Methods and uses of boron compounds for treatment of nontuberculous mycobacterium infections and pharmaceutical compositions for treatment of same

Abstract

The present invention provides organoboron compounds of Formula I, or salts thereof, and pharmaceutical compositions and uses of the organoboron compounds and pharmaceutical compositions for the treatment of non-Mycobacterium tuberculosis infections. # imgabs0 #

Description

Technical Field

[0001] The present application provides an organoboron compound for treating nontuberculous mycobacterium infection and a pharmaceutical composition for treating the same disease. Background Art

[0002] Nontuberculous mycobacterial (NTM) lung disease (NTM-PD) is a severe, progressive disease caused by certain mycobacteria that may require complex treatment for more than 12 months with multiple antimycobacterial drugs or combinations of such antibiotics (e.g., reviewed by Daley et al. in Clin. Infect. Dis. 2020 Aug 15;71(4):905–913). NTM refers to all mycobacterial species except Mycobacterium tuberculosis complex and Mycobacterium leprae. To date, more than 190 species of NTM bacteria have been discovered, and although most are parasitic bacteria, only a few are opportunistic pathogens that cause human infections. However, in recent years, the incidence and prevalence of NTM diseases have increased worldwide with the increase in patients with acquired immunodeficiency syndrome and immunosuppressed populations. In addition, NTM resistance to antibiotics is increasing. In particular, the resistance rate in relapsed patients is very high, which may pose difficulties for clinical treatment. Due to inappropriate treatment and high treatment failure rates, the mortality rate of NTM-PD is higher than that of Mycobacterium tuberculosis (MTB).

[0003] The Runyon classification method is used to divide NTM flora into four groups based on growth temperature, growth rate, colony morphology, and the relationship between pigment production and light response. The first three groups are slow-growing mycobacteria, while the fourth group is fast-growing mycobacteria. Group I is photochromogenic bacteria, mainly composed of Mycobacterium kansasii, Mycobacterium marineum, and Mycobacterium simum, while Group II is dark-chromogenic bacteria, mainly composed of Mycobacterium scrofula, Mycobacterium gordonii, and Mycobacterium surga. Group III is non-photochromogenic bacteria, including Mycobacterium avium complex (MAC), Mycobacterium haemophilum, Mycobacterium ulcerans, Mycobacterium toad, Mycobacterium malmoe, Mycobacterium terrestris, and Mycobacterium gasteri. Group IV, fast-growing mycobacteria (RGM), includes Mycobacterium abscessus complex (MABC), Mycobacterium fortuitum, Mycobacterium chelonae, Mycobacterium margaritum, Mycobacterium exogenum, Mycobacterium smegmatis, and Mycobacterium vaccae.

[0004] Because NTM include a group of bacteria that cause severe lung infections, treatment is often complicated and requires prolonged therapy. In addition, because most NTM are inherently resistant to standard anti-TB drugs and different species display different resistance phenotypes, available therapeutic drugs and regimens are limited.

[0005] For many patients with bacterial infections who require long-term antibiotic therapy, oral formulations are the most appropriate option. Advantages of oral administration over the intravenous route include the absence of catheter-related infections, lower drug costs, and reduced hospital costs (e.g., the need for health professionals and equipment to administer antibiotics intravenously). Oral therapy is also particularly important to ensure compliance in those patients who require long-term treatment. For example, treatment of Mycobacterium avium and Mycobacterium abscessus infections often requires several months.

[0006] Therefore, new therapeutic agents are needed that have novel modes of action, potent activity against resistant isolates, minimal side effects, and convenient oral administration. Summary of the invention

[0007] The present application provides a boron compound and a pharmaceutical composition thereof for treating nontuberculous mycobacterium infection.

[0008] The boron organic compounds shown below belong to a class of antibiotics with high antimicrobial activity, both against Gram-negative and Gram-positive microorganisms, and against mycobacteria.

[0009] As described in U.S. Pat. No. 8,530,452, this tricyclic boron compound is particularly active against Gram-negative bacteria, such as Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae. However, the activity of this compound against mycobacteria has not been reported. In fact, the cell envelope of mycobacteria is very different from that of typical Gram-positive and Gram-negative bacteria, and it cannot be assumed that antibiotics have antibacterial efficacy against both Gram-negative bacteria and mycobacteria. As described in the present application, it has been found that the salt form of this boron compound unexpectedly exhibits activity against mycobacteria. In addition, as described below, the compound exhibits only moderate oral bioavailability. In contrast, certain prodrugs described in the present application exhibit enhanced oral bioavailability and improved systemic exposure, which is critical for eradication of pathogens. Certain compounds described in the present application exhibit important advantageous dual therapeutic properties: efficacy against mycobacteria and oral bioavailability. This represents a significant improvement over most antibiotics, such as cephalosporins, which can only be administered intravenously in hospitals.

