutically acceptable salts, esters and prodrugs. In other aspects, the present invention relates to the processes for preparing the compounds of Formula I and to the synthetic intermediates useful in such processes. The compounds of the invention comprise asymmetrically substituted carbon atoms. Such asymmetrically substituted carbon atoms can result in the compounds of the invention comprising mixtures of stereoisomers at a particular asymmetrically substituted carbon atom or a single stereoisomer. As a result, racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention are included in the present invention. The terms "S" and "R" configuration, as used herein, are as defined by the IUPAC 1974 RECO MENDAΉONS FOR SECTION E, FUNDAMENTAL STEREOCHEMISTRY, Pure Appl. Chem. 45:13-30 (1976). The terms α and β are employed for ring positions of cyclic compounds. The α-side of the reference plane is that side on which the preferred substituent lies at the lower numbered position. Those substituents lying on the opposite side of the reference plane are assigned β descriptor. It should be noted that this usage differs from that for cyclic stereoparents, in which "α" means "below the plane" and denotes absolute configuration. The terms α and β configuration, as used herein, are as defined by the CHEMICAL ABSTRACTS INDEX GUIDE- APPENDDC IV (1987) paragraph 203. The present invention also relates to the processes for preparing the compounds of the invention and to the synthetic intermediates useful in such processes, as described in detail below. In yet a further aspect of the present invention, pharmaceutical compositions are provided which comprise a compound of the present invention in combination with a pharmaceutically acceptable carrier. In general, the compounds of the invention can be prepared by the processes illustrated in reaction scheme I (Figure 1), reaction scheme II (Figure 2) and reaction scheme III (Figure 3). Referring to reaction scheme I shown in Figure 1, 2,4-dihalo-5-fluoro-α- oxobenzenepropanoate 1 is treated with trialkylorthoformate 2 in the presence of an acid anhydride, preferably acetic anhydride, to obtain 2,4-dihalo-β-ethoxymethylene- 5-fluoro-α-oxobenzenepropanoate 3. In the 2,4-dihalo-5-fluoro-α- oxobenzenepropanoate 1, X may be a chloro or a fluoro group, J may be an alkyl group of, for example, 1 to 10 carbon atoms, but is preferably lower alkyl, such as methyl or ethyl, R 6 is an acid-labile hydroxy-protecting group, for example, methoxymethyl and A may be a carbon or nitrogen group. Alternatively, A may be a carbon atom with a fluorine or alkoxy group substituent. In the trialkylorthoformate 2, R 5 may be an alkyl group of, for example, 1 to 10 carbon atoms, but is preferably lower alkyl, such as methyl or ethyl. Reaction with the trialkylorthoformate is preferably conducted at elevated temperatures, such as from about 50 °C to about 150 °C, preferably from about 100 °C to 140 °C. The 2,4-dihalo-β-ethoxymethylene-5-fluoro-α-oxobenzenepropanoate 3 is then treated with the substituted aromatic amine 4 to obtain the enaminoketoester 5. The reaction is preferably conducted in an appropriate aprotic or protic solvent, preferably methylene chloride or tetrahydrofuran, and may be conducted at room temperature or suitable elevated temperature, as . desired. The enaminoketoester 5 is then cyclized, such as by treatment with a base, preferably sodium hydride or potassium carbonate, to obtain the l-aryl-l,4-dihydro- 6-fluoro-4-oxoquinoline-3-carboxylic acid ester 6. Cyclization is conducted in the presence of an aprotic solvent such as 1,2-dimethoxymethane, dimethylformamide, or tefrahydrofuran, and is preferably conducted at temperatures of about 20 °C to 150 °C, more preferably at the reflux temperature of the solvent employed. The ester 6 is then subjected to hydrolysis, such as by treatment with sodium hydroxide, to form the free acid 7, followed by displacement of the 7-halo radical with substituted or unsubstituted piperazine or other heterocyclic amines 8 as described above by techniques known in the art to obtain the desired l-aryl-6-fluoro- 7-substituted amino- l,4-dihydro-4-oxoquinoline-3 -carboxylic acid 9. The reactions described above to form the 4-oxoquinolone 9 is a widely used approach (D. T. W. Chu J. Heterocyclic Chem. 1985, 22, 1022) for the preparation of quinolone derivatives. The l-aryl-6-fluoro-7-substituted amino-l,4-dihydro-4-oxoquinoline-3- carboxylic acid 9 is then converted into the corresponding ester 10 by conventional esterification procedures, such as by treating the free acid 9 with the appropriate alcohol, for example benzyl alcohol, in the presence of a esterification catalyst in an appropriate aprotic solvent, preferably dichloromethane or tetrahydrofuran and is preferably conducted at the reflux temperature ofthe solvent employed. The l-aryl-6-fluoro-7-substituted amino- 1,4-dihy dro-4-oxoquinoline-3- carboxylic acid ester 10 is then subjected to acid hydrolysis, such as by treatment with hydrochloric acid, trimethylsilyl iodide or boron trifluoride, preferably hydrochloric acid, to obtain the phenol 11. The hydrolysis is conducted in the presence of an aprotic solvent such as dichloromethane or dimethylformamide, and is preferably conducted at temperatures of about -10 °C to room temperature, more preferably at 0 °C. The l-aryl-6-fiuoro-7-substituted amino-l,4-dihydro-4-oxoquinoline-3- carboxylic acid ester 11 is then treated with substituted phosphoryl chloride 12 in the presence of a base, preferably sodium hydride or l,8-diazabicyclo[5.4.0]undec-7-ene to obtain the l-arylphosphonate-6-fluoro-7-substituted amino- l,4-dihydro-4- oxoquinoline-3 -carboxylic acid ester 13. In the substituted phosphoryl chloride 12, R 8 and R 9 may be independently hydrogen or lower alkyl group, but are preferably benzyl groups. Reaction of ester 12 with the substituted phosphoryl chloride 13 is preferably conducted in a polar aprotic solvent, preferably dimethylformamide or dimethylsulfoxide, and is preferably conducted at temperatures of about -10 °C to room temperature, more preferably at 0 °C. The 1 -arylphosphonate-6-fluoro-7-substituted amino- 1 ,4-dihydro-4-oxo- quinoline-3 -carboxylic acid ester 13 can then be converted into the corresponding acid (R ls R 2 , R 3 = hydrogen), if desired, by conventional hydrolysis procedures, such as by treating ester 13 . with hydrogen gas in the presence of palladium metal in a protic solvent, such as water, methanol or ethanol, . preferably at room temperature, to obtain the l-arylphosphonate-6-fluoro-7-substituted amino- l,4-dihydro-4- oxoquinoline-3-carboxylic acid 14. Referring to reaction scheme II shown in Figure 2, 2,4,5-trifluorobenzoyl chloride 1 is treated with malonate potassium salt 2 in the presence of a amine base, preferably triethyl amine, to obtain 2,4,5-trifluoro-α-oxobenzenepropanoate 3, according to the procedure of R. J. Clay et al Synthesis 1993, 291. In the 2,4,5- trifluorobenzoyl chloride 1, A may be a C or N group. Alternatively, A may be a carbon atom with a fluorine or alkoxy group substituent. In the malonate potassium salt 2, R4 may be an alkyl group of, for example, 1 to 10 carbon atoms, but is preferably lower alkyl, such as methyl or ethyl. Reaction with the potassium malonate salt is preferably conducted in anhydrous aprotic solvent, preferably acetonitrile or tetrahydrofuran at temperatures between 0 °C at room temperature, preferably between 10 and 15 °C. The β-ketoester 3 is then treated with a trialkylorthoformate 4 in the presence of an acid anhydride, preferably acetic anhydride, followed by reaction with hydroxyaniline 5 to obtain the enaminoketoester 6. In the trialkylorthoformate 4, R 5 may be an alkyl group of, for example, 1 to 10 carbon atoms, but is preferably lower alkyl, such as methyl or ethyl. Reaction with the trialkylorthoformate is preferably conducted at elevated temperatures, such as from about 50 °C to about 150 °C, preferably 100 °C, to obtain an oil as an unisolated intermediate (shown in brackets in the reaction scheme). Reaction ofthe latter with the hydroxyaniline 5 is preferably conducted in an appropriate aprotic solvent, preferably dimethyl sulfoxide or dichloromethane, and may be conducted at room temperature or suitable elevated temperature, as desired. The enaminoketoester 6 is then cyclized, such as by treatment with a base, preferably sodium hydride or potassium carbonate, to obtain the l-aryl-l,4-dihydro- 6, 7-difluoro-4-oxoquinoline-3 -carboxylic acid ester 7. Cyclization is conducted in the presence of an aprotic solvent such as 1,2-dimethoxymethane, dimethylformamide, or tetrahydrofuran, and is preferably conducted at temperatures of about 20 °C to 150 °C, more preferably at the reflux temperature of the solvent employed. In accordance with reaction scheme II, the l-aryl-l,4-dihydro-6,7-difluoro-4- oxoquinoline-3 -carboxylic acid ester 7 can undergo displacement of the 7-fluoro radical with substituted or unsubstituted piperazine or other heterocyclic amines 8 as described above by techniques known in the art to obtain the desired l-aryl-6-fluoro- 7-substituted amino- l,4-dihydro-4-oxoquiiιoline-3-carboxylic acid ester 9. Alternatively, ester 