MX2007009625A - Boron-containing small molecules - Google Patents
Boron-containing small moleculesInfo
- Publication number
- MX2007009625A MX2007009625A MXMX/A/2007/009625A MX2007009625A MX2007009625A MX 2007009625 A MX2007009625 A MX 2007009625A MX 2007009625 A MX2007009625 A MX 2007009625A MX 2007009625 A MX2007009625 A MX 2007009625A
- Authority
- MX
- Mexico
- Prior art keywords
- substituted
- unsubstituted
- species
- compound
- selected element
- Prior art date
Links
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 title claims 5
- 229910052796 boron Inorganic materials 0.000 title claims 5
- 150000003384 small molecules Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract 23
- 241000233866 Fungi Species 0.000 claims abstract 10
- 210000000282 nail Anatomy 0.000 claims abstract 4
- 208000010195 Onychomycosis Diseases 0.000 claims abstract 3
- 201000005882 tinea unguium Diseases 0.000 claims abstract 3
- 230000000699 topical effect Effects 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims 21
- 241000894007 species Species 0.000 claims 21
- 125000004429 atom Chemical group 0.000 claims 20
- 239000008194 pharmaceutical composition Substances 0.000 claims 19
- 125000000217 alkyl group Chemical group 0.000 claims 16
- 125000004404 heteroalkyl group Chemical group 0.000 claims 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims 15
- 125000001072 heteroaryl group Chemical group 0.000 claims 15
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 15
- 125000003118 aryl group Chemical group 0.000 claims 14
- 208000015181 infectious disease Diseases 0.000 claims 13
- 229910052736 halogen Inorganic materials 0.000 claims 11
- 150000002367 halogens Chemical class 0.000 claims 11
- -1 methoxy, ethoxy Chemical group 0.000 claims 8
- 244000005700 microbiome Species 0.000 claims 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 7
- 229910052760 oxygen Inorganic materials 0.000 claims 7
- 239000001301 oxygen Substances 0.000 claims 7
- 241001465754 Metazoa Species 0.000 claims 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 5
- 150000003839 salts Chemical class 0.000 claims 5
- 241000283690 Bos taurus Species 0.000 claims 4
- 241001480035 Epidermophyton Species 0.000 claims 4
- 206010041736 Sporotrichosis Diseases 0.000 claims 4
- 230000001684 chronic effect Effects 0.000 claims 4
- 201000004624 Dermatitis Diseases 0.000 claims 3
- 208000002584 Fungal Eye Infections Diseases 0.000 claims 3
- 206010034016 Paronychia Diseases 0.000 claims 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 3
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 claims 2
- 206010063409 Acarodermatitis Diseases 0.000 claims 2
- 201000004384 Alopecia Diseases 0.000 claims 2
- 241000223600 Alternaria Species 0.000 claims 2
- 241001480043 Arthrodermataceae Species 0.000 claims 2
- 241000228212 Aspergillus Species 0.000 claims 2
- 241000335423 Blastomyces Species 0.000 claims 2
- 206010005098 Blastomycosis Diseases 0.000 claims 2
- 206010005913 Body tinea Diseases 0.000 claims 2
- 241000222120 Candida <Saccharomycetales> Species 0.000 claims 2
- 241000282472 Canis lupus familiaris Species 0.000 claims 2
- 241000283707 Capra Species 0.000 claims 2
- 241000700198 Cavia Species 0.000 claims 2
- 241001337994 Cryptococcus <scale insect> Species 0.000 claims 2
- 208000002506 Darier Disease Diseases 0.000 claims 2
- 206010048768 Dermatosis Diseases 0.000 claims 2
- 208000032541 Epidermal naevus Diseases 0.000 claims 2
- 206010053177 Epidermolysis Diseases 0.000 claims 2
- 241000283086 Equidae Species 0.000 claims 2
- 206010015146 Erysipeloid Diseases 0.000 claims 2
- 206010015150 Erythema Diseases 0.000 claims 2
- 241000282326 Felis catus Species 0.000 claims 2
- 208000014260 Fungal keratitis Diseases 0.000 claims 2
- 241000223218 Fusarium Species 0.000 claims 2
- 241000287828 Gallus gallus Species 0.000 claims 2
- 241000699694 Gerbillinae Species 0.000 claims 2
- 206010018612 Gonorrhoea Diseases 0.000 claims 2
- 206010018691 Granuloma Diseases 0.000 claims 2
- 208000007514 Herpes zoster Diseases 0.000 claims 2
- 241000228402 Histoplasma Species 0.000 claims 2
- 208000030148 Inflammatory linear verrucous epidermal nevus Diseases 0.000 claims 2
- 206010023369 Keratosis follicular Diseases 0.000 claims 2
- 208000004204 Larva Migrans Diseases 0.000 claims 2
- 206010024229 Leprosy Diseases 0.000 claims 2
- 241000555676 Malassezia Species 0.000 claims 2
- 241001480037 Microsporum Species 0.000 claims 2
- 241000041810 Mycetoma Species 0.000 claims 2
- 206010068058 Nail atrophy Diseases 0.000 claims 2
- 206010028698 Nail dystrophy Diseases 0.000 claims 2
- 241000283973 Oryctolagus cuniculus Species 0.000 claims 2
- 206010033554 Palmoplantar keratoderma Diseases 0.000 claims 2
- 208000005775 Parakeratosis Diseases 0.000 claims 2
- 241000029132 Paronychia Species 0.000 claims 2
- 241001494479 Pecora Species 0.000 claims 2
- 206010034277 Pemphigoid Diseases 0.000 claims 2
- 241000721454 Pemphigus Species 0.000 claims 2
- 241000228143 Penicillium Species 0.000 claims 2
- 241000286209 Phasianidae Species 0.000 claims 2
- 241000222831 Phialophora <Chaetothyriales> Species 0.000 claims 2
- 241000101040 Pityriasis Species 0.000 claims 2
- 201000004681 Psoriasis Diseases 0.000 claims 2
- 206010037575 Pustular psoriasis Diseases 0.000 claims 2
- 208000033464 Reiter syndrome Diseases 0.000 claims 2
- 241000235527 Rhizopus Species 0.000 claims 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims 2
- 241000447727 Scabies Species 0.000 claims 2
- 241000132889 Scedosporium Species 0.000 claims 2
- 241000223255 Scytalidium Species 0.000 claims 2
- 241000282887 Suidae Species 0.000 claims 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 2
- 201000009594 Systemic Scleroderma Diseases 0.000 claims 2
- 206010042953 Systemic sclerosis Diseases 0.000 claims 2
- 208000002474 Tinea Diseases 0.000 claims 2
- 208000007712 Tinea Versicolor Diseases 0.000 claims 2
- 206010043866 Tinea capitis Diseases 0.000 claims 2
- 201000010618 Tinea cruris Diseases 0.000 claims 2
- 206010049591 Tinea imbricata Diseases 0.000 claims 2
- 206010043871 Tinea nigra Diseases 0.000 claims 2
- 206010056131 Tinea versicolour Diseases 0.000 claims 2
- 241000223238 Trichophyton Species 0.000 claims 2
- 208000034784 Tularaemia Diseases 0.000 claims 2
- 208000001924 Tungiasis Diseases 0.000 claims 2
- 230000001154 acute effect Effects 0.000 claims 2
- 231100000360 alopecia Toxicity 0.000 claims 2
- 208000004631 alopecia areata Diseases 0.000 claims 2
- 230000001580 bacterial effect Effects 0.000 claims 2
- 230000015572 biosynthetic process Effects 0.000 claims 2
- 244000309464 bull Species 0.000 claims 2
- 208000000594 bullous pemphigoid Diseases 0.000 claims 2
- 235000013330 chicken meat Nutrition 0.000 claims 2
- 201000001981 dermatomyositis Diseases 0.000 claims 2
- 230000037304 dermatophytes Effects 0.000 claims 2
- 201000010099 disease Diseases 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 2
- 231100000321 erythema Toxicity 0.000 claims 2
- 208000001786 gonorrhea Diseases 0.000 claims 2
- 230000002757 inflammatory effect Effects 0.000 claims 2
- 230000002401 inhibitory effect Effects 0.000 claims 2
- 201000004607 keratosis follicularis Diseases 0.000 claims 2
- 201000011486 lichen planus Diseases 0.000 claims 2
- 201000006506 lobomycosis Diseases 0.000 claims 2
- 206010025135 lupus erythematosus Diseases 0.000 claims 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 2
- 201000008743 palmoplantar keratosis Diseases 0.000 claims 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 2
- 125000004660 phenylalkylthio group Chemical group 0.000 claims 2
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 2
- 201000000508 pityriasis versicolor Diseases 0.000 claims 2
- 208000002574 reactive arthritis Diseases 0.000 claims 2
- 208000005687 scabies Diseases 0.000 claims 2
- 208000017520 skin disease Diseases 0.000 claims 2
- 239000004575 stone Substances 0.000 claims 2
- 229910052717 sulfur Inorganic materials 0.000 claims 2
- 239000011593 sulfur Substances 0.000 claims 2
- 238000003786 synthesis reaction Methods 0.000 claims 2
- 208000006379 syphilis Diseases 0.000 claims 2
- 230000009885 systemic effect Effects 0.000 claims 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims 2
- 201000009642 tinea barbae Diseases 0.000 claims 2
- 201000003875 tinea corporis Diseases 0.000 claims 2
- 208000009189 tinea favosa Diseases 0.000 claims 2
- 201000004647 tinea pedis Diseases 0.000 claims 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 2
- 201000008827 tuberculosis Diseases 0.000 claims 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 1
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 claims 1
- 208000011068 Bazex syndrome Diseases 0.000 claims 1
- 208000034068 Bazex-Dupré-Christol syndrome Diseases 0.000 claims 1
- 206010008803 Chromoblastomycosis Diseases 0.000 claims 1
- 208000015116 Chromomycosis Diseases 0.000 claims 1
- 206010012442 Dermatitis contact Diseases 0.000 claims 1
- 208000009889 Herpes Simplex Diseases 0.000 claims 1
- 241000122799 Scopulariopsis Species 0.000 claims 1
- 208000010668 atopic eczema Diseases 0.000 claims 1
- 208000010247 contact dermatitis Diseases 0.000 claims 1
- 210000004904 fingernail bed Anatomy 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000005059 halophenyl group Chemical group 0.000 claims 1
- 201000005473 herpetic whitlow Diseases 0.000 claims 1
- 208000020298 milker nodule Diseases 0.000 claims 1
- 230000000149 penetrating effect Effects 0.000 claims 1
- 229920006395 saturated elastomer Polymers 0.000 claims 1
- 125000003107 substituted aryl group Chemical group 0.000 claims 1
- 208000011580 syndromic disease Diseases 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 206010017533 Fungal infection Diseases 0.000 abstract 2
- 208000031888 Mycoses Diseases 0.000 abstract 2
- 210000000078 claw Anatomy 0.000 abstract 1
- 210000004209 hair Anatomy 0.000 abstract 1
- 210000000003 hoof Anatomy 0.000 abstract 1
- 230000035515 penetration Effects 0.000 abstract 1
- 210000003491 skin Anatomy 0.000 abstract 1
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.
