US2016251380A1PendingUtilityA1
Tricyclic benzoxaborole compounds and uses thereof
Assignee: GLAXOSMITHKLINE INTELLECTUAL PROPERTY (NO 2) LTDPriority: Aug 9, 2013Filed: Aug 8, 2014Published: Sep 1, 2016
Est. expiryAug 9, 2033(~7.1 yrs left)· nominal 20-yr term from priority
Inventors:M.R.K. (Dickon) AlleyVincent S. HernandezJacob J. PlattnerXianfeng LiDavid Barros-AguirreIlaria Giordano
A61P 31/04A61P 43/00A61P 35/00A61P 31/06A61P 15/00A61P 17/00A61P 11/00A61P 21/00C07F 5/04A61K 31/69A61K 45/06C07F 5/025A61P 1/04
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Claims
Abstract
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.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having a structure as shown in Formula II:
wherein X is selected from fluoro, chloro, bromo or iodo and 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 ; or a salt thereof.
2 . A compound according to claim 1 or a salt thereof, wherein X is chloro or bromo.
3 . A compound according to claim 1 , or a salt thereof, which is
4 . A compound according to claim 3 , which is
5 . A compound according to claim 3 which is:
6 . A compound according to claim 1 which is:
7 . A compound according to claim 1 which is:
8 . A compound having a structure as shown in Formula IIa:
wherein X is fluoro, chloro, bromo or iodo, and 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 , or a salt thereof.
9 . A compound according to claim 8 , or a salt thereof, which is
10 . A compound according to claim 8 which is
11 . A compound according to claim 8 which is
12 . A compound according to claim 8 which is
13 . A compound according to claim 8 which is
14 . A compound, (S)-(3-bromo-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine, having the formula:
or a pharmaceutically acceptable salt thereof.
15 . A compound, (S)-(3-chloro-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine, having the formula:
16 . A compound, (S)-(3-chloro-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine, having the formula:
or a pharmaceutically acceptable salt thereof.
17 . A pharmaceutically acceptable salt of a compound, (S)-(3-chloro-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine, having the formula:
18 . A pharmaceutical composition comprising a compound, (S)-(3-chloro-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine, having the formula:
together with at least one pharmaceutically acceptable excipient.
19 . A compound, (S)-(3-bromo-8,8-dimethyl-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine, having the formula:
20 . A compound, (S)-(3-bromo-8,8-dimethyl-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine, having the formula:
or a pharmaceutically acceptable salt thereof.
21 . A pharmaceutically acceptable salt of a compound, (S)-(3-bromo-8,8-dimethyl-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine, having the formula:
22 . A pharmaceutical composition comprising a compound, (S)-(3-bromo-8,8-dimethyl-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine, having the formula:
together with at least one pharmaceutically acceptable excipient.
23 . A compound selected from the group consisting of:
(3-bromo-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine; (S)-(3-bromo-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine; (3-chloro-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine; (S)-(3-chloro-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine; (3-chloro-8-methyl-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine; (3-bromo-8-methyl-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine; (3-bromo-8,8-dimethyl-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine; (S)-(3-bromo-8,8-dimethyl-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine; (3-chloro-8,8-dimethyl-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine; (S)-(3-chloro-8,8-dimethyl-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine; (3-fluoro-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine; and (S)-(3-iodo-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine,
or a pharmaceutically acceptable salt thereof.
24 . A compound according to any of claim 1 , 8 or 23 wherein the pharmaceutically acceptable salt is selected from a hydrochloride, a hydrobromide, a hydriodide, a nitride, a carbonate, a monohydrogencarbonate, a phosphate, a monohydrogenphosphate, a dihydrogenphosphate, a sulfate, a monohydrogensulfate, a dihydrogensulfate, or a phosphonate salt.
25 . A compound according to claim 1 , 8 or 23 , wherein the pharmaceutically acceptable salt is an acetate, a propionate, an isobutyrate, a maleate, a malonate, a benzoate, a succinate, a suberate, a fumarate, a glucaronate, a galacturonate, a lactate, a mandelate, a phthalate, a benzenesulfonate, a p-tolylsulfonate, a citrate, a tartrate, or a methanesulfonate salt.
26 . A compound according to any of claim 1 , 8 or 23 , wherein the pharmaceutically acceptable salt is a salt of an amino acid including an arginate or a lysinate salt.
27 . A compound according to claim 24 wherein the pharmaceutically acceptable salt is a hydrochloride salt or a dihydrogensulfate salt.
28 . A combination comprising:
a first therapeutic agent, which is a compound of Formula II or Formula IIa, or a pharmaceutically acceptable salt thereof, according to any of claims 1 through 27 ; optionally a second therapeutic agent; optionally a third therapeutic agent; optionally a fourth therapeutic agent; optionally a fifth therapeutic agent; and optionally a sixth therapeutic agent,
wherein the optional second, third, fourth, fifth, or sixth therapeutic agent is not a compound of Formula II or Formula IIa.
29 . A combination according to claim 27 , wherein the optional second, third, fourth, fifth and sixth 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, a dinitrobenzamide and an antiviral agent including an antiretroviral agent.