7 is treated with substituted phosphoryl chloride 10 in the presence of a base, preferably sodium hydride or l,8-diazabicyclo[5.4.0]undec-7-ene to obtain the l-arylphosphonate-6,7-difluoro-l,4-dihydro-4-oxoquinoline-3- carboxylic acid ester 12, followed by reaction with substituted or unsubstituted piperazine or other heterocyclic amines 8 as described above for the conversion of ester 7 to ester 9, to give l-arylphosphonate-6,fluoro-l,4-dihydro-4-oxoquinoline-3- carboxylic acid ester 11. In the substituted phosphoryl chloride 10, R 8 and R 9 may be independently hydrogen or lower alkyl group, but are preferably benzyl groups. Reaction of ester 7 (or ester 9) with the substituted phosphoryl chloride 10. is preferably conducted in a polar aprotic solvent, preferably dimethylformamide or dimethylsulfoxide, and is preferably conducted at temperatures of about -10 °C to room temperature, more preferably at 0 °C to room temperature. The l-arylphosphonate-6-fluoro-7-substituted amino- l,4-dihydro-4- oxoquinoline-3 -carboxylic acid ester 11 can then be converted into the corresponding acid (R 1? R 2 , R 3 = hydrogen), if desired, by conventional hydrolysis procedures, such as by treating ester 11 with hydrogen gas in the presence of palladium metal in a protic solvent, such as water, methanol or ethanol containing sodium or lithium hydroxide, preferably at room temperature, to obtain the l-arylphosphate-6-fluoro-7- substituted amino-l,4-dihydro-4-oxoquinoline-3-carboxylic acid 13. Referring to reaction scheme III shown in Figure 3, 2,4-dihalo-5-fluoro- benzoyl chloride 1 is treated with alkyl 3-substituted aminoacrylate 2 in the presence of a amine base, preferably triethyl amine, to obtain enaminoketoester 3, according to the procedure of K. Grohe et al Liebigs Ann. Chem. 1987, 1, 29. In the 2,4-dihalo-5- fluoro-benzoyl chloride 1, A may be a C or N group. Alternatively, A may be a carbon atom with a fluorine or alkoxy group substituent. In the alkyl 3-substituted aminoacrylate 2, j may be an alkyl group of, for example, 1 to 10 carbon atoms, but is preferably lower alkyl, such as methyl or ethyl; R 5 is an acid-labile hydroxy- protecting group, for example, methoxymethyl. The reaction is preferably conducted in a appropriate aprotic solvent, preferably dichloromethane or tefrahydrofuran, and may be conducted at room or suitable elevated temperature, as desired. Enaminoketoester 6 can then be converted into the corresponding ester 4 in an analogous series of reactions as described above (Scheme I: 5 → 14). The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochlori.de, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-napthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of formula (I), or separately by reacting carboxylic acid moieties with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations, based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. The compounds ofthe invention are useful in vitro in inhibiting the growth of pathogenic microbes, and in vivo in human and animal hosts for treating pathogenic microbial infections, including infections of Acinetobacter Spp., Aeromona Spp., Bacteroides fragilis, Citrobacter Spp., Campylobacter Sp., Chlamydia trachomatis, Enterobacter Spp., Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Haemophilus influenzae, Klebsiella Spp., Legionella pneumophila, Moraxella catarhalis, Morganella Spp., Neisseria Spp., Proteus Spp., Providencia Spp., Pseudomonas aeruginosa, Salmonella Spp., Shigella Spp., Staphylococcus aureus, Coagulase-negative Staphylococcus Spp., Steptococcus pyogenes, Streptococcus pneumonia and Yersinia Spp. The compounds may be used alone or in compositions together with a pharmaceutically acceptable carrier. Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 1000 mg/kg body weight daily and more preferred from 1.0 to 30 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy. The compounds of the present invention may be administered orally, parenterally, sublingually, by aerosolization or inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or ionophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Suppositories for rectal administration ofthe drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa, butter and polyethylene glycols, which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug. Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents. The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi- lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any nontoxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Celt Biology, Volume XIN, Academic Press, New York, N.W., p. 33 et seq (1976). In other aspects, the current invention concerns concentrated quinoline formulations, such as concentrated formulations of the l,4-dihydro-6-fluoro-4-oxo- quinoline-3 -carboxylic acids of the invention, suitable for efficacious delivery of the quinoline by aerosolization into endobronchial space. This aspect ofthe invention is most preferably suitable for formulation of concentrated quinolines for aerosolization by jet, vibrating porous plate or ultrasonic nebulizers to produce average quinoline aerosol particle sizes between 1 and 5 μ necessary for efficacious delivery of the quinolines into the endobronchial space to treat Streptococcus pneumoniae, Haemophilus influenza , Staphylococcus aureus Moraxella catarhalis and Legionella pneumonia, Chlamydia pneumoniae, and Mycoplasma pneumoniae infections. The formulation contains minimal yet efficacious amounts of a quinoline of the invention formulated in the smallest possible volume of physiologically acceptable solution having a salinity, or dry powder, adjusted to permit generation of quinoline aerosol well-tolerated by patients but preventing the development of secondary undesirable side effects such as bronchospasm and cough. Primary requirements for any aerosolized formulation are its safety and efficacy. Additional advantages are lower treatment cost, practicality of use, long- shelf life, storage and optimization of nebulizer. The aerosol formulations of the invention are nebulized predominantly into particle sizes, which can be delivered to the terminal, and respiratory bronchioles where the susceptible bacteria reside in patients with chronic bronchitis and pneumonia. Many susceptible bacteria are present throughout in airways down to bronchi, bronchioli and lung parenchema. However, it is most predominant in terminal and respiratory bronchioles. During exacerbation of infection, bacteria can also be present in alveoli. It is therefore clear that any therapeutic formulation must be delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue. Aerosolized quinoline formulations are formulated for efficacious delivery of a quinoline compound of the invention to the lung endobronchial space. A specific jet, vibrating porous plate, mechanical or gas-propelled droplet extrusion, or ultrasonic nebulizer is selected to allow the formation of quinoline aerosol particles having with a mass medium average diameter predominantly between 1 to 5 μ. The formulated and delivered amount of the quinoline is efficacious for treatment and prophylaxis of endobronchial infections, particularly those caused by the bacteria Acinetobacter Spp., Aeromona Spp., Bacteroides fragilis, Citrobacter Spp., Campylobacter Sp., Chlamydia trachomatis, Enterobacter Spp., Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Haemophilύs influenzae, Klebsiella Spp., Legionella pneumophila, Moraxella catarhalis, Morganella Spp., Neisseria Spp., Proteus Spp., Providencia Spp., Pseudomonas aeruginosa, ' Salmonella Spp., Shigella Spp., Staphylococcus aureus, Coagulase-negative Staphylococcus Spp., Steptococcus pyogenes, Streptococcus pneumonia and Yersinia Spp. The formulation has salinity adjusted to permit generation of quinoline aerosol well tolerated by patients. Further, the formulation has balanced osmolarity ionic strength and chloride concentration. The formulation has a smallest possible aerosolizable volume able to deliver effective dose of a quinoline ofthe invention to the site ofthe infection. Additionally, the aerosolized formulation does not impair negatively the functionality ofthe airways and does not cause undesirable side effects. Aerosolized quinoline formulations according to the invention contain from 10-150 mg, preferably 30 mg, of a quinoline antibiotic drug per 1 mL of aqueous solution, or 10-150, preferably 30 mg of a quinoline antibiotic drug per 1 mL of the quarter normal saline. This corresponds to amounts of quinoline that are minimal yet efficacious amounts of quinoline to suppress Acinetobacter Spp., Aeromona Spp., Bacteroides fragilis, Citrobacter Spp., Campylobacter Sp., Chlamydia trachomatis, Enterobacter Spp., Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Haemophilus influenzae, Klebsiella Spp., Legionella pneumophila, Moraxella catarhalis, Morganella Spp., Neisseria Spp., Proteus Spp., Providencia Spp., Pseudomonas aeruginosa, Salmonella Spp., Shigella Spp., Staphylococcus aureus, Coagulase-negative Staphylococcus Spp., Steptococcus pyogenes, Stj-eptococcus pneumonia and Yersinia Spp. infections in the endobronchial space. The most preferred