HK1108285A - Carbo- and hetero-cyclic antibiotics and use thereof - Google Patents

Description

Carbon-and hetero-cyclic nitrofuran antibiotics and use thereof

Cross Reference to Related Applications

The benefit of U.S. provisional patent application No. 60/612,148, filed on 23/9/2004, which is hereby incorporated by reference.

Technical Field

The present invention relates to novel antibiotics and their use in the treatment or prevention of microbial infections, or their use as antiseptics, bactericides or disinfectants. These compounds exhibit an extended spectrum of antimicrobial activity and reduced undesirable toxic side effects, as well as antibiotic activity against a broad spectrum of microorganisms, including organisms resistant to multiple antibiotic families.

Background

The following review of the background of the invention is provided only to aid in the understanding of the invention, and neither this review nor any references cited therein are admitted to be prior art to the invention.

Controlling hospital or community acquired bacterial infections is becoming increasingly difficult due to the emergence of bacteria resistant to one or more families of antibiotics. Unfortunately, the widespread and indiscriminate use of antibiotics has led to a rapid increase in the number of antibiotic-resistant bacterial strains. More importantly, drug resistance has emerged in clinically important microorganisms that threaten the use of the currently available antibiotic repertoire. The increase in resistance to antibiotics is well documented in the world health organization and scientific literature as a global trend with wide variation depending on geographical regions.

There is a need for new and effective antibiotics that are particularly active against microorganisms that are resistant to currently available drugs. For example, the development of resistance to trimethoprim-sulfamethoxazole, β -lactams, and fluoroquinolones by bacteria causing urinary tract infections is becoming a major factor in controlling such infections. Although nitrofuran antibiotics have been used mainly for decades for the treatment of Urinary Tract infections, the resistance of this family of agents to commonly encountered microorganisms remains low (0-2%) (Gupta K., Addressance resistance Mon.2003 month 2; 49 (2): 99-110; Nicollele, Urinary track Infection: Traditional pharmacological therapeutics applications, month 2 2003; 49 (2): 111-. Nitrofurans have also been shown to be useful in the treatment of serious infections caused by microorganisms resistant to a variety of antibiotics.

However, only a few nitrofuran antibiotics are currently used in humans for the treatment of infectious diseases and are known by their common names nitrofurantoin (trade names include nitrofurantoin capsule (Macrobid), nitrofurantoin (Macrodantin), and Furadantin). It is used in adults and children for the treatment of acute urinary tract infections and the prevention of recurrent urinary tract infections. Nitrofurantoin has the drawbacks that it does not have good efficacy (i.e., requires relatively high amounts to exert its antibacterial activity) and that it does not have broad spectrum antibacterial activity, which limits the use of this compound in the treatment of bacterial infections. Furthermore, U.S. patent nos. 3,970,648, 3,973,021, and 3,974,277 disclose nitrofuran antibiotics of the formula: 2- [2- (5-nitro-2-furyl) vinyl ] -4- (anilino) -quinazoline, 2- [2- (5-nitro-2-furyl) vinyl ] -4- (p-hydroxy-anilino) -quinazoline, 2- [2- (5-nitro-2-furyl) vinyl ] -4- (o-hydroxyanilino) -quinazoline, and 2- [2- (5-nitro-2-furyl) vinyl ] -4- (m-hydroxyanilino) -quinazoline. These patents teach the use of these compounds as pesticides and animal growth promoters to improve the feed efficiency of animals such as poultry, swine and cattle. Although these molecules gain properties that are sufficient edible feed additives to promote animal growth in contrast to quinazoline molecules having a nitrofuranyl group directly bound to them (U.S. patent No. 3,542,784), a disadvantage of the compounds from the above patents (nos. 3,970,648, 3,973,021 and 3,974,277) is that the patents teach that they are currently not active against important pathogens such as Escherichia coli, Staphylococcus aureus and Salmonella (Salmonella). It would be desirable to obtain nitrofurans that provide a significant efficacy improvement and an extended spectrum of antimicrobial activity. This means that lower amounts of compounds are required for in vitro and in vivo (in animals) antimicrobial action against a wider variety of pathogens that infect animals and humans.

New antibiotics with better antimicrobial efficacy and improved pharmacological properties would provide an alternative to the treatment of severe infections caused by antibiotic sensitive and antibiotic resistant microorganisms.

Summary of The Invention

The present invention relates to chemical entities containing nitrofurans or other antibiotics attached to an activity enhancing terminal ring system either directly or via an imine group, a vinyl group, a carbon-or hetero-cyclic chain or ring, or a combination of an imine group or a vinyl group and a carbon-or hetero-cyclic chain or ring. For example, antibiotic activity is obtained from the nitrofuran moiety, while the remaining structure of the molecule contributes to additional antimicrobial activity and/or extends the antimicrobial activity spectrum, while also contributing to pharmacological properties (absorption, body distribution, and others), by promoting nitroreduction of microorganisms, uptake in target bacteria, and/or intracellular penetration. The invention has been described with reference to nitrofurans as the antibiotic moiety, however it is to be understood that reference to nitrofurans throughout denotes any moiety having antibiotic activity.

When present, the carbonyl or heterocyclic chain or ring (referred to herein as the "central structure") possesses the dual role of enhancing the activity of antibiotics such as nitrofurans and serving as a binding site for the terminal ring system. The central structure may be a monocyclic ring of 3 to 8 atoms, preferably pyrazine or triazine, but also bicyclic systems consisting of 4 to 14 atoms, preferably quinazoline. The terminal ring system is bound to the central structure together with nitrofuran or other antibiotic functional groups at the optimal position for activity.

The terminal ring system is either a hydroxyphenyl, catechol, bis-catechol, tris-catechol (the first two being held together by a suitable backbone), thiazole, thiazoline, oxazole, oxazoline, imidazole or imidazoline. When the terminal ring system is a thiazole, thiazoline, oxazole, oxazoline, imidazole or imidazoline, the 5-position of the terminal ring system is bound to the active optimal position of the central structure, while the other combinations of substituted or unsubstituted phenyl or pyridine or aliphatic or aromatic carbocyclic or heterocyclic structures having essentially (in nature) 3 to 8 atoms are bound at the 2-position. The terminal ring system can also be a substituted or unsubstituted mono-or bi-carbocyclic or heterocyclic ring structure having 4 to 14 atoms that is aliphatic or aromatic in nature, and any combination with an aliphatic or aromatic structure having 3 to 8 atoms that has a substituted or unsubstituted mono-or bi-carbocyclic or heterocyclic ring. In some cases, the terminal ring system can also be replaced by an open chain structure containing one or more functional groups like hydroxamic acid that contribute to the antimicrobial activity or spectrum of activity. The term "terminal ring system" as used herein includes such open chain structures.

In the terminal ring system, 2-phenyl oxazoline, oxazoles, thiazolines, thiazoles, imidazolines, imidazoles or catechols are structurally involved in biologically active microbial components such as mycobacterials or tosiderophores used by Pseudomonas (Pseudomonas), Burkholderia (Burkholderia) and other bacteria, and also in inhibitors of bacterial lipid a biosynthesis. The present invention exploits the properties of these cyclic structures to enhance and extend the antibacterial and pharmacological properties of nitrofurans.

The invention also includes pharmaceutically acceptable formulations of the compounds that exhibit antibiotic activity against a broad spectrum of microorganisms, including organisms that are not normally susceptible to nitrofurans and organisms that are resistant to multiple antibiotic families. These novel compounds are useful as antibacterial agents for the treatment or prevention of bacterial infections, or as preservatives, or as bactericidal or disinfectant agents.

