WO2007133803A2 - Traitement d'infections mycobactériennes - Google Patents

Traitement d'infections mycobactériennes Download PDF

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Publication number
WO2007133803A2
WO2007133803A2 PCT/US2007/011722 US2007011722W WO2007133803A2 WO 2007133803 A2 WO2007133803 A2 WO 2007133803A2 US 2007011722 W US2007011722 W US 2007011722W WO 2007133803 A2 WO2007133803 A2 WO 2007133803A2
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use according
present
medicament
mediated
compounds
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PCT/US2007/011722
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WO2007133803A3 (fr
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Joyce A. Sutcliffe
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Rib-X Pharmaceuticals, Inc.
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Publication of WO2007133803A2 publication Critical patent/WO2007133803A2/fr
Publication of WO2007133803A3 publication Critical patent/WO2007133803A3/fr

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42Oxazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • A61P31/06Antibacterial agents for tuberculosis

Definitions

  • the present invention relates to methods for treating, reducing the risk of, or preventing mycobacterial infections, for example infections caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria, using a safe and effective amount of an antibiotic compound.
  • Tuberculosis is a chronic, infectious disease that is caused by infection with Mycobacterium tuberculosis (M. tuberculosis). It is a major disease in developing countries, as well as an increasing problem in developed areas of the world, with about 8 million new cases and 3 million deaths each year. Although the infection may be asymptomatic for a considerable period of time, the disease is most commonly manifested as a chronic inflammation of the lungs, resulting in fever and respiratory symptoms. If left untreated, significant morbidity and death can result.
  • tuberculosis can generally be controlled, such treatment is not always sufficient to prevent the spread of the disease. Infected individuals may be asymptomatic, but contagious, for some time. Moreover, therapy usually requires long-term treatment (usually six to eight months), often using a combination of two or more drug actives, many of which have undesirable toxicities and side effects. Compliance with the treatment regimen is critical to success. Long treatment times outside the hospital environment make it difficult to monitor patient behavior. Consequently, some patients do not complete the course of treatment, which can lead to ineffective treatment and the development of drug resistant mycobacterial strains. The increasing incidence of resistant and highly virulent strains of M. tuberculosis is presenting a further public health concern.
  • the present invention relates to methods for treating, reducing the risk of, or preventing mycobacterial infections, for example infections caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria, using a safe and effective amount of an antibiotic compound.
  • the present invention provides compositions useful in the present invention and provides the use of an antibiotic compound in the manufacture of a medicament useful for treating, reducing the risk of, or preventing mycobacterial infections, for example infections caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria.
  • the present invention relates to the use of and compositions of antibiotic compounds of formula I:
  • R 2 is selected from OH and H; R 3 is selected from CH 2 CH 2 F and
  • R 4 is H; R 5 is C(O)CH 3 , or together R 4 and R 5 form " ⁇ ; and Re is selected from H
  • the present invention also relates to the use of such medicaments to treat, reduce the risk of and prevent mycobacterial infections.
  • the present invention relates to methods for treating, reducing the risk of, or preventing mycobacterial infections, for example infections caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria, using a safe and effective S amount of an antibiotic compound.
  • patient means the human or animal (in the case of an animal, more typically mammals and domestic animals) subject that would be considered to be in need of the methods of treating, reducing the risk of, or preventing an infection caused or 0 mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria.
  • the phrase "pharmaceutically acceptable” refers to those compounds, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • mycobacterial infection refers to, for example, an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculosis mycobacterium and in particular an infection caused or mediated by a resistant or highly virulent strain of a mycobacterium.
  • treating means to cure an already present infection caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria in a patient or subject.
  • preventing means, to completely or almost completely stop an infection caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria from occurring in a patient or subject, especially when the patient or subject is predisposed to such.
  • Preventing can also include inhibiting, i.e. arresting the development of, an infection caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria.
  • reducing the risk of means to lower the likelihood or probability of an infection caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria from occurring, especially when the patient or subject is predisposed to such occurrence.
  • the term "pharmaceutically effective amount” refers to an amount of a compound, or a combination of compounds, of the present invention effective when administered alone or in combination with other active ingredients are useful to treat, prevent, or reduce the risk of an infection caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria.
  • a pharmaceutically effective amount refers to an amount of the compound present in a formulation or on a medical device given to a recipient patient or subject sufficient to elicit biological activity, for example, activity against an infection caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria.
  • the combination of compounds optionally is a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. vol. 22, pp. 27-55 (1984), occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent.
  • Synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds.
  • Synergy can be in terms of lower cytotoxicity, increased antiproliferative and/or anti-infective effect, or some other beneficial effect of the combination compared with the individual components.
  • prophylactically effective amount means an effective amount of a compound or compounds, of the present invention that is administered to prevent or reduce the risk of an infection caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria — in other words, an amount to needed provide a preventative or prophylactic effect.