[0010] In one aspect, the present application provides a method for treating nontuberculous mycobacterium infection, comprising administering a therapeutically effective amount of a compound of formula (I): or a pharmaceutically acceptable salt thereof to a mammal in need of treatment; in: R 1 Selected from H, C 1-24Alkyl-C(=O)-, C 1-24 Alkoxy-C(=O)-, C 3-7 Cycloalkyl-C(═O)-, heteroalkyl-C(═O)-, aryl-C(═O)-, heteroaryl-C(═O)-, and (5-methyl-1,3-dioxol-2-one-4-yl)methyl; and R 2 Selected from C 1-24 Alkyl-C(=O)-, C 1-24 Alkoxy-C(=O)-, C 3-7 Cycloalkyl-C(═O)-, heteroalkyl-C(═O)-, aryl-C(═O)-, heteroaryl-C(═O)-, and (5-methyl-1,3-dioxol-2-one-4-yl)methyl; or R 1 and R 2 Together, they form a heterocyclic group selected from 1,3-dioxane, 2-C 1-6 Alkyl-1,3-dioxane, 2,2-di(C 1-6 alkyl)-1,3-dioxane, 2-methyl-1,3-dioxane, 2-aryl-1,3-dioxane, 2-(2-carboxyphenyl)-1,3-dioxane, 2-(4-carboxyphenyl)-1,3-dioxane and 2-C 1-6 Alkyl OC(=O)-1,3-dioxane; each of which is optionally substituted by one to four R 3 replace; R 3 is independently selected at each occurrence from the group consisting of halogen, hydroxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 alkoxy, aryl and heteroaryl groups; or When attached to adjacent carbons, the two R 3 The groups, together with the carbon to which they are attached, form a fused C 3 -C 6 Cycloalkyl; or when attached to the same carbon, two R 3 The groups together with the carbon to which they are attached form a spiro 3 -C 6 Cycloalkyl; Each R 3 Optionally independently 1-3 halogen, hydroxyl or C 1 -C 3 Alkyl substitution; or The hydrogen of the -OH bonded to the boron atom is absent, and R 2The oxygen connected to the boron atom forms a compound of formula II. Therefore, in another aspect, the present application provides a method for treating non-tuberculous mycobacterium infection, comprising administering a therapeutically effective amount of a compound of formula II: or a pharmaceutically acceptable salt thereof to a mammal in need of treatment; in: R 1 Selected from H, C 1-24 Alkyl-C(=O)-, C 1-24 Alkoxy-C(=O)-, C 3-7 Cycloalkyl-C(═O)-, heteroalkyl-C(═O)-, aryl-C(═O)-, heteroaryl-C(═O)- and (5-methyl-1,3-dioxol-2-on-4-yl)methyl.

[0011] In another aspect, the present application provides the use of a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating nontuberculous mycobacterium infection.

[0012] In another aspect, the present application provides a pharmaceutical composition comprising a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier for treating nontuberculous mycobacterium infection.

[0013] Nontuberculous mycobacteria include, but are not limited to, Mycobacterium scrofulaceum, Mycobacterium gordonae, Mycobacterium avium, Mycobacterium abscessus, Mycobacterium intercelleulare, Mycobacterium fortuitum, Mycobacterium peregrinum, Mycobacterium smegmatis, and Mycobacterium massiliense. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 is a graph showing the colony forming unit (CFU) counts in the lungs of mice 14 days after administration of the compound of Example 4 (10 mg / kg subcutaneously, daily), GSK656 (100 mg / kg subcutaneously, daily), linezolid (100 mg / kg orally, daily), or clarithromycin (200 mg / kg orally, daily) described in Example 7; Figure 2A are images of H&E-stained tissue sections of mice not infected with Mycobacterium abscessus CIP108297 in the following Mycobacterium abscessus mouse lung infection model; Figure 2B are images of H&E-stained tissue sections of mice infected with Mycobacterium abscessus CIP108297 but untreated 14 days after infection in the Mycobacterium abscessus mouse lung infection model described below; Figure 2C are images of H&E stained tissue sections of mice infected with M. abscessus CIP108297 and treated with the compound of Example 4 after 14 days in the M. abscessus mouse lung infection model described below. DETAILED DESCRIPTION

[0015] Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

[0016] The terms alkyl, alkenyl, etc. refer to both straight and branched chain groups, but references to individual groups such as "propyl" include only straight chain groups and branched chain isomers such as "isopropyl" include only branched chain isomers. Alkyl, alkenyl, etc. groups may be optionally substituted with one, two or three radicals selected from halogen, aryl, Het 1 or Het 2 Representative examples include, but are not limited to, difluoromethyl, 2-fluoroethyl, trifluoroethyl, -CH=CH-aryl, -CH=CH-Het 1 、-CH 2 -phenyl, etc.

[0017] The term "cycloalkyl" refers to a cyclic saturated monovalent hydrocarbon group having 3 to 6 carbon atoms, such as cyclopropyl, cyclohexyl, etc. The cycloalkyl group may be optionally substituted by one, two or three radicals selected from halogen, aryl, Het 1 or Het 2 substituted by a substituent.

[0018] The term "heteroalkyl" refers to an alkyl or cycloalkyl group as defined above having a radical selected from N, O or S(O) n A heteroatom substituent, wherein n is an integer from 0 to 2, including hydroxyl (OH), C 1-4 Alkoxy, amino, thio (-SH), etc. Representative substituents include -NR a R b 、-OR a or -S(O) n -R c , where R a It is H, C 1-4 Alkyl, C 3-6cycloalkyl, optionally substituted aryl, optionally substituted heterocycle, or -COR (wherein R is C 1-4 Alkyl); R b It is H, C 1-4 Alkyl, -SO 2 R (where R is C 1-4 Alkyl or C 1-4 Hydroxyalkyl), -SO 2 NRR' (wherein R and R' are independently H or C 1-4 alkyl), -CONR'R" (wherein R' and R" are independently H or C 1-4 -alkyl); n is an integer from 0 to 2; and R c It is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, optionally substituted aryl or NR a R b , where R a and R b As defined above. Representative examples include, but are not limited to, 2-methoxyethyl (-CH 2 CH 2 OCH 3 ), 2-hydroxyethyl (-CH 2 CH 2 OH), hydroxymethyl (-CH 2 OH), 2-aminoethyl (-CH 2 CH 2 NH 2 ), 2-dimethylaminoethyl (-CH 2 CH 2 NHCH 3 ), benzyloxymethyl, thiophen-2-ylthiomethyl, and the like.

