4-substituted benzoxaborole compounds and uses thereof
Substituted benzoxaboroles whose structure comprises Formula (III), wherein R 3 is selected from —CH 3 , —CII 2 CII 3 , —CII 2 ═CII 2 , —CII 2 CII 2 CII 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 ═CH 2 , and cyclopropyl, R 1 and R 2 are each independently selected from H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , and —CH(CH 3 ) 2 ; compositions containing such compounds, 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 IIIa:
2. A combination comprising:
a first therapeutic agent that is the compound of claim 1 , and
a second therapeutic agent.
3. The combination according to claim 2 , wherein the second therapeutic agent is a therapeutic agent approved or recommended for the treatment of tuberculosis.
4. The combination according to claim 2 , 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.
5. The combination according to claim 2 , wherein the second therapeutic agent is an oxazolidinone selected from linezolid, tedizolid, radezolid, sutezolid (PNU-100480), and posizolid (AZD-5847).
6. The combination according to claim 2 , wherein the second therapeutic agent is an antiviral agent including an antiretroviral agent.
7. The combination according to claim 2 , wherein the second therapeutic agent is an antiretroviral agent including 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 combination according to claim 2 , wherein the second therapeutic agent is an antiretroviral agent including GSK1349572 or GSK1265744.
9. A method of killing and/or inhibiting replication of a mycobacterium in an animal, the method comprising administering to the animal a therapeutically effective amount of a compound according to claim 1 .
10. The method according to claim 9 , wherein the mycobacterium is Mycobacterium tuberculosis or Mycobacterium avium.
11. The method according to claim 9 , wherein the mycobacterium is a drug resistant variant.
12. The method according to claim 9 , wherein the mycobacterium is a multi-drug resistant variant.
13. The method according to claim 9 , wherein the Mycobacterium is a multi-drug resistant Mycobacterium tuberculosis or an extensive drug resistant Mycobacterium tuberculosis.
14. The method according to claim 9 , wherein the mycobacterium is a non-tuberculosis complex or clade.
15. The method according to claim 9 , wherein the Mycobacterium is a member of the Mycobacterium tuberculosis complex (MTC), the Mycobacterium avium complex (MAC), the Mycobacterium avium - intracellulare complex (MAIC), Mycobacterium gordonae clade, Mycobacterium kansasii clade, Mycobacterium chelonae clade, Mycobacterium fortuitum clade, Mycobacterium parafortuitum clade, or Mycobacterium vaccae clade.
16. A method of killing and/or inhibiting replication of a Mycobacterium , the method comprising contacting the Mycobacterium with an effective amount of a compound according to claim 1 .
17. The method according to claim 16 , wherein the Mycobacterium is Mycobacterium tuberculosis or Mycobacterium avium.
18. The method according to claim 16 , wherein the Mycobacterium is a drug resistant variant.
19. The method according to claim 16 , wherein the Mycobacterium is a multi-drug resistant Mycobacterium tuberculosis or an extensive drug resistanti Mycobacterium tuberculosis.
20. The method according to claim 16 , wherein the Mycobacterium is a member of the Mycobacterium tuberculosis complex (MTC), the Mycobacterium avium complex (MAC), the Mycobacterium avium - intracellulare complex (MAIC), Mycobacterium gordonae clade, Mycobacterium kansasii clade, Mycobacterium chelonae clade, Mycobacterium fortuitum clade, Mycobacterium parafortuitum clade, or Mycobacterium vaccae clade.