aerosol quinoline formulation according to the invention contains 10-150 mg of quinoline per 1 mL of the quarter normal saline. This corresponds to 10-150 mg/mL of quinoline that is minimal yet efficacious amount of quinoline to suppress the bacterial infections in endobronchial space. Both patients and aerosol generating devices are sensitive to the osmolarity, pH, and ionic strength of the formulation. It has now been discovered that this problem is conveniently solved by formulating some quinoline solutions in quarter normal saline, that is saline containing 0.225% of sodium chloride, and that l Λ N saline is a suitable vehicle for delivery of quinoline into the endobronchial space. Chronic bronchetic patients and other patients with chronic endobronchial infections have a high incidence of bronchospastic or asthmatic airways. These airways are sensitive to hypotonic or hypertonic aerosols, to the presence of a permanent ion, particularly a halide such as chloride, as well as to aerosols that are acidic or basic. The effects of irritating the airways can be clinically manifested by cough or bronchospasm. Both of these conditions can prevent efficient delivery of aerosolized quinoline into the endobronchial space. In certain aspects, the aerosolized quinoline formulations of the invention A NS with 10-150 mg of quinoline per ml of % NS have an osmolarity in the range of 130-550 mOsm/L. This is within the safe range of aerosols administered to a chronic bronchitis patient. The pH of the aerosolized formulations of the invention is also important for aerosol delivery. When the aerosol is either acidic or basic, it can cause bronchospasm and cough. The safe range of pH is relative; some patients will tolerate a mildly acidic aerosol that in others will cause bronchospasm. Any aerosol with a pH of less than 4.5 usually will induce bronchospasm in a susceptible individual; aerosols with a pH between 4.5 and 5.0 will occasionally cause this problem. An aerosol with a pH between 5.0 and 8.4 is considered to be safe. The optimum pH for the aerosol formulation was determined to be between pH 7.0 and 8.4. The aerosolized formulations of the invention are nebulized predominantly into particle sizes allowing a delivery of the drug into the terminal and respiratory bronchioles and lower airways and tissues where the bacteria reside. For efficacious delivery of the quinoline ofthe invention to the lung endobronchial space of airways in an aerosol, the formation of aerosol particles having a mass medium average diameter predominantly between 1 to 5 μ is necessary. The formulated and delivered amount of quinoline for treatment and prophylaxis of endobronchial infections, particularly those caused by the bacteria Acinetobacter Spp., Aeromona Spp., Bacteroides fragilis, Citrobacter Spp., Campylobacter Sp., Chlamydia trachomatis, Enterobacter Spp., Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Haemophilus influenzae, Klebsiella Spp., Legionella pneumophila, Moraxella catarhalis, Morganella Spp., Neisseria Spp., Proteus Spp., Providencia Spp., Pseudomonas aeruginosa, Salmonella Spp., Shigella Spp., Staphylococcus aureus, Coagulase-negative Staphylococcus Spp., Steptococcus pyogenes, Streptococcus pneumonia and Yersinia Spp., must effectively target the lung surface. The formulation must have a smallest possible aerosolizable volume able to deliver effective dose of quinoline to the site of the infection. The formulation must additionally provide conditions that would not adversely affect the functionality of the airways. Consequently, the formulation must contain enough of the drug formulated under the conditions, which allow its efficacious delivery, while avoiding undesirable reactions. The new formulations according to the invention meet all these requirements. The formulated dose of quinoline of 10-150 mg/mL of one-quarter diluted saline at pH 7.5-8.0 has been found to be optimal for the most efficacious delivery. Although in some instances both lower and higher doses, typically from 1-200 mg/mL may be advantageously used, the 30-150 mg/mL dose of quinoline is preferred. According to this aspect of the invention, quinoline is formulated in a dosage form intended for inhalation therapy by patients with chronic bronchitis and pneumonia. Since the patients reside throughout the world, it is imperative that the formulation has reasonably long shelf life. Storage conditions and formulation stability thus become important. As discussed above, the pH of the solution is important. A pH between 5.0 and 8.4, preferably about 6.5, is optimal from the storage and longer shelf-life point of view. The formulation is typically stored in a one-milliliter low-density polyethylene (LDPE) vials. The vials are aseptically filled using a blow-fill-seal process. The vials are sealed in foil overpouches. Stability of the formulation with respect to oxidation is another very important issue. If the drug is degraded before aerosolization, a smaller amount of the drug is delivered to the lung, thus impairing the treatment as well as provoking conditions that could lead to the development of resistance to quinoline, because the delivered dose would be too small. Moreover, quinoline degradation products may provoke bronchospasm and cough. To prevent oxidative degradation of quinoline and in order to provide acceptable stability, a product with low oxygen content is produced by packaging the LDPE vials in oxygen-protective packaging comprising foil overpouches, six vials per overpouch. Prior to vial filling, the solution in the mixing tank is nitrogen sparged and the annular overpouch headspace is nitrogen purged. In this way, both hydrolysis and oxidation of quinoline is prevented. Another important part of this aspect of the invention is an aerosolization device, such as a jet, vibrating porous plate, mechanical or gas-propelled droplet extrusion, or ultrasonic nebulizer, that is able to nebulize the formulation of the invention into aerosol particle size predominantly in the size range from 1-5 μ. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 μ range. Nebulizers such as jet, ultrasonic, vibrating porous plate, and energized dry powder inhalers, that can produce and deliver particles between the 1 and 5 μm particle size that is optimal for treatment of Acinetobacter Spp., Aeromona Spp., Bacteroides fragilis, Citrobacter Spp., Campylobacter Sp., Chlamydia trachomatis, Enterobacter Spp., Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Haemophilus influenzae, Klebsiella Spp., Legionella pneumophila, Moraxella catarhalis, Morganella Spp., Neisseria Spp., Proteus Spp., Providencia Spp., Pseudomonas aeruginosa, Salmonella Spp., Shigella Spp., Staphylococcus aureus, Coagulase-negative Staphylococcus Spp., Steptococcus pyogenes, Streptococcus pneumonia and Yersinia Spp. infections, are currently available or under development. A jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets. While a variety of devices are available, only a limited number of these nebulizers are suitable for the purposes of this aspect of the invention. Preferred nebulizers useful in the present invention include, for example, AeroNeb and AeroDose vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream nebulizers (Medic-Aid Ltd., West Sussex, England), Pari (it) f ) LC and Pari LC Star jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and Aerosonic (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers. While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more other agents used in the treatment of pathogenic mycobacterial infections. Representative agents useful in combination with the compounds of the invention for the treatment of M. tuberculosis include, for example, isoniazid, rifampin, pyrazinamide, ethambutol, rifabutin, streptomycin, ciprofloxacin and the like. Representative agents useful in combination with the compounds of the invention for the treatment of Clostridium include, for example, vancomycin, metronidazole, bacitracin and the like. Representative agents useful in combination with the compounds of the invention for the treatment of Cryptosporidium include, for example, furoate, furazolidone, quinine, spiramycin, alpha-difluoromthyl-ormthine, interleukin-2 and the like. Representative agents useful in combination with the compounds of the invention for the treatment of Helicobacter include, for example, azithromycin, amoxycillin, clarithromycin and the like. The compounds of the invention may also be administered in combination with β-lactams, such as cephalosporins, carbapenems and/or monobactams, or other agents useful in the treatment of pneumonia. The above compounds to be employed in combination with the compounds of the invention will be used in therapeutic amounts as indicated in the PHYSICIANS' DESK REFERENCE (PDR) 47th Edition (1993), which is incorporated herein by reference, or such therapeutically useful amounts as would be known to one of ordinary skill in the art. The compounds of the invention and the other antiinfective agent can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient. The combination can be administered as separate compositions or as a single dosage form containing both agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions, which are given at the same time or different times, or the therapeutic agents, can be given as a single composition. The foregoing may be better understood from the following examples, which are presented for the purposes of illustration and are not intended to limit the scope of the inventive concepts. Example 1 4-Methoxymethoxynitrobenzene A stirred solution of 4-nitrophenol (13.9 g, 100 mmol) in dichloromethane (75 mL) at room temperature was treated with diisopropylethylamine (17.4 mL, 100 mmol). The mixture was cooled in an ice-bath and a solution of bromomethyl methyl ether (8.2 mL, 100 mmol) in dichloromethane (75 mL) was added dropwise. After the addition was complete the mixture was stirred for 1 h, diluted with dichloromethane (150 mL) and washed with 0J N hydrochloric acid, sodium bicarbonate, brine and finally dried over magnesium sulfate. The mixture was filtered, concentrated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate, 8:1) to give 4- methoxymethoxynitrobenzene as light yellow crystals in 88% yield: 1H NMR (400 MHz, CDC1 3 ) δ 8.16 (d 2H), 7.14 (d, 2H), 5.26 (s, 2H), 3.50 (s, 3H). Example 2 4-Methoxymethoxyaniline To a stirred solution of 4-methoxymethoxynitrophenol (6.6 g, 36 mmol) in ethanol (50 mL) at room temperature was added palladium (600 mg, 10% on activated carbon). The mixture was placed under a hydrogen atmosphere for 24 h, followed by removal ofthe catalyst by filtration. The filtrate was concentrated under reduced pressure to give 4-methoxmethoxyaniline (99% yield) and was used without further purification: 1H NMR (400 MHz, CDC1 3 ) δ 6.88 (d, 2H), 6.62 (d, 2H), 5.06 (s, 2H), 3.44 (s, 3H). Example 3 Methyl 2-Fluoro-4,5-dichloro-β-ethoxymethylene-α-oxobenzeneproρanoate Methyl 2-fluoro-4,5-di-chloro-α-oxobenzenepropanoate (Recon Limited; 16/2, OVH Road, Basavanagudi, Bangalore, India) (9.6 g, 36 mmol) was added to a solution of triethyl orthoformate (43 mL) and acetic anhydride (127 mL), according to the procedure of J. Burnie et al Drugs Fut. 1984, 9, 179. The mixture was heated for 2 h at 130 °C. After allowing to cool, the solvent was removed under reduced pressure to give methyl 2-fluoro-4,5-dichloro-β-ethoxymethylene-α- oxobenzenepropanoate and was used without further purification. Example 4 Methyl 2,4-Dichloro-5-fluoro-β-(r4-methoxymethoxyphenyl)aminolmethylene-α- oxobenzenepropanoate To a stirred solution of methyl 2-fluoro-4,5-di-chloro-β-ethoxymethylene-α- oxobenzenepropanoate (11 g, 36 mmol) in dichloromethane (20 L) at room temperature was added 4-methoxymethoxy aniline (5.48 g, 36 mmol). The mixture was stirred for 30 min. and then concentrated under reduced pressure. Silica gel column chromatography purification (hexane:ethyl acetate, 6:1 to 4:1) gave a yellow solid in 84% yield: mp 95-99 °C; 1H NMR (400 MHz, CDC1 3 ) δ 12.74 (d, IH), 8.52 (d, IH), 7.30 (d, IH), 7.12 (d, 2H) 7.00 (d, 2H), 6.94 (d, 2H), 5.20 (s, 2H), 3.60 (s, 3H), 3.50 (s, 3H). Example 5 Methyl 1 ,4-Dihydro-6-fluoro-7-chloro- 1 -(4-methoxymethoxyphenyl)-4- oxoquinoline-3 -carboxylate To a solution of methyl 2,4-dichloro-5-fluoro-β-([4-methoxymethoxy- phenyl)amino]-methylene-α-oxobenzenepropanoate (13.4 g, 30.0 mmol) dissolved in dimethoxyethane (110 mL) at room temperature was added sodium hydride (1.33 g, 33.3 mmol) in portions. The mixture was heated to 80 °C and maintained at this temperature for 2 h. After the mixture was cooled to room temperature solvent was removed under reduced pressure and the residue was distributed between ethyl acetate and water. The precipitate was collected by filtration to give a yellow solid in 76% yield: mp 216-217 °C; 1H NMR (400 MHz, CDC1 3 ) δ 8.42 (d,lH), 8.24 (d, IH), 7.26-7.30 (m, 4H), 5.30 (s, 2H), 3.90 (s, 3H), 3.58 (s, 3H). Example 6 l,4-Dihy(ho-6-fluoro-7-cMoro-l-(4-methoxymethoxyphenyl)-4-oxoquinoline-3- carboxylic acid A solution of methyl l,4-dihydro-6-fϊuoro-7-chloro-l-(4- methoxymethoxyphenyl)-4-oxoquinoline-3 -carboxylate (14 g, 36 mmol) in ethanol (140 mL) and 0.5 N aqueous sodium hydroxide (140 mL) was heated to reflux for 3 h. The . ethanol was removed under reduced pressure and to the resultant aqueous layer was added dichloromethane (200 mL). The mixture was then acidified with IN hydrochloric acid to pH~l-2. The organic layer was separated, washed with water and dried (magnesium sulfate). Filtration and solvent removal under reduced pressure gave a white solid in 97% yield: mp 191-193 °C; 1H NMR (400 MHz, DMSO-</ 6 ) δ 14.50 (br,lH), 8.70 (s, IH), 8.28 (d, IH), 7.62 (d, 2H), 7.30 (d, 2H), 5.34 (s, 2H), 3.50 (s, 3H). Example 7 1 ,4-Dihydro 6-fluoro- 1 -(4-methoxymethoxyphenyl)-7-(4-methyl- 1 -piperazinyl)-4- oxoquinoline-3-carboxylic acid A stirred suspension of l,4-dihydro-6-fluoro-7-chloro-l-(4-methoxy- methoxyphenyl)-4-oxoquinoline-3-carboxylic acid (3.6 g, 9.5 mmol) in dimethyl- sulfoxide (10 mL) at room temperature was treated with N-methylpiperazine (5.3 mL, 48 mmol). The mixture was stirred at 130 °C for 40 min., cooled to 90 °C and the solvent removed under reduced pressure. The residue was diluted with warm ethanol (10 mL) and cooled to room temperature. The precipitate was collected by filtration to give a yellow solid in 71% yield: mp 200 °C (dec); 1H ΝMR (400 MHz, OMSO-d 6 ) δ 15.20 (br. IH), 8.66 (s, IH), 8.04 (d, IH), 7.70 (d, 2H), 7.34 (d, 2H), 6.50 (d, IH), 5.44 (s, 2H), 3.50 (s, 3H), 3J0 (m, 4H), 2.60 (m, 4H), 2.3 (s, 3H). Example 8 Benzyl 1 ,4-Dihydro-6-fluoro-7-(4-methyl- 1 -piperazinyl)- 1 -(4- methoxymethoxyphenyl)-4-oxoquinoline-3-carboxylate To a stirred solution of l,4-dihydro-6-fluoro-l-(4-methoxymethoxyphenyl)-7- (4-methyl-l-piperazinyl)-4-oxoquinoline-3 -carboxylic acid (3.0 g, 6.8 mmol) in - dichloromethane (20 mL) at room temperature was added benzyl alcohol (7.0 mL, 68 mmol), 1,3-dicyclohexylcarbodiimide (2J g, 10 mmol) and 4- dimethylaminopyridine (83 mg, 0.68 mmol). The mixture was heated to 50 °C for 2 h. The mixture was cooled to room temperature and the resultant precipitate was removed. The filtrate was diluted with dichloromethane (20 mL), washed by 0J N hydrochloric acid, saturated aqueous sodium bicarbonate, brine and then dried (magnesium sulfate). The mixture was filtered, concentrated under reduced pressure and the residue was poured into 200 mL of hexane, filtered and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give a yellow solid in 63% yield: mp 108-110 °C; 1H NMR (400 MHz, CDC1 3 ) δ 8.28 (s, IH), 7.94 (d, IH), 7.40 (d, 2H), 7.12-7.24 (m, 7H), 6.28 (d, IH), 5.30 (s, 2H), 5.20 (s, 2H), 5.16 (s, 2H), 3.48 (s, 3H), 2.96 (m, 4H), 2.40 (m, 4H), 2.28 (s, 3H). Example 9 Benzyl 1 ,4-Dihydro- 1 -(4-hydroxyphenyl)-6-fluoro-7-(4-methyl- 1 -piperazinyl)-4- oxoquinoline-3-carboxylate A stirred . solution of benzyl l,4-dihydro-6-fluoro-l-(4- methoxymethoxyphenyl)-7-(4-methyl-l-piperazinyl)-4-oxoquinoline-3-carboxylate (1.9 g, 3.6 mmol) in dichloromethane (10 mL) at 0 °C was treated with 4.0 M hydrochloric acid in p-dioxane (5 mL, 0 °C) and maintained at this temperature for 30 min. The mixture was concentrated under reduced pressure and the residue dissolved in methanol (10 mL). The mixture was adjusted to pH 7 using triethylamine and the mixture concentrated under reduced pressure. The residue was washed with cold methanol to give a pale yellow solid in 80% yield: mp > 300 °C (dec); 1H NMR (400 MHz, CD 3 OD) δ 8.68 (s, IH), 8.10 (d, IH), 7.58 (d, 2H), 7.44 (m, 5H), 7.10 (d, 2H), 6.56 (d, IH), 5.42 (s, 2H), 3.24 (m, 4H), 2.68 (m, 4H), 2.44 (s, 3H). Example 10 Benzyl l,4-Dihydro-6-fluoro-7-(4-methyl-l-piperazinyl)-4-oxoquinoline-l-[4-O- (phosphoric acid dibenzyl ester)phenyll-3-carboxylate To a stirred mixture of benzyl 6-fluoro-l,4-dihydro-l-(4-hydroxyphenyl)-7- (4-methyl-l-piperazinyl)-4-oxoquinoline-3-carboxylate (1.0 g, 2.0 mmol) in DMF (14 mL) at 0 °C was added sodium hydride (96 mg, 2.4 mmol). The mixture was stirred for 30 min and then treated with dibenzylphosphoryl chloride (14 mL, 4 mmol in benzene). The mixture was stirred for 40 min., water added (5 mL) and stirring continued at room temperature for a further 2 h. The mixture was concentrated under reduced pressure and the residue dissolved in dichloromethane (10 mL), washed with sat. aqueous sodium bicarbonate, water, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5% methanol in dichloromethane) to give a pale yellow solid in 49% yield: 1H NMR (400 MHz, CDC1 3 ) δ 8.632 (s, IH), 7.98 (d, IH), 7.44 (d, 2H), 7.30 (m, 17H), 6.20 (d, IH), 5.36 (s, 2H), 5J6 (s, 2H), 5J4 (s, 2H), 3.06 (m, 4H), 2.50 (m, 4H), 2.30 (s, 3H). Example 11 1 ,4-Dihydro-6-fluoro-7-(4-methyl- 1 -piperazinyl)-4-oxoquinoline- 1 -[4-O-(phosphoric acid)pheny!1- 3-carboxylic Acid TPA 2808] A stirred solution of benzyl l,4-dihydro-6-fluoro-7-(4-methyl-l-piperazinyl)- 4-oxoquinoline-l-[4-O-(phosphoric acid dibenzyl ester)phenyl]-3-carboxylate (0.68 g, 0.91 mmol) in methanol at room temperature was treated with palladium (68 mg, 10% on activated carbon) and cyclohexylamine (0.3 g, 3 mmol). The mixture was placed under a hydrogen atmosphere for 1 h. The mixture was filtered and then acidified using 4.0 M hydrochloric acid in p-dioxane to pH ~ 1-2 followed by concentration under