Description
SMALL MOLECULES CONTAINING BORO Field of the Invention The present invention relates to compounds useful for the treatment of fungal infections, more specifically to the topical treatment of onychomycosis and / or cutaneous fungal infections. BACKGROUND OF THE INVENTION Infections of the nails and hooves, known as ungular and / or periungular infections, pose serious problems in dermatology. These ungular or periungular infections can be caused by sources such as fungi, viruses, yeasts, bacteria and parasites. Onychomycosis is an example of these serious ungular and / or periungular infections and is caused by at least one fungus. The common treatment for ungular and / or periungular infections is generally considered in three categories: the systemic administration of medicine; the surgical removal of all or part of the nail or hoof followed by the topical treatment of the exposed tissue; or the topical application of conventional creams, lotions, gels or solutions, often including the use of bandages to keep these dosage forms in place over the nail or hoof. All of these methods have major disadvantages. The following description is particularly directed to the disadvantages associated with Ref. 185089 common treatment of ungulate and / or periungular antifungal infections. Long-term systemic (oral) administration of an antifungal agent for the treatment of onychomycosis is often required to produce a therapeutic effect on the nail bed. For example, oral treatment with the antifungal compound ketoconazole typically requires administration of 200 to 400 mg / day for 6 months before any significant therapeutic benefit is obtained. Such systemic therapy of: high dose, in the long term, can have significant adverse effects. For example, ketoconazole has been reported to have toxic effects on the liver and reduce testosterone levels in the blood due to adverse effects on the testes. Patient comfort is a problem with long-term therapies, especially those that involve serious adverse effects. In addition, this type of long-term therapy is inconvenient in the treatment of horses or other ruminants afflicted with fungal infections of the hooves. Consequently, the risks associated with parenteral treatments generate significant dissuasive elements against their use and considerable elements that are not comfortable for the patient. The surgical removal of all or part of the nail followed by the topical treatment also has several disadvantages. The pain and discomfort associated with surgery and the undesirable cosmetic appearance of the nail or the nail bed represent significant problems, particularly for female patients or those who are more sensitive to physical appearance. In general, this type of treatment is not realistic for ruminants such as horses. Topical therapy also has significant problems. Topical dosage forms such as creams, lotions, gels, etc., can not keep the drug in intimate contact with the infected area for therapeutically effective periods of time. The bandages have been used to keep the drug deposits in place in an attempt to improve the absorption of the pharmaceutical agent. However, bandages are thick, cumbersome, problematic and generally lead to poor comfort for the patient. Topical antifungal solutions have also been developed that form a hydrophilic and hydrophobic film. These dosage forms provide improved contact between the drug and the nail, but the films are not occlusive. Typical formulations for the treatment of fungal infection have broadly attempted to deliver the drug to the target site (a bed of the uninfected nail) by diffusion through or along the nail.
The nail is more hair-like than the stratum corneum with respect to chemical composition and permeability. Nitrogen is the main component of the nail that testifies to the proteinaceous nature of the nail. The total lipid content of the mature nail is 0.1-1.0%, while the lipids of the corneal dandruff are approximately 10% w / w. The nail is 100-200 times thicker than the stratum corneum and has a very high capacity and affinity for the agglutination and retention of antifungal drugs. Consequently, little, in the best case, of the drug, penetrates through the nail to reach the target site. Because of these reasons, topical therapy for fungal infections has generally been ineffective. Compounds known as penetration or permeation enhancers are well known in the art to produce an increase in the permeability of the skin or other membranes of the body to a pharmacologically active agent. The increased permeability allows an increase in the rate at which the drug permeates through the skin and enters the bloodstream. Penetration enhancers have been useful in overcoming the impermeability of pharmaceutical agents through the skin. However, the thin stratum corneum of the skin, which is approximately 10 to 15 cells thick and is formed naturally by cells migrating to the surface of the skin from the basal surface, has been easier to penetrate. that nails. In addition, known enhancers of penetration have not proven that they will be useful in facilitating the migration of the drug through the nail tissue. Antimicrobial compositions for controlling fungal and bacterial infections, comprising a metal chelate of 8-hydroxyquinoline and an alkylbenzene sulfonic acid, have been shown to be effective due to the increased ability of the hydrophilic group to penetrate the lipoid layers of the microcells. . However, the compounds do not effectively increase the ability to transport the pharmaceutically active antifungal via the cornified layer or stratum corneum of the skin. The U.S. patent No. 4,602,011, West et al, July 22, 1996; U.S. Patent No. 4,766,113, West et al., August 23, 1988. Therefore, there is a need in the art for compounds that can effectively penetrate the nail. There is also a need in the art for compounds that can effectively treat ungular or periungular infections. This and other needs are solved by the present invention. Brief Description of the Invention In a first aspect, the invention provides a compound having a structure according to formula I:
where B is boron. Rla is a selected element of a negative charge, a counterion of a salt, H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and heteroaryl replaced or not replaced. My is a selected element of oxygen, sulfur and NR2a. R2a is a selected element of 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. Jl is an element selected from (CR3aR4a) ni and CR5a. R3a, R4a, and R5a are elements 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 heteroaryl replaced or not replaced. The index ni is an integer selected from 0 to 2. Wl is a selected element of C = 0 (carbpnil), (CR6aR7a) mi and CR8a. R6a, R7a, and R8a are elements 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 index mi is an integer selected from 0 and 1. Al is a selected element of CR9a and N. DI is a selected element of CR10a and N. It is a selected element of CRlla and N. Gl is a selected element of CR12a and N. R9a, R10a, Rlla and R12a are elements 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 1 nitrogens (Al + DI + El + Gl) is an integer selected from 0 to 3. A selected element of R3a, R4a, and R5a and a. The selected element of R6a, R7a and R8a, together with the atoms to which they are attached, are optionally bonded to form a ring of 4 to 7 elements. R3a and R4a, together with the atoms to which they are attached, are optionally attached to form a ring of 4 to 7 elements. R6a and R7a, together with the atoms to which they are attached, are optionally linked to form a ring of 4 to 7 elements. R9a and R10a, together with the atoms to which they are attached, are optionally bonded to form a ring of 4 to 7 elements. R10a and Rlla, together with the atoms to which they are attached, are optionally bonded to form a ring of 4 to 7 elements .. Rlla and R12a, together with the atoms to which they are attached, are optionally attached to form a ring of 4 to 7 elements. The aspect has the condition that when MI is oxygen, Wl is a selected element of (CR3aR4a) ni, where neither is 0, Jl is a selected element of (CR6aR7a) mi, where mi is 1, Al is CR9a, DI is CR10a, El is Rlla, Gl is CR12a, then R9a is not halogen, methyl, ethyl, or optionally linked with R10a to form a phenyl ring; R10a is not unsubstituted phenoxy, C (CH3) 3, halogen, CF3, methoxy, ethoxy, or optionally linked with R9a to form a phenyl ring; Rlla is not halogen or is optionally linked with R10a to form a phenyl ring, and R12a is not halogen. The ajspect has the additional condition that when MI is oxygen, Wl is a selected element of (CR3aR4a) ni, where neither is 0, Jl is a selected element of (CR6aR7a) mi, where mi is 1, Al is CR9a , DI is CR10a, He is CRll, Gl is CR12a, then neither R6a nor R7a are halophenyl. The aspect has the additional condition that when MI is oxygen, Wl is a selected element of (CR3aRa) ni, where neither is 0, Jl is a selected element of (CR6 R7a) mi, where mi is 1, Al is CR9a, DI is CR10a, El is CRlla, Gl is CR12a, and R9a, R10a and Rlla are H, so R6a, R7a and R12a are not H. The aspect has the additional condition that when MI is oxygen where neither is 1 , Jl is an element selected from (CR6aRa) mi, where mi is 0, Al is CR9a, DI is CR10a, He is CRlla, Gl is CR12a, R9a is H, R10a is H, Rlla is H, R6a is H, R7a is H, R12a is H, then W1 is not C = 0 (carbonyl). The aspect has the additional condition that when Mi is oxygen, Wl is CR5a, Jl is CR8a, Al is CR9a, DI is CR10a, El is CRlla, Gl is CR12a, R6a, R7a, R9a, R10a, Rlla and R12a are H , then R5a and R8a, together with the atoms to which they are attached, do not form a phenyl ring. In a second aspect, the invention provides a pharmaceutical formulation comprising: (a) a pharmaceutically acceptable excipient; and (b) a compound having a structure according to formula II:
where B is boron. Rlb is a selected element of a negative charge, a counterion of a salt, H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and heteroaryl replaced or not replaced. M2 is a selected element of oxygen, sulfur and NR2b. R2b is a selected element of 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 an element selected from (CR3bR b) n2 and CR5b. R3b, R4b, and R5b are elements 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 Index n2 is an integer selected from 0 to 2. W2 is a selected element of C = 0 (carbonyl), (CR6bR7b) m2 and CR8b. R6b, R7b, and R8b are elements 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 m2 index is an integer selected from 0 and 1. A2 is a selected element of CR9b and N. D2 is a selected element of CR10b and N. E2 is a selected element of CRllb and N. G2 is a selected element of CR12b and N. R9b, R10b, Rllb and R12b are elements independently selected from H, OH, NH2, SH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted aryl or unsubstituted, and substituted or unsubstituted heteroaryl. The combination of nitrogens (A2 + D2 + E2 + G2) is an integer selected from 0 to 3. A selected element of R3b, Rb, and R5b and a; The selected element of R6b, R7 and R8b, together with the atoms to which they are attached, are optionally bonded to form a ring of 4 to 7 elements. R3b and R4b, together with the atoms to which they are attached, are optionally attached to form a ring of 4 to 7 elements. R6b and R7b, together with the atoms to which they are attached, are optionally linked to form a ring of 4 to 7 elements. R9b and R10b together with the atoms to which they are attached are optionally bonded to form a ring of 4 to 7 elements. R10b and Rllb together with the atoms to which they are attached are optionally bonded to form a ring of 4 to 7 elements. Rllb and R12b, together with the atoms to which they are attached, are optionally linked to form a ring of 4 to 7 elements. In another aspect, the invention provides a method of killing a microorganism, comprising contacting the microorganism with a therapeutically effective amount of a compound of the invention. In another aspect, the invention provides a method of inhibiting the growth of a microorganism, comprising contacting the microorganism with a therapeutically effective amount of a compound of the invention. In another aspect, the invention provides a method of treating an infection in an animal, comprising administering to the animal a therapeutically effective amount of a compound of the invention. In another aspect, the invention provides a method of preventing an infection in an animal, comprising administering to the animal a therapeutically effective amount of a compound of the invention. In another aspect, the invention provides a method of treating a systemic infection or an ungular or periungular infection in a human being, comprising administering to the animal a therapeutically effective amount of a compound of the invention. In another aspect, the invention provides a method of treating onychomycosis in a human being, comprising administering to the animal a therapeutically effective amount of a compound of the invention. In another