combination

Abstract

In particular, the present invention relates to the treatment of nontuberculous mycobacteria-associated disease in humans with epetravorole.

Description

Detailed Description of the Invention

[0001] [Priority claim] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 286,989, filed December 7, 2021, and U.S. Provisional Application Serial No. 63 / 416,059, filed October 14, 2022. Each of these U.S. provisional applications is incorporated herein by reference in its entirety.

[0002] BACKGROUND OF THEINVENTION Nontuberculous mycobacterial (NTM) infections are increasing in humans. Standard treatment requires 18–24 months of treatment with at least three antibiotics. Despite this, treatment outcomes remain poor.

[0003] A new treatment for infection with NTM would represent an advancement in the art.

[0004] Summary of the Invention In a first aspect, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; ethambutol to a human; thereby treating nontuberculous mycobacterial infections in humans; This is the method.

[0005] In a second aspect, the present invention provides a method of treating a nontuberculous mycobacteria-associated disease in a human, the method comprising: epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof; ethambutol to a human; thereby treating nontuberculous mycobacteria-associated disease in humans; This is the method.

[0006] Detailed Description of the Invention I. Definitions and Abbreviations In order to more fully understand this application, several definitions are provided below. Such definitions are intended to encompass all grammatical equivalents.

[0007] The term "about" in connection with a numerical value can include the numerical value itself as well as a range of values ​​from that numerical value plus or minus 10%. For example, the amount "about 10" includes 10 and any amount between 9 and 11. For example, the term "about" in connection with a numerical value can also include ranges of values ​​from the numerical value plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.

[0008] Certain embodiments disclosed herein may be further limited in the claims using the terms "consisting of" or "consisting essentially of." When used in a claim, whether as filed or added by amendment, the transitional term "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional term "consisting essentially of" limits the claim to the materials or steps specified and those materials or steps that do not materially affect the basic and novel characteristics. The embodiments of the disclosure described in the claims are essentially or explicitly described and operative in the present specification.

[0009] As used in the context of describing this disclosure (particularly in the context of the claims which follow), the terms "a," "an," "the," and similar reference words are intended to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0010] The abbreviations used herein generally have their conventional meaning within the chemical and biological arts.

[0011] The following abbreviations are used: AMK-amikacin; ATCC-American Type Culture Collection; CA-MHB-cation adjusted Mueller Hinton broth; CFU-colony forming units; CLSI-Clinical and Laboratory Standards Institute; CLR-clarithromycin; EBO-epetravorole hydrochloride; EMB-ethambutol; IC-inhibitory concentration; LeuRS-leucyl-tRNA synthetase; MAC-Mycobacterium avium complex; MIC-minimum inhibitory concentration; NTM-nontuberculous mycobacteria; OADC-oleic acid, bovine albumin, glucose, and catalase; RFB-rifabutin; spp.-species; subspp.-subspecies.

[0012] As used herein, "epetravorol of the present invention" refers to epetravorol, salts (e.g., pharma- ceutically acceptable salts), solvates, and hydrates of these compounds.

[0013] "Moiety" refers to a radical of a molecule that is attached to the remainder of the molecule.

[0014] symbol

[0015] [ka]

[0016] indicates the point at which the displayed moiety is attached to the remainder of the molecule, whether utilized as a bond or displayed perpendicular to a bond.

[0017] The term "pharmaceutical acceptable salt" is meant to include salts of the epetravorole of the present invention prepared using relatively non-toxic acids or bases depending on the specific substituents found on the compounds described herein. When the epetravorole of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutical acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino (choline, or diethylamine, or amino acids such as d-arginine, l-arginine, d-lysine or l-lysine), or magnesium salts, or similar salts. When the epetravorole of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and the like, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginates, and salts of organic acids such as glucuronic acid or galactunoric acid (see, e.g., Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0018] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0019] In addition to salt forms, the present invention provides compounds in the form of prodrugs. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment.

[0020] Certain compounds of the present invention can exist not only in unsolvated form but also in solvated form, including hydrated form. In general, solvated forms are equivalent to unsolvated forms and are within the scope of the present invention. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms.

[0021] Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the present invention. Graphical representations of racemic, ambiscalemic and scalemic compounds, or enantiomerically pure compounds used herein are described in Maehr, J. Chem. Ed. 1985, 62: 114-120. Solid or broken wedges are used to indicate the absolute configuration of stereocenters, unless otherwise indicated. Where the compounds described herein are centers of olefinic double bonds or other geometric asymmetry, and unless otherwise indicated, the compounds are intended to include both E and Z geometric isomers. Similarly, all tautomers are included.

[0022] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention intends that all such compounds are included within the scope of the present invention, including cis and trans isomers, (-) and (+) enantiomers, (R) and (S) enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures thereof, and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures. Additional asymmetric carbon atoms may be present in a substituent, such as an alkyl group. All such isomers and mixtures thereof are intended to be included in the present invention.

