# US 10,308,668 B2 · Tricyclic benzoxaborole compounds and uses thereof

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- Number: US 10,308,668 B2
- Document ID: US10308668B2
- Status: Granted
- Kind: B2
- Application number: 15/792,251
- Filed: 2017-10-24
- Published: 2018-02-15
- Granted: 2019-06-04
- Earliest claimed: 2013-08-09
- Assignees: GlaxoSmithKline Intellectual Property (No. 2) Limited; Anacor Pharmaceuticals, Inc.
- Applicants: Glaxosmithkline Intellectual Property (No.2) Limited; Anacor Pharmaceuticals Inc.
- Inventors: Michael Richard Kevin Alley; Vincent Hernandez; Jacob J. Plattner; Xianfeng Li; David Barros-Aguirre; Ilaria Giordano
- Web page: https://patentgrep.com/patent/US10308668B2

## CPC

- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- C07F 5/04: Esters of boric acids
- A61K 31/69: Boron compounds
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 31/04: Antibacterial agents
- A61P 31/06: for tuberculosis
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07F 5/025: {Boronic and borinic acid compounds}
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Compounds of Formula II, wherein X is selected from chloro, fluoro, bromo and iodo, R1 and R2 are each independently selected from H, —CH3, —CH2CH3, —CH2CH2CH3, or —CH(CH3)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

### Claim 1

A compound having a structure as shown in Formula II:
wherein X is selected from chloro or bromo and R1 and R2 are each independently selected from H and —CH3; or a pharmaceutically acceptable salt thereof.

### Claim 2

A compound having a structure as shown in Formula IIa:
wherein X is chloro or bromo and R1 and R2 are each independently selected from H and —CH3; or a pharmaceutically acceptable salt thereof.

### Claim 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.

### Claim 4

A pharmaceutically acceptable salt, ((S)-(3-chloro-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine dihydrogensulfate.H2O.

### Claim 5 (depends on 4)

A pharmaceutical composition comprising the pharmaceutically acceptable salt of claim 4, together with at least one pharmaceutically acceptable excipient.

### Claim 6 (depends on 4)

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.

### Claim 7 (depends on 6)

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.

### Claim 8 (depends on 7)

The combination according to claim 7, wherein the oxazolidinone is linezolid, tedizolid, radezolid, sutezolid (PNU-100480), or posizolid (AZD-5847).

### Claim 9 (depends on 6)

The combination according to claim 6, wherein the second therapeutic agent is a therapeutic agent approved or recommended for the treatment of tuberculosis.

### Claim 10 (depends on 6)

The combination according to claim 6, wherein the second therapeutic agent is an antiviral agent.

### Claim 11 (depends on 10)

The combination according to claim 10, wherein the antiviral agent is an antiretroviral agent.

### Claim 12 (depends on 11)

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.

### Claim 13 (depends on 4)

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.

### Claim 14 (depends on 13)

The method according to claim 13, wherein the mycobacteria is Mycobacterium tuberculosis or Mycobacterium avium.

### Claim 15 (depends on 14)

The method according to claim 14, wherein the disease is tuberculosis.

### Claim 16 (depends on 14)

The method according to claim 14, wherein the animal is a human.

### Claim 17 (depends on 4, 5, 6)

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.

### Claim 18 (depends on 17)

The method according to claim 17, wherein the mycobacterium is Mycobacterium tuberculosis or Mycobacterium avium.

### Claim 19 (depends on 18)

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.

### Claim 20 (depends on 18)

The method according to claim 18, wherein the disease is tuberculosis.

### Claim 21 (depends on 4)

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.

### Claim 22 (depends on 19)

The method according to claim 19, wherein the mycobacterial infection is a Mycobacterium tuberculosis infection and the mammal is a human.