aspect, the invention provides a method of synthesizing a compound of the invention. In another aspect, the invention provides a method of delivering a compound from the dorsal layer of the nail plate to the nail bed. The method comprises contacting the cell with a compound capable of penetrating the nail plate, under conditions sufficient to penetrate the nail plate, and thereby supply the compound. The compound has a molecular weight of between about 100 and about 200 Da. The compound also has a P log value between about 1.0 and about 2.6. The compound has a solubility in water between about 0.1 mg / ml and 1.0 g / ml octanol / saturated water. BRIEF DESCRIPTION OF THE DRAWINGS Figures 1A-1C are tables of CBO (MIC) inhibitory concentration (MIC) data against various fungi. Figure 2A shows the minimum inhibitory concentration (MIC) for its CIO, cyclopirox, terbinafine, fluconazole and itraconazole (comparative drugs) against 19 fungal test strains. Figure 2B shows the minimum fungicidal concentration (MFC) for its CIO, cyclopirox, terbinafine and itraconazole (comparative drugs) against 2 test strains of fungi). Figure 3 shows a comparison of normalized CIO and cyclopirox equivalent in each part of the nail plate samples after 14 days of treatment. Figure 4 shows a comparison of CIO and the equivalent of ciclopirox in bed samples that support a cotton ball after a 14-day treatment. Figure 5 shows the results of a placebo for CIO (50:50 of propylene glycol and ethyl acetate) applied per day for five days. The growth of a complete carpet of the organism T. rubrum was observed. Figure 6 shows the results of an aliquot of 40 μ? / Cm2 of CIO from a 10% w / v solution applied per day for five days. The zones of inhibition (in the order of the cells shown in the figure) of 100%, 67%, 46%, 57%, 38% and 71% were observed for the growth of T. rubrum. The green arrow indicates the measurement of the inhibition zone. Figure 7 shows the results of an aliquot of 40 μ? / Cm2 of CIO from a 10% w / v solution applied per day for five days. The zones of inhibition (in the order of the cells shown in the figure) of 74%, 86%, 100%, 82%, 100% and 84% were observed for the growth of T. rubrum. Figure 8 shows the results of an aliquot of 40 μ? / Cm2 of 8% ciclopirox in a commercial lacquer w / w applied per day for five days. No zone of inhibition was observed; there was a growth of full carpet of T. rubrum. Figure 9 shows the results of an aliquot of 40 μ? / Cm 2 of 5% amorolfine w / v in a commercial lacquer applied per day for five days. No zone of inhibition was observed; Total carpet growth of T. rubrum was observed. Detailed Description of the Invention Definitions and abbreviations The abbreviations used herein generally have their conventional meaning within the chemical and biological arts. "Compound of the invention", as used herein, refers to the compounds described herein, pharmaceutically acceptable salts and prodrugs of these compounds. MIC, or minimum inhibitory concentration, is the point where the compound stops more than 90% its cell growth in relation to an untreated control. Where the substituent groups are specified by their conventional chemical formulas, written from left to right, they also encompass the chemically identical substituents, which could result from the writing of the structure from the right to the left, for example, -CH20 - is proposed to also define -OCH2-. The term "poly" as used herein means at least 2. For example, a polyvalent metal ion is a metal ion having a valence of at least 2. "Portion" refers to the radical of one molecule that is attached to another portion. The symbol, whether used as a link or displayed perpendicular to a link, indicates the point at which the portion displayed is attached to the rest of the molecule. The term "alkyl", by itself, or as part of another substituent, means, unless stated otherwise, a straight or branched chain, or a cyclic hydrocarbon radical, or a combination thereof, which may be fully saturated, mono- or poly-unsaturated and may include radicals, multivalenites, having the designated carbon atom number (ie, Ci-Cio means 1 to 10 carbons). Examples of the saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,
(cyclohexyl) methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of the unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl), ethynyl , 1- and 3-propynyl, 3-butynyl, and the higher homologues and isomers. The term "alkyl", unless otherwise indicated, also means that it includes those alkyl derivatives defined in greater detail below, such as "heteroalkyl". Alkyl groups that are limited to hydrocarbon groups are called "homoalkyl". The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified, but not limited, by -CH 2 CH 2 CH 2 CH 2 -, and further includes those groups further described as "heteroalkylene". Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or a smaller number of carbon atoms that are preferred in the present invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, which generally has eight or a smaller number of carbon atoms. The terms "alkoxy", "alkylamino" and "alkylthio"
(or thioalkoxy) are used in this conventional sense, and refer to those alkyl groups attached to the rest of the molecule by means of an oxygen atom, an amino group, or a sulfur atom, respectively. The term "heteroalkyl" by itself or in combination with another term means, unless otherwise stated, a straight or branched, stable chain, a cyclic hydrocarbon radical, or a combination thereof, consisting of the established number of carbon atoms and at least one heteroatom. In an exemplary embodiment, the heteroatoms may be selected from the group consisting of B, 0, N and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom (s) of B, 0, N and S can be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the rest of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N (CH3) -CH3, -CH2-S-CH2-CH3, - CH2-CH2-S (O) -CH3, -CH2-CH2-S (O) 2-CH3, -CH = CH-0-CH3, -CH = M-OCH3, and -CH = CH-N (CH3) -CH3. Up to two heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited to, -CH2-CH2-S-CH2-CH2- and - CH2-S-CH2-CH2-NH-CH2-. For the heteroalkylene groups, the heteroatoms may also occupy either or both of the chain ends (eg, alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for the alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C (0) 2R'- represents both -C (0) 2R'- and -R'C (0) 2-. The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl" respectively. Additionally, for the heterocycloalkyl, a heteroatom may occupy the position in which the heterocycle is attached to the rest of the molecule. Examples of the cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl and the like. Examples of the heterocycloalkyl include, but are not limited to, 1- (1, 2, 5, 5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2- ilo, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. The terms "halo" or "halogen" by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are understood to include monohaloalkyl and polyhaloalkyl. For example, the term "halo (C1-C4) alkyl" is meant to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. The term "aryl" means, unless otherwise stated, an aromatic, polyunsaturated substituent, which may be a single ring or multiple rings (preferably from 1 to 3 rings), which are fused together or bound together covalently The term "heteroaryl" refers to aryl groups (or rings) containing from one to four heteroatoms. In an exemplary embodiment, the heteroatom is selected from B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom (s) are optionally quaternized. A heteroaryl group can be attached to the rest of the molecule by means of a heteroatom. Non-limiting examples of the aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 2-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. The substituents for each of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. For reasons of brevity, the term "aryl" when used in combination with other terms (eg, aryloxy, arylthioxy, arylalkyl) includes the both aryl and heteroaryl rings as defined above. Accordingly, the term "arylalkyl" is understood to include those radicals in which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom ( for example, a methylene group) has been replaced by, for example, an oxygen atom (eg, phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy) propyl, and the like.) Each of the foregoing terms (e.g. "alkyl", "heteroalkyl", "aryl", and "heteroaryl") are understood to include both substituted and unsubstituted forms of the indicated radical.The preferred substituents for each type of radical are provided below. alkyl and heteroalkyl (including those groups frequently referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocyclic oalkenyl) are generically referred to as "alkyl group substituents" and may be one or more of a variety of groups selected from, but not limited to: -OR ', = 0, = NR', = N-0R ' , -NR'R ", -SR", -halogen, -0C (0) R ', -C (0) R', -C02R ', -CONR'R ", -0C (0) NR'R", -NR "C (0) R ', -NR' -C (0) NR" R "', -NR" C (0) 2R', -NR-C (NR 'R "R"') = NR " ", -NR-C (NR 'R' ') = NR' '', -S (0) R ', -S (0) 2R', -S (0) 2NR'R ", -NRS02R ', -CN and -N02 in a number ranging from 0 to (2m '+ l), where m' is the total number of carbon atoms in such a radical R ', R' ', R' '' and R '' ' 'each independently preferably refers to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, for example, aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl When a compound of the present invention includes more than one group R, for example, each of the groups R is independently selected such that each is the groups R ', R ", R' '' and R ' When more than one of these groups is present, when R 'and R "are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a ring of 5, 6 or 7 elements. For example, -NR 'R' 'is understood which includes, but will not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the foregoing description of substituents, a person skilled in the art will understand that the term "alkyl" is understood to include groups that include carbon atoms attached to different groups of hydrogen groups, such as haloalkyl (e.g. -CF3 and -CH2CF3) and acyl (for example, -C (0) CH3, -C (0) CF3, -C (O) CH2OCH3, and the like). Similar to the substituents described for the alkyl radical, the substituents for the aryl and heteroaryl groups are generically retained as "aryl group substituents". The substituents are selected, for example, from: halogen, -0R ', = 0, = NR', = N-OR ', -NR'R ", -SR', -halogen, -OC (0) R ', -C (0) R ', -C02R', -CON 'R', -0C (0) NR'R ", -NR" C (0) R ', -NR' -C (0) NR "R" ', -NR "C (0) 2R', -NR-C (NR '" R "') = NR" ", -NR-C (NR 'R") = NR' '', -S (0 ) R ', -S (0) 2R', -S (0) 2NR'R ", -NRS02R ', -CN and -N02, -R', -N3, -CH (Ph) 2, fluoro- (Ci) -C4) alkoxy, and fluoro (C1-C4) alkyl, in a number ranging from 0 to the total number of open valencies on the aromatic ring system; and wherein R ', R' ', R' '' and R "'' 'are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, and substituted heteroaryl or not replaced. When a compound of the invention includes more than one group R, for example, each of the groups R is independently selected so that they are each the groups R ', R ", R' '' and R" "when More than one of these groups is present. Two of the substituents on the adjacent atoms of the aryl or heteroaryl ring can be optionally replaced with a substituent of the formula -TC (O) - (CRR ') qU-, where T and U are independently -NR, -O- , -CRR'- or a single bond and q is an integer from 0 to 3. Alternatively, two of the substituents on the adjacent atoms of the aryl or heteroaryl ring can be optionally replaced with a substituent of the formula -A- (CH2 ) rB-, where B and A are independently -CRR'-, -O-, -NR-, -S-, -S (O) -, -S (0) 2-, -S (0) 2NR ' -, or a single bond, and R is an integer from 1 to 4. One of the single atoms of the new ring thus formed can be optionally replaced with a double bond. Alternatively, two of the substituents on the adjacent atoms of the aryl o-heteroaryl ring can optionally be replaced with a substituent of the formula - (CRR ') SX- (CR' 'R' '') d-, where syd they are independently integers from 0 to 3, and X is -0-, -NR'-, -S-, S (0) 2-, or -S (0) 2NR'-. The substituents R, R ', R "and R"' are preferably selected independently from hydrogen or from alkyl. { i- e) substituted or unsubstituted. "Ring" as used herein, means a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. A ring includes portions of merged canilló. The number of atoms in a ring is typically defined by a number of elements in the ring. For example, a "ring of 5 to 7 elements" means that there are 5 'to 7 atoms in the surrounding array. The ring optionally included a heteroatom. Accordingly, the term "ring of 5 to 7 elements" includes, for example, pyridinyl and piperidinyl. The term "ring" also includes a system. of rings comprising one or more of a "ring" wherein each "ring" is independently defined as above.