  • the terms "caused or mediated by” mean that the infection has some connection, relation, or etiology to the designated microorganism, i.e. Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria.
  • "Caused by” means that the designated microorganism is at least partially, but may be fully, responsible for initiation of the infection.
  • Mediated by means that the designated microorganism is at least partially, but may be fully, responsible for any worsening of the infection e.g., spread of the infection or increased severity.
  • topical and “topically” means that the antibiotic compounds of the present invention can alternatively be administered or applied to the skin of the patient or subject, or to other non-internal organs or parts of the patient or subject including, for example, the hair, fur, feathers, scales, shells, eyes, and ears.
  • the antibiotic compounds useful in the present invention the following terms can be applicable, however, it should be kept in mind that more specific definitions are also given in the references referred to and incorporated by reference herein:
  • the antibiotic compounds described herein can have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom can be isolated in optically active or racemic forms.
  • optically active forms such as by resolution of racemic forms or by synthesis from optically active starting materials.
  • Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic, and geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the antibiotic compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, N-methyl glutamic acid (i.e.
  • glycoHc glycollyarsanilic
  • hexylresorcinic hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauiyl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amino acids, e.g., glycine, alanine, phenylalanine, arginine, etc.
  • amino acids e.g., glycine, alanine,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990).
  • salts can include, but are not limited to, the hydrochloride and acetate salts of the aliphatic amine-containing, hydroxyl amine-containing, and imines-containing compounds of the present invention.
  • the compounds of the present invention for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
  • Nonlimiting examples of hydrates include monohydrates, dihydrates, etc.
  • Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.
  • the compounds of the present invention can also be prepared as esters, for example pharmaceutically acceptable esters.
  • a carboxylic acid function group in a compound can be converted to its corresponding ester, e.g., a methyl, ethyl, or other ester.
  • an alcohol group in a compound can be converted to its corresponding ester, e.g., an acetate, propionate, or other ester.
  • the compounds of the present invention can also be prepared as prodrugs, for example pharmaceutically acceptable prodrugs. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention can be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. "Prodrugs" are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
  • Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation, and as appropriate, purification from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components.
  • methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps.
  • steps or order for performing certain actions is immaterial so long as the invention remains operable.
  • two or more steps or actions can be conducted simultaneously.
  • the present invention relates to methods for treating infections caused or mediated by
  • Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria by administering to a patient in need thereof a safe and effective amount of an antibiotic compound.
  • the present invention relates to methods for preventing infections caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria by administering to a patient in need thereof a safe and effective amount of an antibiotic compound.
  • the present invention relates to methods for reducing the risk of infections caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria by administering to a patient in need thereof a safe and effective amount of an antibiotic compound.
  • nontuberculosis i.e.
  • mycobacteria include, inter alia, Mycobacterium avium (also MAC which is referred to as mycobacterial avium complex which is a combination of strains), Mycobacterium intracellular, MAC (, Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium fortuitum, Mycobacterium terrae, Mycobacterium xenopi, Mycobacterium simiae, Mycobacterium marinum, Mycobacterium szulgai, and Mycobacterium malmoense.
  • Mycobacterium avium also MAC which is referred to as mycobacterial avium complex which is a combination of strains
  • Mycobacterium intracellular MAC (, Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium fortuitum, Mycobacterium terrae, Mycobacterium xenopi, Mycobacterium simiae, Mycobacterium marinum, Mycobacterium
  • the antibiotic compounds of the present invention are useful for treating, preventing, or reducing the risk of these microbial infections.
  • the methods of the present invention can be usefully applied to patients, whether human or animal. More particularly it is found that the antibiotic agents useful herein generally are effective against the mycobacterial microorganisms of interest at relatively low concentrations, i.e. the compounds are relatively potent Consequently, these compounds have the potential advantage during administration of less undesired side effects and toxicities and undesired drug-drug interactions. This potential advantage can in turn mean that the compounds can be administered for relatively long durations and in combination with other agents. Therefore, the methods, compositions, and uses of the present invention have the potential for better safety, efficacy, and patient compliance relative to currently available therapies.
  • the tissue and/or blood level in the patient or subject, of the compound administered to provide the therapeutic effect be of an appropriate level for a sufficient time interval. Also, because it often takes a finite amount of time to achieve such blood or tissue levels, it is important that the compound is administered at some appropriate time. The appropriate time for administration of the compound will depend upon the pharmacokinetic profile of the compound and its formulation, route of administration, time required for completing administration, patient characteristics, desired clinical outcome, etc.
  • the antibiotic i.e. antimicrobial compounds or antibiotic agents useful herein are those that are particularly effective against infections caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria.
  • a wide range of antibiotic compounds can be used in the methods, compositions, and uses of the present invention. These antibiotic compounds can provide their therapeutic effect by a variety of biochemical or biophysical mechanisms.