[0019] The term aryl refers to phenyl, biphenyl or naphthyl, which is optionally substituted with 1-3 substituents independently selected from halogen, -C 1-4 Alkyl, -OH, -OC 1-4 Alkyl, -S(O) n C 1-4 Alkyl (n is 0, 1 or 2), -C 1-4 Alkyl NH 2 、-NHC 1-4 Alkyl, -C(=O)H or -C=N-OR d (R d H or -C 1-4 alkyl).

[0020] Het 1is independently at each occurrence a C-linked 5- or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from O, N and S within the ring. 2 is independently at each occurrence an N-linked 5- or 6-membered heterocyclic ring having 1-4 N and optionally one O or S within the ring. "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "aryl optionally mono- or di-substituted with alkyl" means that alkyl may but need not be present, and that the description includes instances where aryl is mono- or di-substituted with alkyl and instances where aryl is not substituted with alkyl.

[0021] "Pharmaceutically acceptable carrier" means a carrier that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, has no biological significance, and has no other undesirable contents, including carriers that can be used in veterinary and human medicines. "Pharmaceutically acceptable carrier" as used in the specification and claims includes one or more such carriers.

[0022] A "pharmaceutically acceptable salt" of a compound is a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include: (1) Acid addition salts, formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-Hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptanoic acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) Salts formed when the acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth ions or aluminum ions; or coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, butanetriolamine, N-methylglucamine, etc.

[0023] The term "tautomer" refers to two or more forms or isomers of an organic compound that can be interconverted by a common chemical reaction called tautomerization, generally similar to that reviewed by Smith et al. in Advanced Organic Chemistry. 2001, 5th Ed. NY: Wiley Interscience., pp. 1218–1223. The concept of tautomerism is called tautomerism. Tautomerism may be accompanied by a change from a ring structure to an open structure, for example, as observed, the interconversion between the cyclic pyran form and the open chain form of glucose by the formation and cleavage of the C-O bond. The degree of tautomerism is generally affected by solvent effects, such as hydration with water and medium acidity. The relevant process for cyclic boron compounds may involve the formation and cleavage of the B-O bond, as shown below:

[0024] “Treating” or “treatment” of a disease includes: (1) preventing a disease, that is, preventing clinical symptoms of a disease from developing in a mammal that may be exposed to or susceptible to the disease but does not yet experience or show symptoms of the disease, (2) inhibit the disease, i.e., prevent or reduce the development of the disease or its clinical symptoms, or (3) Relieve the disease, that is, cause the disease or its clinical symptoms to disappear.

[0025] "Therapeutically effective amount" refers to the amount of a compound sufficient to affect the treatment of a disease when administered to a mammal to treat the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[0026] "Prodrug" refers to any compound that releases an active parent drug in vivo when the prodrug is administered to a mammalian subject. Prodrugs of the compounds described herein are prepared by modifying functional groups present in the compounds described herein so that the modifications can be cleaved in vivo to release the parent compound. Prodrugs include compounds described herein wherein a hydroxyl, sulfhydryl, amide, or amino group in the compound is bound to any group that can be cleaved in vivo to regenerate a free hydroxyl, amide, amino, or sulfhydryl group, respectively.

[0027] "Patient" refers to animals, such as mammals, including non-primates (such as cows, pigs, horses, cats, dogs, rats and mice) and primates (such as monkeys, such as cynomolgus monkeys, chimpanzees and humans); and for example humans. In certain embodiments, the patient is a human. Illustrative Embodiments

[0028] In one aspect, the present application provides a method for treating nontuberculous mycobacterium infection, comprising administering a therapeutically effective amount of a compound of formula (I): or a pharmaceutically acceptable salt thereof to a patient in need of treatment; in: R 1 Selected from H, C 1-24 Alkyl-C(=O)-, C 1-24 Alkoxy-C(=O)-, C 3-7 Cycloalkyl-C(═O)-, heteroalkyl-C(═O)-, aryl-C(═O)-, heteroaryl-C(═O)-, and (5-methyl-1,3-dioxol-2-one-4-yl)methyl; and R 2 Selected from C 1-24 Alkyl-C(=O)-, C 1-24 Alkoxy-C(=O)-, C 3-7 Cycloalkyl-C(═O)-, heteroalkyl-C(═O)-, aryl-C(═O)-, heteroaryl-C(═O)-, and (5-methyl-1,3-dioxol-2-one-4-yl)methyl; or R 1 and R 2 Together, they form a heterocyclic group selected from 1,3-dioxane, 2-C 1-6 Alkyl-1,3-dioxane, 2,2-di(C 1-6 -alkyl)-1,3-dioxane, 2-methyl-1,3-dioxane, 2-aryl-1,3-dioxane, 2-(2-carboxyphenyl)-1,3-dioxane, 2-(4-carboxyphenyl)-1,3-dioxane and 2-C 1-6 -alkyl OC(=O)-1,3-dioxane; each of which is optionally substituted by one to four R 3 replace; R 3 is independently selected at each occurrence from the group consisting of halogen, hydroxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 - alkoxy, aryl and heteroaryl groups; or When attached to adjacent carbons, the two R 3 The groups, together with the carbon to which they are attached, form a fused C 3 -C 6 Cycloalkyl; or when attached to the same carbon, two R 3The groups together with the carbon to which they are attached form a spiro 3 -C 6 Cycloalkyl; Each R 3 Optionally independently 1-3 halogen, hydroxyl or C 1 -C 3 Alkyl substitution; or The hydrogen of the -OH bonded to the boron atom is absent, and R 2 Together with the oxygen attached to the boron atom, a compound of formula II is formed. Therefore, in another aspect, the present application provides a method for treating non-tuberculous mycobacterium infection, comprising administering a therapeutically effective amount of a compound of formula II: or a pharmaceutically acceptable salt thereof to a patient in need of treatment; in: R 1 Selected from H, C 1-24 Alkyl-C(=O)-, C 1-24 Alkoxy-C(=O)-, C 3-7 Cycloalkyl-C(═O)-, heteroalkyl-C(═O)-, aryl-C(═O)-, heteroaryl-C(═O)- and (5-methyl-1,3-dioxol-2-on-4-yl)methyl.

