Therapeutic agents for nontuberculous mycobacterial infections in mammals

Abstract

The present invention provides an organic boron compound of formula I or a salt thereof, a pharmaceutical composition thereof, and uses of the organic boron compound and the pharmaceutical composition in the treatment of non-tuberculous mycobacterial infections. [Chemical 1] TIFF2025520237000027.tif49159

Description

Technical Field

[0001] The present application provides an organoboron compound used for the treatment of nontuberculous mycobacterial infections and a pharmaceutical composition used for the treatment of the same disease.

Background Art

[0002] Pulmonary nontuberculous mycobacteriosis (NTM-PD) is a severe progressive disease caused by certain mycobacteria and may require complex treatment with multiple antimycobacterial drugs or combinations of such antibiotics for more than 12 months (see, for example, the content described by Daley et al. in Clin. Infect. Dis. 2020 Aug 15;71(4):905-913). NTM refers to all Mycobacterium species except the Mycobacterium tuberculosis complex. More than 190 NTM bacteria have been discovered so far, but most of them are parasitic bacteria, and only a small number are conditional pathogens that infect humans. However, in recent years, with the increase in the number of patients with acquired immunodeficiency syndrome and immunosuppressed groups, the incidence and prevalence of NTM diseases have been increasing worldwide. In addition, the resistance of NTM to antibiotics is also increasing. In particular, the drug resistance rate of recurrent patients is very high, which may make clinical treatment difficult. NTM-PD has a higher mortality rate than Mycobacterium tuberculosis (MTB) due to inappropriate treatment and a high treatment failure rate.

[0003] NTM flora is classified into four groups according to Runyon classification, depending on the growth temperature, growth rate, colony morphology, and the relationship between pigment production and light reaction. The first three groups are slow-growing mycobacteria, and the fourth group is fast-growing mycobacteria. Group I is photochromogens, mainly composed of M. kansasii, M. marinum, and M. simiae. Group II is scotochromogens, mainly composed of M. scrofulaceum, M. gordonae, and M. szulgai. Group III is non-photochromogens, including M. avium complex (MAC), M. haemophilum, M. ulcerans, M. xenopi, M. malmoense, M. terrae, and M. gasteri. Group IV is rapidly growing mycobacteria (RGM), including M. abscessus complex (MABC), M. fortuitum, M. chelonae, M. margeritense, M. peregrinum, M. smegmatis, and M. vaccae.

[0004] Since NTM includes bacterial flora that causes severe lung infections, treatment is usually complex and requires long-term treatment. In addition, many NTM have intrinsic resistance to standard anti-tuberculosis drugs and show different resistance phenotypes depending on the type, so available treatment drugs and programs are limited.

[0005] Oral formulations are the optimal choice for many patients with bacterial infections that require long-term antibiotic treatment. Oral administration has the advantages of avoiding catheter-related infections, reducing drug costs, and reducing hospital costs (such as the need for healthcare professionals and facilities for intravenous administration of antibiotics) compared to the intravenous administration route. Oral administration is also particularly important for ensuring compliance in patients who require long-term treatment. For example, the treatment of M. avium or M. abscessus infections usually takes several months.

[0006] Therefore, there is a need for a new therapeutic agent that has a new mode of action, has effective activity against drug-resistant isolates, has few side effects, and is easy to administer orally.

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0008] The present application provides a boron compound and a pharmaceutical composition thereof for treating non-tuberculous mycobacterial infections.

Means for Solving the Problems

[0009] The following organic boron compounds are a kind of antibiotics having high antibacterial activity against Gram-negative bacteria, Gram-positive bacteria, mycobacteria, etc.

[0010]

Chemical Formula

[0011] Such tricyclic boron compounds are active against Gram-negative bacteria (e.g., Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae), as described in U.S. Patent No. 8,530,452. However, the activity of such compounds against Mycobacterium has not been reported. In fact, the cell envelope of Mycobacterium is quite different from that of typical Gram-positive and Gram-negative bacteria, and it cannot be assumed that an antibiotic will have antibacterial activity against both Gram-negative bacteria and Mycobacterium. As described in the present application, the salt form of such boron compounds has unexpectedly been found to be active against Mycobacterium. Also, as described below, this compound exhibits only moderate oral bioavailability. In contrast, the specific prodrugs described in the present application show improved oral bioavailability and improved systemic exposure, which is important for eradicating pathogens. The specific compounds described in the present application exhibit the important and advantageous dual therapeutic properties of efficacy against Mycobacterium and oral bioavailability. This represents a significant advance over most antibiotics, such as cephalosporins, which can only be administered intravenously in a hospital setting.

