How to treat mycobacterial infections using tetracycline compounds

Abstract

The present invention provides a method for treating mycobacterial infections or mycobacterial diseases. [Solution] A method comprising the step of administering a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 726,738 filed on 4 September 2018, U.S. Provisional Patent Application No. 62 / 731,410 filed on 14 September 2018, U.S. Provisional Patent Application No. 62 / 746,039 filed on 16 October 2018, and U.S. Provisional Patent Application No. 62,760,131 filed on 13 November 2018. The entire contents of each of the above applications are incorporated herein by reference.

[0002] government support This invention was made in recognition of a joint research and development agreement with the U.S. government agency, the Department of Veterans Affairs, which holds certain rights to this invention. [Background technology]

[0003] Introduction The genus Mycobacterium is currently known to include more than 180 bacterial species, many of which are known human pathogens. For example, this genus includes M. tuberculosis, the causative agent of tuberculosis, and M. leprae, the causative agent of leprosy. Other members of the genus Mycobacterium, also called interchangeable or synonymously atypical mycobacteria, non-tuberculous mycobacteria (NTM), or mycobacteria other than Mycobacterium tuberculosis (MOTT), can be opportunistic and sometimes lethal pathogens. For example, these organisms can cause localized diseases in the lungs, lymph nodes, skin, wounds, or bones, and sometimes disseminated diseases.

[0004] Mycobacterial infections are treated with antibiotics or combinations of antibiotics, and the treatment period is usually long, lasting for weeks, months, or even years. For example, Mycobacterium tuberculosis infections are usually treated with isoniazid, rifampicin, ethambutol, and pyrazinamide, and Mycobacterium leprae infections are usually treated with rifampicin, dapsone, and clofazimine. Macrolide antibiotics, such as clarithromycin and azithromycin, are usually used in combination with other antibiotics to treat NTM infections. For example, as described by Ryu et al., Tuberc. Respir. Dis. 2016, 79:74-84, the standard treatment for lung disease caused by infection with NTM mycobacteria belonging to Mycobacterium Avium Complex (MAC) includes the administration of rifampicin, ethambutol, and macrolide antibiotics, such as azithromycin. In cases of severe disease, amikacin or streptomycin may be added to the antibiotic regimen. In another example, lung disease caused by infection with the Mycobacterium species Mycobacterium kansasii includes the administration of macrolide antibiotics rifampicin and ethambutol. In yet another example, pulmonary infections in patients with cystic fibrosis caused by the M. Abscessus complex typically require oral macrolides, intravenous amikacin, and one or more additional antibiotics, such as cefoxitine, impenem, or tigecycline (Floto et al., Thorax 2016 Jan;71 Suppl 1:i1-22).

[0005] Antibiotics within the tetracycline family have also been tested for their activity against mycobacteria. For example, Wallace et al., Antimicrob. Agents Chemother. 2002, 46(10):3164~3167, describe a comparison of the in vitro activities of tigecycline, tetracycline, minocycline, and doxycycline against slow-growing NTMs, e.g., M. marinum, M. kansasii, M. xenopi, and M. simiae, as well as rapidly growing NTMs, e.g., M. fortuitum, M. abscessus, and M. chelonae. Wallace et al. demonstrated that different tetracycline compounds exhibit a wide range of different activities against various NTM strains. For example, minocycline, doxycycline, and tetracycline show very low activity against M. abscessus, while tigecycline shows good activity against this species. In another example, minocycline was found to have higher activity than tigecycline against M. marinum and M. kansasii.

[0006] Tigecycline is recognized as a promising antibiotic for treating mycobacterial infections. However, its clinical use is limited by its associated adverse effects, particularly gastrointestinal effects such as nausea and vomiting. For example, Myojin et al., International J. Infect. Diseases 2018, 74:10-12, describe the use of tigecycline in combination with clarithromycin and amikacin to treat mycobacterial otitis in a 10-year-old boy. The patient required the use of an additional medication, ondansetron, to control nausea and vomiting experienced after tigecycline infusion. In another example, Wallace et al., J. Antimicrob. Chemother. 2014, 69:1945-1953, describe their clinical experience with 52 patients who received tigecycline-containing regimens to treat M. abscessus and M. chelonae infections. Wallace et al. report that "there was significant interpersonal variability in tigecycline administration, and it was clear that the target dose was not achieved in most patients. Nearly half of the patients had their doses reduced due to nausea, vomiting, or loss of appetite." Wallace et al. also report that the tigecycline dosage was adjusted based on the level of tolerability, and that the use of antiemetics, such as ondansetron, was necessary to improve patient tolerability. The practical applicability of tigecycline for treating mycobacterial infections may be limited because many mycobacterial infections require the administration of one or more antibiotics for extended periods, such as several months or even years. Therefore, there is a need for safe and effective antibiotics to treat mycobacterial infections. [Overview of the project]

[0007] The present invention is based on the remarkable discovery that certain tetracycline compounds, such as omadacycline, or pharmaceutically acceptable salts thereof, may be particularly effective in treating or preventing mycobacterial infections. Omadacycline, also known herein as OMC, PTK 0796, or Compound 1, is a 9-aminomethyltetracycline derivative currently in advanced clinical development for the treatment of various bacterial infections, marketed under the trade name NUZYRA®. Omadacycline is (4aS,5aR,12aS)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-9-((neopentylamino)methyl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, or 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, and is formulated as (4):

[0008] [ka] It is represented as follows.

[0009] In some cases, omadacycline is also given by formula (5):

[0010] [ka] It can be represented as follows.

[0011] The inventors have surprisingly discovered that omadacyclin has promising activity against certain mycobacterial species, such as NTM, e.g., Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum. Furthermore, surprisingly, omadacyclin has been found to have promising activity, either alone or in combination with clarithromycin or linezolid, against Calmette-Guérin bacilli (BCG), a weakened form of Mycobacterium bovis, a species closely related to Mycobacterium tuberculosis.

[0012] Furthermore, administration of omadacycline to healthy volunteers was shown to result in higher omadacycline concentrations in the lungs, and particularly in the intraepithelial fluid (ELF) and alveolar cells (AC), such as alveolar macrophages (AM), than in the plasma omadacycline concentrations at the same time. Infections with mycobacteria, such as NTM or Mycobacterium tuberculosis, often cause pulmonary disease, and mycobacteria persist extracellularly in biofilms or within macrophages and other cells in the infected host. Mycobacterial infections also cause granulomatous inflammation and abscess formation, and mycobacteria can be trapped within granulomas. Therefore, tetracycline compounds, such as omadacycline, or pharmaceutically acceptable salts thereof, that can penetrate infected tissues, such as the lungs, and infected cells, such as macrophages, are particularly advantageous for treating mycobacterial infections. Furthermore, mobile omadacyclin-loaded macrophages may facilitate site-specific delivery of omadacycline into granulomas, thereby promoting the clearance of infectious mycobacteria.

[0013] Furthermore, omadacycline may be administered orally to a patient, for example, once or twice a day, and the administration of omadacycline is known to be associated with relatively few side effects, such as gastrointestinal side effects, such as nausea and / or vomiting. Therefore, omadacycline is eminently suitable for the treatment of mycobacterial infections that often require administration of antibiotics for long periods, such as several weeks, several months or even several years. On the other hand, tigecycline, which can only be administered intravenously, is often associated with significant side effects, such as nausea and vomiting. Therefore, the practicality of tigecycline in the treatment of mycobacterial infections is very limited.

[0014] Thus, in some embodiments, the present invention is a method of treating or preventing a mycobacterial infection in a subject that requires treatment or prevention of a mycobacterial infection, comprising administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester or prodrug thereof, such that the mycobacterial infection in the subject is treated or prevented, the tetracycline compound being of formula (1):

[0015]

Chemical formula

[0016] In some embodiments, R 9The formula is -CH2NR'R" where R' and R" are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, carbonyl, acyl, aryl, heteroaryl, cycloalkyl, and cycloalkenyl groups; or R' and R" together form a ring.

[0017] In some embodiments, the tetracycline compound is of formula (2):

[0018] [ka] (In the formula, J 5 and J 6 Each of these is independently a hydrogen atom, an alkyl atom, an alkenyl atom, an alkynyl atom, an aryl atom, an sulfonyl atom, an acyl atom, an alkoxycarbonyl atom, an alkaminocarbonyl atom, an alkaminothiocarbonyl atom, a substituted thiocarbonyl atom, a substituted carbonyl atom, or an alkoxythiocarbonyl atom, or linked together to form a ring; J 7 and J 8 (These are alkyl, halogen, or hydrogen, respectively.) It is represented as follows.

[0019] In some embodiments, X is CR 6' R 6 And R 6 and R 6' Both are hydrogen.

[0020] In some embodiments, R 4 is NR 4' R 4" And R 4' and R 4" Each of them is an alkyl group independently.

[0021] In some embodiments, R 7 It is a dialkylamino compound.

[0022] In some embodiments, the tetracycline compound is of formula (3):

[0023] [ka] (In the formula, J 5 It is alkyl; J 6 (It is hydrogen.) It is represented as follows.

[0024] In some embodiments, the tetracycline compound is of formula (4):

[0025] [ka] This is omadacycline, represented by [formula].

[0026] In a further embodiment, omadacycline is given by formula (5):

[0027] [ka] It is represented as follows.

[0028] In some embodiments, the present invention relates to a method for treating or preventing a mycobacterial infection in a subject requiring treatment or prevention of a mycobacterial infection, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject so as to treat or prevent a mycobacterial infection in the subject, wherein omadacycline is of formula (4):

[0029] [ka] This provides a method that can be represented by [this].

[0030] In a further embodiment, omadacycline is given by formula (5):

[0031] [ka] It is represented as follows.

[0032] In some aspects, mycobacterial infections are caused by slow-growing mycobacteria.

[0033] In some aspects, slow-growing mycobacteria belong to the Terrae lineage. In a further aspect, slow-growing mycobacteria include the following species: M. terrae, M. algericus, M. arupensis, M. engbaekii, M. heraklionensis, M. hiberniae, M. icosiumassiliensis, M. kumamotonensis, M. longobardus, M. minnesotensis, M. nonchromogenicus, M. paraterrae, M. senuense, M. sinensis (M. It belongs to the group of mycobacteria species selected from M. sinensis and M. virginiensis.

[0034] In some embodiments, slow-growing mycobacteria belong to the Triviale lineage. In further embodiments, slow-growing mycobacteria belong to mycobacterial species selected from the group consisting of the following species: M. trivialis, M. koreensis, and M. parakoreensis.

[0035] In some embodiments, slow-growing mycobacteria belong to the Tuberculosis-Simiae lineage. In further embodiments, the slow-growing mycobacteria include the following species: M. tuberculosis, M. tuberculosis subspecies tuberculosis, M. africanum, M. alsense, M. angelicum, M. arosiense, M. asiaticum, M. avium, M. avium subspecies avium, M. avium subspecies paratuberculosis, M. avium subspecies silvaticum, M. avium M. avium) subspecies hominissuis, M. bohemicum, M. botniense, M. bouchedurhonense, M. bourgelatii, M. bovis, M. bovis subspecies bovis, M. bovis subspecies caprae, M. branderi, M. canettii, M. caprae, M. celatum, M. chimaera, M. colombiense, M. conspicuum, M. kookii (M. M. cookii), M. europaeum, M. florentinum, M. fragae, M. gastri, M. genavsnse, M. gordonae, M. haemophilum, M. heckshornense, M.M. heidelbergense, M. indicus pranii, M. interjectum, M. intermedium, M. intracellulare, M. kansasii, M. kubicae, M. kyorinense, M. lacus, M. lentiflavum, M. leprae, M. lepraemurium, M. lepromatosis, M. liflandii, M. malmoense, M. mantenii M. mantenii), M. marinum, M. marseillense, M. microti, M. monteriorense, M. mungi, M. nebraskense, M. novomagense, M. orygis, M. palustre, M. paraense, M. parraffinicum, M. paragordonae, M. paraintracellulare, M. parascrofulaceum, M. paraseculense, M. palmense (M. M. parmense), M. perscum, M. pinnipedii, M. pseudoshotsii, M. riyadhense, M. saskatchewanense, M. scrofulaceum, M. seculense, M. sherrisii, M.It belongs to the group of mycobacteria species selected from the following: M. shimoidei, M. shinjukuense, M. shottsii, M. simiae, M. stomatepiae, M. szulgai, M. timonense, M. triplex, M. ulcerans, M. xenopi, and M. yongonense.

[0036] In some embodiments, slow-growing mycobacteria belong to the Mycobacterium tuberculosis complex (MTBC). In further embodiments, slow-growing mycobacteria belong to mycobacterial species selected from the group consisting of the following species: M. africanum, M. bovis, M. bovis BCG, M. canetti, M. caprae, M. microti, M. mungi, M. orygis, M. pinnipedii, M. suricattae, and M. tuberculosis. In one further embodiment, slow-growing mycobacteria belong to the mycobacterial species M. tuberculosis.

[0037] In some embodiments, slow-growing mycobacteria are non-tuberculous mycobacteria (NTMs). In some embodiments, NTMs belong to the Mycobacterium avium complex (MAC). In further embodiments, NTMs belong to mycobacterial species selected from the group consisting of the following species: M. avium, M. avium paratuberculosis, M. avium silvaticum, M. avium "hominissuis", M. Colombiense, M. chimaera, M. indicus pranii, and M. intracellulare.

[0038] In some embodiments, mycobacterial infections are caused by rapidly growing mycobacteria. In some embodiments, rapidly growing mycobacteria are NTMs. In further embodiments, rapidly growing mycobacteria belong to the Abscessus-Chelonae lineage. In some cases, rapidly growing mycobacteria belong to a group of mycobacteria species selected from the following species: M. abscessus, M. abscessus subspecies abscessus, M. abscessus subspecies bolletii, M. abscessus subspecies massiliense, M. chelonae, M. chelonae subspecies chelonae, M. immunogenum, M. salmoniphilum, M. franklinii, and M. saopaulense.

[0039] In one embodiment, rapidly growing mycobacteria belong to the mycobacterium species M. abscessus. In another embodiment, rapidly growing mycobacteria belong to the mycobacterium species M. chelonae.

[0040] In some aspects, rapidly growing mycobacteria belong to the Fortuitum-Vaccae lineage. In further embodiments, rapidly growing mycobacteria include the following species: M. fortuitum, M. fortuitum subspecies fortuitum, M. fortuitum subspecies acetamidolyticum, M. acapulcense, M. agri, M. aichiense, M. alvei, M. anyangense, M. arabiense, M. arcueilence, M. aromaticivorans, M. aubagnense, M. aurum M. aurum), M. austroafrinacum, M. bacteremicum, M. boenickei, M. brisnanense, M. brumae, M. canariasense, M. Celeriflavum, M. chitae, M. chlorophenolicum, M. chubuense, M. conceprionense, M. confluentis, M. cosmeticum, M. crocinum, M. ziernhoferi (M. M. diernhoferi), M. doricum, M. duvalii, M. elephantis, M. fallax, M. facinogenes, M. flavescens, M. fluoranthenivorance (M.M. fluoranthenivorans), M. frederikspergense, M. gadium, M. gilvum, M. goodii, M. hassiacum, M. helvum, M. hippocampi, M. hodieri, M. holsaticum, M. houstonense, M. insubricum, M. iranicum, M. komanii, M. komossense, M. litorale, M. latzelense (M. M. llatzerense), M. lutetiense, M. madagascariense, M. mageritense, M. malmesburyense, M. monacense, M. montmartrense, M. moriokaense, M. mucogenicum, M. murale, M. neoaurum, M. neworleansense, M. novocastrense, M. obuense, M. oryzae, M. parens (M. M. pallens), M. parafortuitum, M. peregrinum, M. phlei, M. phocaicum, M. porcinum, M. ponferae, M. psychrotolerans, M. pulvens, M. pyrenivorans, M. rhodesiae, M. ruhum (M.M. rufum), M. rutilum, M. sarraceniae, M. sediminis, M. senegalense, M. septicum, M. setense, M. smegmatis, M. sphagni, M. thermoresistibile, M. tokaiense, M. tusciae, M. vaccae, M. vanbaalenii, M. vulneris and M. wallinskii It belongs to a mycobacterial species selected from the group consisting of (wolinskyi). In a further embodiment, rapidly growing mycobacteria belong to the mycobacterial species M. fortuitum.

[0041] In some embodiments, the mycobacterial infection is located in the lungs of the subject.

[0042] In some embodiments, the subjects additionally have a lung disease. In further embodiments, the lung disease is selected from the group consisting of chronic obstructive pulmonary disease (COPD), occupational lung disease, tuberculosis, bronchiectasis, cystic fibrosis, and alpha-1 antitrypsin deficiency. In some embodiments, the subjects have undergone a lung transplant.

[0043] In some embodiments, the mycobacterial infection is in the lymph nodes of the subject. In some embodiments, the mycobacterial infection is a bone-joint infection. In some embodiments, the mycobacterial infection is in the joints or bones of the subject. In some embodiments, the mycobacterial infection is a skin or soft tissue infection (SSTI). In some embodiments, the mycobacterial infection causes a disease selected from the group consisting of pool granuloma and Buruli ulcer.

[0044] In some embodiments, mycobacterial infections are associated with foreign bodies placed in a subject. In further embodiments, the foreign body is selected from the group consisting of medical devices, implants, and tattoo inks. In some embodiments, the medical device is a cardiac pacemaker. In some embodiments, the implant is selected from the group consisting of cardiovascular implants, orthopedic implants, and cosmetic implants. In some embodiments, the cardiovascular implant is a heart valve. In some embodiments, the orthopedic implant is selected from the group consisting of pins, rods, screws, and plates. In some embodiments, the cosmetic implant is selected from the group consisting of breast implants, nasal prostheses, and injectable fillers.

[0045] In some embodiments, the present invention is also a method of treating or preventing a mycobacterial disease in a subject that requires treatment or prevention of a mycobacterial disease, the method comprising administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that the mycobacterial disease in the subject is treated or prevented, wherein the tetracycline compound is of formula (1):

[0046]

Chemical formula

[0047] In some embodiments, the present invention also relates to a method for controlling or reducing the progression, severity, or effects of a mycobacterial disease in a subject requiring control of the mycobacterial disease or reduction of its progression, severity, or effects, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that the mycobacterial disease in the subject is controlled or the progression, severity, or effects of the mycobacterial disease in the subject are reduced, wherein the tetracycline compound is of formula (1):

[0048] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0049] In some embodiments, R 9 The formula is -CH2NR'R" where R' and R" are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, carbonyl, acyl, aryl, heteroaryl, cycloalkyl, and cycloalkenyl groups; or R' and R" together form a ring.

[0050] In some embodiments, the tetracycline compound has the formula (2):

[0051]

Chem.

[0052] In some embodiments, X is CR 6' R 6 and R 6 and R 6' are both hydrogen.

[0053] In some embodiments, R 4 is NR 4' R 4" and R 4' and R 4" are each independently alkyl.

[0054] In some embodiments, R 7 is dialkylamino.

[0055] In some embodiments, the tetracycline compound has the formula (3):

[0056]

Chem.

[0057] In some embodiments, the tetracycline compound is given by formula (4):

[0058] [ka] This is omadacycline, represented by [formula].

[0059] In one further embodiment, omadacycline is given by formula (5):

[0060] [ka] It is represented as follows.

[0061] In some embodiments, the present invention also relates to a method for treating or preventing a mycobacterial disease in a subject requiring treatment or prevention of a mycobacterial disease, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that a mycobacterial disease in the subject is treated or prevented, wherein omadacycline is of formula (4):

[0062] [ka] This provides a method that can be represented by [this].

[0063] In some embodiments, the present invention also relates to a method for controlling or reducing the progression, severity, or effects of a mycobacterial disease in a subject requiring control of the mycobacterial disease or reduction of its progression, severity, or effects, comprising the step of administering an effective amount of omadacycline or a pharmaceutically acceptable salt, ester, or prodrug thereof to a subject such that the mycobacterial disease in the subject is controlled or the progression, severity, or effects of the mycobacterial disease in the subject are reduced, wherein omadacycline is of formula (4):

[0064] [ka] This provides a method that can be represented by [this].

[0065] In some embodiments, omadacycline is given by formula (5):

[0066] [ka] It is represented as follows.

[0067] In some embodiments, mycobacterial disease is caused by an infection with slow-growing mycobacteria. In further embodiments, the slow-growing mycobacteria belong to the Mycobacterium tuberculosis complex (MTBC). In some embodiments, the slow-growing mycobacteria belong to the mycobacterium species M. tuberculosis. In one embodiment, the mycobacterial disease is tuberculosis.

[0068] In some embodiments, mycobacterial diseases are caused by infections with rapidly growing mycobacteria.

[0069] In some aspects, mycobacterial diseases are caused by infections with NTM. In some aspects, NTM belongs to mycobacterial species selected from the group consisting of the following species: M. avium, M. kansasii, M. scrofulaceum, M. xenopi, M. simiae, M. habana, M. szulgai, M. fortuitum, M. vaccae, M. malmoense, M. heckeshornense, M. chelonae, and M. abscessus. In some aspects, NTM belongs to a group of mycobacterial species selected from the following species: M. abscessus, M. chelonae, and M. fortuitum.

[0070] In some embodiments, mycobacterial diseases are selected from the group consisting of tuberculosis, leprosy, pulmonary diseases, lymphadenitis, skin diseases, eye diseases, soft tissue diseases, bone diseases, fish tank granulomas, and Buruli ulcers. In further embodiments, pulmonary diseases are selected from the group consisting of bronchiectasis and pulmonary infections.

[0071] In some embodiments, mycobacterial diseases are associated with mycobacterial infections in the lymph nodes, joints, bones, skin, and soft tissues of the affected area.

[0072] In some embodiments, the mycobacterial disease is related to a mycobacterial infection associated with a foreign body placed on the subject. In further embodiments, the foreign body is selected from the group consisting of medical devices, implants, and tattoo inks.

[0073] In a further embodiment, the medical device is a cardiac pacemaker. In a further embodiment, the implant is selected from the group consisting of cardiovascular implants, orthopedic implants and cosmetic implants. In a further embodiment, the cardiovascular implant is a heart valve. In a further embodiment, the orthopedic implant is selected from the group consisting of pins, rods, screws and plates. In a further embodiment, the cosmetic implant is selected from the group consisting of breast implants, prosthetic noses and injectable fillers.