[0029] In some embodiments, the method of treating nontuberculous mycobacterial infection comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 It is C 1-4 Alkyl-C(=O)- and R 2 It is C 1-4 Alkyl-C(═O)—.

[0030] In another aspect, the present application provides the use of a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating nontuberculous mycobacterium infection.

[0031] Nontuberculous mycobacteria include, but are not limited to, Mycobacterium scrofulae, Mycobacterium gordonii, Mycobacterium avium, Mycobacterium abscessus, Mycobacterium intracellulare, Mycobacterium fortuitum, Mycobacterium exogenum, Mycobacterium smegmatis, and Mycobacterium massiliense.

[0032] The compound of formula I or formula II can be administered in the form of its free base, or in the form of a salt and / or hydrate. In some embodiments, the compound of formula I or formula II is administered in the form of its hydrochloride salt.

[0033] Formula I or Formula II compound or its pharmaceutically acceptable salt can be administered by various routes of administration, including but not limited to being selected from oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular injection, rectal, buccal, intranasal, inhalation, vaginal, intraocular (intraoccularly), local, subcutaneous, intrafatty (intraadiposally), intraarticular, intraperitoneal and intrathecal routes. In a certain embodiment, administration is oral.

[0034] The amount of the compound of formula I or formula II or its pharmaceutically acceptable salt can be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity and / or the age and health of the patient. In some embodiments, the amount of the compound of formula I or formula II or its pharmaceutically acceptable salt is 10-1000 mg. In some embodiments, the amount of the compound of formula I or formula II or its medically acceptable salt is 100-600 mg. In some embodiments, the amount of the compound of formula I or formula II or its pharmaceutically acceptable salt is 200-400 mg.

[0035] The compound of formula I or formula II or its pharmaceutically acceptable salt can be administered once or more per day. In some embodiments, the compound of formula I or formula II or its pharmaceutically acceptable salt is administered once per day in the form of a single dose. In one embodiment, the compound is administered twice per day in the form of a single dose. In one embodiment, the compound is administered twice per day in a single dose suitable for oral solid formulations.

[0036] In another aspect, the present application provides the use of a compound of formula I or formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating nontuberculous mycobacterium infection. Nontuberculous mycobacteria include, but are not limited to, Mycobacterium scrofulae, Mycobacterium gordonii, Mycobacterium avium, Mycobacterium abscessus, Mycobacterium intracellulare, Mycobacterium fortuitum, Mycobacterium exogenum, Mycobacterium smegmatis, and Mycobacterium massiliense.

[0037] In some embodiments, the pharmaceutical composition is a preparation suitable for oral administration, which includes but is not limited to tablets, capsules, powders, granules, drops, pastes, powders, etc. In a preferred embodiment, tablets and capsules are used. Tablets can be ordinary tablets, dispersible tablets, effervescent tablets, sustained-release tablets, controlled-release tablets or enteric-coated tablets, and capsules can be ordinary capsules, sustained-release capsules, controlled-release capsules or enteric-coated capsules. The oral preparation can be prepared by conventional methods of pharmaceutically acceptable carriers known in the art. Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, etc. Fillers include starch, lactose, mannitol, microcrystalline cellulose, etc.; absorbents include calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents include water, ethanol, etc.; binders include hydroxypropyl methylcellulose, povidone, microcrystalline cellulose, etc.; disintegrants include cross-linked sodium carboxymethyl cellulose, cross-linked povidone, surfactants, low-substituted hydroxypropyl cellulose, etc.; lubricants include magnesium stearate, talc, polyethylene glycol, sodium lauryl sulfate, talc, etc. Pharmaceutical excipients also include colorants, sweeteners and the like.

[0038] In one embodiment, the pharmaceutical composition is a solid dosage form suitable for oral administration. For example, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or in liquid media), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In a specific embodiment, the pharmaceutical composition is a capsule.

[0039] In preparing a formulation, it may be necessary to grind the active compound to provide a suitable particle size prior to combining with other ingredients. If the active compound is substantially insoluble, it is generally ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size is generally adjusted by grinding to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0040] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methylcellulose. The formulation may also include: lubricants, such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives, such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents. The compositions described herein can be prepared using procedures known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to the patient.