[0012] In one aspect, the present application provides a method for treating non-tuberculous mycobacterial infections, 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,

[0013]

Chemical formula

[0014] wherein, R 1 is selected from the group consisting of 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-dioxo-2-one-4-yl)methyl, and, R2 is 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-dioxo-2-one-4-yl)methyl, or R 1 and R 2 form a heterocyclic group selected from the group consisting of 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 alkylOC(=O)-1,3-dioxane, and each of them is optionally substituted with 1 to 4 R 3 groups, R 3 is, each time it appears, independently selected from the group consisting of halogen, hydroxyl group, C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 alkoxy group, aryl group, heteroaryl group, or when bonded to adjacent carbons, two R 3 groups together with the carbon to which they are bonded form a fused C3-C6 cycloalkyl group, or when bonded to the same carbon, two R 3 groups together with the carbon to which they are bonded form a spiro C3-C6 cycloalkyl group, wherein each R 3 is independently optionally substituted with 1 to 3 halogen, hydroxyl group or C1-C3 alkyl group, or the hydrogen in -OH bonded to the boron atom is absent, and R 2and oxygen bonded to a boron atom form a compound of Formula II. Accordingly, in another aspect, the present application provides a method for treating non-tuberculous mycobacterial infections, 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,

[0015]

Chemical formula

[0016] wherein, R 1 is selected from the group consisting of 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-dioxo-2-one-4-yl)methyl.

[0017] 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 manufacture of a medicament for treating non-tuberculous mycobacterial infections.

[0018] In another aspect, the present application provides a pharmaceutical composition for treating non-tuberculous mycobacterial infections, comprising a compound of Formula I or II or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0019] Non-tuberculous mycobacteria include, but are not limited to, M. scrofulaceum, M. gordonae, M. avium, M. abscessus, M. intercelleulare, M. fortuitum, M. peregrinum, M. smegmatis, M. massiliense.

Brief Description of the Drawings

[0020]

Figure 1

Figure 2A

Figure 2B

Figure 2C

Mode for Carrying Out the Invention

[0021] Unless otherwise specified, the following terms used in the specification and claims have the meanings shown below.

[0022] The terms such as alkyl group and alkenyl group mean linear and branched chain groups. However, for individual groups such as "propyl group", only the linear chain group is included, and for branched chain isomers such as "isopropyl group", only the branched isomer is included. Groups such as alkyl group and alkenyl group may be substituted with 1, 2 or 3 substituents selected from the group consisting of halogen group, aryl group, Het 1 or Het 2 and may be substituted with 1, 2 or 3 substituents selected from the group consisting of. Representative examples include difluoromethyl group, 2-fluoroethyl group, trifluoroethyl group, -CH=CH-aryl group, -CH=CH-Het 1 , -CH2-phenyl group and the like, but are not limited thereto.

[0023] The term "cycloalkyl group" means a cyclic saturated monovalent hydrocarbon group having 3 to 6 carbon atoms such as a cyclopropyl group or a cyclohexyl group. The cycloalkyl group may be substituted with 1, 2 or 3 substituents selected from the group consisting of a halogen group, an aryl group, Het 1 or Het 2 and may be substituted with 1, 2 or 3 substituents selected from the group consisting of.

[0024] The term "heteroalkyl" means an alkyl group or a cycloalkyl group as defined above having a substituent containing a heteroatom selected from N, O or S(O) n , wherein n is an integer from 0 to 2, and the substituents include a hydroxyl group (OH), C 1-4 alkoxy group, amino group, thio group (SH), etc. Representative substituents are -NR a R b , -OR a or -S(O) n -R c , wherein R a is H, C 1-4 alkyl group, C 3-6 cycloalkyl group, optionally substituted aryl group, optionally substituted heterocycle or -COR (wherein R is C 1-4 alkyl group), R b is H, C 1-4 alkyl group, -SO2R (wherein R is C 1-4 alkyl group or C 1-4 hydroxyalkyl group), -SO2NRR' (wherein R and R' are independently of each other H or C 1-4 alkyl group), -CONR'R'' (wherein R' and R' are independently of each other H or C 1-4 alkyl group), n is an integer from 0 to 2, R c is H, C 1-4 alkyl group, C 3-6 cycloalkyl group, optionally substituted aryl group or NR a R b , wherein R a and R bis as defined above. Representative examples include, but are not limited to, 2-methoxyethyl (-CH2CH2OCH3), 2-hydroxyethyl (-CH2CH2OH), hydroxymethyl (-CH2OH), 2-aminoethyl (-CH2CH2NH2), 2-dimethylaminoethyl (-CH2CH2NHCH3), benzyloxymethyl, thiophen-2-ylthiomethyl, etc.

[0025] The term aryl group means a phenyl group, biphenyl group or naphthyl group optionally substituted with 1 to 3 substituents independently selected from halogen, -C 1-4 alkyl group, -OH, -OC 1-4 alkyl group, -S(O) n C 1-4 alkyl group (n is 0, 1 or 2), -C 1-4 alkyl NH2, -NHC 1-4 alkyl group, -C(=O)H or -C=N-OR d (R d is H or -C 1-4 alkyl group).