The invention includes compounds of formula (1.0)

Wherein

W is absent, is vinyl (cis or trans-CH ═ CH-, preferably trans) or-N ═ CH-; w' is absent, or with R¹、R²And R³Is shown as

(center structure)

Wherein D, D ', X, M, A and Z are each independently selected from CH, C, O, S, NH and N, however at least one of D or X is C, and preferably no more than two D, X, M, A or Z are O, S, NH or N, and D' must be C or CH, unless R is C, O, S, NH, N, D is C, O, S, N, O, Z, O, S, N, S²And R³Together form a ring, the dotted line is an optional bond (no cyclic structure), and p and n are each independently selected from 0, 1, and 2; r¹、R²And R³Each independently selected from the group consisting of absent, hydrogen, halogen (including halogen atoms fluorine, chlorine, bromine and iodine), CH₃、C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₁-C₁₀Alkoxy radical, C₂-C₁₀Alkenoxy group, C₂-C₁₀Alkynyloxy, aryl, OH, trifluoromethyl, methylenedioxy, phenoxy, OR⁴、CO₂R⁴、SO₂R⁴、PO(OR⁴)₂、CON(R⁴)₂、OAr、NH₂、NHR⁴、NR⁴、N(R⁴)₂、NHAr、SH、SR⁴SAr, ═ O, hydroxamic acids, heterocycles, solubilizing groups as defined below, and VQT moieties (terminal ring systems) as defined below, where alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy OR alkynyloxy may be unsubstituted OR preferably have from 1 to 5 halogen atoms OR from 1 to 2 OR atoms⁴And aryl is preferably selected from the group consisting of phenyl, naphthyl, indolyl, biphenyl, phenoxyphenyl, pyridinyl, furanyl, thienyl (thiophenyl) and bithienyl (bithienyl), said aryl group being optionally substituted with preferably 1 to 3 groups selected from the group consisting of: r⁴A solubilizing group as defined below, and a portion VQT as defined below; the solubilizing group may be, but is not limited to, preferably

Wherein G and EEach independently selected from CH₂、CH₂CH₂And CH₂CH-alkyl; and J is O, NH or NCH₃；

R⁴Is selected from CH₃、C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₁-C₁₀Alkoxy radical, C₂-C₁₀Alkenoxy group, C₂-C₁₀Alkynyloxy, aryl, heterocyclic, solubilizing group as defined above, and aryl is preferably selected from the group consisting of: phenyl, naphthyl, indolyl, biphenyl, substituted or unsubstituted mono-or bi-carbon-or hetero-cyclic structures having 4 to 14 atoms, which are aliphatic or aromatic in nature, and any combination with substituted or unsubstituted mono-or bi-carbon-or heterocyclic aliphatic or aromatic structures having 3 to 8 atoms;

v is C, CH, N, NH or O;

q acts as a stable or labile linker (linker), e.g. selected from absent, C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₁-C₁₀Amine, C₁-C₁₀Alkoxy radical, C₂-C₁₀Alkenoxy group, C₂-C₁₀Alkynyloxy, phenyl, heterocycle, -C (═ O) -, -SO₂-、-PO(OT)₂-、-NOH、-(CH₂)_t-C (═ O) -, and- (CH)₂)_t-NH-C (═ O) -, where t is 0 to 10; and T is

Wherein A and M are independently selected from C, CH, O, NH, N and S; p, n and v are each independently selected from 0 and 1; and the dotted line represents an optional additional bond; and R is⁵、R⁶、R⁷、R⁸And R⁹Each independently selected from absent or as for R¹As defined;

preferred R⁵Is that

Wherein D is independently selected from CH, C, O, S, NH, and N;

and wherein R¹⁰Is absent or as for R¹As defined;

l as a stable or unstable linker, e.g. selected from absent, C₁To C₁₀Alkyl radical, C₂To C₁₀Alkenyl radical, C₂To C₁₀Alkynyl, C₁-C₁₀Amine, C₁-C₁₀Alkoxy radical, C₂-C₁₀Alkenoxy group, C₂-C₁₀Alkynyloxy, phenyl, -C (═ O) -, -PO (OT)₂-、-NOH-、-(CH₂)_t-C (═ O) -, and- (CH) where t is 0 to 10₂)_t-NH-C (═ O) -, and heterocycles, wherein said heterocycles are preferably

Wherein A and M are independently selected from C, CH, N, NH, O, or S; and wherein R¹¹And R¹²Independently selected from absent, or as for R¹As defined; and wherein the dotted line represents an optional additional bond;

R²and R³When taken together in formula 1.0, (wherein W' is the central structure), the D and D "atoms of the central structure to which they are fused combine to form the following groups:

wherein X, D, D ', D', D *, Z are each independently selected from CH, C, O, S, NH, and N; and n is selected from 0, 1 and 2;

wherein R is¹³And R¹⁴Each independently of the others as for R¹As defined; and when R is²And R³When taken together in the formula 1.0,

R¹as defined above, or

Wherein R is¹⁵And R¹⁶Each independently of the others as for R⁴As defined;

with the proviso that at least one VQT moiety must be present at 1, 2 or 3 positions in the compound of formula 1.0 selected from one or more of the following groups:

-V-Q，-V-Q-T，

or an enantiomer thereof;

wherein the compound of formula 1.0 has 1 to 9 Ts, and each V and Q and T is independently selected;

and pharmaceutically acceptable salts of the compounds.

The invention also includes compounds similar to formula 1.0 wherein the nitrofuran moiety is replaced with another antibiotic moiety. Such another antibiotic would be bonded to the remainder of compound 1.0 via W. Examples of preferred T are as follows:

more preferably, T is selected from

Wherein A is selected from O, NH, NR and S; d is CH or N; and Y is absent or OH.

Brief Description of Drawings

FIG. 1 shows the binding of a radiolabelled precursor to a macromolecule in the presence of 2- [2- (5-nitro-2-furyl) vinyl ] -4- (3, 4-dihydroxyaniline) quinazoline (compound VI of example 1).

Detailed Description

The present invention includes novel catechol pyrazine analogs of the formula

Wherein R is²And R³Is hydrogen, alkyl, aryl, OH, OR, OAr, NH₂NHR, NHAr, SH, SR, or SAr, and n ═ 0, 1, or 2.

Catechol quinazolines and other catechol-heterobicyclic analogs have the formula:

wherein R is²And R³Together as defined above.

The catechol triazene analogs have the following structure:

wherein R is³Is hydrogen, alkyl, aryl, OH, OR, OAr, NH₂NHR, NHAr, SH, SR, or SAr.

The bis-catechol containing nitrofuran derivatives have the following structure:

wherein R is²And R³Together as defined above.

Pyrazine-based derivatives have the following structure:

wherein A is O, NH, NR, S; r²And R³Is hydrogen, alkyl, aryl, OH, OR, OAr, NH₂NHR, NHAr, SH, SR, or SAr, and B is CH or N.

The quinazoline-based derivative has the following structure:

wherein A is O, NH, NR, or S; b is CH or N, and R²And R³Together as defined above.

Derivatives based on hydroxyaryl thiazolines, hydroxyaryl oxazolines and hydroxyaryl imidazolines have the following structures:

wherein A is O, NH, NR or S, R¹³And R¹⁴Is hydrogen, alkyl, aryl, OH, OR, OAr, NH₂NHR, NHAr, SH, SR, or SAr; and B is CH or N.

The compounds of the present invention can be generally produced by the following general methods. The hydrochloric acid is reacted with anthranilamide (anthranilamide) and methanol to form anthranilamide hydrochloride. To this was added hydrochloric acid, acetic anhydride and aqueous ammonia stepwise to form 2-methyl-4- (3H) quinazolinone. Followed by the addition of 5-nitro-2-furaldehyde (5-nitro-2-furancarboxaldehy) with acetic anhydride and sulfuric acid to form 2- [2- (5-nitro-2-furyl) vinyl ] -4- (3H) quinazolinone, which is used to prepare chloro and anilino derivatives. For example, phosphorus pentachloride and phosphorus oxychloride are added to form a 2- [2- (5-nitro-2-furyl) vinyl ] -4-chloroquinazoline in which various functional groups may be added to the 4-position on the quinazoline. The present inventors describe these methods in more detail with reference to examples.