[0074] In some embodiments, the present invention also relates to a method for treating or preventing tuberculosis in a subject requiring treatment or prevention of tuberculosis, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that tuberculosis in the subject is treated or prevented, wherein the tetracycline compound is of formula (1):

[0075] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0076] In some embodiments, the present invention also relates to a method for controlling tuberculosis or reducing its progression, severity or impact in a subject requiring control of tuberculosis or reduction of its progression, severity or impact, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester or prodrug thereof, to a subject such that tuberculosis in the subject is controlled or the progression, severity or impact of tuberculosis in the subject is reduced, wherein the tetracycline compound is of formula (1):

[0077] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0078] In some embodiments, the present invention also relates to a method for treating or preventing leprosy in a subject requiring treatment or prevention of leprosy, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that leprosy in the subject is treated or prevented, wherein the tetracycline compound is of formula (1):

[0079] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0080] In some embodiments, the present invention also relates to a method for controlling leprosy or reducing its progression, severity or effects in subjects requiring control of leprosy or reduction of its progression, severity or effects, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester or prodrug thereof, to a subject such that leprosy is controlled in the subject or the progression, severity or effects of leprosy are reduced in the subject, wherein the tetracycline compound is of formula (1):

[0081] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2', R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0082] In some embodiments, the present invention also relates to a method for treating or preventing bronchiectasis in a subject requiring treatment or prevention of bronchiectasis, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that bronchiectasis in the subject is treated or prevented, wherein the tetracycline compound is of formula (1):

[0083] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6'Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0084] In some embodiments, the present invention also relates to a method for controlling bronchiectasis or reducing its progression, severity or effects in subjects requiring control of bronchiectasis or reduction of its progression, severity or effects, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester or prodrug thereof, to a subject such that bronchiectasis in the subject is controlled or the progression, severity or effects of bronchiectasis in the subject are reduced, wherein the tetracycline compound is of formula (1):

[0085] [ka] (In the formula, X is CHC(R 13 Y'Y), CR6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0086] In some embodiments, the present invention also relates to a method for treating or preventing cavitary lung disease in a subject requiring treatment or prevention of cavitary lung disease, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that cavitary lung disease in the subject is treated or prevented, wherein the tetracycline compound is of formula (1):

[0087] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0088] In some embodiments, the present invention also relates to a method for controlling cavitary lung disease or reducing its progression, severity or effects in subjects requiring control of cavitary lung disease or reduction of its progression, severity or effects, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester or prodrug thereof, to a subject such that the cavitary lung disease in the subject is controlled or the progression, severity or effects of cavitary lung disease in the subject are reduced, wherein the tetracycline compound is of formula (1):

[0089] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0090] In some embodiments, the present invention also relates to a method for treating or preventing lymphadenitis in a subject requiring treatment or prevention of lymphadenitis, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that lymphadenitis in the subject is treated or prevented, wherein the tetracycline compound is of formula (1):

[0091] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6, or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0092] In some embodiments, the present invention also relates to a method for controlling lymphadenitis or reducing its progression, severity or effects in subjects requiring control of lymphadenitis or reduction of its progression, severity or effects, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester or prodrug thereof, to a subject such that the lymphadenitis in the subject is controlled or the progression, severity or effects of lymphadenitis in the subject are reduced, wherein the tetracycline compound is of formula (1):

[0093] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2', R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0094] In some embodiments, the present invention also relates to a method for treating or preventing a soft tissue disease in a subject requiring treatment or prevention of the soft tissue disease, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that the soft tissue disease in the subject is treated or prevented, wherein the tetracycline compound is of formula (1):

[0095] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6'Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0096] In some embodiments, the present invention also relates to a method for controlling or reducing the progression, severity, or effects of a soft tissue disease in a subject requiring control of the soft tissue disease or reduction of its progression, severity, or effects, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that the soft tissue disease in the subject is controlled or the progression, severity, or effects of the soft tissue disease in the subject are reduced, wherein the tetracycline compound is of formula (1):

[0097] [ka] (In the formula, X is CHC(R 13 Y'Y), CR6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0098] In a further embodiment, the soft tissue disease is a skin disease, such as cellulitis.

[0099] In some embodiments, the present invention also relates to a method for treating or preventing aquarium granuloma in a subject requiring treatment or prevention of aquarium granuloma, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that aquarium granuloma in the subject is treated or prevented, wherein the tetracycline compound is of formula (1):

[0100] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4"Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0101] In some embodiments, the present invention also relates to a method for controlling aquarium granuloma or reducing its progression, severity or effects in subjects requiring control of aquarium granuloma or reduction of its progression, severity or effects, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester or prodrug thereof, to a subject such that the aquarium granuloma in the subject is controlled or the progression, severity or effects of aquarium granuloma in the subject are reduced, wherein the tetracycline compound is of formula (1):

[0102] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0103] In some embodiments, the present invention also relates to a method for treating or preventing Buruli ulcer in a subject requiring treatment or prevention of Buruli ulcer, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject so as to treat or prevent Buruli ulcer in the subject, wherein the tetracycline compound is of formula (1):

[0104] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0105] In some embodiments, the present invention also relates to a method for controlling Buruli ulcers or reducing their progression, severity or impact in subjects requiring control of Buruli ulcers or reduction of their progression, severity or impact, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester or prodrug thereof, to a subject such that Buruli ulcers are controlled or the progression, severity or impact of Buruli ulcers is reduced, wherein the tetracycline compound is of formula (1):

[0106] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0107] In some embodiments, the present invention also relates to a method for treating or preventing an eye disease in a subject requiring treatment or prevention of the eye disease, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that the eye disease in the subject is treated or prevented, wherein the tetracycline compound is of formula (1):

[0108] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0109] In some embodiments, the present invention also relates to a method for controlling or reducing the progression, severity, or effects of an eye disease in a subject requiring control of the eye disease or reduction of its progression, severity, or effects, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that the eye disease in the subject is controlled or the progression, severity, or effects of the eye disease in the subject are reduced, wherein the tetracycline compound is of formula (1):

[0110] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0111] In some embodiments, the present invention also relates to a method for treating or preventing a bone disease in a subject requiring treatment or prevention of the bone disease, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that the bone disease in the subject is treated or prevented, wherein the tetracycline compound is of formula (1):

[0112] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0113] In some embodiments, the present invention also relates to a method for controlling or reducing the progression, severity, or effects of a bone disease in a subject requiring control of the bone disease or reduction of its progression, severity, or effects, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that the bone disease in the subject is controlled or the progression, severity, or effects of the bone disease in the subject are reduced, wherein the tetracycline compound is of formula (1):

[0114] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0115] In some embodiments, the present invention also comprises a method for treating a subject having a lung disease, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject so as to treat the subject, wherein the tetracycline compound is of formula (1):

[0116] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6'Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0117] In further embodiments, the lung disease is selected from the group consisting of cystic fibrosis, chronic obstructive pulmonary disease (COPD), occupational lung disease, bronchiectasis, cavitary lung disease, primary ciliary dysplasia, allergic bronchopulmonary aspergillosis, alpha-1 antitrypsin deficiency, pneumoconiosis, interstitial lung disease, chronic aspiration syndrome, and alveolar proteinosis.

[0118] In one further embodiment, the lung disease is cystic fibrosis. In another further embodiment, the lung disease is COPD. In yet another further embodiment, the lung disease is bronchiectasis. In yet another embodiment, the lung disease is cavitary lung disease. In yet another further embodiment, the lung disease is alpha-1 antitrypsin deficiency.

[0119] In some embodiments, the present invention also comprises a method for treating a subject having an immunosuppressed state, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject so that the subject is treated, wherein the tetracycline compound is of formula (1):

[0120] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6'Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. This provides a method that can be represented by [this].

[0121] In one further embodiment, the immunosuppressed state is associated with HIV infection or AIDS. In another further embodiment, the immunosuppressed state is associated with the administration of immunosuppressive drugs. In yet another further embodiment, immunosuppressive drugs are administered as part of anti-cancer treatment. In yet another further embodiment, immunosuppressive drugs are administered as immunosuppressive therapy after organ transplantation.

[0122] In one embodiment, an immunosuppressive state is a genetic disorder resulting in an immunological defect. In a further embodiment, a genetic disorder resulting in an immunological defect includes a genetic defect in the interferon-γ receptor or interleukin-12.

[0123] In some embodiments, R 9The formula is -CH2NR'R" where R' and R" are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, carbonyl, acyl, aryl, heteroaryl, cycloalkyl, and cycloalkenyl groups; or R' and R" together form a ring.

[0124] In some embodiments, the tetracycline compound is of formula (2):

[0125] [ka] (In the formula, J 5 and J 6 Each of these is independently a hydrogen atom, an alkyl atom, an alkenyl atom, an alkynyl atom, an aryl atom, an sulfonyl atom, an acyl atom, an alkoxycarbonyl atom, an alkaminocarbonyl atom, an alkaminothiocarbonyl atom, a substituted thiocarbonyl atom, a substituted carbonyl atom, or an alkoxythiocarbonyl atom, or linked together to form a ring; J 7 and J 8 (These are alkyl, halogen, or hydrogen, respectively.) It is represented as follows.

[0126] In some embodiments, X is CR 6' R 6 And R 6 and R 6' Both are hydrogen.

[0127] In some embodiments, R 4 is NR 4' R 4" And R 4' and R 4" Each of them is an alkyl group independently.

[0128] In some embodiments, R 7 It is a dialkylamino compound.

[0129] In some embodiments, the tetracycline compound is of formula (3):

[0130] [ka] (In the formula, J 5 It is alkyl; J 6 (It is hydrogen.) It is represented as follows.

[0131] In some embodiments, the tetracycline compound is of formula (4):

[0132] [ka] This is omadacycline, represented by [formula].

[0133] In a further embodiment, omadacycline is given by formula (5):

[0134] [ka] It is represented as follows.

[0135] In some embodiments, the present invention also comprises a method for treating or preventing tuberculosis in a subject requiring treatment or prevention of tuberculosis, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that tuberculosis in the subject is treated or prevented, wherein omadacycline is of formula (4):

[0136] [ka] This provides a method that can be represented by [this].

[0137] In some embodiments, the present invention also relates to a method for controlling tuberculosis or reducing its progression, severity or impact in a subject requiring control of tuberculosis or reduction of its progression, severity or impact, comprising the step of administering an effective amount of omadacycline or a pharmaceutically acceptable salt, ester or prodrug thereof to a subject such that tuberculosis in the subject is controlled or the progression, severity or impact of tuberculosis in the subject is reduced, wherein omadacycline is of formula (4):

[0138] [ka] This provides a method that can be represented by [this].

[0139] In some embodiments, the present invention also provides a method for treating or preventing leprosy in a subject requiring treatment or prevention of leprosy, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that leprosy in the subject is treated or prevented, wherein omadacycline is of formula (4):

[0140] [ka] This provides a method that can be represented by [this].

[0141] In some embodiments, the present invention also relates to a method for controlling leprosy or reducing its progression, severity or effects in subjects requiring control of leprosy or reduction of its progression, severity or effects, comprising the step of administering an effective amount of omadacycline or a pharmaceutically acceptable salt, ester or prodrug thereof to a subject such that leprosy is controlled in the subject or the progression, severity or effects of leprosy are reduced in the subject, wherein omadacycline is of formula (4):

[0142] [ka] This provides a method that can be represented by [this].

[0143] In some embodiments, the present invention also provides a method for treating or preventing bronchiectasis in a subject requiring treatment or prevention of bronchiectasis, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that bronchiectasis in the subject is treated or prevented, wherein omadacycline is of formula (4):

[0144] [ka] This provides a method that can be represented by [this].

[0145] In some embodiments, the present invention also relates to a method for controlling bronchiectasis or reducing its progression, severity or effects in subjects requiring control of bronchiectasis or reduction of its progression, severity or effects, comprising the step of administering an effective amount of omadacycline or a pharmaceutically acceptable salt, ester or prodrug thereof to a subject such that bronchiectasis in the subject is controlled or the progression, severity or effects of bronchiectasis in the subject are reduced, wherein omadacycline is of formula (4):

[0146] [ka] This provides a method that can be represented by [this].

[0147] In some embodiments, the present invention also relates to a method for treating or preventing cavitary lung disease in a subject requiring treatment or prevention of cavitary lung disease, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that cavitary lung disease in the subject is treated or prevented, wherein omadacycline is of formula (4):

[0148] [ka] This provides a method that can be represented by [this].

[0149] In some embodiments, the present invention also relates to a method for controlling cavitary lung disease or reducing its progression, severity or effects in subjects requiring control of cavitary lung disease or reduction of its progression, severity or effects, comprising the step of administering an effective amount of omadacycline or a pharmaceutically acceptable salt, ester or prodrug thereof to a subject such that cavitary lung disease is controlled or the progression, severity or effects of cavitary lung disease are reduced in the subject, wherein omadacycline is of formula (4):

[0150] [ka] This provides a method that can be represented by [this].

[0151] In some embodiments, the present invention also relates to a method for treating or preventing lymphadenitis in a subject requiring treatment or prevention of lymphadenitis, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that lymphadenitis in the subject is treated or prevented, wherein omadacycline is of formula (4):

[0152] [ka] This provides a method that can be represented by [this].

[0153] In some embodiments, the present invention also relates to a method for controlling lymphadenitis or reducing its progression, severity or effects in subjects requiring control of lymphadenitis or reduction of its progression, severity or effects, comprising the step of administering an effective amount of omadacycline or a pharmaceutically acceptable salt, ester or prodrug thereof to a subject such that the lymphadenitis in the subject is controlled or the progression, severity or effects of lymphadenitis in the subject are reduced, wherein omadacycline is of formula (4):

[0154] [ka] This provides a method that can be represented by [this].

[0155] In some embodiments, the present invention also relates to a method for treating or preventing a soft tissue disease in a subject requiring treatment or prevention of the soft tissue disease, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that the soft tissue disease in the subject is treated or prevented, wherein omadacycline is of formula (4):

[0156] [ka] This provides a method that can be represented by [this].

[0157] In some embodiments, the present invention also relates to a method for controlling or reducing the progression, severity, or effects of a soft tissue disease in a subject requiring control of the soft tissue disease or reduction of its progression, severity, or effects, comprising the step of administering an effective amount of omadacycline or a pharmaceutically acceptable salt, ester, or prodrug thereof to a subject such that the soft tissue disease in the subject is controlled or the progression, severity, or effects of the soft tissue disease in the subject are reduced, wherein omadacycline is of formula (4):

[0158] [ka] This provides a method that can be represented by [this].

[0159] In a further embodiment, the soft tissue disease is a skin disease, such as cellulitis.

[0160] In some embodiments, the present invention also provides a method for treating or preventing aquarium granuloma in a subject requiring treatment or prevention of aquarium granuloma, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject so as to treat or prevent aquarium granuloma in the subject, wherein omadacycline is of formula (4):

[0161] [ka] This provides a method that can be represented by [this].

[0162] In some embodiments, the present invention also relates to a method for controlling aquarium granuloma or reducing its progression, severity or effects in subjects requiring control of aquarium granuloma or reduction of its progression, severity or effects, comprising the step of administering an effective amount of omadacycline or a pharmaceutically acceptable salt, ester or prodrug thereof to a subject such that the aquarium granuloma in the subject is controlled or the progression, severity or effects of aquarium granuloma in the subject are reduced, wherein omadacycline is of formula (4):

[0163] [ka] This provides a method that can be represented by [this].

[0164] In some embodiments, the present invention also provides a method for treating or preventing Buruli ulcer in a subject requiring treatment or prevention of Buruli ulcer, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject so as to treat or prevent Buruli ulcer in the subject, wherein omadacycline is of formula (4):

[0165] [ka] This provides a method that can be represented by [this].

[0166] In some embodiments, the present invention also relates to a method for controlling Buruli ulcers or reducing their progression, severity or impact in subjects requiring control of Buruli ulcers or reduction of their progression, severity or impact, comprising the step of administering an effective amount of omadacycline or a pharmaceutically acceptable salt, ester or prodrug thereof to a subject such that Buruli ulcers are controlled or the progression, severity or impact of Buruli ulcers is reduced in the subject, wherein omadacycline is of formula (4):

[0167] [ka] This provides a method that can be represented by [this].

[0168] In some embodiments, the present invention also comprises a method for treating or preventing an eye disease in a subject requiring treatment or prevention of an eye disease, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that the eye disease in the subject is treated or prevented, wherein omadacycline is of formula (4):

[0169] [ka] This provides a method that can be represented by [this].

[0170] In some embodiments, the present invention also relates to a method for controlling or reducing the progression, severity, or effects of an eye disease in a subject requiring control of the eye disease or reduction of its progression, severity, or effects, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that the eye disease in the subject is controlled or the progression, severity, or effects of the eye disease in the subject are reduced, wherein omadacycline is of formula (4):

[0171] [ka] This provides a method that can be represented by [this].

[0172] In some embodiments, the present invention also comprises a method for treating or preventing a bone disease in a subject requiring treatment or prevention of the bone disease, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that the bone disease in the subject is treated or prevented, wherein omadacycline is of formula (4):

[0173] [ka] This provides a method that can be represented by [this].

[0174] In some embodiments, the present invention also relates to a method for controlling or reducing the progression, severity, or effects of a bone disease in a subject requiring control of the bone disease or reduction of its progression, severity, or effects, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject such that the bone disease in the subject is controlled or the progression, severity, or effects of the bone disease in the subject are reduced, wherein omadacycline is of formula (4):

[0175] [ka] This provides a method that can be represented by [this].

[0176] In some embodiments, the present invention also comprises a method for treating a subject having a lung disease, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject so that the subject is treated, wherein omadacycline is of formula (4):

[0177] [ka] This provides a method that can be represented by [this].

[0178] In some embodiments, the lung disease is selected from the group consisting of cystic fibrosis, chronic obstructive pulmonary disease (COPD), occupational lung disease, bronchiectasis, cavitary lung disease, primary ciliary dysplasia, allergic bronchopulmonary aspergillosis, alpha-1 antitrypsin deficiency, pneumoconiosis, interstitial lung disease, chronic aspiration syndrome, and alveolar proteinosis.

[0179] In one embodiment, the lung disease is cystic fibrosis. In another embodiment, the lung disease is COPD. In yet another embodiment, the lung disease is bronchiectasis. In yet another embodiment, the lung disease is cavitary lung disease. In yet another embodiment, the lung disease is alpha-1 antitrypsin deficiency.

[0180] In some embodiments, the present invention also comprises a method for treating a subject having an immunosuppressed state, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject so that the subject is treated, wherein omadacycline is of formula (4):

[0181] [ka] This provides a method that can be represented by [this].

[0182] In some embodiments, the immunosuppressed state is associated with HIV infection or AIDS. In other embodiments, the immunosuppressed state is associated with the administration of immunosuppressive drugs. In other embodiments, immunosuppressive drugs are administered as part of anti-cancer treatment. In other embodiments, immunosuppressive drugs are administered as immunosuppressive therapy after organ transplantation.

[0183] In some embodiments, the immunosuppressed state is a hereditary disorder resulting in an immunological defect, such as a genetic defect in the interferon-γ receptor or interleukin-12.

[0184] In some embodiments, omadacycline is given by formula (5):

[0185] [ka] It is represented as follows.

[0186] In some embodiments, tetracycline compounds, or pharmaceutically acceptable salts, esters, or prodrugs thereof, are administered as monotherapy.

[0187] In other embodiments, a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is administered in combination with at least one additional antimycobacterial agent. In further embodiments, the at least one additional antimycobacterial agent is diarylquinolone, rifapentin, rifaradyl, nitroimidazole, benzothiadinone, capreomycin, clofazimine, cycloserine, dapsone, thiocarbamide, ethambutol, DC-159a, nitrobenzthiazole, stezolid (PNU-100480), AZD-5847, posisolid (AZD-2563), para-aminosalicylic acid, SQ-109, SQ -609 is selected from the group consisting of capramycin, caprazen nucleoside, isothiazoloquinolone, thioridazine, thiasetazone, zilithromycin, roxithromycin, telithromycin, azithromycin, clarithromycin, erythromycin, amikacin, kanamycin, streptomycin, levofloxacin, moxifloxacin, gatifloxacin, linezolid, rifaradyl, imipenem, meropenem, clavulanate, and isoniazid.

[0188] In some embodiments, tetracycline compounds, or their pharmaceutically acceptable salts, esters, or prodrugs, are administered for a period of approximately 1 to 12 weeks. In some embodiments, tetracycline compounds, or their pharmaceutically acceptable salts, esters, or prodrugs, are administered for a period of approximately 1 to 24 months. In other embodiments, tetracycline compounds, or their pharmaceutically acceptable salts, esters, or prodrugs, are administered for a period exceeding 24 months.

[0189] In some embodiments, tetracycline compounds, or their pharmaceutically acceptable salts, esters, or prodrugs, are administered parenterally, orally, topically, or aerosolically. In some embodiments, tetracycline compounds, or their pharmaceutically acceptable salts, esters, or prodrugs, are administered parenterally, for example, intravenously. In some embodiments, tetracycline compounds, or their pharmaceutically acceptable salts, esters, or prodrugs, are administered intravenously in doses of about 100 to about 300 mg. In further embodiments, tetracycline compounds, or their pharmaceutically acceptable salts, esters, or prodrugs, are administered intravenously in doses of about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg.

[0190] In some embodiments, the tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is administered orally. In some embodiments, the tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is administered orally in doses of about 150 to about 600 mg. In further embodiments, the tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is administered orally in doses of about 150, about 300 mg, about 450 mg, or about 600 mg.

[0191] In some embodiments, tetracycline compounds, or pharmaceutically acceptable salts, esters, or prodrugs thereof, are administered by aerosol. In some embodiments, the aerosol administration of tetracycline compounds, or pharmaceutically acceptable salts, esters, or prodrugs thereof, involves the use of an aerosol dispenser containing a dose of approximately 1 mg to approximately 1000 mg of tetracycline compounds, or pharmaceutically acceptable salts, esters, or prodrugs thereof. In a further embodiment, the aerosol dispenser contains a tetracycline compound or a pharmaceutically acceptable salt, ester, or prodrug thereof in doses of approximately 1 mg, approximately 5 mg, approximately 10 mg, approximately 30 mg, approximately 50 mg, approximately 80 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 450 mg, approximately 500 mg, approximately 550 mg, approximately 600 mg, approximately 650 mg, approximately 700 mg, approximately 750 mg, approximately 800 mg, approximately 850 mg, approximately 900 mg, approximately 950 mg, or approximately 1000 mg.

[0192] In some embodiments, a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is administered topically by applying a pharmaceutical composition configured for topical administration, comprising the tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the affected area.

[0193] In some embodiments, the pharmaceutical composition contains a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, at a concentration of about 0.01% to about 20% w / v based on the volume of the composition. In some embodiments, the pharmaceutical composition contains a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, at a concentration of about 0.01% w / v, about 0.05% w / v, about 0.1% w / v, about 0.5% w / v, about 1% w / v, about 5% w / v, about 10% w / v, about 15% w / v, or about 20% w / v.

[0194] In some embodiments, the pharmaceutical composition contains a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, at a concentration of about 0.01% to about 20% w / w based on the volume of the composition. In some embodiments, the pharmaceutical composition contains a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, at a concentration of about 0.01% w / w, about 0.05% w / w, about 0.1% w / w, about 0.5% w / w, about 1% w / w, about 5% w / w, about 10% w / w, about 15% w / w, or about 20% w / w.

[0195] In some embodiments, the administration of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, includes administering one or more loading doses of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, followed by one or more maintenance doses of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof.

[0196] In some embodiments, the loading dose is an intravenous or oral dose. In further embodiments, the loading dose is an intravenous daily dose of about 200 mg or an oral daily dose of about 450 mg. In some embodiments, the maintenance dose is an intravenous daily dose of about 100 mg or an oral daily dose of about 300 mg.

[0197] In some embodiments, the administration of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, includes administering the same dose of the tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, over a period of treatment.

[0198] In some embodiments, the subject is immune. In other embodiments, the subject is immunodeficient.

[0199] In some embodiments, the subject is a mammal. In further embodiments, the mammal is selected from the group consisting of humans, non-human primates, cattle, sheep, pigs, goats, horses, dogs, cats, mice, rats, and guinea pigs. In certain embodiments, the subject is a human.

[0200] In some embodiments, the subject is determined to have a mycobacterial infection.

[0201] In some embodiments, the method of the present invention further includes the step of determining whether a subject has a mycobacterial infection before administering a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject. [Brief explanation of the drawing]

[0202] [Figure 1A] This graph shows the concentration and time-dependent bactericidal activity of omadacycline against the M. abscessus subspecies abscessus. [Figure 1B] This graph shows the concentration and time-dependent bactericidal activity of tigecycline against the M. abscessus subspecies abscessus. [Figure 2] This is a series of graphs showing the concentration-effect curves of omadacycline (OMC, upper left), tigecycline (TGC, upper right), and both omadacycline and tigecycline (OMC and TGC, lower left) against the subspecies M. abscessus after 7 days of drug exposure. In the graphs, dlog represents the difference between the initial inoculation and the mycobacterial load on day 7. [Figure 3] This graph shows the mean concentrations of omadacycline over time in plasma, intraepithelial fluid, and alveolar cells after administration of omadacycline to healthy volunteers. [Modes for carrying out the invention]

[0203] Methods for treating or preventing mycobacterial infections The present invention provides a method for treating or preventing mycobacterial infections, or for treating or preventing mycobacterial diseases in subjects requiring such treatment or prevention. The method for treating or preventing mycobacterial infections comprises the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject so as to treat or prevent a mycobacterial infection or mycobacterial disease in the subject, wherein the tetracycline compound is of formula (1):

[0204] [ka] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. It is represented as follows.