reduced pressure. The resultant solid was washed with cold methanol to give a pale yellow solid in 82% yield: mp > 300 °C (dec); 1H NMR (400 MHz, CD 3 OD) δ 8.44 (s, IH), 7.98 (d, IH), 7.60 (d, 2H), 7.30 (d, 2H), 6.48 (d, IH), 3.06 (m, 4H), 2.54 (m, 4H), 2.30 (s, 3H). Example 12 Ethyl 2,4,5-Trifluoro- -oxobenzenepropanoate A stirred solution of potassium ethyl malonate (13 g, 76 mmol) in anhydrous acetonitrile (120 mL) under nitrogen was cooled to 10-15 °C. To this mixture was added triethylamine (10.4 mL, 74.6 mmol) followed by magnesium chloride (8.8 g, 93 mmol) and stirring continued at 20-25 °C for 2.5 h. The resultant slurry was recooled to 0 °C and 2,4,5-trifluorobenzoyl chloride (4.8 mL, 37 mmol) added dropwise over 15 min. followed by the addition of triethylamine (1.0 mL, 7.2 mmol). The mixture was allowed to stir at room temperature for 18 h and then concentrated under reduced pressure to remove acetonitrile. Toluene (60 mL) was added and the mixture concentrated under reduced pressure. More toluene (60 mL) was added and the mixture stirred and cooled to 10-15 °C. Aqueous hydrochloric acid (13%, 75 mL) was added while keeping the temperature below 25 °C. The aqueous layer was separated and the organic layer washed with aqueous Hydrochloric acid (12%, 2 X 65 mL) followed by water (2 X 50 mL) and then concentrated under reduced pressure to give a mixture of trifluorobenzoyl acetates as keto and enol tautomers (pale yellow oil) in 90% yield: 1H NMR (enol form, 400 MHz, CDC1 3 ) δ: 12.71 (s, IH), 7.74 (m, IH), 7.00 (m, IH), 5.84 (s, IH), 4.26 (q, 2H), 1.34 (t, 3H); (keto form, 400 MHz, CDC1 3 ) δ: 7.82 (m, IH), 7.02 (m, IH), 4.21 (q, 2H), 3.94 (d, 2H), 1.26 (t, 3H); (lit: Chu, D. T. W. et al /. Med Chem. 1991, 34, 168). Example 13 Ethyl 2,3,4,5-Tetrafluoro-α-oxobenzenepropanoate Using the procedure in example 12 and replacing 2,4,5-trifluorobenzoyl chloride with 2,3,4,5-tetrafluorobenzoyl chloride gives the title compound (lit: Chu, D. T. W. et al J. Heterocyclic Chem. 1987, 24, 453). Example 14 Ethyl 2,6-Dichloro-5-fluoro-β-oxo-3-pyridinepropanoate Using the procedure in example 12 and replacing 2,4,5-trifluorobenzoyl chloride with 2,6-dichloro-5-fluoronicotinoyl chloride gives the title compound (lit: Miyamoto, T. et al Chem. Pharm. Bull. 1990, 38, 3211). Example 15 Ethyl 3-Methoxy-2,4,5-trifluoro-α-oxobenzenepropanoate Using the procedure in example 12 and replacing 2,4,5-trifluorobenzoyl chloride with 3-methoxy-2,4,5-trifluorobenzoyl chloride (prepared according to the procedure of Sanchez, J.P. et al, J. Med. Chem. 1986, 30, 2283) gives the title compound. Example 16 Ethyl 6,7-Difluoro-l,4-dihydro-l-(4-hydroxyphenyl)-4-oxoquinoline-3-carboxylate To a stirred solution of ethyl 2,4,5-trifluoro-α-oxobenzenepropanoate (9J g, 37 mmol) in acetic anhydride (10 mL, 103 mmol) at room temperature was added triethylorthoformate (9.0 mL, 55 mmol). The mixture was heated to reflux and maintained at this temperature for 4 h. The mixture was cooled to 45 °C and then concentrated under reduced pressure as the bath temperature was increased to 98 °C. The residual oil was diluted with dimethyl sulfoxide (50 mL) and treated with 4- aminophenol (10 g, 92 mmol) in portions over 10 min. while maintaining the temperature between 15-20 °C. After the addition was complete, dimethyl sulfoxide (50 mL) was added and the mixture stirred for 18 h at room temperature. The mixture was freated with potassium carbonate (2J g, 15 mmol) and then heated to 95 °C and maintained at this temperature for 70 min. The mixture was filtered hot and the resultant solid washed with warm dimethylsulfoxide (50 mL) followed by water washes (4 X 50 mL) and dried under reduced pressure (60 °C) for 24 h to give a yellow solid in 74% yield: mp 280 °C (dec); 1H NMR (400 MHz, DMSO-</ 6 ) δ 10.11 (s, IH), 8.35 (s, IH), 8.04 (m, IH), 7.41 (d, 2H), 6.94 (d, 2H), 6.89 (m, IH), 4.15 (q, 2H), 1.20 (t, 3H); (lit: Narita, H. et al Yakugaku Zasshi 1986, 106, 795). Example 17 Ethyl 1 ,4-Dihydro-6-fluoro- 1 -(4-hydroxyphenyl)-7-(4-methyl- 1 -piperazyl)-4- A stirred solution of ethyl 6,7-difluoro-l,4-dihydro-l-(4-hydroxyphenyl)-4- oxoquinoline-3-carboxylate (1.0 g, 2.9 mmol) in dimethyl sulfoxide (5 mL) was heated to 115 °C and treated with N-methylpiperazine (1.6 mL, 14 mmol). The mixture was stirred for 90 min, allowed to cool and then filtered. The solid was washed with warm dimethyl sulfoxide (20 mL), water (4 X 50 mL) and dried under reduced pressure to give a pale yellow solid in 65% yield: mp 263 °C (dec); 1H ΝMR (400 MHz, DMSO-cfe) δ 10.10 (br s, IH), 8.29 (s, IH), 7.78 (d, IH), 7.43 (m, 2H), 6.99 (d, 2H), 6.32 (m, IH), 4J8 (q, 2H), 3.00 (br s, 4H), 2.39 (br s, 4H), 2J5 (s, 3H), 1.22 (t, 3H); (lit: Jung, M. et al J. Med. Chem. 1999, 42, 3899). Example 18 Ethyl 1 ,4-Dihydro-6-fluoro-7-(4-methyl- 1 -piperazyl)-4-oxoquinoline- 1 - f4-O- (phosphoric acid monobenzyl ester)-phenyl ~ l-3-carboxylate A stirred solution of ethyl l,4-dihydro-6-fluoro-l-(4-hydrophenyl)-7-(4- methyl-l-piperazyl)-4-oxoquinoline-3-carboxylate (1.0 g, 2.3 mmol) in a 1:1 dimethylformamide: tetrahydrofuran mixture (15 mL) was cooled to 0 °C and treated with l,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL, 3.0 mmol) dropwise. The mixture was stirred for 10 min and then treated with dibenzylphosphoryl chloride (18 mL, 0.26 M in benzene) over 10 min. and allowed to stir for 18 h at room temperature. The mixture was concentrated under reduced pressure and the resultant oil purified by silica gel chromatography (EtOAcMeOH, 9:1) to give a pale yellow solid in 30% yield: mp 210 °C (dec); 1H ΝMR (400 MHz, DMSO- ) δ 10.22 (br s, IH), 8.37 (s, IH), 7.88 (d, IH), 7.62 (m, 2H), 7.41 (m, 2H), 7.38 (m,5H), 6.43 (d, IH), 5.02 (m, 2H), 4.21 (q, 2H), 3.46 (br m, 4H), 3.18 (br m, 2H), 2.96 (br m, 2H), 2.80 (s, 3H), 1.27 (t, 3H). Example 19 1 ,4-Dihydro-6-fluoro-7-(4-methyl- 1 -piperazyl)-4-oxoquinoline- 1 -r4-O-(phosphoric acid monobenzyl ester)-phenyll -3 -carboxylic Acid To a stirred solution of ethyl l,4-dihydro-6-fluoro-7-(4-methyl-l-piperazyl)- 4-oxoquinoline-l-[4-O-(phosphoric acid monobenzyl ester)-phenyl]-3-carboxylate (0.50 g, 0.84 mmol) in 2:1 methanoLwater (30 mL) at room temperature was added. lithium hydroxide monohydrate (0J4 g, 3.3 mmol). The mixture was stirred for 5 h, filtered and concentrated under reduced pressure to give a white solid in 81% yield: mp 280 °C (dec); 1H NMR (400 MHz, CD 3 OD) δ 8.58 (s, IH), 7.90 (d, IH), 7.35 (m, 4H), 7.23 (m, 5H), 6.39 (d, IH), 4.93 (d, 2H), 2.97 (br s, 2H), 2.44 (br s, 2H), 2.20 (s, 3H). Example 20 Ethyl 1 ,4-Dihydro-6-fluoro- 1 -(4-dibenzylphosphonophenyl)-7-(4-methyl- 1 - piperazyl)-4-oxoquinoline-3-carboxylate Using the procedure in example 18 and substituting ethyl l,4-dihydro-6- fluoro- 1 -(4-hydrophenyl)-7-(4-methyl- 1 -piperazyl)-4-oxoquinoline-3 -carboxylate with ethyl 1 ,4-dihydro-6-fluoro- 1 -(4-hydrophenyl)-7-(4-methyl- 1 -piperazyl)-4- oxoquinoline-3 -carboxylate gave the title compound in 45% yield: mp 101 °C; 1H NMR (400 MHz, CDC1 3 ) δ 8.52 (s, IH), 8.40 (m, IH), 7.47 (m, 10H) 7.40 (m, 4H), 6.84 (m, IH), 5.30 (m, 4H), 4.46 (q, 2H), 1.48 (t, 3H). Example 21 1 ,4-Dihydro-6-fluoro-7-(4-methyl- 1 -ρiperazinyl)-4-oxoquinoline- 1 -r4-O-(phosphoric acid)phenyl " |- 3-carboxylic Acid fPA 2808 - Alternate Synthesis] To a stirred solution of l,4-dihydro-6-fluoro-7-(4-methyl-l-piperazyl)-4- oxoquinoline-l-[4-O-(phosphoric acid monobenzyl ester)-phenyl]-3-carboxylic acid (50 mg, 0.09 mmol) in 3:1 methanohwater (3 mL) was added palladium (24 mg, 10% on activated carbon). The mixture was placed under a hydrogen atmosphere and stirred at room temperature for 5 h. The mixture was filtered and concentrated under reduced pressure. The residue was dissolved in aqueous sodium bicarbonate concentrated and treated with methanol. The mixture was filtered and then acidified using 4.0 M hydrochloric acid in />-dioxane to pH~l-2 followed by concentration under reduced pressure. The resultant solid was washed with cold methanol to give a pale yellow solid in 41% yield: mp > 300°C (dec); 1H NMR (400 MHz, CD 3 OD) δ 8.44 (s, IH), 7.98 (d, IH), 7.60 (d, 2H), 7.30 (d, 2H), 6.48 (d, IH), 3.06 (m, 4H), 2.54 (m, 4H), 2.30 (s, 3H). Anal. Calcd for C 2 ιH 21 FN 3 O 7 P: C, 52.84; H, 4.43; N, 8.80. Found: C, 52.61; H, 4.63; N, 8.56. Example 22 l,4-Dihydro-6,8-difluoro-7-(4-methyl-l-piperazinyl)-4-oxoquinoline-l-[ " 4-O- (phosphoric acid)pheny!1- 3-carboxylic Acid Using the procedure in example 13 and replacing ethyl 2,4,5-trifluoro-α- oxobenzenepropanoate with ethyl 2,3,4,5-tetrafluoro-α-oxobenzenepropionate example 13) gives ethyl l,4-dihydro-6,7,8-trifluoro-l-(4-hydroxyphenyl)-4~ oxoquinoline-3 -carboxylate. This can then be converted to the title compound according to procedures in Scheme II. Example 23 1,4-Dihydro -6-fluoro-7-(4-methyl- 1 -piperazinyl)- ■1 ,8-naphthyridine -40XO-H4-O- (phosphoric acid)phenyll- 3-carboxylic Acid Using the procedure in example 13 and replacing ethyl 2,4,5-trifluoro-α- oxobenzenepropanoate with ethyl 2,6-dichloro-5-fluoro-β-oxo-3-pyridinepropanoate (example 14) gives ethyl 7-chloro-l,4-dihydro-6-fluoro-l-(4-hydroxyphenyl)-l,8- naphthyridine-4-oxo-3-carboxylate. This can then be converted to the title