In vitro and in vivo (in animals) experiments showed the unique antimicrobial properties of the compound 2- [2- (5-nitro-2-furyl) vinyl ] -4- (3, 4-dihydroxyanilino) quinazoline and derivatives, and showed that the activity spectrum of these molecules is well suited for the treatment of human infections that are difficult to treat. In particular, 2- [2- (5-nitro-2-furyl) vinyl ] -4- (3, 4-dihydroxy-anilino) quinazoline demonstrated activity against a variety of gram-positive and gram-negative bacteria. Such a property is comparable to commercially available drugs of the macrolide, beta-lactam, or fluoroquinolone class. Furthermore, 2- [2- (5-nitro-2-furyl) vinyl ] -4- (3, 4-dihydroxyanilino) quinazoline, which belongs to a different structural class, is not affected by the commonly found mechanism of microbial resistance, which has developed over the last few years against most antimicrobial agents in clinical use today. Also the applicant demonstrated that 2- [2- (5-nitro-2-furyl) vinyl ] -4- (3, 4-dihydroxyanilino) -quinazoline administered by gavage worked in vivo in a mouse model of infection, thus demonstrating oral bioavailability and relatively low toxicity. Initial mode of action studies have also demonstrated the antibiotic effect of producing 2- [2- (5-nitro-2-furyl) vinyl ] -4- (3, 4-dihydroxyanilino) quinazoline by inhibiting the basic cellular processes of microorganisms in which DNA is metabolized. All of these antimicrobial and chemical properties represent those antibiotic molecules that are effective and safe. Certain terms used in this application are described below.

The term "alkyl" refers to 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, tert-butyl, pentyl, isopentyl, hexyl, and the like. The alkyl group may be (C)₁-C₁₀) Alkyl, more preferably (C)₁-C₆) Alkyl and even more preferably (C)₂-C₄) An alkyl group.

The term "alkyl" may include "substituted alkyl" groups having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents may include: for example, halogen, hydroxyl, carbonyl (such as carboxyl, ketones (including alkylcarbonyl and arylcarbonyl) and esters (including alkoxycarbonyl and aryloxycarbonyl)), thiocarbonyl, acyloxy, alkoxy, phosphoryl, phosphonate, phosphite, amino, acylamino, amido, amidine, imino, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. If appropriate, the substituted moieties on the hydrocarbon chain may themselves be substituted. For example, substituents of substituted alkyl groups may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonates and phosphites), sulfonyl (including sulfates, sulfonamido, phosphonato,sulfamoyl and sulfonate) and silyl groups, and ethers, alkylthio groups, carbonyl groups (including ketones, aldehydes, carboxylates and esters), -CF₃CN, -CN, etc. Typical substituted alkyl groups are described below. Cycloalkyl may be further substituted by alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF₃And CN, etc.

The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but containing at least one double or triple bond, respectively. An "alkenyl" group is an unsaturated branched, straight chain or cyclic hydrocarbon group having at least one carbon-carbon double bond. The groups may be in cis or trans conformation with respect to the double bond. Typical alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, tert-butenyl, pentenyl, hexenyl, and the like. An "alkynyl group" is an unsaturated branched, straight chain or cyclic hydrocarbon group with at least one carbon-carbon triple bond. Typical alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like.

The term "halogen" refers to fluorine (fluor), chlorine (chloro), bromine (bromo) or iodine (iodo) or to fluoride, chloride, bromide or iodide or to fluorine, chlorine (chlorine), bromine (bromine) or iodine (iododine).

The term "amine" refers to a nitrogen-containing organic compound containing (C)₁-C₁₀) More preferably (C)₁-C₆) And even more preferably (C)₂-C₄) Carbon atoms, this compound may also have one or more substituents as set out above in the definition of alkyl.

The term "alkoxy" refers to a straight chain saturated hydrocarbon or a branched chain saturated hydrocarbon bonded through an oxy group (oxy). Examples of the alkoxy group include (C)₁-C₁₀) Alkoxy, more preferably (C)₁-C₆) Alkoxy and even more preferably (C)₂-C₄) An alkoxy group. Included within the definition of the term "alkoxy" are those that also have an alkyl group as defined aboveAlkoxy of one or more substituents as set forth in the description.

The terms "alkenyloxy" and "alkynyloxy" refer to organic compounds similar in length and possible substitution to the above-described alkoxy groups, but containing at least one double or triple bond, respectively.

The term "aryl" refers to an aromatic group having 3 to 14 ring atoms and at least one ring bearing a conjugated pi electron system, and includes "heteroaryl" compounds. Preferably at least two, more preferably at least four of the ring atoms are carbon atoms. The term "heteroaryl" refers to an aromatic heterocyclic group typically bearing one or more, preferably no more than two, heteroatoms in the ring selected from O, S and N, and whose aryl and heteroaryl groups are similar to the above-described aryl groups in possible substitution.

The term "heterocycle" refers to a ring structure having 3 to 14 ring atoms which may be saturated, unsaturated or aromatic, with one or more, preferably no more than two heteroatoms selected from O, S and N in the ring, and which ring may also have one or more substituents as set forth above in the alkyl definition. Preferably at least two, more preferably at least four ring atoms are carbon atoms.

The term "solubilizing group" refers to any group that improves the water solubility of the compound. Such groups may include, without limitation, the following:

wherein G and E are each independently selected from CH₂、CH₂CH₂And CH₂CH-alkyl, and J is O, NH or NCH₃。

In various embodiments, the nitrofurans of the present invention can be used therapeutically in formulations or medicaments for the prevention or treatment of bacterial infections. The present invention provides corresponding medical methods, wherein a therapeutic dose of nitrofurans of the present invention is administered, e.g. in the form of a pharmaceutically acceptable formulation, to a patient or subject in need thereof. Accordingly, the present invention also provides a therapeutic composition comprising a nitrofuran of the present invention and a pharmaceutically acceptable diluent, adjuvant, excipient or carrier. In one embodiment, such compositions comprise a therapeutically or prophylactically effective amount of a nitrofuran of the present invention sufficient to treat or prevent a bacterial infection. The therapeutic composition may be dissolved in an aqueous solution at a physiologically acceptable pH.

"therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic effect, such as the reduction of bacterial infection. The therapeutically effective amount of nitrofurans of the present invention may vary depending on such factors as the disease condition, 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 an amount at which any toxic or deleterious effects of the compound are more important than their 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 effect, such as preventing or inhibiting the rate of disease development or progression associated with bacterial infection. A prophylactically effective amount can be determined as described above for a therapeutically effective amount. For any particular subject, the specific dosage regimen may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition.

As used herein, "pharmaceutically acceptable carrier" or "excipient" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. In one embodiment, the carrier is suitable for parenteral administration. Alternatively, the carrier may 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 dispersions. 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 may also be incorporated into the compositions.

Therapeutic compositions generally must be sterile and stable under the conditions of manufacture and storage. The compositions may be formulated as solutions, microemulsions, liposomes or other ordered structures suitable for high drug concentrations. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. For example, suitable fluidity can be maintained, for the case of dispersions, by the use of coating materials, such as lecithin, by the maintenance of the required particle size, and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyols, such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin. In addition, the nitrofurans of the present invention can be administered in the form of a timed release formulation, for example in a composition comprising a sustained release polymer. Carriers that prevent rapid release of the compound can be used to prepare the active compound, such as controlled release formulations, including implant microencapsulated delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and polylactic-polyglycolic acid copolymer (PLG) may be used. For example, therapeutic compositions formulated as liposomes or other ordered structures can be prepared with antibodies to facilitate delivery of nitrofurans of the present invention to a particular microorganism, cell, tissue, or organ. Many methods for preparing such formulations have been patented or are generally known to those skilled in the art.

Sterile injectable solutions can be prepared by incorporating the active compound (e.g., nitrofuran of the invention) in the required amount in an appropriate solvent with one or a combination of the ingredients enumerated above, as required, followed by sterile filtration. 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 the resulting powder from a previously sterile-filtered solution to yield the active ingredient plus any additional desired ingredient. According to alternative aspects of the present invention, the nitrofurans of the present invention may be formulated using one or more other compounds that enhance the solubility of the nitrofurans.

According to another aspect of the invention, there may be provided therapeutic compositions of the invention comprising a nitrofuran of the invention in a container or commercial package further comprising instructions for the use of the nitrofuran in the prevention and/or treatment of a bacterial infection.

Accordingly, the present invention further provides a commercial package comprising a nitrofuran of the invention, or a therapeutic composition as described above, together with instructions for use in the prevention and/or treatment of a bacterial infection.

The invention further provides the use of the nitrofurans of the invention for the prevention and/or treatment of bacterial infections. The invention further provides the use of the nitrofurans of the invention for the preparation of a medicament for the prevention and/or treatment of bacterial infections.

The invention further provides the use of the nitrofurans of the invention as preservatives, bactericides or disinfectants.

All patents, patent applications, and publications mentioned herein above and below are hereby incorporated by reference.