30 . A combination according to claim 27 , wherein the oxazolidinone is linezolid, tedizolid, radezolid, sutezolid (PNU-100480), or posizolid (AZD-5847).
31 . A combination according to claim 27 , wherein the optional second, third, fourth, fifth and sixth therapeutic agent is selected from a therapeutic agent approved or recommended for the treatment of tuberculosis.
32 . A combination according to claim 27 , 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.
33 . A pharmaceutical formulation comprising a first therapeutic agent, said first therapeutic agent being a therapeutically effective amount of a compound of Formula II or Formula IIa, or a pharmaceutically acceptable salt thereof, according to any of claims 1 - 27 ; or a combination according to any of claims 28 - 32 , and a pharmaceutically acceptable excipient, adjuvant or diluent.
34 . A pharmaceutical formulation according to claim 33 , further comprising a second therapeutic agent.
35 . A method of killing a mycobacteria and/or inhibiting the replication of mycobacteria that cause disease in an animal, comprising contacting mycobacterial or an animal infected with mycobacteria with a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any of claims 1 - 25 , so as to kill the mycobacteria and/or prevent the replication of the mycobacteria.
36 . A method according to claim 35 , wherein the mycobacteria is Mycobacterium tuberculosis.
37 . A method according to claim 35 , wherein the disease is tuberculosis.
38 . A method according to claim 35 , wherein the animal is a human.
39 . A method of treating a mycobacterial infection in an animal comprising: administering to the animal any one of: (i) a therapeutically effective amount of a compound of Formula II or Formula IIa, or a pharmaceutically acceptable salt thereof, according to any of claims 1 - 27 ; (ii) a therapeutically effective amount of a combination according to any of claims 32 - 35 ; or (iii) a therapeutically effective amount of a pharmaceutical formulation according to any of claims 333 - 34 , so as to treat the mycobacterial infection in the animal.
40 . A method according to claim 39 , wherein the mycobacterial infection is an infection of a mycobacterium selected from Mycobacterium tuberculosis, Mycobacterium avium including subspecies (subsp.) Mycobacterium avium subsp. avium, Mycobacterium avium subsp. hominissuis, Mycobacterium avium subsp. silvaticum , and Mycobacterium avium subsp. paratuberculosis; 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 tuberculosis complex. (MTC), 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.
41 . A method according to claim 39 , wherein the mycobacteria is Mycobacterium tuberculosis.
42 . A method according to claim 39 , wherein the disease is tuberculosis.
43 . A compound of Formula II or Formula IIa according to any of claims 1 - 27 , or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease resulting from a mycobacterial infection in an animal.
44 . A compound according to claim 43 , wherein the mycobacterial infection is a Mycobacterium tuberculosis infection.
45 . A compound according to claim 43 , wherein the disease is selected from tuberculosis, leprosy, Johne's disease, Buruli or Bairnsdale ulcer, Crohn's disease, pulmonary disease or pulmonary infection. pneumonia, bursa, synovial, tendon sheaths, localized abscess, lymphadenitis, skin and soft tissue infections Lady Windermere syndrome, 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.
46 . A compound according to claim 45 , wherein the disease is tuberculosis.
47 . A compound according to claim 43 , wherein the animal is a human.
48 . A use of a compound of Formula II or Formula IIa according to any of claims 1 - 27 , or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a mycobacterial infection in an animal.
49 . The use of claim 48 , wherein the mycobacterial infection is a Mycobacterium tuberculosis infection.
50 . The use of claim 49 wherein the animal is a human.
51 . A method of treating a disease resulting from a mycobacterial infection a mammal, which method comprises administering to the animal in need of such treatment an effective amount of a compound of Formula II or Formula IIa according to any of claims 1 - 27 , or a pharmaceutically acceptable salt thereof.
52 . A method of treating a disease according to claim 51 , wherein the mammal is a human.
53 . A method according to claim 51 , wherein the mycobacterial infection is a Mycobacterium tuberculosis infection.
54 . A method according to claim 4951 wherein the disease is selected from tuberculosis, leprosy, Johne's disease, Buruli or Bairnsdale ulcer, Crohn's disease, pulmonary disease or pulmonary infection. pneumonia, bursa, synovial, tendon sheaths, localized abscess, lymphadenitis, skin and soft tissue infections Lady Windermere syndrome, MAC lung disease, disseminated Mycobacterium avium complex (DMAC), disseminated Mycobacterium avium intracellulare complex (DMAIC), hot-tub lung, MAC mastitis, MAC pyomyositis, Mycobacterium avum paratuberculosis , or granuloma disease.
55 . A method according to claim 51 , wherein the disease is tuberculosis.
56 . A method according to claim 51 , wherein the animal is a human.
57 . A method of treating a mycobacterial infection in an animal, particularly in a mammal, which method comprises administering to the animal in need of such treatment an effective amount of a compound according to any of claims 1 - 27 , or a pharmaceutically acceptable salt thereof.
58 . A method according to claim 57 , wherein the mycobacterial infection is a Mycobacterium tuberculosis infection.
59 . A method according to claim 57 , wherein the animal is a human.Join the waitlist — get patent alerts
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