[0041] In order to prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a uniform mixture of the compounds described herein. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. This solid preformulation is then subdivided into the unit dosage forms of the above types.

[0042] In one embodiment, the pharmaceutical composition for treating non-tuberculous mycobacterium infection is formulated into a single dosage form. In one embodiment, the single dosage form comprises 10 mg-1000 mg of a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof. In some embodiments, the single dosage form comprises 100 mg-600 mg of a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the single dosage form comprises 200 mg-400 mg of a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof, preferably 200 mg-400 mg of a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof.

[0043] Tablet or pill described in the present application can be coated or otherwise compound to provide the dosage form of the advantage of prolonged effect.For example, tablet or pill can comprise inner dosage component and outer dosage component, and the latter is the encapsulated form on the former.These two kinds of compositions can be separated by enteric layer, and it is used to resist the disintegration in the stomach, and allows inner component to enter duodenum or delay release intactly.Multiple materials can be used for this enteric layer or coating, and this material comprises the mixture of multiple polymeric acid and polymeric acid and the material such as shellac, spermol and cellulose acetate.

[0044] In some embodiments, the continuous administration is 4-18 months, preferably 4-6 months.

[0045] In another embodiment, the pharmaceutical composition is administered in combination with other antibiotics currently used to treat NTM infections, such as amikacin, clarithromycin, azithromycin, or ciprofloxacin.

[0046] Herein, unless otherwise indicated, the dosages and ranges provided therein are based on the molecular weight of the free base form of the compound of Formula I or Formula II.

[0047] Preferred compounds of formula II are: or a pharmaceutically acceptable salt thereof.

[0048] Additional preferred compounds of formula I include the following structures, or a pharmaceutically acceptable salt thereof.

[0049] Preferred compounds of formula II include the following structures: or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, the pharmaceutically acceptable salt form of the compound of Formula I or II is the hydrochloride salt. Example

[0051] The embodiments described in the following examples are intended to illustrate but not to limit the scope of the present disclosure. Common abbreviations familiar to those of ordinary skill in the art of synthesis technology are used throughout. Unless otherwise specified, 1 H NMR spectroscopy was performed using DMSO-d 6 Recorded on a 300 MHz instrument. Mass spectral data are provided for the positive ionization method. Unless otherwise specified, chromatography is silica gel chromatography. TLC is thin layer chromatography. HPLC is reverse phase HPLC. Unless otherwise specified, all reagents are either from commercial sources or prepared by conventional methods described in the existing literature. Example 1

[0052] (2S)-3-Acetoxy-1-{[(3S)-3-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[2,1-c][1,2]oxaborol-7-yl]oxy}propyl-2-yl acetate hydrochloride

[0053] Preparation scheme of the compound of Example 1:

[0054] Intermediate 2. To a solution of Intermediate 1 (60 mg, 0.26 mmol, prepared as described in US Application US2013 / 0165411) and pyridine (31 uL, 0.33 mmol) in DCM (2 mL) was added dropwise Ac 2 O (32uL, 0.33mmol), and the resulting mixture was stirred for 2 hours. After the reaction was completed, the solvent was removed by concentration, and the residue was purified on pre-HPLC to obtain intermediate 2 (25mg). MS (m / z): 438 [M+H].

[0055] Example 1. Intermediate 2 was dissolved in a 5M HCl (2 mL) dioxane solution at room temperature, and the resulting mixture was stirred for 1 hour. The mixture was then lyophilized to obtain the compound of Example 1 (16.9 mg) as a light yellow powder. MS (m / z): 338 [M+H]. 1 H NMR: (400 MHz, D 2O): 7.48 (t, J=8.0Hz, 1H); 7.01 (d, J=7.6Hz, 1H); 6.92 (dd, J=12.0, 8.0Hz, 1H); 5.35 (dd, J=7.4, 3.0Hz, 1H) ); 4.35~4.17(m, 5H); 3.73~3.60(m, 1H); 3.56~3.51(m, 2H); 3.08~3.01(m, 1H); 1.99(s, 3H), 1.98(s, 3H).

[0056] The following compounds were synthesized according to the procedure described in Example 1. Example 4

[0057] [(2S,6R)-2-(Aminomethyl)-4-boron-3,5,8-trioxacyclo[7.3.1.04,13]trideca-1(12),10-dien-6-yl]methanol hydrochloride The compound of Example 4 was prepared according to the method described in US application US2013 / 0165411. Example 5

[0058] [(2S,6S)-2-(Aminomethyl)-4-boron-3,5,8-trioxacyclo[7.3.1.04,13]trideca-1(12),9(13),10-trien-6-yl]methyl-2-methylpropanoate hydrochloride The compound of Example 5 was prepared according to the method described in US application US2013 / 0165411. Example 7

[0059] [(2S,6S)-2-(Aminomethyl)-4-boron-3,5,8-trioxacyclo[7.3.1.04,13]trideca-1(12),9(13),10-trien-6-yl]acetate methyl hydrochloride The compound of Example 7 was prepared according to the method described in US application US2013 / 0165411. Example 8

[0060] [(2S,6S)-2-(Aminomethyl)-4-boron-3,5,8-trioxacyclo[7.3.1.04,13]trideca-1(12),9(13),10-trien-6-yl]propanoic acid methyl ester hydrochloride The compound of Example 8 was prepared according to the method described in US application US2013 / 0165411. Utility and testing

[0061] The compounds described in this application are boron compounds and their prodrugs. The prodrugs will be converted into the parent boron compounds in vivo to exert antibacterial effects. Therefore, the antibacterial activity of the prodrug compounds described in this application is tested with the parent boron compounds. In vitro activity of representative compounds against mycobacteria

[0062] The in vitro activity of the parent boron compounds described herein is evaluated by standard testing procedures, such as the determination of the minimum inhibitory concentration (MIC) as described in the Clinical and Laboratory Standards Institute (CLSI) document M24-A2. Lower MIC values ​​indicate higher antibacterial activity, while higher MIC values ​​indicate reduced antibacterial activity. Generally, MIC values ​​of about <2 mg / L indicate that the antibacterial drug has good therapeutic (i.e., suitable for treatment) efficacy, while MIC values ​​of >8 mg / L indicate that the test compound lacks therapeutically useful activity.