While the invention has been described in connection with certain specific embodiments and will be described in the following examples, it is to be understood that it is not so limited since modifications and variations can be made within the full and intended scope of the following claims.

Now to define certain embodiments of the invention more specifically, the following examples provide detailed descriptions of specific compounds of the invention, methods of their production, and results produced by testing the compounds.

2-methyl-4- (3H) quinazolinone (I)

Anthranilamide hydrochloride (anthranilamide hydrochloride) was prepared by adding 20ml of concentrated hydrochloric acid (37% by weight) to a solution of 27.3g anthranilamide in 200ml methanol.

The mixture was cooled in an ice bath to precipitate the hydrochloride salt, which was then collected and dried to obtain the product. 17.4g (0.1 mol) of the hydrochloride thus obtained were refluxed with 100ml of acetic anhydride for 3 hours and allowed to stand overnight. The mixture was then cooled in an ice bath and the solid was collected by filtration on a buchner funnel. The filter cake was slurried in 100ml of water and warmed to promote dissolution and then 28% aqueous ammonia was added until the mixture was basic. After cooling, the 2-methyl-4- (3H) quinazolinone was then collected as a solid precipitate, washed with a small amount of cold water and dried at 70 ℃ to give 6.72g of the desired product.

5-Nitro-2-Furaldehyde (II)

A total of 86.5g of 5-nitrofurfurylidene (nitrofurylidene) diacetate was added in small portions over a period of 10 to 15 minutes to 90ml of sulfuric acid (73% by weight). The mixture was stirred at ambient temperature for 30 minutes, at 50 ℃ for 10 minutes, cooled to 30 ℃, and then poured onto 150g of crushed ice. The mixture is filtered and sucked as dry as possible on a Buchner funnel with the aid of a rubber barrier (dental dam), this procedure giving 51.5g of 5-nitro-2-furaldehyde, which melts at 32 ℃ to 34 ℃.

2- [2- (5-Nitro-2-furyl) ethenyl]-4- (3H) quinazolinone (III)

To 16g (0.1 mole) of 6-fluoro-2-methyl-4- (3H) quinazolinone, 100ml of acetic anhydride, 0.5ml of 96% sulfuric acid and 20g (0.14 mole) of 5-nitro-2-furfural were added, and the mixture was stirred at 50-60 ℃ for 2 hours. The reaction mixture was poured into water and boiled for 10 minutes. After standing overnight, the product was collected by filtration, washed with water and then methanol. A yellow solid was obtained. The solid 2- [2- (5-nitro-2-furyl) vinyl ] -4- (3H) quinazolinone was used to prepare the following chloro- (IV) and anilino (V) derivatives.

2- [2- (5-Nitro-2-furyl) ethenyl]-4-chloroquinazoline (IV)

To a 500ml 3-necked flask equipped with a stirrer, reflux condenser and protected with a calcium chloride trap were added 9.0g of phosphorus pentachloride (0.043 moles) and 70ml of phosphorus oxychloride and the mixture was stirred. 11.3g (0.04 mol) of 2- [2- (5-nitro-2-furyl) vinyl ] -4- (3H) quinazolinone was added thereto and rinsed into the flask with 15ml of phosphorus oxychloride. The mixture was heated at reflux for 4 hours, cooled in an ice bath and diluted with 150ml of diethyl ether. The precipitated 6-fluoro-2- [2- (5-nitro-2-furyl) vinyl ] -4-chloroquinazoline was collected by filtration, washed with 100-150ml of diethyl ether, stirred in 100ml of diethyl ether to prepare a slurry and then filtered to obtain 8.09g of the desired product.

3, 4-Dihydroxyaniline (V)

Concentrated hydrochloric acid (10ml) was added to a mixture of 4-nitro-1, 2-catechol (12g) and tin (II) chloride (2g) in ethanol (100 ml). The mixture was heated for 2h and cooled to ambient temperature. The desired aniline was purified by flash chromatography.

2- [2- (5-Nitro-2-furyl) ethenyl]-4- (3, 4-dihydroxyanilino) quinazoline (VI)

The following is a general procedure for obtaining 4- [ aminocatechol ] derivatives of 2- [2- (5-nitro-2-furyl) vinyl ] quinazoline. To a round bottom flask equipped with a magnetic stirrer and a heating oil bath were added 3, 4-dihydroxyaniline (1 mole) and 3ml of dimethylformamide. After dissolving the 3, 4-dihydroxyaniline by stirring, 2- [2- (5-nitro-2-furyl) vinyl ] -4-chloroquinazoline (IV) (0.9mmol) was added. The reaction mixture was then heated at 70-90 ℃ for 2 hours, after which 5ml water was added and the cooled solution was crystallized in a refrigerator. After 3 days, a tan solid was collected, washed first with water, then with methanol and then dried to give the desired product.

Example II

2- [2- (5-Nitro-2-furyl) ethenyl]-4- [2- (3, 4-dihydroxyphenyl) ethylamino]Quinazoline (VII)

This compound was prepared in the same manner as in example I, but using 2- (3, 4-dihydroxyphenyl) -ethylamine (1mmol) instead of 3, 4-dihydroxyaniline (V) to give the desired product as a solid after flash chromatography.

Example III

2- [2- (5-Nitro-2-furyl) ethenyl]-4-aminoquinazoline (I)

2M ammonia in toluene (5mmol) was added to a solution of 2- [2- (5-nitro-2-furyl) vinyl ] -4-chloroquinazoline in toluene (3 mmol). The vessel was sealed and the mixture was heated to 80 ℃ for 4 h. The mixture was cooled and evaporated. The desired compound was purified by flash chromatography.

2- (2-hydroxyphenyl) -2-thiazole-4-carbonyl (carboxoyl) chloride (II)

2- (2-hydroxyphenyl) -2-thiazole-4-carboxylic acid (3mmol), obtained as described in U.S. Pat. No. 6,403,623, was treated with thionyl chloride (3.1mmol) in dichloromethane (50ml) and catalytic amounts of dimethylformamide at 0 ℃. The reaction was allowed to warm to ambient temperature for 2 h. The solvent was removed and the mass was dried under vacuum.

2- [2- (5-Nitro-2-furyl) ethenyl]-4- [2- (2-hydroxyphenyl) -2-thiazole-4-carboxamido]Quinazoles Quinoline (III)

Anhydrous dichloromethane (100ml) was added to the product of (II) (1mmol) and the mixture was cooled in an ice bath. The product of (I) was dissolved in pyridine (0.9mmol in 20 ml) and added to the dichloromethane solution over 10 min. The reaction was stirred at ambient temperature for 2 h. The solvent was removed under reduced pressure. The desired product was purified by flash chromatography.

Example IV

(S) -2- (2-hydroxyphenyl) -2-thiazoline-4-carbonyl (carboxoyl) chloride (I)

(S) -2- (2-hydroxyphenyl) -2-thiazoline-4-carboxylic acid (3mmol) obtained as described in U.S. Pat. No. 6,403,623 was treated with thionyl chloride (3.1mmol) in dichloromethane (50ml) and a catalytic amount of dimethylformamide at 0 ℃. The reaction was allowed to warm to ambient temperature for 2 h. The solvent was removed and the mass was dried under vacuum.

(S) -2- [2- (5-Nitro-2-furyl) ethenyl]-4- [2- (2-hydroxyphenyl) -2-thiazoline-4-carboxamido] Quinazoline (II)

This compound was obtained in the same manner as described in example III, except that (S) -2- (2-hydroxy-phenyl) -2-thiazoline-4-carbonyl chloride (1mmol) was used with 2- [2- (5-nitro-2-furanyl) vinyl ] -4-aminoquinazoline (0.9 mmol). The product was purified by flash chromatography.

Example V

(R) -2- (2-hydroxyphenyl) -2-thiazoline-4-carbonyl chloride (I)

(R) -2- (2-hydroxyphenyl) -2-thiazoline-4-carboxylic acid (3mmol) obtained as described in U.S. Pat. No. 6,403,623 was treated with thionyl chloride (3.1mmol) in dichloromethane (50ml) and a catalytic amount of dimethylformamide at 0 ℃. The reaction was allowed to warm to ambient temperature for 2 h. The solvent was removed and the mass was dried under vacuum.