[0023] Optically active (R) and (S) isomers, as well as d and l isomers, can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. For example, if a particular enantiomer of a compound of the present invention is desired, said enantiomer can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, the resulting diastereomeric mixture separated, and the auxiliary cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino group, or an acidic functional group, such as a carboxyl group, a diastereomeric salt can be formed with an appropriate optically active acid or base, and the diastereomers thus formed can then be resolved by fractional crystallization or chromatographic means known in the art, after which the pure enantiomers can be recovered. Furthermore, separation of enantiomers and diastereomers is frequently achieved using chromatography with chiral stationary phases, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).

[0024] The compounds of the present invention may also contain unconventional proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain tritium ( 3 H), Iodine-125( 125 I), or carbon-14 ( 14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0025] The term "pharmaceutical acceptable carrier" or "pharmaceutical acceptable vehicle" refers to any formulation or carrier medium that provides suitable delivery of an effective amount of an active agent, as defined herein, does not interfere with the effectiveness of the biological activity of the active agent, and is sufficiently non-toxic to the host or patient. Representative carriers include water, both vegetable and mineral oils, cream bases, lotion bases, ointment bases, and the like. These bases include suspending agents, thickening agents, penetration enhancers, and the like. These formulations are well known to those skilled in the art of cosmetics and topical pharmaceuticals. Additional information regarding carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), which is incorporated herein by reference.

[0026] The term "excipient" is conventionally known to mean a carrier, diluent and / or vehicle used in formulating a pharmaceutical composition effective for a desired use.

[0027] The term "microbial infection" or "infection by a microorganism" refers to an infection of a host tissue by an infectious agent, including, but not limited to, bacteria or protozoa (e.g., Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al., eds., 12th ed. 1991); Williams et al., J. of Medicinal Chem. 42:1481- 1485 (1999), each of which is incorporated herein by reference in its entirety).

[0028] As used herein, "biological medium" refers to both in vitro and in vivo biological media. Exemplary in vitro "biological media" include, but are not limited to, cell culture, tissue culture, homogenate, plasma and blood. In vivo applications are generally performed in mammals, preferably humans.

[0029] "Inhibit" and "block" are used interchangeably herein to refer to the partial or complete blocking of an enzyme. In an exemplary embodiment, the enzyme is a tRNA synthetase.

[0030] Boron, in the present invention, can under certain circumstances form additional covalent or divalent bonds with oxygen, sulfur or nitrogen.

[0031] Embodiments of the invention also include compounds that are poly- or multi-valent species, including, for example, species such as dimers, trimers, tetramers and higher order homologs of the compounds used in the invention, or reactive analogs thereof.

[0032] "Salt counterion" as used herein refers to a positively charged ion that is associated with the compounds of the present invention when boron is fully or partially negatively charged. Examples of salt counterions include H + , H3O + , ammonium, potassium, calcium, magnesium (such as choline, or diethylamine, or amino acids such as d-arginine, l-arginine, d-lysine, or l-lysine), and sodium.

[0033] Compounds containing boron bonded to carbon and three heteroatoms (such as the three oxygens discussed in this section) can optionally contain a fully negatively charged boron or a partially negatively charged boron. This negative charge can cause a positively charged counterion to associate with the compound and form a salt. An example of a salt counterion is H. +, H3O + , ammonium, potassium, calcium, magnesium (such as choline, or diethylamine, or amino acids such as d-arginine, l-arginine, d-lysine, or l-lysine), and sodium. Salts of compounds are implicit in the description of these compounds.

[0034] As used herein, a "treatment-resistant" infection refers to an infection in humans in which sputum cultures remain positive for nontuberculous mycobacteria even after six months of treatment with azithromycin (or clarithromycin), rifampicin (or rifabutin), and ethambutol.

[0035] (II. Introduction) Epetravorole has been found to be useful in the treatment of certain nontuberculous mycobacterial infections. Additionally, a combination of epetravorole and ethambutol has been found to be useful in the treatment of certain nontuberculous mycobacterial infections.

[0036] III.Compound Epetravorol or its salts, hydrates, or solvates Epetraborole has a structure according to the following formula:

[0037] [ka]

[0038] Epetravorole can be prepared according to methods such as those disclosed in PCT Patent Publication No. WO2008 / 157726 (PCT Patent Application No. PCT / US2008 / 07550); U.S. Patent No. 7,816,344 (U.S. Patent Application No. 12 / 142,692); PCT Patent Publication No. WO2011 / 127143 (Patent Application No. PCT / US2011 / 031384); and U.S. Patent No. 9,243,003 (U.S. Patent Application No. 13 / 639,594).

[0039] Epetraborole may form hydrates with water; may form solvates with alcohols such as methanol, ethanol, propanol, etc.; may form adducts with amino compounds such as ammonia, methylamine, ethylamine, etc.; may form adducts with acids such as formic acid, acetic acid, etc.; may form complexes with ethanolamine, quinoline, amino acids, etc.