When used herein, the term "heteroatom" includes atoms other than carbon (C) and hydrogen (H). Examples include oxygen (0), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al) and boron (B). The symbol "R" is a general abbreviation representing a substituent group which is selected from the groups of: substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl substituted and substituted or unsubstituted heterocycloalkyl. By "effective" amount of a drug, formulation, or permeation agent, is meant a sufficient amount of an active agent to provide the desired local or systemic effect. An "effective topically", "cosmetically effective", "pharmaceutically effective" or "therapeutically effective" amount refers to an amount of a drug necessary to carry out the desired therapeutic result. "Topically effective" refers to a material that, when applied to the skin, nails, hair, claws or hooves produces a desired pharmacological result either locally at the site of application or systemically as a result of the transdermal passage of an active ingredient in the material. "Cosmetically effective" refers to a material, which when applied to the skin, nails, hair, claws or hooves, produces a desired cosmetic result locally at the site of the application of an active ingredient in the material. The term "pharmaceutically acceptable salts" is understood to include the salts of the compounds of the invention which are prepared with relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functionalities, the basic addition salts can be obtained by having the neutral form of such components in contact with a sufficient amount of the desired base, either pure or in a suitable inert solvent. Examples of the pharmaceutically acceptable basic addition salts include the sodium, potassium, calcium, ammonium, organic amino, or magnesium salts or a similar salt. When the compounds of the present invention contain relatively basic functionalities, the basic addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in the form of a suitable inert solvent. . Examples of the addition salts; basic pharmaceutically acceptable include those derived from inorganic acids similar to hydrochloric, hydrobromic, nitric, carbonic, monohydrogen-carbon, phosphoric, mono-hydrogen-phosphoric, dihydrogen-phosphoric, sulfuric, mono-hydrogen sulfuric, hydroiodic, or phosphorous acids and the like, as well as salts derived from relatively non-toxic organic acids similar to acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, italic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and similar. Also included are amino acid salts such as arginate and the like, and salts of organic acids similar to glucuronic or galacturonic acids and the like (see, for example, Berge et al., "Pharmaceuticals Salts" Journal of Pharmaceutical Science 6: 1-19 (1977)). Certain specific compounds of the present invention may contain both acidic and basic functionalities that allow the compounds to be converted into the addition salts, either acidic or basic. The neutral forms of the compounds are preferably generated by contacting the salt with a base or an acid and isolating the original compounds in the conventional manner. The original form of the compound differs from the various forms of the salt in certain physical properties such as solubility in polar solvents. In addition to the forms of salt, the present invention provides compounds that are in a prodrug form. The prodrugs of the compounds or complexes described herein easily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, the prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex-environment. Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention. Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the present invention. The compounds of the present invention may also contain unnatural proportions of the atomic isotopes in one or more of the atoms that make up such compounds. For example, the compounds can be radioactivated with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are proposed to be encompassed within the scope of the present invention. The term "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable carrier" refers to any formulation or medium transported that provides the appropriate supply of an effective amount of an active agent as defined herein, which does not interfere with the effectiveness of the biological activity of the active agent, and which is sufficiently Non-toxic for the host animal or patient. Representative carriers include water, oils, both vegetable and mineral, cream bases, lotion bases, ointment bases and the like. These bases include suspending agents, thickening agents, penetration enhancers, and the like. Its formulation is well known to those skilled in the art of cosmetic and topical pharmaceutical formulations. Additional information regarding carriers can be found at Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott, Williams & Wilkins (2005) which is incorporated here for reference. "Pharmaceutically acceptable topical carrier" and the equivalent terms refer to carriers as described herein above, suitable for topical application. A liquid or cream vehicle, inactive, capable of suspension or dissolution of the active agent (s), which includes and has the properties that it is non-toxic and inflammatory when applied to the skin, nails, hair, claws or hooves, is an example of a pharmaceutically acceptable topical carrier. This term is specifically proposed to encompass the carrier materials approved for use also in topical cosmetic substances. The term "pharmaceutically acceptable additive" refers to preservatives, antioxidants, fragrances, emulsifiers, dyes and excipients known or used in the field of formulation. of drugs and that do not unduly interfere with the efficacy of the biological activity of the active agent, and that is sufficiently non-toxic for the patient or host animal. The additives for the topical formulations are well known in the art, and can be added to the topical composition, provided that they are pharmaceutically acceptable and not deleterious to the epithelial cells or their function. In addition, they should not cause deterioration in the stability of the composition. For example, inert fillers, anti-irritants, tackifying agents, excipients, fragrances, opacifiers, antioxidants, gelling agents, stabilizers, surfactants, emollients, coloring agents, preservatives, buffering agents, other permeation enhancers, and others. Conventional components of topical or transdermal delivery formulations are as known in the art. The terms "improvement", "improvement of penetration" or "improvement of permeation" refer to an increase in the permeability of the skin, nails, hair, claws or hooves for a drug, to increase the speed at which permeates the drug through the skin, nails, hair, claws or hooves. The improved permeation effected through the use of such enhancers can be observed, for example, by measuring the diffusion rate of the drug through the skin, nails, hair, claws or hooves of the human or animal, using an apparatus of broadcast cells. A cell or diffusion cell is described by Merritt et al. Diffusion Apparatus for Skin Penetration, J of Controlled Relay, 1 (1984) pp. 161-162. The term "permeation enhancer" or "penetration enhancer" means an agent or a mixture of agents, which, alone or in combination, act to increase the permeability of the skin, nails, hair or hooves with respect to a drug. The term "excipients" is conventionally known to mean the carriers, diluents and / or vehicles used in the formulation of the formulation drug compositions, effective for the intended use. The term "topical administration" refers to the application of a pharmaceutical agent to the outer surface of the skin, nails, hair, claws or hooves, in such a way that the agent crosses the external surface of the skin, nails, hair, claws or hooves and is introduced to the underlying tissues. Topical administration includes the application of the composition to the skin, nails, hair, claws or hooves intact, or to an open, broken or fragmented wound of the skin, nails, hair, claws or hooves. Topical administration of a pharmaceutical agent can lead to a limited distribution of the agent with respect to the skin and surrounding tissues or, when the agent is removed from the treatment area by the bloodstream, it can lead to the systemic distribution of the agent. The term "transdermal delivery" refers to the diffusion of an agent through the barrier of skin, nails, hair, claws or hooves resulting from topical administration or other application of a composition. The stratum corneum acts as a barrier and few pharmaceutical agents are able to penetrate intact skin. In contrast, the epidermis and dermis are permeable to many solutes and the absorption of drugs occurs more easily through the skin, nails, hair, claws or hooves, which is subjected to abrasion or otherwise detached from the skin. corneal layer to expose the dermis. The transdermal delivery includes injection or other delivery through any portion of the skin, nails, hair, claws or hooves or mucous membrane and absorption or permeation through the remaining portion. Absorption through intact skin, nails, hair, claws or hooves can be improved by placing the active agent in a pharmaceutically acceptable vehicle, appropriate, before application to the skin, nails, hair, claws or hooves. Passive topical administration may consist of applying the active agent directly to the treatment site in combination with emollients or penetration enhancers. When used herein, the transdermal delivery is proposed to include permeation delivery through, or once the integument has passed, ie, skin, nails, hair, claws or hooves. II. Introduction The present invention provides novel boron compounds and methods for the preparation of these molecules. The invention further provides boron compounds as analogs comprising a functional moiety, such as a portion of the drug and methods of use for the analogous substances. III. The Compounds In a first aspect, the invention provides a compound having a structure in accordance with Formula I:
where B is boron. Rla is a selected element of a negative charge, a counterion of a salt, H, substituted or unsubstituted alkyl, substituted or unsubstituted heteropalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and heteroaryl replaced or not replaced. My is a selected element of oxygen, sulfur and NR2a. R2a is a selected element of 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. Jl is an element selected from (CR3aRa) ni and CR5a. R3a, R and R5a are elements 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 heteroaryl replaced or not replaced. The index is not an integer selected from 0 to 2. Wl is a selected element of C = 0 (carbonyl), (CR6aR7a) ml and CR8a. R6a, R7a, and R8a are elements 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 index mi is an integer selected from 0 and 1. Al is a selected element of CR9a and N. DI is a! selected element of CR10a and N. It is a selected element of CRlla and N. Gl is a selected element of CR12a and N. R9a, R10a, Rlla and R12a are elements independently selected from H, OH, NH2, SH, substituted alkyl or unsubstituted, 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 (Al + Di + El + Gl) is an integer selected from 0 to 3. A selected element of R, R, and R and a selected element of R6a, R7a and R8a, together with the atoms at which are fixed, are optionally joined to form a ring of 4 to 7 elements. R3a and R4a, together with the atoms to which they are attached, are optionally attached to form a ring of 4 to 7 elements. R6a and R7a, together with the atoms to which they are attached, are optionally linked to form a ring of 4 to 7 elements. R9a and R10a together with the atoms to which they are attached are optionally bonded to form a ring of 4 to 7 elements. R10a and Rlla, together with the atoms to which they are attached, are optionally bonded to form a ring of 4 to 7 elements. Rlla and R12a, together with the atoms to which they are attached, are optionally linked to form a ring of 4 to 7 elements. The aspect has the condition that when Mi is oxygen, Wl is an element selected from (CR3aR4a) ni, where neither is 0, Jl is an element selected from (CR6aR7a) mi where mi is 1, Al is CR9a, DI is CR10a, He is Rlla, Gl is CR12a, then R9a is not halogen, methyl, ethyl, or optionally linked with R10a to form a phenyl ring; R10a is not unsubstituted phenoxy, C (CH3) 3, halogen, CF3, methoxy, ethoxy, or optionally linked with R9a to form a phenyl ring; Rlla is not halogen, or is optionally linked with R10a to form a phenyl ring, and R12a is not halogen. The aspect has the additional condition that when Mi is oxygen, Wl is a selected element of (CR3aRa) ni, where neither is 0, Jl is a selected element of (CR6aR7a) mi, where mi is 1, Al is CR9 \ Al is CR10a, He is CRlla, Gl is CR12a, so neither R6a nor R7a are halophenyl. The appearance has the additional condition that when MI is oxygen, Wl is an element selected from (CR3aRa) ni / where neither is 0, Jl is a selected element of (CR6aR7a) mi, where mi is 1, Al is CR9a, DI is CR10a, He is CRlla, Gl is CR12a , and R9a, R10a and Rlla are H, then R6a, R7a and R12a are not H. The aspect has the additional condition that when MI is oxygen where neither is 1, J1 is an element selected from (CR6aR7a) mi, in where mi is 0, Al is CR9a, DI is CR10a, El is CRlla, Gl is CR12a, R9a is H, R10a is H, Rlla is H, R6a is H, R7a is H, R12a is H, then W1 is not C = 0 (carbonyl). The aspect has the additional condition that when MI is oxygen, W1 is CR5a, J1 is CR8a, Al is CR9a, DI is CR10a, El is CRlla, Gl is CR12a, R6a, R7a, R9a, R10a, Rlla and R12a are H , then R5a and R8a, together with the atoms to which they are attached, do not form a phenyl ring. In an exemplary embodiment, the compound has the structure in accordance with the formula (the :)
da) wherein B is boron, R a is a selected element of a negative charge, a counterion of a salt, 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. R6a are elements 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 . R9a, R10a, Rlla and R12a are elements 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. R9a and R10 together with the atoms to which they are attached are optionally attached to form a ring of 4 to 7 elements. R10a and Rlla, together with the atoms to which they are attached, are optionally linked to form a ring of 4 to 7 elements. Rlla and R12a, together with the atoms to which they are attached, are optionally linked to form a ring of 4 to 7 elements. This embodiment has the proviso that R9a is not halogen, methyl, ethyl, or is optionally linked with R10a to form a ring of 4 to 7 elements. This embodiment has the proviso that R10a is not unsubstituted phenoxy, C (CH3) 3, halogen, CF3, methoxy, ethoxy, optionally linked with R9a to form a ring of 4 to 7 elements, or optionally linked with Rlla to form a Ring of 4 to 7 elements. This embodiment has the proviso that Rlla is not halogen or is optionally linked with R10a to form a ring of 4 to 7 elements. This embodiment has the condition that R12a is not halogen. In an exemplary embodiment, the compound has the structure according to formula (Ib):
(Ib)
where B is boron. Rxl is a member selected from substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 1 -C 5 heteroalkyl. Ryl and Rzl are selected elements of 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. R6a are elements 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 . R9a, R10a, Rlla, and R12a are elements 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. R10a and Rlla, together with the atoms to which they are attached, are optionally linked to form a ring of 4 to 7 elements. This embodiment has the proviso that when R9, Rlla and R12a are H, R10a is not H, halogen, unsubstituted phenoxy or t-butyl. This embodiment has the additional condition that when R9a is H, R10a and Rlla together with the atoms to which they are fixed, they are not joined to form a phenyl ring. This embodiment has the additional condition that when Rlla is H, R9a and R10, together with the atoms to which they are fixed, they are not joined to form a phenyl ring. In another aspect, the invention provides a compound having the structure according to formula II:
