WO2008113161A1 - Phosphate prodrugs of quinazolinyl nitrofurans, methods of obtaining, and use of same - Google Patents

Abstract

There is provided phosphate prodrugs of quinazolinyl nitrofurans having improved water solubility that are hydrolyzed to their respective quinazolinyl nitrofurans in vivo, upon administration to an animal. There is also provided methods of obtaining such phosphate prodrugs of quinazolinyl nitrofurans as well as methods of using. Formula (I).

Description

PHOSPHATE PRODRUGS OF QUINAZOLINYL NITROFURANS, METHODS OF

OBTAINING, AND USE OF SAME

This application claims the benefit of U.S. provisional application No. 60/895,574 filed March 19, 2007, the entirety of which is incorporated herein by reference.

Field of the invention

The present invention is directed to quinazolinyl nitrofurans antibiotic phosphate compounds, including phosphate quinazolinyl nitrofurans antibiotics having improved water solubility. The present invention is further directed to methods of obtaining such phosphate prodrug compounds and to their use as antibacterial/antimicrobial agents .

Background of the invention

The following review of the state of the art is merely provided to aid in the understanding of the present invention and neither it nor any of the references cited within it are admitted to be prior art to the present invention.

Quinazolinyl nitrofurans compounds have been described as having antimicrobial activity, see for instance in US patent application publication No. 2006/0258693, in US 3,970,648, US 3,973,021, and US 3,974,277, and in Canadian Patent No. 859,164 against a wide spectrum of microorganisms. Such microorganisms include, for instance, microorganisms that are resistant to multiple antibiotic families that are useful as antibacterial agents for treatment or prophylaxis of bacterial infections, or for use as antiseptics, as agents for sterilization or for disinfection. The general structural feature of these compounds is a nitrofuran linked to the 2 position of a quinazoline directly or via a vinyl group. It is believed that the nitrofuran is essential for antimicrobial activity while the quinazoline, preferentially as substituted, e.g., with an halogen and/or a morpholino group, improves antibacterial potency, expands the spectrum of activity (e.g., activity against microorganisms that are resistant to multiple antibiotics) , provides a bactericidal (lethal) activity (i.e., as opposed to a bacteriostatic growth-inhibitory activity) , provides in vivo activity, and improves pharmacological properties generally known to those skilled in the art. This aspect of the present invention is well described in US patent application Publication No. 2006/0258693 (Chamberland et al . ) and its CIP application USSN 11/871,897.

For instance, the following formula (1.0) is an illustrative representation of the class of quinazolinyl nitrofurans compounds:

(1.0) wherein:

X is absent, or a cis or trans vinyl (-CH=CH-) ; Ri is (Ci-Cio) alkyl unsubstituted or substituted by- one to three hydroxy, (C₂-Ci₀) alkenyl unsubstituted or substituted by one to three hydroxy, (C₂-Ci₀) alkynyl unsubstituted or substituted by one to three hydroxy, or aryl unsubstituted or substituted by one to three hydroxy;

R₂ is hydrogen, alkyl, alkenyl, alkynyl or aryl,

wherein Ri and R₂ when taken together form a (C₂-Ci₀) cycloalkyl unsubstituted or substituted by one to three hydroxy;

Y and Z are independently either CH or N; and

R³ and R⁴ are, independently of each other, H, halogen, or

⁽1.1⁾

wherein:

E and R are each independently selected from CH₂, CH₂CH₂ and CH₂CHT where T is alkyl,

A is absent or -(CH₂CH₂O)_n-, and n = 1 or 2 ; and

Q is 0, S, NH or NCH₃;

with the proviso that at least one of R³ and R⁴ is a halogen; or

a pharmaceutically acceptable salt thereof. However, due to limited water solubility, solution stability, formulation suitability, body distribution, or a combination thereof, of certain of these quinazolinyl nitrofurans compounds, limited amounts can be given through various parenteral, intranasal, intrabucal, subcutaneous, oral or topical routes, thus limiting efficiency or the therapeutic applicability of some of these compounds .

There is therefore a need for modified quinazolinyl nitrofurans compounds having improved water solubility, solution stability, formulation suitability, body distribution, or a combination thereof.

SUMMARY OF THE INVENTION

The present invention therefore, provides phosphate prodrug quinazolinyl nitrofurans compounds. These prodrug compounds have, inter alia, any one of enhanced water solubility, solution stability, formulation suitability, greater body distribution, or a combination thereof, relative to the native non-prodrug compound. In one embodiment, these phosphate prodrug compounds are rapidly and efficiently converted in vivo to their native non-prodrug compound .

The present invention further provides a method of obtaining such phosphate prodrug compounds .

The present invention further provides a method of preventing or treating an infection in a subject, or sterilizing an object, including a human, or for antisepsis and/or disinfection by using a prodrug compound of the invention. In one aspect of the invention, there is provided a compound of formula (1.2) :

(1.2)

wherein

R and R can be absent or as defined above;

R , R , X, Y and Z are as defined above,-

R⁵ or R⁶ are independently taken from absent or

PO₃H₂ ; and

W and W are independently taken from absent, 0,

NH or S,

with the proviso that

at least one of R⁴ and R⁵ is not absent;

at least one of R³ and R⁴ is a halogen;

when R⁵ is PO₃H₂ then R¹ is not H; and

when R⁶ is PO₃H₂ then R² is not H; or a pharmaceutically acceptable salt thereof.

The person skilled in the art will readily understand that, in the context of the invention, when the phosphorus (PO₃H₂) or pharmaceutical acceptable salt thereof is at position R⁵ (or R⁶) and R¹ and W¹ (or R² and W²) are absent, then the phosphorus or pharmaceutical acceptable salt thereof is linked by its phosphor atom directly to the nitrogen at the 4 -position of quinazoline.

Thus, an illustrative example of an embodiment of the prodrug of the invention is a phosphorus group at the 4 position of the phenylamine group itself (at the 4 position of the quinazoline nitrofuran) or a pharmaceutically acceptable salt thereof .