[0040] In an exemplary embodiment, the invention provides epetravorol, or a salt, hydrate, or solvate thereof, or a combination thereof. In an exemplary embodiment, the invention provides epetravorol, or a salt, hydrate, or solvate thereof. In an exemplary embodiment, the invention provides epetravorol, or a salt thereof. In an exemplary embodiment, the salt is a pharma- ceutically acceptable salt. In an exemplary embodiment, the invention provides the hydrochloride salt of epetravorol.

[0041] In an exemplary embodiment, the invention provides epetravorole, or a hydrate thereof.In an exemplary embodiment, the invention provides epetravorole, or a solvate thereof.

[0042] Standard treatment for NTM infections According to published recommendations, NTM infections in humans can be treated with a combination of ethambutol, rifampin or rifabutin, and a macrolide (clarithromycin or azithromycin).

[0043] Ethambutol or its salts, hydrates, or solvates Ethambutol has a structure according to the following formula:

[0044] [ka]

[0045] Ethambutol is produced commercially by a number of manufacturers, including Sanofi, Cadila, Lupin, and Delmar.

[0046] Rifampin or its salts, hydrates, or solvates Rifampin, also known as rifampicin, is produced commercially by a number of manufacturers, including Novartis, Otto Brandes, Arudavis Labs, and Sichuan Long March Pharma.

[0047] Rifabutin, or a salt, hydrate or solvate thereof Rifabutin is commercially produced by a number of manufacturers, including Pfizer, Chongqing Huapont Pharma, Lupin, and Guangzhou Tosun Pharma.

[0048] Macrolides (clarithromycin or azithromycin) Clarithromycin is produced commercially by a number of manufacturers, including Sandoz, Century Pharmaceuticals, Teva, Wockhardt, and Alembic.

[0049] Azithromycin is produced commercially by a number of manufacturers, including Pfizer, Sandoz, Teva, Alembic, and Lupin.

[0050] Synergistic effect of epetravorol and ethambutol A synergistic effect between epetravorole and ethambutol was discovered, allowing for more effective treatment of NTM infections.

[0051] (IV. Method) In another aspect, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; ethambutol, or a hydrate, solvate, or salt thereof, to a human; Thereby, a method for treating nontuberculous mycobacterial infections in humans.

[0052] In an exemplary embodiment, the method further comprises administering a rifamycin, or a hydrate, solvate, or salt thereof, to the human. In an exemplary embodiment, the rifamycin is rifampicin (rifampin), or a hydrate, solvate, or salt thereof. In an exemplary embodiment, the rifamycin is rifabutin, or a hydrate, solvate, or salt thereof. In an exemplary embodiment, the rifamycin is rifapentine, or a hydrate, solvate, or salt thereof. In an exemplary embodiment, the rifamycin is rifaximin, or a hydrate, solvate, or salt thereof. In an exemplary embodiment, the method further comprises administering a macrolide, or a hydrate, solvate, or salt thereof, to the human. In an exemplary embodiment, the macrolide is clarithromycin, or a hydrate, solvate, or salt thereof. In an exemplary embodiment, the macrolide is azithromycin, or a hydrate, solvate, or salt thereof. In an exemplary embodiment, the epetravorol is a salt of epetravorol, and the salt is a pharma- ceutically acceptable salt. In an exemplary embodiment, the epetravorol is the hydrochloride salt of epetravorol. In an exemplary embodiment, the nontuberculous mycobacteria is M. intracellulare or M. avium. In an exemplary embodiment, in the method of any of this paragraph, no rifamycin, or any hydrate, solvate, or salt thereof, is administered to the human. In an exemplary embodiment, in the method of any of this paragraph, no rifabutin, or any hydrate, solvate, or salt thereof, is administered to the human. In an exemplary embodiment, in the method of any of this paragraph, no macrolide, or any hydrate, solvate, or salt thereof, is administered to the human. In an exemplary embodiment, in the method of any of this paragraph, no azithromycin, or any hydrate, solvate, or salt thereof, is administered to the human. In an exemplary embodiment, in the method of any of this paragraphs, clarithromycin, or any of its hydrates, solvates, or salts, is not administered to a human.

[0053] In another aspect, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; Ethambutol, or a hydrate, solvate, or salt thereof; rifamycin, or a hydrate, solvate, or salt thereof, to a human; thereby treating a nontuberculous mycobacterial infection in a human. In an exemplary embodiment, the nontuberculous mycobacterium is M. intracellulare or M. avium.

[0054] In another aspect, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; Ethambutol, or a hydrate, solvate, or salt thereof; rifabutin, or a hydrate, solvate, or salt thereof, to a human; thereby treating a nontuberculous mycobacterial infection in a human. In an exemplary embodiment, the nontuberculous mycobacterium is M. intracellulare or M. avium.

