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 compound having a structure as shown in Formula II:
wherein X is selected from chloro or bromo and R 1 and R 2 are each independently selected from H and —CH 3 ; or a pharmaceutically acceptable salt thereof.
2. A compound having a structure as shown in Formula IIa:
wherein X is chloro or bromo and R 1 and R 2 are each independently selected from H and —CH 3 ; or a pharmaceutically acceptable salt thereof.
3. A compound, (S)-(3-chloro-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine, or a pharmaceutically acceptable salt thereof.
4. A pharmaceutically acceptable salt, ((S)-(3-chloro-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine dihydrogensulfate.H 2 O.
5. A pharmaceutical composition comprising the pharmaceutically acceptable salt of claim 4 , together with at least one pharmaceutically acceptable excipient.
6. A combination comprising:
a first therapeutic agent which is the pharmaceutically acceptable salt of claim 4 and
a second therapeutic agent
that is not the pharmaceutically acceptable salt of claim 4 .
7. The combination according to claim 6 , 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.
8. The combination according to claim 7 , wherein the oxazolidinone is linezolid, tedizolid, radezolid, sutezolid (PNU-100480), or posizolid (AZD-5847).
9. The combination according to claim 6 , wherein the second therapeutic agent is a therapeutic agent approved or recommended for the treatment of tuberculosis.
10. The combination according to claim 6 , wherein the second therapeutic agent is an antiviral agent.
11. The combination according to claim 10 , wherein the antiviral agent is an antiretroviral agent.
12. The combination according to claim 11 , 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.
13. A method of killing mycobacteria and/or inhibiting the replication of mycobacteria that cause disease in an animal, comprising contacting mycobacteria or an animal infected with mycobacteria with a therapeutically effective amount of the pharmaceutically acceptable salt of claim 4 , so as to kill the mycobacteria and/or inhibit the replication of the mycobacteria.
14. The method according to claim 13 , wherein the mycobacteria is Mycobacterium tuberculosis or Mycobacterium avium.
15. The method according to claim 14 , wherein the disease is tuberculosis.
16. The method according to claim 14 , wherein the animal is a human.
17. A method of treating a disease in a mammal infected with a mycobacterium , which method comprises administering to the mammal infected with the mycobacterium an effective amount of: (i) the pharmaceutically acceptable salt of claim 4 ; (ii) the combination of claim 6 ; or (iii) the pharmaceutical composition of claim 5 , so as to treat the disease in the mammal.
18. The method according to claim 17 , wherein the mycobacterium is Mycobacterium tuberculosis or Mycobacterium avium.
19. The method according to claim 18 , wherein the disease is selected from tuberculosis, Johne's disease, Crohn's disease, pulmonary disease or pulmonary infection, 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 avum paratuberculosis, or granuloma disease.
20. The method according to claim 18 , wherein the disease is tuberculosis.
21. A method of treating a mycobacterial infection in a mammal, which method comprises administering to the animal in need of such treatment an effective amount of the pharmaceutically acceptable salt of claim 4 .
22. The method according to claim 19 , wherein the mycobacterial infection is a Mycobacterium tuberculosis infection and the mammal is a human.