Boron-containing small molecules

• US 20060234981A1
• Filed: 02/16/2006
• Published: 10/19/2006
• Est. Priority Date: 02/16/2005
• Status: Active Grant

• Current Assignee: Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Original Assignee: Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Inventors: Akama, Tsutomu, Plattner, Jacob J., Baker, Stephen J., Maples, Kirk R., Zhang, Yong-Kang, Hernandez, Vincent S., Leyden, James J., Sanders, Virginia, Hold, Karin M., Bellinger-Kawahara, Carolyn
• Granted Patent: US 7,582,621 B2
• Time in Patent Office: Days
• 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 compound having a structure according to Formula I:

2. The compound of claim 1, having a structure according to Formula (Ia):

3. The compound of claim 2, having a structure according to Formula (Ib):

19. A method for killing a microorganism or inhibiting the growth of a microorganism, comprising contacting said microorganism with a therapeutically effective amount of a compound according to claim 1.

20. The method of claim 19, wherein said microorganism is a fungus.

21. The method of claim 19, wherein said fungus 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 class.

22. The method of claim 19, wherein said fungus is a member selected from dermatophytes, Trichophyton, Microsporum, Epidermophyton and yeast-like fungi.

27. A method of treating or preventing an infection in an animal, said method comprising administering to the animal a therapeutically effective amount of the compound according to claim 1.

28. The method of claim 27, wherein said infection is a member selected from a systemic infection, a cutaneous infection, and an ungual or periungual infection.

29. The method of claim 27, wherein said infection is a member selected from chloronychia, paronychias, erysipeloid, onychorrhexis, gonorrhea, swimming-pool granuloma, larva migrans, leprosy, Orf nodule, milkers'"'"' nodules, herpetic whitlow, acute bacterial perionyxis, chronic perionyxis, sporotrichosis, syphilis, tuberculosis verrucosa cutis, tularemia, tungiasis, peri- and subungual warts, zona, nail dystrophy (trachyonychia), dermatological diseases, psoriasis, pustular psoriasis, alopecia aerata, parakeratosis pustulosa, contact dermatosis, Reiter'"'"'s syndrome, psoriasiform acral dermatitis, lichen planus, idiopathy atrophy in the nails, lichin nitidus, lichen striatus, inflammatory linear verrucous epidermal naevus (ILVEN), alopecia, pemphigus, bullous pemphigoid, acquired epidermolysis bullosa, Darier'"'"'s disease, pityriasis rubra pilaris, palmoplantar keratoderma, contact eczema, polymorphic erythema, scabies, Bazex syndrome, systemic scleroderma, systemic lupus erythematosus, chronic lupus erythematosus, dermatomyositus, Sporotrichosis, 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.

30. The method of claim 27, wherein said infection is onychomycosis.

31. The method of claim 27, wherein said animal is a member selected from a human, cattle, goat, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, chicken and turkey.

37. A method for synthesizing the compound of claim 1.

4. A pharmaceutical formulation comprising:

(a) a pharmaceutically acceptable excipient; and

(b) a compound having a structure according to Formula II;

wherein

B is boron;

R^1b is a member selected from a negative charge, a salt counterion, H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

M2 is a member selected from oxygen, sulfur and NR^2b

wherein

R^2b is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

J2 is a member selected from (CR^3bR^4b)_n2 and CR^5b

wherein

R^3b, R^4b, and R^5b are members independently selected from H, OH, NH₂, SH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

n2 is an integer selected from 0 to 2;

W2 is a member selected from C═

O (carbonyl), (CR^6bR^7b)_m2 and CR^8b

wherein

R^6b, R^7b, and R^8b are members independently selected from H, OH, NH₂, SH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

m2 is an integer selected from 0 and 1;

A2 is a member selected from CR^9b and N;

D2 is a member selected from CR^10b and N;

E2 is a member selected from CR^11b and N;

G2 is a member selected from CR^12b and N;

wherein

R^9b, R^10b, R^11b and R^12b are members independently selected from H, OH, NH₂, SH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

the combination of nitrogens (A2+D2+E2+G2) is an integer selected from 0 to 3;

a member selected from R^3b, R^4b and R^5b and a member selected from R^6b, R^7b and R^8b, together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring;

R^3b and R^4b, together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring;

R^6b and R^7b, together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring;

R^9b and R^10b, together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring;

R^10b and R^11b, together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring;

R^11b and R^12b, together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring.