[0026] Het 1 is, each time it appears, independently a 5- or 6-membered C-bonded heterocyclic ring having 1 to 4 heteroatoms selected from O, N and S in the ring. Het 2 is, each time it appears, independently a 5- or 6-membered N-bonded heterocyclic ring having 1 to 4 Ns in the ring and optionally having 1 O or S in the ring. "Optional" or "optionally" means that the event or situation described thereafter may occur but does not necessarily occur, and the description includes both the case where the event or situation occurs and the case where it does not occur. For example, "an aryl group optionally mono- or disubstituted with an alkyl group" means that the alkyl group may or may not be present, and the description includes both the case where the aryl group is mono- or disubstituted with an alkyl group and the case where the aryl group is not substituted with an alkyl group.

[0027] The term "pharmaceutically acceptable carrier" generally refers to a carrier that is safe, non-toxic, and free of biologically or otherwise undesirable substances, and includes carriers useful for preparing pharmaceutical compositions for veterinary and human drugs. The "pharmaceutically acceptable carrier" used in the specification and claims includes one or more such carriers.

[0028] The "pharmaceutically acceptable salt" of a compound means a pharmaceutically usable salt having the pharmacological activity required for 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, or 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, glucoheptonic 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 by substituting acidic protons present in the parent compound with metal ions such as alkali metal ions, alkaline earth metal ions, aluminum ions, etc., or salts formed by combining with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.

[0029] The term "tautomer" means two or more forms or isomers of an organic compound that can be interconverted by a general chemical reaction called tautomerization, and is usually the same as that described by Smith et al. in Advanced Organic Chemistry. 2001, 5th Ed. NY: Wiley Interscience., pp. 1218 - 1223. The concept of tautomerism is called tautomerization. Tautomerization may involve a change from a ring structure to an open structure, for example, as observed in the interconversion between the cyclic pyran form and the open-chain form of glucose by the formation and cleavage of a C - O bond. The degree of tautomerization is usually affected by solvent effects such as hydration with water and medium acidity. The related process for cyclic boron compounds may include the formation and cleavage of B - O bonds as follows.

[0030] [Chem.]

[0031] "Treating" (or "treatment") of a disease includes (1) preventing a disease, i.e., in a mammal that has been exposed to or is susceptible to a disease but has not experienced or manifested the symptoms of the disease, preventing the progression of the clinical symptoms of the disease; (2) suppressing a disease, i.e., arresting or reducing the progression of the disease or its clinical symptoms, or (3) alleviating a disease, i.e., causing regression of the disease or its clinical symptoms.

[0032] "Therapeutically effective amount" means an amount of a compound sufficient to affect the treatment of a disease in a mammal. The "therapeutically effective amount" varies depending on the compound, the disease and its severity, the age, weight, etc. of the mammal to be treated.

[0033] "Prodrug" means a compound that releases an active parent drug in vivo when the prodrug is administered to a mammalian subject. The prodrugs of the compounds described in the present application are prepared by modifying the functional groups present in the compounds provided in the present application, and the modification can cleave in vivo to release the parent compound. A prodrug contains the compound described in the present application, and a hydroxy, sulfhydryl, amide, or amino group in the compound of the present application is bonded to any group that can cleave in vivo to regenerate a free hydroxyl, amide, amide, or sulfhydryl group, respectively.

[0034] "Patient" means an animal such as a mammal including non - primates (such as cows, pigs, horses, cats, dogs, rats, mice, etc.) and primates (such as monkeys such as cynomolgus monkeys, chimpanzees, humans, etc.), for example, a human. In some embodiments, the patient is a human.

[0035] Exemplary embodiments In one aspect, the present application provides a method for treating non - tuberculous mycobacterial infections, which includes administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

[0036]

Chemical formula

[0037] Among them, R 1 is selected from the group consisting of 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 - dioxo - 2 - one - 4 - yl)methyl, and, R 2 is C 1-24 alkyl - C(=O)-, C 1-24 alkoxy - C(=O)-, C 3-7Selected from the group consisting of cycloalkyl-C(=O)-, heteroalkyl-C(=O)-, aryl-C(=O)-, heteroaryl-C(=O)-, and (5-methyl-1,3-dioxo-2-on-4-yl)methyl, or, R 1 and R 2 together form a heterocyclic group selected from the group consisting of 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 alkylOC(=O)-1,3-dioxane, each of which is optionally substituted with 1 to 4 R 3 groups, R 3 is, each time it appears, independently selected from the group consisting of halogen, hydroxyl group, C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 alkoxy group, aryl group, heteroaryl group, or, when attached to adjacent carbons, two R 3 groups together with the carbon to which they are attached form a fused C3-C6 cycloalkyl group, or, when attached to the same carbon, two R 3 groups together with the carbon to which they are attached form a spiro C3-C6 cycloalkyl group, wherein each R 3 is independently optionally substituted with 1 to 3 halogen, hydroxyl groups or C1-C3 alkyl groups, or, the hydrogen in -OH bonded to the boron atom is absent, and R 2 in the compound of formula I and the oxygen bonded to the boron atom form a compound of formula II. Accordingly, in another aspect, the present application provides a method for treating non-tuberculous mycobacterial infections, which comprises administering a compound of formula II or a pharmaceutically acceptable salt thereof to a patient in need of treatment,

[0038]

Chemical formula

[0039] Among them, R 1 is 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-dioxo-2-one-4-yl)methyl selected from the group consisting of.