Furthermore, the person skilled in the art will readily understand that R⁴ and/or R⁵ can be a phosphoric acid (when W¹ or W² = 0) , phosphoramidic acid (when W¹ or W² = NH) , or a phosphorothioic acid (when W¹ or W² = S) , or a pharmaceutically acceptable salt thereof.

The present invention further provides salts (as in the following illustrative example - formula 1.4) of the phosphate prodrug compounds .

(1.3) (1.4)

Such salts may be useful in the stable storage of the phosphate prodrug compound of the invention. In one embodiment, M₁ ⁺ and M₂ ⁺ are independently selected to be either H⁺, or a pharmaceutically acceptable mono-cation or alternatively Mi⁺ and M₂ ⁺ can be taken together as a pharmaceutically acceptable bis-cation.

In one embodiment, Mi⁺ and M₂ ⁺ are independently selected to be H⁺, Na⁺, NH₄ ⁺ or K⁺, or M₁ ⁺ and M₂ ⁺ can both be H⁺, Na⁺, NH₄ ⁺ or K⁺, or Mi⁺ and M₂ ⁺ are taken together to be Mg²⁺ or Ca²⁺.

In one embodiment, M₁ ⁺ and M₂ ⁺ are independently selected from pharmaceutically acceptable counter-ion entities, for example an entity containing a protonated amine or guanidine and the like.

In one embodiment, the phosphate prodrug compound is of formula (1.5) :

(1.5) ; or a pharmaceutically acceptable salt thereof.

In one embodiment, the phosphate prodrug compound is of formula (1.8) :

(1.8); or a pharmaceutically acceptable salt thereof

Other examples of quinazolinyl nitrofurans that are suitable to be derivatized (modified) as phosphate prodrugs, as described herein, are for instance those described in Canadian Patent 859164 (Burch) , US 3,970,648

(Horn et al . ) , US 3,973,021 (Horn et al . ) and US 3,974,277

(Horn et al . ) .

In one aspect of the invention there is provided pharmaceutically acceptable formulations or compositions comprising phosphate prodrug compounds or pharmaceutical salt thereof, as defined above, in a pharmaceutically acceptable excipient, diluent and/or solvent.

In various embodiments, the prodrug of the present invention may be used therapeutically in formulations or medicaments to prevent or treat bacterial infections. The invention provides corresponding methods of medical treatment, in which a therapeutic dose of a prodrug of the present invention is administered in a pharmacologically acceptable formulation, e.g. to a patient or subject in need thereof.

Accordingly, the invention also provides therapeutic compositions comprising a prodrug of the present invention, and a pharmacologically acceptable diluent, adjuvant, excipient or carrier. In one embodiment, such compositions include a prodrug of the present invention in a therapeutically or prophylactically effective amount sufficient to treat or prevent a bacterial infection. The therapeutic composition may be soluble in an aqueous solution at a physiologically acceptable pH.

In accordance with another aspect of the invention, therapeutic compositions of the present invention, comprising a prodrug of the present invention, may be provided in containers or commercial packages which further comprise instructions for use of the prodrug for the prevention and/or treatment of bacterial infection.

Accordingly, the invention further provides a commercial package comprising a prodrug of the present invention, or the above-mentioned therapeutic composition, together with instructions for the prevention and/or treatment of bacterial infection.

In accordance with another aspect of the invention, there is provided use of a prodrug of the present invention for prevention and/or treatment of bacterial infection. The invention further provides use of a prodrug of the present invention for the preparation of a medicament for prevention and/or treatment of bacterial infection. The invention further provides use of a prodrug of the present invention as an antiseptic, sterilizant, or disinfectant.

The following examples are presented in order to provide a more detailed description of specific embodiments of the represent invention and are not to be construed as limiting the scope of the invention.

Brief Description of the Figures

In the figures, which illustrate, by way of example only, embodiments of the present invention:

Figure 1 shows rate and percent conversion of prodrug embodiments of the invention, prodrug Compound IX (full triangles) and prodrug Compound X (open squares) , to their native antibacterial compounds (Compound VII and Compound XI respectively) , in the presence of mouse serum at 37°C.

Figure 2 shows a PK analysis (HPLC) of the native antibacterial Compound VII in rat serum after I.V. injection of prodrug Compound IX (15.1 mg/kg) in Dextrose 5% to rats.

Figure 3 shows a PK analysis (HPLC) of the native antibacterial Compound VII in mouse serum, after I. V. injection of prodrug Compound IX (15.1 mg/kg) in Dextrose 5% to mice.

Figure 4 shows in vivo efficacy of a prodrug embodiment of the invention, prodrug Compound IX and its native antibacterial Compound VII administrated I.V. in a neutropenic murine thigh S. aureus infection model. Results are expressed as mean ± Standard Error of Mean. Significance determined versus control was done by unpaired student t test using the GraphPad™ Software, * p< 0.0001.

Figure 5 shows in vivo efficacy of a prodrug embodiment of the invention, prodrug Compound IX and its native antibacterial Compound VII administrated I.V. in a pneumonia S. pneumoniae infection model in mice. Results are expressed as mean ± Standard Error of Mean. Significance determined versus control was done by unpaired student t test using the GraphPad™ Software, * p< 0.0001.

DETAILED DESCRIPTION

Accordingly, the present invention provides a phosphoric acid modified quinazolinyl nitrofuran or pharmaceutically acceptable salt thereof having, inter alia, enhanced water solubility, relative to the corresponding native compound, and can be used to treat and/or prevent bacterial infections.

In one embodiment, the modified quinazolinyl nitrofuran antibiotic is an esterified, amidated or thioesterified phosphoric acid of a quinazolinyl nitrofuran antibiotic or a pharmaceutically acceptable salt thereof.

In the context of the invention, it will be understood that when referring to a "phosphate" prodrug this also includes the acid prodrug form and pharmaceutically acceptable salt thereof

In one embodiment, when a phosphate prodrug embodiment of the invention is administered to a subject, the esterified, amidated or thioesterified phosphate prodrug of the quinazolinyl nitrofuran antibiotic is efficiently converted to the native quinazolinyl nitrofuran antibiotic .