  • Antibiotic compounds useful in the present invention can include those which bind to or modulate ribosomal RNA, for example bacterial ribosomal RNA.
  • Antibiotic compounds also useful in the present invention can include those which bind to or modulate the large ribosomal subunit, for example the large ribosomal subunit of a bacterial organism.
  • Nonlimiting classes of antibiotic compounds useful herein include oxazolidinone antibiotics and macrolide antibiotics.
  • Oxazolidinone antibiotics are characterized in having an oxazolidinone ring.
  • Macrolide antibiotics are characterized in having a macrocyclic ring, typically a 12-16-membered macrocyclic ring, more typically a 14- 15-membered macrocyclic ring.
  • the antibiotic compounds useful in the present invention can include their pharmaceutically acceptable salts, esters, or prodrugs thereof.
  • the invention further provides methods for synthesizing any one of the antibiotic compounds of the present invention.
  • the invention also provides pharmaceutical compositions comprising an effective amount of one or more of the antibiotic compounds of the present invention and a pharmaceutically acceptable carrier.
  • the present invention further provides methods for making these pharmaceutical compositions.
  • Nonlimiting examples of antibiotic compounds useful herein and their pharmaceutically salts, esters, and prodrugs thereof are disclosed in the documents cited in Table 1. These documents and their disclosures are incorporated by reference herein in their entirety.
  • the present invention relates to a method, composition, or use as described above wherein the antibiotic compound is selected from the group consisting of compounds as described in the documents of Table 1, or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • the present invention relates to a method of treating a mycobacterial infection in a patient comprising administering to the patient a pharmaceutically effective amount of an antibiotic compound of formula I: (I) or a pharmaceutically acceptable salt thereof, wherein R] is
  • R2 is selected from OH and H;
  • R 3 is selected from
  • R * is selected from H, and R * ;
  • R ⁇ is selected from OH and H;
  • R 3 is selected from
  • R ⁇ is selected from H and
  • R 2 is selected from OH and H; R 3 is selected from CH 2 CH 2 F and .
  • R 4 is H; R 5 is C(O)CH 3 , or together R 4 and R 5 form *** ; and Re is selected from H and
  • Rr U selected from H, and Rz ;
  • R 2 is selected from OH and H;
  • R 3 is selected from
  • Rf N' selected from H, and R * ;
  • R 2 is selected from OH and H;
  • R 3 is selected from
  • Re is selected from H and
  • R * is selected from H, and R * ;
  • R2 is selected from OH and H;
  • R 3 is selected from
  • R 4 is H
  • R 5 is C(O)CH 3 , or together R 4 and R 5 form
  • Re is selected from H and
  • the present invention relates to the use of an antibiotic compound in the manufacture of a medicament for treating a mycobacterial infection in a patient, wherein said medicament comprises an antibiotic compound of formula I: (I) or a pharmaceutically acceptable salt thereof, wherein Ri is
  • R 4 is H
  • R 5 is C(O)CH 3 , or together R 4 and R 5 form ;
  • Re is selected from H and
  • the present invention relates to the use of an antibiotic compound in the manufacture of a medicament for preventing a mycobacterial infection in a patient, wherein said medicament comprises a prophylactically effective amount of an antibiotic compound of formula I:
  • R 4 is H;
  • R 5 is C(O)CH 3 , or together R 4 and R 5 form ** ;
  • Re is selected from H and
  • the present invention relates to the use of an antibiotic compound in the manufacture of a medicament for reducing the risk of a mycobacterial infection in a patient, wherein said medicament comprises a prophylactically effective amount of an antibiotic compound of
  • Ri is selected from H, and is selected from OH and H; R 3 is
  • R 4 is H
  • R 5 is C(O)CH 3 , or together R 4 and R 5 form f-N 1
  • the present invention relates to a method, composition, or use as described above wherein the patient is a mammal or a domestic animal.
  • the present invention relates to a method, composition, or use as described above wherein the patient is a human.
  • the present invention relates to a medicament, wherein the medicament is to be administered to a human.
  • the present invention relates to a method, composition, or use as described above wherein the antibiotic compound is administered orally.
  • the present invention relates to a method, composition, or use as described above wherein the antibiotic compound is administered via inhalation.
  • the present invention relates to a method, composition, or use as described above wherein the antibiotic compound is administered topically.
  • the present invention relates to a medicament, wherein the medicament is administered orally.
  • the present invention relates to a medicament, wherein the medicament is administered via inhalation.
  • the present invention relates to a medicament, wherein the medicament is administered topically.
  • antibiotic compounds useful in the present invention include the following compounds shown in Table 2 below.
  • the present invention relates to a method, composition, or use as described above wherein the antibiotic compound is selected from the group consisting of:
  • the present invention relates to a method, composition, or use as described above wherein the antibiotic compound is:
  • the present invention relates to the use of this compound in the manufacture of a medicament.