[0040] In some embodiments, a method for treating a nontuberculous mycobacterial infection comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need of treatment, wherein R 1 is C 1-4 alkyl-C(=O)-, and R 2 is C 1-4 alkyl-C(=O)-.

[0041] 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 manufacture of a medicament for treating a nontuberculous mycobacterial infection.

[0042] Nontuberculous mycobacteria include, but are not limited to, M. scrofulaceum, M. gordonae, M. avium, M. abscessus, M. intercelleulare, M. fortuitum, M. peregrinum, M. smegmatis, M. massiliense.

[0043] The compound of formula I or formula II may 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.

[0044] The compound of formula I or formula II or a pharmaceutically acceptable salt thereof can be administered via various routes of administration including, but not limited to, oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, intravaginal, intraoccularly, topical, subcutaneous, intraadiposally, intraarticular, intraperitoneal, and intrathecal. In one embodiment, the administration is oral administration.

[0045] The amount of the compound of formula I or formula II or a pharmaceutically acceptable salt thereof can be determined based on the severity of the disease, the response to the disease, the toxicity associated with the treatment, and / or the age and health status of the patient. In some embodiments, the amount of the compound of formula I or II or a pharmaceutically acceptable salt thereof is 10 - 1000 mg. In some embodiments, the amount of the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is 100 - 600 mg. In some embodiments, the amount of the compound of formula I or II or a pharmaceutically acceptable salt thereof is 200 - 400 mg.

[0046] The compound of formula I or II or a pharmaceutically acceptable salt thereof may be administered once or multiple times a day. In some embodiments, the compound of formula I or II or a pharmaceutically acceptable salt thereof is administered once a day in the form of a single dose. In one embodiment, the compound is administered twice a day in the form of a single dose. In one embodiment, the compound is administered twice a day in a single dose suitable for an oral solid preparation.

[0047] 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 manufacture of a medicament for treating non - tuberculous mycobacterial infections. Non - tuberculous mycobacteria include, but are not limited to, M. scrofulaceum, M. gordonae, M. avium, M. abscessus, M. intercelleulare, M. fortuitum, M. peregrinum, M. smegmatis, M. massiliense.

[0048] In some embodiments, the pharmaceutical composition is a formulation suitable for oral administration, including but not limited to tablets, capsules, powders, granules, drops, pastes, powders, etc. In preferred embodiments, tablets and capsules are used. Examples of tablets include ordinary tablets, dispersible tablets, effervescent tablets, sustained-release tablets, release-controlled tablets, or enteric-coated tablets. Examples of capsules include ordinary capsules, sustained-release capsules, release-controlled capsules, or enteric-coated capsules. Oral formulations can be prepared by conventional methods using 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 sodium cross-linked carboxymethyl cellulose, crospovidone, surfactants, low-substituted hydroxypropyl cellulose, etc. Lubricants include magnesium stearate, talc, polyethylene glycol, sodium lauryl sulfate, talc, etc. Pharmaceutical excipients further include colorants, sweeteners, etc.

[0049] In one embodiment, the pharmaceutical composition is a solid formulation suitable for oral administration. For example, the composition may be in the form of tablets, pills, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid or liquid media), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders. In certain embodiments, the pharmaceutical composition is a capsule.

[0050] When preparing the formulation, it may be necessary to grind the active compound before combining it with other ingredients in order to provide an appropriate particle size. If the active compound is substantially insoluble, it is usually ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size is usually adjusted by grinding to provide a substantially uniform distribution in the formulation, for example, at about 40 mesh.

[0051] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. Lubricants such as talc, magnesium stearate and mineral oil, wetting agents, emulsifiers and suspending agents, preservatives such as methyl and propyl hydroxybenzoate esters, sweeteners, and flavorings may further be included in the formulation. The compositions described herein can be prepared by employing procedures known to those skilled in the art in order to provide an active ingredient that is released rapidly, sustainably or with a delay after administration to a patient.