[0055] In another aspect, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; Ethambutol, or a hydrate, solvate, or salt thereof; a macrolide, or a hydrate, solvate, or salt thereof, to a human; thereby treating a nontuberculous mycobacterial infection in a human. In an exemplary embodiment, the nontuberculous mycobacterium is M. intracellulare or M. avium.

[0056] In another aspect, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; Ethambutol, or a hydrate, solvate, or salt thereof; and clarithromycin, or a hydrate, solvate, or salt thereof, to a human; thereby treating a nontuberculous mycobacterial infection in a human. In an exemplary embodiment, the nontuberculous mycobacterium is M. intracellulare or M. avium.

[0057] In another aspect, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; Ethambutol, or a hydrate, solvate, or salt thereof; azithromycin, or a hydrate, solvate, or salt thereof, to a human; thereby treating a nontuberculous mycobacterial infection in a human. In an exemplary embodiment, the nontuberculous mycobacterium is M. intracellulare or M. avium.

[0058] In another aspect, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; Ethambutol, or a hydrate, solvate, or salt thereof; a rifamycin, or a hydrate, solvate, or salt thereof; a macrolide, or a hydrate, solvate, or salt thereof, to a human; thereby treating a nontuberculous mycobacterial infection in a human. In an exemplary embodiment, the nontuberculous mycobacterium is M. intracellulare or M. avium.

[0059] In another aspect, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; Ethambutol, or a hydrate, solvate, or salt thereof; a rifamycin, or a hydrate, solvate, or salt thereof; and clarithromycin, or a hydrate, solvate, or salt thereof, to a human; thereby treating a nontuberculous mycobacterial infection in a human. In an exemplary embodiment, the nontuberculous mycobacterium is M. intracellulare or M. avium.

[0060] In another aspect, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; Ethambutol, or a hydrate, solvate, or salt thereof; a rifamycin, or a hydrate, solvate, or salt thereof; azithromycin, or a hydrate, solvate, or salt thereof, to a human; thereby treating a nontuberculous mycobacterial infection in a human. In an exemplary embodiment, the nontuberculous mycobacterium is M. intracellulare or M. avium.

[0061] In another aspect, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; Ethambutol, or a hydrate, solvate, or salt thereof; Rifabutin, or a hydrate, solvate, or salt thereof; a macrolide, or a hydrate, solvate, or salt thereof, to a human; thereby treating a nontuberculous mycobacterial infection in a human. In an exemplary embodiment, the nontuberculous mycobacterium is M. intracellulare or M. avium.

[0062] In another aspect, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; Ethambutol, or a hydrate, solvate, or salt thereof; Rifabutin, or a hydrate, solvate, or salt thereof; and clarithromycin, or a hydrate, solvate, or salt thereof, to a human; thereby treating a nontuberculous mycobacterial infection in a human. In an exemplary embodiment, the nontuberculous mycobacterium is M. intracellulare or M. avium.

[0063] In another aspect, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; Ethambutol, or a hydrate, solvate, or salt thereof; Rifabutin, or a hydrate, solvate, or salt thereof; azithromycin, or a hydrate, solvate, or salt thereof, to a human; thereby treating a nontuberculous mycobacterial infection in a human. In an exemplary embodiment, the nontuberculous mycobacterium is M. intracellulare or M. avium.

[0064] In an exemplary embodiment, the invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; rifamycin, or a hydrate, solvate, or salt thereof, to a human; In an exemplary embodiment, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; rifabutin, or a hydrate, solvate, or salt thereof, to a human; In an exemplary embodiment, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; a macrolide, or a hydrate, solvate, or salt thereof, to a human; In an exemplary embodiment, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; and clarithromycin, or a hydrate, solvate, or salt thereof, to a human; In an exemplary embodiment, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; azithromycin, or a hydrate, solvate, or salt thereof, to a human; In an exemplary embodiment, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; a rifamycin, or a hydrate, solvate, or salt thereof; a macrolide, or a hydrate, solvate, or salt thereof, to a human; In an exemplary embodiment, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; Ethambutol, or a hydrate, solvate, or salt thereof; a rifamycin, or a hydrate, solvate, or salt thereof; and clarithromycin, or a hydrate, solvate, or salt thereof, to a human; In an exemplary embodiment, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; Ethambutol, or a hydrate, solvate, or salt thereof; a rifamycin, or a hydrate, solvate, or salt thereof; azithromycin, or a hydrate, solvate, or salt thereof, to a human; In an exemplary embodiment, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; Rifabutin, or a hydrate, solvate, or salt thereof; a macrolide, or a hydrate, solvate, or salt thereof, to a human; In an exemplary embodiment, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; and clarithromycin, or a hydrate, solvate, or salt thereof, to a human; In an exemplary embodiment, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; azithromycin, or a hydrate, solvate, or salt thereof, to a human; thereby treating a nontuberculous mycobacterial infection in a human. In an exemplary embodiment, the nontuberculous mycobacterium is M. intracellulare or M. avium. In an exemplary embodiment, for any of the methods of this paragraph, ethambutol, or a hydrate, solvate, or salt thereof, is not administered to the human.