compound according to procedures in Scheme I. Example 24 1 ,4-Dihydro-6-fluoro-8-methoxy-7-(4-methyl- 1 -piperazinyl)-4-oxoquinoline- 1 -[4-O- (phosphoric acid)phenyll -3 -carboxylic Acid Using the procedure in example 13 and replacing ethyl 2,4,5-trifluoro-α- oxobenzenepropanoate with ethyl 3-methoxy-2,4,5-trifluoro-α- oxobenzenepropanoate (example 15) gives ethyl 6,7-difluoro-l,4-dihydro-l-(4- hydroxyphenyl)-8-methoxy-4-oxoquinoline-3-carboxylate. This can then be converted to the title compound according to procedures in Scheme II. Example 25 1 ,4-Dihydro-6-fluoro-7-( 1 -piperazinyl)-4-oxoquinoline- 1 -r4-O-(phosphoric acid)phenyl]-3-carboxylic Acid Using the procedure in example 17 and replacing N-methylpiperazine with piperazine gives ethyl l,4-dihydro-6-fluoro-l-(4-hydroxyphenyl)-7-(l-piperazyl)-4- oxoquinoline-3 -carboxylate. This can then be converted to the title compound according to procedures in Scheme I or II. Example 26 1 ,4-Dihydro-6-fluoro-7-(4-hydroxy- 1 -piperazinyl)-4-oxoquinoline- 1 -f4-O- (phosphoric acid)phenyll- 3-carboxylic Acid Using the procedure in example 17 and replacing N-methylpiperazine with 4- hydroxypiperazine gives ethyl l,4-dihydro-6-fluoro-l-(4-hydroxyphenyl)-7-(4- hydroxy-l-piperazyl)-4-oxoquinoline-3 -carboxylate. This can then be converted to the title compound according to procedures in Scheme I or II. Example 27 l,4-Dihydro-6-fluoro-7-(3-amino-l-pyrrolidinyl)-4-oxoquinoline-l-r4-O-(phosphoric acid)phenyll- 3-carboxylic Acid Using the procedure in example 17 and replacing N-methylpiperazine with 3- aminopyrrolidine gives ethyl l,4-dihydro-6-fluoro.-l-(4-hydroxyphenyl)-7-(3-amino- l-pyrrolidinyl)-4-oxoquinoline-3-carboxylate. This can then be converted to the title compound according to procedures in Scheme I or II. Example 28 l,4-Dihydro-6-fluoro-7-(3-hydroxy-l-pyrrolidinyl)-4-oxoquinoline-l-r4-O- (phosphoric acid)phenyι ~ l- 3-carboxylic Acid Using the procedure in example 17 and replacing N-methylpiperazine with 3- hydroxypyrrolidine gives ethyl l,4-dihydro-6-fluoro-l-(4-hydroxyphenyl)-7-(3- hydroxy-l-pyrrolidihyl)-4-oxoquinoline-3-carboxylate. This can then be converted to the title compound according to procedures in Scheme I or II. Example 29 Evaluation ofthe in vitro activity Methods: Minimum inhibitory concentration (MIC; μg/mL) of test drug against reference bacterial strains was determined by the broth microdilution method using procedures in accordance with approved standards of the National Committee for Clinical Laboratory Standards (Reference). Microtiter trays were prepared to contain serial two-fold dilutions ofthe test drug in cation-adjusted Mueller-Hinton broth. The trays were inoculated with the test organisms at ~5E5 CFU/mL and incubated at 35° C for 18-24 hours. The trays were examined visually at the end of incubation. The MIC was determined to be the lowest concentration that resulted in complete inhibition of growth (absence of visible turbidity). Results: 1 ,4-Dihydro-6-fluoro-7-(4-methyl- 1 -piperazinyl)-4-oxoquinoline- 1 -4- oxyphenyl-3 -carboxylic acid, referred to herein as PA2789, which is the phenol drug analog of prodrug PA2808 (Example 11) with the phosphate group removed, showed excellent activity against the panel of organisms tested and showed superior activity (lower MIC) compared to ciprofloxacin for S. aureus and E. faecalis (Table 1). The pro-drug PA2808 also showed activity against E. coli and S. aureus, but the activity was poor against P. aeruginosa and E. faecalis. Table 1 MICs of PA2808 and PA2789 against primary test panel Omanism MIC (μg/mL) Ciprofloxacin PA2789 3 PA2808 b Staphylococcus aureus- 0.25 0J 0.4 Methicillin susceptible Staphylococcus aureus- 0.5 0J 0.4 Methicillin resistant Enterococcus faecalis 1 0.78 12.5 Escherichia coli 0.015 0.05 0.4 Pseudomonas aeruginosa 0.5 0.78 12.5 a PA2789Z0 1ot 3110 b PA2808N3 lot 3139 Reference: National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically- fourth edition; approved standard, M7-A4. Wayne, PA: NCCLS, 1997. Example 30 Bioassay measurements to demonstrate the activation of PA2808 after in vitro exposure to alkaline phosphatase or rat lung homogenate Methods: A. Activation by pure enzyme The Alkaline phosphatase (ALP) and rat lung treated and non-treated PA2808 was put on to filter paper disk then put in to plates which was inoculated with P. aeruginosa or E. coli. If the ALP or ALP in rat lung converts PA2808 to an active drug (hopefully to its parent drug PA2789), that the ALP or rat lung treated PA2808 will have a larger inhibition zone than untreated PA2808. PA2808 was incubated with ALP or homogenized rat lung at 37° C for 2 hours. The unfreated PA2808 and PA2789 were used as the comparators. The lungs without drug were used as negative control. Tobramycin was used as QC. The agar-disk diffusion method was used to evaluate the conversion of PA2808 to the active form as a result of exposure to alkaline phosphatase. If PA2808 exposed to ALP or rat lung homogenate converts to an active drug (the parent drug), then the treated PA2808 will have a bigger inhibition zone than unfreated PA2808. For testing ALP, phosphate buffer solution (buffered at either pH of 7.4 or 10.4) containing 1000 μg/mL of PA2808 was incubated with 0.2 units/mL of ALP and incubated at 37° C for 2 hours. At the end of incubation, 10 μL of the above solutions (treated or untreated) were placed onto sterile filter paper disk, and were used within 10 minutes of preparation. Solutions of PA2808 or PA2789 without ALP were used to prepare disks in the same way for comparison. Disks containing enzyme alone were also prepared and served as negative controls. Commercial disks containing 10 μg of tobramycin were used for quality control of the experiment. A suspension of the organism to be tested was prepared to a density matching that of a 0.5 McFarland and a swab was used to spread this suspension evenly on the surface of Mueller-Hinton agar plate. The prepared disks were applied on the agar plate and the plate was incubated at 37° C for 18-24 hours. At the end of incubation, the inhibition zone around the disk was measured to the nearest tenth of millimeter. B . Activation by rat lung homogenate For testing lung homogenates, rat lungs were obtained and washed by perfusion with Krebs solution (no bovine serum albumen) to remove blood, then placed in 3 L sterile deionized water for each gram of lung. The lungs were homogenized and stored at -20° C until use. A stock solution containing 2500 μg/mL of PA2808 was added to the above homogenized lung suspension resulting in final concentration of 1000 μg/mL of PA2808. This resulted in a 1:10 final dilution of rat lung content. Samples were incubated at 37° C for 2 hours. At the end of incubation, 10 μL of the above solutions (treated or untreated) were placed onto sterile filter paper disk, which were used within 10 minutes of preparation and applied to the agar plates as described above. Results Exposure to ALP or rat lung resulted in conversion of PA2808 to an active form (likely PA2789) as observed by increased zone of inhibition against P. aeruginosa compared to untreated PA2808, which showed no inhibition of P. aeruginosa ( see Table 2). PA2808 alone was active against E. coli without any ALP or lung treatment. However, exposure to ALP or rat lung resulted in increased activity (inhibition zone size) against E. coli indicating conversion of PA2808 to the active form. The rat lung did not show any inhibition zone and Tobramycin QC was in the expected range. Table 2 PA2808 activation condition and disk inhibition zone size Inhibition zone size (mm) Drug and Condition P. aeruginosa 27853 E. coli 25922 PA2808 pH 7.4 buffer 7.0 19.4 pH 10.4 buffer 7.0 19.5 pH 7.4+ ALP 11.6 22.8 pH 10.4 + ALP 16.1 24.7 pH 7.4 + Perfused lung 19.7 25.5 pH 7.4 + Regular lung 20.6 26.6 PA2789 pH 7.4 buffer 23.8 27.8 pH 10.4 buffer 24.9 28.2 Lungs (no drug added) Perfused lung pH 7.4 7.0 7.0 Regular lung pH 7.4 7.0 7.0 Tobramycin QC 22.1 19.4 Expected range 19-25 18-26 Note, the filter paper disk size is 7 mm, 7mm value indicates no inhibition zone Reference: National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial disk susceptibility tests - 6th edition; approved standard, M2-A6. Wayne, Pennsylvania: NCCLS, 1997. Example 31 HPLC measurements to demonstrate the in vitro conversion of PA2808 after exposure to alkaline phosphatase or rat lung homogenate A. Conversion by alkaline phosphatase For testing ALP, 50 μL of PA2808 stock solution (2500 μg/mL) was added to 100 μL of 0.2 units/mL of ALP (buffered at pH 10.4) and incubated at 37° C for 1 hour. A solution of PA2808 without addition of ALP was processed similarly and served as the control. At the end of incubation, an equal volume of 100% methanol was added to stop the enzymatic activity. Samples were subjected to HPLC and the tracings were compared. B. Conversion by rat lung homogenate For testing rat lung homogenates, 50 μL of PA2808 was added to 100 μL of homogenized rat lung buffered at pH 7.4 and processed as described above. Samples were incubated at 37° C for 1 hour. A solution of PA2808 without addition of rat lung was processed similarly and served as the control. At the end