[0052] To prepare a solid composition such as a tablet, the main active ingredient is mixed with a pharmaceutical excipient to form a solid pre-formulation composition comprising a homogeneous mixture of the compounds described herein. These pre-formulation compositions are said to be homogeneous when the active ingredient is uniformly dispersed throughout the composition and the composition can be readily subdivided into equivalent effective unit dosage forms such as tablets, pills, capsules. Then, such solid pre-formulations are subdivided into the above unit dosage forms.

[0053] In one embodiment, a pharmaceutical composition for treating non-tuberculous mycobacterial infections is prepared in a single dosage form. In one embodiment, the single dosage form contains 10 mg to 1000 mg of a compound of formula I or formula II or a pharmaceutically acceptable salt thereof. In some embodiments, the single dosage form contains 100 mg to 600 mg of a compound of formula I or formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the single dosage form contains 200 mg to 400 mg of a compound of formula I or formula II or a pharmaceutically acceptable salt, preferably 200 mg to 400 mg of a compound of formula I or formula II or a pharmaceutically acceptable salt.

[0054] The tablets or pills described in the present application can be coated or otherwise formulated in order to provide a dosage form with the advantage of extended action. For example, the tablets or pills may contain an internal dosage component and an external dosage component, the latter being in the form of an envelope covering the former. These two components can be separated by an enteric layer that resists disintegration in the stomach and allows the internal component to completely enter the duodenum or be released in a delayed manner. Such enteric layers or coatings can use a plurality of polymeric acids and a plurality of materials including mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0055] In some embodiments, continuous administration is carried out for 4 to 18 months, preferably 4 to 6 months.

[0056] In another embodiment, this pharmaceutical composition is administered in combination with other antibiotics currently used to treat NTM infections (e.g., amikacin, clarithromycin, azithromycin, or ciprofloxacin).

[0057] Unless otherwise specified, the dosages and ranges provided herein are based on the molecular weight of the free base form of the compound of formula I or formula II.

[0058] Preferred compounds of formula II are the following structures or pharmaceutically acceptable salts thereof.

[0059]

Chem.

[0060] Furthermore, the preferred compounds of formula I include the following structure or a pharmaceutically acceptable salt thereof.

[0061]

Chem.

[0062] The preferred compounds of formula II include the following structure or a pharmaceutically acceptable salt thereof.

[0063]

Chem.

[0064] In some embodiments, the pharmaceutically acceptable salt form of the compound of formula I or II is the hydrochloride salt.

[0065] Examples The examples described below are for illustrative purposes only and do not limit the scope of the present disclosure. General abbreviations well known to those of ordinary skill in the art of synthetic techniques are used throughout. 1 The 1H NMR spectra are recorded on a 300 MHz instrument using DMSO-d6 unless otherwise specified. This application provides mass spectrometry data by the cationization method. Chromatography is silica gel chromatography unless otherwise specified. TLC is thin layer chromatography. HPLC is reverse phase HPLC. Unless otherwise specified, all reagents are commercially available or prepared by conventional methods described in the existing literature.

[0066] Example 1 (2S)-3-Acetoxy-1-[[(3S)-3-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[2,1-c][1,2]oxaborol-7-yl]oxy]acetic acid 2-propanyl hydrochloride

[0067]

Chem.

[0068] The preparation scheme of the compound of Example 1 is as follows.

Chem.

[0069] Intermediate 2: Ac2O (32 μL, 0.33 mmol) was added dropwise to a solution of Intermediate 1 (60 mg, 0.26 mmol, prepared as described in US Patent Application US 2013 / 0165411) and pyridine (31 μL, 0.33 mmol) in DCM (2 mL), and the resulting mixture was stirred for 2 hours. After completion of the reaction, the solvent was removed by concentration, and the residue was purified by pre-HPLC to obtain Intermediate 2 (25 mg). MS (m / z): 438 [M+H].[[]END]]

[0070] Example 1: Intermediate 2 was dissolved in a dioxane solution of 5M HCl (2 mL) at room temperature, and the resulting mixture was stirred for 1 hour. Then, the mixture was lyophilized to obtain the compound of Example 1 (16.9 mg) as a pale yellow powder. MS (m / z): 338 [M+H].[[]END]] 1 1H NMR: (400 MHz, D2O): 7.48 (t, J = 8.0 Hz, 1H); 7.01 (d, J = 7.6 Hz, 1H); 6.92 (dd, J = 12.0, 8.0 Hz, 1H); 5.35 (dd, J = 7.4, 3.0 Hz, 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).

[0071] The following compounds were synthesized according to the steps described in Example 1.

[0072]

Table 1A

[0073]

Table 1B

[0074] Example 4 [(2S,6R)-2-(Aminomethyl)-4-bora-3,5,8-trioxatricyclo[7.3.1.04,13]trideca-1(12),10-diene-6-yl]methanol hydrochloride

[0075]

Chemical formula

[0076] The compound of Embodiment 4 was prepared according to the method described in US Patent Application No. 2013 / 0165411.