[0065] In another aspect, the present invention provides a method of treating a nontuberculous mycobacterial infection in a human, the method comprising: epetravorole, or a hydrate, solvate, or salt thereof; Ethambutol, or a hydrate, solvate, or salt thereof; a macrolide, or a hydrate, solvate, or salt thereof, to a human; thereby treating a nontuberculous mycobacterial infection in a human. In an exemplary embodiment, the nontuberculous mycobacterium is M. intracellulare or M. avium.

[0066] In an exemplary embodiment, the nontuberculous mycobacteria are rapidly growing. In exemplary embodiments, the nontuberculous mycobacteria are rapidly growing and selective for the following mycobacteria: M. abscessus, M. arabiense, M. aromaticivorans, M. bacteremicum, M. barrassiae, M. bourgelatii, M. celeriflavum, M. chelonae, M. crocinum, M. fukienense, M. hippocampi, M. insubricum, M. iranicum, M. litorale, M. litorale, M. llatzerense, M. monacense, M. pallens, M. rufum, M. rutilum, M. salmoniphilum, M. sediminis, or Mycobacterium setense, or a combination thereof.

[0067] In an exemplary embodiment, the nontuberculous mycobacteria are slow growing. In exemplary embodiments, the nontuberculous mycobacteria are slow growing and include, but are not limited to, M. algericum, M. alsiense, M. arosiense, M. bouchedurhonense, M. engbaekii, M. europaeum, M. fragae, M. heraklionense, M. indicus pranii, M. koreense, M. kumamotonense, M. kyorinense, M. lepromatosis, M. rifflandii, M. liflandii, M. longobardum, M. mantenii, M. marseillense, M. minnesotense, M. noviomagense, M. paraaffinicum, M. paragordonae, M. parakoreense, M. paraseoulense, M. paraterrae, M. riyadhense, M. senuense, M. seoulense, M. sherrisii, M. sigaiense shigaense, M. shinjukuense, M. simulans, M. sinense, M. stomatepiae, M. timonense, M. vulneris, or M. yongonense, or a combination thereof.

[0068] In exemplary embodiments, the nontuberculous mycobacteria is selected from the group consisting of M. abscessus, M. avium complex (MAC), M. chelonae, M. fortuitum, M. gordonae, M. kansasii, M. mucogenicum, M. peregrinum, and M. xenopi. In exemplary embodiments, the nontuberculous mycobacteria is selected from the group consisting of M. abscessus, M. avium complex (MAC), M. fortuitum complex, M. gordonae, M. kansasii, and M. xenopi.

[0069] In an exemplary embodiment, the nontuberculous mycobacteria is Mycobacterium avium complex. In an exemplary embodiment, the nontuberculous mycobacteria is M. avium, M. intracellulare, M. marseillaise, M. timonense, M. bouchedurhonense, M. colombiense, M. vulneris, or M. chimaera. In an exemplary embodiment, the nontuberculous mycobacteria is M. intracellulare. In an exemplary embodiment, the nontuberculous mycobacteria is M. intracellulare subsp. intracellulare, or M. intracellulare subsp. In an exemplary embodiment, the nontuberculous mycobacteria is M. avium.

[0070] In an exemplary embodiment, the human is further suffering from cystic fibrosis, chronic obstructive pulmonary disease, or chronic thromboembolic pulmonary hypertension. In an exemplary embodiment, the human is further suffering from interstitial lung disease, post-inflammatory pulmonary fibrosis, bronchiectasis, neoplastic disease, diabetes, bronchial asthma, hypothyroidism, mediastinal cyst, or rheumatoid arthritis. In an exemplary embodiment, the human is further suffering from interstitial lung disease, the interstitial lung disease being idiopathic pulmonary fibrosis, sarcoidosis, or proteinosis. In an exemplary embodiment, the human is further suffering from neoplastic disease, the neoplastic disease being myelofibrosis or lung cancer. In an exemplary embodiment, the human was previously suffering from tuberculosis.

[0071] In an exemplary embodiment, the infection is an infection in the lungs of a human. In an exemplary embodiment, the infection is an infection in two or more organs in the body. In an exemplary embodiment, the infection is an infection in a lymph node.

[0072] In an exemplary embodiment, the infection is untreated. In an exemplary embodiment, the infection is treatment-resistant.