(R) -2- [2- (5-nitro-2-furyl) ethenyl]-4- [2- (2-hydroxyphenyl) -2-thiazoline-4-carboxamido] Quinazoline (II)

This compound was obtained in the same manner as described in example III, except that (R) -2- (2-hydroxy-phenyl) -2-thiazoline-4-carbonyl chloride (1mmol) was used with 2- [2- (5-nitro-2-furanyl) vinyl ] -4-aminoquinazoline (0.9 mmol). The product was purified by flash chromatography.

Example VI

3- [1, 10-bis (2, 3-dihydroxybenzoyl) sperminylcarbonyl]Propionic acid (I)

Such as Minnick, A.A., McKee, J.A., Dolence, E.K., Miller.M.J.times. microbiological Agents and Chemotherapy, 1992,35: 840-850, McKee, j.a., Sharma, s.k., Miller, m.j., Bioconjugate Chemistry, 1991, 2: this compound was prepared in the manner described in 281-291.

2- [2- (5-Nitro-2-furyl) ethenyl]-4- {3- [1, 10-bis (2, 3-dihydroxybenzoyl) sperminocarbonyl Propionyl amino radical]Quinazoline (III)

Bistrimethylsilyl trifluoroacetamide (100 μ l) was added to a solution of compound I in anhydrous dichloromethane (1ml) (0.1mmol) and the solution was stirred at ambient temperature for 2 h. The solvent was removed to dryness and the product was placed under vacuum. The material was again dissolved in dichloromethane (1ml) and cooled to 0 ℃. Oxalyl chloride (1.1 equivalent (eq)) and catalytic amounts of DMF were added. The reaction was allowed to proceed for 40min after bubbling stopped. A solution of 2- [2- (5-nitro-2-furyl) vinyl ] -4-aminoquinazoline (II) (0.8mmol) in pyridine (200. mu.l) and diethyl ether (200. mu.l) was added and the mixture was stirred overnight. The mixture was concentrated in vacuo and the residue was stirred in the presence of methanol containing a catalytic amount of acetic acid for 2 h. After concentration, the product was purified by flash chromatography.

Example VII

2- [2- (5-Nitro-2-furyl) ethenyl]-4- [ 2-aminoethylamino ] amino]Quinazoline (I)

A solution of 1, 2-diaminoethane (2mmol) in toluene (1ml) was added to a solution of 2- [2- (5-nitro-2-furanyl) vinyl ] -4-chloroquinazoline (1mmol) in DMF (10ml) under a nitrogen atmosphere. The autoclave was sealed and heated to 80 ℃ for 2 h. The mixture was cooled and the solvent was removed under vacuum. The residue was purified by flash chromatography to give the desired product.

2- [2- (5-Nitro-2-furyl) vinyl ] -4- [ 2-pyocheinylaminoethylamino ] quinazoline (II)

Pyrochelin (0.5mmol) was treated with thionyl chloride in dichloromethane (5ml) and a catalytic amount of dimethylformamide at 0 ℃. The reaction was allowed to warm to ambient temperature for 2 h. The solvent was removed and the mass was dried under vacuum.

Anhydrous dichloromethane (5ml) was added to the acid chloride prepared above and the mixture was cooled in an ice bath. Compound II from example III was dissolved in pyridine (0.5mmol in 2 ml) and added to the dichloromethane solution over 10 min. The reaction was stirred at ambient temperature for 2 h. The solvent was removed under reduced pressure. The desired product was purified by flash chromatography.

The synthesis of Pyochelin analogues is described in the following references: zamri, i.j.schalk, f.pattus, m.a.abdallah.bacterial Siderophores: synthesis and biological Activities of Novel Pyrochelin analogs. biorg. Med. chem Lett., 2003, 13, 1147-wall 1150.

Example VIII

Example IX

Example X

Example XI

Example XII

Example XIII

The antimicrobial activity of the prepared compounds was evaluated by the following procedure.

Determination of the Minimum Inhibitory Concentration (MIC).

Bacteria. Sensitivity tests against several bacterial species were performed according to the recommendations of the national clinical standards committee (NCCLS). Examples of microbial strains tested are provided in table 1. A final volume of 100. mu.l of cation-adjusted Mueller Hinton Broth (MHBCA) and 10 were used by the broth microdilution technique⁵-10⁶MICs was determined for bacterial inoculum of Colony Forming Units (CFU)/ml. The inoculum was verified and accurately determined by drop-plating 10- μ l of a 10-fold dilution onto Triptic soybean agar plates. CFU counts were taken after incubation at 35 ℃ for 24 hours. Exclusion exhibits greater than or less than 10⁵-10⁶Any experiment with CFU/ml inoculum. Control antibiotics and test compounds were prepared at concentrations equal to 2-fold the highest desired final concentration. Compounds were then diluted directly in 96-well microtiter plates by serial 2-fold dilutions using multichannel pipettes. The microtiter plates were incubated during 24 hours at 35 ℃ and growth was recorded by visual observation at 650nm using a microtiter plate reader. MIC was defined as the lowest concentration of compound that produced no visible growth. At least two commercial antibiotics (e.g., imipenem and vancomycin) were included throughout each MIC test as internal microtiter plate controls. Results showing a deviation in such control antibiotic MICs (MIC difference was 2-fold more dilution) compared to NCCLS reference data for ATCC strains were excluded from any microtiter plate. It is difficult to cultivate bacteria. The medium for Streptococcus pneumoniae, Listeria monocytogenes, Neisseria meningitidis and Campylobacter jejuni subspecies jejuni was MHBCA containing 2% hemolyzed horse blood. The medium for haemophilus influenzae and branhamella catarrhalis (moraxella catarrhalis) was the NCCLS recommended HTM. The culture of these recalcitrant bacteria was incubated at 35 ℃ and 5% CO₂Keeping the temperature in the air. Culture for bacteroides fragilisThe nutrient was Wilkins Chalgren broth and grown in anaerobic atmosphere at 35 ℃ for 48 hours. MHBCA medium used to grow M.smegmatis before MIC was supplemented with 0.02% Tween-80 and the results from the microtiter plates were read after 48 hours of incubation. The medium for Bacteroides fragilis was Wilkins Chalgren broth and grown in anaerobic atmosphere at 35 ℃ for 48 hours.

A yeast. Susceptibility testing for yeast was also performed according to NCCLS recommendations. The tests differ from those carried out for bacteria in the following manner: (1) the medium proposed and used for Candida albicans (Candidaalbicans) is RPMI; inoculation for the yeast is 0.5X 10³To 2.5X 10³CFU/ml; and (3) incubation at 35 ℃ for 48 h. Also for yeast, after the incubation period, the microtiter plate was carefully vortexed and the MIC was defined as the lowest concentration of compound that caused a significant decrease in turbidity (at least 80% growth inhibition).

Time-kill curve. The bactericidal effect of the compounds was also evaluated over time (time-bactericidal curve experiment). Preparation of 1X 10⁵-5×10⁵Colony Forming Units (CFU)/ml of bacterial inoculum. The inoculum was verified and accurately determined by drop-plating 10-ul 10-fold dilutions onto Triptic soy agar plates. CFU counts were taken after incubation at 35 ℃ for 24 hours. Any experiments showing inoculum greater or less than the desired range CFU/ml were excluded. The time-kill curve experiments were performed in 30ml MHB in 50-ml shake flasks over a 24 hour period. Test compounds and control antibiotics were added at 0 hour, and at each time point a sample was taken from the flask and CFU was determined by plate count as described above. CFU from compound-treated cultures were compared to CFU collected from control flasks without antibiotics. Test compounds and control antibiotics were tested at a concentration of 0.5MIC or MIC as determined by broth microdilution technique as described above.

Study of mode of action. Macromolecular biosynthesis assays are performed to determine the microbial cellular processes selectively acted upon by antibiotic compounds. Growing exponentially in MHBThe bacteria were washed in complete synthesis medium and diluted to an optical density of 0.2 (at 600 nm). The cells were then dispensed into 96-well plates containing, in order, the diluted antibiotic compound and the radiolabeled precursor. The radiolabeled precursor is D-, [2 ], [ alpha ], [ beta ] -a salt for peptidoglycan synthesis³H]Alanine, and a nucleotide sequence for DNA synthesis³H][2 ] -Thymidine deoxynucleoside, for RNA synthesis³H]-uridine and use in protein synthesis³H]-leucine. Conjugation (incorporation) was performed at 35 ℃ for 30 minutes, after which the macromolecules were precipitated on ice in the presence of 10% trichloroacetic acid for 1 hour. The radioactive pellet was then collected on a GC filter and the radioactivity was determined by liquid scintillation counting. Data are expressed as percentage of bound radioactivity compared to control cell growth in the absence of antibiotic compound.