[0077] Example 5 [(2S,6S)-2-(Aminomethyl)-4-bora-3,5,8-trioxatricyclo[7.3.1.04,13]trideca-1(12),9(13),10-triene-6-yl] 2-methylpropanoate methyl hydrochloride

[0078]

Chemical formula

[0079] Example 7 [(2S,6S)-2-(Aminomethyl)-4-bora-3,5,8-trioxatricyclo[7.3.1.04,13]trideca-1(12),9(13),10-triene-6-yl] acetate methyl hydrochloride

[0080] [Chemical formula]

[0081] The compound of Embodiment 7 was prepared according to the method described in US Patent Application No. 2013 / 0165411.

[0082] Example 8 [(2S,6S)-2-(Aminomethyl)-4-bora-3,5,8-trioxatricyclo[7.3.1.04,13]trideca-1(12),9(13),10-triene-6-yl]methyl propionate hydrochloride

[0083] [Chemical formula]

[0084] The compound of Embodiment 8 was prepared according to the method described in US Patent Application No. 2013 / 0165411.

[0085] Utility and Measurement The compounds described in the present application are boron compounds and their prodrugs. The prodrug is converted into the parent boron compound in vivo and exhibits antibacterial effects. Therefore, the antibacterial activity of the prodrug compounds of the present application is measured by the parent boron compound.

[0086] In vitro activity of representative compounds against Mycobacterium The in vitro activity of the parent boron compounds described in the present application is evaluated by standard measurement processes such as the measurement of the minimum inhibitory concentration (MIC) described in the document M24-A2 of the Clinical and Laboratory Standards Institute (CLSI). A lower MIC value indicates higher antibacterial activity, while a higher MIC value indicates lower antibacterial activity. Generally, an MIC value of about ≦2 mg / L indicates that the antibacterial agent has good therapeutic (i.e., suitable for treatment) efficacy, while an MIC value of ≧8 mg / L indicates that the test compound lacks therapeutically useful activity.

[0087] The in vitro activity (efficacy) of the representative compounds described in the present application against Mycobacterium is illustrated by the MIC data in Table 2 below. As is apparent from the data in Table 2, the compounds of Example 4 have high activity against many Mycobacterium pathogens, including M. scrofulaceum, M. gordonae, M. avium, M. abscessus, M. intercelleulare, M. fortuitum, M. peregrinum, M. smegmatis, M. massiliense (MIC range 0.063 - 2 mg / L). In particular, the compounds of Example 4 have surprising efficacy against rapidly growing Mycobacterium (RGM), including M. abscessus, M. intercelleulare, M. fortuitum, Mycobacterium peregrinum, M. smegmatis, M. massiliense (MIC range 0.063 mg / L to 0.125 mg / L).

[0088] Compound GSK656 is another boron compound disclosed in PCT application WO / 2012 / 033858 and is generally relevant to the compositions provided in the present application. Surprisingly, despite some structural similarities, the compounds of Example 4 and GSK656 exhibit very different antibacterial spectra against non-tuberculous mycobacteria. Of great importance is that Example 4 has very strong efficacy against M. fortuitum, M. peregrinum, and M. smegmatis, with an MIC value of 0.125 mg / L, whereas the MIC of GSK656 is ≥ 8 mg / L. Based on these values, the activity of compound GSK656 is more than 64-fold lower than that of the representative compounds of Example 4 of the present application.

[0089] Similarly surprisingly, the compound of Example 4 has a potency 4-fold higher than GSK656 against the NTM pathogens M. avium and M. intracellulare. Such a large difference in the antibacterial spectrum in terms of activity and potency was completely unexpected. In fact, the compound of Embodiment 4 has significantly and surprisingly improved activity compared to the reference compound GSK656, providing antibacterial coverage against NTM pathogens far exceeding the possible antibacterial coverage of GSK656. Another boron compound AN2690 disclosed in US Patent Application US 2006 / 0234981 also has moderate activity or no activity against all measured NTM species. Since NTM infections are complex, it is most beneficial and convenient for clinical use when a compound has a broad-spectrum antibacterial activity covering multiple mycobacteria. Thus, the compositions described herein provide an optimal choice for use in the treatment of such NTM.