where B is boron. Rlb is a selected element of a negative charge, a counterion of a salt, H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and heteroaryl replaced or not replaced. M2 is a selected element of oxygen, sulfur and NR2b. R2b is a selected element of 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 an element selected from (CR3bR4b) n2 and CR5b. R3b, R4b, and R5b are elements 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 index n2 is an integer selected from 0 to 2. W2 is a selected element of C = 0 (carbonyl), (CR6bR7b) m2 and CR8b. R6b, R7b, and R8b are elements 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 m2 index is an integer selected from 0 and 1. A2 is a selected element of CR9b and N. D2 is a selected element of CR10b and N. E2 is a selected element of CRllb and N. G2 is a selected element of CR12b and N. R9b, R10b, Rllb and R12b are elements independently selected from H, OH, NH2, SH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted aryl or unsubstituted, and substituted or unsubstituted heteroaryl. The combination of nitrogens (A2 + D2 + E2 + G2) is an integer selected from 0 to 3. A selected element of R3b, Rb, and R5b and a selected element of R6b, R7b and R8b, together with the atoms at the which are fixed, are optionally joined to form a ring of 4 to 7 elements. R3b and Rb, together with the atoms to which they are attached, are optionally linked to form a ring of 4 to 7 elements. R6b and R7b, together with the atoms to which they are attached, are optionally linked to form a ring of 4 to 7 elements. Rb and R10b together with the atoms to which they are attached are optionally bonded to form a ring of 4 to 7 elements. R10b and RUb together with the atoms to which they are attached are optionally bonded to form a ring of 4 to 7 elements. Rllb and R12b, together with the atoms to which they are attached are optionally attached to form a ring of 4 to 7 elements. In an exemplary embodiment, the aspect has the condition that when M2 is oxygen, W2 is a selected element of (CR3bRb) n2, where n2 is 0, J2 is a selected element of (CR6bR7b) m2, where m2 is 1 , A2 is CR9b, D2 is CR10b, E is CRllb, G is CR12b, then R9b is not a selected element of halogen, methyl, ethyl, or is optionally linked with R10b to form a phenyl ring. In another exemplary embodiment, the mode has the condition that when M2 is oxygen, 2 is a selected element of (CR3 R4b) nf where n2 is 0, J2 is a selected element of (CR6bR7b) m, where m2 is 1 , A2 is CR9b, E2 is CR10b, E2 is CRllb, G2 is CR12b, then R10 is not a selected element of unsubstituted phenoxy, C (CH3) 3, halogen, CF3, methoxy, ethoxy, or optionally linked with R9b to form a phenyl ring. In another exemplary modality, the aspect has the condition that when M2 is oxygen, W2 is a selected element of (CR3bR4b) n, where n2 is 0, J2 is a selected element of (CR6bR7b) m2, where m2 is 1, A2 is CR9b , D2 is CR10b, E2 is CRllb, G2 is CR12, then Rllb is not a selected element of halogen or optionally linked with R10b to form a phenyl ring. In another exemplary embodiment, the aspect has the proviso that when M2 is oxygen, W2 is an element selected from (CR3bRb) n2, where n2 is 0, J2 is an element selected from (CR6bR7b) m2, where m2 is 1 , A2 is CR9b, D2 is CR10b, E2 is CRllb, G2 is CR12b, then R12b is not halogen. In another exemplary embodiment, the aspect has the proviso that when M2 is oxygen, 2 is an element selected from (CR3bR4b) n2, where n2 is 0, J2 is an element selected from (CR6bR7b) m2, where m2 is 1 , A2 is CR9, D2 is CR10b, E2 is CRllb, G2 is CR12b, then R6b is not halophenyl. In another exemplary embodiment, the aspect has the condition that when M2 is oxygen, W2 is an element selected from (CR3bR4b) n2, where n2 is 0, J2 is an element selected from (CR6bR7b) m2, where m2 is 1 , A2 is CR9b, D2 is CR10b, E2 is CRllb, G2 is CR12b, then R7b is not halophenyl. In another exemplary embodiment, the aspect has the condition that when M2 is oxygen, 2 is an element selected from (CR3bR4b) n2, where n2 is 0, J2 is an element selected from (CR6bR7b) ra2, where m2 is 1 , A2 is CR9b, D2 is CR10b, E2 is CRllb, G2 is CR12, then R6b and R7b are not halophenyl. In another exemplary embodiment, the aspect has the proviso that when M2 is oxygen, W2 is an element selected from (CR3bR4b) n2, where n2 is 0, J2 is an element selected from (CR6bR7b) m2, where m2 is 1 A2 is CR9b, D2 is CR10, E2 is CRllb, G2 is and R9b, R10b and Rllb are H, then R6b, R7b and R12b are not H. In another exemplary embodiment, the aspect has the condition that when M2 is oxygen , where n2 is 1, J2 is an element selected from (CR6bR7b) m2, where m2 is 0, A2 is CR9b, D2 is CR10b, E2 is CRllb, G2 is CR12b, R9b is H, R10b is H, R1b is H, R6b is H, R7b is H, R12b is H, then W2 is not C = 0 (carbonyl). In another exemplary embodiment, the aspect has the proviso that when M2 is oxygen, 2 is CR5b, J2 is CR8b, A2 is CR9b, D2 is CR10b, E2 CRllb, G2 is CR12b, R6b, R7b, R9b, R10b, RUb and R12b are H, then R5b and R8b, together with which they are fixed, do not form a phenyl ring. In an exemplary embodiment, the compound has a structure according to the formula (lia):
In another exemplary embodiment, the compound has the structure according to formula (Ilb):
wherein R is a selected element of H, methyl, ethyl and phenyl. R10b is a selected element of H, OH, NH2, SH, halogen, substituted or unsubstituted phenoxy, substituted or unsubstituted phenylalkyloxy, substituted or unsubstituted phenylthio, and substituted or unsubstituted phenylalkylthio. Rllb is an element selected from: H, OH, NH2, SH, methyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenylalkyloxy, substituted or unsubstituted phenylthio and substituted or unsubstituted phenylalkylthio. In another exemplary embodiment, R Ib is a selected element of a negative charge, H and a counterion of a salt. In another exemplary embodiment, R10b and Rllb are H. In another exemplary embodiment, one element selected from R10b and RUb are H and the other element selected from R10b and Rllb is a member selected from halo, methyl, cyano, methoxy, hydroxyl and p. -cyanophenyloxy. In another exemplary embodiment, R 10 and R 1b are elements independently selected from fluoro, chloro, methyl, cyano, methoxy, hydroxymethyl, and p-cyanophenyl. In another particular embodiment, Rlb is a selected element of a negative charge, H and a counterion of a salt; R7b is H; R10b is F and Rllb is H. In another exemplary embodiment, Rllb and R12b, in the company of the atoms to which they are attached, are attached to a phenyl group. In another exemplary embodiment, Rlb is a selected element of a negative charge, H and a counterion of a salt; R¾ is H; R10b is 4-cyanophenoxy, and Rllb is H. In another exemplary embodiment, the compound has a structure according to the formula (lie):
wherein R is a selected element of H, halogen, CN and substituted or unsubstituted Ci_4 alkyl. In another exemplary embodiment, the compound has a formulation that is an element selected from:
in another exemplary embodiment, the compound has a structure according to the formula (lid):
(lid) where B is boron. R is a member selected from substituted or unsubstituted C 1 -C 5 alkyl and substituted or unsubstituted C 1 -C 5 heteroalkyl. Ry2 and Rz2 are elements 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. The compounds of Formulas (I) or (II) can form a hydrate with water, solvates with alcohols such as ethanol, propanol, and the like; adducts with the amino compounds, such as ammonia, methylamine, ethylamine, and the like; adducts with acids, such as formic acid, acetic acid and the like; complexes with ethanolamine, quinoline, amino acids, and the like. Preparation of Small Molecules Containing Boron The following exemplary reaction schemes illustrate the methods of preparation of the boron-containing molecules of the present invention. These methods are not limited to the production of the compounds shown, but can be used to prepare a variety of molecules such as the compounds and complexes described herein. The compounds of the present invention can also be synthesized by methods not explicitly illustrated in the reaction schemes but which are well within the experience of a person with ordinary experience in the art. The compounds can be prepared using materials readily available from the known intermediate compounds. In the following reaction schemes the symbol X represents bromine or iodine. The symbol Y is selected from H, lower alkyl, and arylalkyl. The symbol Z is selected from H, alkyl and aryl. The PG symbol has a protective group. The symbols A, D, E, G, Rx, Ry, Rz, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 can be used to refer to the corresponding symbols in Formulas (I) or (II). For example, the symbol A may refer to Al of the Formula (I), or A2 of the Formula (II), subject to the conditions of each Formula. Preparation Strategy # 1 In reaction scheme 1, steps 1 and 2, compounds 1 or 2 are converted to alcohol 3. In step 1, compound 1 is treated with a reducing agent with an appropriate solvent. Suitable reducing agents include borane complexes, such as borane-tetrahydrofuran, borane-dimethyl sulfide, combinations thereof and the like. Lithium aluminum hydride, or sodium borohydride can also be used as reducing agents. The reducing agents can be used in amounts ranging from 0.5 to 5 equivalents, relative to compounds 1 or 2. Suitable solvents include diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, combinations of: same and similar. The reaction temperatures vary from 0 ° C to the boiling point of the solvent used; the complement times of the reaction vary from 1 to 24 h. In step 2, the carbonyl group of compound 2 is treated with a reducing agent in an appropriate solvent. Suitable reducing agents include borane complexes, such as borane-tetrahydrofuran, borane-dimethyl sulfide, combinations thereof and the like. Lithium aluminum hydride, or sodium borohydride can also be used as reducing agents. The reducing agents can be used in amounts ranging from 0.5 to 5 equivalents, relative to compound 2. Suitable solvents include lower alcohols, such as methanol, ethanol, and propanol, diethyl ether, tetrahydrofuran, 1,4-dioxane and 1 , 2-dimethoxyethane, combinations thereof and the like. The reaction temperatures vary from 0 ° C to the boiling point of the solvent used; the complement times of the reaction vary from 1 to 24 h. In step 3, the hydroxyl group of compound 3 is protected with a protecting group that is stable under neutral or basic conditions. The protecting group is typically selected from methoxymethyl, ethoxyethyl, tetrahydropyran-2-yl, trimethylsilyl, tert-butyldimethylsilyl, tributylsilyl, combinations thereof and the like. In the case of methoxymethyl, compound 3 is treated with 1 to 3 equivalents of chloromethyl methyl ether in the presence of a base. Suitable bases include sodium hydride, potassium tert-butoxide, tertiary amines, such as diisopropylethylamine, triethylamine, 1,8-diazabicyclo [5, 4, 0] undec-7-ene, and inorganic bases, such as sodium hydroxide. , sodium carbonate, potassium hydroxide, potassium carbonate, combinations thereof and the like. The bases can be used in amounts ranging from 1 to 3 equivalents, in relation to compound 3. The reaction temperatures vary from 0 ° C to the boiling point of the solvent used; preferably between 0 and 40 ° C; the complement times of the reaction vary from 1 to 48 h. In the case of tetrahydropyran-2-yl, compound 3 is treated with 1 to 3 equivalents of 3,4-dihydro-2H-pyran in the presence of 1 to 10 mole% of the acid catalyst. Suitable acidic catalysts include p-toluenesulfonic pyridinium acid, p-toluenesulfonic acid, camphor sulfonic acid, hydrogen chloride, sulfuric acid, combinations thereof and the like. Suitable solvents include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene, benzene, and acetonitrile, combinations thereof and the like. The reaction temperatures vary from 0 ° C to the boiling point of the solvent used; preferably between 0 and 40 ° C, and complemented in 1 to 48 h. In the case of the trialkylsilyl, the compound 3 is treated with 1 to 3 equivalents of chlorotrialkylsilane in the presence of 1 to 3 equivalents of the base. Suitable bases include tertiary amines, such as imidazole, diisopropylethylamine, triethylamine, 1,8-diazabicyclo [5, 4, 0] undec-7-ene, combinations thereof and the like. The reaction temperatures range from 0 ° C to the boiling point of the solvent used, preferably between 0 and 40 ° C; the times of the complement of the reaction vary from 1 to 48 h. In step 4, compound 4 is converted to boronic acid (5) by means of the exchange reaction of a halogenated metal. Compound 4 is treated with 1 to 3 equivalents of the alkyl metal reagent relative to compound 4, such as n-butyl-lithium, sec-butyl-lithium, tert-butyl-lithium, or isopropylmagnesium chloride followed by the addition of 1 to 3 equivalents of trialkyl borate relative to compound 4, such as trimethyl borate, triisopropyl borate, or tributyl borate. Suitable solvents include tetrahydrofuran, ether, 1,4-dioxane, 1,2-dimethoxyethane, toluene, hexanes, combinations thereof and the like. The alkyl metal reagent can also be added in the presence of a trialkyl borate. The addition of the butyllithium is carried out between -100 and 0 ° C, preferably between -80 and -40 ° C. The addition of isopropylmagnesium chloride is carried out between -80 and 40 ° C, preferably between -20 and 30 ° C. After the addition of trialkyl borate, the reaction is allowed to warm to room temperature, which is typically between 15 and 30 ° C. When the alkyl metal reagent is added in the presence of trialkyl borate, the reaction mixture is allowed to warm to room temperature after the addition. The complement times of the reaction vary from 1 to 12 h. The compound 5 may not be isolated and may be used for the next step without purification or in a vessel or vessel. In step 5, the protecting group of compound 5 is removed under acidic conditions to give the compound of Formulas (I) and (II). Suitable acids include acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, p-toluenesulfonic acid and the like. The acids can be used in amounts ranging from 1 to 20 equivalents, relative to compound 5. When the protecting group is trialkylsilyl, basic reagents, such as tetrabutylammonium fluoride, can also be used. Suitable solvents include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methanol, ethanol, propanol, acetonitrile, acetone, a combination thereof and the like. The reaction temperatures vary from 0 ° C to the boiling point of the solvent used, preferably between 10 and 40 ° C; the groups of reaction components vary from 0.5 to 48 h. Reaction scheme 1
Stage 5 tVNrw lo II, R '= H, W = (CR6R7) m, m = 0 Preparation Strategy # 2 In reaction scheme 2, step 6, compound 2 is converted to boronic acid (6) by means of of a cross-coupling reaction, catalysed with a transition metal. Compound 2 is treated with 1 to 3 equivalents of bis (pinacolato) dibor or 4, 4, 5, 5-tetramet-il-1,2,3-dioxaborlane in the presence of a metal or transition catalyst, with the use of an appropriate ligand and a base when necessary. Suitable transition metal catalysts include palladium (II) acetate, palladium (II) acetocetonate / tetrakis (triphenylphosphine) palladium, dichlorobis (diphenylphosphine) -palladium, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium
(II), combinations of the same and similar. The catalyst can be used in amounts ranging from 1 to 5 mol% relative to compound 2. Suitable ligands include triphenylphosphine, tri (o-tolyl) phosphine, tricyclohexylphosphin, combinations thereof and the like. The ligand can be used in amounts ranging from 1 to 5 equivalents relative to compound 2. Suitable bases include sodium carbonate, potassium carbonate, potassium phenoxide, triethylamine, combinations thereof and the like. The base can be used in amounts ranging from 1 to 5 equivalents relative to compound 2. Suitable solvents include N, W-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, toluene, combinations thereof and the like . The reaction temperatures vary from 20 ° C to the boiling point of the solvent used; preferably between 50 and 150 ° C; the complement times of the reaction vary from 1 to 72 h. The pinacol ester is then oxidically cleaved to give compound 6. The pinacol ester is treated with sodium periodate, followed by an acid. The sodium periodate can be used in amounts ranging from 2 to 5 equivalents relative to compound 6. Suitable solvents include tetrahydrofuran, 1,4-dioxane, acetonitrile, methanol, ethanol, combinations thereof and the like. Suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, combinations thereof and the like. The reaction temperatures vary from 0 ° C to the boiling point of the solvent used; preferably between 0 and 50 ° C; the complement times of the reaction vary from 1 to 72 h. In step 7, the carbonyl group of compound 6 is treated with a reducing agent in a suitable solvent to give a compound of formulas (I) and (II). Suitable reducing agents include borane complexes, such as borane-tetrahydrofuran, dimethyl borane sulfoxide, combinations thereof and the like. Lithium aluminum hydride or sodium borohydride can also be used as reducing agents ^. The reducing agents can be used in amounts ranging from 0.5 to 5 equivalents, relative to compound 6. Suitable solvents include a lower alcohol, such as methanol, ethanol, and propanol, diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, combinations thereof and the like. The reaction temperatures vary from 0 ° C to the boiling point of the solvent used; the times of the complement of the reaction vary from 1 to 24 h. Reaction scheme 2
Preparation Strategy # 3 In the reaction scheme 3 * step 8, the compounds of the formulas (I) and (II) can be prepared in one step from the compound 3. The compound 3 is mixed with trialkyl borate then deals with the alkyl metal reagent. Suitable alkylmetal reagents include n-butyllithium, sec-butyllithium, tert-butyllithium, combinations thereof and the like. Suitable trialkyl borates include trimethyl borate, triisopropyl borate, tributyl borate, combinations thereof and the like. The addition of butyl lithium is carried out between -100 and 0 ° C, preferably between -80 and -40 ° C. The reaction mixture is allowed to warm to room temperature after the addition. The complement times of the reaction vary from 1 to 12 h. The trialkyl borate can be used in amounts ranging from 1 to 5 equivalents relative to the compound 3. The alkyl metal reagent can be used in amounts ranging from 1 to 2 equivalents relative to the compound 3. Suitable solvents include tetrahydrofuran, ether , 1,4-dioxane, 1,2-dimethoxyethane, toluene, hexanes, combinations thereof and the like. The complement times of the reaction vary from 1 to 2 h. Alternatively, a mixture of compound 3 and trialkyl borate can be refluxed for 1 to 3 h and the alcohol molecule formed during ester exchange can be removed by distillation prior to the addition of the alkyl metal reagent.