[0073] In a further aspect, the invention provides a method of treating a nontuberculous mycobacteria-associated disease in a human, the method comprising: epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof; ethambutol to a human; and administering to the human a rifabutin or a salt thereof, or a rifamycin or a salt thereof. In an exemplary embodiment, the method further comprises administering to the human a macrolide or a salt thereof. In an exemplary embodiment, the macrolide is clarithromycin or azithromycin. In an exemplary embodiment, the epetravorol is a salt of epetravorol, which is a pharmaceutically acceptable salt. In an exemplary embodiment, the epetravorol is the hydrochloride salt of epetravorol. In an exemplary embodiment, the nontuberculous mycobacteria-associated disease is nontuberculous mycobacteria lung disease, disseminated nontuberculous mycobacteria disease, or nontuberculous mycobacteria-associated lymphadenitis. In an exemplary embodiment, the nontuberculous mycobacteria-associated disease is Mycobacterium avium complex (MAC) pulmonary disease, disseminated Mycobacterium avium complex (MAC) disease, and Mycobacterium avium complex (MAC)-associated lymphadenitis. In an exemplary embodiment, the nontuberculous mycobacteria-associated disease is nodular bronchiectasis. In an exemplary embodiment, the nontuberculous mycobacteria-associated disease is fibroconfluent.

[0074] In an exemplary embodiment, the nontuberculous mycobacteria-associated disease is untreated. In an exemplary embodiment, the nontuberculous mycobacteria-associated disease is treatment-resistant.

[0075] In an exemplary embodiment, the disease is treated by oral administration of a compound of the invention. In an exemplary embodiment, the disease is treated by intravenous administration of a compound of the invention. In an exemplary embodiment, the disease is treated by subcutaneous administration of a compound of the invention.

[0076] V. Pharmaceutical Preparations In another embodiment, the present invention provides a pharmaceutical formulation, the formulation comprising: a) epetravorol, or a salt, hydrate, or solvate thereof; and b) a pharma- ceutically acceptable excipient.

[0077] It is to be understood that the present invention covers all combinations of aspects and / or embodiments described herein, as well as suitable, convenient and preferred groupings.

[0078] The invention is further illustrated by the following examples, which are not intended to either define or limit the scope of the invention.

[0079] [Example] Example 1 Determination of minimum inhibitory concentration (MIC): MIC values ​​for putative EBO-resistant mutants were determined by broth microdilution (BMD) in cation-adjusted Mueller Hinton broth according to Clinical and Laboratory Standards Institute document M24-A3 (Clinical and Laboratory Standards Institute. Susceptibility Testing of Mycobacteria, Nocardia spp., and Other Aerobic Actinomycetes. 3rd ed. CLSI standard M24. Clinical and Laboratory Standards Institute, Wayne, PA: 2018). Agar MIC values ​​were determined using 7H10 Middlebrook agar and 5% OADC essentially as described in CLSI M24-A3.

[0080] The in vitro activities of EBO, clarithromycin (CLR), ethambutol (EMB), rifabutin, amikacin, and bedaquiline were tested against five MAC strains and two rapidly growing mycobacterial strains. The MIC results are shown in the table below.

[0081] [Table 1]

[0082] Example 2 Dual combination with epetravorol Epetravorole hydrochloride is a small polar molecule with a novel mechanism of action (MoA) and a broad spectrum of antibacterial activity, including activity against mycobacteria. Current standard treatments for Mycobacterium avium complex (MAC) pulmonary disease include macrolides, ethambutol, and rifamycin. The activity of epetravorole hydrochloride in dual combination with clarithromycin, rifabutin, and ethambutol against seven species of nontuberculous mycobacteria, including five slow-growing and two fast-growing mycobacteria, was evaluated. The activity of epetravorole hydrochloride was also evaluated in the presence of amikacin and bedaquiline. The results are shown in Table 2.

[0083] Materials and Methods chemicals EBO was obtained from AN2 Therapeutics Inc., bedaquiline was purchased from 1Click Chemistry (Kendall Park, NJ), clarithromycin was purchased from Carbosynth (San Diego, CA), and amikacin, ethambutol, and rifabutin were purchased from Sigma-Aldrich, (St. Louis, MO). Frozen stocks of drugs were prepared at 5 mg / ml or 2 mg / ml and stored frozen at -20°C. On the day of the experiment, stocks were thawed and diluted to the appropriate concentrations. Middlebrook 7H9 broth and agar, CA-MH agar, and Middlebrook OADC were all purchased from Becton-Dickinson and Company (Sparks, MD).

[0084] KK M. avium 2285R (Verma et al. Microbiol (2019) 10: 693) and M. intracellulare DNA000111 were obtained from Diane Ordway (Colorado State University, Fort Collins, CO). M. chimaera 20-S-05 and macrolide / bedaquiline-resistant M. intracellulare 20-S-13 isolates were obtained from Barbara Brown-Elliott (Mycobacteria / Nocardia Research Laboratory, University of Texas Health Science Center, Tyler Tx). Strains M. abscessus ATCC 19977, M. avium ATCC 700898, and M. peregrinum ATCC 700686 were obtained from the American Type Culture Collection (ATCC, Manassas, VA). Stocks of isolates were prepared and frozen at -80°C. Fresh cultures (1-2 weeks old) of each isolate were grown on either 7H10 agar + 5% OADC or CAMH agar + 5% OADC and used for each experiment.