  • the present invention relates to a method, composition, or use as describe above wherein the pharmaceutically acceptable salt is a hydrochloride salt.
  • the present invention relates to a method, composition, or use as described above wherein said hydrochloride salt is a monohydrochloride salt.
  • the present invention relates to a method, composition, or use as described above wherein the antibiotic compound comprises an amount per unit dosage selected from the group consisting of about 0.10 mg, about 0.15 mg, about 0.20 mg, about 0.25 mg, about 0.30 mg, about 0.35 mg, about 0.40 mg, about 0.45 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15, mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 100 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 175 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 225 mg, about 230 mg, about 240
  • the present invention relates to a method of administering an amount of an antibiotic compound dosage selected from the group consisting of about 0.10 mg, about 0.15 mg, about 0.20 mg, about 0.25 mg, about 0.30 mg, about 0.35 mg, about 0.40 mg, about 0.45 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15, mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 100 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 175 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg, about 275
  • the present invention relates to a method, composition, or use as described above wherein said antibiotic compound comprises an amount per unit dosage selected from the group consisting of about 0.1 mg to about 10 mg, from about 10 mg to about 50 mg, from about 50 mg to about 250 mg, from about 250 mg to about 500 mg, from about 500 mg to about 1000 mg, and from about 1000 mg to about 1500 mg.
  • the present invention relates to a method, composition, or use as described above wherein the antibiotic compound includes an amount per unit dosage selected from the group consisting of about 0.1 mg to about 10 mg, from about 10 mg to about 50 mg, from about 50 mg to about 250 mg, and from about 250 mg to about 450 mg.
  • the present invention relates to a method, composition, or use wherein the dosage of the antibiotic compound is less than 500 mg.
  • the present invention relates to a method, composition, or use wherein the dosage of the antibiotic compound is less than 450 mg.
  • the present invention relates to a method, composition, or use wherein the dosage of the antibiotic compound is less than 250 mg.
  • the present invention relates to a method, composition, or use as described above, further comprising an additional pharmaceutical agent, particularly, one or more compounds typically used for treating, preventing, or reducing the risk of an infection caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria.
  • the present invention relates to a method as described above further comprising an additional pharmaceutical agent, particularly, one or more compounds typically used for treating, preventing, or reducing the risk of an infection caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria.
  • the present invention relates to a composition as described above further comprising an additional pharmaceutical agent, particularly, one or more compounds typically used for treating, preventing, or reducing the risk of an infection caused or mediated by
  • Mycobacterium tuberculosis or nontuberculosis mycobacteria relates to a use as described above further comprising an additional pharmaceutical agent, particularly, one or more compounds typically used for treating, preventing, or reducing the risk of an infection caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria.
  • the present invention relates to a medicament as described above further comprising an additional pharmaceutical agent, particularly, one or more compounds typically used for treating, preventing, or reducing the risk of an infection caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria.
  • the present invention relates to a method, composition, or use as described above, wherein the infection is caused or mediated by resistant or highly virulent strains of mycobacteria.
  • the present invention relates to a medicament as described above, wherein the infection is caused or mediated by resistant or highly virulent strains of mycobacteria.
  • the present invention relates to a method, composition, or use as described above further comprising one or more additional pharmaceuticals agents selected from the group consisting of isoniazid, rifampin, rifapentine, rifabutin, ethambutol, pyrazinamide, cycloserine, ethionamide, levofloxacin, moxifloxacin, gatifloxacin, ⁇ -aminosalicylic acid, streptomycin, amikacin, kanamycin, capreomycin, PA-824, OPC-67683 and other nitroimidazole analogs, pleuromutilins, multifunctional antibiotics, peptide deformylase inhibitors, electron transport inhibitors, nonfluoroquinolone topoisomerase inhibitors, quinolones and fluoroquinolones, InhA inhibitors, riminophenazines, capuromycins, malate synthase inhibitors, protease inhibitors, proteasome
  • a useful compound herein is the monohydrochloride salt form of compound 1, shown in Table 2, above.
  • Antibiotic compounds designed, selected and/or optimized for use in the present invention, after being produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity.
  • the antibiotic compounds can be characterized by conventional assays, including but not limited to those assays described below, to determine whether the compounds have a predicted activity, binding activity and/or binding specificity.
  • high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to screen rapidly the molecules described herein for activity, for example as anti-bacterial. Also, it can be possible to assay how the compounds interact with a ribosome or ribosomal subunit and/or are effective as modulators (for example, inhibitors) of protein synthesis using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin, High Throughput Screening, (Marcel Dekker, 1998); and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.
  • SPR surface plasmon resonance
  • One device (BIAcore Biosensor RTM from Pharmacia Biosensor, Piscataway, N.J.) provides a focused beam of polychromatic light to the interface between a gold film (provided as a disposable biosensor "chip”) and a buffer compartment that can be regulated by the user.
