Tricyclic benzoxaborole compounds and uses thereof
Compounds of Formula II, wherein X is selected from chloro, fluoro, bromo and iodo, R 1 and R 2 are each independently selected from H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , or —CH(CH 3 ) 2 ; compositions containing them, their use in therapy, including their use as anti-mycobacterial agents, for example in the treatment of a mycobacterial infection in a mammal, and methods for the preparation of such compounds, are provided.
1. A method of treating a disease resulting from a mycobacterial infection in an animal, the method comprising:
administering to the animal in need of such treatment a combination comprising
a first therapeutic agent which is (S)-(3-chloro-7,8-dihydro-2H -1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine or a pharmaceutically acceptable salt thereof, and
a second therapeutic agent which is not the first therapeutic agent.
2. The method according to claim 1 , wherein the first therapeutic agent is ((S)-(3-chloro-7,8-dihydro-2H-1,6,9-trioxa-9a -borabenzo[cd]azulen-2-yl)methanamine dihydrogensulfate.H 2 O.
3. The method according to claim 1 , wherein the second therapeutic agent is independently selected from isoniazid, rifampin, pyrazinamide, ethambutol, moxifloxacin, rifapentine, clofazimine, bedaquiline (TMC207), nitroimidazo-oxazine PA-824, delamanid (OPC-67683), an oxazolidinone, EMB analogue SQ109, a benzothiazinone, and a dinitrobenzamide.
4. The method according to claim 3 , wherein the oxazolidinone is linezolid, tedizolid, radezolid, sutezolid (PNU-100480), or posizolid (AZD-5847).
5. The method according to claim 1 , wherein the second therapeutic agent is an antiviral agent.
6. The method according to claim 5 , wherein the antiviral agent is an antiretroviral agent.
7. The method according to claim 6 , wherein the antiretroviral agent is zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, lersivirine, GSK2248761, TMC-278, TMC-125, etravirine, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir, tipranavir, palinavir, lasinavir, enfuvirtide, T-20, T-1249, PRO-542, PRO-140, TNX-355, BMS-806, BMS-663068 and BMS-626529, 5-Helix, raltegravir, elvitegravir, GSK1349572, GSK1265744, vicriviroc (Sch-C), Sch-D, TAK779, maraviroc, TAK449, didanosine, tenofovir, lopinavir, or darunavir.
8. The method according to claim 1 , wherein the combination includes a pharmaceutically acceptable excipient, adjuvant, or diluent.
9. The method according to claim 1 , wherein the second therapeutic agent is a therapeutic agent approved or recommended for the treatment of tuberculosis.
10. The method according to claim 1 , wherein the mycobacterial infection is an infection of a mycobacterium selected Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium kansasii, Mycobacterium malmoense, Mycobacterium simiae, Mycobacterium szulgai, Mycobacterium xenopi, Mycobacterium scrofulaceum, Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium haemophilum, Mycobacterium leprae, Mycobacterium marinum, Mycobacterium fortuitum, Mycobacterium parafortuitum, Mycobacterium gordonae, Mycobacterium vaccae, Mycobacterium bovis, Mycobacterium bovis BCG, Mycobacterium africanum, Mycobacterium canetti, Mycobacterium caprae, Mycobacterium microti, Mycobacterium pinnipedi, Mycobacterium leprae, Mycobacterium ulcerans, Mycobacterium intracellulare, Mycobacterium avium complex (MAC), Mycobacterium avian -intracellulare complex (MAIC), Mycobacterium gordonae clade; Mycobacterium kansasii clade; Mycobacterium chelonae clade; Mycobacterium fortuitum clade; Mycobacterium parafortuitum clade; and Mycobacterium vaccae clade.
11. The method according to claim 10 , wherein the mycobacterium is Mycobacterium avium.
12. The method according to claim 10 , wherein the mycobacterium is Mycobacterium abscessus.
13. The method according to claim , wherein the disease is tuberculosis.
14. The method according to claim 1 , wherein the disease is selected from Johne's disease, Crohn's disease, Lady Windermere syndrome, Mycobacterium avium complex (MAC) lung disease, disseminated Mycobacterium avium complex (DMAC), disseminated Mycobacterium avium intraceullulare complex (DMAIC), hot-tub lung, MAC mastitis, MAC pyomyositis, Mycobacterium avium paratuberculosis, or granuloma disease.
15. The method according to claim 1 , wherein the animal is a mammal.
16. The method according to claim 1 , wherein the animal is a human.
17. The method according to claim 10 , wherein Mycobacterium avium comprises subspecies (subsp.) Mycobacterium avium subsp. avium, Mycobacterium avium subsp. hominissuis, Mycobacterium avium subsp. silvaticum , or Mycobacterium avium subsp. paratuberculosis.
18. The method according to claim 1 , wherein the disease is a pulmonary disease or a pulmonary infection.