[0063] The in vitro activity (potency) of representative compounds described in this application against mycobacteria is illustrated by the MIC data in Table 1 below. It is apparent from the data in Table 1 that the compound of Example 4 has high activity against many mycobacterial pathogens, including Mycobacterium scrofulae, Mycobacterium gordonii, Mycobacterium avium, Mycobacterium abscessus, Mycobacterium intracellulare, Mycobacterium fortuitum, Mycobacterium exogenum, Mycobacterium smegmatis, and Mycobacterium massi (MIC ranges from 0.063 to 2 mg / L). In particular, the compound of Example 4 has surprising potency against rapidly growing mycobacteria (RGM), including Mycobacterium abscessus, Mycobacterium intracellulare, Mycobacterium fortuitum, Mycobacterium exogenum, Mycobacterium smegmatis, and Mycobacterium massi (MIC ranges from 0.063 to 0.125 mg / L).

[0064] Compound GSK656 is a different boron compound disclosed in PCT application WO / 2012 / 033858, which is generally related to the compositions provided herein. Surprisingly, despite some structural similarities, the compound of Example 4 and GSK656 show very different antibacterial spectra against non-tuberculous mycobacteria. Crucially, Example 4 has strong efficacy against Mycobacterium fortuitum, Mycobacterium exogenum, and Mycobacterium smegmatis, with an MIC value of 0.125 mg / L, while GSK656 MIC ≥ 8 mg / L. Based on these values, the activity of compound GSK656 is more than 64 times lower than the representative compound of Example 4 provided by the present invention.

[0065] Equally surprising is that the compound of Example 4 is also 4 times more potent than GSK656 against the NTM pathogens Mycobacterium avium and Mycobacterium intracellulare. Such a huge difference in antibacterial spectrum activity and efficacy is completely unexpected. In fact, the compound of Example 4 has significantly and surprisingly improved activity over the reference compound GSK656 and provides antibacterial coverage against NTM pathogens that far exceeds the possible antibacterial coverage of GSK656. Another boron compound AN2690 disclosed in U.S. patent application US2006 / 0234981 also has moderate or no activity against all NTM species tested. Due to the complexity of NTM infections, it is most beneficial and convenient for clinical use when the compound has broad-spectrum antibacterial activity covering multiple mycobacteria. Therefore, the composition provided in the present application provides the best choice for treating such NTM infections.

[0066] Table 1 In vitro antibacterial activity against mycobacterial pathogens

[0067] In order to further characterize the antibacterial properties of the compounds described in the present application, the minimum bactericidal concentration (MBC) was also determined according to the Clinical and Laboratory Standards Institute (CLSI) document M24-A2. Both GSK656 and the compound of Example 4 tested MIC and MBC against 20 clinical isolates of the Mycobacterium abscessus complex, including Mycobacterium abscessus and Mycobacterium masai. As shown in Table 2, GSK656 and the compound of Example 4 had similar MICs in clinical isolates. However, it was very surprising that the compound of Example 4 had a lower MBC for all isolates tested. If the MBC / MIC ratio is <4, the antibiotic is considered bactericidal, and if the ratio is >4, it is considered bacteriostatic. Therefore, the compound of Example 4 is bactericidal for half of the isolates, while GSK656 is bacteriostatic for all isolates. Due to the roughly similar structure and MIC distribution, this differentiation in favor of the compound of Example 4 is very surprising. In fact, bactericidal properties are very important for more effective and efficient elimination of bacterial infections. Specifically, bactericidal compounds can kill or completely eradicate pathogens, whereas bacteriostatic compounds can only prevent bacterial growth. In the latter case, the remaining bacteria may develop bacterial resistance to the drug, thereby rendering the treatment ineffective, or re-infection after cessation of the initial antimicrobial therapy. Therefore, bactericidal agents are preferred over bacteriostatic agents, especially for eradication of persistent mycobacterial infections.

[0068] Table 2 MICs and MBCs for clinical isolates of Mycobacterium abscessus complex Activity of representative compounds in the Mycobacterium abscessus mouse lung infection model

[0069] In order to establish the efficacy of the compounds described in the present application in vivo, a mouse lung infection model with Mycobacterium abscessus was established. Each group of BALB / c mice (mice were randomly divided into groups, 6 mice in each group) was administered cyclophosphamide one week before infection, and then intranasally inoculated with Mycobacterium abscessus CIP108297 (10 7 CFU / mouse). Three days after infection, mice were subsequently treated with 10 mg / kg of the compound of Example 4 or GSK656 subcutaneously daily, or 100 mg / kg of linezolid (an approved antibiotic) or 200 mg / kg of clarithromycin (an approved antibiotic) by oral gavage daily. Figure 1 As shown, the CFU of Mycobacterium abscessus in the lungs was quantified 2 weeks after infection. The results showed that the compound of Example 4 caused a significant reduction in bacteria compared to the untreated group (~7.8log10 CFU). In addition, the organisms in the lungs of mice treated with the compound of Example 4 were significantly reduced compared to animals treated with GSK656. Considering the similar structure and MIC distribution between GSK656 and the compound of Example 4, this significantly improved efficacy is unexpected. This can be attributed to the surprisingly low MBC found in the compound of Example 4. In addition, the compound of Example 4 also shows a higher clearance potential for Mycobacterium abscessus relative to linezolid or clarithromycin, which is given at very high doses.