  • a 100 nm thick "hydrogel" composed of carboxylated dextran that provides a matrix for the covalent immobilization of analytes of interest is attached to the gold film.
  • plasmon resonance is enhanced.
  • the resulting reflected light is spectrally depleted in wavelengths that optimally evolved the resonance.
  • the BIAcore establishes an optical interface which accurately reports the behavior of the generated surface plasmon resonance.
  • the plasmon resonance (and thus the depletion spectrum) is sensitive to mass in the evanescent field (which corresponds roughly to the thickness of the hydrogel). If one component of an interacting pair is immobilized to the hydrogel, and the interacting partner is provided through the buffer compartment, the interaction between the two components can be measured in real time based on the accumulation of mass in the evanescent field and its corresponding effects of the plasmon resonance as measured by the depletion spectrum. This system permits rapid and sensitive real-time measurement of the molecular interactions without the need to label either component.
  • Fluorescence polarization is a measurement technique that can readily be applied to protein-protein, protein-ligand, or RNA-ligand interactions in order to derive ICsos and Kds of the association reaction between two molecules.
  • one of the molecules of interest is conjugated with a fluorophore. This is generally the smaller molecule in the system (in this case, the compound of interest).
  • the sample mixture containing both the ligand-probe conjugate and the ribosome, ribosomal subunit or fragment thereof, is excited with vertically polarized light. Light is absorbed by the probe fluorophores, and re-emitted a short time later. The degree of polarization of the emitted light is measured.
  • Polarization of the emitted light is dependent on several factors, but most importantly on viscosity of the solution and on the apparent molecular weight of the fluorophore. With proper controls, changes in the degree of polarization of the emitted light depends only on changes in the apparent molecular weight of the fluorophore, which in-turn depends on whether the probe-ligand conjugate is free in solution, or is bound to a receptor. Binding assays based on FP have a number of important advantages, including the measurement of IC 50 S and Kds under true homogenous equilibrium conditions, speed of analysis and amenity to automation, and ability to screen in cloudy suspensions and colored solutions. (3) Protein Synthesis.
  • the compound of interest can also be characterized as a modulator (for example, an inhibitor of protein synthesis) of the functional activity of the ribosome or ribosomal subunit.
  • a modulator for example, an inhibitor of protein synthesis
  • more specific protein synthesis inhibition assays can be performed by administering the compound to a whole organism, tissue, organ, organelle, cell, a cellular or subcellular extract, or a purified ribosome preparation and observing its pharmacological and inhibitory properties by determining, for example, its inhibition constant (IC 50 ) for inhibiting protein synthesis.
  • IC 50 inhibition constant
  • a change in the amount or the rate of protein synthesis in the cell in the presence of a molecule of interest indicates that the molecule is a modulator of protein synthesis.
  • a decrease in the rate or the amount of protein synthesis indicates that the molecule is a inhibitor of protein synthesis.
  • the antibiotic compounds can be assayed for anti-proliferative or anti- infective properties on a cellular level.
  • the activity of compounds of interest can be assayed by growing the microorganisms of interest in media either containing or lacking the compound. Growth inhibition can be indicative that the molecule could be acting as a protein synthesis inhibitor.
  • the activity of the compounds of interest against bacterial pathogens can be demonstrated by the ability of the compound to inhibit growth of defined strains of human pathogens, particularly M. tuberculosis and nontuberculosis mycobacteria and resistant strains thereof.
  • a panel of bacterial strains can be assembled to include a variety of target pathogenic species, some containing resistance mechanisms that have been characterized. Use of such a panel of organisms permits the determination of structure-activity relationships not only in regards to potency and spectrum, but also with a view to obviating resistance mechanisms.
  • the assays can be performed in microtiter trays according to conventional methodologies as published by The National Committee for Clinical Laboratory Standards (NCCLS) guidelines [CLSI.
  • the methods of the present invention can be practiced by delivering the antibiotic compounds of the present invention using any suitable carrier.
  • the dose of antibiotic compound, mode of administration and use of suitable carrier will depend upon the intended patient or subject and the targeted microorganism, e.g., the target bacterial organism.
  • the formulations, both for human medical use and veterinary use, of the antibiotic compounds according to the present invention typically include such antibiotic compounds in association with a pharmaceutically acceptable carrier.
  • the carrier(s) should be "acceptable” in the sense of being compatible with compounds of the present invention and not deleterious to the recipient.
  • Pharmaceutically acceptable carriers are intended to include any and all solvents, dispersion media, coatings, absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the antibiotic compound, use thereof in the compositions is contemplated. Supplementary antibiotic compounds (identified or designed according to the invention and/or known in the art) also can be incorporated into the compositions.