Reaction scheme 3
Preparation Strategy # 4 Reaction Scheme 4, step 10, the methyl group of compound 7 is brominated using N-bromosuccinimide. The -bromosuccinimide can be used in amounts ranging from 0.9 to 1.2 equivalents relative to compound 7. Suitable solvents include carbon tetrachloride, tetrahydrofuran, 1,4-dioxane, chlorobenzene, combinations thereof and the like. The reaction temperatures vary from 20 ° C to the boiling point of the solvent using. Preferably between 50 and 150 ° C; the complement times of the reaction vary from 1 to 12 h. In step 11, the bromomethylene group of compound 8 is converted to the benzyl alcohol. Compound 8 is treated with sodium acetate or potassium acetate. These acetates can be used in amounts ranging from 1 to 10 equivalents relative to compound 8. Suitable solvents include tetrahydrofuran, 1,4-dioxane N, N-dimethylformamide, N, -dimethylacetamide, N, N-methylpyrrolidone, sulfoxide, dimethyl, combinations thereof and the like. The reaction temperatures vary from 20 ° C to the boiling point of the solvent used; preferably between 50 and 100 ° C; Complementation times vary from 1 to 12 h. The resulting acetate is hydrolyzed to compound 3 under basic conditions. Suitable bases include sodium hydroxyl, lithium hydroxyl, potassium hydroxide, combinations thereof and the like. The base can be used in amounts ranging from 1 to 5 equivalents relative to the compound 8. Suitable solvents include methanol, ethanol, tetrahydrofurate, water, combinations thereof and the like. The temperature of the reaction varies from 20 ° C to the boiling point of the solvent used; preferably between 50 and 100 ° C; the complement times of the reaction vary from 1 to 12 h. Alternatively, compound 8 can be converted directly into compound 3 under the above similar conditions. Steps 3 to 5 convert compound 3 to a compound of Formulas (I) and (II). Reaction scheme 4
I or II, R '= H, W = (CR6R7) m, m = 0 Preparation Strategy # 5 In reaction scheme 5, step 12, compound 2 is treated with (methoxymethyl) triphenylphosphonium chloride or bromide ( methoxymethyl) triphenylphosphonium in the presence of a base followed by acid hydrolysis to give compound 9. Suitable bases include sodium hydride, potassium tert-butoxide, lithium diisopropylamide, butyllithium, lithium hexamethyldisilazane, combinations thereof and similar. The (methoxymethyl) triphenylphosphonium salt can be used in amounts ranging from 1 to 5 equivalents relative to compound 2. The base can be used in amounts ranging from 1 to 5 equivalents relative to compound 2. Suitable solvents include tetrahydrofuran , 1,2-dimethoxyethane, 1,4-dioxane, ether, toluene, hexane, N, N-dimethylformamide, combinations thereof and the like. The temperature of the reaction varies from 0 ° C to the boiling point of the solvent used; preferably between 0 and 30 ° C; the complement times of the reaction vary from 1 to 12 h. The enolic ether formed is hydrolyzed under acidic conditions. Suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, and the like. Suitable solvents include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, methanol, ethanol, combinations thereof and the like. The reaction temperatures vary from 20 ° C to the boiling point of the solvent used; preferably between 50 and 100 ° C; the complement times of the reaction vary from 1 to 12 h. Steps 2 to 5 convert compound 9 to a compound of Formulas (I) and (II). Reaction scheme 5
l or II, R '= H Preparation Strategy # 6 In the reaction scheme 6, the compound (I) wherein R1 is H is converted to the compound (I) wherein R1 is alkyl by mixing with the corresponding alcohol, R1OH. Suitable solvents include tertiary hydroxide, 1,2-dimethoxyethane, 1,4-dioxane, toluene, combinations thereof and the like. Alcohol (Rx0H) can be used as the solvent as well. The reaction temperatures vary from 20 ° C to the boiling point of the solvent used; preferably between 50 ° C and 100 ° C; the complement times of the reaction vary from 1 to 12 h.
Reaction scheme 6
what [I.R '= H lo II, R1? H
Preparation Strategy # 7 In the reaction scheme 7, the compound (Ia) is converted to its amino alcohol complex (Ib). The compound (la) is treated with HOR1NRlaRlb. The amino alcohol can be used in amounts ranging from 1 to 10 equivalents relative to the compound (la). Suitable solvents include methanol, ethanol, propanol, tetrahydrofuran, acetone, acetonitrile, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N, N-dimethylformamide, water, combinations thereof and the like. The reaction temperatures vary from 20 ° C to the boiling point of the solvent used; preferably between 50 and 100 ° C; the complement times of the reaction vary from 1 to 24 h. Reaction scheme 7
The compounds of Formulas (I) or (II) can be converted into hydrates and solvates by methods similar to those described above. IV. Methods of Inhibiting the Growth of Microorganisms or of Extermination of Microorganisms In another aspect, the invention provides a method of inhibiting the growth of a microorganism, or of killing a microorganism, or both, comprising contacting the microorganism with a compound of conformity with Formulas (I) or (II). Microorganisms are selected elements of fungi, yeasts, viruses, bacteria and parasites. In another exemplary embodiment, the microorganism is inside, or on the surface of an animal. In an exemplary embodiment, the animal is a selected member of humans, cattle, deer, reindeer, goats, honey bees, pigs, sheep, horses, cows, bulls, dogs, guinea pigs, gerbils, rabbits, cats, camels, yaks, elephants, ostriches, otters, chickens, ducks, geese, guinea fowl, pigeons, swans and turkeys. In another exemplary embodiment, the animal is a human being. In an exemplary embodiment, the microorganism is a selected element of a fungus and a yeast. In another exemplary embodiment, the fungus or yeast is a selected element of the Candida species, the Trychophyton species, the Microsporium species, the Aspergillus species, the Cryptococcus species, the Blastomyces species, Species of Cocciodiodes, of Histoplasma species, of Paracoccidiodes species, of Phycomycetes species, of Malassezia species, of Fusarium species, of Epidermophyton species, of Scytalidium species, of species of Scopulariopsis, of the Alternaria species, of the Penicillium species, of the Phialophora species, of the Rhizopus species, of the Scedosporium species, and of the Zygomicetes class. In another exemplary embodiment, the fungus or yeast is a member selected from Aspergillus fumigatus (A. fumigatus), Blastomyces dermatitidis, Candida Albicans (C. albicans, the strains both resistant and sensitive to fluconazole, Candida glabrata (C. glabrata), Candida krusei (C. krusei), Cryptococcus neoformans (C. neoformans), Candida parapsilosis (C. parapsilosis), Candida tropicalis (C. troplicalis), Candida immitis, epidermophyton floccosum (E. floccosum), Fusarium solani (F. solani ), Histoplasma capsulatum, Malassezia fúrfur. { M. fúrfur), Malassezia pachydermatis. { M. pachydermatis), Malassezia sympodialis. { M. sympodialis), Microsporum audouinii. { M. audouinii), Microsporum canis. { M. canis), Microsporum gypseum. { M. gypseum), Paracoccidiodes brasiliensis and Phycomycetes spp, Trichophyton mentagrophytes (G. mentagrophytes), Trichophyton rubrum (G. rubrum), Trichophyton tonsurans (T. tonsurans). In another embodiment, the fungus or yeast is a selected member of Trichophyton concentricum, T. violaceum, T. schoenleinii, T. verrucosum, T. soudanense, Microsporum gypseum, M. equinum, Candida guilliermondii, Malassezia globosa, N. obtuse, M restricted, M. slooffiae, and Aspergillus flavus. In another exemplary modality, the fungus or yeast is a selected member of dermatophytes, Trichophyton, Microsporum, Epidermophyton and fungi similar to yeast. In an exemplary embodiment, the microorganism is a bacterium. In an exemplary embodiment, the bacterium is a gram-positive bacterium. In another exemplary embodiment, the gram-positive bacterium is a member selected from Staphylococcus species, from Streptococcus species, from Bacillus species, from Mycobacterium species, from Corynebacterium species (from Propionibacterium species). , of Clostridium species, of Actinomyces species, of Enterococcus species and of Streptomyces species. In another exemplary embodiment, the bacterium is a gram-negative bacterium. In another exemplary embodiment, the gram-negative bacterium is a member selected from the Acitenobacter species, from the Ñeisseria species, from the Pseudomonas species, from the Brucella species, from the Agrobacterium species, from the Bordetella species, of the Escherichia species, the Shigelia species, the Yersinia species, the Salmonella species, the Klebsiella species, the Enterobacter species, the Haemophilus species, the Pasteurella species, the Streptobacillus species, spirochete species, Campylobacter species, Vibrio species and Helicobacter species. In another exemplary embodiment, the bacterium is a selected element of Propionibacterium acnes; Staphylococcus aureus; Staphylococcus epidermídis, Staphylococcus saprophyticus; Streptococcus pyogenes; Streptococcus agalactiae;
Streptococcus pneumoniae; Enterococcus faecalis; Enterococcus faecium; Bacillus anthracis; Mycobacterium avium-intracellulare; Mycobacterium tuberculosis, Acinetobacter baumanii; Corynebacterium diphtheria; Clostridium perfringens; Clostridium botulinum; Clostridium tetani; Neisseria gonorrhoeae; Neisseria meningitidis; Pseudomonas aeruginosa; Legionella pneumophila; Escherichia coli; Yersinia pestis; Haemophilus influenzae; Helicobacter pylori; Campylobacter fetus; Campylobacter jejuni; Vibrio cholerae; Vibrio parahemolyticus; Treponema pallidum; Actinomyces israeli; Rickettsia prowazekíi; Rickettsia rickettsii; Chlamydia trachomatis; Chlamydia psittaci; Brucella abortus; Agrobacterium tumefaciens; and Francisella tularensis. In an exemplary embodiment, the microorganism is a bacterium, which is a selected element of a stable bacterium in acidic conditions, including Mycobacterium species, including Bacillus species, Corynebacterium species (also Propionibacterium), and Clostridium species. , filamentous bacteria, including Actinomyces species, and Streptomyces species, such as Pseudomonas species, Brucella species, Agrobacterium species, Bordetella species, Escherichia species, Shigelia species, species of Yersinia, the species of Salmonella, the species of Klebsiella, the species of Enterobacter, the species of Hae ophilus, the species of Pasteurella, and the species of Streptobacillus; species of spirochetes, Campylobacter species, Vibrio species; and intracellular bacteria including Rickettsiae and Chlamydia species. In an exemplary embodiment, the microorganism is a virus. In an exemplary embodiment, the virus is a selected element of hepatitis AB, human rhinovirus, yellow fever virus, human respiratory coronavirus, severe acute respiratory syndrome (SARS), respiratory syncytial virus, virus of influenza, parainfluenza virus 1-4, human immunodeficiency virus 1 (HIV-1), human immunodeficiency virus 2 (HIV-2), herpes simplex virus (HSV-1), herpes virus 2 simplex (HSV-2), human cytomegalovirus (HCMV), varicella zoster virus, Epstein-Barr virus (EBV), poliovirus, coxsaquievirus, ecovirus, rubella, neurodermatropic virus, variola virus, papovirus, rabies virus, dengue virus, East Nile virus, and SARS virus (for its acronym in English). In another exemplary embodiment, the virus is a member selected from pi cornaviridae, flavivi ridae, coronaviridae, pa ramyxoviridae, orthomyxovirida e, retrovi rida e, herpersviridae, and hepadnavirida e. In another exemplary embodiment, the virus is a selected member of a virus included in the following table: Table A. Virus
Table A (Cont.)