The in vivo efficacy. The antibacterial activity of the compounds was also evaluated in a mouse model of systemic infection with staphylococcus aureus. To produce systemic infection, CD-1 female mice (20g) were injected intraperitoneally with 10⁷CFU of Staphylococcus aureus strain Newman suspended in 0.5ml endotoxin-free PBS containing 5% mucin (w/v). Compound (15mg/kg) was administered by oral gavage 1 hour post infection and kidneys were removed and collected from each animal 5 hours post bacterial inoculation. Tissues were homogenized in PBS and homogenates were sequentially diluted and plated for CFU determination.

Compounds were evaluated against several microorganisms in order to determine their microbial growth inhibitory activity and the breadth of the spectrum.

For example, compound VI of example 1 is active against a wide variety of clinical isolates and reference strains of gram-positive and gram-negative bacteria. Compound VI of example 1 was tested side-by-side with other antibiotic representatives of various classes of commercially available compounds. Compound VI of example 1 was potent against e.coli and its activity was superior to other nitrofurans (e.g. furazolidone, nitrofurantoin and nitrofurazone) (table 2). Initial mode of action studies have shown that the antibiotic effect of compound VI of example 1 can be produced by inhibition of the DNA metabolism of the essential cellular processes of the microorganism (see FIG. 1). This effect is similar to that observed for norfloxacin, a known inhibitor of DNA topoisomerase and DNA metabolism, and is different from that observed for chloramphenicol (a protein synthesis inhibitor) and vancomycin, an inhibitor of cell wall peptidoglycan synthesis (data not shown). Compound VI of example 1 was active in a mouse model of systemic infection with staphylococcus aureus. The results show that compound VI of example 1 reduces the presence of viable bacteria in the kidney. This result demonstrates the bioavailability of compound VI of example 1 and its lower in vivo toxicity.

Compound "q" of example VIII shows antibacterial activity against bacteria that generally cause serious opportunistic and/or nosocomial infections. These include gram-positive (methicillin-resistant and methicillin-sensitive Staphylococcus aureus strains [ MRSA and MSSA, respectively, with MICs of 4-8. mu.g/ml ], and enterococci like enterococci faecalis with MIC of 8. mu.g/ml) and gram-negative bacteria (including species causing refractory infections like Yersinia enterocolitica (Yersinianterocolytica) and Burkholderia cepacia with MIC of 8. mu.g/ml) and anaerobic bacteria (with MIC of 8. mu.g/ml). Example VIII the MIC (μ g/ml) of compound "q" is superior to conventional antibiotic classes like β -lactams, fluoroquinolones or macrolides in bacterial strains showing resistance mechanisms to these antibiotics (table 3), but also greater antibacterial activity than observed for nitrofurantoin, which is a conventional nitrofuranantibiotic lacking the novel structural features described in this patent.

Compound "q" of example VIII also showed growth inhibitory activity (MIC of 1 μ g/ml) against typical respiratory pathogens causing community-acquired otitis media and pneumonia, such as haemophilus influenzae and branhamella (moraxella catarrhalis) mucositis. In addition, the compound "q" of example VIII also showed inhibitory activity against Mycobacterium genus (MIC of 8. mu.g/ml). The bacterium Mycobacterium tuberculosis, a causative agent of tuberculosis, is also a member of the genus Mycobacteria. Furthermore, the compound "q" of example VIII also showed very good activity (MIC of 8. mu.g/ml) against Bacillus species of three bacteria (i.e., Bacillus cereus, Bacillus subtilis and Bacillus atrophaeus). Bacillus anthracis, the bacterial pathogen causing anthrax, is also a member of that genus.

Table 1. examples of microbial species used to evaluate the antimicrobial activity of compounds.

Original strain group:

gram-positive bacteria.

Staphylococcus aureus ATCC 29213

Staphylococcus aureus MRSA COL

Staphylococcus epidermidis ATCC 12228

Staphylococcus saprophyticus ATCC 15305

Enterococcus faecalis ATCC 29212

Enterococcus faecium ATCC 35667

Bacillus cereus ATCC 11778

Bacillus subtilis ATCC 6633

Bacillus atrophaeus ATCC 9372

Streptococcus pneumoniae ATCC 49619

Listeria monocytogenes ATCC 13932

Gram-negative bacteria.

Escherichia coli ATCC 25922

Citrobacter freundii ATCC 8090

Klebsiella oxytoca ATCC 43165

Klebsiella pneumoniae ATCC 13883

Enterobacter aerogenes ATCC 35029

Enterobacter cloacae ATCC 35030

Proteus mirabilis ATCC 25933

Serratia marcescens ATCC 8100

Pseudomonas aeruginosa ATCC 27283

Acinetobacter baumannii ATCC 10606

Burkholderia cepacia ATCC 27515

Yersinia enterocolitica ATCC 23715

Haemophilus influenzae ATCC 49247

Haemophilus influenzae ATCC 49766

Bryococcus catarrhalis (moraxella catarrhalis) ATCC 8176

Neisseria meningitidis ATCC 13102

Jejunum campylobacter jejuni subspecies ATCC 33291

And (4) anaerobic bacteria.

Bacteroides fragilis ATCC 25285

Yeast and fungi.

Candida albicans ATCC 10231

TABLE 2 MICs in μ g/ml of control antibiotic obtained for E.coli and Compound VI of example 1

Antibiotic	Escherichia coli
		ATCC 25922
	Example 1, Compound VI		0.5
Ampicillin		4-8
	Cefotaxime		0.06-0.12
Ceftriazine thiaxime		0.03-0.06
	Chloromycetin		4-8
Erythromycin		64
	Furazolidones		1-2
Gentamicin		0.5-2
	Imipenem		0.12
Meropenem		0.015-0.06
	Nitrofurantoin		8-16
Furacilin		8-16
	Norfloxacin hydrochloride		0.03-0.06
Oxacillin		512-＞512
	Rifampicin		8
TMP/SMX(1/19)		0.25/4.75-0.5/9.5
	Vancomycin		＞64

TABLE 3 MICs in μ g/ml of control antibiotics obtained for multiple antibiotic-resistant MRSA strains and Compound "q" of example VIII

MRSA strains	Compound of example VIII "q"	Oxacillin	Erythromycin	Norfloxacin hydrochloride	Gentamicin	Nitrofurantoin
							Sa211c	8	16-32	＞32	＞32	1	16-32
Sa212c	8	16	＞32	＞32	0.25	32
							Sa220c	4	8-16	0.5	＞32	0.5	16
Sa224c	8	32-64	＞32	＞32	0.25	16
							Sa228c	8	128	＞32	＞32	32	16-32
Sa234c	8	32-＞128	＞32	＞32	1	16-32
							Sa248c	8	512	＞128	32	＞128	16
Sa249c	8	512	＞128	32	＞128	16
							Sa253c	8	1024	＞128	＞128	＞128	16

The claims (modification according to treaty clause 19)

1. A compound of formula (1.0)

Wherein

W is absent, vinyl (cis or trans-CH ═ CH-, preferably trans) or-N ═ CH-;

w' is absent, or with R¹、R²And R³Is shown as

Wherein the dotted line together with the solid line either represents a single bond or a double bond, D, D', X, M and Z are each independently selected from CH, C, O, S, NH and N and A is selected from C, N or P, whereas at least one of D or XIs C, and preferably no more than two D, X, M, A or Z are O, S, NH or N, and D' must be C or CH, unless R is²And R³Together form a ring such as quinazoline; and p and n are each independently selected from 0, 1, and 2;