  • the formulations can conveniently be presented in dosage unit form and can be prepared by any of the methods well known in the art of pharmacy/microbiology. In general, some formulations are prepared by bringing the compound into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • a pharmaceutical composition of the invention can be formulated to be compatible with its intended route of administration. These can include solids and semisolids. Solutions or suspensions can include the following components: a sterile diluent such as water, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl parabens
  • antioxidants such as ascorbic acid or sodium bisul
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • acids or bases such as hydrochloric acid or sodium hydroxide.
  • a wide variety of formulations and administration methods can be found in S.K. Niazi, ed., Handbook of Pharmaceutical Formulations, VoIs. 1-6 [Vol. 1 Compressed Solid Products, Vol. 2 Uncompressed Drug Products, Vol. 3 Liquid Products, Vol.4 Semi-Solid Products, Vol. 5 Over the Counter Products, and Vol. 6 Sterile Products], CRC Press, April 27, 2004.
  • Useful solutions for oral or parenteral administration can be prepared by any of the methods well known in the pharmaceutical art, described, for example, in Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990).
  • Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • Suppositories for rectal administration also can be prepared by mixing the drug with a non-irritating excipient such as cocoa butter, other glycerides, or other compositions which are solid at room temperature and liquid at body temperatures.
  • Formulations also can include, for example, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, and hydrogenated naphthalenes.
  • Formulations for direct administration can include glycerol and other compositions of high viscosity.
  • Other potentially useful parenteral carriers for these drugs include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation administration can contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally.
  • Retention enemas also can be used for rectal delivery.
  • Formulations of the present invention suitable for oral administration can be in the form of: discrete units such as capsules, gelatin capsules, sachets, tablets, troches, or lozenges, each containing a predetermined amount of the drug; a powder or granular composition; a solution or a suspension in an aqueous liquid or non-aqueous liquid; or an oil-in-water emulsion or a water-in-oil emulsion.
  • the drug can also be administered in the form of a bolus, electuary or paste.
  • a tablet can be made by compressing or molding the drug optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared by compressing, in a suitable machine, the drug in a free-flowing form such as a powder or granules, optionally mixed by a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding, in a suitable machine, a mixture of the powdered drug and suitable carrier moistened with an inert liquid diluent
  • Oral compositions generally include an inert diluent or an edible carrier.
  • the antibiotic compound can be incorporated with excipients.
  • Oral compositions prepared using a fluid carrier for use as a mouthwash include the compound in the fluid carrier and are applied orally and swished and expectorated or swallowed.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disinte grating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose
  • a disinte grating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol), 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.
  • isotonic agents for example, sugars, polyalcohols such as manitol, 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, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the antibiotic compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization.
  • dispersions are prepared by incorporating the antibiotic compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • methods of preparation include 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.
  • Formulations suitable for intra-articular administration can be in the form of a sterile aqueous preparation of the drug that can be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension.
  • Liposomal formulations or biodegradable polymer systems can also be used to present the drug for both intra-articular and ophthalmic administration.
  • Formulations suitable for topical administration, including eye treatment include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in- oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops.
  • Formulations for topical administration to the skin surface can be prepared by dispersing the drug with a dermatologically acceptable carrier such as a lotion, cream, ointment or soap.
  • a dermatologically acceptable carrier such as a lotion, cream, ointment or soap.
  • the agent can be dispersed in a liquid tissue adhesive or other substance known to enhance adsorption to a tissue surface.
  • tissue-coating solutions such as pectin-containing formulations can be used.
  • the carrier for a topical formulation can be in the form of a hydroalcoholic system (e.g. liquids and gels), an anhydrous oil or silicone based system, or an emulsion system, including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and oil-in-water-in-silicone emulsions.
  • a hydroalcoholic system e.g. liquids and gels
  • an anhydrous oil or silicone based system emulsion system
  • emulsion system including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and oil-in-water-in-silicone emulsions.
  • the emulsions can cover a broad range of consistencies including thin lotions (which can also be suitable for spray or aerosol delivery), creamy lotions, light creams, heavy creams, and the like.
  • the emulsions can also include microemulsion systems
  • topical carriers include anhydrous solids and semisolids (such as gels and sticks); and aqueous based mousse systems.
  • topical carrier systems useful in the present invention are described in the following four references, all of which are incorporated herein by reference in their entirety: "Sun Products Formulary”, Cosmetics & Toiletries, vol. 105, pp. 122-139 (December 1990); “Sun Products Formulary”, Cosmetics & Toiletries, vol. 102, pp. 117-136 (March 1987); U.S. Pat. No. 4,960,764 to Figueroa et al., issued Oct 2, 1990; and U.S. Pat. No. 4,254,105 to Fukuda et al., issued Mar. 3, 1981.
  • the pharmaceutically-acceptable topical carriers typically comprise from about 0.1% to about 99.8% by weight of the compositions useful in the present invention, preferably from about 80% to about 99%, and most preferably from about 85% to about 95%.