[0205] In some examples, R 9R' is an aminomethyl group, for example, -CH2NR'R''. In some examples, each of R' and R'' of the aminomethyl group can be independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, carbonyl, acyl, aryl, heteroaryl, cycloalkyl, or cycloalkenyl groups, or R' and R'' together can form a ring, for example, a cycloalkyl, cycloalkenyl, or aryl group.

[0206] In some examples, R' of the aminomethyl moiety is hydrogen, and R'' of the aminomethyl moiety is alkyl, cycloalkyl, or cycloalkenyl. In further examples, R'' is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In other further examples, R'' is alkyl, e.g., alkyl substituted with methyl, ethyl, isopropyl, or tert-butyl.

[0207] In some examples, the R' and R'' of the aminomethyl moiety combine to form a ring, for example, a cycloalkyl moiety, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some examples, the cycloalkyl moiety may be further substituted with, for example, alkyl, cycloalkyl, heterocyclyl, or halogen. In some examples, the cycloalkyl moiety may be bicyclic or tricyclic.

[0208] In other examples, R 9 -CH2NR 9c C(=Z')ZR 9a And in the formula, Z is CR 9d R 9e , S, NR 9b or O; Z' is NR 9f , O or S; R 9a , R 9b , R 9c , R 9d , R 9e and R 9fEach of these is independently a hydrogen atom, an acyl atom, an alkyl atom, an alkenyl atom, an alkynyl atom, an alkoxy atom, an alkylthio atom, an alkyl sulfinyl atom, an alkylsulfonyl atom, an alkylamino atom, an arylalkyl atom, an aryl atom, a heterocyclic atom, a heterocyclic aromatic ring, or a prodrug moiety.

[0209] In some examples, R 9 -CH2NR 9c C(=Z')ZR 9a That is. R 9c Examples include hydrogen. In some embodiments, Z' may be S, NH, or O. Examples of Z include NR 9b (For example, R 9b (If hydrogen is present, alkyl, etc.), it contains O or S.

[0210] R 9a Examples of groups include aryl groups, such as substituted and unsubstituted phenyl groups. 9a Examples of possible substituents on the group are not limited to these, but include alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, perfluoromethyl, perchloroethyl, etc.), alkenyl, halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxyl, alkoxy (e.g., methoxy, ethoxy, propoxy, perfluoromethoxy, perchloromethoxy, etc.), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, arylalkylaminocarbon This includes nyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amide, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, acetyl, alkyl, cyano, azide, heterocyclyl, alkylaryl, aryl, and heteroaryl groups.

[0211] In certain embodiments, at least one substituent present on the substituted phenyl is nitro, alkoxy (e.g., methoxy, methylenedioxy, perfluoromethoxy), alkyl (e.g., methyl, ethyl, propyl, butyl, or pentyl), acetyl, halogen (e.g., fluorine, chlorine, bromine, or iodine), or amino (e.g., dialkylamino). In certain embodiments, the alkoxy group is perhalogenated, for example, perfluoromethoxy.

[0212] Aryl R 9a Examples of the groups include, but are not limited to, unsubstituted phenyl, para-nitrophenyl, para-methoxyphenyl, para-perfluoromethoxyphenyl, para-acetylphenyl, 3,5-methylenedioxyphenyl, 3,5-diperfluoromethylphenyl, para-bromophenyl, para-chlorophenyl, and para-fluorophenyl.

[0213] Aryl R 9a Other examples of the groups include substituted and unsubstituted heterocycles (e.g., furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, methylenedioxyphenyl, indolyl, thienyl, pyrimidyl, pyrazinyl, purinyl, pyrazolyl, pyrrolidinyl, oxazolyl, isoxazolyl, naphthilidinyl, thiazolyl, isothiazolyl, or deazapurinyl), as well as substituted and unsubstituted biaryl groups, such as naphthyl and fluorene.

[0214] R 9aIt may also be a substituted or unsubstituted alkyl group, such as methyl, ethyl, propyl, butyl, pentyl, etc. Examples of substituents are not limited to these, but include halogens (e.g., fluorine, bromine, chlorine, iodine, etc.), hydroxyl, alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, etc.), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, arylalkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, alkenyl, heterocyclyl, alkylaryl, aryl, and heteroaryl.

[0215] R 9a It may also be a substituted or unsubstituted alkenyl. Alkenyl R 9a Examples of substituents on the group are alkyl R 9a This includes the groups listed above. Alkenyl R 9a Examples of the group include penta-1-enyl.

[0216] In one embodiment, Z' is NH, Z is NH, and R 9a It is alkyl.

[0217] In some examples, the method of the present invention is represented by formula (2):

[0218] [ka] (In the formula, J 5 and J 6Each of these is independently a hydrogen atom, an alkyl atom, an alkenyl atom, an alkynyl atom, an aryl atom, an sulfonyl atom, an acyl atom, an alkoxycarbonyl atom, an alkaminocarbonyl atom, an alkaminothiocarbonyl atom, a substituted thiocarbonyl atom, a substituted carbonyl atom, or an alkoxythiocarbonyl atom, or linked together to form a ring; J 7 and J 8 These are alkyl, halogen, or hydrogen, respectively. X, R 2 , R 2' , R 3 , R 4 , R 4' , R 4" , R 5 , R 6 , R 6' , R 7 , R 8 , R 10 , R 11 and R 12 (This is as defined above with respect to equation (1)). The procedure includes administering a tetracycline compound represented by [formula], or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a target.

[0219] In some embodiments of formulas (1) and (2), X is CR 6' R 6 In further examples, R 6 and R 6' Both are hydrogen atoms.

[0220] In some embodiments of formulas (1) and (2), R 4 is NR 4' R 4" And R 4' and R 4" Each of them is an alkyl group independently. In further examples, R 4' and R 4" Each of these is methyl.

[0221] In some embodiments of formulas (1) and (2), R 7 This is a dialkylamino, for example, dimethylamino.

[0222] In some embodiments of formulas (1) and (2), R 5 It is hydrogen.

[0223] In some embodiments of formulas (1) and (2), R 8 It is hydrogen.

[0224] In some examples, the method of the present invention is represented by formula (3):

[0225] [ka] (In the formula, J 5 is alkyl; J 6 (It is hydrogen.) The procedure includes administering a tetracycline compound represented by [formula], or a pharmaceutically acceptable salt, prodrug, or ester thereof, to a target.

[0226] In some examples, the methods of the present invention for treating or preventing mycobacterial infections or mycobacterial diseases include the step of administering any 9-aminomethyl-substituted tetracycline compound, such as those listed in U.S. Patents 7,326,696, 7,553,828, and 9,365,499, the entire contents of which are incorporated herein by reference.

[0227] In some cases, the methods of the present invention for treating or preventing mycobacterial infections or mycobacterial diseases include the step of administering any of the tetracycline compounds listed in Table 1 below to a subject in need.

[0228] [Table 1] JPEG2026086890000072.jpg248146JPEG2026086890000073.jpg250153JPEG2026086890000074.jpg248147 JPEG2026086890000075.jpg244139JPEG2026086890000076.jpg241136JPEG2026086890000077.jpg252153 JPEG2026086890000078.jpg245145JPEG2026086890000079.jpg245146JPEG2026086890000080.jpg251152 JPEG2026086890000081.jpg253144JPEG2026086890000082.jpg249146JPEG2026086890000083.jpg152153

[0229] As used herein, the term "alkyl" includes saturated aliphatic groups, including linear alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.) and branched alkyl groups (e.g., isopropyl, tert-butyl, isobutyl, etc.). The term alkyl also includes alkyl groups that may further contain oxygen, nitrogen, sulfur, or phosphorus atoms replacing one or more carbon atoms in the hydrocarbon backbone. In some examples, linear or branched alkyl groups may have six or fewer carbon atoms in their backbone (e.g., C1-C6 for linear groups, C3-C6 for branched groups), more preferably four or fewer carbon atoms. The term "C1-C6" includes alkyl groups containing one to six carbon atoms.

[0230] When used herein, the terms “alkoxyalkyl,” “alkylaminoalkyl,” and “thioalkoxyalkyl” include the aforementioned alkyl groups, which further include oxygen, nitrogen, or sulfur atoms in which one or more carbon atoms of the hydrocarbon skeleton are replaced, for example, oxygen, nitrogen, or sulfur atoms.

[0231] Furthermore, the term alkyl includes both "unsubstituted alkyl" and "substituted alkyl," the latter referring to an alkyl moiety having substituents that replace hydrogens on one or more carbon atoms of a hydrocarbon skeleton. Such substituents may include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, aryl, or heteroaryl. The "alkylaryl" or "arylalkyl" portion is an alkyl group substituted with an aryl group (e.g., phenylmethyl(benzyl)).

[0232] As used herein, the term "alkenyl" includes unsaturated aliphatic groups that are similar to the alkyls described above in terms of length and possible substitutions, but contain at least one double bond. For example, the term "alkenyl" includes linear alkenyl groups (e.g., ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.) and branched alkenyl groups. The term "alkenyl" may also include alkenyl groups containing oxygen, nitrogen, sulfur, or phosphorus atoms that replace one or more carbon atoms in the hydrocarbon skeleton. In some examples, linear or branched alkenyl groups may have six or fewer carbon atoms in their skeleton (e.g., C2-C6 for linear groups, C3-C6 for branched groups). The term "C2-C6" includes alkenyl groups containing two to six carbon atoms.

[0233] Furthermore, the term "alkenyl" includes both "unsubstituted alkenyls" and "substituted alkenyls," the latter referring to an alkenyl moiety having substituents that replace hydrogens on one or more carbon atoms of the hydrocarbon skeleton. Such substituents may include, for example, the substituents listed above with respect to alkyl groups.

[0234] The term "alkynyl," as used herein, includes unsaturated aliphatic groups that are similar to the alkyls described above in terms of length and possible substitutions, but contain at least one triple bond. For example, the term "alkynyl" includes linear alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, noninyl, desynyl, etc.) and branched alkynyl groups. The term "alkynyl" further includes alkynyl groups that may contain oxygen, nitrogen, sulfur, or phosphorus atoms replacing one or more carbon atoms in the hydrocarbon backbone. In certain embodiments, linear or branched alkynyl groups have six or fewer carbon atoms in their backbone (e.g., C2-C6 for linear groups, C3-C6 for branched groups). The term "C2-C6" includes alkynyl groups containing two to six carbon atoms.

[0235] Furthermore, the term "alkynyl" includes both "unsubstituted alkynyls" and "substituted alkynyls," the latter referring to an alkynyl moiety having substituents that replace hydrogens on one or more carbon atoms of the hydrocarbon skeleton. Such substituents may include, for example, the substituents listed above with respect to alkyl groups.

[0236] As used herein, the term "cycloalkyl" includes fully saturated cyclic hydrocarbon groups comprising 1 to 4 rings and 3 to 8 carbon atoms per ring. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The term "cycloalkyl" also includes cycloalkyl groups further comprising heterocyclyl groups, i.e., oxygen, nitrogen, sulfur, or phosphorus atoms replacing one or more carbon atoms of the hydrocarbon skeleton. The term "cycloalkyl" also includes "polycyclyl" moieties comprising two or more rings, for example, rings that are "fused rings," where two or more carbon atoms are shared by two adjacent rings. Rings linked via non-adjacent atoms are called "bridged" rings.

[0237] Furthermore, the term "cycloalkyl" includes both "unsubstituted cycloalkyl" and "substituted cycloalkyl," the latter referring to a cycloalkyl moiety having substituents that replace hydrogens on one or more carbon atoms of the hydrocarbon skeleton. Such substituents may include, for example, the substituents listed above with respect to alkyl groups.

[0238] As used herein, the term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbon atoms per ring. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like. The term "cycloalkenyl" also includes "polycyclyl" moieties containing two or more rings, such as rings that are "fused rings," where two or more carbon atoms are shared by two adjacent rings. In some examples, the polycyclyl moieties may be bicyclic or tricyclic. Rings linked via non-adjacent atoms are called "bridged" rings.

[0239] The term "cycloalkenyl" includes both "unsubstituted cycloalkenyls" and "substituted cycloalkenyls," the latter referring to a cycloalkenyl moiety having substituents that replace hydrogens on one or more carbon atoms of the hydrocarbon skeleton. Such substituents may include, for example, the substituents listed above with respect to alkyl groups.

[0240] As used herein, the term "aryl" refers to a cyclic aromatic hydrocarbon group containing 1 to 5 aromatic rings, particularly monocyclic or bicyclic groups, such as phenyl, biphenyl, or naphthyl. If it contains two or more aromatic rings (e.g., bicyclic or tricyclic), the aromatic rings of the aryl group may be linked at a single point (e.g., biphenyl) or fused (e.g., naphthyl, phenantrenyl, etc.). The term "aryl" may also include 5-membered and 6-membered monocyclic aromatic groups that may contain 0 to 4 heteroatoms, such as pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, and pyrimidine. Furthermore, the term "aryl" includes polycyclic aryl groups such as tricyclic and bicyclic groups, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, or indoridine. These aryl groups having heteroatoms in their ring structure are also called "aryl heterocycles," "heterocycles," "heteroaryls," or "heterocyclic aromatic rings."

[0241] The term "aryl" also includes "polycyclyl" moieties, which contain two or more rings, such as rings that are "fused rings," where two or more carbon atoms are shared by two adjacent rings. Rings linked via non-adjacent atoms are called "bridged" rings.

[0242] Furthermore, the term "aryl" includes both "unsubstituted aryls" and "substituted aryls," the latter referring to an aryl moiety having a substituent that replaces a hydrogen on the aromatic ring. Such substituents may include, for example, the substituents listed above with respect to alkyl groups.

[0243] As used herein, the term "acyl" includes compounds and moieties containing an acyl group (CH3CO-) or a carbonyl group. The term "substituted acyl" includes an acyl group in which one or more hydrogen atoms are replaced by substituents selected from the group of substituents listed above, for example with respect to alkyl groups.

[0244] As used herein, the term "acylamino" includes a moiety in which an acyl group is bonded to an amino group. For example, this term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido groups.

[0245] As used herein, the term "alkoxy" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups.

[0246] The terms "amino" or "amine," as used herein, include a portion in which a nitrogen atom is covalently bonded to at least one carbon or heteroatom. The terms also include "alkylamino," in which nitrogen is bonded to at least one additional alkyl group, and "dialkylamino," in which nitrogen is bonded to at least two additional alkyl groups. The terms also include "arylamino" and "diarylamino," in which nitrogen is bonded to at least one or two aryl groups, respectively. The terms also include "alkylarylamino," "alkylaminoaryl," or "arylaminoalkyl," in which nitrogen is bonded to at least one alkyl group and at least one aryl group. The terms also include "alkaminoalkyl," in which an alkyl, alkenyl, or alkynyl group is bonded to a nitrogen atom bonded to an alkyl group.

[0247] The terms "aminocarbonyl" or "amide," as used herein, include compounds or moieties containing a nitrogen atom bonded to a carbonyl or thiocarbonyl group. This term includes "alkaminocarbonyl" or "alkylaminocarbonyl" groups, in which an alkyl, alkenyl, aryl, or alkynyl group is bonded to an amino group bonded to a carbonyl group. This term also includes arylaminocarbonyl groups, which contain an aryl or heteroaryl moiety bonded to an amino group bonded to a carbonyl or thiocarbonyl group. The terms "alkylaminocarbonyl," "alkenylaminocarbonyl," "alkynylaminocarbonyl," "arylaminocarbonyl," "alkylcarbonylamino," "alkenylcarbonylamino," "alkynylcarbonylamino," and "arylcarbonylamino" are also included in the term "amide." Amides also include urea groups (aminocarbonylamino) and carbamates (oxycarbonylamino).

[0248] The terms "carbonyl" or "carboxyl," as used herein, include compounds and parts containing a carbon atom bonded to an oxygen atom by a double bond. Examples of carbonyl-containing parts include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, and the like.

[0249] The terms "thiocarbonyl" or "thiocarboxy," as used herein, include compounds and parts containing a carbon atom bonded to a sulfur atom by a double bond.

[0250] As used herein, the term "ether" includes compounds or moieties containing oxygen bonded to different carbon atoms or heteroatoms. For example, the term includes "alkoxyalkyl," which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom covalently bonded to another alkyl group.

[0251] As used herein, the term "ester" includes compounds and parts containing a carbon or heteroatom bonded to an oxygen atom bonded to a carbon of a carbonyl group. For example, this term includes alkoxycarboxyl groups, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, and the like.

[0252] As used herein, the term "thioether" includes compounds and moieties containing a sulfur atom bonded to two different carbon or heteroatoms. Examples of thioethers, but not limited to, include alkthioalkyl, alkthioalkenyl, and alkthioalkynyl. "Alkthioalkyl" includes compounds having an alkyl, alkenyl, or alkynyl group bonded to an alkyl group-bonded sulfur atom. Similarly, "alkthioalkenyl" and "alkthioalkynyl" refer to compounds or moieties in which an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom covalently bonded to an alkynyl group.

[0253] The terms "hydroxy" or "hydroxyl" as used herein refer to -OH or -O - It contains a group having a group.

[0254] The term "halogen" includes fluorine, bromine, chlorine, iodine, etc. The term "perhalogenation" generally refers to a portion where all hydrogen atoms have been replaced by halogen atoms.

[0255] As used herein, the term "heteroatom" includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur, and phosphorus.

[0256] In some embodiments, the tetracycline compound administered to subjects related to the present invention is omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof. The term "omadacycline," which may be used interchangeably herein with the terms "OMC," "PTK 0796," "Compound 1," or its trade name NUZYRA®, refers to (4aS,5aR,12aS)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-9-((neopentylamino)methyl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, or 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof. Omadacycline is formulated with formula (4):

[0257] [ka] It can be represented as follows.

[0258] In some cases, omadacycline is given by equation (5):

[0259] [ka] It can be represented as follows.

[0260] In some cases, omadacycline may be administered to a subject in the form of a salt, such as a pharmaceutically acceptable salt, such as a tosylate. The tosylate of omadacycline may be amorphous or crystalline, and may be, for example, a polymorph of form 1, form 2, or form 3 of the crystalline tosylate of omadacycline described in U.S. Patent No. 8,383,610, which is incorporated herein by reference in its entirety. In some cases, omadacycline may be administered to a subject in the form of a free base, such as a crystalline free base.

[0261] As used herein, the term "mycobacterial infection" refers to an infection caused by mycobacteria, i.e., bacteria belonging to the genus Mycobacterium. The methods of the present invention encompass the treatment of infections caused by bacteria belonging to any species within the genus Mycobacterium. Mycobacteria are typically in the form of straight or slightly curved rods and have a thick, hydrophobic, waxy cell wall. The cell wall of mycobacteria consists of a hydrophobic mycolate layer and a peptidoglycan layer, rich in mycolic acid and mycolate, and held together by the polysaccharide arabinogalactan. The thick cell wall of mycobacteria is one of the factors that contribute to the particular difficulty in treating mycobacterial infections.

[0262] Currently, approximately 188 bacterial species have been identified as belonging to the genus Mycobacterium. Several classification schemes are used to divide mycobacteria into subgroups. For example, a classification scheme based on phylogenomics and comparative genomic analysis is described by Gupta et al., Frontiers in Microbiology 2018, 9:67, the full content of which is incorporated herein by reference. This classification scheme identifies five major phylogenetic groups of mycobacterial species: the Abscessus-Chelonae group, the Fortuitum-Vaccae group, the Terrae group, the Triviale group, and the Tuberculosis-Simiae group. Of these lineages, the Abscessus-Chelonae and Fortuitum-Vaccae lineages include rapidly growing mycobacteria, i.e., mycobacteria that take less than 7 days to form colonies, while the Terrae, Triviale, and Tuberculosis-Simiae lineages include slow-growing mycobacteria, i.e., mycobacteria that take more than 7 days to form colonies.

[0263] The Abscessus-Chelonae lineage includes the following mycobacterial species: M. abscessus, M. abscessus subspecies abscessus, M. abscessus subspecies bolletii, M. abscessus subspecies massiliense, M. chelonae, M. chelonae subspecies chelonae, M. immunogenum, M. salmoniphilum, M. franklinii, and M. saopaulense.

[0264] The "Fortuitum-Vaccae" lineage includes the following mycobacterial species: M. fortuitum, M. fortuitum subspecies fortuitum, M. fortuitum subspecies acetamidolyticum, M. acapulcense, M. agri, M. aichiense, M. alvei, M. anyangense, M. arabiense, M. arcueilence, M. aromaticivorans, M. auburnens M. aubagnense), M. aurum, M. austroafrinacum, M. bacteremicum, M. boenickei, M. brisnanense, M. brumae, M. canariasense, M. Celeriflavum, M. chitae, M. chlorophenolicum, M. chubuense, M. conceprionense, M. confluentis, M. cosmeticum, M. crocinum (M. M. crocinum), M. diernhoferi, M. doricum, M. duvalii, M. elephantis, M. fallax, M. facinogenes, M. flavescens, M. fluoranthenivorans, M. frederikspergense, M.M. gadium, M. gilvum, M. goodii, M. hassiacum, M. helvum, M. hippocampi, M. hodieri, M. holsaticum, M. houstonense, M. insubricum, M. iranicum, M. komanii, M. komossense, M. litorale, M. llatzerense, M. lutetiense M. lutetiense), M. madagascariense, M. mageritense, M. malmesburyense, M. monacense, M. montmartrense, M. moriokaense, M. mucogenicum, M. murale, M. neoaurum, M. neworleansense, M. novocastrense, M. obuense, M. oryzae, M. pallens, M. paraholtzium (M. M. parafortuitum), M. peregrinum, M. phlei, M. phocaicum, M. porcinum, M. ponferae, M. psychrotolerans, M. pulvens, M. pyrenivorans, M. rhodesiae, M. rufum, M. rutilum, M. sarraceniae, M.M. sediminis, M. senegalense, M. septicum, M. setense, M. smegmatis, M. sphagni, M. thermoresistibile, M. tokaiense, M. tusciae, M. vaccae, M. vanbaalenii, M. vulneris, and M. wolinskyi.

[0265] The "Terrae" lineage includes the following mycobacterial species: M. terrae, M. algericus, M. arupensis, M. engbaekii, M. heraklionensis, M. hiberniae, M. icosiumassiliensis, M. kumamotonensis, M. longobardus, M. minnesotensis, M. nonchromogenicus, M. paraterrae, M. senuense, M. sinensis M. sinensis and M. virginiensis.

[0266] The "Triviale" lineage includes the following mycobacterial species: M. trivialis, M. koreensis, and M. parakoreensis.