5. The pharmaceutical formulation of claim 4, wherein said compound has a structure according to Formula (IIa):

6. The pharmaceutical formulation of claim 4, wherein said compound has a structure according to Formula (IIb):

7. The pharmaceutical formulation of claim 4, wherein said compound has a structure according to Formula (IIc):

8. The pharmaceutical formulation of claim 4, wherein said compound has a structure which is a member selected from:

9. The pharmaceutical formulation of claim 6, wherein R^1b is a member selected from a negative charge, H and a salt counterion.

10. The pharmaceutical formulation of claim 9, wherein R^10b and R^11b are H.

11. The pharmaceutical formulation of claim 6, wherein one member selected from R^10b and R^11b is H and the other member selected from R^10b and R^11b is a member selected from halo, methyl, cyano, methoxy, hydroxymethyl and p-cyanophenyloxy.

12. The pharmaceutical formulation of claim 6, wherein R^10b and R^11b are members independently selected from fluoro, chloro, methyl, cyano, methoxy, hydroxymethyl, and p-cyanophenyl.

13. The pharmaceutical formulation of claim 6, wherein R^1b is a member selected from a negative charge, H and a salt counterion;

R^7b is H;

R^10b is F and R^11b is H.

14. The pharmaceutical formulation of claim 6, wherein R^1b is a member selected from a negative charge, H and a salt counterion;

R^7b is H;

R^10b is 4-cyanophenoxy and R^11b is H.

15. The pharmaceutical formulation of claim 4, wherein R^11b and R^12b, along with the atoms to which they are attached, are joined to form a phenyl group.

16. The pharmaceutical formulation of claim 4, wherein said compound has a structure according to Formula (IId):

17. The pharmaceutical formulation of claim 4, wherein said excipient is a pharmaceutically acceptable topical carrier.

18. The pharmaceutical formulation of claim 4, wherein said compound is present in said pharmaceutical formulation in a concentration of from about 1% to about 10%.

23. A method for killing a microorganism or inhibiting the growth of a microorganism, comprising contacting said microorganism with a therapeutically effective amount of a pharmaceutical formulation according to claim 4.

24. The method of claim 23, wherein said microorganism is a fungus.

25. The method of claim 23, wherein said fungus 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 class.

26. The method of claim 23, wherein said fungus is a member selected from dermatophytes, Trichophyton, Microsporum, Epidermophyton and yeast-like fungi.

32. A method of treating or preventing an infection in an animal, said method comprising administering to the animal a therapeutically effective amount of the pharmaceutical formulation according to claim 4.

33. The method of claim 32, wherein said infection is a member selected from a systemic infection and an ungual or periungual infection.

34. The method of claim 32, wherein said infection is a member selected from chloronychia, paronychias, erysipeloid, onychorrhexis, gonorrhea, swimming-pool granuloma, larva migrans, leprosy, Orf nodule, milkers'"'"' nodules, herpetic whitlow, acute bacterial perionyxis, chronic perionyxis, sporotrichosis, syphilis, tuberculosis verrucosa cutis, tularemia, tungiasis, peri- and subungual warts, zona, nail dystrophy (trachyonychia), dermatological diseases, psoriasis, pustular psoriasis, alopecia aerata, parakeratosis pustulosa, contact dermatosis, Reiter'"'"'s syndrome, psoriasiform acral dermatitis, lichen planus, idiopathy atrophy in the nails, lichin nitidus, lichen striatus, inflammatory linear verrucous epidermal naevus (ILVEN), alopecia, pemphigus, bullous pemphigoid, acquired epidermolysis bullosa, Darier'"'"'s disease, pityriasis rubra pilaris, palmoplantar keratoderma, contact eczema, polymorphic erythema, scabies, Bazex syndrome, systemic scleroderma, systemic lupus erythematosus, chronic lupus erythematosus, dermatomyositus, Sporotrichosis, 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.

35. The method of claim 32, wherein said infection is onychomycosis.

36. The method of claim 32, wherein said animal is a member selected from a human, cattle, goat, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, chicken and turkey.

38. A method for synthesizing the pharmaceutical formulation of claim 4.

39. A method of delivering a compound from the dorsal layer of the nail plate to the nail bed, said method comprising:

contacting said cell with a compound capable of penetrating the nail plate, under conditions sufficient to penetrate said nail plate,

wherein

said compound has a molecular weight of between about 100 and about 200 Da;

said compound has a log P value of between about 1.0 and about 2.6;

said compound has a water solubility greater than about 0.1 mg/mL octanol/saturated water

thereby delivering said compound.