[0090]

Table 2

[0091] To further characterize the antibacterial properties of the compounds described in the present application, the minimum bactericidal concentration (MBC) was also measured based on the Clinical and Laboratory Standards Institute (CLSI) document M24-A2. Both GSK656 and the compound of Example 4 were measured for MIC and MBC against 20 clinical isolates of the Mycobacterium abscessus complex (MABC) including M. abscessus and M. massiliense. As shown in Table 3, GSK656 and the compound of Example 4 have similar MICs in clinical isolates. However, very surprisingly, the compound of Example 4 has a lower MBC against all the measured isolates. An antibiotic is considered bactericidal if the MBC / MIC ratio is <4 and bacteriostatic if >4. Thus, the compound of Example 4 is bactericidal against half of the isolates, and GSK656 is bacteriostatic against all the isolates. Since the structures and MIC distributions are similar, it is very surprising that this is beneficial for the differentiation of the compound of Example 4. In fact, bactericidal properties are very important for more effectively and efficiently eliminating bacterial infections. Specifically, bactericidal compounds can kill or completely eradicate pathogens, while bacteriostatic compounds can only inhibit the growth of bacteria. In the latter case, the remaining bacteria may become resistant to the drug, rendering the treatment ineffective or causing the infection to relapse after the initial antibacterial treatment is discontinued. Therefore, especially for eradicating persistent Mycobacterium infections, bactericidal agents are preferred over bacteriostatic agents.

[0092]

Table 3

[0093] Activity of representative compounds in a murine model of M. abscessus lung infection To establish the in vivo efficacy of the compounds described in the present application, a murine model of M. abscessu lung infection was created. Cyclophosphamide was administered to each group of BALB / c mice (randomly grouped 6 mice per group) 1 week before infection, and M. abscessus CIP108297 (10 7(CFU / mouse) were inoculated intranasally. Three days after infection, the mice were treated by subcutaneous administration of 10 mg / kg of the compound of Example 4 or GSK656, or by forced oral administration of 100 mg / kg of linezolid (an approved antibiotic) or 200 mg / kg of clarithromycin (an approved antibiotic). As shown in Figure 1, the M. abscessus CFU in the lungs was quantified two weeks after infection. As a result, the compound of Example 4 significantly reduced the bacteria (~7.8 log10 CFU) compared to the untreated group. Also, the mice treated with the compound of Example 4 had a significantly reduced number of microorganisms in the lungs compared to the animals treated with GSK656. Considering the similar structure and MIC distribution between GSK656 and the compound of Example 4, this significantly improved effect was unexpected. This can be attributed to the surprising finding of the low MBC in the compound of Example 4. Furthermore, the compound of Example 4 showed a higher clearance potential against M. abscessus compared to linezolid or clarithromycin administered at very high doses.

[0094] H&E stained tissue sections showed severe alveolar wall thickening, inflammatory cell infiltration and erythrocyte exudation in the lungs of the control group mice two weeks after infection. In contrast, as shown in Figures 2A - 2C, in the group treated with the compound of Example 4, pathological changes were rare and lung damage was negligible. These findings demonstrate the effect of the compound of Example 4 in inhibiting the replication of M. abscessus in a murine pneumonia model.

[0095] Pharmacokinetic data upon oral administration of representative prodrugs To further elucidate the therapeutic potential of drug compounds, pharmacokinetic (PK) data are generally used to establish important parameters for predicting treatment outcomes, such as the area under the curve (AUC) that monitors the change in drug concentration over time in the whole body. The higher the AUC value, the greater the drug exposure, and since there is more drug available for combating infections, it is generally associated with greater therapeutic potential. Conversely, a lower AUC value indicates less drug exposure, leading to a decrease in the amount of antibiotic available for combating bacterial infections. Therefore, the compounds described in this application were tested in an orally administered rat PK model in a manner similar to the method described in the monograph "Current Protocols in Pharmacology, 2005, 7.1.1 - 71.26, John Wiley & Sons, Inc.".

[0096] All compounds were administered to Sprague - Dawley rats either intravenously or by forced oral administration (rats were randomly grouped into groups of three). Prodrugs are converted into parent drug molecules in vivo. As a result, in all measurement samples, the analysis and quantification of the parent compound were performed only in Example 4. As shown in Table 4, the parent compound of Example 4 has a moderate oral bioavailability of 15%. The pharmacokinetic data of the prodrugs described in this application show that at the same dose of 5 mg / kg, the systemic exposure and C max were significantly improved. For example, the compound of Example 2 shows that the exposure (AUC) is 2906 hr*ng / ml and C max is 870 ng / ml. This unexpected result shows that compared with the compound of Example 4, the in - vivo drug exposure of the compound of Example 2 is 3.4 times, and C maxThis indicates that they each increased significantly by threefold. Based on the good therapeutic effects of the compounds of Example 4 confirmed in the M. abscessus mouse lung infection model (see above), the AUC data obtained suggest strongly that the corresponding prodrugs with higher exposure (AUC) have higher therapeutic potential. Importantly, the data show that this can be achieved by oral administration. Furthermore, based on the known comparison between rodent measurements and human data (e.g., the known interspecies PK scale), treatment at low doses is possible for humans.