In another embodiment, the microorganism is a parasite.
In one embodiment, the parasite is a selected member of
Plasmodium falciparum, P. vivax, P. Ovale, P. malarie, P. berghei, Laishmania donovani, L. infantum, L. chagasi, L. mexicana, L. amazonensis, L. venezuelensis, L. tropics, L. major, L. minor, L. aethiopica, L. biana braziliensis, L. (V.) guyanensis, L. (V.) panamensis, L. (V.) peruviana, Trypanosoma brucei rhodesiense, T. brucei gambiense, T. cruzi, Giardia intestinalis, G. lambda, Toxoplasma gondii, Entamoeba hitolytica, Trichomonas vaginalis, Pneumocystis carinii, and Cryptosporidium parvum. V. Methods of Treatment or Prevention of Infections In another aspect, the invention provides a method of treating or preventing an infection, or both. The method includes administering to the animal a therapeutically effective amount of the compound of the invention, sufficient to treat or prevent infection. In an exemplary embodiment, the compound of the invention is in accordance with Formulas (I) or (II). In another exemplary modality, the animal is a selected member of one of the humans, cattle, deer, reindeer, goats, honey bees, pigs, sheep, horses, cows, bulls, dogs, guinea pigs, gerbils, rabbits, cats, camels, yaks, elephants, ostriches, otters, chickens, ducks, geese, guinea fowl, pigeons, swans and turkeys. In another exemplary embodiment, the animal is a human being. In another exemplary embodiment, the infection is a selected element of a systemic infection, a skin infection, and an ungular or periungular infection. V. a) Methods of Treatment or Prevention of Ungular and / or Perivmular Infections In another aspect, the invention provides a method of treating or preventing an ungular and / or periungular infection. The method includes administering to an animal a therapeutically effective amount of the compound of the invention, sufficient to treat or prevent infection. In another exemplary embodiment, the method includes administering the compound of the invention to a site that is a selected element of the skin, nails, head, claws, hooves and the skin surrounding the nails, hair, claws and hooves. V. a) 1) Onychomycosis Onychomycosis is a disease of the nails caused by a yeast, dermatophytes, or other molds, and represents approximately 50% of all nail disorders. Infection of toenails is quantified in approximately 80% of the incidence of onychomycosis, while fingernails are affected in approximately 20% of cases. Dermatophytes are the most frequent cause of invasion of the nail plate, particularly in nail onychomycosis of the toes. The onychomycosis caused by the dermatophyte is called Tinea unguium. Trichophyton rubrum is by far the most frequently isolated dermatophyte, followed by T. mentagrophytes. Distal subungual onychomycosis is the most common presentation of Tinea unguium, with the main entry site through hyponychium (the thickened epidermis of the free lateral end of a nail) that progresses over time to involve the l ine of the nail and the plate of the nail. Discoloration, onycholysis, and accumulation of subungual debris and dystrophy of the nail plate characterize the disease. The disease adversely affects the quality of life of its victims, with complaints from subjects ranging from unpleasant nails and discomfort with footwear, to more serious complications that include secondary bacterial infections. Many methods for the treatment of fungal infections are already known, including the oral and topical use of antibiotics (e.g., nystatin and amphotericin B), antifungal imidazole agents such as miconazole, clotrimazole, fluconazole, econazole and sulconazole, and agents fungi different from imidazole such as the derivatives of allylamine, terbinafine and naftifine, and benzylamine butenafine. However, onychomycosis has proven that it will be resistant to most treatments. Fungal infections of the nails are located in a difficult area to be accessed by conventional topical treatment and antifungal drugs can not easily penetrate the nail plate to reach sites of infection under the nail. Therefore, onychomycosis has traditionally been treated by the oral administration of antifungal drugs.; however, this is clearly undesirable because of the potential for side effects of such drugs, in particular those caused by the more potent antifungal drugs, such as itraconazole and ketoconazole. One method of treating onychomycosis is by removing the nail before treatment with a topically active antifungal agent; such a method of treatment is equally undesirable. Systemic antifungal agents require prolonged use and have the potential for significant side effects. Topical agents have usually been of small benefit, mainly because of the poor penetration of the antifungal agents into and through the nail mass. In an exemplary embodiment, the invention provides a method of treatment and prevention of onychomycosis. The method includes administering to the animal a therapeutically effective amount of a pharmaceutical formulation of the invention, sufficient to treat or prevent onychomycosis. In another exemplary embodiment, the method includes administering the pharmaceutical formulation of the invention to a site that is a selected element of the skin, nails, hair, claws, hooves and the skin surrounding the nails, hair, claws, and hooves. . In another exemplary embodiment, the pharmaceutical formulation includes a compound having a structure according to formula (Ilb). In another embodiment, Rlb is H. In another exemplary embodiment, R10b and Rllb are H. In another exemplary embodiment, one element selected from Riob and Riib is H and the other selected element from R10b and Rllb is a selected element from halo, methyl , cyano, methoxy, hydroxymethyl and p-cyanophenyloxy. In another exemplary embodiment, R and R are independently selected from fluoro, chloro, methyl, cyano, methoxy, hydroxymethyl and p-cyanophenyl. In another exemplary embodiment, Rlb is H; R7b is H; R10b is F and Rllb is H. In another exemplary embodiment, Rllb and R12b, in the company of the atoms to which they are attached, are bonded to form a phenyl group. V. a) 2). Other Ungular and Periungular Infections In another exemplary modality; The invention provides a method of treating or preventing an ungular or periungular infection in a mammal. This method comprises administering to the mammal a therapeutically effective amount of a compound of the invention, whereby ungular or periungular infection is treated or prevented. In an exemplary embodiment, the ungular or periungular infection is a selected member of: chloronychia, paronychias, erysipeloid, onychorhexis, gonorrhea, swimming pool granuloma, larva migrans, leprosy, Orf's nodule, milker's nodules, herpetic whitlow, bacterial perionixis acute, chronic peronixis, sporotrichosis, syphilis, verrucous skin tuberculosis, tularemia, tungiasis, peri-sublingual warts, nail dystrophy (trachyonychia) and dermatological diseases with effect on the nails, such as psoriasis, pustular psoriasis, alopecia areata, pustular parakeratosis, contact dermatosis, Reiter's syndrome, psoriasiform acral dermatitis, lichen planus, idiopathic nail atrophy, clear lichen, striated lichen, inflammatory linear warty epidermal nevus (ILVEN), alopecia, pemphigus, bullous pemphigoid, acquired bullous epidermolysis, Darier's disease, pityriasis pilaris red, keratoderma palmopla ntar, contact eczema, polymorphic erythema, scabies, Bazex syndrome, systemic scleroderma, systemic lupus erythematosus, chronic lupus erythematosus, dermatomyositis. The compounds and pharmaceutical compositions of the invention which are useful for ungular and periungular applications also find application in the cosmetic field, in particular for the treatment of nail irregularities, coilonychia, Beau lines, longitudinal cordons, nails growing towards inside. In an exemplary modality, the infection is of the skin, nails, claws or hooves, hair, ears and eyes and is a selected element of sporotrichosis, fungal keratitis, oculomycosis of extension, endogenous oculomicosis, lobomycosis, mycetoma, black stone, pityriasis versicolor, Tinea corporis, Tinea cruris , Tinea pedis, Tinea barbae, Tinea capitis, Tinea nigra, Otomicosis, Tinea favosa, cromomycosis, and Tinea imbricata. V. b) Methods of Treating Slsemic Diseases Another aspect, the invention provides a method of treating a systemic disease. The method involves contacting an animal with a compound of the invention. The delivery method for the treatment of systemic diseases can be oral, intravenous or transdermal. In an exemplary embodiment, the infection is systemic and is a selected element of candidiasis, aspergillosis, coccidiodomicosis, cryptococcosis, histoplasmosis, blastomycosis, paracoccidiodomicosis, zygomycosis, phacohipomycosis, and rhinosporidiosis. V. c) Methods of Treatment of Diseases Involving Viruses The compounds of the invention are useful for the treatment of diseases of both animals and humans, involving viruses. In an exemplary embodiment, the disease is a selected element of hepatitis A-B C, yellow fever, virus: respiratory syncytial, influenza, AIDS, herpes simplex, varicella, varicella zoster and Epstein-Barr disease. V. d) Methods of Treatment of Diseases Involving Parasites The compounds of the invention are useful for the treatment of diseases of both humans and animals, which involve parasites. In an exemplary embodiment, the disease is a selected element of malaria, Chagas disease, Leishmaniasis, African sleeping sickness (African human trypanosomiasis), giardiasis, toxoplasmosis, amebiasis and cryptosporidiosis. SAW. Nail Penetration Methods It is believed that poor penetration of the active agent through the nail plate or hoof and / or excessive agglutination to keratin, (the main protein in the nails and hair) are the reasons for the poor efficacy of ciclopirox at 8% w / w in a commercial lacquer and other topical treatments that have failed in clinical trials. In mild cases of onychomycosis, the pathogenic fungus lies on the nail plate only. In moderate to severe cases, the pathogenic fungus establishes a presence on the nail plate and on the nail bed. If the infection is removed from the nail plate but not from the nail bed, the fungal pathogen can reinfect the nail plate. Therefore, to effectively treat onychomycosis, the infection must be removed from the nail plate and the nail bed. To do this, the active agent must penetrate and disseminate substantially from beginning to end of the nail plate and nail bed. It is believed that for an active agent to be effective once disseminated from beginning to end of the infected area, it must be bioavailable to the fungal pathogen and thus can not be tightly and / or preferentially bound to the keratin so that the drug is come back inactive An understanding of the morphology of the nail plate suggests certain physicochemical properties of the active agent that could facilitate the penetration of the nail plate. The desired physicochemical properties are described from beginning to end. The test compounds of the present invention are capable of penetrating the nail plate and were also active against Trichophyton rubrum and mentagrophytes and other species. In addition, the tested compounds are also active against Trichophyton rubrum in the presence of 5% keratin powder. In another aspect, the invention provides a method of delivering a compound from the dorsal layer of the nail plate to the nail bed. This method comprises contacting the cell with a compound capable of penetrating the nail plate., under conditions sufficient to penetrate the nail. The compound has a molecular weight of between about 100 and about 200 Da. The compound also has a P log value of between about 1.0 and about 2.6. The compound additionally has a solubility in water between about 0.1 mg / ml and 1 g / ml of water saturated with octanol, whereby the compound is supplied. In a preferred embodiment, the physicochemical properties of the compound of the invention, described by the predictive amounts for the migration of the compound through the nail plate, including, but not limited to, the molecular weight, P log and the solubility in the water, and the like, are effective to provide substantial penetration of the nail