In order to more fully appreciate the instant invention, the following definitions are provided.

As used herein, the term "alkyl" refers to the radical of saturated aliphatic groups including straight chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, etc. In one embodiement, the alkyl group is (C₁-C₁₀) alkyl, or (C₁-C₆) alkyl, or (C₂-C₄) alkyl.

The term "alkyl" further encompasses heteroalkyl groups wherein one or more carbons of the hydrocarbon backbone are replaced with a heteroatom, e.g. N, 0 or S .

The "alkyl" is optionally substituted, i.e. having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, halogen, hydroxyl, carbonyl [such as carboxyl, ketones (including alkylcarbonyl and arylcarbonyl groups) , and esters (including alkyloxycarbonyl and aryloxycarbonyl groups)], alkoxyl, phosphoryl, phosphonate, phosphate, amino, acylamino, amido, imino, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido. The moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

As used herein, the terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, preferably (C₂-Ci₀) , and more preferably (C₂-C₆) alkyl and even more preferably (C₂-C₄) , but that contain at least one double or triple bond respectively. An "alkenyl" is an unsaturated branched, straight chain, or cyclic hydrocarbon radical with at least one carbon-carbon double bond. The radical can be in either the cis or trans conformation about the double bond(s) . Typical alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, tert-butenyl, pentenyl, hexenyl, etc. An "alkynyl" is an unsaturated branched, straight chain, or cyclic hydrocarbon radical with at least one carbon-carbon triple bond. Typical alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, etc.

As used herein, the term "aryl" refers to aromatic radicals having 3-14 ring atoms and at least one ring having a conjugated pi electron system. In one embodiment, at least two, or at least four, of the ring atoms are carbon atoms. For example aryl may be a C₅, C₆, C₇, C₈, C₉ or Cio ring.

The term "aryl" encompasses "heteroaryl" compounds. The term "heteroaryl" refers to an aromatic heterocyclic group usually with one or more heteroatoms selected from 0, S and N in the ring. The "aryl" is optionally substituted. Examples of aryl include, without limitation, phenyl, substituted phenyl, pyridyl, substituted pyridyl, pyridinyl, substituted pyridinyl, thiophenyl, substituted thiophenyl, furanyl, substituted furanyl, thiazole, oxazole or substituted or unsubstituted imidazole. Such substituents can include, for example, halogen, hydroxy1, carbonyl [such as carboxyl, ketones (including alkylcarbonyl and arylcarbonyl groups) , and esters (including alkyloxycarbonyl and aryloxycarbonyl groups)], thiocarbonyl , acyloxy, alkoxyl, phosphoryl, phosphonate, phosphinate, phosphate, amino, acylamino, amido, amidine, imino, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonyl, sulfonate, sulfamoyl, sulfonamido, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. The moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

As used herein, the term "halogen" refers to fluoro, chloro, bromo or iodo; or fluoride, chloride, bromide or iodide; or fluorine, chlorine, bromine or iodine .

The foregoing aspects of the present invention are well described in US patent application 2006/0258693 and its CIP application USSN 11/871,897.

As used herein, the term "prodrug" is a modified compound that undergoes a chemical modification in vivo, enzymatically or chemically, resulting in the native compound. The chemical modification confers an activity to the compound, such as an antibacterial activity, which is characteristic of the non-prodrug native compound. As used herein, the term "pharmaceutically acceptable salt" refers to salts of the compounds of the invention wherein the salts are substantially nontoxic to living organisms e.g. sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate , dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, hydrobromide, iodide, acetate, propionate, decanoate, caprate, caprylate, acrylate, ascorbate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, glucuronate, glutamate, propionate, phenylpropionate , salicylate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymateate , mandelate, mesylate, nicotinate, isonicotinate, cinnamate, hippurate, nitrate, stearate, phthalate, teraphthalate, butyne-1, 4-dioate, butyne-1,4-dicarboxylate , hexyne-1,4-dicarboxylate , hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydrozybenzoate , methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, phthalate, p-toluenesulfonate, p-bromobenzenesulfonate, p-chlorobenzenesulfonate, xylenesulfonate, phenylacetate, trifluoroacetate, phenylpropionate, phenylbutyrate, citrate, lactate, alpha-hydroxybutyrate, glycolate, tartrate, hemitartrate, benzenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, hydroxyethanesuIfonate, 1-naphthalenesulfonate , 2 -naphthalenesulfonate , 1, 5-naphthalenedisulfonate, mandelate, tartarate and the like known to those skilled in the art.

As used herein, a "pharmaceutical composition" refers to a formulation of a phosphate, phosphoramidate , phosphorothiolate ester of a quinazolinyl nitrofuran antibiotic, including salts thereof, of the present invention (e.g., a quinazolinyl nitrofuran antibiotic phosphate prodrug) with a pharmaceutically acceptable exipient, diluent and/or carrier. In a particular embodiment, the carrier is a solvent (e.g., water) .

As used herein, an "excipient" refers to an inert substance added to a pharmacological composition to further facilitate administration of an active ingredient. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols .

As used herein "pharmaceutically acceptable carrier" or "excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. In one embodiment, the carrier is suitable for parenteral administration. Alternatively, the carrier can be suitable for intravenous, intraperitoneal, intramuscular, sublingual or oral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions. Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, polysorbate 20, polysorbate 80, cremophor EL, solutol and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin. Moreover, a nitrofuran of the present invention can be administered in a time release formulation, for example in a composition which includes a slow release polymer. The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG) . Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. Sterile injectable solutions can be prepared by incorporating the active compound (e.g. a prodrug of the present invention) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. In accordance with an alternative aspect of the invention, a prodrug of the present invention may be formulated with one or more additional compounds that enhance the properties of the prodrug .

