Boron-containing small molecules

• US 8,889,656 B2
• Filed: 04/30/2013
• Issued: 11/18/2014
• 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., Leyden, James J., Maples, Kirk R., Plattner, Jacob J., Sanders, Virginia, Zhang, Yong-Kang, Bellinger-Kawahara, Carolyn
• Primary Examiner(s): SHIAO, REI TSANG
• Application Number:
  US13/874,329
• Publication Number:
  US 20130244980A1
• Time in Patent Office: 567 Days
• Field of Search: 514/64, 558/288
• US Class Current: 514/64
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 9/0012 Galenical forms characterised by the site of application
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/08 for leprosy
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/02 : Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/04 : Amoebicides
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 33/08 : for Pneumocystis carinii
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: C07F 5/02 : Boron compounds
• CPC Class Codes: C07F 5/025 : Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/027 : Organoboranes and organoborohydrides
• 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 composition, comprising:

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

(b) a pharmaceutically acceptable excipient for use in an animal suffering from an infection by a microorganism.

2. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition is for topical administration.

3. The pharmaceutical composition of claim 1, wherein said excipient is a pharmaceutically acceptable topical carrier.

4. The pharmaceutical composition of claim 1, wherein said formulation is a member selected from a lacquer, lotion, cream, gel, ointment, and spray.

5. The pharmaceutical composition of claim 1, wherein said composition is a lacquer.

6. The pharmaceutical composition of claim 1, wherein said composition is a gel.

7. The pharmaceutical composition of claim 1, wherein said composition further comprises one or more members selected from an emulsifier, emollient, antioxidant, preservative, chelating agent, neutralizing agent, viscosity increasing agent, penetration enhancer, anti-inflammatory agent, vitamin, anti-aging agent, sunscreen, and acne-treating agent.

8. The pharmaceutical composition of claim 1, wherein said composition further comprises a member selected from the group consisting of a thickener, a gel phase carrier, nail penetration enhancer, and a viscosity increasing agent.

9. The pharmaceutical composition of claim 1, wherein said composition comprises a chelating agent.

10. The pharmaceutical composition of claim 9, wherein said chelating agent is selected from the group selected from citric acid, ethylene diamine tetraacetic acid (EDTA), ethylene glycol-bis(beta-aminoethyl ether)-N,N,N′

,N′

-tetraacetic acid (EGTA) and 8-Amino-2-[(2-amino-5-methylphenoxy)methyl]-6-methoxyquinoline-N,N,N′

,N′

-tetraacetic acid, tetrapotassium salt (QUIN-2).

11. The pharmaceutical composition of claim 9, wherein said chelating agent is ethylene diamine tetraacetic acid.

12. The pharmaceutical composition of claim 9, wherein said chelating agent is present in an amount of between 0.005% to 2% by weight.

13. The pharmaceutical composition of claim 1, wherein said composition comprises alcohol.

14. The pharmaceutical composition of claim 1, wherein said composition comprises alcohol and water.

15. The pharmaceutical composition of claim 1, wherein said composition comprises one or more members selected from ethanol and propylene glycol.

16. The pharmaceutical composition of claim 1, wherein said 1,3-dihydro-5-chloro-1-hydroxy-2,1-benzoxaborole is present in said composition in a concentration from about 0.5% to about 15% w/v.

17. The pharmaceutical composition of claim 1, wherein said 1,3-dihydro-5-chloro-1-hydroxy-2,1-benzoxaborole is present in said composition in a concentration from about 0.1% to about 12.5% w/v.

18. The pharmaceutical composition of claim 1, wherein said 1,3-dihydro-5-chloro-1-hydroxy-2,1-benzoxaborole is present in said composition in a concentration from about 1% to about 5% w/v.

19. The pharmaceutical composition of claim 1, wherein said 1,3-dihydro-5-chloro-1-hydroxy-2,1-benzoxaborole is present in said composition in a concentration from about 2% to about 8% w/v.

20. The pharmaceutical composition of claim 1, wherein said 1,3-dihydro-5-chloro- 1-hydroxy-2,1-benzoxaborole is present in said composition in a concentration from about 4% to about 9% w/v.

21. The pharmaceutical composition of claim 1, wherein said 1,3-dihydro-5-chloro-1-hydroxy-2,1-benzoxaborole is present in a form which is a member selected from a hydrate with water, a solvate with an alcohol, an adduct with an amino compound, and an adduct with an acid.

22. The pharmaceutical composition of claim 1, wherein a site of said topical administration is skin or nail or hair or skin surrounding the nail or skin surrounding the hair.

