Boron-Containing Small Molecules

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.

What is claimed is: 
     
         1 . A compound having a structure according to Formula I: 
       
         
           
           
               
               
           
         
         wherein
 B is boron; 
 R 1a  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; 
 M1 is a member selected from oxygen, sulfur and NR 2a ; 
 wherein
 R 2a  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; 
 
 J1 is a member selected from (CR 3a R 4a ) n1  and CR 5a    
 wherein
 R 3a , R 4a , and R 5a  are members independently 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; and 
 n1 is an integer selected from 0 to 2; 
 
 W1 is a member selected from C═O (carbonyl), (CR 6a R 7a ) m1  and CR 8 a;
 R 6a , R 7a , and R 8a  are members independently 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; 
 m1 is an integer selected from 0 and 1; 
 
 A1 is a member selected from CR 9a  and N; 
 D1 is a member selected from CR 10a  and N; 
 E1 is a member selected from CR 11a  and N; 
 G1 is a member selected from CR 12a  and N; 
 wherein
 R 9a , R 10a , R 11a  and R 12a  are members independently selected from H, OH, NH 2 , 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 (A1+D1+E1+G1) is an integer selected from 0 to 3; 
 
 wherein
 a member selected from R 3a , R 4a  and R 5a  and a member selected from R 6a , R 7a  and R 8a , together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring; 
 R 3a  and R 4a , together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring; 
 R 6a  and R 7a , together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring; 
 R 9a  and R 10a , together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring; 
 R 10a  and R 11a , together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring; 
 R 11a  and R 12a , together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring; 
 
 with the proviso that when M1 is oxygen, W1 is a member selected from (CR 3a R 4a ) n1 , wherein n1 is 0, J1 is a member selected from (CR 6a R 7a ) m1 , wherein m1 is 1, A1 is CR 9a , D1 is CR 10a , E1 is CR 11a , G1 is CR 12a , then R 9a  is not halogen, methyl, ethyl, or optionally joined with R 10a  to a form phenyl ring; R 10a  is not unsubstituted phenoxy, C(CH 3 ) 3 , halogen, CF 3 , methoxy, ethoxy, or optionally joined with R 9a  to form a phenyl ring; R 11a  is not halogen or optionally joined with R 10a  to form a phenyl ring; and R 12a  is not halogen; 
 with the further proviso that when M1 is oxygen, W1 is a member selected from (CR 3a R 4a ) n1 , wherein n1 is 0, J1 is a member selected from (CR 6a R 7a ) m1 , wherein m1 is 1, A1 is CR 9a , D1 is CR 10a , E1 is CR 11a , G1 is CR 12a , then neither R 6a  nor R 7a  are halophenyl; 
 with the further proviso that when M1 is oxygen, W1 is a member selected from (CR 3a R 4a ) n1 , wherein n1 is 0, J1 is a member selected from (CR 6a R 7a ) m1 , wherein m1 is 1, A1 is CR 9a , D1 is CR 10a , E1 is CR 11a , G1 is CR 12a , and R 9a , R 10a  and R 11a  are H, then R 6a , R 7a  and R 12a  are not H; 
 with the further proviso that when M1 is oxygen n1 is 1, J1 is a member selected from (CR 6a R 7a ) m1 , wherein m1 is 0, A1 is CR 9a , D1 is CR 10a , E1 is CR 11a , G1 is CR 12a , R 9a  is H, R 11a  is H, R 6a  is H, R 6a  is H, R 7a  is H, R 12a  is H, then W1 is not C═O (carbonyl); 
 with the further proviso that when M1 is oxygen, W1 is CR 5a , n1 is 1, J1 is CR 8a , m1 is 1, A1 is CR 9a , D1 is CR 10a , E1 is CR 11a , G1 is CR 12a , R 6a , R 7a , R 9a , R 10a , R 11a  and R 12a  are H, then R 5a  and R 8a , together with the atoms to which they are attached, do not form a phenyl ring. 
 
       
     
     
         2 . The compound of  claim 1 , having a structure according to Formula (Ia): 
       
         
           
           
               
               
           
         
         wherein
 R 9a , R 10a , R 11a  and R 12a  are members independently 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; and 
 wherein
 R 9a  and R 10a , together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring; 
 R 10a  and R 11a , together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring; and 
 R 11a  and R 12a , together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring 
 
 with the proviso that R 9a  is not halogen, methyl, ethyl, or optionally joined with R 10a  to form a 4 to 7 membered ring; 
 with the proviso that R 10a  is not unsubstituted phenoxy, C(CH 3 ) 3 , halogen, CF 3 , methoxy, ethoxy, optionally joined with R 9  to form a 4 to 7 membered ring, or optionally joined with R 11  to form a 4 to 7 membered ring; 
 with the proviso that R 11a  is not halogen or optionally joined with R 10  to form a 4 to 7 membered ring; 
 with the proviso that R 12a  is not halogen. 
 
       
     
     
         3 . The compound of  claim 2 , having a structure according to Formula (Ib): 
       
         
           
           
               
               
           
         
         wherein
 B is boron; 
 R x1  is a member selected from substituted or unsubstituted C 1 -C 5  alkyl, substituted or unsubstituted C 1 -C 5  heteroalkyl; 
 R y1  and R z1  are members independently 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; 
 R 6a  are members independently 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; and 
 R 9a , R 10a , R 11a  and R 12a  are members independently 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; and
 wherein
 R 11a  and R 12a , together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring 
 
 with the proviso that when R 9a , R 11a  and R 12a  are H, R 10a  is not H, halogen, unsubstituted phenoxy or t-butyl 
 with the further proviso that when R 9a  is H, R 10a  and R 11a  together with the atoms to which they are attached, are not joined to form a phenyl ring; 
 with the further proviso that when R 11a  is H, R 9a  and R 10a  together with the atoms to which they are attached, are not joined to form a phenyl ring. 
 
       
     
     
         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 3b R 4b ) n2  and CR 5b    
 wherein
 R 3b , R 4b , and R 5b  are members independently selected from H, OH, NH 2 , 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 6b R 7b ) m2  and CR 8b    
 wherein
 R 6b , R 7b , and R 8b  are members independently selected from H, OH, NH 2 , 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, NH 2 , 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): 
       
         
           
           
               
               
           
         
         wherein
 R 7b  is a member selected from H, methyl, ethyl and phenyl; 
 R 10b  is a member selected from H, halogen, substituted or unsubstituted phenoxy, substituted or unsubstituted phenylalkyloxy, substituted or unsubstituted phenylthio and substituted or unsubstituted phenylalkylthio; and 
 R 11b  is a member selected from H, OH, methyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenylalkyloxy, substituted or unsubstituted phenylthio and substituted or unsubstituted phenylalkylthio. 
 
       
     
     
         7 . The pharmaceutical formulation of  claim 4 , wherein said compound has a structure according to Formula (IIc): 
       
         
           
           
               
               
           
         
         wherein
 R 10b  is a member selected from H, halogen, CN and substituted or unsubstituted C 1-4  alkyl. 
 
       
     
     
         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): 
       
         
           
           
               
               
           
         
         wherein
 B is boron; 
 R x2  is a member selected from substituted or unsubstituted C 1 -C 5  alkyl and substituted or unsubstituted 5 heteroalkyl;
 R y2  and R z2  are members independently 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. 
 
 
       
     
     
         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%. 
     
     
         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,  Paracoccidioides  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. 
     
     
         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,  Paracoccidioides  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. 
     
     
         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. 
     
     
         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. 
     
     
         37 . A method for synthesizing the compound of  claim 1 . 
     
     
         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.