As used here, a "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as a reduction of bacterial infection. A therapeutically effective amount of a prodrug of the present invention may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as preventing or inhibiting the rate of bacterial infection-related disease onset or progression. A prophylactically effective amount can be determined as described above for the therapeutically effective amount. For any particular subject, specific dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

As used herein, an "aprotic solvent" refers to an organic solvent that does not include one or more hydrogen atoms bonded to an oxygen, nitrogen or sulfur atom, which hydrogen is capable of dissociation or participation in hydrogen bonding.

As used herein, a "suitable" solvent refers to a solvent in which the reactants can dissolve and which does not adversely participate in the reaction, either by itself reacting with one or more components of the reaction mixture, or by interfering with the reaction of the components with one another. For any given reaction, selecting a suitable solvent is well within the ability of those skilled in the art and can be accomplished without undue experimentation.

As used here, the term "subject" refers to an animal species capable of being infected by a pathogenic bacterium, and in a particular embodiment includes humans. Appropriate animal subjects also include those in the wild, livestock (e.g., raised for meat, milk, butter, eggs, fur, leather, feathers and/or wool) , beasts of burden, research animals, companion animals, as well as those raised for/in zoos, wild habitats and/or circuses or fish.

The prodrug derivatives of the invention can be made through total synthesis or derivatization of an appropriate functional group found in the molecule according to methods commonly used by those skilled in the art. The quinazolinyl nitrofuran can either be converted directly to the prodrug by placing the quinazolinyl nitrofuran in a suitable solvent which includes aprotic solvents and treated with the appropriate reagents to obtain the prodrug or a chemically protected form of the prodrug that can then be converted to the prodrug.

Phosphates, phosphoramidates and phosphorothioates prodrugs embodiments of the invention can be prepared by the direct esterification of an alcohol, amine or thiol respectively. The derivative can either be the desired prodrug or an intermediate ester of the prodrug where the intermediate ester can be later removed to reveal the desired prodrug.

An illustrative example of the synthesis of a phosphate prodrug of a quinazolinyl nitrofuran is by treatment of a 4-chloroquinazolinyl nitrofuran with the appropriate disodium aminoalkyl or aryl phosphate in a suitable solvent to give the desired phosphate prodrug directly.

Another illustrative example of the synthesis of a phosphate prodrug of a quinazolinyl nitrofuran is by treatment of a quinazolinyl nitrofuran with phosphorus oxychloride in the presence of pyridine and a suitable solvent followed by the addition of water containing a counter ion such as sodium or potassium.

Yet another illustrative example of the synthesis of a phosphate prodrug of a quinazolinyl nitrofuran is by treating quinazolinyl nitrofuran with diethyl phosphoryl chloride in the presence of a base, such as triethylamine, in a suitable solvent. This approach produces the diethyl phosphate ester that is converted to the quinazolinyl nitrofuran prodrug by first the treatment with reagents such as trimethylsilyl bromide followed by the addition of water containing a counter ion such as sodium or potassium.

An illustrative example of the synthesis of a phosphoramidate prodrug at the 4 position of quinazolinyl nitrofuran is to use a variation of the procedure to couple an aromatic amide with an aromatic halogenated compounds as described by Buchwald et al. (Organic Letters, 1999, vol. 1, 35-37 and Organic Letters, 2000, vol. 2, 1101-1104) using a palladium catalyst in the presence of a phosphine ligand. This approach involves the coupling of an appropriately protected phospharamidate with a 4-halogenoquinazolinyl nitrofuran followed by the deprotection of the phosphoramidate with a halogenated trimethylsilane as described above.

Illustrative examples of an embodiment of the phosphate prodrug compounds of the invention include, but are not limited to, the following (shown as a pharmaceutically acceptable disodium salt, but which include the corresponding acid and other pharmaceutically acceptable salts) :

Salt of Compound IX

Salt of Compound X

As noted before, when a quinazolinyl nitrofuran is dissolved in water, the maximum concentration attainable is typically approximately 200 micrograms per milliliter. However, in commercial formulations, substantially higher concentrations are often desirable. To achieve higher concentrations, organic solvents may be used in which a quinazolinyl nitrofuran may have higher solubility. Unfortunately, many of these organic solvents cause irritations or have adverse effects which are sometimes quite severe and may therefore, limit their applicability in a commercial and pharmaceutical setting. The present invention provides a solution to this problem by providing a phosphate prodrug of quinazolinyl nitrofuran compounds which when dissolved in water, saline or D5W, typically concentrations greater than 35 milligrams per milliliter are obtained, and which can be used in an effective and efficient in vivo delivery of the quinazolinyl nitrofuran compounds. Achieving this end, however, proved not to be a trivial matter.

An attempt was made to make an amino acid ester prodrug derivative but the compound showed limited stability in an aqueous environment.

(amino acid ester)

Another attempt was made to make an amino acid amide prodrug derivative but the compound was assessed as having too great a serum stability to be of use as a prodrug .

In one embodiment, the phosphate prodrug moiety can be attached to a reactive functional group such as a phenol and be removed in vivo to reveal the phenol and produce sodium phosphate as a by-product .

Salt of Compound IX Compound VII

Salt of Compound X Compound XI

Quite surprisingly, the phosphate prodrugs of the quinazolinyl nitrofuran compounds of the present invention were found to not only have increased water solubility, i.e. over 35 mg/ml, but also to convert to quinazolinyl nitrofurans efficiently and in substantial amounts. This conversion is exemplified in Table 2, which demonstrates the in vitro conversion of a prodrug embodiment of the invention to the corresponding native antibacterial compound by the addition of alkaline phosphatase in the test medium. These levels of conversion in vitro would be considered by those skilled in the art as good indicators of therapeutically-effective conversion in vivo. As predicted, substantial concentrations of quinazolinyl nitrofuran were detected in vivo in rats (see Example V) and in mice (see Example VI) after the intravenous (i.v.) administration of a prodrug embodiment of the invention (Compound IX) . In these examples, the concentration of the active native compound was quantified in serum using extraction and chromatographic methods which are commonly used and understood by those skilled in the art.