  • inhalation of powder (self-propelling or spray formulations) dispensed with a spray can a nebulizer, or an atomizer can be used.
  • Such formulations can be in the form of a fine powder for pulmonary administration from a powder inhalation device or self-propelling powder-dispensing formulations.
  • self-propelling solution and spray formulations the effect can be achieved either by choice of a valve having the desired spray characteristics (i.e., being capable of producing a spray having the desired particle size) or by incorporating the active ingredient as a suspended powder in controlled particle size.
  • the compounds also can be delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration also can be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants generally are known in the art, and include, for example, for transmucosal administration, detergents and bile salts.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the antibiotic compounds typically are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the antibiotic compounds can be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • 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, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.
  • Oral or parenteral compositions can be formulated in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of antibiotic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the antibiotic compound and the therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an antibiotic compound for the treatment of individuals.
  • administration can be by periodic injections of a bolus, or can be made more continuous by intravenous, intramuscular or intraperitoneal administration from an external reservoir (e.g., an intravenous bag).
  • the composition can include the drug dispersed in a fibrinogen-thrombin composition or other bioadhesive.
  • the compound then can be painted, sprayed or otherwise applied to the desired tissue surface.
  • the drugs can be formulated for parenteral or oral administration to humans or other mammals, for example, in effective amounts, e.g., amounts that provide appropriate concentrations of the drug to target tissue for a time sufficient to induce the desired effect.
  • pharmacogenomics i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug
  • Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug.
  • a physician or clinician can consider applying knowledge obtained in relevant pharmacogenomics studies in determining whether to administer a drug as well as tailoring the dosage and/or therapeutic regimen of treatment with the drug.
  • an effective amount of dosage of antibiotic compound will be in the range of from about 0.01 to about 100 mg/kg of body weight/day.
  • the amount administered will also likely depend on such variables as the condition to be treated, the severity of the condition, the age and overall health status of the patient, the relative biological efficacy of the compound delivered, the formulation of the compound, the presence and types of excipients in the formulation, and the route of administration. Also, it is to be understood that the initial dosage administered can be increased beyond the above upper level in order to rapidly achieve the desired tissue level or blood level, or the initial dosage can be smaller than the optimum.
  • Nonlimiting doses of antibiotic comprise from about 0.1 mg to about 1500 mg per unit dose.
  • Nonlimiting examples of doses, which can be formulated as a unit dose for convenient administration to a patient include those selected from the group consisting of: about 0.10 mg, about 0.15 mg, about 0.20 mg, about 0.25 mg, about 0.30 mg, about 0.35 mg, about 0.40 mg, about 0.45 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15, mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 100 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 175 mg, about 180 mg, about 190 mg, about 200 mg, about
  • Other useful ranges are from about 0.1 mg to about 10 mg, from about 10 mg to about 50 mg, from about 50 mg to about 250 mg, from about 250 mg to about 500 mg, from about 500 mg to about 1000 mg, and from about 1000 mg to about 1500 mg.
  • the foregoing doses are useful for administering the compounds of the present invention according to the methods of the present invention.
  • the dosage is given on the basis of the parent or active moiety. Therefore, if a salt, hydrate, or another form of the parent or active moiety is used, a corresponding adjustment in the weight of the compound is made, although the dose is still referred to on the basis of the parent or active moiety delivered.
  • the parent or active moiety of interest is a monocarboxylic acid having a molecular weight of 250, and if the monosodium salt of the acid is desired to be delivered to be delivered at the same dosage, then an adjustment is made recognizing that the monosodium salt would have a molecular weight of approximately 272 (i.e.
  • a 250 mg dosage of the parent or antibiotic compound would correspond to about 272 mg of the monosodium salt, which would also deliver 250 mg of the parent or antibiotic compound. Said another way, about 272 mg of the monosodium salt would be equivalent to a 250 mg dosage of the parent or antibiotic compound.
  • the present invention relates to a method composition or use further comprising an additional pharmaceutical agent, particularly, one or more compounds typically used for treating, preventing, or reducing the risk of an infection caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria.
  • an additional pharmaceutical agent particularly, one or more compounds typically used for treating, preventing, or reducing the risk of an infection caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria.
  • Nonlimiting examples of such compounds include, e.g., isoniazid, rifampin, rifapentine, rifabutin, ethambutol, pyrazinamide, cycloserine, ethionamide, levofioxacin, moxifloxacin, gatifloxacin, ⁇ -aminosalicylic acid, streptomycin, amikacin, kanamycin, capreomycin, PA-824, OPC-67683 and other nitroimidazole analogs, pleuromutilins, multifunctional antibiotics, peptide deformylase inhibitors, electron transport inhibitors, nonfluoroquinolone topoisomerase inhibitors, quinolones and fluoroquinolones, InhA inhibitors, riminophenazines, capuromycins, malate synthase inhibitors, protease inhibitors, proteasome inhibitors, SQ- 109 and other diamine analogs, or a
  • compositions useful in the present invention can also be incorporated.