[0097]

Table 4

[0098] Furthermore, in the lung distribution study conducted in Balb / C mice (3 mice at each time point), the exposure in the lung of Example 2 was much higher than the exposure in plasma (evaluated by the area under the plasma / lung concentration-time curve (AUC)). As shown in Table 5, the compounds of Example 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 measured. The prodrug (Example 2) was rapidly converted to Example 4 so that almost no prodrug was detected in plasma. Comparing with the AUC by intravenous administration of Example 4, the oral bioavailability of Example 4 generated in Example 2 in mice was 83.95%. Although the prodrug was rapidly converted, surprisingly, even more Example 4 was detected in the lung, and the lung / plasma AUC ratio was 5.24, which is nearly 2.2 times the AUC of intravenously administered Example 4.

[0099]

Table 5

[0100] From the above complete representative data, the compounds of the present application show surprisingly excellent therapeutic potential, indicating beneficial and unexpected advantages that were not predicted by previous patents or publications regarding boron anti-infective agents in terms of efficacy, effectiveness, and exposure. The significant and surprising improvements in the clearly different important parameters of the antibacterial compounds provided in the present application include, but are not limited to, improved bactericidal activity, excellent in vivo effectiveness, convenience of oral administration during long-term treatment periods, and reduction of possible side effects, providing significant advantages for the treatment of humans or mammals.

[0101] The disclosure content of each patent, patent application, and publication (such as periodicals, articles, and / or textbooks) cited in the present application is incorporated herein by reference in its entirety. Further, as used in this specification and the appended claims, singular articles such as "a", "an", and "one" are intended to mean singular or plural. The present application describes embodiments in connection with preferred aspects, but those skilled in the art can affect changes, equivalent alternatives, and other changes to the above-described embodiments after reading the foregoing content. Each of the above aspects can also include or incorporate such changes or aspects disclosed with respect to any or all other aspects. The present application is not limited to the specific aspects described herein, but is intended as a single illustration of the various aspects provided in the present application. Without departing from the spirit and scope of the present disclosure, many modifications and changes can be made to the present disclosure, which can be easily conceived by those skilled in the art. In addition to the methods listed in the present application, functionally equivalent methods within the scope of the present application can be easily conceived by 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 it is natural that these methods, reagents, and materials can change. It should also be understood that the terms used in the present application are used only to describe specific aspects and are not intended to be limiting. Therefore, this specification should be regarded as illustrative.

Claims

1. A therapeutic agent for treating nontuberculous mycobacterial infections in mammals, comprising as an active ingredient a compound of formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, 【Chemistry 1】 In Formula I, R 1 is C 1-4 alkyl-C(═O)—, R 2 is C1-4 alkyl-C(=O)-, and the nontuberculous mycobacteria are selected from M. scrofulaceum, M. gordonae, M. avium, M. abscessus, M. intercelleulare, M. fortuitum, M. peregrinum, M. smegmatis, and M. massiliense; A drug for the treatment of nontuberculous mycobacterial infections.

2. A therapeutic agent for treating nontuberculous mycobacterial infections in mammals, comprising as an active ingredient a compound of formula II or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, 【Chemistry 2】 In Formula II, R 1 is H and C 1-24 alkyl-C(=O)-; and the nontuberculous mycobacteria are selected from M. scrofulaceum, M. gordonae, M. abscessus, M. fortuitum, M. peregrinum, M. smegmatis, and M. massiliense; A drug for the treatment of nontuberculous mycobacterial infections.

3. The compound is 【Transformation 3】 The method of claim 1, wherein the compound is selected from the group consisting of:

4. The compound is 【Chemistry 4】 The method of claim 2, wherein the compound is selected from the group consisting of:

5. The method for treating a nontuberculous mycobacterial infection in a mammal according to claim 1 or 2, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

6. 3. The therapeutic agent for treating a nontuberculous mycobacterial infection in a mammal according to claim 1 or 2, wherein the compound or a pharmaceutically acceptable salt thereof is administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, bucally, intranasally, by inhalation, intravaginally, intraocularly, topically, subcutaneously, intraadiposely, intraarticularly, intraperitoneally or intrathecally.

7. The method for treating nontuberculous mycobacterial infections in a mammal according to claim 1 or 2, wherein the compound or a pharmaceutically acceptable salt thereof is administered in the form of a single dose within the range of 10 to 1000 mg once or twice daily.

8. 3. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof is administered twice daily in a single dose suitable for oral solid formulation.

9. 3. The method of claim 1, wherein the infection is a skin, soft tissue, respiratory, blood, intraperitoneal, urinary, bone, or ocular infection.

10. The method of claim 1 or 2 for treating a nontuberculous mycobacterial infection in a mammal, wherein the compound or pharmaceutical composition is administered for 4 to 12 months.

11. The method for treating nontuberculous mycobacterial infections in mammals according to claim 1 or 2, wherein the compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered in a dosage form suitable for oral administration.

12. The therapeutic agent for treating nontuberculous mycobacterial infections in a mammal according to claim 1 or 2, wherein the compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered in a dosage form suitable for oral administration, and the compound exhibits oral bioavailability of about 50% to 100%.

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