The phosphate prodrug of the invention can be administered to a subject by any conventional means, including orally, topically or by injection.

The present invention may be better understood by reference to the following non- limiting examples, which are provided as exemplary of the invention. The following examples are presented in order to more fully illustrate embodiments of the invention and should in no way be construed as limiting the broad scope of the invention.

Example I. Synthesis of Quinazolinyl Nitrofuran Phosphate Prodrugs

Compound I: 4-Fluoro-5-morpholin-4-yl-2-nitro- benzoic acid. A mixture of 2-nitro-4 , 5-difluorobenzoic acid (18.0 g, 88.626 mmol) and morpholine (400 mL) was heated at 80⁰C for 3 h. After cooling, the mixture was concentrated in vacuo and dried under vacuum (60⁰C) to provide the morpholine salt of the Compound I (39.0 g) as a yellow solid. MS (M+H) 271.1. Compound II: 2-Amino-4-fluoro-5-morpholin-4-yl- benzoic acid. A mixture of Compound I (39.0 g) prepared above and 10% Pd/C (50% wet, 5 g) in ethanol (1.0 L) was subjected to hydrogenation at ambient temperature and 30 psi for 3h. The mixture was filtered through celite, washed by ethanol and water, and the filtrate was concentrated in vacuo to afford Compound II (36.0 g) as an off-white solid. This compound was still the morpholine salt. MS (M+H) 241.1.

Compound III: 2-acetamido-4-fluoro-5- morpholinobenzoic acetic anhydride . A suspension of Compound II prepared above (36.0 g) in acetic anhydride (1.0 L) was refluxed overnight and then acetic anhydride was evaporated under vacuum in a rotavap to give an off- white solid.

Compound IV: 7-Fluoro-2-methyl-6-morpholin-4-yl- 3H-quinazolin-4-one. To the solid Compound III was slowly added ammonium hydroxide solution (500 mL) under cooling with an ice bath and the resulting mixture was stirred overnight at ambient temperature. To the reaction mixture thus formed was added 10 wt% sodium hydroxide (400 mL) . After refluxing for 1 hour, the reaction mixture was allowed to cool to ambient temperature and adjusted to pH 8 with cone, hydrochloric acid. The precipitate was filtered and washed with water, chased with toluene and dried under vacuum at 6O⁰C overnight to give Compound IV (19.8 g, 85% overall yield for 3 steps) as an off-white solid. MS (M+H) 283.1.

Compound V: 7-Fluoro-6-morpholin-4-yl~2- [2- (5- nitro-furan-2-yl) -vinyl] -3H-quinazolin-4-one . To a solution of Compound IV (19.8 g, 75.2 mmol) in acetic acid (400 mL) was added 5-nitrofuraldehyde (15.91 g, 112.8 mmol) and cone, sulfuric acid (0.5 mL) . After the reaction mixture was refluxed for one day, it was cooled to ambient temperature and concentrated in vacuo. The residue was triturated with EtOAc and dried under vacuum (5O⁰C) to afford the desired Compound V (30.0 g, 99% yield) as a brown solid. MS (M+H) 283.1.

Compound VI: 4-Chloro~7-fluoro-6-morpholin-4-yl- 2- [2- (5-nitro-furan-2-yl) -vinyl] -quinazoline. To a suspension of Compound V (30.0 g, -75.2 mmol) in phosphorus oxychloride (400 mL) was added phosphorus pentachloride (29.5 g) . After refluxing overnight, the reaction mixture was cooled, concentrated in vacuo, and diluted with ethyl ether. The precipitate was collected, washed with ethyl ether and dried under vacuum to give Compound VI (30.5 g) as a dark-brown solid. MS (M+H) 405.0. ¹H NMR (300 MHz, DSMOd₆) δ 3.09 (m) , 3.79 (m) , 7.11 (d) , 7.26 (d) , 7.45 (d) , 7.60 (d) , 7.79 (m) . ¹⁹F NMR (282 MHz, DSMOd₆) δ -113.0.

Compound VII:

(compound VII)

4-{7-Fluoro-6-morpholin-4-yl-2-[2~(5-nitro-furan-2-yl) - vinyl] -quinazolin-4-ylamino} -phenol: A mixture of Compound VI (6.07 g, 15 mmol) and 4-aminophenol (4.09 g, 37.5 mmol) in NMP (30 mL) was heated at 90⁰C for 3 h. After cooling to ambient temperature, the mixture was poured into water (200 mL) and the precipitate was filtered, washed with water, methanol, and dried under vacuum at 50⁰C to afford Compound VII as a dark-brown solid. MS (M+H) 478.2. ¹H NMR (300 MHz, DSMOd₆) δ 3.19 (m) , 3.82 (m) , 6.85 (d) , 7.21 (d) , 7.27 (d) , 7.56 (m) , 7.78 (d) , 7.93 (d) , 9.63 (s). ¹⁹F NMR (282 MHz, DSMOd₆) δ -114.6.

Compound VIII: Sodium 4-aminophenyl phosphate. A mixture of sodium 4-nitrophenyl phosphate (15 g) and 10% Pd/C (50% wet, 4.0 g) in ethanol (1 L) and water (100 mL) was subjected to hydrogenation at ambient temperature and 30 psi for 2 h. The mixture was filtered through Celite™ and washed with water and ethanol. The filtrate was concentrated in vacuo to afford Compound VIII as a white solid.