[0267] The "Tuberculosis-Simiae" lineage includes the following mycobacterial species: M. tuberculosis, M. tuberculosis subspecies tuberculosis, M. africanum, M. alsense, M. angelicum, M. arosiense, M. asiaticum, M. avium, M. avium subspecies avium, M. avium subspecies paratuberculosis, M. avium subspecies silvaticum, M. avium subspecies M. avium) subspecies hominissuis, M. bohemicum, M. botniense, M. bouchedurhonense, M. bourgelatii, M. bovis, M. bovis subspecies bovis, M. bovis subspecies caprae, M. branderi, M. canettii, M. caprae, M. celatum, M. chimaera, M. colombiense, M. conspicuum, M. kookii (M. M. cookii), M. europaeum, M. florentinum, M. fragae, M. gastri, M. genavsnse, M. gordonae, M. haemophilum, M. heckshornense, M. heidelbergense, M. indicus planii (M.M. indicus pranii), M. interjectum, M. intermedium, M. intracellulare, M. kansasii, M. kubicae, M. kyorinense, M. lacus, M. lentiflavum, M. leprae, M. lepraemurium, M. lepromatosis, M. liflandii, M. malmoense, M. mantenii, M. marinum, M. marseirense (M. M. marseillense), M. microti, M. monteriorense, M. mungi, M. nebraskense, M. novomagense, M. orygis, M. palustre, M. paraense, M. parraffinicum, M. paragordonae, M. paraintracellulare, M. parascrofulaceum, M. paraseculense, M. parmense, M. perscum, M. pinnipedii (M. M. pinnipedii), M. pseudoshotsii, M. riyadhense, M. saskatchewanense, M. scrofulaceum, M. seculense, M. sherrisii, M. shimoidei, M. shinjukense (M.*M. shinjukuense*, *M. shottsii*, *M. simiae*, *M. stomatepiae*, *M. szulgai*, *M. timonense*, *M. triplex*, *M. ulcerans*, *M. xenopi*, and *M. yongonense*.

[0268] Accordingly, the present invention provides a method for treating or preventing a mycobacterial infection in a subject requiring treatment or prevention of a mycobacterial infection, comprising the step of administering the above-mentioned tetracycline compound, e.g., omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the mycobacterial infection may be caused by mycobacteria belonging to any of the mycobacterial species listed above. In some examples, the mycobacterial infection may be caused by mycobacteria belonging to two or more of the mycobacterial species listed above.

[0269] In some cases, mycobacteria may belong to the mycobacterial species M. leprae or M. lepromatosis.

[0270] In some cases, mycobacteria may belong to the Mycobacterium tuberculosis complex (MTBC). MTBC is a group of genetically related Mycobacterium species that can cause tuberculosis in subjects, such as humans. MTBC includes the following species: M. africanum, M. bovis, M. bovis BCG, M. canetti, M. caprae, M. microti, M. mungi, M. orygis, M. pinnipedii, M. suricattae, and M. tuberculosis. In one specific example, the mycobacteria belong to the mycobacterium species M. tuberculosis.

[0271] In some cases, mycobacteria may be non-tuberculous mycobacteria (NTMs). As used herein, the term "NTM" refers to a group of Mycobacterium species that do not cause tuberculosis or leprosy but can cause pulmonary diseases that may resemble tuberculosis, as well as diseases resulting from infections of the lymph nodes, skin and soft tissues, bones, and various puncture and wounds. The term "NTM" may be used herein interchangeably with the terms "environmental mycobacteria," "atypical mycobacteria," or "non-tuberculous mycobacteria (MOTT)."

[0272] In some cases, NTM may belong to the Mycobacterium avium complex (MAC). MAC is a group of mycobacteria that may include the mycobacterium species M. avium, M. avium paratuberculosis, M. avium silvaticum, M. avium "hominissuis", M. Colombiense, M. chimaera, M. indicus pranii, and M. intracellulare. In further examples, NTM mycobacterial species may be selected from the group consisting of M. avium, M. avium paratuberculosis, and M. intracellulare.

[0273] In other instances, NTM may belong to the Mycobacterium chelonae lineage, which may include the following mycobacterial species: M. abscessus, M. bolletii, M. chelonae, M. immunogenum, and M. stephanolepidis. In one particular instance, NTM may be M. abscessus. In another particular instance, NTM may be M. chelonae.

[0274] NTM may also belong to the Mycobacterium fortuitum lineage. The Mycobacterium fortuitum lineage may include the following mycobacterial species: M. boenickei, M. brisbanense, M. cosmeticum, M. fortuitum, M. fortuitum subspecies acetamidolyticum, M. houstonense, M. mageritense, M. neworleansense, M. peregrinum, M. porcinum, M. senegalense, and M. septicum. (septicum). In one specific case, the mycobacteria that causes mycobacterial infections is the mycobacterium species M. fortuitum.

[0275] In some cases, NTM may also belong to one or more of the following mycobacterial species: M. kansasii, M. genavsnse, M. gordonae, M. haemophilum, M. immunogenum, M. malmoense, M. marinum, M. mucogenicum, M. nonchromogenicum, M. scrofulaceum, M. simiae, M. smegmatis, M. szulgai, M. terae Terracee complex, M. ulcerans and M. xenopi.

[0276] In other cases, NTM may also belong to one or more of the following mycobacterial species: M. avium, M. intracellulare, M. kansasii, M. paratuberculosis, M. scrofulaceum, M. simiae, M. habana, M. interjectum, M. xenopi, M. heckeshornense, M. szulgai, M. fortuitum, M. immunogenum, M. chelonae, M. marinum (M. M. marinum), M. genavsnse, M. haemophilum, M. celatum, M. conspicuum, M. malmoense, M. ulcerans, M. smegmatis, M. wolinskyi, M. goodii, M. thermoresistible, M. neoaurum, M. vaccae, M. palustre, M. elephantis, M. bohemicum, and M. septicum.

[0277] In some instances, the present invention provides a method for treating or preventing a mycobacterial infection in a subject requiring treatment or prevention of a mycobacterial infection, comprising the step of administering the subject one of the tetracycline compounds described above, e.g., omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein the mycobacterial infection is caused by slow-growing mycobacteria. The terms "slow-growing mycobacterium" or SGM, which may be used interchangeably with the terms "slowly-growing mycobacterium," "slowly-growing mycobacteria," and "slow-growing mycobacteria," refer to mycobacteria that take more than 7 days to form colonies, for example, colonies visible to the naked eye when cultured in vitro.

[0278] As mentioned above, the Terrae, Triviale, and Tuberculosis-Simiae lineages include slow-growing mycobacteria.

[0279] The "Terrae" lineage, which includes slow-growing mycobacteria, includes the following mycobacterial species: M. terrae, M. algericus, M. arupensis, M. engbaekii, M. heraklionensis, M. hiberniae, M. icosiumassiliensis, M. kumamotonensis, M. longobardus, M. minnesotensis, M. nonchromogenicus, M. paraterrae, M. senuense M. senuense, M. sinensis, and M. virginiensis.

[0280] The "Triviale" lineage, which includes slow-growing mycobacteria, includes the following mycobacterial species: M. trivialis, M. koreensis, and M. parakoreensis.

[0281] The "Tuberculosis-Simiae" lineage, which includes slow-growing mycobacteria, includes the following mycobacterial species: M. tuberculosis, M. tuberculosis subspecies tuberculosis, M. africanum, M. alsense, M. angelicum, M. arosiense, M. asiaticum, M. avium, M. avium subspecies avium, M. avium subspecies paratuberculosis, M. avium M. avium subspecies silvaticum, M. avium subspecies hominissuis, M. bohemicum, M. botniense, M. bouchedurhonense, M. bourgelatii, M. bovis, M. bovis subspecies bovis, M. bovis subspecies caprae, M. branderi, M. canettii, M. caprae, M. celatum, M. chimaera, M. colombiensis (M. M. colombiense), M. conspicuum, M. cookii, M. europaeum, M. florentinum, M. fragae, M. gastri, M. genavsnse, M. gordonae, M. haemophilum, M. heckshornense, M. heidelbergense, M.M. indicus pranii, M. interjectum, M. intermedium, M. intracellulare, M. kansasii, M. kubicae, M. kyorinense, M. lacus, M. lentiflavum, M. leprae, M. lepraemurium, M. lepromatosis, M. liflandii, M. malmoense, M. mantenii, M. marinum M. marinum), M. marseillense, M. microti, M. monteriorense, M. mungi, M. nebraskense, M. novomagense, M. orygis, M. palustre, M. paraense, M. parraffinicum, M. paragordonae, M. paraintracellulare, M. parascrofulaceum, M. paraseculense, M. parmense, M. perscum (M. M. perscum), M. pinnipedii, M. pseudoshotsii, M. riyadhense, M. saskatchewanense, M. scrofulaceum, M. seculense, M. sherrisii, M. shimoidei, M. shinjukense (M.*M. shinjukuense*, *M. shottsii*, *M. simiae*, *M. stomatepiae*, *M. szulgai*, *M. timonense*, *M. triplex*, *M. ulcerans*, *M. xenopi*, and *M. yongonense*.

[0282] In some cases, slow-growing mycobacteria may be mycobacteria belonging to NTM, for example, MAC. MAC includes the following mycobacterial species: M. avium, M. avium paratuberculosis, M. avium silvaticum, M. chimaera, M. avium "hominissuis", M. colombiense, M. indicus pranii, and M. intracellulare. In other examples, slow-growing mycobacteria may belong to mycobacterial species selected from the group consisting of M. haemophilum, M. kansasii, M. malmoense, M. marinum, M. simiae, and M. xenopi.

[0283] In some cases, slow-growing mycobacteria may belong to the Mycobacterium tuberculosis complex (MTBC), for example, to one of the following mycobacterial species: M. africanum, M. bovis, M. bovis BCG, M. canetti, M. caprae, M. microti, M. mungi, M. orygis, M. pinnipedii, M. suricattae, and M. tuberculosis. In one particular case, slow-growing mycobacteria belong to the mycobacterial species M. tuberculosis.

[0284] In some cases, the present invention provides a method for treating or preventing a mycobacterial infection in a subject requiring treatment or prevention of a mycobacterial infection, comprising the step of administering the above-mentioned tetracycline compound, e.g., omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the mycobacterial infection is caused by rapidly growing mycobacteria. The term "rapid-growing mycobacterium," also referred to herein as "RGM" and interchangeable with the terms "rapidly-growing mycobacterium," "rapidly-growing mycobacteria," and "rapid-growing mycobacteria," refers to mycobacteria that take less than 7 days to form colonies, e.g., colonies visible to the naked eye when cultured in vitro.

[0285] As mentioned above, the Abscessus-Chelonae and Fortuitum-Vaccae lineages include rapidly growing mycobacteria.

[0286] The "Abscessus-Chelonae" lineage, which includes rapidly growing mycobacteria, includes the following mycobacterial species: M. abscessus, M. abscessus subspecies abscessus, M. abscessus subspecies bolletii, M. abscessus subspecies massiliense, M. chelonae, M. chelonae subspecies chelonae, M. immunogenum, M. salmoniphilum, M. franklinii, and M. saopaulense. In some embodiments, the mycobacteria belonging to the "Abscessus-Chelonae" lineage are NTMs.

[0287] The "Fortuitum-Vaccae" lineage, which includes rapidly growing mycobacteria, includes the following mycobacterial species: M. fortuitum, M. fortuitum subspecies fortuitum, M. fortuitum subspecies acetamidolyticum, M. acapulcense, M. agri, M. aichiense, M. alvei, M. anyangense, M. arabiense, M. arcueilence, M. aromaticiborans. M. aromaticivorans), M. aubagnense, M. aurum, M. austroafrinacum, M. bacteremicum, M. boenickei, M. brisnanense, M. brumae, M. canariasense, M. Celeriflavum, M. chitae, M. chlorophenolicum, M. chubuense, M. conceprionense, M. confluentis, M. cosmeticum (M. M. cosmeticum), M. crocinum, M. diernhoferi, M. doricum, M. duvalii, M. elephantis, M. fallax, M. facinogenes, M. flavescens, M. fluoranthenivorans, M. frederikspergense (M.frederikspergense), M. gadium, M. gilvum, M. goodii, M. hassiacum, M. helvum, M. hippocampi, M. hodieri, M. holsaticum, M. houstonense, M. insubricum, M. iranicum, M. komanii, M. komossense, M. litorale, M. llatzerense, M. lutetiense (M. M. lutetiense), M. madagascariense, M. mageritense, M. malmesburyense, M. monacense, M. montmartrense, M. moriokaense, M. mucogenicum, M. murale, M. neoaurum, M. neworleansense, M. novocastrense, M. obuense, M. oryzae, M. pallens, M. paraholtzium (M. M. parafortuitum), M. peregrinum, M. phlei, M. phocaicum, M. porcinum, M. ponferae, M. psychrotolerans, M. pulvens, M. pyrenivorans, M. rhodesiae, M. rufum, M. rutilum, M. sarraceniae (M.Mycobacteria belonging to the "Fortuitum-Vaccae" lineage are NTMs. .

[0288] In some cases, rapidly growing mycobacteria may belong to the NTM, for example, mycobacteria belonging to the following mycobacteria species: M. abscessus, M. chelonae, M. fortuitum, M. smegmatis, M. peregrinum, or M. mucogenicum.

[0289] In some cases, mycobacteria may be drug-resistant mycobacteria, such as multidrug-resistant mycobacteria, such as broadly drug-resistant (XDR) mycobacteria or pandrug-resistant (PDR) mycobacteria. For example, mycobacteria may be resistant to at least one drug selected from the group consisting of rifampicin, isoniazid, INH-ethionamide, streptomycin, fluoroquinolone, pyrazinamide, ethambutol, linezolid, clofazimine, macrolide antibiotics, β-lactam antibiotics, or combinations thereof. Macrolide antibiotics may be selected from the group consisting of azithromycin, clarithromycin, erythromycin, fidaxomicin, telithromycin, carbomycin A, josamycin, kitasamycin, midecamycin / medecamycin acetate, oleandomycin, solithromycin, spiramycin, troleandomycin, tyrosine / tyrosine, and roxithromycin. Beta-lactam antibiotics include penicillins, such as penicillin G, penicillin V, benzylpenicillin, pheneticillin, cloxacillin, dicloxacillin, flucloxacillin, methicillin, nafcillin, oxacillin, temocillin, amoxicillin, ampicillin, mecillinum, carbenicillin, ticarcillin, azurocillin, mezlocillin and piperacillin; and cephalosporins, such as cefazolin, cephalexin, cephalosporin C, cephalothin, cefaclor, cephamandol, cefuroxime, cefotetan, cefoxime. The following may be selected: cefixime, cefotaxime, cefpodoxime, ceftazidime, ceftriaxone, cefepime, cefpirome and cephthaloline; carbapenems, such as biapenem, doripenem, ertapenem, faropenem, imipenem, meropenem, panipenem, razpenem, tebipenem and thienamicin; monobactams, such as aztreonam, tigemonam, nocardicin A and tabutoxinin β-lactam; and β-lactamase inhibitors, such as clavulanic acid, tazobactam, sulbactam and avibactam.

[0290] In one example, mycobacteria may be resistant to rifampicin. In another example, mycobacteria may be resistant to isoniazid. In yet another example, mycobacteria may be resistant to a combination of rifampicin and isoniazid. In yet another example, mycobacteria may be resistant to macrolide antibiotics. In yet another example, mycobacteria may be resistant to amikacin, ethambutol, moxifloxacin, rifampicin, or streptomycin.

[0291] The term "resistance" or "resistant" refers to the ability of a microorganism, such as mycobacteria, to resist the effects of an antibiotic drug, e.g., its ability to survive and continue to grow after exposure to an antibiotic. The term also encompasses the known lack of effectiveness of a particular antibiotic against a particular species of mycobacteria. In some cases, the term also refers to antibiotic / biostandards as defined by the Clinical and Laboratories Standards Institute (CLSI) and / or the Food and Drug Administration (FDA).

[0292] Methods for treating or preventing diseases associated with mycobacterial infections The present invention also provides a method for treating or preventing mycobacterial diseases in subjects requiring treatment or prevention of mycobacterial diseases. The method for treating or preventing mycobacterial diseases comprises the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject, wherein the tetracycline compound is represented by formula (1), formula (2), formula (3), formula (4), or formula (5) described above.

[0293] In some examples, the tetracycline compound administered to a subject related to the present invention is omadacycline (also known as "OMC," "PTK 0796," or "Compound 1," NUZYRA®), or a pharmaceutically acceptable salt, ester, or prodrug thereof, formula (4):

[0294] [ka] It is represented as follows.

[0295] In some cases, omadacycline is given by equation (5):

[0296] [ka] It can be represented as follows.

[0297] As used herein, the term "mycobacterial disease" refers to a disease that may be associated with, for example, a mycobacterial infection. A mycobacterial infection may be an infection with any one or more of the mycobacterial species listed above.

[0298] In some cases, tetracycline compounds, such as omadacycline, or pharmaceutically acceptable salts, esters, or prodrugs thereof, may be administered to subjects in the form of salts to treat or prevent mycobacterial diseases. The salt may be a pharmaceutically acceptable salt, such as a tosylate. For example, the tosylate of omadacycline may be amorphous or crystalline, and may be, for example, a polymorph of form 1, form 2, or form 3 of the crystalline tosylate of omadacycline described in U.S. Patent No. 8,383,610, which is incorporated herein by reference in its entirety. In some cases, tetracycline compounds, such as omadacycline, or pharmaceutically acceptable salts, esters, or prodrugs thereof, may be administered to subjects in the form of a free base, such as a crystalline free base.

[0299] In some cases, mycobacterial diseases can be caused by infections with mycobacteria belonging to the MTBC, such as M. tuberculosis. For example, the disease may be tuberculosis. Tuberculosis generally affects the lungs, but can also affect other parts of the body, such as the kidneys, spine, and brain. Latent tuberculosis is asymptomatic but can progress to an active disease, which, if left untreated, can be fatal for about half of those infected. Typical symptoms of active tuberculosis include a chronic cough with bloody sputum, fever, night sweats, and weight loss.

[0300] In some cases, mycobacterial diseases can be caused by infections with mycobacteria belonging to the species M. leprae or M. lepromatosis. For example, a mycobacterial disease may be leprosy, also known as Hansen's disease (HD). Symptoms of Hansen's disease may include granulomas of the nerves, airways, skin, and eyes. This can eventually lead to loss of pain sensation and partial loss of limbs due to repeated injuries or infections resulting from failing to notice wounds. Weakness and low vision may also be symptoms.

[0301] In some cases, mycobacterial diseases may be pulmonary diseases. Not limited examples of pulmonary diseases may include bronchiectasis, e.g., idiopathic or nodular bronchiectasis, pulmonary infections, e.g., mycobacterial pulmonary infections, and combinations thereof.

[0302] In some cases, mycobacterial diseases may be NTM diseases, i.e., they may be associated with NTM infections. Mycobacterial diseases associated with NTM infections are described, for example, in Katoch, Indian J. Med. Res. 2004, 120:290-304, the full content of which is incorporated herein by reference. For example, an NTM disease may be a pulmonary (pulmonary) NTM disease characterized by symptoms that may include one or more of the following: chronic or recurrent cough, sputum production, fatigue, malaise, dyspnea (i.e., difficulty breathing or labored breathing), fever, hemoptysis (i.e., blood or bloody mucus from the bronchi, pharynx, trachea or lungs), chest pain, and weight loss. In certain cases, a pulmonary NTM disease may be caused by an infection with M. abscessus. In other cases, pulmonary NTM disease may be associated with MAC, for example, infection with mycobacteria belonging to one of the following mycobacterial species: M. avium, M. kansasii, M. scrofulaceum, M. xenopi, M. simiae, M. habana, M. szulgai, M. fortuitum, M. vaccae, M. malmoense, or M. heckeshornense.

[0303] In some cases, the pulmonary disease may be a cavitary lung disease. The term “cavitary lung disease,” as used herein, refers to any disease characterized by the presence of cavities in the lung. The terms “cavity” or “cavity present in the lung,” as used herein, may refer to any radiopaque area having an internal low-attenuation region, regardless of wall thickness. In one example, the cavity may be a gas-filled space within a hardened zone or mass or nodule of the lung, generated by the discharge of necrotic tissue of a lesion through the bronchial tree. In another example, the cavity may also include or not include a low-attenuation region within a hardened zone, mass or nodule of the lung, and even a fluid level, and may be a low-attenuation region within the lung, usually surrounded by walls of varying thicknesses.

[0304] Cavities may arise from any pathological process, such as purulent necrosis (e.g., purulent lung abscess), caseous necrosis (e.g., tuberculosis), ischemic necrosis (e.g., pulmonary embolism), saccular dilation of lung structures (e.g., bulbar valve obstruction and Pneumocystis pneumonia), or displacement of lung tissue due to cystic structures (e.g., echinococcus).

[0305] In one example, cavitary lung disease may result from a mycobacterial infection, for example, from any of the mycobacterial species listed above. In another example, cavitary lung disease may result from an infection with M. tuberculosis. In yet another example, cavitary lung disease may result from an infection with M. abscessus.

[0306] The severity of pulmonary disease can range from asymptomatic to severe; for example, pulmonary disease can be asymptomatic, mild, moderate, or severe. In one particular case, pulmonary disease may be asymptomatic bronchiectasis, mild bronchiectasis, moderate bronchiectasis, or severe bronchiectasis.

[0307] In other cases, NTM disease may be lymphadenitis. Lymphadenitis is a lymphatic disorder characterized by symptoms that may include the presence of enlarged lymph nodes, which may sometimes rupture and may be accompanied by the formation of sinus ducts resulting in prolonged local drainage. In some cases, lymphadenitis may be associated with MAC, infection with mycobacteria belonging to one of the following species: M. avium, M. scrofulaceum, M. bohemicum, M. szulgai, or M. interjectum.

[0308] NTM diseases may also be skin diseases, eye diseases, soft tissue diseases, or bone diseases, which in some cases are associated with NTM infection at wound or open trauma sites and result in lesions. In some cases, NTM diseases may be skin infections, such as cellulitis, or eye diseases caused by eye infections by mycobacteria belonging to the Mycobacterium chelonae lineage, such as mycobacteria belonging to the Mycobacterium chelonae species M. chelonae. Such infections may arise from M. chelonae mycobacteria contaminating various equipment and / or electrical appliances, such as water heaters, pedicure beds, tattoo parlors, and hospitals. In some cases, M. chelonae may become resistant to common disinfectants, such as chlorine and glutaraldehyde. In some cases, subjects infected with mycobacteria belonging to the Mycobacterium chelonae lineage, such as M. chelonae, may be immune. In other cases, subjects infected with mycobacteria belonging to the Mycobacterium chelonae lineage, such as M. chelonae, may be immunocompromised.

[0309] In other cases, NTM disease may be a soft tissue infection or a hospital-acquired or postoperative infection, and may be associated with infections caused by bacteria belonging to the Mycobacterium fortuitum lineage, such as the Mycobacterium species M. fortuitum.

[0310] NTM disease may also be a disease associated with bone and joint infections, such as an NTM infection in the joint or bone in question.

[0311] In other cases, NTM disease may also be aquarium granuloma, also known as "fish tank granuloma" or "pool granuloma." Aquarium granuloma may be a skin lesion caused by infection with M. marinum.

[0312] NTM disease may also be Buruli ulcers caused by skin and / or bone infections, for example, by M. ulcerans.

[0313] NTM disease may also be associated with NTM infections at the site where a foreign body has been introduced or implanted in the subject. For example, infections may be associated with the site where a medical device, implant, or tattoo ink has been introduced in the subject. Medical devices may be, for example, cardiac pacemakers. Implants may be cardiovascular implants, such as heart valves; orthopedic implants, such as pins, rods, screws, or plates; or cosmetic implants, such as breast implants, prosthetic noses, or injectable fillers.

[0314] In other instances, NTM disease may be disseminated. Disseminated NTM disease primarily affects immunocompromised subjects, such as those infected with HIV and those infected with AIDS. In some cases, disseminated NTM disease in HIV-infected subjects may be characterized by symptoms that may include one or more of the following: fever, night sweats, weight loss, abdominal pain, or diarrhea. In some cases, the disseminated disease is associated with infections of the nervous system, such as the central nervous system (CNS), such as meningitis.