  • Vitamin B6 - Vitamin B6 can be used in combination with the compounds used in the present invention, as it is used for alleviating the associated numbness and tingling in the hands and feet
  • NSAIDS and Steroidal Anti-Inflammatory Drugs are non-steroidal anti-inflammatory drugs (NSAIDS).
  • the NSAIDS can be selected from the following categories: propionic acid derivatives; acetic acid derivatives; fenamic acid derivatives; biphenylcarboxylic acid derivatives; and oxicams. All of these NSAIDS are fully described in the U.S. Pat. No. 4,985,459 to Sunshine et al., issued Jan. 15, 1991 , incorporated by reference herein.
  • propionic NSAIDS including but not limited to aspirin, acetaminophen, ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen and bucloxic acid.
  • steroidal anti-inflammatory drugs including hydrocortisone and the like.
  • compositions useful in the methods of the present invention can optionally comprise one or more surfactants.
  • the surfactants can be present at a level from about 0.1% to about 10%, alternatively from about 0.2% to about 5%, and yet alternatively from about 0.2% to about 2.5%.
  • Suitable surfactants include, but are not limited to, nonionic surfactants such as polyalkylene glycol ethers of fatty alcohols, and anionic surfactants such as taurates and alkyl sulfates.
  • nonionic surfactants such as polyalkylene glycol ethers of fatty alcohols
  • anionic surfactants such as taurates and alkyl sulfates.
  • Nonlimiting examples of these surfactants include isoceteth-20, sodium methyl cocoyl taurate, sodium methyl oleoyl taurate, and sodium lauryl sulfate. See U.S. Pat. No.
  • Antibiotic Compound any of compounds of formula I 0.1 - 1500 mg 0.4 - 6000 g or Compounds 1-5)
  • the antibiotic compound (e.g., any of the compounds of formula I or any of
  • Compounds 1-5, or a pharmaceutically acceptable salt, ester or prodrug thereof), equivalent to the desired delivery strength, e.g., 0.1 to 1500 mg per tablet) is premixed with 1/3 of the microcrystalline cellulose NF and 1/2 of the anhydrous lactose NF in a ribbon blender for 5 minutes at 20 RPM. To the premix is added the remaining 2/3 of the microcrystalline cellulose NF and the remaining 1/2 of the anhydrous lactose NF. This is blended for 10 minutes at 20 RPM. Crosscarmellose sodium is added to the blended powders and mixed for 5 minutes at 20 RPM. Finally the magnesium stearate is added to the mixture by passing through a 90 mesh screen and blended for an additional 5 minutes at 20 RPM. The lubricated mixture is compressed to provide tablets containing 0.1-1500 mg active ingredient per tablet.
  • These tablets are useful for administration to a patient for treating, preventing, or reducing the risk of infections caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria.
  • These tablets are useful for the manufacture of a medicament for treating, preventing, or reducing the risk of infections caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria
  • Formulations above are based per each ml of volume.
  • the antibiotic compound (e.g., any of the compounds of formula I or any of Compounds 1-5, or a pharmaceutically acceptable salt, ester or prodrug thereof) is dissolved with stirring in the ethanol, and if needed, the solution is gently heated to aid dissolution. Next the glycerin is added with stirring. The sucrose and sodium benzoate are added to about 50 ml of water and stirred to dissolve. The ethanol mixture is then added to the aqueous mixture with stirring and the remaining water is added to achieve a final volume of 100 ml.
  • This liquid composition is useful for administration to a patient for treating, preventing, or reducing the risk of infections caused or mediated by Mycobacterium tuberculosis or nontuberculosis mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria.

Abstract

La présente invention concerne des méthodes de traitement, de réduction du risque et de prévention d'infections mycobactériennes, telles que les infections causées ou médiées par Mycobacterium tuberculosis ou les mycobactéries non tuberculeuses, et notamment les infections causées ou médiées par les souches mycobactériennes résistantes ou hautement virulentes, au moyen d'une dose sûre et efficace d'un composé antibiotique.
PCT/US2007/011722 2006-05-15 2007-05-15 Traitement d'infections mycobactériennes WO2007133803A2 (fr)

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WO2011139832A2 (fr) * 2010-04-28 2011-11-10 Rib-X Pharmaceuticals, Inc. Méthode de traitement des infections mycobactériennes
KR101791709B1 (ko) * 2009-10-13 2017-10-30 멜린타 테라퓨틱스, 인크. 약학 조성물
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US10144741B2 (en) 2014-10-22 2018-12-04 Merck Sharp & Dohme Corp. Nargenicin compounds and uses thereof as antibacterial agents

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