Compound IX:

(di-sodium salt of compound IX)

Phosphoric acid mono- (4-{ 7-fluoro-6-morpholin-4- yl-2- [2- (5-nitro-furan-2-yl) -vinyl] -quinazolin-4-ylamino} - phenyl) ester di-sodium salt: A mixture of Compound VII (6.07 g, 15 mmol) and sodium 4-aminophenyl phosphate (Compound VIII) (7.0 g, 30 mmol) in DMF (60 mL) was heated to 90⁰C for 3 h. The mixture was concentrated under reduced pressure to remove most of DMF, and the residue was diluted with water (300 mL) and filtered to give the crude product as a black solid. This solid was dissolved in 0. IM NaOH solution and subjected to a reverse-phase chromatography (Amber-Chrom™ resin also called HP20™, eluted by DUIF water to 10% ACN/water to 15% ACN/water) . The fractions containing the product with the desired purity profile as analyzed by HPLC were combined and water was removed first by rotavap under vacuo, then by vacuum oven (ambient temperature) to afford Compound IX as a brown solid. MS (M+H) 558.1. ¹H NMR (300 MHz, D₂O) δ 2.90 (m) , 3.76 (m) , 6.29 (m) , 6.67 (d) , 6.79 (d) , 7.10 (m) , 1.38 (m) . ¹⁹F NMR (282 MHz, D₂O) δ -113.3. ³¹P NMR (121 MHz, D₂O) δ 1.55.

Compound X :

(di-sodium salt of compound X)

Sodium (E) -4- (7-fluoro-2- (2- (5-nitrofuran-2- yl) vinyl) quinazolin-4-ylamino)phenyl phosphate. This compound was prepared in the same manner as Compound IX but using 4-fluoroanthranilic acid as a starting material. The final product is a brown solid. MS (M+H) 483.1. ¹H NMR (300 MHz, D₂O) δ 6.31 (d) , 6.44 (m) , 6.64 (m) , 6.88 (m) , 7.07 (d) , 7.19 (m) , 7.29 (d) , 7.50 (m) . ¹⁹F NMR (282 MHz, D₂O) δ -105.53. ³¹P NMR (121 MHz, D₂O) δ 1.90. Compound XI :

(compound XI)

4-{7-Fluoro-4-yl-2-[2- (5-nitro-furan-2-yl) -vinyl] - quinazolin-4-ylamino) -phenol . This compound was prepared in the same manner as Compound VII but using 4-fluoroanthranilic acid as a starting material. The final product is a brown solid. MS (M+H) 392.9. ¹H NMR (300 MHz, DMSO_d6) δ 6.85 (d) , 7.21 (d) , 7.32 (d) , 7.50 (d) , 7.60 (m) , 7.80 (d) , 8.51 (m) , 9.40 (s) , 9.79 (s) . ¹⁹F NMR (282 MHz, DMSO_d6) δ -106.34 (m) .

Compound XII

Compound XIII

1. TMSI, Et₃N, Dioxane

2. NaHCO₃, H₂O

Compound XIV Compound XII: Diethyl pyridin-3- ylphosphoramidate. To a solution of 3-aminopyridine (0.94 g, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added triethylamine (1.01 g, 10 mmol), followed by the addition of diethylchlorophosphate dropwise. The reaction mixture was stirred at room temperature for 2 hrs and the salt formed was filtered off. The solvent was removed under vacuum to afford a crude product, which was used for the next step without further purification.

Compound XIII: (E) -diethyl 7-fluoro-2- (2- (5- nitrofuran-2-yl) vinyl) quinazolin-4-yl (pyridin-3- yl)phosphoramidate . To a solution of 4-chloro-7-fluoro-2- (2- (5-nitrofuran-2-yl) vinyl) quinazoline (2.56 g, 8 mmol) and phosphoramidate compound XII (2.3 g, 10 mmol) in 1,4- dioxane (25 mL) was added cesium carbonate (3.65 g, 11.2 mmol, 1.4 equiv) . The solution was purged with nitrogen for 20 minutes, then Pd₂(dba)₃ (5% loading, 0.368 g) and xantphos (15%, 1.2 mmol, 0.59 g) were added. The mixture was purged for another 20 minutes and then heated to reflux overnight. The reaction was monitored by LC-MS. The reaction mixture was filtered and the solvent removed under vacuum at ambient temperature. The desired compound was purified by column chromatography (10-15% methanol/ethylacetate) . The fractions containing the desired compound by LC-MS (M+l 514.1) were combined and concentrated to give a solid.

Compound XIV: Sodium (E) -7-fluoro-2- (2- (5- nitrofuran-2-yl) vinyl) quinazolin-4-yl (pyridin-3- yl) phosphoramidate . To a solution of compound XIII (105 mg, 2 mmol) in 1,4-dioxane (1 mL) was added iodotrimethylsilane (180 μL, 6 equivalents) at ambient temperature. The reaction was protected from light and stirred at ambient temperature for 2Oh. The mixture was filtered and the solvent removed under vacuum. The residue was dissolved in 1,4-dioxane and methanol 1:1 (1 mL) and treated with IN NaHCO₃ and subjected to a reverse-phase chromatography (AmberChrom™ resin also called HP20™, eluted by DUIF water to 10% ACN/water to 15% ACN/water) . The fractions containing the product with the desired purity profile as analyzed by HPLC were combined and water was removed first by rotavap under vacuo, then by vacuum oven (ambient temperature) to afford Compound XIV as a solid.

Example II. Stability of Phosphate Prodrug in Injection Solvents .

Compound IX was dissolved to a final concentration of 2 mg/ml in saline, water for injection (WFI) , dextrose 5% (D5W) , or a solution of L-arginine 1 mg/ml in WFI . The percent recovery was measured by HPLC and the results are shown in Table 1.

Table 1. Recovery of Prodrug Compound IX in Various Solutes at 25°C.

Formulations % Recovery (24 hrs)

Saline^* 99

WFI^* >99

D5W^* >99

L-ArgHCl (1:1)^** >99

* Concentration of Compound IX is 2 mg/ml

** Concentration of Compound IX is 1 mg/ml The results shown in Table 1 demonstrate that Compound IX is stable in aqueous solutions suitable for injection over 24 hrs .

When a quinazolinyl nitrofurans, such as Compound VII or Compound XI, is dissolved in water, typically the maximum concentration attainable is approximately 200 micrograms per milliliter. When the corresponding prodrug, as described herein, such as respective Compound IX or Compound X, is dissolved in water, saline or D5W, typically concentrations greater than approximately 35 milligrams per milliliter are obtained.