[0315] In some embodiments, the present invention also provides a method for treating or preventing tuberculosis in subjects requiring treatment or prevention of tuberculosis, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by formula (1), (2), (3), (4), or (5) above. In some examples, the present invention also provides a method for controlling or reducing the progression, severity, or impact of tuberculosis in subjects requiring control of tuberculosis or reduction of its progression, severity, or impact, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by formula (1), (2), (3), (4), or (5) above. In certain embodiments, the tetracycline compound is omadacycline or a pharmaceutically acceptable salt thereof.

[0316] In some embodiments, the present invention also provides a method for treating or preventing leprosy in subjects requiring treatment or prevention of leprosy, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by formula (1), (2), (3), (4), or (5) above. In some examples, the present invention also provides a method for controlling or reducing the progression, severity, or impact of leprosy in subjects requiring control of leprosy or reduction of its progression, severity, or impact, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by formula (1), (2), (3), (4), or (5) above. In certain embodiments, the tetracycline compound is omadacycline or a pharmaceutically acceptable salt thereof.

[0317] In some embodiments, the present invention also provides a method for treating or preventing bronchiectasis in subjects requiring treatment or prevention of bronchiectasis, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by formula (1), (2), (3), (4), or (5) above. In some embodiments, the present invention also provides a method for controlling or reducing the progression, severity, or effects of bronchiectasis in subjects requiring control of bronchiectasis or reduction of its progression, severity, or effects, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by formula (1), (2), (3), (4), or (5) above. In certain embodiments, the tetracycline compound is omadacycline or a pharmaceutically acceptable salt thereof.

[0318] In some embodiments, the present invention also provides a method for treating or preventing cavitary lung disease in subjects requiring treatment or prevention of cavitary lung disease, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by formula (1), (2), (3), (4), or (5) above. In some examples, the present invention also provides a method for controlling or reducing the progression, severity, or effects of cavitary lung disease in subjects requiring control of cavitary lung disease or reduction of its progression, severity, or effects, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by formula (1), (2), (3), (4), or (5) above. In certain embodiments, the tetracycline compound is omadacycline or a pharmaceutically acceptable salt thereof.

[0319] In some embodiments, the present invention also provides a method for treating or preventing lymphadenitis in subjects requiring treatment or prevention of lymphadenitis, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by formula (1), (2), (3), (4), or (5) above. In some examples, the present invention also provides a method for controlling or reducing the progression, severity, or effects of lymphadenitis in subjects requiring control of lymphadenitis or reduction of its progression, severity, or effects, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by formula (1), (2), (3), (4), or (5) above. In certain embodiments, the tetracycline compound is omadacycline or a pharmaceutically acceptable salt thereof.

[0320] In some embodiments, the present invention also provides a method for treating or preventing a soft tissue disease in a subject requiring treatment or prevention of the soft tissue disease, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by the above-described formulas (1), (2), (3), (4), or (5). In some examples, the present invention also provides a method for controlling or reducing the progression, severity, or effects of a soft tissue disease in a subject requiring control of the soft tissue disease or reduction of its progression, severity, or effects, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein the tetracycline compound is represented by the above-described formulas (1), (2), (3), (4), or (5). In certain embodiments, the soft tissue disease is a skin disease, such as cellulitis. In certain embodiments, the tetracycline compound is omadacycline or a pharmaceutically acceptable salt thereof.

[0321] In some embodiments, the present invention also provides a method for treating or preventing aquarium granuloma in subjects requiring treatment or prevention of aquarium granuloma, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by formula (1), (2), (3), (4), or (5) above. In some examples, the present invention also provides a method for controlling or reducing the progression, severity, or impact of aquarium granuloma in subjects requiring control of aquarium granuloma or reduction of its progression, severity, or impact, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by formula (1), (2), (3), (4), or (5) above. In certain embodiments, the tetracycline compound is omadacycline or a pharmaceutically acceptable salt thereof.

[0322] In some embodiments, the present invention also provides a method for treating or preventing Buruli ulcer in subjects requiring treatment or prevention of Buruli ulcer, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by formula (1), (2), (3), (4), or (5) above. In some examples, the present invention also provides a method for controlling or reducing the progression, severity, or impact of Buruli ulcer in subjects requiring control of Buruli ulcer or reduction of its progression, severity, or impact, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by formula (1), (2), (3), (4), or (5) above. In certain embodiments, the tetracycline compound is omadacycline or a pharmaceutically acceptable salt thereof.

[0323] In some embodiments, the present invention also provides a method for treating or preventing an eye disease in a subject requiring treatment or prevention of the eye disease, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by formula (1), (2), (3), (4), or (5) above. In some examples, the present invention also provides a method for controlling or reducing the progression, severity, or effects of an eye disease in a subject requiring control of the eye disease or reduction of its progression, severity, or effects, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by formula (1), (2), (3), (4), or (5) above. In certain embodiments, the tetracycline compound is omadacycline or a pharmaceutically acceptable salt thereof.

[0324] In some embodiments, the present invention also provides a method for treating or preventing bone disease in subjects requiring treatment or prevention of bone disease, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by formula (1), (2), (3), (4), or (5) above. In some examples, the present invention also provides a method for controlling or reducing the progression, severity, or effects of bone disease in subjects requiring control of bone disease or reduction of its progression, severity, or effects, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by formula (1), (2), (3), (4), or (5) above. In certain embodiments, the tetracycline compound is omadacycline or a pharmaceutically acceptable salt thereof.

[0325] Administration of tetracycline compounds for the treatment or prevention of mycobacterial infections or mycobacterial diseases. Tetracycline compounds, such as omadacycline, or pharmaceutically acceptable salts, esters, or prodrugs thereof, may be administered alone or as part of a pharmaceutical composition to subjects in need to treat or prevent mycobacterial infections or mycobacterial diseases. Any exemplary pharmaceutical composition comprising a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, may comprise an effective amount of a tetracycline compound, such as a salt of omadacycline or a free base of omadacycline, and optionally a pharmaceutically acceptable carrier. The tetracycline compound, such as a salt of omadacycline, such as a tosylate, or a free base of omadacycline, may be in amorphous or crystalline form.

[0326] The term "pharmaceutically acceptable carrier" includes substances that can be administered co-administered with tetracycline compounds, such as omadacycline, or their pharmaceutically acceptable salts, esters, or prodrugs, which may enable both to perform their intended functions, such as treating or preventing bacterial infections. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, saline solutions, alcohols, vegetable oils, polyethylene glycol, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffins, fragrance oils, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, and the like. The pharmaceutical composition may be sterilized and, if desired, may be mixed with auxiliary agents that do not react adversely with omadacycline or its pharmaceutically acceptable salts, esters, or prodrugs, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts affecting osmotic pressure, buffers, colorants, fragrances, and / or aromatic substances.

[0327] Pharmaceutical compositions that can be used in the methods of the present invention for treating or preventing mycobacterial infections or mycobacterial diseases may be configured for administration via oral, parenteral, or topical routes. In some examples, pharmaceutical compositions that can be used in the methods of the present invention may also be configured for aerosol delivery. Generally, tetracycline compounds are administered in an effective dose, most preferably depending on the body weight and condition of the subject being treated, as well as the specific route of administration selected. Variations may occur depending on the species of the subject being treated and its individual response to the tetracycline compound, as well as the type of pharmaceutical composition selected, and the duration and interval over which such administration is performed.

[0328] For oral administration, tetracycline compounds, such as omadacycline, or pharmaceutically acceptable salts, esters, or prodrugs thereof, may be administered in the form of tablets or capsules. The tablets or capsules may contain various excipients, selected from the group consisting of, for example, microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate, and glycine. The tablets or capsules may also contain disintegrants, such as starch (and preferably corn, potato, or tapioca starch), alginic acid, and certain complex silicates. The tablets or capsules may also contain granulation binders, such as sucrose, gelatin, or acacia. Furthermore, lubricants, such as magnesium stearate, sodium lauryl sulfate, and talc, may also be added to the tablets or capsules for tableting purposes.

[0329] For parenteral administration (including intraperitoneal, subcutaneous, intravenous, intradermal, or intramuscular injection), the present invention also provides injectable formulations comprising the above-mentioned tetracycline compounds, such as omadacycline, or pharmaceutically acceptable salts, esters, or prodrugs thereof. Such injectable formulations may be in the form of a dry, for example, lyophilized powder, which is restored before administration with a carrier, for example, an aqueous carrier, for example, with water. In some embodiments, the injectable formulations may also contain at least one additional component, such as a lyoprotectant, an antioxidant, and a pH-adjusting compound.

[0330] Certain pharmaceutical compositions comprising omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, which may be suitable for use in the method of the present invention, are described, for example, in U.S. Patent No. 9,315,475, which is incorporated herein by reference in its entirety.

[0331] In the method of the present invention, a tetracycline compound of formula (1), formula (2), formula (3), formula (4), or formula (5), such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, may also be administered to a subject by aerosol. The aerosol pharmaceutical composition comprising the tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, may be in the form of a solution, suspension, powder formulation, or liposome formulation. The aerosol pharmaceutical composition comprising the tetracycline compound, such as omadacycline, may, in some examples, be contained in an aerosol dispenser, which may also include a metered-dose spray device. In some examples, the aerosol dispenser may be a nebulizer, such as a small volume nebulizer (SVN), a pressurized metered-dose inhaler (pMDI), or a dry powder inhaler (DPI). The administration of tetracycline compounds in aerosols related to the present invention, such as omadacycline, or pharmaceutically acceptable salts, esters, or prodrugs thereof, may be particularly useful in the treatment of pulmonary diseases, such as pulmonary diseases associated with mycobacterial infections.

[0332] For topical administration, tetracycline compounds, such as omadacycline, or their pharmaceutically acceptable salts, esters, or prodrugs, may also be administered to a subject as part of a pharmaceutical composition formulated for topical administration. Such compositions may be in the form of gels, ointments, lotions, or creams and may contain tetracycline compounds appropriately mixed in a pharmacologically inert topical carrier. The pharmacologically inert topical carrier may contain water, glycerol, alcohol, propylene glycol, fatty alcohol, triglycerides, fatty acid esters, or mineral oil. Other possible topical carriers may include liquid petrolatum, isopropyl palmitate, polyethylene glycol, ethanol, polyoxyethylene monolaurate, sodium lauryl sulfate, etc. Furthermore, materials such as antioxidants, humectants, and viscosity stabilizers may also be added as desired.

[0333] The tetracycline compounds described herein, such as omadacycline, or their pharmaceutically acceptable salts, esters, or prodrugs, may be administered to a subject in doses of about 100–200 mg, about 100–300 mg, about 100–400 mg, about 100–500 mg, about 100–600 mg, about 200–500 mg, or about 300–600 mg, for example, a daily dose, to treat or prevent mycobacterial infections or mycobacterial diseases. In further examples, the tetracycline compounds, such as omadacycline, or their pharmaceutically acceptable salts, esters, or prodrugs may be administered orally. In further examples, the tetracycline compounds, such as omadacycline, or their pharmaceutically acceptable salts, esters, or prodrugs may be administered intravenously.

[0334] In some embodiments, tetracycline compounds, such as omadacycline, or pharmaceutically acceptable salts, esters, or prodrugs thereof may be administered to subjects in doses of about 50 to about 150 mg, about 50 to about 400 mg, about 50 to about 300 mg, about 50 to about 200 mg, about 100 to about 300 mg, or about 200 to about 300 mg, or about 100 mg. For example, a tetracycline compound may be administered to a subject in doses of about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg, for example, as a daily dose. In one embodiment, the dose is an intravenous dose.

[0335] In some embodiments, tetracycline compounds, such as omadacycline, or pharmaceutically acceptable salts, esters, or prodrugs thereof may be administered to subjects in doses of about 50 to about 800 mg, about 100 to about 700 mg, about 250 to about 600 mg, about 300 to about 500 mg, about 100 to about 400 mg, about 100 to about 600 mg, or about 300 mg. For example, a tetracycline compound may be administered in doses of about 300 mg, about 450 mg, or about 600 mg. In one embodiment, the dose is an oral dose.

[0336] In one embodiment, a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof may be administered intravenously in doses of about 100 mg, about 200 mg, or about 300 mg. In another embodiment, omadacycline or a salt thereof may be administered orally in doses of about 300 mg, about 600 mg, or about 900 mg.

[0337] In some cases, tetracycline compounds, such as omadacycline, or pharmaceutically acceptable salts, esters, or prodrugs thereof may be administered in aerosol doses, for example, delivered using an aerosol dispenser. In some cases, an aerosol dispenser may contain tetracycline compounds, such as omadacycline, or pharmaceutically acceptable salts, esters, or prodrugs thereof in doses of about 1 to about 2000 mg, for example, about 1 to about 500 mg, about 25 to about 300 mg, about 50 to about 400 mg, about 100 to about 500 mg, about 200 to about 800 mg, about 500 mg to about 1000 mg, about 10 mg to about 200 mg, or about 300 mg to about 700 mg. In some cases, the aerosol dispenser may contain a dose of approximately 1 mg, approximately 5 mg, approximately 10 mg, approximately 30 mg, approximately 50 mg, approximately 80 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 450 mg, approximately 500 mg, approximately 550 mg, approximately 600 mg, approximately 650 mg, approximately 700 mg, approximately 750 mg, approximately 800 mg, approximately 850 mg, approximately 900 mg, approximately 950 mg, or approximately 1000 mg of a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof.

[0338] In some cases, a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof may be administered topically, for example, by applying a pharmaceutical composition prepared for topical administration containing the tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the affected area. For example, the pharmaceutical composition prepared for topical administration may be in the form of a solution and may contain a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof at a concentration of about 0.01% to about 20% w / v, for example, about 0.01% to about 10% w / v, about 0.1% to about 20% w / v, about 0.5% to about 5% w / v, about 1% to about 10% w / v, or about 5% to about 20% w / v based on the volume of the composition. For example, a pharmaceutical composition configured for topical administration may contain a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, at a concentration of about 0.01% w / v, about 0.05% w / v, about 0.1% w / v, about 0.5% w / v, about 1% w / v, about 5% w / v, about 10% w / v, about 15% w / v, or about 20% w / v.

[0339] In another example, a pharmaceutical composition configured for topical administration may contain a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, at a concentration of about 0.01% to about 20% w / w, for example, about 0.01% to about 10% w / w, about 0.1% to about 20% w / w, about 0.5% to about 5% w / w, about 1% to about 10% w / w, or about 5% to about 20% w / w, based on the volume of the composition. For example, a pharmaceutical composition configured for topical administration may contain a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, at a concentration of about 0.01% w / w, about 0.05% w / w, about 0.1% w / w, about 0.5% w / w, about 1% w / w, about 5% w / w, about 10% w / w, about 15% w / w, or about 20% w / w.

[0340] In some cases, a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, may be administered at least once daily, for example, once daily, twice daily, three times daily, or four times daily, in the doses described above. In further cases, a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is administered to the subject twice daily. In one particular case, a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is administered orally to the subject twice daily.

[0341] It should be understood that the administration of dose ranges including the doses listed above is also included in the present invention. For example, any of the above doses may be at the bottom or top of the dose range included in the method of the present invention. Furthermore, it should be understood that all enumerations or sets of numbers used throughout this application are also intended to include ranges of numbers in which any of the enumerated numbers may be at the bottom or top of the range. These ranges are intended to be included in the present invention.

[0342] In one embodiment, the oral dose of a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, may be three times greater than the intravenous dose of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof.

[0343] For all the listed embodiments, the dose of a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is understood to be an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof.

[0344] In one embodiment, an effective dose of a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, when administered orally, may be about 100 to about 1000 mg, for example, about 200 to about 750 mg, about 100 to about 500 mg, about 200 to about 600 mg, or about 400 to about 600 mg of the tetracycline compound. In further examples, an effective dose of a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, when administered orally, may be about 300 mg, about 450 mg, or about 600 mg of the tetracycline compound.

[0345] In another embodiment, an effective amount of a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, when administered intravenously, may be about 50 to about 500 mg, for example, about 50 to about 400 mg, about 100 to about 300 mg, or about 50 to about 200 mg of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof. For example, an effective amount of a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, when administered orally, may be about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg.

[0346] In some cases, tetracycline compounds, e.g., omadacycline, or their pharmaceutically acceptable salts, esters, or prodrugs may be administered in connection with the present invention by oral, parenteral, systemic, topical, or aerosol delivery. Generally, tetracycline compounds, e.g., omadacycline, or their pharmaceutically acceptable salts, esters, or prodrugs are administered in an effective dose, most preferably depending on the body weight and condition of the subject being treated, as well as the selected specific route of administration. Variations may occur depending on the species of the subject being treated, its individual response to the pharmacopoeia, as well as the type of pharmaceutical formulation selected, and the duration and intervals during which such administration is performed.

[0347] In some embodiments, a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof may be administered for at least 3 days, at least 7 days, at least 14 days, at least 21 days, at least 30 days, at least 60 days, at least 5 weeks, at least 10 weeks, at least 15 weeks, at least 20 weeks, at least 30 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months, or at least 24 months. For example, administration of tetracycline compounds, such as omadacycline, or their pharmaceutically acceptable salts, esters, or prodrugs is recommended for 3-7 days, 3-14 days, 3-21 days, 3-30 days, 3-60 days, 7-14 days, 7-21 days, 7-30 days, 7-60 days, 14-21 days, 14-30 days, 14-60 days, 21-30 days, 21-60 days, and 30-60 days. 0 days, 1 to 5 weeks, 3 to 10 weeks, 5 to 20 weeks, 10 to 30 weeks, 20 to 35 weeks, 1 week to 1 month, 2 weeks to 2 months, 1 month to 3 months, 1 month to 6 months, 1 month to 9 months, 3 months to 12 months, 6 months to 12 months, 9 months to 12 months, 9 months to 16 months, 12 months to 18 months, 14 months to 24 months, 12 months to 24 months, or may continue for 24 months or longer.

[0348] For example, tetracycline compounds, such as omadacycline, or their pharmaceutically acceptable salts, esters, or prodrugs are used on days 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 5 It may be administered for 8 days, 59 days, 60 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, or 24 months. In other examples, tetracycline compounds, such as omadacycline, or pharmaceutically acceptable salts, esters, or prodrugs thereof may be administered for more than 24 months, for example, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 months, or more than 48 months.

[0349] In some embodiments, administration to a subject of a tetracycline compound, e.g., omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, may include administering one or more loading doses of the tetracycline compound, followed by one or more maintenance doses of the tetracycline compound. In some embodiments, the one or more loading doses of the tetracycline compound, e.g., omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof may be greater than the one or more maintenance doses of the tetracycline compound, e.g., omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof. For example, the loading dose may be about 450 mg per day, e.g., an oral daily dose, while the maintenance dose may be about 300 mg per day, e.g., an oral daily dose. In another example, the loading dose may be about 200 mg per day, e.g., an intravenous daily dose, while the maintenance dose may be about 100 mg per day, e.g., an intravenous daily dose, or 300 mg per day, e.g., an oral daily dose.

[0350] The loading dose of a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, and the maintenance dose of a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, may be administered via the same or different routes. For example, the loading dose may be administered intravenously, and the maintenance dose may be administered orally. In other embodiments, both the loading dose and the maintenance dose may be administered orally, or both the loading dose and the maintenance dose may be administered intravenously.

[0351] In some cases, the loading dose of a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, may be an oral or intravenous dose administered twice daily, and the maintenance dose may be an oral or intravenous dose administered once daily. For example, a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, may be administered as an intravenous loading dose of 100 mg twice daily, followed by an intravenous maintenance dose of 100 mg once daily. In another case, a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, may be administered as an intravenous loading dose of 100 mg twice daily, followed by an oral maintenance dose of 300 mg once daily. In yet another example, a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, may be administered as an oral loading dose of 300 mg twice daily, followed by an oral maintenance dose of 300 mg once daily.

[0352] In other examples, the administration of a tetracycline compound, e.g., omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, does not necessarily involve the administration of one or more loading doses of the tetracycline compound. Therefore, in some examples, a tetracycline compound, e.g., omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, may be administered to the subject at the same dose over the course of treatment. For example, a tetracycline compound, e.g., omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, may be administered to the subject in intravenous doses of approximately 100 mg, approximately 200 mg, or approximately 300 mg. The intravenous dose may be administered to the subject once or twice daily over the course of treatment. In other examples, a tetracycline compound, e.g., omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, may be administered to the subject in oral doses of approximately 300 mg, approximately 450 mg, or approximately 600 mg. The oral dose may be administered once daily to the patient over the duration of treatment.

[0353] In some cases, tetracycline compounds, e.g., omadacycline, or their pharmaceutically acceptable salts, esters, or prodrugs may be administered to a subject alone or in combination with at least one additional antimycobacterial agent to treat or prevent mycobacterial infections or mycobacterial diseases. The phrase “in combination with” an antimycobacterial agent is intended to include simultaneous administration of a tetracycline compound, e.g., omadacycline, or its pharmaceutically acceptable salts, esters, or prodrugs and an antimycobacterial agent; administration of an antimycobacterial agent following an initial administration of a tetracycline compound, e.g., omadacycline, or its pharmaceutically acceptable salts, esters, or prodrugs; and administration of a tetracycline compound, e.g., omadacycline, or its pharmaceutically acceptable salts, esters, or prodrugs following an initial administration of an antimycobacterial agent.

[0354] In some examples, a tetracycline compound, e.g., omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, and at least one additional antimycobacterial agent may be administered to a subject as part of the same pharmaceutical composition. In further examples, the pharmaceutical composition comprising a tetracycline compound, e.g., omadacycline, and at least one additional antimycobacterial agent may be an aerosol pharmaceutical composition. In other examples, the pharmaceutical composition comprising a tetracycline compound, e.g., omadacycline, and at least one additional antimycobacterial agent may be a pharmaceutical composition configured for topical administration.

[0355] Any antimycobacterial agent known or thought to be effective against mycobacterial infections, or any antimycobacterial agent shown to have additive or synergistic activity with the tetracycline compounds described herein, such as omadacycline, or pharmaceutically acceptable salts, esters, or prodrugs thereof, may be used in the method of the present invention. In some examples, the antimycobacterial agent is diarylquinolone, rifapentin, rifaradyl, nitroimidazole, benzothiadinone, capreomycin, clofazimine, cycloserine, dapsone, thiocarbamide, ethambutol, DC-159a, nitrobenzthiazole, stezolid (PNU-100480), AZD-5847, posisolid (AZD-2563), para-aminosalicylic acid, SQ-109, SQ-609, cap The group consisting of ramycin, caprazen nucleoside, isothiazoloquinolone, thioridazine, thiasetazone, zilithromycin, roxithromycin, telithromycin, azithromycin, clarithromycin, erythromycin, amikacin, kanamycin, streptomycin, levofloxacin, moxifloxacin, gatifloxacin, linezolid, rifaradyl, imipenem, meropenem, clavulanate, and isoniazid may be selected. In other examples, the antimycobacterial agent may be selected from the group consisting of rifampicin, isoniazid, INH-ethionamide, streptomycin, fluoroquinolone, pyrazinamide, ethambutol, linezolid, clofazimine, macrolide antibiotics, or combinations thereof. In further examples, macrolide antibiotics may be selected from the group consisting of azithromycin, clarithromycin, erythromycin, fidaxomicin, telithromycin, carbomycin A, josamycin, kitasamycin, midecamycin / medecamycin acetate, oleandmycin, solithromycin, spiramycin, troleandmycin, tyrosine / tyrosine, and roxithromycin.

[0356] The terms “to treat” or “treatment,” as used herein, include (a) inhibiting, controlling, stopping, reducing or delaying the progression or onset of a mycobacterial infection or mycobacterial disease, or, in the case of maintenance treatment, its recurrence, or at least one clinical or potential symptom thereof; and / or (b) alleviating, i.e., improving or reducing one or more clinical or potential symptoms of at least one mycobacterial infection or mycobacterial disease. The benefit to the treated subject is statistically significant, or at least recognizable to the subject or physician.