[0085] Antibacterial synergy test Synergy and antagonism were tested using Middlebrook 7H9 + 5% OADC (Dubos et al. Am Rev Tuberc (1947) 56:334-45) as the microbial growth medium, using the checkerboard method. The first antibiotic in the combination, EBO, was serially diluted along the x-axis, while the second antibiotic was diluted along the y-axis. Synergistic or antagonistic activity was determined using the sum of fractional inhibitory concentration (ΣFIC) indices. The FIC index was calculated as the sum of FIC A + FIC B, where FIC A is the MIC of drug A in the combination of drugs A and B divided by the MIC of drug A alone, plus the MIC of drug B in the combination of drugs A and B divided by the MIC of drug B alone. A drug combination is considered to be synergistic if the FIC is 0.5 or less, additive if the FIC is greater than 0.5 to 1, indifferent if the FIC is greater than 1 to 2, and antagonistic if the FIC is greater than 2 (EUCAST. Clin. Microbiol. Infect. (2000) 6: 503-508).

[0086] [Table 2]

[0087] Results and Discussion The in vitro activity of EBO was tested in the presence of the main components of standard of care drugs for the treatment of MAC lung disease (clarithromycin, ethambutol, rifabutin, as well as other known active NTM drugs, amikacin and bedaquiline). EBO activity was not antagonized by these drugs in any of the NTM strains tested. In most cases, especially in two rapidly growing NTM strains, M. abscessus ATCC 19977 and M. peregrinum ATCC 700686, EBO activity was independent of the addition of a second drug. The only exception was ethambutol, which showed synergistic effects in two of a total of five MAC strains tested, and additive effects in two more. Interestingly, the clarithromycin-resistant strain M. intracellulare 20-S-13 was the only MAC strain that showed no association with ethambutol and EBO, and had the highest ethambutol MIC of 64 mg / L.

[0088] conclusion No antagonism was observed with any combination of strains or EBO, and most interactions were largely irrelevant, especially for the two fast-growing NTM strains, M. abscessus ATCC 19977 and M. peregrinum ATCC 700686. The only exception was ethambutol, which showed synergy with two and additivity with two out of a total of five MAC strains tested. Interestingly, the MAC strain with the highest ethambutol MIC value of 64 mg / L was the only one that showed irrelevance.

[0089] Example 3 Determination of spontaneous resistance frequency: RFs of M. avium ATCC 700898 at 2, 4, and 8 times the MIC of EBO (8 mg / L) were determined, as were RFs of EBO in combination with CLR, RBT, AMK, or EMB. MICs of selected EBO mutants were determined against AMK, BDQ, CLR, RBT, EMB, and clofazimine (CFZ), and mutants were further characterized by genomic DNA analysis. Resistant colonies were confirmed by replica plating on agar plates containing the same antibiotic concentration as that used for selection of resistant strains. Control plates without drug were prepared for determination of inoculum size. RFs were calculated by dividing the total CFU / mL of resistant colonies by the total CFU / mL of the inoculum.

[0090] The spontaneous resistance frequency of EBO was 1.58 × 10 when selected at 2-8 agar MICs. -7 From 8.48 x 10 -9(Table 3). The resistance frequency of EBO was similar to that of standard of care (SOC) antimicrobials (Table 4). However, the addition of EMB, CLR, RFB, or AMK to EBO reduced the resistance frequency to both drugs by more than 700-fold (Table 4). Further characterization of the EBO-resistant mutants showed that the MIC value of EBO increased by more than 128-fold, whereas the MIC values ​​of amikacin, bedaquiline, clofazimine, clarithromycin, and ethambutol did not change by more than 4-fold (Table 5). The only tested drug that changed more than 4-fold from the wild-type MIC value was rifabutin, which was changed 8-fold with a single EBO-resistant mutant, 64-4A (Table 5). However, this was only at a single MIC value, the duplicate of which differed from the wild-type by only 4-fold. An eight-fold difference in activity against the related rifamycin rifampin has previously been reported for this strain (M. avium ATCC 700898) (Zelinski C, Killian SC, Sulivan N, Allen S. Mycobacterium avium ssp. avium ATCC 700898 (QC) culture differences demonstrate variable MIC susceptibility results in the Sensititre® SLOMYCO plate. ASM General Meeting 2010, San Diego CA C-153). This eight-fold difference is within the margin of error. The activity of the major antimycobacteria tested was not affected by EBO resistance, suggesting that no cross-resistance has occurred.

[0091] [Table 3]

[0092] [Table 4]

[0093] [Table 5]

[0094] It is to be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to those skilled in the art and are to be included within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. 1. A composition for treating a nontuberculous mycobacterial infection or a nontuberculous mycobacterial-associated disease in a human, comprising: The composition comprises epetravorole, or a hydrate, solvate, or salt thereof, and ethambutol, and is administered to a human to thereby treat a nontuberculous mycobacterial infection or a nontuberculous mycobacterial-associated disease in the human.