Example III. Conversion of Phosphate Prodrug to Quinazolinyl Nitrofuran Antibiotics.

Phosphate prodrug quinazolinyl nitrofurans antibiotics of the invention (e.g. Compound IX) can be converted to their native quinazolinyl nitrofurans antibiotics (e.g. Compound VII) by the action of alkaline phosphatases, which are ubiquitous enzymes in the body of any subject.

Accordingly, Table 2 shows that addition of increasing amounts of alkaline phosphatase in the test medium in vitro can increase the conversion of the phosphate prodrug Compound IX into an antibacterial compound of increasing potency. This is shown by the decreasing minimal inhibitory concentration (MIC) of the test compound needed to inhibit growth of the bacterial pathogen Staphylococcus aureus (see Table 2) . On the other hand, the MICs of the non-prodrug antibiotics vancomycin or cefotaxime are not changed by the addition of alkaline phosphatase .

Table 2. Effect of Alkaline Phosphatase on the Conversion of a Prodrug to the Native Quinazolinyl Nitrofuran Antibiotic.

MIC (micrograms/ml) of test compounds against S. aureus ATCC29213

_ . , in the presence of increasing amounts of Test compound ^c _a alkaline phosphatase (U)

0.05 0.1 0.25 1 4

Prodrug

1 0.5 0.25 0.06 0.06 Compound IX

Cefotaxime 2 2 2 2 2

Vancomycin 1 1 1 1 1

a: One unit (U) of alkaline phosphatase is the amount of enzyme that hydrolyzes 1 micromol of p-nitrophenylphosphate to p-nitrophenol in one minute at 37⁰C in a one ml volume.

b: The MIC of the non-prodrug antibiotic Compound VII is 0.06 micrograms/ml .

Example IV. Conversion of Prodrug Compound IX to Antibacterial Compound VII in mouse serum.

65 microliters of a 200 microgram per milliliter solution of Compound IX was added to 585 microliters of fresh mouse serum to a final concentration of 20 microgram per milliliter. Five 100 microliter aliquots were separated and incubated at 37°C. 100 microliters of acetonitrile was added to individual aliquotes at the following time points 0, 15, 30, 60 and 180 minutes and vortex mixed. The proteins were removed by centrifugation and the supernatant analyzed by HPLC at a wavelength of 380 nanometers.

The results are reported in Figure 1 and show that Compound IX is converted to Compound VII over the 180 minute study. The experiment was repeated with Compound X and showed its conversion to Compound XI.

Example V. Conversion of Prodrug Compound IX to Antibacterial Compound VII in Rats.

Compound IX was dissolved in dextrose 5% to a final concentration of 15 milligrams per milliliter. The solution was injected into rats to provide a dose of 15.1 milligrams per kilograms of rat body weight. Three serum samples from three different animals were collected at each time point. The serum proteins were precipitated by the addition of one equivalent volume of acetonitrile and vortex mixing. The proteins were removed by centrifugation and the supernatant analyzed by HPLC at a wavelength of 380 nanometers. Compound VII was directly measured in the serum (Figure 2) . These data demonstrate that prodrug Compound IX is converted to Compound VII in vivo.

Example VI . Conversion of Prodrug Compound IX to Antibacterial Compound VII in Mice.

Compound IX was dissolved in dextrose 5% to a final concentration of 2 milligrams per milliliter. The solution was injected into mice to provide a dose of 15.1 milligrams per kilograms of mouse body weight. Three serum samples from three different animals were collected at each time point. The serum proteins were precipitated by the addition of one equivalent volume of acetonitrile and vortex mixing. The proteins were removed by centrifugation and the supernatant analyzed by HPLC at a wavelength of 380 nanometers. Compound VII was directly measured in the serum (Figure 3) . These data demonstrate that prodrug Compound IX is converted to Compound VII in vivo in a second species.

Example VII. Antibacterial effect of Prodrug Compound IX in Mice .

A neutropenic mouse thigh infection model was used as one experimental model. Mice were challenged with Staphylococcus aureus ATCC 29213 administered intramuscularly (i.m.) in 0.1 ml volume to each thigh. To determine efficacy, compounds were delivered by intraveneous administration (I. V.) in a single dose 2h post infection. Mice (3 mice or more per treatment) were euthanized 8h post infection. The thigh tissue (two samples per animal) was recovered, homogenized, and CFU/g tissue determined by plating appropriate dilutions on agar. Statistical analysis was done by unpaired Student's t-test using the GraphPad Prism™ software. Values of p ≤ 0.05 were considered to be significant.

Results of Figure 4 show that although the native antibacterial Compound VII was much more potent in vitro with an MIC of 0.06 micrograms/ml, both the injection to mice of Compound VII and the prodrug Compound IX were equally effective in controlling the infection by S. aureus. This demonstrates that the conversion of the prodrug Compound IX to the native antibacterial Compound VII, as previously shown in Example V, is effective in producing the therapeutic effect in vivo.

A murine pneumococcal pneumonia model was used as another experimental model. Mice were challenged by intra-nasal instillation of Streptococcus pneumoniae ATCC 6301. To determine efficacy, compounds were administered twice by I. V. route, 18 and 24hr after bacterial inoculation. Mice (8 per group) were killed 16hr after last injection. Their lungs were recovered, homogenized and CFU counts/g of tissues was determined by plating dilution on agar. Results of Figure 5 show that although the native antibacterial Compound VII was much more potent in vitro with an MIC of 0.03 micrograms/ml against S. pneumoniae, both the injection to mice of Compound VII and the prodrug Compound IX were equally effective in controlling the infection by S. pneumoniae. This demonstrates that the conversion of the prodrug Compound IX to the native antibacterial Compound VII, as previously shown in Example V, is effective in producing the therapeutic effect in vivo. This also shows the overall therapeutic efficacy of an embodiment of the prodrug Compound of the invention, i.e. Compound IX, for the treatment of various microbial infections at different body sites.

All patents, patent applications and publications mentioned herein, both supra and infra, are hereby incorporated by reference.