[0070] H&E-stained tissue sections showed severe alveolar wall thickening, inflammatory cell infiltration, and red blood cell infiltration in the lungs of control mice 2 weeks after infection. Figures 2A-2C As shown, pathological changes were rare and lung damage was negligible in the group treated with the compound of Example 4. These findings demonstrate the efficacy of the compound of Example 4 in inhibiting the replication of M. abscessus in a mouse model of pneumonia. Pharmacokinetic data of representative orally administered prodrugs

[0071] In order to further illustrate the therapeutic potential of drug compounds, pharmacokinetic (PK) data are often used to establish key parameters for predicting treatment outcomes, such as the area under the curve (AUC) that monitors systemic drug concentration over time. The higher the AUC value, the greater the exposure of the drug, which is generally associated with greater therapeutic potential, because the amount of drug that can be applied to fight infection is higher. On the contrary, the lower the AUC value, the less exposure the drug has, resulting in a reduction in the amount of antibiotics that can be used to fight bacterial infections. For this reason, the compounds described in the present application are tested in an oral rat PK model, which is implemented by a method similar to that described in the monograph Current Protocols in Pharmacology, 2005, 7.1.1-71.26, John Wiley & Sons, Inc.

[0072] All compounds were administered to SD rats by intravenous or oral gavage (rats were randomly divided into groups, 3 rats per group). The prodrug was converted into the parent drug molecule in vivo. Therefore, only the parent compound Example 4 was analyzed and quantified in all the test samples. As shown in Table 3, the parent compound in Example 4 has a moderate oral bioavailability of 15%. The pharmacokinetic data of the prodrug described in this application show that at the same dose of 5 mg / kg, the systemic exposure and C max For example, the compound of Example 2 showed a significant improvement in exposure (AUC) and C max 2906hr*ng / ml and 870ng / ml respectively. Compared with the compound of Example 4, this unexpected result indicates that the in vivo drug exposure and Cmax of the compound of Example 2 are significantly increased by 3.4 times and 3 times respectively. The AUC data obtained in the context of the good efficacy of the compound of Example 4 confirmed in the Mycobacterium abscessus mouse lung infection model (see above) strongly indicate that the corresponding prodrug with higher exposure (AUC) has further improved therapeutic potential. Importantly, the data show that this can be achieved by oral administration. In addition, based on the known comparison of rodent tests with human data (such as known interspecies PK scales), it is possible to treat at a lower dose in humans.

[0073] Table 3 Pharmacokinetic data of representative prodrugs in rats

[0074] In addition, in a lung distribution study conducted in Balb / C mice (three mice per time point), the exposure of Example 2 in the lung was much higher than that in the plasma (assessed by the area under the lung / plasma concentration-time curve (AUC)). As shown in Table 4, the compounds of Examples 4 and 2 were administered at 10 mg / kg by intravenous injection and oral administration, respectively. In the analysis of Example 2, the concentrations of the parent compound (Example 4) and the prodrug (Example 2) in plasma and lung were determined. The prodrug (Example 2) was rapidly converted to Example 4, and the prodrug was almost undetectable in plasma. Compared to the AUC of Example 4 administered intravenously, the oral bioavailability of Example 4 produced by Example 2 was 83.95% in mice. Despite the rapid conversion of the prodrug, surprisingly, more Example 4 was detected in the lung, with a lung / plasma AUC ratio of 5.24, almost 2.2 times the AUC of Example 4 administered intravenously.

[0075] Table 4. Lung and plasma distribution of Examples 4 and 2 in mice

[0076] The above complete representative data reveal the surprisingly superior therapeutic potential of the compounds of the present application, with beneficial unexpected advantages in terms of efficacy, efficacy and exposure that were not anticipated by any previous patents or publications on boron anti-infective agents. The significant and surprising improvements in significantly different key parameters of the antibacterial compounds provided by the present application provide significant benefits for the treatment of humans or mammals, including but not limited to improved bactericidal activity, superior in vivo efficacy, convenient oral administration for long treatment durations, and reduced potential adverse reactions.

[0077] The disclosure of each patent, patent application and publication (such as journals, articles and / or textbooks) cited in this application is incorporated by reference in its entirety. In addition, as used in this application and the appended claims, singular articles such as "a", "an" and "one" are intended to refer to the singular or plural. Although the present application describes embodiments in conjunction with preferred aspects, those of ordinary skill in the art, after reading the foregoing description, can affect changes, equivalent replacements and other types of changes to the embodiments described in this application. Each aspect described above may also include or incorporate such changes or aspects disclosed with respect to any or all other aspects. The description of this application is also not limited to the specific aspects described in this application, which is intended to be a single illustration of the various aspects provided by this application. Without departing from its spirit and scope, many modifications and changes may be made to this disclosure, which will be apparent to those skilled in the art. In addition to the methods listed in this application, functionally equivalent methods within the scope of this specification will be apparent to those skilled in the art from the foregoing description. It should be understood that this specification is not limited to specific methods, reagents, process conditions, materials, etc., and of course these methods, reagents and materials may vary. It should also be understood that the terminology used in the present application is for describing particular aspects only and is not intended to be limiting. Therefore, this specification is to be regarded as illustrative.