2. further comprising rifamycin or a salt thereof, 2. The composition of claim 1, wherein optionally, the rifamycin is rifampicin (rifampin), rifabutin, rifapentine, or rifaximin.

3. further comprising a macrolide or a salt thereof; 3. The composition of claim 1 or 2, wherein optionally the macrolide is clarithromycin or azithromycin.

4. the epetraborole is a salt of epetraborole, and the salt is a pharmaceutically acceptable salt; Optionally, the epetraborol is the hydrochloride salt of epetraborol.

5. the nontuberculous mycobacteria grow rapidly; Optionally, the nontuberculous mycobacteria are rapidly growing and are selected from the group consisting of M. abscessus, M. arabiense, M. aromaticivorans, M. bacteremicum, M. barrassiae, M. bourgelatii, M. celeriflavum, M. chelonae, M. crocinum, M. franklinii, M. fukienense, M. hippocampi, M. insubricum, M. iranicum, M. fluviatilis ... selected from the group consisting of M. litorale, M. llatzerense, M. monacense, M. pallens, M. rufum, M. rutilum, M. salmoniphilum, M. sediminis, and Mycobacterium setense, or the nontuberculous mycobacteria grow slowly; Optionally, the nontuberculous mycobacteria are slow-growing and are selected from the group consisting of M. algericum, M. alsiense, M. arosiense, M. bouchedurhonense, M. engbaekii, M. europaeum, M. fragae, M. heraklionense, M. indicus pranii, M. koreense, M. kumamotonense, M. kyorinense, M. lepromatosis, M. M. liflandii, M. longobardum, M. mantenii, M. marseillense, M. minnesotense, M. noviomagense, M. paraffinicum, M. paragordonae, M. parakoreense, M. paraseoulense, M. paraterrae, M. riyadhense, M. senuense, M. seoulense, M. sherrisii, M. shigaense, M. selected from the group consisting of M. shinjukuense, M. simulans, M. sinense, M. stomatepiae, M. timonense, M. vulneris, and M. yongonense, or Optionally, the nontuberculous mycobacteria are selected from the group consisting of M. abscessus, M. avium complex (MAC), M. chelonae, M. fortuitum, M. gordonae, M. kansasii, M. mucogenicum, M. peregrinum, and M. xenopi, or Optionally, the nontuberculous mycobacteria are selected from the group consisting of M. abscessus, M. avium complex (MAC), M. fortuitum complex, M. gordonae, M. kansasii, and M. xenopi, or Optionally, the nontuberculous mycobacteria is Mycobacterium avium complex, or Optionally, the nontuberculous mycobacteria are M. avium, M. intracellulare, M. marseillaise, M. timonense, M. bouchedurhonense, M. colombiense, M. vulneris, and M. chimaera, or Optionally, the nontuberculous mycobacteria is M. intracellulare, or Optionally, the nontuberculous mycobacteria is M. intracellulare subsp. intracellulare or M. intracellulare subsp. chimaera, or Optionally, the nontuberculous mycobacteria is M. avium, or 2. The composition of claim 1, optionally wherein the nontuberculous mycobacterium is M. avium subsp. avium, M. avium subsp. hominissium, M. avium subsp. silvaticum, or M. avium subsp. paratuberculosis.

6. the human further suffers from cystic fibrosis, chronic obstructive pulmonary disease, or chronic thromboembolic pulmonary hypertension, or the human further suffers from interstitial lung disease, post-inflammatory pulmonary fibrosis, bronchiectasis, neoplastic disease, diabetes, bronchial asthma, hypothyroidism, mediastinal cyst, or rheumatoid arthritis; Optionally, the interstitial lung disease is idiopathic pulmonary fibrosis, sarcoidosis, or proteinosis, and the neoplastic disease is myelofibrosis or lung cancer. The composition of claim 1.

7. The composition of claim 1 , wherein the human previously had tuberculosis.

8. the infection is an infection in the human lung, or the infection is in two or more organs of the body, or The composition of claim 1 , wherein the infection is an infection in a lymph node.

9. the infection or the nontuberculous mycobacterial disease is untreated, or 10. The composition of claim 1, wherein the infection or the nontuberculous mycobacterial-associated disease is resistant to treatment.

10. the nontuberculous mycobacterial-associated disease is nontuberculous mycobacterial lung disease, disseminated nontuberculous mycobacterial disease, or nontuberculous mycobacterial-associated lymphadenitis; or the non-tuberculous mycobacteria-associated disease is Mycobacterium avium complex (MAC) pulmonary disease, disseminated Mycobacterium avium complex (MAC) disease, and Mycobacterium avium complex (MAC)-associated lymphadenitis; or the nontuberculous mycobacteria-associated disease is nodular bronchiectasis, or The composition of claim 1, wherein the nontuberculous mycobacteria-associated disease is fibroconfluent.