[0357] The terms “prevention,” “prevent,” “prevention,” or “prevention,” as used herein, include preventing or reducing the risk of mycobacterial infection or mycobacterial disease. In some cases, the terms include preventing or delaying the onset of clinical symptoms of mycobacterial infection or mycobacterial disease in subjects who may already be infected with mycobacteria but have not yet developed a mycobacterial disease, or who have not shown symptoms of a mycobacterial infection or mycobacterial disease. In some cases, the terms also include reducing the likelihood that subjects exposed to mycobacteria will develop a mycobacterial infection, a mycobacterial disease, or symptoms thereof.

[0358] The therapeutic or preventive effect is evident when there is a statistically significant improvement in one or more parameters of the disease state, or otherwise when the expected symptoms are not aggravated or developed. For example, a favorable change of at least 10%, preferably at least 20%, 30%, 40%, 50%, or more, in a measurable parameter of the symptoms of a mycobacterial infection or mycobacterial disease may indicate an effective treatment. In another example, any positive change resulting in a reduction in the severity of the symptoms of a mycobacterial infection or mycobacterial disease, as measured using an appropriate scale, represents appropriate treatment with a tetracycline compound described herein, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof.

[0359] When used herein, the term “effective dose” includes the amount of a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, necessary to treat or prevent a mycobacterial infection or mycobacterial disease. For example, the term “effective dose” represents a level of potency sufficient to achieve the desired therapeutic effect by killing mycobacteria and / or inhibiting mycobacterial growth. In one embodiment, the effective dose is sufficient to eradicate the mycobacteria causing the mycobacterial infection or mycobacterial disease.

[0360] The term "subject" includes animals exposed to mycobacterial infection or mycobacterial disease. Examples of subjects include animals, such as livestock (e.g., cattle, pigs, horses, goats, rabbits, sheep, chickens, etc.), laboratory animals (mice, rats, monkeys, chimpanzees, etc.), pets (e.g., dogs, cats, ferrets, hamsters, etc.), birds (e.g., chickens, turkeys, ducks, geese, crows, ravens, sparrows, etc.), primates (e.g., monkeys, gorillas, chimpanzees, bonobos, and humans), and other animals (e.g., squirrels, raccoons, mice, rats, etc.). In one embodiment, the subject is a mouse or a rat. In one embodiment, the subject is a cattle, pig, or chicken. In one embodiment, the subject is a human.

[0361] In some cases, in addition to mycobacterial infection or mycobacterial disease, the subject may have another disease or condition. In some cases, the other disease or condition may be a lung disease, such as chronic obstructive pulmonary disease (COPD), occupational lung disease, tuberculosis, bronchiectasis, such as idiopathic or nodular bronchiectasis, cystic fibrosis, primary ciliary dysplasia, allergic bronchopulmonary aspergillosis, alpha-1 antitrypsin deficiency, pneumoconiosis, interstitial lung disease (of any cause), chronic aspiration syndrome, or alveolar proteinosis.

[0362] In other cases, the subject may be immunocompromised, that is, may have another disease or condition that may be associated with an immunological defect or immunosuppressive state. Immunological defects or immunosuppressive states may be associated with HIV infection and / or AIDS; the use of immunosuppressive drugs, e.g., anticancer drugs or drugs to suppress the immune system after organ transplantation; the use of biological anti-inflammatory agents, e.g., acetaminophen; unclassified immunoglobulin deficiency syndrome; or hereditary disorders resulting in immunological defects, e.g., genetic defects in the interferon-γ receptor or interleukin-12. In some cases, the immunocompromised subject is a subject with cancer. In such subjects, the suppression of the immune system may be due to the action of cancer or the action of drugs taken by the subject for the treatment of cancer, e.g., chemotherapy drugs.

[0363] In one example, the subject may have a lung disease. Examples of lung diseases that are not limited to these include cystic fibrosis, chronic obstructive pulmonary disease (COPD), alpha-1 antitrypsin deficiency, and bronchiectasis, such as idiopathic or nodular bronchiectasis. In another example, the subject may be immunocompromised or immunosuppressed, such as having HIV infection and / or AIDS. In yet another example, the subject may have undergone organ transplantation, such as a lung transplant.

[0364] In some embodiments, the subjects may be immunocompromised. In other embodiments, the subjects may be immune. In some embodiments, the subjects may have previously been treated for tuberculosis.

[0365] In some cases, subjects have been determined to have a mycobacterial infection prior to administration of a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof. Therefore, the method of the present invention may also include the step of determining whether a subject has a mycobacterial infection prior to administration of a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof. Determination of whether a subject has a mycobacterial infection can be achieved by any method known in the art for diagnosing mycobacterial infections.

[0366] In some embodiments, the present invention also provides a method for treating a subject having a lung disease, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by formula (1), (2), (3), (4), or (5) above. In certain embodiments, the tetracycline compound is omadacycline or a pharmaceutically acceptable salt thereof.

[0367] In some cases, lung diseases may be selected from a group consisting of cystic fibrosis, chronic obstructive pulmonary disease (COPD), occupational lung disease, bronchiectasis, cavitary lung disease, primary ciliary dysplasia, allergic bronchopulmonary aspergillosis, alpha-1 antitrypsin deficiency, pneumoconiosis, interstitial lung disease, chronic aspiration syndrome, and alveolar proteinosis.

[0368] In one example, the lung disease may be cystic fibrosis. In another example, the lung disease may be chronic obstructive pulmonary disease (COPD). In yet another example, the lung disease may be occupational lung disease. In yet another example, the lung disease may be bronchiectasis, such as idiopathic or nodular bronchiectasis. In yet another example, the lung disease may be cavitary lung disease. In yet another example, the lung disease may be primary ciliary dysplasia. In yet another example, the lung disease may be allergic bronchopulmonary aspergillosis. In yet another example, the lung disease may be alpha-1 antitrypsin deficiency. In yet another example, the lung disease may be pneumoconiosis. In yet another example, the lung disease may be interstitial lung disease. In yet another example, the lung disease may be chronic aspiration syndrome. In yet another example, the lung disease may be alveolar proteinosis.

[0369] In some embodiments, the present invention also provides a method for treating a subject having an immunosuppressed state, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject, wherein the tetracycline compound is represented by formula (1), (2), (3), (4), or (5) above. In certain embodiments, the tetracycline compound is omadacycline or a pharmaceutically acceptable salt thereof.

[0370] In one example, the immunosuppressed state may be associated with HIV infection or AIDS. In another example, the immunosuppressed state may be associated with the administration of immunosuppressive drugs, such as chemotherapeutic agents administered as part of cancer treatment; immunosuppressants administered after organ transplantation; or anti-inflammatory agents, such as acetaminophen. In yet another example, the immunosuppressed state may be the result of an immunological defect, i.e., a defect in the function of the immune system caused by a disease, such as AIDS or cancer, or a genetic defect. For example, in some embodiments, the immunosuppressed state may be the result of a hereditary disorder, such as a genetic defect in the interferon-γ receptor or interleukin-12.

[0371] In some embodiments, administration of a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to a subject for the treatment or prevention of a mycobacterial infection, or for the treatment or prevention of a disease caused by or associated with a mycobacterial infection, results in no substantial adverse effects. In some examples, the administration may be oral. In some examples, the adverse effects may be gastrointestinal adverse effects, such as nausea or vomiting. In some embodiments, administration of a tetracycline compound, such as omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, by the method of the present invention does not require the administration of an antiemetic, such as ondansetron.

[0372] As used herein, the term "about" refers to a range of values ​​that may be 15%, 10%, 8%, 5%, 3%, 2%, 1%, or 0.5% greater or less than a specified value. For example, "about 10%" could be between 8.5% and 11.5%. In one embodiment, the term "about" refers to a range of values ​​that are 5% greater or less than a specified value. In another embodiment, the term "about" refers to a range of values ​​that are 2% greater or less than a specified value. In yet another embodiment, the term "about" refers to a range of values ​​that are 1% greater or less than a specified value.

[0373] In this specification, whenever values ​​and ranges are given for, for example, the age of the target population, dosage, duration, etc., it should be understood that all values ​​and ranges encompassed by these values ​​and ranges are intended to be included within the scope of the present invention. Furthermore, all values ​​within these values ​​and ranges may also be upper or lower limits of the range.

[0374] [Examples] Examples of the present invention

[0375] [Example 1] In vitro activity of omadacycline against M. abscessus, M. chelonae, and M. fortuitum. Infections caused by Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum are difficult to treat. The purpose of this study was to evaluate the in vitro activity of omadacyclin against clinical isolates of Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum, and to compare it with the in vitro activities of doxycycline, tigecycline, and amikacin against the same clinical isolates.

[0376] method In total, 24 clinical isolates of Mycobacterium abscessus, 22 clinical isolates of Mycobacterium chelonae, and 20 isolates of Mycobacterium fortuitum were tested in the study. This study also used the antibiotics tigecycline, doxycycline, and amikacin for comparison. Omadacycline, tigecycline, and doxycycline were dissolved in distilled water, sterilized by filtration, and frozen at -20°C. Amikacin was dissolved in DMSO and frozen at -20°C. For susceptibility testing, the stock solutions of the antibiotic compounds were serially diluted in 50 μL of cation-modified Mueller-Hinton broth (CAMHB) in a polystyrene 96-well round-bottom microtiter plate. Add 50 μL of appropriate mycobacterial cell suspension to each well, approximately 1 × 10⁶ 5 The final concentration of CFU / mL was obtained. The inoculum used for each isolate was measured by titration in saline containing Tween 80 and by seeding onto MH agar. Mycobacterium abscessus and Mycobacterium fortuitum titer plates were incubated in ambient air at 37°C for 3–4 days and 5–7 days, respectively. Mycobacterium chelonae titer plates were incubated in ambient air at 30°C for 3–5 days. Each isolate was tested at least twice. MIC was defined as the lowest concentration of antimicrobial agent that did not produce visible turbidity.

[0377] result The MIC values ​​measured for each Mycobacterium abscessus isolate are shown in Table 2 below. MIC values ​​measured for Mycobacterium abscessus isolates 50 and MIC 90The results are shown in Table 3 below. Tigecycline was tested against a subset of Mycobacterium abscessus isolates (N=14) and was determined to have similar activity to omadacycline against Mycobacterium abscessus isolates.

[0378] [Table 2]

[0379] [Table 3]

[0380] The MIC values ​​measured for each Mycobacterium chelonae isolate are shown in Table 4 below. MIC values ​​measured for Mycobacterium chelonae isolates 50 and MIC 90 This is shown in Table 5 below.

[0381] [Table 4]

[0382] [Table 5]

[0383] The MIC values ​​measured for each Mycobacterium fortuitum isolate are shown in Table 6 below. MIC values ​​measured for Mycobacterium fortuitum isolates 50 and MIC 90 This is shown in Table 7 below.

[0384] [Table 6]

[0385] [Table 7]

[0386] conclusion The results shown in Tables 2-7 demonstrate that omadacyclin exhibits promising activity against isolates of Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum.

[0387] [Example 2] In vitro activity of omadacycline against M. abscessus. Introduction Mycobacterium abscessus belongs to a heterogeneous group of nontuberculous mycobacteria (NTMs) and can cause severe infections in patients with underlying structural lung diseases, such as cystic fibrosis (CF). The incidence of NTM infections in CF patients is increasing, and M. abscessus is one of the most frequently isolated species (Adjemian et al., Ann Am Thorac Soc. 2018, 15(7):817~26). This is significant because pulmonary infections caused by M. abscessus have been shown to be the cause of the most rapid decline in lung function compared to other pathogens (Qvist et al., J Cyst Fibros. 2016, 15(3):380~5). Furthermore, M. abscessus infections are relatively contraindicated in lung transplantation at most medical centers. Therefore, appropriate management of M. abscessus infections in CF patients is extremely important.

[0388] Among the various NTM species, M. abscessus is well known for its inherent resistance to multiple antibiotics. This is especially true for the M. abscessus subspecies abscessus, characterized by the presence of a functional erythromycin ribosomal methylase (erm) gene and the conferral of inducible resistance to macrolides considered the baseline drug in treatment (Guo et al., Antimicrob Agents Chemother., 2018, 62(5)). As a result, M. abscessus infections are extremely difficult to treat and require long-term combinations of different intravenous and oral antimycobacterial drugs. Drug regimens are usually poorly tolerated, and even intensive treatment yields disappointing results (Pasipanodya et al., Antimicrob Agents Chemother., 2017;61(11)).

[0389] The purpose of this study was to explore the potential use of omadacycline for the treatment of M. abscessus infections. In connection with this, the in vitro activity of omadacycline against M. abscessus was evaluated and compared with the activity of tigecycline.

[0390] method Bacterial strains and cultures M. abscessus subspecies abscessus CIP 104536 (Collection of Institute Pasteur, Paris, France) was cultured at 37°C under 96 rpm shaking conditions in cation-modified Mueller-Hinton II broth (Becton, Dickinson and Company (BD), Sparks, MD, USA) supplemented with 10% oleic acid-albumin-dextrose-catalase concentrate (OADC, BD) and 0.5% glycerol (Scharlau Chemie SA, Sentmenat, Spain). Vials containing the M. abscessus suspension were stored at -80°C. Cultures in solid medium were grown for 10 days at 37°C and 5% CO2 on Mueller-Hinton II agar (BD) supplemented with 10% OADC and 0.5% glycerol. According to the guidelines of the Clinical and Laboratory Standards Institutes (CLSI), the minimum inhibitory concentration (MIC) for antibiotic susceptibility was 4 mg / L for both omadacycline and tigecycline.

[0391] Antibiotics Omadacycline was supplied by Paratek Pharmaceuticals (Boston, NY, USA). Tigecycline was purchased from Pfizer (New York, NY, USA).

[0392] Time-death kinetics assay The concentration- and time-dependent killing capacity of omadacycline and tigecycline was determined as previously described (de Steenwinkel et al., J. Antimicrob Chemother., 2010, 65(12):2582~9; Bax et al., Antimicrob. Agents Chemother., 2016, 60(4):2577~9). Briefly, M. abscessus cultures were exposed to antibiotics at a 4-fold increase in concentration for 7 days at 37°C under shaking conditions of 96 rpm. In the absence of drug, the mycobacterial population increased to 3.6 × 10⁶ in incubation within 7 days. 5 From cfu / mL to 3.5 × 10 8 An average increase to cfu / mL was observed. Drug concentrations ranged from 0.063 to 256 mg / L for both compounds. The concentrations tested were based on the MIC values ​​of individual drugs ranging from 1 / 64×MIC to 64×MIC, encompassing a wide range for in vitro drug activity studies. Samples were collected on days 1, 3, and 7 of drug exposure, centrifuged at 14000×g to avoid carryover of anti-NTM drugs, and serially diluted (10-fold, 10-fold). 0 ~10 7 The cells were subcultured in solid medium. The plates were incubated at 37°C and 5% CO2 for 10 days, and the colony-forming unit (cfu) count was determined. The detection limit was 5 cfu / mL (log 0.7). All experiments were performed twice. Time-death curves and concentration-effect curves were obtained.

[0393] Selection of drug-resistant M. abscessus To evaluate the selection of drug-resistant mutations after 7 days of drug exposure, subcultures were also performed in solid media containing omadacycline and tigecycline. The drug concentration in the subculture plates was 4 times the MIC concentration, i.e., 16 mg / L, for both tigecycline and omadacycline.

[0394] Stability of antimicrobial agents As previously described in detail (Bennett et al., Appl. Microbiol. 1966, 14(2):170~7), the time-course antimicrobial activity was evaluated using a standard large-plate agar diffusion assay. Specifically, omadacycline-susceptible Staphylococcus aureus strains and tigecycline-susceptible Micrococcus luteus strains were seeded on solid diagnostic susceptibility (DST) agar (Oxoid, Hampshire, UK). A 2x increase standard concentration series was prepared. The standard concentration series of omadacycline and tigecycline, along with two test concentrations, were added to DST medium, and the inhibition zone was determined on days 1, 3, and 7. By comparing the inhibition zone of the standard concentration series with the zone of the test concentrations, the time-course concentrations of omadacycline and tigecycline, representing antibiotic stability, could be determined. A 20% decrease in omadacycline concentration was observed within the first 24 hours, and previously, an 80% decrease in tigecycline concentration per day had been shown (Bax et al., Antimicrob. Agents Chemother., 2016, 60(4):2577~9). To compensate for this, 20% omadacycline and 80% tigecycline concentrations were added daily.

[0395] result The concentration and time-dependent activity of omadacycline and tigecycline are shown in panels A and B of Figure 1, respectively. Both omadacycline and tigecycline exhibited concentration-dependent antimicrobial activity. Omadacycline inhibited mycobacterial growth at 4 mg / L and killed mycobacteria at concentrations of 16 mg / L and above, but elimination was not achieved. Tigecycline killed mycobacteria at concentrations of 4 mg / L and above, and achieved elimination at concentrations of 16 mg / L and above on days 3 to 7. Except for small percentages of 1.5% and 0.6% at 4 mg / L omadacycline and 4 mg / L tigecycline, respectively, no selection of drug resistance exceeding the spontaneous mutation frequency was observed at any of the tested concentrations of omadacycline or tigecycline.

[0396] Figure 2 shows the concentration-response relationship after 7 days of exposure. The concentration-response curves showed equilibrium 1 and 2 log mycobacterial killing at 3.3, 4.0, and 4.8 mg / L for omadacycline, and at 2.2, 2.7, and 3.4 mg / L for tigecycline.

[0397] Consideration This in vitro study demonstrated that omadacycline exhibits good activity against *M. abscessus* subspecies *M. abscessus*, one of the most difficult-to-treat species of NTM. While tigecycline's in vitro activity was found to be slightly higher, the clinical relevance of this finding remains questionable given the favorable pharmacokinetic properties of omadacycline. Tigecycline has high protein binding affinity, and therefore its free active fraction is lower compared to that of omadacycline. The 24-hour area under the curve for omadacycline has been shown to be approximately three times higher than that of tigecycline in intraepithelial fluid, alveolar cells, and plasma (Gotfried et al., Antimicrob Agents Chemother. 2017, 61(9)).

[0398] In this study, both omadacycline and tigecycline demonstrated clear concentration-dependent antibacterial activity. This is consistent with observations in recent pharmacokinetic / pharmacodynamic studies on tigecycline activity against M. abscessus. In that study, doubling the currently used clinical dose was necessary to achieve an optimal response that also demonstrated a dose-response effect in patients (Ferro et al., Antimicrob Agents Chemother. 2016, 60(5):2895~900). However, in that study, the simulated concentration was based on the total tigecycline concentration rather than the free fraction, and therefore omadacycline is likely to be more active in vivo.

[0399] [Example 3] In vitro activity of tetracycline compounds against Mycobacterium tuberculosis strain. The purpose of this study was to test the activity of selected tetracycline compounds against the H37Rv strain of Mycobacterium tuberculosis. The minimum inhibitory concentrations (MICs) of various tetracycline compounds against the H37Rv strain were determined and are shown in Table 8.

[0400] [Table 8] JPEG2026086890000095.jpg255137JPEG2026086890000096.jpg250139JPEG202 6086890000097.jpg255137JPEG2026086890000098.jpg255139JPEG20260868900 00099.jpg253136JPEG2026086890000100.jpg248144JPEG2026086890000101.j pg251144JPEG2026086890000102.jpg248139JPEG2026086890000103.jpg131143

[0401] The results shown in Table 8 indicate that certain tetracycline compounds can inhibit the growth of the H37Rv strain of Mycobacterium tuberculosis.

[0402] [Example 4] In vitro activity of omadacycline in combination with linezolid or clarithromycin against BCG. The objective of this study was to evaluate the in vitro activity of omadacycline (OMC) in combination with linezolid (LZD) or clarithromycin (CLA) against Bacillus calmette-Guérin (BCG). BCG is an attenuated form of Mycobacterium bovis, a species closely related to Mycobacterium tuberculosis.

[0403] method The in vitro activity of omadacycline in combination with linezolid or clarithromycin was evaluated using a disk diffusion assay. BCG cell suspension at a density of 3 MacFarland units was seeded onto agar plates, and antibiotic-containing disks were also added. The antibiotic-containing disks contained the following antibiotics: 15 μg omadacycline; 15 μg clarithromycin; 30 μg linezolid; a combination of 15 μg clarithromycin and 15 μg omadacycline; a combination of 30 μg linezolid and 15 μg omadacycline; and a combination of 5 μg linezolid and 5 μg omadacycline. The plates were incubated in ambient air at 37°C for approximately 1 month. The plates were then evaluated for bacterial growth.

[0404] result The results of the disk diffusion assay are shown in Table 9 below.

[0405] [Table 9]

[0406] conclusion The results shown in Table 9 indicate that omadacycline, alone or in combination with clarithromycin or linezolid, exhibits promising activity against BCG. Based on these results, omadacycline is also expected to have activity against Mycobacterium tuberculosis.

[0407] [Example 5] An open-label, parallel-group, multi-IV dose study to evaluate steady-state intrapulmonary concentrations of omadacycline and tigecycline in healthy adults. Introduction For antibiotics to be effective in treating respiratory infections, they must reach sufficient concentrations in the respiratory tissue to affect respiratory pathogens once administered. Infection-causing pathogens can be extracellular or intracellular; therefore, for antibiotics to be active against both extracellular and intracellular pathogens in vivo, both extracellular and intracellular concentrations of the antibiotic must be sufficient. Antibiotic concentrations in the bronchial mucosa provide a reliable indicator of bronchial penetration and can be a better predictor of clinical efficacy than serum levels.

[0408] The intraepithelial fluid (ELF) and alveolar cells (AC), primarily alveolar macrophages (AMs), are important infection sites for common extracellular and intracellular pathogens, respectively. For example, mycobacteria that infect the lungs, such as M. tuberculosis or NTM, can persist as intracellular infections within macrophages. Furthermore, mycobacteria, such as NTM, are known to persist extracellularly as biofilms.

[0409] Direct measurement of antimicrobial agent concentrations in the airway fluid (ELF) enables the determination of appropriate antibiotic doses and the evaluation of pharmacokinetics (PK) and exposure-response targets for respiratory infections. Bronchoalveolar lavage (BAL), including fluid and tissue sampling from the airways, has become a standard method for confirming both extracellular and intracellular antibiotic concentrations after systemic administration of antibiotics. Extracellular concentrations are calculated from fluids reflecting the ELF, while intracellular concentrations are measured in the airway cortex (AC), including macrophages.

[0410] Previous studies have shown that the in vitro activity of omadacycline is not affected by serum or lung surface, which is a key characteristic that aligns with its potential practical applications in the treatment of respiratory infections. Furthermore, omadacycline has been shown to be effective in treating mouse models of respiratory infections. In mice, omadacycline concentrations in lung tissue are 3.7 to 4.4 times higher than plasma concentrations. In vitro results and tissue culture experiments against intracellular bacteria have shown that omadacycline is concentrated in mammalian cells.

[0411] The objective of this study was to determine the concentration of omadacycline in lung compartments (pulmonary AC, including the pulmonary pulmonary foci (ELF) and pulmonary amniotic fluid (AM)) and to clarify the time course of intrapulmonary distribution compared with plasma pharmacokinetic (PK) profiles. Tigecycline has a similar PK profile to omadacycline, and given the reported concentration levels achieved in human ELF, the inclusion of tigecycline was intended to provide assay sensitivity in this study.