23. The pharmaceutical composition of claim 1, wherein the microorganism is a fungus or a yeast.

24. The pharmaceutical composition of claim 23, wherein said fungus or yeast is a member selected from Candida species, Trichophyton species, Microsporium species, Aspergillus species, Cryptococcus species, Blastomyces species, Cocciodiodes species, Histoplasma species, Paracoccidiodes species, Phycomycetes species, Malassezia species, Fusarium species, Epidermophyton species, Scytalidium species, Scopulariopsis species, Alternaria species, Penicillium species, Phialophora species, Rhizopus species, Scedosporium species and Zygomycetes species.

25. The pharmaceutical composition of claim 23, wherein said fungus or yeast is a member selected from Aspergilus fumigatus, Blastomyces dermatitidis, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus neoformans, Candida parapsilosis, Candida tropicalis, Cocciodiodes immitis, Epidermophyton floccosum, Fusarium solani, Histoplasma capsulatum, Malassezia furfur, Malassezia pachydermatis, Malassezia sympodialis, Microsporum audouinii, Microsporum canis, Microsporum gypseurn, Paracoccidiodes brasiliensis, Trichophyton mentagrophytes, Trichophyton rubrum and Trichophyton tonsurans.

26. The pharmaceutical composition of claim 23, wherein said fungus or yeast is a member selected from Trichophyton concentricum, Trichophyton violaceum, Trichophyton schoenleinii, Trichophyton verrucosum, Trichophyton soudanense, Microsporum gypseum, Microsporum equinum, Candida guilliermondii, Malassezia globosa, Malassezia obtuse, Malassezia restricta, Malassezia slooffiae and Aspergillus flavus.

27. The pharmaceutical composition of claim 23, wherein said fungus or yeast is a dermatophyte.

28. The pharmaceutical composition of claim 23, wherein said fungus or yeast is a member selected from Tinea unguium, Trichophyton rubrum and Trichophyton mentagrophytes.

29. The pharmaceutical composition of claim 1, wherein the infection is a cutaneous infection.

30. The pharmaceutical composition of claim 1, wherein the infection is a member selected from an ungual, periungual and subungual infection.

31. The pharmaceutical composition of claim 1, wherein the infection is onychomycosis.

32. The pharmaceutical composition of claim 1, wherein the animal is a human.

33. The pharmaceutical composition of claim 1, wherein said composition is in a cosmetically effective amount.

34. The pharmaceutical composition of claim 1, wherein said composition is in a therapeutically effective amount.

35. A method of treating an infection in an animal, said method comprising administering to the animal a therapeutically effective amount of 1,3-dihydro-5-chloro-1-hydroxy-2,1-benzoxaborole, or a pharmaceutically acceptable salt thereof, sufficient to treat said infection.

36. The method of claim 35, wherein said infection is a member selected from a systemic infection, a cutaneous infection, and an ungual or periungual infection.

37. The method of claim 35, wherein said infection is a member selected from chloronychia, paronychia, erysipeloid, gonorrhea, swimming-pool granuloma, leprosy, acute bacterial perionyxis, sporotrichosis, syphilis, tuberculosis verrucosa cutis, tularemia, Mycotic keratitis, Extension oculomycosis, Endogenous oculomycosis, Lobomycosis, Mycetoma, Piedra, Pityriasis versicolor, Tinea corporis, Tinea cruris, Tinea pedis, Tinea barbae, Tinea capitis, Tinea nigra, Otomycosis, Tinea favosa, Chromomycosis, and Tinea imbricata.

38. The method of claim 35, wherein said infection is onychomycosis.

39. The method of claim 35, wherein said onychomycosis is tinea unguium.

40. The method of claim 35, wherein said animal is a member selected from a cattle, goat, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, chicken, and turkey.

41. The method of claim 35, wherein said animal is a human.

42. The method of claim 35, wherein, the administering is at a site which is a member selected from the skin, nail, hair, hoof and claw.

43. The method of claim 42, wherein said skin is the skin surrounding the nail, hair, hoof or claw.

44. The method of claim 35, wherein said infection is a fungal infection.

45. A method of treating onychomycosis in a human, said method comprising administering to the human a therapeutically effective amount of 1,3-dihydro-5-chloro-1-hydroxy-2,1-benzoxaborole, or a pharmaceutically acceptable salt thereof, sufficient to treat said onychomycosis.

46. A method of inhibiting the growth of a fungus in a human, said method comprising administering to the human a therapeutically effective amount of 1,3-dihydro-5-chloro-1-hydroxy-2,1-benzoxaborole, or a pharmaceutically acceptable salt thereof.