of incubation, an equal volume of 100% methanol was added to stop the enzymatic activity. Samples were subjected to HPLC and the tracing was measured. Results: PA2808 has been shown to be stable in the absence of alkaline phosphatase at pH 10.4 and at pH 7.4. While the preferred embodiment of the invention has been illustrated and described, it will be appreciated that various changes can be made therein without departing from the spirit and scope ofthe invention. Example 32 Pharmacokineti.es of PA2808 (Dose 1 mg) using Isolated Perfused Rat Lung Model Method: Forty milligrams of PA2808 was weighed and transferred to glass vial, and 2 ml of MilliQ water was added. The pH ofthe solution was adjusted to 8 by adding 1 N NaOH. The final volume of the solution was adjusted to 4 ml by adding MilliQ water. The concentration ofthe resulting solution was 10 mg/ml. Male Sprague Dawley rats (200-220g) were used as animal model. After anesthetizing the rats, tracheal and pulmonary cannulation was performed. The lungs were isolated and mounted in artificial glass thorax. Krebs buffer (pH 7.4) was circulated through pulmonary circulation at the rate of 15 ml/min. The temperature was maintained at 37° C by circulating water bath. One milligram dose (0J ml) of PA2808 was administered to the lungs by using a dosing cartridge. Two hundred microliter aliquots were removed from the drug reservoir at 1, 2, 5, 10, 15, 20, 30 minutes and replaced with equal volume of Krebs buffer. Experiments were performed for 30 minutes. The lungs were collected at the end ofthe experiment and analyzed for the drug concentrations. PA2808 and PA2789 concentrations in the perfusate and lung were determined simultaneously by using a validated reverse phase LC-MS method. Two hundred microliters of perfusate samples were transferred to microcentrifuge tubes containing 50 μl of 10 % trichloroacetic acid (TCA) and 10 μl of 10 μg/ml ciprofloxacin was. added as an internal standard. The samples were immediately vortexed and centrifuged (10 min, 10,000 rpm. 5° C). The supernatant was transferred to HPLC centrifilters and centrifuged (10 min, 10,000 rpm. 5° C). Ten microliters of extracted sample volume was injected on to the LCMS. The mobile phase composition was 0J % formic acid in 10 mM ammonium acetate (85%) and acetonitrile (15%). A stainless steel analytical column (Zorbax SB-C18, 2J mm ID x 150 mm, 5 μm with a Phenomenex cartridge guard column) was used as the stationary phase. The column temperature was maintained at 50° C. Detection of PA2808 and PA2789 was performed using a HP 1100 LC/MSD API Microspray System. Data acquisition was set in the selective ion-monitoring mode. Lungs were homogenized in cold MilliQ water immediately after the last time point was taken. The homogenate (235 μl) was transferred to microcentrifuge tubes containing 50 μl of 10 % TCA to precipitate the proteins, and 10 μl of 10 μg/ml ciprofloxacin was added as an internal standard. The samples were vortexed and centrifuged (10,000 rpm, 10 min, 5° C). The supernatant was transferred to HPLC centrifilters and centrifuged. The filtrate was transferred to HPLC autosampler vials and injected (10 μl) on to LCMS. The mobile phase composition was 0J % formic acid in 10 mM ammonium acetate (85%) and acetonitrile (15%). A stainless steel analytical column (Zorbax SB-C18, 2J mm ID x 150 mm, 5 μm with a Phenomenex cartridge guard column) was used as the stationary phase. The column temperature was maintained at 50° C. Detection of PA 2808 and PA 2789 was performed using a HP 1100 LC/MSD API Microspray System. Data acquisition was set in the selective ion-monitoring mode. Results: The amounts of PA2808 and PA2789 transported across lung epithelium were calculated from concentrations in the perfusate. The lung concentrations at 30 minutes were obtained from the lung homogenates. The perfusate concentration-time profiles of PA2808 and PA2789 are shown in Figure 6. The amounts of PA2808 and PA2789 at the end of 30 minutes in the perfusate were found to be 348.56 μg and 174.5 μg respectively. The amounts of PA2808 and PA2789 at the end of 30 minutes in the lung were found to be 157 μg and 68.2 μg, respectively. Conclusion: PA2808 was converted enzymatically to its parent compound PA2789 in rat lung. Example 33 Efficacy of PA-2808 in the Systemic Mouse and Rat Pneumonia model of E. coli Infection Methods: Rat Pneumonia Model: Male Sprague-Dawley rats are infected by intratracheal administration with 100 microliters of E. coli (ATCC # 25922) prepared in agar beads. The inoculum was prepared by suspending a broth culture of E. coli in molten agar, suspending the agar in sterile mineral oil with mixing to generate small beads of agar containing the bacteria. The beads are recovered by centrifugation, resuspended in sterile saline, and administered to each animal through a tracheal incision by injection directly into the lung. PA-2808 solutions are prepared in sterile deionized water. Antibiotic was administered either by intravenous injection into the tail vein. Treatment is initiated 24 hours after infection and continued twice per day, for 3 days. On day four after infection and a minimum of 12 hours after the last dose, animals are sacrificed and lungs surgically removed. After removal, lungs are homogenized, diluted and quantitatively plated onto blood agar. Plates are incubated for 24 hours and colonies of E. coli counted to determine bacterial load. Results and conclusions PA-2808 was clearly demonstrated to convert to the active component PA- 2789 and showed significant efficacy by the intravenous route at 5 mg/ml. At the 10 mg/kg dose intravenous PA-2808 reduced the lung burden of E. coli to below the limits of detection (10 CFU/gram of lung) as shown in Table 3. Table 3 Efficacy of PA-2808 vs. E. coli in the Rat Pneumonia Model Route Dose (mg/kg bid) CFU/gram Recovered IN 0 2.23 x 10 5 1 3J5 x l0 5 5 4.58 x lO 2 10 BQL* *BQL=Below Quantitation Limit Acute Systemic Efficacy Model: This model is used to determine the efficacy of the test . compound by inducing a lethal systemic infection in mice (Balb/c ) with a dose of E. coli comparable to 100 times the LD 50 dose. Mice are infected by the intraperitoneal route with the inoculum. The mice are then treated at one and five hours post infection typically by the intravenous route. The mice are then monitored over the following five days. The dose that allows 50% of the mice to survive is called the ED 50 dose. Table 4 Efficacy of PA-2789 and PA-2808 in Acute Systemic Infection Model . Survivors 1 {%) Calculated 0.5 mg/kg 1 mg/kg 2 mg/kg 5 mg/kg 10 mg/kg ED50 dose PA-2789 25 57.14 100 100 100 .88 mgkg PA-2808 16.67 83.3 100 100 100 .74 mg/kg Example 34 Aerosolization Methods: PA2808 was formulated using several different salts with the intent of spraying using the LC Star Jet Nebulizer. The maximum solubility ofthe prodrug PA2808 and ofthe drug PA2789 was determined as follows. 10 to 70 mg of compound were weighed into 4 mL vials. Approximately 1 mL of water was added to each sample and the samples were sonicated to disperse compound. 0.5 molar equivalence of IN sodium hydroxide was added to each sample repeatedly until most of sample was dissolved. If a sample appeared to be completely dissolved at the higher concentrations, then the pH was adjusted down with dilute HCl until noticeable precipitation was observed. The sample solutions were then filtered and analyzed by HPLC to determine concentration of PA2808 (or PA2789). This procedure was repeated using potassium hydroxide and ammonium hydroxide with PA2808. The pH was measured using a Coming model 340 pH meter equipped with semi-micro probe. The results are shown in Figure 4. Three PA 2808 formulations were prepared as a sodium, potassium and ammonium salt solution. After the samples were formulated they were analyzed by HPLC to determine the starting concentrations of PA2808 (time zero). An aliquot of each formulation was then stored at 60 °C while the remainder was stored at 25 °C. The samples stored at 60 °C were analyzed by HPLC after one, six and seventeen days. The samples stored at 25 °C were analyzed after seventeen days. The concentrations determined by HPLC at each time point were then divided by the concentration of each sample at time zero to determine the percent recovery of PA2808. Density was measured using a 2 mL volumetric pipette and an analytical balance. 2 mL of solution were quantitatively transferred to a 20 mL vial tared on the balance. The procedure was performed in triplicate for each solution. The mean, standard deviation and %RSD were calculated. The results are shown in Figure 7. Viscosity was measured using a Crossarm Niscometer, size 1. The viscosity was calculated using the following formula: (the viscometer constant) 0.00272 * the time in seconds ofthe solution through the viscometer * the density in g/mL. The results are shown in Figure 8. Osmola ity was measured using a Micro Osmometer Model 3300. Measurements are based on freezing point depression. A 20 μL sample was used to determine osmolality. The optimum osmolality for aerosol inhalation falls between 150-550 mOsm/Kg. As shown in Figure 9, the two 20 mg/mL formulations fall within this range and the 10 mg/mL formulation does not. For commercial formulations the concentration of permeant ions, such as chloride, needs to be between 3 ImM and 300mM, hence these formulations allow for the addition of a permeant ion without exceeding the osmolality limit. The final set of data was obtained using a Malvern Mastersizer that measures the particle (droplet) size ofthe solutions being aerosolized. This experiment used the LC Star Jet Nebulizer with a compressor to generate the spray. The test volume was 2.5 mL per analysis and each sample was analyzed three times. The particle size (MMD), output and percentage of particles in the l-5μ range are shown in Figures 10-12 as the mean ofthe triplicate analyses. The following Table 3 summarizes the supporting data as well as spray data obtained from these samples. Table 5 Characteristics of PA-2808 For Aerosolization Mean % in Density Viscosity Osmolality MMD Output l-5μ Sample (g/mL) (c ) (mOsm/Kg) (μm) (ml/min) range 2808 K 20 mg/mL 1.0158 0.96428 130 3.55 0.27 64.50 2808 Na 10 mg/mL 1.0039 0.91475 59 3.73 0.21 60.40 2808 NH 4 20 1.0102 0.95069 128 3.73 0.25 67.85