R¹、R²and R³Each independently selected from the group consisting of absent, hydrogen, halogen (including halogen atoms fluorine, chlorine, bromine and iodine), CH³、C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₁-C₁₀Alkoxy radical, C₂-C₁₀Alkenoxy group, C₂-C₁₀Alkynyloxy, aryl, OH, trifluoromethyl, methylenedioxy, phenoxy, OR⁴、CO₂R⁴、SO₂R⁴、PO(OR⁴)₂、CON(R⁴)₂、OAr、NH₂、NHR₄、NR₄、N(R⁴)₂、NHAr、SH、SR⁴SAr, ═ O, hydroxamic acids, heterocycles, solubilizing groups as defined below, and VQT moieties (terminal ring systems) as defined below, with the proviso that VQT is present at least once, wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy OR alkynyloxy can be unsubstituted OR preferably has from 1 to 5 halogen atoms OR from 1 to 2 OR atoms⁴Substituted with groups and the aryl group is preferably selected from the group consisting of phenyl, naphthyl, indolyl, biphenyl, phenoxyphenyl, pyridyl, furyl, thienyl and bithiophenyl, said aryl group being optionally substituted with preferably 1 to 3 groups selected from: r⁴A solubilizing group as defined below, and a portion VQT as defined below;

the solubilizing group may be, but is not limited to, preferably

Wherein G and E are each independently selected from CH₂、CH₂CH₂And CH₂CH-alkyl; and J isO, NH or NCH₃；

R⁴Is selected from CH₃、C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₁-C₁₀Alkoxy radical, C₂-C₁₀Alkenoxy group, C₂-C₁₀Alkynyloxy, aryl, heterocyclic, solubilizing group as defined above, and aryl is preferably selected from the group consisting of: phenyl, naphthyl, indolyl, biphenyl, substituted or unsubstituted, mono-or bi-carbon-or hetero-cyclic structures having 4 to 14 atoms, which mono-or bi-carbon-or hetero-cyclic structures are aliphatic or aromatic in nature, and any combination with substituted or unsubstituted, mono-or bi-carbon-or hetero-cycloaliphatic or aromatic structures having 3 to 8 atoms;

v is C, CH, N, NH, O or

Q acts as a stable or labile linker, e.g. selected from absent, C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₁-C₁₀Amine, C₁-C₁₀Alkoxy radical, C₂-C₁₀Alkenoxy group, C₂-C₁₀Alkynyloxy, phenyl, heterocycle, -C (═ O) -, -SO₂-、-PO(OR¹)-、-NOH、-(CH₂)_t-C (═ O) -, and- (CH)₂)_t-NH-C (═ O) -, where t is 0 to 10; and is

T is

Wherein A and M are independently selected from C, CH, O, NH, N and S; p, n and v are each independently selected from 0 and 1, preferably n ═ 1 and p ═ 0; and the dotted line together with the solid line represents a single bond or a double bond; and is

R⁵、R⁶、R⁷、R⁸And R⁹Each independently selected from absent or as for R¹As defined;

preferred R⁵Is that

Wherein M' is independently selected from CH, C and N;

and wherein R¹⁰Is absent or as for R¹As defined;

l as a stable or unstable linker, e.g. selected from absent, C₁To C₁₀Alkyl radical, C₂To C₁₀Alkenyl radical, C₂To C₁₀Alkynyl, C₁-C₁₀Amine, C₁-C₁₀Alkoxy radical, C₂-C₁₀Alkenoxy group, C₂-C₁₀Alkynyloxy, phenyl, -C (═ O) -, -PO (OR)¹)-、-NOH-、-(CH₂)_t-C (═ O) -, and- (CH) where t is 0 to 10₂)_t-NH-C (═ O) -, and heterocycles, wherein said heterocycles are preferably

Wherein A and M are independently selected from C, CH, N, NH, O, or S; and wherein R¹¹And R¹²Independently selected from absent, or as for R¹As defined; and wherein the dotted line together with the solid line represents a single bond or a double bond;

when n is 0 in T, R⁵、R⁶、R⁷、R⁸Or R⁹Must be a catechol as shown:

or hydroxamic acids (R) as shown below¹H) or hydroxamates (R)¹As described above):

R²and R³When taken together in formula 1.0, (wherein W' is the central structure), the D and D "atoms of the central structure to which they are fused combine to form the following groups:

wherein the dotted line together with the solid line either represents a single bond or a double bond, X, D, D', D ", D *, Z are each independently selected from CH, C, O, S, NH, and N; and n is selected from 0, 1 and 2;

wherein R is¹³And R¹⁴Each independently of the others as for R¹Define or together form a ring such as, for example, quinazoline;

and when R is²And R³When taken together in the formula 1.0,

R¹as defined above, or

Wherein R is¹⁵And R¹⁶Each independently of the others as for R⁴As defined;

with the proviso that at least one VQT moiety must be present at 1, 2 or 3 positions in the compound of formula 1.O selected from one or more of the following groups:

-V-Q，-V-Q-T，

or an enantiomer thereof;

wherein the compound of formula 1.0 has 1 to 9 Ts, and each V and Q and T is independently selected;

or a pharmaceutically acceptable salt of the compound.

2. A compound of the formula

Wherein

W is absent or is vinyl (cis or trans-CH ═ CH-, preferably trans); D. x, M and Z are each independently selected from CH, C and N; v is NH, O, S or

Q as a stable or unstable linker, e.g. selected from absent, C₁To C₁₀Alkyl radical, C₂To C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₁-C₁₀Amine, C₁-C₁₀Alkoxy radical, C₂-C₁₀Alkenoxy group, C₂-C₁₀Alkynyloxy, phenyl, heterocycle, -C (═ O) -, -PO (OR)¹)-、-SO₂-、-NOH、-(CH₂)_t-C (═ O) -, and- (CH)₂)_t-NH-C (═ O) -, where t is 0 to 10;

t is selected from

Wherein A is selected from O, NH, NR and S; m' is CH or N; y is H or OH;

R³is hydrogen, alkyl, aryl, OH, OR, OAr, NH₂NHR, NHAr, SH, SR, or SAr; and is

R¹And R²Each independently selected from:

is absent (when R is₁Or R₂When bonded X is N OR CH), hydrogen, alkyl, aryl, OH, OR, OAr, NH₂NHR, NHAr, SH, SR, and SAr;

R¹⁵selected from the group consisting of H, alkyl, and substituted alkyl;

R¹⁶selected from the group consisting of alkyl, substituted alkyl, phenyl and substituted phenyl;

R²⁰is halogen, a solubilizing group as defined in claim 1 or as for R³Defining; or a pharmaceutically acceptable salt of the compound.

3. A compound according to claim 1, wherein R is²And R³Are formed together

Wherein the dotted line along with the solid line represents a single or double bond, X, D, D ', D', D *, Z are each independently selected from CH, C, O, S, NH, and N; and n is selected from 0, 1 and 2; and wherein R¹³And R¹⁴Each independently of the others as for R¹As defined.

4. A compound according to claim 2, wherein R²⁰Is halogen or a solubilising group as defined in claim 1.

5. A composition comprising a compound according to any one of claims 1 to 4 and a carrier, diluent or excipient.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

7. A method for the treatment of a bacterial infection in a human, said method comprising administering to said human a therapeutically effective amount of a compound according to any one of claims 1 to 4.

8. A method for the prevention of a bacterial infection in a human, said method comprising administering to said human a prophylactically effective amount of a compound according to any one of claims 1 to 4.

9. A method for disinfecting bacteria on the surface of an object, including a human, the method comprising: selecting a surface area for disinfection and applying a compound according to any one of claims 1 to 4 to the surface of the object in an amount and for a time sufficient to obtain the desired degree of disinfection.

10. A method for sterilizing bacteria on the surface of an object, including a human, the method comprising: selecting an area of a sterilized surface and applying a compound according to any one of claims 1 to 4 to the surface of the object in an amount and for a time sufficient to obtain sterilization.

11. Use of a compound according to any one of claims 1 to 4 for the treatment or prophylaxis of a bacterial infection.

12. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment or prevention of a bacterial infection.