While the invention has been described with reference to certain specific embodiments and described in the foregoing Examples, it is understood that it is not to be so limited since alterations and changes may be made therein which are within the full and intended scope of the appended claims.

Claims

Claims :

1. A compound of formula (1.2)

(1.2)

wherein

X is absent, or vinyl (-CH=CH-) ;

Y and Z are as a group absent or independently either CH or N;

R¹ is taken from absent, hydrogen, (Ci-Ci₀) alky1 unsubstituted or substituted by one to three hydroxy, (C₂-Ci₀) alkenyl unsubstituted or substituted by one to three hydroxy, (C₂-Ci₀) alkynyl unsubstituted or substituted by one to three hydroxy, or aryl unsubstituted or substituted by one to three hydroxy,-

R² is taken from absent, hydrogen, alkyl, alkenyl, alkynyl or aryl,

wherein R_x and R₂ when taken together form a (C₂-Ci₀) cycloalkyl unsubstituted or substituted by one to three hydroxy; R³ and R⁴ are, independently of each other, H,

halogen, or

(1-1)

wherein

E and R are each independently selected from CH₂, CH₂CH₂ and CH₂CHT, where T is alkyl,

A is absent or -(CH₂CH₂O)_n- and n = 1 or 2, and

Q is 0, S, NH or NCH₃;

R⁵ or R⁶ are independently taken from absent or PO₃H₂ ; and

W¹ and W² are independently taken from absent, 0, NH or S,

with the proviso that

at least one of R⁴ and R⁵ is not absent;

at least one of R³ and R⁴ is a halogen;

when R⁵ is PO₃H₂ then R¹ is not H; and

when R⁶ is PO₃H₂ then R² is not H; or

a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, having the formula (1.5) :

(1.5) ;

or a pharmaceutically acceptable salt thereof

3. The compound of claim 1, having the formula (1.8) :

(1.8) ;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3, which is

or a pharmaceutically acceptable salt thereof.

5. A process for obtaining the compound of claim 2, the process comprising reacting

a compound of formula (2.0)

(2.0)

wherein V is a leaving group selected from the group consisting of a halogen, an ester, an alkyl, or an aryl sulfonate; and

a compound of formula (2.1)

(2.1) , or a pharmaceutically acceptable salt thereof.

6. A process for obtaining the compound of claim 2, the process comprising reacting a compound of formula (2.2)

( 2 . 2 )

wherein W is absent, OH, NH₂ or SH; with

when X is vinyl: a phosphorus oxychloride reagent; or

when X is absent: N,N-diethyl di-tert- butylphosphoramidite and a base, then oxydation of the phosphorus followed by deprotection.

7. A method for treating an infection caused by an organism which is a Gram positive organism, Gram negative organism, or an anaerobic bacteria, the method comprising administering to a subject the compound of any one of claims 1 to 4.

8. The method of claim 7, wherein the Gram positive organism is selected from the group consisting of

Staphylococcus aureus, Staphylococcus epidermidis, coagulase negative staphylococci, Staphylococcus saprophyticus, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus suis, Streptococcus pyogenes, Group B Streptococcus, Bacillus anthracis, Clostridium difficile, and Clostridium perfringens .

9. The method of claim 7, wherein the Gram negative organism is selected from the group consisting of

Enterobacteriaceae, Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Enterobacter cloacae, Serratia marcescens, Salmonella typhi, Salmonella typhimurium, Salmonella enteritidis, Citrobacter freundii, Proteus mirabilis, Proteus vulgaris, Yersinia enterolytica, Yersinia pestis, Pseudomonads, Pseudomonas aeruginosa, Acinetobacter baumannii, Xanthomonas, Burkholderia cepacia, and Stenotrophomonas .

10. A method for treating an infection caused by an organism selected from the group consisting of Haemophilus influenzae, Neisseria gonorrhoaea, Neisseria meningitidis, Moraxella (Branhamella) catarrhalis, Mycobacterium tuberculosis, Mycobacterium bovis, Listeria monocytogenes, Campylobacter jejuni, Bacteroides fragilis, fusobacterium, Treponema pallidum, Vibrio cholerae, Helicobacter pylori, Trichomonas vaginalis, and Chlamydia trachomatis, the method comprising administering to a subject the compound of any one of claims 1 to 4.

11. A method for treating an infection caused by a so-called antibiotic-resistant or antibiotic-susceptible microorganism, the method comprising administering to a subject the compound of any one of claims 1 to 4.

12. The method of claim 11, wherein the microorganism is selected from the group consisting of methicillin-resistant staphylococci, penicillin-resistant streptococci, vancomycin-resistant staphylococci or enterococci, and bacteria with extended spectrum beta-lactamases .

13. A method for treating an infection caused by a so-called virulent or pathogenic strain, the method comprising administering to a subject the compound of any one of claims 1 to 4.

14. The method of claim 13, wherein the strain is selected from the group consisting of Escherichia coli (E. coli) 0157 :H7, enteropathogenic E. coli, enterohemorrhagic E. coli, and uropathogenic E. coli.

15. The method of claim 13, wherein the infection is selected from the group consisting of respiratory infections (lower and upper) , otitis, sinusitis, throat and lung infections, urinary tract infections, uro-genital infections, brain infections, meningitis, abscesses, enteric infections, soft tissue and skin infections, endocarditis, and sexually transmitted infections.

16. A method for treating an infection caused by an eukaryotic pathogen, comprising administering to a subject the compound of any one of claims 1 to 4.

17. A method for treatment or prophylaxis against infections pre- or post-surgery, comprising administering to a subject the compound of any one of claims 1 to 4.

18. A method for sterilization, antisepsis and/or disinfection, comprising administering to a subject the compound of any one of claims 1 to 4.

19. The method of any one of claims 7 to 18, wherein the subject is selected from the group consisting of poultry, mammals and fish.

20. The method of claim 19, wherein the subject is a human .

21. The method of any one of claims 7 to 16, wherein the subject is selected from the group consisting of a plant, food and other agriculture products.