[0412] method This study was designed as a single-center, multi-dose, open-label study to determine the concentrations of omadacycline and tigecycline in lung compartments (ELF and AC) in healthy adult subjects after administration of omadacycline and tigecycline to steady-state drug levels. A total of 62 healthy volunteers were randomized in a 2:1 ratio to receive either omadacycline or tigecycline. Of these, 42 received omadacycline as five 100 mg intravenous doses administered as 30-minute infusions at t=0, 12, 24, 48, and 72 hours. The remaining 20 subjects received a single 100 mg intravenous dose as a 30-minute infusion at t=0, followed by six 50 mg intravenous doses of tigecycline as 30-minute infusions at t=12, 24, 36, 48, 60, and 72 hours. A final examination was conducted the day after the last dose of the test substance. The final follow-up assessment was conducted 7 to 14 days after the last administration of the test substance to the subjects, and this could be completed by telephone contact or other communication techniques unless tests were required to assess any adverse events or abnormalities noticed at the study completion consultation.

[0413] Plasma PK samples were collected before administration and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after administration on day 4. 24-hour samples were collected only for omadacycline. On day 4, one BAL sample was collected from each subject. Subjects were randomized to one of the following sampling times: 0.5, 1, 2, 4, 8, 12, or 24 hours after administration. 24-hour samples were collected only for omadacycline.

[0414] We used a previously developed omadacycline population PK model to explain omadacycline plasma PK (Van Wart et al., ECCMID 2015. Abstr. 1739). Furthermore, we modeled PK data for omadacycline and tigecycline using linear 3-compartment and 2-compartment models in which ELF is incorporated into the first peripheral compartment, and computer-calculated the ratio of total drug ELF to total drug plasma AUC, and the ratio of total drug ELF AUC to free drug plasma AUC for both omadacycline and tigecycline.

[0415] result Parameters calculated using a previously developed Omada cycline population PK model. For subjects administered omadacycline, the mean (±SD) plasma PK parameters after the fifth dose of omadacycline were as follows: C max : 2.26±0.76 μg / mL Distribution volume: 165±58L Clearance: 8.03 ± 1.43 L / hour; and Exclusion half-life: 14.7 ± 4.2 hours.

[0416] The mean (±SD) concentrations (μg / mL) of omadacycline measured at the time of bronchoscopy and BAL in different compartments are shown in Table 10 below.

[0417] [Table 10]

[0418] The data shown in Table 10 are also illustrated graphically in Figure 3. Specifically, Figure 3 shows the time course of omadacycline concentrations in plasma, endothelial fluid, and alveolar cells. The data show that the mean omadacycline concentration in alveolar cells is at least an order of magnitude higher (approximately 25 times higher) than the mean omadacycline concentration in plasma, while the mean omadacycline concentration in endothelial fluid is at least approximately 40% higher than the mean omadacycline concentration in plasma. See Table 11 below for the ratios of omadacycline concentrations at different time points.

[0419] [Table 11]

[0420] Mean omadacycline concentration and median AUC of omadacycline concentration in intraepithelial fluid and plasma. 0-24 The transmission ratios based on the values ​​were 1.47 and 1.42, respectively, while the mean omadacycline concentration and median omadacycline concentration AUC in alveolar cells and plasma were different. 0-24 The transmittance ratios based on the values ​​were 25.8 and 24.8, respectively. See Table 12 below. "AUC mean "AUC" refers to the area under the curve based on the average concentration at each BAL sample collection. median This refers to the area under the curve based on the median concentration at each BAL sample collection.

[0421] [Table 12]

[0422] Parameters calculated using linear 3-part and 2-part models in which ELF is incorporated into the first peripheral part. The ratio of total drug ELF AUC to free drug plasma AUC, calculated by a model computer, is shown in Table 13 below.

[0423] [Table 13]

[0424] conclusion The experimental data obtained in this study demonstrate that intravenous administration of omadacycline results in both extracellular and intracellular concentrations of omadacycline in the lungs that are higher than those in plasma. Specifically, the extracellular concentration of omadacycline achieved in the lungs, i.e., the concentration in the intraepithelial fluid, is more than 1.4 times higher than the plasma concentration of omadacycline. The intracellular concentration of omadacycline achieved in the lungs, i.e., the concentration in alveolar cells, such as macrophages, is significantly higher than the plasma concentration of omadacycline, approximately 25 times higher. Therefore, the results demonstrate that omadacycline, when administered to subjects, is concentrated in the alveolar cells of the lungs, such as macrophages. Since these cells are also often sites of mycobacterial infection, omadacycline is very suitable for treating mycobacterial infections in the lungs.

[0425] [Example 6] Comparison of the in vitro susceptibility of omadacycline to nontuberculous mycobacterial isolates with tigecycline, minocycline, doxycycline, and other comparative antimicrobial agents. Introduction The objective of this study was to compare the in vitro susceptibility of nontuberculous mycobacteria (NTM) isolates recovered in the United States to treatment with omadacycline, as well as with tigecycline, minocycline, doxycycline, and other antimicrobial agents as comparators.

[0426] Materials and methods A total of 65 NTM isolates were tested. Of the tested isolates, 50 were rapidly growing mycobacteria (RGM) isolates and 15 were slow-growing mycobacteria (SGM) isolates. Upon receipt by laboratory, isolates were species-specific by genetic sequencing (including erm gene sequencing) to determine inducible macrolide susceptibility and were tested for other antimicrobial susceptibility. The erythromycin-resistant methylase (erm) gene confers inducible resistance to macrolides. For less commonly found species, isolates were supplemented by using a stock of well-characterized U.S. isolates from diverse geographical sites collected within the past five years. The antimicrobial agents tested against RGM included amikacin, ciprofloxacin, clarithromycin, doxycycline, cefoxitine, imipenem, linezolid, minocycline, moxifloxacin, omadacycline, trimethoprim-sulfamethoxazole, and tigecycline. The antimicrobial agents tested against RGM also included tobramycin, which was tested only against M. chelonae. The antimicrobial agents tested against SGM included amikacin, ciprofloxacin, doxycycline, linezolid, minocycline, moxifloxacin, omadacycline, rifampicin, rifabutin, and trimethoprim-sulfamethoxazole.

[0427] MIC values ​​were determined using a 2-fold serial dilution of Mueller-Hinton broth, in accordance with the method of the Clinical and Laboratory Standards Institutes (CLSI) (Performance Standards for Susceptibility Testing of Mycobacteria, Norcadia spp., and Other Aerobic actinomycetes, M62, 1st edition).

[0428] result The MIC values ​​measured for RGM isolates are shown in Table 14 below.

[0429] [Table 14] JPEG2026086890000110.jpg253152JPEG2026086890000111.jpg253157JPEG2026086890000112.jpg25347

[0430] The MIC values ​​measured for slow-growing NTM isolates are shown in Table 15 below.

[0431] [Table 15]

[0432] conclusion Omadacycline has shown activity against various RGM species, including clinical isolates of M. abscessus complex, M. chelonae, M. fortuitum, M. immunogenum, M. mucogenium, and M. smegmatis, and MIC 50 The value is 0.25, MIC 90 The value was 0.5 μg / mL. Omadacycline showed lower activity against the small number of SGM isolates tested, and its MIC value was higher than the highest concentration evaluated.

[0433] Equal parts Those skilled in the art will recognize, or confirm by conventional experimentation, many equivalents of the specific embodiments and methods described herein. Such equivalents are intended to be included within the scope of the present invention. All patents, patent applications and references cited herein are expressly incorporated herein by reference.

Claims

1. A method for treating or preventing a mycobacterial infection in a subject requiring treatment or prevention of such an infection, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that the mycobacterial infection in the subject is treated or prevented, wherein the tetracycline compound is of formula (1): 【Chemistry 1】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 、R 4' 、R 4" are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocycle, heteroaromatic ring or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by [this method].

2. R 9 ga-CH 2 The method according to claim 1, wherein NR'R" is formed by R' and R" being independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, carbonyl, acyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl groups; or R' and R" together form a ring.

3. Tetracycline compounds are given by formula (2): 【Chemistry 2】 (In the formula, J 5 and J 6 Each of these is independently a hydrogen atom, an alkyl atom, an alkenyl atom, an alkynyl atom, an aryl atom, an sulfonyl atom, an acyl atom, an alkoxycarbonyl atom, an alkaminocarbonyl atom, an alkaminothiocarbonyl atom, a substituted thiocarbonyl atom, a substituted carbonyl atom, or an alkoxythiocarbonyl atom, or linked together to form a ring; J 7 and J 8 (These are alkyl, halogen, or hydrogen, respectively.) The method according to claim 1 or 2, as represented by the following:

4. X is CR 6' R 6 And R 6 and R 6' The method according to any one of claims 1 to 3, wherein both are hydrogen.

5. R 4 NR 4' R 4" And R 4' and R 4" The method according to any one of claims 1 to 4, wherein each of them is independently alkyl.

6. R 7 The method according to any one of claims 1 to 5, wherein is a dialkylamino.

7. The tetracycline compound is of formula (3): 【Transformation 3】 (In the formula, J 5 is alkyl; J 6 (It is hydrogen.) The method according to any one of claims 1 to 6, as represented by the following:

8. The tetracycline compound is of formula (4): 【Chemistry 4】 The method according to any one of claims 1 to 7, wherein the omadacycline is represented by [formula].

9. Omadacycline is given by equation (5): 【Transformation 5】 The method according to claim 8, as represented by the statement.

10. A method for treating or preventing a mycobacterial infection in a subject requiring treatment or prevention of such an infection, comprising the step of administering to the subject an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that the mycobacterial infection in the subject is treated or prevented, wherein omadacycline is of formula (4): 【Transformation 6】 A method represented by the following:

11. Omadacycline is given by equation (5): 【Transformation 7】 The method according to claim 10, as represented by the present invention.

12. The method according to any one of claims 1 to 11, wherein the mycobacterial infection is caused by slow-growing mycobacteria.

13. The method according to claim 12, wherein the slow-growing mycobacteria belong to the Terrae lineage.

14. Slow-growing mycobacteria include the following species: M. terrae, M. algericus, M. arupensis, M. engbaekii, M. heraklionensis, M. hiberniae, M. icosiumassiliensis, M. kumamotonensis, M. longobardus, M. minnesotensis, M. nonchromogenicus, M. paraterrae, M. senuense, M. sinensis (M. The method according to claim 13, comprising a mycobacterium species selected from the group consisting of M. sinensis and M. virginiensis.

15. The method according to claim 12, wherein the slow-growing mycobacteria belong to the Triviale lineage.

16. The method according to claim 15, wherein the slow-growing mycobacteria belong to a mycobacterial species selected from the group consisting of the following species: M. trivialis, M. koreensis, and M. parakoreensis.

17. The method according to claim 12, wherein the slow-growing mycobacteria belong to the Tuberculosis-Simiae lineage.

18. Slow-growing mycobacteria include the following species: M. tuberculosis, M. tuberculosis subspecies tuberculosis, M. africanum, M. alsense, M. angelicum, M. arosiense, M. asiaticum, M. avium, M. avium subspecies avium, M. avium subspecies paratuberculosis, M. avium subspecies silvaticum, M. avium M. avium) subspecies hominissuis, M. bohemicum, M. botniense, M. bouchedurhonense, M. bourgelatii, M. bovis, M. bovis subspecies bovis, M. bovis subspecies caprae, M. branderi, M. canettii, M. caprae, M. celatum, M. chimaera, M. colombiense, M. conspicuum, M. kookii (M. M. cookii), M. europaeum, M. florentinum, M. fragae, M. gastri, M. genavsnse, M. gordonae, M. haemophilum, M. heckshornense, M. heidelbergense, M. indicus pranii, M. interjectum (M.M. intermedium, M. intracellulare, M. kansasii, M. kubicae, M. kyorinense, M. lacus, M. lentiflavum, M. leprae, M. lepraemurium, M. lepromatosis, M. liflandii, M. malmoense, M. mantenii, M. marinum, M. marseillense, M. microti (M. Microti), M. monteriorense, M. mungi, M. nebraskense, M. novomagense, M. orygis, M. palustre, M. paraense, M. parraffinicum, M. paragordonae, M. paraintracellulare, M. parascrofulaceum, M. paraseculense, M. parmense, M. perscum, M. pinnipedii, M. pseudoshotzii (M. M. pseudoshotsii), M. riyadhense, M. saskatchewanense, M. scrofulaceum, M. seculense, M. sherrisii, M. shimoidei, M. shinjukuense, M. shottsii, M. simie (M.The method according to claim 17, comprising a mycobacterium species selected from the group consisting of M. simiae, M. stomatepiae, M. szulgai, M. timonense, M. triplex, M. ulcerans, M. xenopi, and M. yongonense.

19. The method according to claim 12, wherein the slow-growing mycobacteria belong to the Mycobacterium tuberculosis complex (MTBC).

20. The method according to claim 19, wherein the slow-growing mycobacteria belong to a mycobacterial species selected from the group consisting of the following species: M. africanum, M. bovis, M. bovis BCG, M. canetti, M. caprae, M. microti, M. mungi, M. orygis, M. pinnipedii, M. suricattae, and M. tuberculosis.

21. The method according to claim 20, wherein the slow-growing mycobacteria belong to the mycobacterium species M. tuberculosis.

22. The method according to claim 12, wherein the slow-growing mycobacteria are non-tuberculous mycobacteria (NTM).

23. The method according to claim 22, wherein NTM belongs to the Mycobacterium avium complex (MAC).

24. The method according to claim 23, wherein NTM belongs to a mycobacterial species selected from the group consisting of the following species: M. avium, M. avium paratuberculosis, M. avium silvaticum, M. avium "hominissuis", M. Colombiense, M. chimaera, M. indicus pranii, and M. intracellulare.

25. The method according to any one of claims 1 to 11, wherein a mycobacterial infection is caused by rapidly growing mycobacteria.

26. The method according to claim 25, wherein the rapidly growing mycobacteria is NTM.

27. The method according to claim 25 or 26, wherein the rapidly growing mycobacteria belong to the Abscessus-Chelonae lineage.

28. The method according to claim 27, wherein the rapidly growing mycobacteria belong to a mycobacterial species selected from the group consisting of the following species: M. abscessus, M. abscessus subspecies abscessus, M. abscessus subspecies bolletii, M. abscessus subspecies massiliense, M. chelonae, M. chelonae subspecies chelonae, M. immunogenum, M. salmoniphilum, M. franklinii, and M. saopaulense.

29. The method according to claim 28, wherein the rapidly growing mycobacteria belong to the mycobacteria species M. abscessus.

30. The method according to claim 28, wherein the rapidly growing mycobacteria belong to the mycobacteria species M. chelonae.

31. The method according to claim 25 or 26, wherein the rapidly growing mycobacteria belong to the Fortuitum-Vaccae lineage.

32. Rapidly growing mycobacteria include the following species: M. fortuitum, M. fortuitum subspecies fortuitum, M. fortuitum subspecies acetamidolyticum, M. acapulcense, M. agri, M. aichiense, M. alvei, M. anyangense, M. arabiense, M. arcueilence, M. aromaticivorans, M. aubagnense, M. aurum M. aurum), M. austroafrinacum, M. bacteremicum, M. boenickei, M. brisnanense, M. brumae, M. canariasense, M. Celeriflavum, M. chitae, M. chlorophenolicum, M. chubuense, M. conceprionense, M. confluentis, M. cosmeticum, M. crocinum, M. ziernhoferi (M. M. diernhoferi), M. doricum, M. duvalii, M. elephantis, M. fallax, M. facinogenes, M. flavescens, M. fluoranthenivorans, M. frederikspergense, M. gadium, M. gilbum (M.M. gilvum), M. goodii, M. hassiacum, M. helvum, M. hippocampi, M. hodieri, M. holsaticum, M. houstonense, M. insubricum, M. iranicum, M. komanii, M. komossense, M. litorale, M. llatzerense, M. lutetiense, M. madagascariensis (M. M. madagascariense), M. mageritense, M. malmesburyense, M. monacense, M. montmartrense, M. moriokaense, M. mucogenicum, M. murale, M. neoaurum, M. neworleansense, M. novocastrense, M. obuense, M. oryzae, M. pallens, M. parafortuitum, M. peregrinum (M. M. peregrinum), M. phlei, M. phocaicum, M. porcinum, M. ponferae, M. psychrotolerans, M. pulvens, M. pyrenivorans, M. rhodesiae, M. rufum, M. rutilum, M. sarraceniae, M. sediminis, M. senegalense (M.The method according to claim 31, comprising a mycobacterium species selected from the group consisting of M. senegalense, M. septicum, M. setense, M. smegmatis, M. sphagni, M. thermoresistibile, M. tokaiense, M. tusciae, M. vaccae, M. vanbaalenii, M. vulneris, and M. wolinskyi.

33. The method according to claim 32, wherein the rapidly growing mycobacteria belong to the mycobacteria species M. fortuitum.

34. The method according to any one of claims 1 to 33, wherein the mycobacterial infection is in the lung of the subject.

35. The method according to claim 34, wherein the subject also has a lung disease.

36. The method according to claim 34, wherein the lung disease is selected from the group consisting of chronic obstructive pulmonary disease (COPD), occupational lung disease, tuberculosis, bronchiectasis, cystic fibrosis, and alpha-1 antitrypsin deficiency.

37. The method according to claim 34, wherein the subject has undergone a lung transplant.

38. The method according to any one of claims 1 to 33, wherein the mycobacterial infection is in the lymph node of interest.

39. The method according to any one of claims 1 to 33, wherein the mycobacterial infection is a bone and joint infection.

40. The method according to claim 39, wherein the mycobacterial infection is in the joint or bone of the subject.

41. The method according to any one of claims 1 to 33, wherein the mycobacterial infection is a skin or soft tissue infection (SSTI).

42. The method according to claim 41, wherein a mycobacterial infection causes a disease selected from the group consisting of pool granuloma and Buruli ulcer.

43. The method according to any one of claims 1 to 33, wherein the mycobacterial infection is related to a foreign body placed in a target.

44. The method according to claim 43, wherein the foreign body is selected from the group consisting of medical devices, implants, and tattoo inks.

45. The method according to claim 44, wherein the medical device is a cardiac pacemaker.

46. The method according to claim 44, wherein the implant is selected from the group consisting of cardiovascular implants, orthopedic implants, and cosmetic surgery implants.

47. The method according to claim 46, wherein the cardiovascular implant is a heart valve.

48. The method according to claim 46, wherein the orthopedic implant is selected from the group consisting of pins, rods, screws and plates.

49. The method according to claim 46, wherein the cosmetic surgery implant is selected from the group consisting of breast implants, prosthetic noses, and injectable fillers.

50. A method for treating or preventing a mycobacterial disease in a subject requiring treatment or prevention of such disease, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that the mycobacterial disease in the subject is treated or prevented, wherein the tetracycline compound is of formula (1): 【Transformation 8】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

51. A method for controlling or reducing the progression, severity, or effects of a mycobacterial disease in a subject requiring control of the mycobacterial disease or reduction of its progression, severity, or effects, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that the mycobacterial disease in the subject is controlled or the progression, severity, or effects of the mycobacterial disease in the subject are reduced, wherein the tetracycline compound is of formula (1): 【Chemistry 9】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

52. R 9 ga-CH 2 The method according to claim 34 or 35, wherein NR'R" is formed by R' and R" being independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, carbonyl, acyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl groups; or R' and R" together form a ring.

53. The tetracycline compound is of formula (2): 【Chemistry 10】 (In the formula, J 5 and J 6 Each of these is independently a hydrogen atom, an alkyl atom, an alkenyl atom, an alkynyl atom, an aryl atom, an sulfonyl atom, an acyl atom, an alkoxycarbonyl atom, an alkaminocarbonyl atom, an alkaminothiocarbonyl atom, a substituted thiocarbonyl atom, a substituted carbonyl atom, or an alkoxythiocarbonyl atom, or linked together to form a ring; J 7 and J 8 is each alkyl, halogen, or hydrogen) The method according to any one of claims 50 to 52, as represented by the following:

54. X is CR 6' R 6 And R 6 and R 6' The method according to any one of claims 50 to 53, wherein both are hydrogen.

55. R 4 is NR 4' R 4" and R 4' and R 4" The method according to any one of claims 50 to 54, wherein R and R are each independently alkyl.

56. R 7 The method according to any one of claims 50 to 55, wherein is a dialkylamino.

57. The tetracycline compound is of formula (3): 【Chemistry 11】 (In the formula, J 5 is alkyl; J 6 (It is hydrogen.) The method according to any one of claims 50 to 56, as represented by the following:

58. The tetracycline compound is of formula (4): 【Chemistry 12】 The method according to any one of claims 50 to 57, wherein the omadacycline is represented by [formula].

59. Omadacycline is given by equation (5): 【Chemistry 13】 The method according to claim 58, as represented by the following:

60. A method for treating or preventing a mycobacterial disease in a subject requiring treatment or prevention of a mycobacterial disease, comprising the step of administering to the subject an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that the mycobacterial disease in the subject is treated or prevented, wherein omadacycline is of formula (4): 【Chemistry 14】 A method represented by the following:

61. A method for controlling a mycobacterial disease or reducing its progression, severity, or impact in a subject requiring control of the mycobacterial disease or reduction of its progression, severity, or impact, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject such that the mycobacterial disease in the subject is controlled or the progression, severity, or impact of the mycobacterial disease in the subject is reduced, wherein omadacycline is of formula (4): 【Chemistry 15】 A method represented by the following:

62. Omadacycline is given by equation (5): 【Chemistry 16】 The method according to claim 60 or 61, as represented by the following:

63. The method according to any one of claims 50 to 62, wherein the mycobacterial disease is caused by an infection of slow-growing mycobacteria.

64. The method according to claim 63, wherein the slow-growing mycobacteria belong to the Mycobacterium tuberculosis complex (MTBC).

65. The method according to claim 63, wherein the slow-growing mycobacteria belong to the mycobacterium species M. tuberculosis.

66. The method according to claim 65, wherein the mycobacterial disease is tuberculosis.

67. The method according to any one of claims 50 to 62, wherein the mycobacterial disease is caused by an infection of rapidly growing mycobacteria.

68. The method according to claim 63 or claim 67, wherein the mycobacterial disease is caused by an infection of NTM.

69. The method according to claim 68, wherein the NTM belongs to a mycobacterial species selected from the group consisting of the following species: M. avium, M. kansasii, M. scrofulaceum, M. xenopi, M. simiae, M. habana, M. szulgai, M. fortuitum, M. vaccae, M. malmoense, M. heckeshornense, M. chelonae, and M. abscessus.

70. The method according to claim 69, wherein the NTM belongs to a mycobacterial species selected from the group consisting of the following species: M. abscessus, M. chelonae, and M. fortuitum.

71. The method according to any one of claims 50 to 62, wherein the mycobacterial disease is selected from the group consisting of tuberculosis, leprosy, pulmonary disease, lymphadenitis, skin disease, eye disease, soft tissue disease, bone disease, fish tank granuloma, and Buruli ulcer.

72. The method according to claim 71, wherein the pulmonary disease is selected from the group consisting of bronchiectasis and pulmonary infection.

73. The method according to any one of claims 50 to 62, wherein the mycobacterial disease is related to a mycobacterial infection in the lymph nodes, joints, bones, skin, or soft tissues of the subject.

74. The method according to any one of claims 50 to 62, wherein the mycobacterial disease is related to a mycobacterial infection associated with a foreign body placed on the target.

75. The method according to claim 74, wherein the foreign body is selected from the group consisting of medical devices, implants, and tattoo inks.

76. The method according to claim 75, wherein the medical device is a cardiac pacemaker.

77. The method according to claim 75, wherein the implant is selected from the group consisting of cardiovascular implants, orthopedic implants, and cosmetic surgery implants.

78. The method according to claim 77, wherein the cardiovascular implant is a heart valve.

79. The method according to claim 77, wherein the orthopedic implant is selected from the group consisting of pins, rods, screws, and plates.