13. Use of a compound according to any one of claims 1 to 4 for disinfection.

14. Use of a compound according to any one of claims 1 to 4 for preserving.

15. Use of a compound according to any one of claims 1 to 4 for sterilization.

16. The compound of claim 1, wherein V is C, CH, N, NH, or O.

17. The compound of claim 2, wherein V is NH or O.

Claims (15)

1. A compound of formula (1.0)

Wherein

W is absent, is vinyl (cis or trans-CH ═ CH-, preferably trans) or-N ═ CH-;

w' is absent, or with R¹、R²And R³Is shown as

(center structure)

Wherein D, D ', X, M, A and Z are each independently selected from CH, C, O, S, NH and N, however at least one of D or X is C, and preferably no more than two D, X, M, A or Z are O, S, NH or N, and D' must be C or CH, unless R is²And R³Together form a ring; the dotted line is an optional bond (acyclic structure); and p and n are each independently selected from 0, 1, and 2;

R¹、R²and R³Each independently selected from the group consisting of absent, hydrogen, halogen (including halogen atoms fluorine, chlorine, bromine and iodine), CH₃、C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₁-C₁₀Alkoxy radical, C₂-C₁₀Alkenoxy group, C₂-C₁₀Alkynyloxy, aryl, OH, trifluoromethyl, methylenedioxy, phenoxy, OR⁴、CO₂R⁴、SO₂R⁴、PO(OR⁴)₂、CON(R⁴)₂、OAr、NH₂、NHR₄、NR₄、N(R⁴)₂、NHAr、SH、SR⁴SAr, ═ O, hydroxamic acids, heterocycles, solubilizing groups as defined below, and VQT moieties (terminal ring systems) as defined below, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy OR alkynyloxy groups may be unsubstituted OR preferably have from 1 to 5 halogen atoms OR from 1 to 2 OR atoms⁴And aryl is preferably selected from the group consisting of phenyl, naphthyl, indolyl, biphenyl, phenoxyphenyl, pyridinyl, furanyl, thienyl and bithienyl (bithienyl), said aryl group being optionally substituted with preferably 1-3 groups selected from the group consisting of: r⁴A solubilizing group as defined below, and a portion VQT as defined below;

the solubilizing group may be, but is not limited to, preferably

Wherein G and E are each independently selected from CH₂、CH₂CH₂And CH₂CH-alkyl; and J is O, NH or NCH₃；

R⁴Is selected from CH₃、C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₁-C₁₀Alkoxy radical, C₂-C₁₀Alkenoxy group, C₂-C₁₀Alkynyloxy, aryl, heterocyclic, solubilizing group as defined above, and aryl is preferably selected from the group consisting of: phenyl, naphthyl, indolyl, biphenyl, substituted or unsubstituted, mono-or bi-carbon-or hetero-cyclic structures having 4 to 14 atoms, which mono-or bi-carbon-or hetero-cyclic structures are aliphatic or aromatic in nature, and any combination with substituted or unsubstituted, mono-or bi-carbon-or hetero-cycloaliphatic or aromatic structures having 3 to 8 atoms;

v is C, CH, N, NH or O;

q acts as a stable or labile linker, e.g. selected from absent, C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₁-C₁₀Amine, C₁-C₁₀Alkoxy radical, C₂-C₁₀Alkenoxy group, C₂-C₁₀Alkynyloxy, phenyl, heterocycle, -C (═ O) -, -SO₂-、-PO(OT)₂-、-NOH、-(CH₂)_t-C (═ O) -, and- (CH)₂)_t-NH-C (═ O) -, where t is 0 to 10; and is

T is

Wherein A and M are independently selected from C, CH, O, NH, N and S; p, n and v are each independently selected from 0 and 1; and the dotted line represents an optional additional bond; and is

R⁵、R⁶、R⁷、R⁸And R⁹Each independently selected from absent or as for R¹As defined;

preferred R⁵Is that

Wherein D is independently selected from CH, C, O, S, NH, and N;

and wherein R¹⁰Is absent or as for R¹As defined;

l as a stable or unstable linker, e.g. selected from absent, C₁To C₁₀Alkyl radical, C₂To C₁₀Alkenyl radical, C₂To C₁₀Alkynyl, C₁-C₁₀Amine, C₁-C₁₀Alkoxy radical, C₂-C₁₀Alkenoxy group, C₂-C₁₀Alkynyloxy, phenyl, -C (═ O) -, -PO (OT)₂-、-NOH-、-(CH₂)_t-C (═ O) -, and- (CH) where t is 0 to 10₂)_t-NH-C (═ O) -, and heterocycles, wherein said heterocycles are preferably

Wherein A and M are independently selected from C, CH, N, NH, O, or S; and wherein R¹¹And R¹²Independently selected from absent, or as for R¹As defined; and wherein the dotted line represents an optional additional bond;

R²and R³When taken together in formula 1.0, (wherein W' is the central structure), the D and D "atoms of the central structure to which they are fused combine to form the following groups:

wherein X, D, D ', D', D *, Z are each independently selected from CH, C, O, S, NH, and N; and n is selected from 0, 1 and 2;

wherein R is¹³And R¹⁴Each is independentFor R¹As defined;

and when R is²And R³When taken together in the formula 1.0,

R¹as defined above, or

Wherein R is¹⁵And R¹⁶Each independently of the others as for R⁴As defined;

with the proviso that at least one VQT moiety must be present at 1, 2 or 3 positions in the compound of formula 1.0 selected from one or more of the following groups:

or an enantiomer thereof;

wherein the compound of formula 1.0 has 1 to 9 Ts, and each V and Q and T is independently selected;

or a pharmaceutically acceptable salt of the compound.

2. A compound of the formula

Wherein

W is absent or is vinyl (cis or trans-CH ═ CH-, preferably trans);

D. x, M and Z are each independently selected from CH, C and N;

v is NH or O;

q as a stable or unstable linker, e.g.Selected from absent, C₁To C₁₀Alkyl radical, C₂To C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₁-C₁₀Amine, C₁-C₁₀Alkoxy radical, C₂-C₁₀Alkenoxy group, C₂-C₁₀Alkynyloxy, phenyl, heterocycle, -C (═ O) -, -PO (OT)₂-、-SO₂-、-NOH、-(CH₂)_t-C (═ O) -, and- (CH)₂)_t-NH-C (═ O) -, where t is 0 to 10;

t is selected from

Wherein A is selected from O, NH, NR and S; d is CH or N; y is absent or OH;

R³is hydrogen, alkyl, aryl, OH, OR, OAr, NH₂NHR, NHAr, SH, SR, or SAr; and is

R¹And R²Each independently selected from:

is absent (when R is₁Or R₂When bonded X is N OR CH), hydrogen, alkyl, aryl, OH, OR, OAr, NH₂NHR, NHAr, SH, SR, and SAr;

R¹⁵selected from the group consisting of H, alkyl, and substituted alkyl;

R¹⁶selected from the group consisting of alkyl, substituted alkyl, phenyl and substituted phenyl;

R²⁰is halogen or as for R³Defining;

d is either hydrogen or a halogen,

or a pharmaceutically acceptable salt of the compound.

3. A compound according to claim 1, wherein R²And R³Are formed together

Wherein X, D, D', D ", D *, Z are each independently selected from CH, C, O, S, NH, and N; and n is selected from 0, 1 and 2; and wherein R¹³And R¹⁴Each independently of the others as for R¹As defined; and R is¹³And R¹⁴At least one of (a) and (b) is halogen.

4. A compound according to claim 2, wherein R²⁰Is a halogen.

5. A composition comprising a compound according to any one of claims 1 to 4 and a carrier, diluent or excipient.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

7. A method for the treatment of a bacterial infection in a human, said method comprising administering to said human a therapeutically effective amount of a compound according to any one of claims 1 to 4.

8. A method for the prevention of a bacterial infection in a human, said method comprising administering to said human a prophylactically effective amount of a compound according to any one of claims 1 to 4.

9. A method for disinfecting bacteria on the surface of an object, including a human, the method comprising: selecting a surface area for disinfection and applying a compound according to any one of claims 1 to 4 to the surface of the object in an amount and for a time sufficient to obtain the desired degree of disinfection.

10. A method for sterilizing bacteria on the surface of an object, including a human, the method comprising: selecting an area of a sterilized surface and applying a compound according to any one of claims 1 to 4 to the surface of the object in an amount and for a time sufficient to obtain sterilization.

11. Use of a compound according to any one of claims 1 to 4 for the treatment or prophylaxis of a bacterial infection.

12. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment or prevention of a bacterial infection.

13. Use of a compound according to any one of claims 1 to 4 for disinfection.

14. Use of a compound according to any one of claims 1 to 4 for preserving.

15. Use of a compound according to any one of claims 1 to 4 for sterilization.