Claims: The embodiments ofthe invention in which an exclusive property or privilege is claimed are defined as follows: 1. A compound of the formula (I) : wherein R is hydrogen or a phosphate group having the formula: O II / OR 2 OR 3 wherein R 2 and R are each independently hydrogen or -(CH 2 ) n -R4, wherein R 4 is phenyl, aminodialkylamino, heterocyclo or lower alkyl, and n is 1-6; Ri is hydrogen, lower alkyl or a carboxy protecting group; A is selected from the group -C-R 5 , -N and-CH-O-R 6 wherein R 5 is hydrogen or halo and R 6 is lower alkyl; Z is an amino group having the formula: -N wherein R 7 is hydrogen or lower alkyl, and R 8 is lower alkyl, -NH 2 , mono-(C 1 -C 4 ) alkylamino or di-(Cι-C 4 ) alkylamino, or Z is a substituted or unsubstituted aromatic heterocyclic ring, or an aliphatic heterocyclic ring ofthe formula: wherein R 9 is -NH, CH2=N-OCH 3 , or (CH 2 ) n NRπ, wherein Rπ is hydrogen, loweralkyl, loweralkoxy, hydroxy loweralkyl, aminoloweralkyl, oximinoether, iminoamine, alkylcarboxylic acid or ester, alkylsulphate, alkylphosphate and n is 0, 1 or 2; and R 10 is hydrogen, amino, or aminoalkyl; provided that when R is hydrogen, Z is a substituted or unsubstituted aromatic or aliphatic heterocyclic ring; and the pharmaceutically acceptable salts, esters and prodrugs thereof. 2. A compound of Claim 1 having the formula (I): 3. A compound of Claim 1 wherein A is -CF-. 4. A compound of Claim 1 wherein Z is substituted or unsubstituted piperazinyl. 5. A compound of Claim 1 selected from the group consisting of benzyl 1 ,4-dihydro-6-fluoro-7-(4-methyl- 1 -piperazinyl)-4-oxoquinoline- 1 -[4-O-(phosphoric acid dibenzyl ester)phenyl]-3-carboxylate, l,4-dihydro-6-fluoro-7-(4-methyl-l- piperazinyl)-4-oxoquinoline-l -[4-O-(phosphoric acid)phenyl]-3-carboxylic acid, ethyl l,4-dihydro-6-fluoro-7-(4-methyl-l-piperazyl)-4-oxoquinoline-l-[4-O- (phosphoric acid monobenzyl ester)-phenyl]-3-carboxylate, l,4-dihydro-6-fluoro-7- (4-methyl-l-piperazyl)-4-oxoquinoline-l-[4-O-(phosphoric acid monobenzyl ester)- phenyl]-3-carboxylic acid, ethyl l,4-dihydro-6-fluoro-l-(4- dibenzylphosphonophenyl)-7-(4-methyl-l-piperazyl)-4-oxoquinoline-3-carboxylate, l,4-dihydro-6-fluoro-7-(4-methyl-l-piperazinyl)-4-oxoquinoline-l-[4-O-(phosphoric acid)phenyl]- 3-carboxylic acid, l,4-dihydro-6,8-difluoro-7-(4-methyl-l- piperazinyl)-4-oxoquinoline-l-[4-O-(phosphoric acid)phenyl]- 3-carboxylic acid, 1 ,4-dihydro-6-fluoro-7-(4-methyl- 1 -piperazinyl)- 1 ,8-naphthyridine-4oxo-l -[4-O- (phosphoric acid)phenyl]- 3-carboxylic acid, l,4-dihydro-6-fluoro-8-methoxy-7-(4- methyl- 1 -piperazinyl)-4-oxoquinoline-l -[4-O-(phosphoric acid)phenyl]-3-carboxylic acid, 1 ,4-dihydro-6-fluoro-7-(l -piperazinyl)-4-oxoquinoline- 1 -[4-O-(phosphoric acid)phenyl]-3-carboxylic Acid, 1 ,4-dihydro-6-fluoro-7-(4-hydroxy- 1 -piperazinyl)-4- oxoquinoline-l-[4-O-(phosphoric acid)phenyl]- 3-carboxylic acid, l,4-dihydro-6- fluoro-7-(4-hydroxy- 1 -piperazinyl)-4-oxoquinoline- 1 -[4-O-(phosphoric acid)- 02/18345 - y- phenyl]- 3-carboxylic acid, l,4-dihydro-6-fluoro-7-(3-amino-l-pyrrolidinyl)-4-oxo- quinoline-l-[4-O-(phosphoric acid)phenyl]- 3-carboxylic acid, l,4-dihydro-6-fluoro- 7-(3-hydroxy-l-pyrrolidinyl)-4-oxoquinoline-l-[4-O-(phosphoric acid)phenyl]- 3- carboxylic acid and the pharmaceutically acceptable salts, esters and prodrugs thereof. 6. A method of inhibiting the growth of pathogenic microbes, comprising contacting the microbes with a growth inhibitory amount of a compound ofthe formula (I): wherein R is hydrogen or a phosphate group having the formula: O II ^ wherein R 2 and R 3 are each independently hydrogen or -(CH 2 ) n -R4, wherein R 4 is phenyl, aminodialkylamino, heterocyclo or lower alkyl, and n is 1-6; Ri is hydrogen, lower alkyl or a carboxy protecting group; A is selected from the group -C-R 5 , -N and-CH-O-R 6 wherein R is hydrogen or halo and R 6 is lower alkyl; Z is an amino group having the formula: -N \ Rs wherein R 7 is hydrogen or lower alkyl, and R 8 is lower alkyl, -NH 2 , mono-(CrC 4 ) alkylamino or di-(CrC 4 ) alkylamino, or Z is a substituted or unsubstituted aromatic heterocyclic ring, or an aliphatic heterocyclic ring ofthe formula: wherein R 9 is -NH, CH2=N-OCH3, or (CH 2 ) n NRπ, wherein Rπ is hydrogen, loweralkyl, loweralkoxy, hydroxy loweralkyl, aminoloweralkyl, oximinoether, iminoamine, alkylcarboxylic acid or ester, alkylsulphate, alkylphosphate and n is 0, 1 or 2; and RI Q is hydrogen, amino, or aminoalkyl; provided that when R is hydrogen, Z is a substituted or unsubstituted aromatic or aliphatic heterocyclic ring; and and the pharmaceutically acceptable salts, esters and prodrugs thereof. 7. A method of Claim 6 wherein the inhibited microbe is selected from the group consisting of Acinetobacter Spp., Aeromona Spp., Bacteroides fragilis, Citrobacter Spp., Campylobacter Sp., Chlamydia trachomatis, Enterobacter Spp., Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Haemophilus influenzae, Klebsiella Spp., Legionella pneumophila, Moraxella catarhalis, Morganella Spp., Neisseria Spp., Proteus Spp., Providencia Spp., Pseudomonas aeruginosa, Salmonella Spp., Shigella Spp., Staphylococcus aureus, Coagulase- negative Staphylococcus Spp., Steptococcus pyogenes, Streptococcus pneumonia and Yersinia Spp. 8. A method of Claim 6 wherein the microbe is contacted with the compound under conditions in which at least one solubilizing moiety on the compound is cleaved to form an antimicrobially effective analog ofthe compound. 9. A method of treating a mammal in need of such treatment, comprising administering to the mammal a microbial growth inhibitory amount of a compound ofthe formula (I): wherein R is hydrogen or a phosphate group having the formula: wherein R 2 and R 3 are each independently hydrogen or -(CH 2 ) n -R4, wherein R 4 is phenyl, aminodialkylamino, heterocyclo or lower alkyl, and n is 1-6; Ri is hydrogen, lower alkyl or a carboxy protecting group; A is selected from the group -C-R 5 , -N and-CH-O-R 6 wherein R 5 is hydrogen or halo and R 6 is lower alkyl; Z is an amino group having the formula: -N \ R 8 wherein R 7 is hydrogen or lower alkyl, and R 8 is lower alkyl, -NH 2 , mono-(C 1 -C 4 ) alkylamino or di-(CrC 4 ) alkylamino, or Z is a substituted or unsubstituted aromatic heterocyclic ring, or an aliphatic heterocyclic ring ofthe formula: wherein R 9 is -NH, CH 2 =N-OCH3, or (CH 2 ) n NRπ, wherein Rπ is hydrogen, loweralkyl, loweralkoxy, hydroxy loweralkyl, aminoloweralkyl, oximinoether, iminoamine, alkylcarboxylic acid or ester, alkylsulphate, alkylphosphate and n is 0, 1 or 2; and R 10 is hydrogen, amino, or aminoalkyl; provided that when R is hydrogen, Z is a substituted or unsubstituted aromatic or aliphatic heterocyclic ring; and; and the pharmaceutically acceptable salts, esters and prodrugs thereof. 10. A method of Claim 9 wherein the inhibited microbe is selected from the group consisting of Acinetobacter Spp., Aeromona Spp., Bacteroides fragilis, Citrobacter Spp., Campylobacter Sp., Chlamydia trachomatis, Enterobacter Spp., Enterococcus faecalis, Enterococcus faecium, Escherichia eoli, Haemophilus influenzae, Klebsiella Spp., Legionella pneumophila, Moraxella catarhalis, Morganella Spp., Neisseria Spp., Proteus Spp., Providencia Spp., Pseudomonas aeruginosa, Salmonella Spp., Shigella Spp., Staphylococcus aureus, Coagulase- negative Staphylococcus Spp., Steptococcus pyogenes, Streptococcus pneumonia and Yersinia Spp. 11. A method of Claim 9 wherein the compound is administered to the mammal orally, parenterally, sublingually, by inhalation aerosol or spray, rectally, or topically.

Inventors: BAKER WILLIAM R, CAI SHAOPEI, DIMITROFF MARTIN, RYCKMAN DAVID M, SHANG XIAO, BAKER, WILLIAM, R., CAI, SHAOPEI, DIMITROFF, MARTIN, RYCKMAN, DAVID, M., SHANG, XIAO
Applicants: BAKER WILLIAM R, CAI SHAOPEI, CHIRON CORP, DIMITROFF MARTIN, RYCKMAN DAVID M, SHANG XIAO, BAKER, WILLIAM, R., CAI, SHAOPEI, CHIRON CORPORATION, DIMITROFF, MARTIN, RYCKMAN, DAVID, M., SHANG, XIAO
Application year: 2001
Main classification: C07D215
IPC codes: A61K31, C07D215, C07D471, C07F9