Boron-containing small molecules

• US 9,566,289 B2
• Filed: 02/17/2016
• Issued: 02/14/2017
• Est. Priority Date: 02/16/2005
• Status: Active Grant

• Current Assignee: Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Original Assignee: Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Inventors: Baker, Stephen J., Akama, Tsutomu, Hernandez, Vincent S., Hold, Karin M., Maples, Kirk, Plattner, Jacob J., Sanders, Virginia, Zhang, Yong-Kang, Fieldson, Gregory T., Leyden, James J.
• Primary Examiner(s): SHIAO, REI TSANG
• Application Number:
  US15/046,322
• Publication Number:
  US 20160151399A1
• Time in Patent Office: 363 Days
• Field of Search: 514/64
• US Class Current: 1/1
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 9/0012 Galenical forms characterised by the site of application
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/04 Esters of boric acids
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C07H 23/00 Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12 esters with inorganic acids C07H11/00; metal salts, see parent compounds
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

This invention relates to compounds useful for treating fungal infections, more specifically topical treatment of onychomycosis and/or cutaneous fungal infections. This invention is directed to compounds that are active against fungi and have properties that allow the compound, when placed in contact with a patient, to reach the particular part of the skin, nail, hair, claw or hoof infected by the fungus. In particular the present compounds have physiochemical properties that facilitate penetration of the nail plate.

Claims

1. A pharmaceutical formulation, comprising:

1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, or a pharmaceutically acceptable salt thereof; and

a pharmaceutically acceptable topical carrier.

2. The pharmaceutical formulation of claim 1, wherein the pharmaceutically acceptable topical carrier comprises one or more members selected from polymers, thickeners, buffers, neutralizers, chelating agents, preservatives, surfactants or emulsifiers, antioxidants, waxes or oils, emollients, sunscreens, and a solvent or mixed solvent system.

3. The pharmaceutical formulation of claim 1, wherein the pharmaceutically acceptable topical carrier comprises a solvent system and a chelating agent;

wherein the solvent system comprises ethanol and propylene glycol; and

wherein

the chelating agent is ethylene diamine tetraacetic acid (EDTA) or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical formulation, comprising:

1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, or a pharmaceutically acceptable salt thereof;

a solvent system and

a chelating agent.

5. The pharmaceutical formulation of claim 4, wherein the solvent system comprises ethanol.

6. The pharmaceutical formulation of claim 4, wherein the solvent system consists of ethanol.

7. The pharmaceutical formulation of claim 4, wherein the solvent system comprises ethanol and propylene glycol.

8. The pharmaceutical formulation of claim 4, wherein the chelating agent is ethylene diamine tetraacetic acid (EDTA) or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical formulation of claim 8, wherein the ethylene diamine tetraacetic acid (EDTA) or a pharmaceutically acceptable salt thereof, is present in a concentration of from about 0.005% to about 2.0% w/w.

10. The pharmaceutical formulation of claim 4, wherein the 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, or a pharmaceutically acceptable salt thereof, is present in a concentration of about 5% w/w.

11. The pharmaceutical formulation of claim 4, wherein the formulation is suitable for the treatment of onychomycosis of a toenail due to Trichophyton rubrum or Trichophyton mentagrophytes by topical application of the formulation to the toenail.

12. A pharmaceutical formulation, comprising:

about 5% w/w 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, or a pharmaceutically acceptable salt thereof;

propylene glycol;

ethanol; and

ethylene diamine tetraacetic acid (EDTA) or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical formulation of claim 12, wherein the formulation is suitable for the treatment of onychomycosis of a toenail due to Trichophyton rubrum or Trichophyton mentagrophytes by topical application of the formulation to the toenail.

14. The pharmaceutical formulation of claim 12, wherein the ethylene diamine tetraacetic acid (EDTA) or a pharmaceutically acceptable salt thereof, is present in a concentration of from about 0.005% to about 2.0% w/w.

15. The pharmaceutical formulation of claim 14, wherein the formulation is suitable for the treatment of onychomycosis of a toenail due to Trichophyton rubrum or Trichophyton mentagrophytes by topical application of the formulation to the toenail.