Claims

1. A method for treating nontuberculous mycobacterial infection, comprising administering to a mammal in need of treatment a compound of formula I: or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof; in: R 1 Selected from H, C 1-24 Alkyl-C(=O)-, C 1-24 Alkoxy-C(=O)-, C 3-7 Cycloalkyl-C(═O)-, heteroalkyl-C(═O)-, aryl-C(═O)-, heteroaryl-C(═O)-, and (5-methyl-1,3-dioxol-2-one-4-yl)methyl; and R 2 Selected from C 1-24 Alkyl-C(=O)-, C 1-24 Alkoxy-C(=O)-, C 3-7 Cycloalkyl-C(═O)-, heteroalkyl-C(═O)-, aryl-C(═O)-, heteroaryl-C(═O)-, and (5-methyl-1,3-dioxol-2-one-4-yl)methyl; or R 1 and R 2 Together, they form a heterocyclic group selected from 1,3-dioxane, 2-C 1-6 Alkyl-1,3-dioxane, 2,2-di(C 1-6 alkyl)-1,3-dioxane, 2-methyl-1,3-dioxane, 2-aryl-1,3-dioxane, 2-(2-carboxyphenyl)-1,3-dioxane, 2-(4-carboxyphenyl)-1,3-dioxane and 2-C 1-6 Alkyl OC(=O)-1,3-dioxane; each of which is optionally substituted by one to four R 3 replace; R 3 is independently selected at each occurrence from a group comprising halogen, hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, aryl and heteroaryl; or When attached to adjacent carbons, the two R 3 The groups, together with the carbon to which they are attached, form a fused C3-C6 cycloalkyl; or When attached to the same carbon, the two R 3 The groups together with the carbon to which they are attached form a spiro C3-C6 cycloalkyl; Each R 3 Optionally independently substituted with 1-3 halogen, hydroxyl or C1-C3 alkyl; And wherein the nontuberculous mycobacterium is selected from the group consisting of Mycobacterium scrofulae, Mycobacterium gordonii, Mycobacterium avium, Mycobacterium abscessus, Mycobacterium intracellulare, Mycobacterium fortuitum, Mycobacterium exogenum, Mycobacterium smegmatis and Mycobacterium massiliense.

2. A method for treating nontuberculous mycobacterial infection, comprising administering to a mammal in need of treatment a compound of formula II: or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof; in: R 1 Selected from H, C 1-24 Alkyl-C(=O)-, C 1-24 Alkoxy-C(=O)-, C 3-7 Cycloalkyl-C(═O)-, heteroalkyl-C(═O)-, aryl-C(═O)-, heteroaryl-C(═O)-, and (5-methyl-1,3-dioxol-2-one-4-yl)methyl; And wherein the nontuberculous mycobacterium is selected from the group consisting of Mycobacterium scrofulae, Mycobacterium gordonii, Mycobacterium avium, Mycobacterium abscessus, Mycobacterium intracellulare, Mycobacterium fortuitum, Mycobacterium exogenum, Mycobacterium smegmatis and Mycobacterium massiliense.

3. The method according to claim 1, characterized in that R 1 C 1-4 Alkyl-C(=O)- and R 2 C 1-4 Alkyl-C(═O)—.

4. The method according to claim 1, characterized in that: The compound is selected from: or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

5. The method according to claim 2, characterized in that: The compound is selected from: or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

6. The method according to any one of claims 1 to 5, characterized in that The pharmaceutically acceptable salt is hydrochloride.

7. The method according to any one of claims 1 to 6, characterized in that The compound or a pharmaceutically acceptable salt thereof is administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, buccally, intranasally, by inhalation, vaginally, intraocularly, topically, subcutaneously, intrafatally, intraarticularly, intraperitoneally, or intrathecally.

8. The method according to any one of claims 1 to 7, characterized in that The compound or a pharmaceutically acceptable salt thereof is administered in a single dose in the range of 10-1000 mg.

9. The method according to any one of claims 1 to 8, characterized in that The compound or a pharmaceutically acceptable salt thereof is administered in a single dose in the range of 100-400 mg.

10. The method according to any one of claims 1 to 9, characterized in that The compound or a pharmaceutically acceptable salt thereof is administered once or twice daily in a single dose.

11. The method according to any one of claims 1 to 10, characterized in that: The compound or a pharmaceutically acceptable salt thereof is administered twice daily in a single dose suitable for oral solid dosage form.

12. The method according to any one of claims 1 to 11, characterized in that The infection is a skin, soft tissue, respiratory tract, blood, intra-abdominal, urinary, bone or eye infection.

13. The method according to any one of claims 1 to 12, characterized in that The compound or pharmaceutical composition is administered for 4-12 months.

14. The method according to any one of claims 1 to 13, characterized in that The compound or its pharmaceutically acceptable salt or its pharmaceutical composition is administered in a dosage form suitable for oral administration.

15. The method according to any one of claims 1 to 14, characterized in that The compound or its pharmaceutically acceptable salt or its pharmaceutical composition is administered in a dosage form suitable for oral administration, and the compound exhibits an oral bioavailability of about 50%-100%.

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