80. The method according to claim 77, wherein the cosmetic surgery implant is selected from the group consisting of breast implants, prosthetic noses, and injectable fillers.

81. A method for treating or preventing tuberculosis in a subject requiring treatment or prevention of tuberculosis, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that the tuberculosis in the subject is treated or prevented, wherein the tetracycline compound is of formula (1): 【Chemistry 17】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

82. A method for controlling tuberculosis or reducing its progression, severity or impact in a subject requiring control of tuberculosis or reduction of its progression, severity or impact, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester or prodrug thereof, such that the tuberculosis in the subject is controlled or the progression, severity or impact of the tuberculosis in the subject is reduced, wherein the tetracycline compound is of formula (1): [Chemistry 18] (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

83. A method for treating or preventing leprosy in a subject requiring treatment or prevention of leprosy, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that the leprosy in the subject is treated or prevented, wherein the tetracycline compound is of formula (1): 【Chemistry 19】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

84. A method for controlling leprosy or reducing its progression, severity or impact in a subject requiring control of leprosy or reduction of its progression, severity or impact, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester or prodrug thereof, such that the leprosy in the subject is controlled or the progression, severity or impact of leprosy in the subject is reduced, wherein the tetracycline compound is of formula (1): 【Chemistry 20】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

85. A method for treating or preventing bronchiectasis in a subject requiring treatment or prevention of bronchiectasis, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that the bronchiectasis in the subject is treated or prevented, wherein the tetracycline compound is of formula (1): 【Chemistry 21】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

86. A method for controlling bronchiectasis or reducing its progression, severity or effects in subjects requiring control of bronchiectasis, or reduction of its progression, severity or effects, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester or prodrug thereof, such that the bronchiectasis is controlled or the progression, severity or effects of the bronchiectasis are reduced, wherein the tetracycline compound is of formula (1): 【Chemistry 22】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

87. A method for treating or preventing cavitary lung disease in a subject requiring treatment or prevention of cavitary lung disease, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that the cavitary lung disease in the subject is treated or prevented, wherein the tetracycline compound is of formula (1): 【Chemistry 23】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

88. A method for controlling cavitary lung disease or reducing its progression, severity, or effects in subjects requiring control of cavitary lung disease or reduction of its progression, severity, or effects, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that the cavitary lung disease is controlled or its progression, severity, or effects are reduced, wherein the tetracycline compound is of formula (1): 【Chemistry 24】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

89. A method for treating or preventing lymphadenitis in a subject requiring treatment or prevention of lymphadenitis, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that the lymphadenitis in the subject is treated or prevented, wherein the tetracycline compound is of formula (1): 【Chemistry 25】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

90. A method for controlling lymphadenitis or reducing its progression, severity, or impact in a subject requiring control of lymphadenitis or reduction of its progression, severity, or impact, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that the lymphadenitis in the subject is controlled or the progression, severity, or impact of the lymphadenitis in the subject is reduced, wherein the tetracycline compound is of formula (1): 【Chemistry 26】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

91. A method for treating or preventing a soft tissue disease in a subject requiring treatment or prevention of the soft tissue disease, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that the soft tissue disease in the subject is treated or prevented, wherein the tetracycline compound is of formula (1): 【Chemistry 27】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

92. A method for controlling soft tissue disease or reducing its progression, severity, or effects in subjects requiring control of soft tissue disease or reduction of its progression, severity, or effects, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject such that the soft tissue disease in the subject is controlled or the progression, severity, or effects of the soft tissue disease in the subject are reduced, wherein the tetracycline compound is of formula (1): 【Chemistry 28】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

93. The method according to claims 91 and 92, wherein the soft tissue disease is a skin disease.

94. The method according to claim 93, wherein the skin disease is cellulitis.

95. A method for treating or preventing aquarium granuloma in a subject requiring treatment or prevention of aquarium granuloma, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that the aquarium granuloma in the subject is treated or prevented, wherein the tetracycline compound is of formula (1): 【Chemistry 29】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

96. A method for controlling aquarium granulomas or reducing their progression, severity, or impact in subjects requiring control of aquarium granulomas or reduction of their progression, severity, or impact, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject such that the aquarium granulomas in the subject are controlled or the progression, severity, or impact of the aquarium granulomas in the subject are reduced, wherein the tetracycline compound is of formula (1): 【Transformation 30】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

97. A method for treating or preventing Buruli ulcer in a subject requiring treatment or prevention of Buruli ulcer, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that the Buruli ulcer in the subject is treated or prevented, wherein the tetracycline compound is of formula (1): 【Chemistry 31】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

98. A method for controlling Buruli ulcers or reducing their progression, severity, or impact in subjects requiring control of Buruli ulcers or reduction of their progression, severity, or impact, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject such that the Buruli ulcers in the subject are controlled or the progression, severity, or impact of the Buruli ulcers in the subject are reduced, wherein the tetracycline compound is of formula (1): 【Chemistry 32】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

99. A method for treating or preventing an eye disease in a subject requiring treatment or prevention of the eye disease, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that the eye disease in the subject is treated or prevented, wherein the tetracycline compound is of formula (1): 【Transformation 33】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

100. A method for controlling an eye disease or reducing its progression, severity or effects in a subject requiring control of the eye disease or reduction of its progression, severity or effects, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester or prodrug thereof, such that the eye disease in the subject is controlled or the progression, severity or effects of the eye disease in the subject are reduced, wherein the tetracycline compound is of formula (1): 【Transformation 34】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

101. A method for treating or preventing a bone disease in a subject requiring treatment or prevention of the bone disease, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that the bone disease in the subject is treated or prevented, wherein the tetracycline compound is of formula (1): 【Chemistry 35】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

102. A method for controlling a bone disease or reducing its progression, severity or impact in a subject requiring control of the bone disease or reduction of its progression, severity or impact, comprising the step of administering an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester or prodrug thereof, to the subject such that the bone disease in the subject is controlled or the progression, severity or impact of the bone disease in the subject is reduced, wherein the tetracycline compound is of formula (1): 【Transformation 36】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

103. A method for treating a subject with a lung disease, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein the tetracycline compound is of formula (1): 【Chemistry 37】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

104. The method according to claim 103, wherein the lung disease is selected from the group consisting of cystic fibrosis, chronic obstructive pulmonary disease (COPD), occupational lung disease, bronchiectasis, cavitary lung disease, primary ciliary dysplasia, allergic bronchopulmonary aspergillosis, alpha-1 antitrypsin deficiency, pneumoconiosis, interstitial lung disease, chronic aspiration syndrome, and alveolar proteinosis.

105. The method according to claim 104, wherein the lung disease is cystic fibrosis.

106. The method according to claim 104, wherein the lung disease is COPD.

107. The method according to claim 104, wherein the lung disease is bronchiectasis.

108. The method according to claim 104, wherein the lung disease is a cavitary lung disease.

109. The method according to claim 104, wherein the lung disease is alpha-1 antitrypsin deficiency.

110. A method for treating an immunosuppressed subject, comprising the step of administering to the subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein the tetracycline compound is of formula (1): 【Transformation 38】 (In the formula, X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 4 , NR 4' R 4" , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R 2 , R 4' , R 4" Each of these is independently a hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heterocyclic aromatic ring, or prodrug moiety; R 2' , R 3 , R 10 , R 11 and R 12 These are, respectively, hydrogen or the prodrug portion; R 5 These are hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaloyl, aryl, heterocyclic aromatic ring, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R 6 and R 6' Each of these is independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 7 and R 8 Each of these is independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; R 9 It is an aminoalkyl; R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; Y' and Y are, independently, hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl. A method represented by the following:

111. The method according to claim 110, wherein the immunosuppressed state is related to HIV infection or AIDS.

112. The method according to claim 110, wherein the immunosuppressed state is related to the administration of an immunosuppressant drug.

113. The method according to claim 110, wherein the immunosuppressant drug is administered as part of anticancer treatment.

114. The method according to claim 110, wherein the immunosuppressant drug is administered as immunosuppressive therapy after organ transplantation.

115. The method according to claim 110, wherein the immunosuppressive state is a genetic disorder resulting in an immunological defect.

116. The method according to claim 115, wherein the hereditary disorder resulting in an immunological defect comprises a genetic defect in the interferon-γ receptor or interleukin-12.

117. R 9 ga-CH 2 The method according to any one of claims 81 to 116, wherein NR'R" is formed by R' and R" being independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, carbonyl, acyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl groups; or R' and R" together form a ring.

118. Tetracycline compounds are given by formula (2): 【Chemistry 39】 (In the formula, J 5 and J 6 Each of these is independently a hydrogen atom, an alkyl atom, an alkenyl atom, an alkynyl atom, an aryl atom, an sulfonyl atom, an acyl atom, an alkoxycarbonyl atom, an alkaminocarbonyl atom, an alkaminothiocarbonyl atom, a substituted thiocarbonyl atom, a substituted carbonyl atom, or an alkoxythiocarbonyl atom, or linked together to form a ring; J 7 and J 8 (These are alkyl, halogen, or hydrogen, respectively.) The method according to any one of claims 81 to 117, as represented by the following:

119. X is CR 6' R 6 And R 6 and R 6' The method according to any one of claims 81 to 118, wherein both are hydrogen.

120. R 4 NR 4' R 4" And R 4' and R 4" The method according to any one of claims 81 to 119, wherein each of them is independently alkyl.

121. R 7 The method according to any one of claims 81 to 120, wherein is a dialkylamino.

122. Tetracycline compounds are given by formula (3): 【Chemistry 40】 (In the formula, J 5 is alkyl; J 6 (It is hydrogen.) The method according to any one of claims 81 to 121, as represented by the following:

123. The tetracycline compound is of formula (4): 【Chemistry 41】 The method according to any one of claims 81 to 122, wherein the omadacycline is represented by [formula].

124. Omadacycline is given by equation (5): 【Chemistry 42】 The method according to claim 123, as represented by the present invention.

125. A method for treating or preventing tuberculosis in a subject requiring treatment or prevention of tuberculosis, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject such that the tuberculosis in the subject is treated or prevented, wherein omadacycline is of formula (4): 【Chemistry 43】 A method represented by the following:

126. A method for controlling tuberculosis or reducing its progression, severity or impact in a subject requiring control of tuberculosis or reduction of its progression, severity or impact, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester or prodrug thereof, to the subject such that the tuberculosis in the subject is controlled or the progression, severity or impact of tuberculosis in the subject is reduced, wherein omadacycline is of formula (4): 【Chemistry 44】 A method represented by the following:

127. A method for treating or preventing leprosy in a subject requiring treatment or prevention of leprosy, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject such that the leprosy in the subject is treated or prevented, wherein omadacycline is of formula (4): 【Chemistry 45】 A method represented by the following:

128. A method for controlling leprosy or reducing its progression, severity or impact in a subject requiring control of leprosy or reduction of its progression, severity or impact, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester or prodrug thereof, to the subject such that the leprosy in the subject is controlled or the progression, severity or impact of leprosy in the subject is reduced, wherein omadacycline is of formula (4): 【Chemistry 46】 A method represented by the following:

129. A method for treating or preventing bronchiectasis in a subject requiring treatment or prevention of bronchiectasis, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject such that the bronchiectasis in the subject is treated or prevented, wherein omadacycline is of formula (4): 【Chemistry 47】 A method represented by the following:

130. A method for controlling bronchiectasis or reducing its progression, severity or effects in subjects requiring control of bronchiectasis, or reduction of its progression, severity or effects, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester or prodrug thereof, to the subject such that the bronchiectasis in the subject is controlled or the progression, severity or effects of bronchiectasis in the subject are reduced, wherein omadacycline is of formula (4): 【Chemistry 48】 A method represented by the following:

131. A method for treating or preventing cavitary lung disease in a subject requiring treatment or prevention of cavitary lung disease, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject such that the cavitary lung disease in the subject is treated or prevented, wherein omadacycline is of formula (4): 【Chemistry 49】 A method represented by the following:

132. A method for controlling cavitary lung disease or reducing its progression, severity, or effects in subjects requiring control of cavitary lung disease or reduction of its progression, severity, or effects, comprising the step of administering an effective amount of omadacycline or a pharmaceutically acceptable salt, ester, or prodrug thereof to the subject such that the cavitary lung disease in the subject is controlled or the progression, severity, or effects of the cavitary lung disease in the subject are reduced, wherein omadacycline is of formula (4): [Transformation 50] A method represented by the following:

133. A method for treating or preventing lymphadenitis in a subject requiring treatment or prevention of lymphadenitis, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject such that the lymphadenitis in the subject is treated or prevented, wherein omadacycline is of formula (4): 【Chemistry 51】 A method represented by the following:

134. A method for controlling lymphadenitis or reducing its progression, severity or impact in a subject requiring control of lymphadenitis or reduction of its progression, severity or impact, comprising the step of administering an effective amount of omadacycline or a pharmaceutically acceptable salt, ester or prodrug thereof to the subject such that the lymphadenitis in the subject is controlled or the progression, severity or impact of the lymphadenitis in the subject is reduced, wherein omadacycline is of formula (4): 【Chemistry 52】 A method represented by the following:

135. A method for treating or preventing a soft tissue disease in a subject requiring treatment or prevention of the soft tissue disease, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject such that the soft tissue disease in the subject is treated or prevented, wherein omadacycline is of formula (4): 【Chemistry 53】 A method represented by the following:

136. A method for controlling soft tissue disease or reducing its progression, severity or effects in subjects requiring control of soft tissue disease or reduction of its progression, severity or effects, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester or prodrug thereof, to the subject such that the soft tissue disease in the subject is controlled or the progression, severity or effects of the soft tissue disease in the subject are reduced, wherein omadacycline is of formula (4): 【Chemistry 54】 A method represented by the following:

137. The method according to claim 135 or 136, wherein the soft tissue disease is a skin disease.

138. The method according to claim 137, wherein the skin disease is cellulitis.

139. A method for treating or preventing aquarium granuloma in a subject requiring treatment or prevention of aquarium granuloma, comprising the step of administering to the subject an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that the aquarium granuloma in the subject is treated or prevented, wherein omadacycline is of formula (4): 【Transformation 55】 A method represented by the following:

140. A method for controlling aquarium granuloma or reducing its progression, severity, or impact in subjects requiring control of aquarium granuloma or reduction of its progression, severity, or impact, comprising the step of administering an effective amount of omadacycline or a pharmaceutically acceptable salt, ester, or prodrug thereof to the subject such that the aquarium granuloma is controlled or its progression, severity, or impact is reduced, wherein omadacycline is of formula (4): 【Transformation 56】 A method represented by the following:

141. A method for treating or preventing Buruli ulcer in a subject requiring treatment or prevention of Buruli ulcer, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject such that the Buruli ulcer in the subject is treated or prevented, wherein omadacycline is of formula (4): 【Chemistry 57】 A method represented by the following:

142. A method for treating or preventing an eye disease in a subject requiring treatment or prevention of the eye disease, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject such that the eye disease in the subject is treated or prevented, wherein omadacycline is of formula (4): 【Transformation 58】 A method represented by the following:

143. A method for controlling an eye disease or reducing its progression, severity or impact in a subject requiring control of the eye disease or reduction of its progression, severity or impact, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester or prodrug thereof, to the subject such that the eye disease in the subject is controlled or the progression, severity or impact of the eye disease in the subject is reduced, wherein omadacycline is of formula (4): 【Chemistry 59】 A method represented by the following:

144. A method for treating or preventing a bone disease in a subject requiring treatment or prevention of the bone disease, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject such that the bone disease in the subject is treated or prevented, wherein omadacycline is of formula (4): 【Transformation 60】 A method represented by the following:

145. A method for controlling a bone disease or reducing its progression, severity or impact in a subject requiring control of the bone disease or reduction of its progression, severity or impact, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester or prodrug thereof, to the subject such that the bone disease in the subject is controlled or the progression, severity or impact of the bone disease in the subject is reduced, wherein omadacycline is of formula (4): 【Chemistry 61】 A method represented by the following:

146. A method for controlling Buruli ulcers or reducing their progression, severity, or impact in subjects requiring control of Buruli ulcers or reduction of their progression, severity, or impact, comprising the step of administering an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to the subject such that the Buruli ulcers in the subject are controlled or the progression, severity, or impact of the Buruli ulcers in the subject are reduced, wherein omadacycline is of formula (4): 【Transformation 62】 A method represented by the following:

147. A method for treating a subject having a lung disease, comprising the step of administering to the subject an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein omadacycline is of formula (4): 【Transformation 63】 A method represented by the following:

148. The method according to claim 147, wherein the lung disease is selected from the group consisting of cystic fibrosis, chronic obstructive pulmonary disease (COPD), occupational lung disease, bronchiectasis, cavitary lung disease, primary ciliary dysplasia, allergic bronchopulmonary aspergillosis, alpha-1 antitrypsin deficiency, pneumoconiosis, interstitial lung disease, chronic aspiration syndrome, and alveolar proteinosis.

149. The method according to claim 148, wherein the lung disease is cystic fibrosis.

150. The method according to claim 148, wherein the lung disease is COPD.

151. The method according to claim 148, wherein the lung disease is bronchiectasis.

152. The method according to claim 148, wherein the lung disease is a cavitary lung disease.

153. The method according to claim 148, wherein the lung disease is alpha-1 antitrypsin deficiency.

154. A method for treating an immunosuppressed subject, comprising the step of administering to the subject an effective amount of omadacycline, or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein omadacycline is of formula (4): 【Chemistry 64】 A method represented by the following:

155. The method according to claim 154, wherein the immunosuppressed state is related to HIV infection or AIDS.

156. The method according to claim 154, wherein the immunosuppressed state is related to the administration of an immunosuppressive drug.

157. The method according to claim 156, wherein the immunosuppressant drug is administered as part of anticancer treatment.

158. The method according to claim 156, wherein the immunosuppressant drug is administered as immunosuppressive therapy after organ transplantation.

159. The method according to claim 144, wherein the immunosuppressive state is a genetic disorder resulting in an immunological defect.

160. The method according to claim 159, wherein the hereditary disorder resulting in an immunological defect comprises a genetic defect in the interferon-γ receptor or interleukin-12.

161. Omadacycline is given by equation (5): 【Transformation 65】 The method according to any one of claims 125 to 160, as represented by the following:

162. The method according to any one of claims 1 to 161, wherein a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is administered as monotherapy.

163. The method according to any one of claims 1 to 161, wherein a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is administered in combination with at least one additional anti-mycobacterial agent.

164. At least one additional antimycobacterial agent is diarylquinolone, rifapentin, rifaradyl, nitroimidazole, benzothiadinone, capreomycin, clofazimine, cycloserine, dapsone, thiocarbamide, ethambutol, DC-159a, nitrobenzthiazole, stezolid (PNU-100480), AZD-5847, posisolid (AZD-2563), para-aminosalicylic acid, SQ-109, SQ-609, or capramycin. The method according to claim 163, selected from the group consisting of caprazen nucleoside, isothiazoloquinolone, thioridazine, thiasetazone, zilithromycin, roxithromycin, telithromycin, azithromycin, clarithromycin, erythromycin, amikacin, kanamycin, streptomycin, levofloxacin, moxifloxacin, gatifloxacin, linezolid, rifaradyl, imipenem, meropenem, clavulanate, and isoniazid.

165. The method according to any one of claims 1 to 164, wherein the tetracycline compound is administered for a period of about 1 to 12 weeks.

166. The method according to any one of claims 1 to 164, wherein the tetracycline compound is administered for a period of about 1 month to about 24 months.

167. The method according to any one of claims 1 to 164, wherein the tetracycline compound is administered for a period of more than 24 months.

168. The method according to any one of claims 1 to 167, wherein a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is administered parenterally, orally, topically, or aerosolically.

169. The method according to claim 168, wherein a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is administered parenterally.

170. The method according to claim 169, wherein a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is administered intravenously.

171. The method according to claim 170, wherein a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is administered intravenously in a dose of about 100 to about 300 mg.

172. The method according to claim 171, wherein a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is administered intravenously in a dose of about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg.

173. The method according to claim 168, wherein a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is administered orally.

174. The method according to claim 173, wherein a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is administered orally in a dose of about 150 to about 600 mg.

175. The method according to claim 174, wherein a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is administered orally in doses of about 150, about 300 mg, about 450 mg, or about 600 mg.

176. The method according to claim 168, wherein a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is administered by aerosol.

177. The method according to claim 176, wherein the aerosol administration of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, comprises the use of an aerosol dispenser containing a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof in a dose of about 1 mg to about 1000 mg.

178. The method according to claim 177, wherein the aerosol dispenser comprises a tetracycline compound in doses of approximately 1 mg, approximately 5 mg, approximately 10 mg, approximately 30 mg, approximately 50 mg, approximately 80 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 450 mg, approximately 500 mg, approximately 550 mg, approximately 600 mg, approximately 650 mg, approximately 700 mg, approximately 750 mg, approximately 800 mg, approximately 850 mg, approximately 900 mg, approximately 950 mg, or approximately 1000 mg, or a pharmaceutically acceptable salt, ester, or prodrug thereof.

179. The method according to claim 168, wherein a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is administered topically by applying a pharmaceutical composition configured for topical administration, comprising a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, to an affected area.

180. The method according to claim 179, wherein the pharmaceutical composition comprises a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, in a concentration of about 0.01% to 20% w / v based on the volume of the composition.

181. The method according to claim 180, wherein the pharmaceutical composition comprises a tetracycline compound in a concentration of about 0.01% w / v, about 0.05% w / v, about 0.1% w / v, about 0.5% w / v, about 1% w / v, about 5% w / v, about 10% w / v, about 15% w / v, or about 20% w / v, or a pharmaceutically acceptable salt, ester, or prodrug thereof.

182. The method according to claim 179, wherein the pharmaceutical composition comprises a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, in a concentration of about 0.01% to 20% w / w based on the volume of the composition.

183. The method according to claim 182, wherein the pharmaceutical composition comprises a tetracycline compound in a concentration of about 0.01% w / w, about 0.05% w / w, about 0.1% w / w, about 0.5% w / w, about 1% w / w, about 5% w / w, about 10% w / w, about 15% w / w, or about 20% w / w, or a pharmaceutically acceptable salt, ester, or prodrug thereof.

184. The method according to any one of claims 1 to 183, wherein the administration of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, comprises administering one or more loading doses of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, followed by administering one or more maintenance doses of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof.

185. The method according to claim 184, wherein the loading dose is an intravenous dose or an oral dose.

186. The method according to claim 185, wherein the loading dose is an intravenous daily dose of approximately 200 mg or an oral daily dose of approximately 450 mg.

187. The method according to claim 184, wherein the maintenance dose is approximately 100 mg per day intravenous or approximately 300 mg per day oral.

188. The method according to claim 168, wherein the administration of a tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof, comprises administering the same dose of the tetracycline compound, or a pharmaceutically acceptable salt, ester, or prodrug thereof over a period of treatment.

189. The method according to any one of claims 1 to 188, wherein the subject has immune capabilities.

190. The method according to any one of claims 1 to 188, wherein the subject is immunodeficient.

191. The method according to any one of claims 1 to 190, wherein the subject is a mammal.

192. The method according to claim 191, wherein the mammal is selected from the group consisting of humans, non-human primates, cattle, sheep, pigs, goats, horses, dogs, cats, mice, rats, and guinea pigs.

193. The method according to claim 192, wherein the subject is a human.

194. The method according to any one of claims 1 to 193, wherein the subject is determined to have a mycobacterial infection.

195. The method according to any one of claims 1 to 194, further comprising the step of determining whether a subject has a mycobacterial infection before administering a tetracycline compound or a pharmaceutically acceptable salt, ester, or prodrug thereof to the subject.

Images