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Tricyclic benzoxaborole compounds and uses thereof

a technology of benzoxaborole and compound, applied in the field of compound, can solve the problems of increasing the number of mtb strains, difficult treatment of mycobacterium, and deadly combination of hiv and mtb, and achieve the effect of preventing the replication of mycobacteria

Inactive Publication Date: 2016-09-01
ANACOR PHARMA INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention is about new compounds called tricyclic benzoxaborole that can stop the growth of tuberculosis bacteria without causing harmful effects on human cells. These compounds have a similar effect to current drugs used to treat tuberculosis, but they may be more effective when used in combination with other drugs. The invention also provides a method for using these compounds to kill or prevent the growth of tuberculosis bacteria.

Problems solved by technology

Mycobacterium tuberculosis (MTB) is a small aerobic non-motile high-GC bacillus with an “outer-membrane” that is unusually thick, “waxy,” hydrophobic, rich in mycolic acids, and extremely impermeable, making mycobacterium infections difficult to treat.
In addition, the combination of HIV and MTB is deadly and increasing numbers of MTB strains are becoming resistant to standard of care drugs; approximately 300,000 new cases of multidrug resistant (MDR) M. tuberculosis are reported each year.
Add to these issues the ease of transmission, as shown in FIG. 2, the globalization of travel, and the ongoing relocation and emigration of many segments of the world's population and it is apparent that MTB is becoming a global crisis.
The limitations of tuberculosis therapy and prevention are well known.
The current available vaccine, BCG was introduced in 1921 and fails to protect most people past childhood.
Alternatively the continuation phase could include Isoniazid and ethambutol for six months when adherence cannot be assessed, but according to this report, a longer continuation phase is associated with a higher rate of failure and relapse, especially in patients with HIV infection.
Daily dosing is required in these treatment phases and poor compliance drives the emergence and spread of multi-drug-resistant strains, which are challenging to treat.
However, moxifloxacin is not yet approved for treatment of TB, and the once-weekly treatment protocol is not yet endorsed or approved as an alternative standard of care treatment—guideline panels at international and national levels will need to review the published evidence to determine if this alternative continuation treatment protocol should be recommended and adopted.
In addition, rifapentine is expensive, and interactions between rifapentine and antiretroviral drugs in the non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor classes may prevent its use in TB patients who are also HIV positive and taking antiretroviral medicines.
Thus, at present, the costs / benefits analysis of a continuation treatment with weekly rifapentine versus daily rifampicin is yet to be fully assessed.
The global rise of bacteria and other microorganisms resistant to antibiotics and antimicrobials in general, poses a major threat.

Method used

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  • Tricyclic benzoxaborole compounds and uses thereof
  • Tricyclic benzoxaborole compounds and uses thereof
  • Tricyclic benzoxaborole compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

3-bromo-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine hydrochloride (G1-Br)

[0230]

(a) 2-bromo-3-hydroxybenzaldehyde

[0231]

[0232]A suspension of 3-hydroxybenzaldehyde (5 g, 40 mmol), iron powder (172 mg, 3 mmol) and sodium acetate (6.72 g, 80 mmol) in acetic acid (40 mL) was warmed until a clear solution was obtained and then cooled to room temperature. To this mixture was added dropwise a solution of bromine (7.2 g, 45 mmol) in glacial acetic acid (10 mL) over 15 min. After the addition, the reaction mixture was stirred for 2 h and then poured into ice-water. The resulting mixture was extracted with dichloromethane (3×50 mL). The combined extracts were dried over anhydrous Na2SO4 and concentrated. The residue was recrystallized from dichloromethane to afford the product (2.3 g, 28%). 1H NMR (300 MHz, DMSO-d6): δ 10.75 (s, 1H), 10.26 (s, 1H), 7.38-7.24 (m, 3H).

(b) 2-bromo-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzaldehyde

[0233]

[0234]Dihydropyran (1.26 g, 15 m...

example 2

(S)-(3-bromo-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine hydrochloride (G2-Br)

[0247]

Method A

(a) Title compound

[0248]

[0249]The racemic compound tert-butyl((3-bromo-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methyl)carbamate (Example 1, (g)) was separated via supercritical fluid chromatography (SFC) (chiral column CHIRALCEL OJ-H, eluted with MeOH (15%) and CO2 (85%) and two chiral compounds (S)-tert-butyl ((3-bromo-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methyl)carbamate (second eluting isomer, RT=3.8 min) and (R)-isomer tert-butyl ((3-bromo-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methyl)carbamate (first eluting isomer, RT=3.3 min) were obtained. Each of the chiral compounds (1.2 g, 3.13 mmol) in saturated HCl (gas) in Et2O (20 mL) was stirred at room temperature for 1 h and concentrated to dryness (water bath+.

(S)-(3-bromo-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine hydrochloride

[0250]1H NMR ...

example 3

3-chloro-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methanamine hydrochloride (G3-Cl)

[0256]

(a) 3-chloro-2-(nitromethyl)-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulene

[0257]

[0258]To a solution of 2-(nitromethyl)-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulene (29 g, 123.4 mmol) (Example 1, (d)) in DMF (250 mL) at 80° C. was added a solution of NCS (16.5 g, 123.4 mmol) in DMF (100 mL). The mixture was stirred for 30 min at 80° C. The reaction mixture was poured into ice-water and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by re-crystallization from petroleum ether / ethyl acetate (10:1) to give 24 g of crude product. MS (ESI) m / z=270 [M+H]+. 1H NMR (300 MHz, DMSO-d6): δ 7.52-7.49 (d, 1H), 6.99-6.96 (d, 1H), 5.96-5.93 (m, 1H), 5.42-5.30 (m, 1H), 4.80-4.61 (m, 2H), 4.43-4.17 (m, 3H).

(b) Title compound

[0259]

[0260]A solution of 3-chlor...

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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.

Description

PRIORITY[0001]This application is filed pursuant to 35 U.S.C. §371 as a United States National Phase Application of International Patent Application Serial No. PCT / US2014 / 050370 filed Aug. 8, 2014, which claims priority to U.S. Provisional Application No. 61 / 864,496 filed Aug. 9, 2013, and U.S. Provisional Application No. 61 / 918,976 filed Dec. 20, 2013, and the entire contents of each of the foregoing applications are hereby incorporated by reference.FIELD OF THE INVENTION[0002]This invention relates to compounds, compositions containing them, their use in therapy, including their use as anti-mycobacterials, for example in the treatment of tuberculosis, and methods for the preparation of such compounds.BACKGROUND OF THE INVENTION[0003]Mycobacterium is a genus in the class of bacteria called Actinobacteria with its own distinct family known as Mycobacteriacae. Mycobacterium contains various obligate and opportunistic pathogens of animals, which may also be transmitted to humans and c...

Claims

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Application Information

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IPC IPC(8): C07F5/04A61K31/69A61K45/06
CPCC07F5/04A61K31/69A61K45/06C07F5/025A61P11/00A61P15/00A61P17/00A61P21/00A61P31/04A61P31/06A61P35/00A61P43/00A61P1/04A61K2300/00
Inventor HERNANDEZ, VINCENT S.PLATTNER, JACOBLI, XIANFENGBARROS-AGUIRRE, DAVIDGIORDANO, ILARIA
Owner ANACOR PHARMA INC
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