plate. Compounds with a molecular weight of less than 200 Da penetrate the nail plate in a manner superior to the commercially available treatment for onychomycosis. In one embodiment of the present invention, the compound has a molecular weight of between 130 and 200. In another embodiment of this invention, the compound has a molecular weight of from about 140 to about 200 Da. In another embodiment of this invention, the compound has a molecular weight of from about 170 to about 200 Da. In another embodiment of this invention, the compound has a molecular weight from about 155 to about 190 Da. In another embodiment of this invention, the compound has a molecular weight of from about 165 to about 185 Da. In another embodiment of this invention, the compound has a molecular weight from about 145 to about 170 Da. In yet another embodiment, the molecular weight is either 151.93 or 168.39 Da. In one embodiment of the present invention, the compound has a P log value of between about -3.5 to about 2.5. In another exemplary embodiment, the compound has a P log value from about -1.0 to about 2.5. In another exemplary embodiment, the compound has a P log value from about -1.0 to about 2.0. In another exemplary embodiment, the compound has a P log value from about -0.5 to about 2.5. In another exemplary embodiment, the compound has a P log value from about -0.5 to about 1.5. In another exemplary embodiment, the compound has a P log value from about 0.5 to about 2.5. In another exemplary embodiment, the compound has a P log value from about 1.0 to about 2.5. In yet another exemplary embodiment, the compound has a P log value of 1.9 or 2.3. Also contemplated by the present invention is a compound with a P log value of less than 2.5, with a molecular weight of less than 200 Da, which is still capable of penetrating the nail plate. In one embodiment of the present invention, the compound has a solubility in water between about 0.1 mg / ml up to 1 g / ml in water saturated with octanol. In one embodiment of the present invention, the compound has a solubility in water of between 0.1 mg / ml and 100 mg / ml. In another embodiment of this invention, the compound has a solubility in water of about 0.1 mg / ml and 10 mg / ml. In another embodiment of this invention, the compound has a solubility in water of between about 0.1 mg / ml and 1 mg / ml. In another embodiment of this invention, the compound has a solubility in water of about 5 mg / ml and 1 g / ml. In another embodiment of this invention, the compound has a solubility in water of about 10 mg / ml and 500 g / ml. In another embodiment of this invention, the compound has a solubility in water of about 80 mg / ml and 250 mg / ml. In an exemplary embodiment, the present invention provides a compound with a P log value selected from a previous range, with a molecular weight selected from a previous range, which is still able to penetrate the nail plate. In an exemplary embodiment, the present invention provides compounds with a molecular weight selected from a previous range, with a solubility in water selected from a previous range, which are still capable of penetrating the nail plate. In an exemplary embodiment, the present invention provides compounds with a P log value of a previous range, with a solubility in water selected from a previous range, which are still capable of penetrating the skin plate. In an exemplary embodiment, the present invention provides compounds with a molecular weight selected from a previous range, with a P log value selected from a previous range, and with a solubility in water selected from a previous range, which are capable of penetrating the nail plate. The penetration of the nail by the active ingredient can be effected by the polarity of the formulation. However, the polarity of the formulation is not expected to have as much influence on the penetration of the nail as some of the other factors, such as the molecular weight or the P log value of the active ingredient. The presence of penetration enhancing agents in the formulation is likely to increase the penetration of the active agent when compared to similar formulations that do not contain a penetration enhancing agent. Some examples of molecules with optical physicochemical properties are given in the following table.
The compound 3 given below is an example of a compound similar in its molecular weight to ciclopirox, and similarly to ciclopirox, penetrates the nail plate poorly.
In a preferred embodiment, topical formulations that include a compound of Formulas (I) or (II) previously structurally described, have a molecular weight of less than 200 Da, have a P Log value of less than 2.5, and a minimal, inhibitory concentration against Trichophyton rubrum that substantially remained unchanged in the presence of 5% keratin. This invention is still further directed to methods for the treatment of a viral infection mediated at least in part by dermatdfitos, of the species Trichophyton, Microsporum or Epidermophyton or a fungus similar to a yeast that includes the Candida species, in mammals, such a method comprises administering to a mammal, which has been diagnosed with the viral infection or that is at risk of developing the viral infection, a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound described herein or mixtures of one or more of such compounds. In one embodiment, the infection is onychomycosis. The compounds contemplated by the present invention may have broad spectrum antifungal activity and as such may be candidates for use against other cutaneous fungal infections. The methods provided in this aspect of the invention are useful in the penetration of the nails and hooves, as well as in the treatment of ungular and periungular conditions. VII. Pharmaceutical Formulations In another aspect, the invention is a pharmaceutical formulation that includes: (a) a pharmaceutically acceptable excipient; and (b) a compound of the invention. In another aspect, the invention is a pharmaceutical formulation that includes: (a) a pharmaceutically acceptable excipient; and (b) a compound having a structure according to formulas (I), (a), (Ib) (Ic), or (Id). In another aspect, the invention is a pharmaceutical formulation that includes: (a) a pharmaceutically acceptable excipient; and (b) a compound having the structure according to formulas (II), (Ha), (Ilb), (lie), (lid). In another aspect, the invention is a pharmaceutical formulation comprising: (a) a pharmaceutically acceptable excipient; and (b) a compound having a structure according to Formula (II):
where B is boron. Rlb is a selected element of a negative charge, a counterion of salt, H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted heteroaryl or not replaced. M2 is a selected element of oxygen, sulfur and NR2b. R2b is a selected element of H, unsubstituted substituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. J2 is an element selected from (CR3bR4b) n2 and CR5b. R3b, Rb, and R5b are elements 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 index n2 is an integer selected from 0 to 2. 2 is a selected element of C = 0 (carbonyl), (CR6bR7b) m2 and CR8b. R6b, R7b, and R8b are elements 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 m2 index is an integer selected from 0 and 1. A2 is a selected element of CR9b and N. D2 is a selected element of CR10b and N. E2 is a selected element of CRllb and N. G2 is a selected element of CR12b and N. R9b, R10b, Rllb and R12b are elements independently selected from H, OH, NH2, SH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted aryl or unsubstituted, and substituted or unsubstituted heteroaryl. The combination of nitrogens (A2 + D2 + E2 + G2) is an integer selected from 0 to 3. A selected element of R3b, R4b, and R5b and a selected element of R6b, R7b and R8b, together with the atoms at which are fixed, are optionally joined to form a ring of 4 to 7 elements. R3b and R4b, together with the atoms to which they are attached, are optionally attached to form a ring of 4 to 7 elements. R6b and R7b, together with the atoms to which they are attached, are optionally linked to form a ring of 4 to 7 elements. R9b and R10b together with the atoms to which they are attached are optionally bonded to form a ring of 4 to 7 elements. R10b and Rllb together with the atoms to which they are attached are optionally bonded to form a ring of 4 to 7 elements. Rllb and R12b, together with the atoms to which they are attached are optionally attached to form a ring of 4 to 7 elements. In an exemplary embodiment, the aspect has the condition that when M2 is oxygen, W2 is a selected element of (CR3bR b) n2 where n2 is 0, J2 is a selected element of (CR6bR7b) m2, where m2 is 1 ,? 2 is CR9b, D2 is CR10b, E is CRllb, G is CR12b, then R9b is a selected element of halogen, methyl, ethyl, or is optionally linked with R10b to form a phenyl ring. In another exemplary embodiment, the mode has the condition that when M2 is oxygen, 2 is an element selected from (CR3bRb) n, where n2 is 0, J2 is a selected element of (CR6bR7b) m, where m2 is 1 , A2 is CR, D2 is CR1, E2 is CRllb, G2 is CR12b, then R10b is not a selected element of unsubstituted phenoxy, C (CH3) 3, halogen, CF3, methoxy, ethoxy, or optionally linked with R9b to form a phenyl ring. In another exemplary embodiment, the aspect has the condition that when M2 is oxygen, W2 is an element selected from (CR3bR4b) n, where n2 is 0, J2 is an element selected from (CR6bR7b) m2, where m2 is 1 , A2 is CR9b, D2 is CR10b, E2 is CRllb, G2 is CR12b, then Rllb is not a selected element of halogen or optionally linked with R10b to form a phenyl ring. In another embodiment, the aspect has the condition that when M2 is oxygen, W2 is a selected element of (CR3bR4b) n2, where n2 is 0, J2 is a selected element of (CR6bR7b) m2, where m2 is 1, A2 is CR9b, D2 is CR10b, E2 is CRUb, G2 is CR12b, then R12b is not halogen. In another exemplary embodiment, the aspect has the proviso that when M2 is oxygen, W2 is an element selected from (CR3bR b) n2, where n2 is 0, J2 is an element selected from (CR6 R7b) m2, where m2 is 1, A2 is CR9, D2 is CR10b, E2 is CRllb, G2 is CR12b, then R6b is not halophenyl. In another exemplary embodiment, the aspect has the condition that when M2 is oxygen, W2 is an element selected from (CR3bRb) n2, where n2 is 0, J2 is an element selected from (CR6bR7b) m2, where m2 is 1 , A2 is CR9b, D2 is CR10b, E2 is CRllb, G2 is CR12b, then R7 is not halophenyl. In another exemplary embodiment, the aspect has the proviso that when M2 is oxygen, W2 is a selected element of CR3bR4b) n2, where n2 is 0, J2 is a selected element of (CR6bR7b) m2, where m2 is 1, A2 is CR9b, D2 is CR10b, E2 is CRll, G2 is CR12b, then R6b and R7b are not halophenyl. In another exemplary embodiment, the aspect has the proviso that when M2 is oxygen, W2 is an element selected from (CR3bR4b) n2, where n2 is 0, J2 is an element selected from (CR6bR7b) m2r where m2 is 1, A2 is CR9b, D2 is CR10b, E2 is CRllb, G2 is CR12b, and R9b, R10b and Rnb are H, then R6b, R7b and R12b are not H. In another exemplary embodiment, the aspect has the condition that when M2 is oxygen, where n2 is 1, J2 is an element selected from (CR6bR7b) m2, where m2 is 0, A2 is CR9b, D2 is CR10b, E2 is CRllb, G2 is CR12b, R9b is H, R10b is H, Rllb is H, R6b is H, R7b is H, R12b is H, then W2 is not OO (carbonyl). In another exemplary embodiment, the aspect has the proviso that when M2 is oxygen, 2 is CR5b, J2 is CR8b, A2 is CR9b, and D2 is CR10b, E2 is CRllb, G2 is CR12b, R6b, R7b, R9b, R10b, Rllb and R12b are H, then R5b and R8b, together with the atoms to which they are attached, do not form a phenyl ring. In an exemplary embodiment, the pharmaceutical formulation has a compound with a structure according to the formula (lia):
In another exemplary embodiment, the pharmaceutical formulation has a compound having the structure according to Formula (Ilb):
wherein R is a selected element of H, methyl, ethyl and phenyl. R10b is a selected element of H, OH, NH2, SH, halogen, substituted or unsubstituted phenoxy, substituted or unsubstituted phenylalkyloxy, substituted or unsubstituted phenylthio, and substituted or unsubstituted phenylalkylthio. Rllb is a selected element of H, OH, NH2, SH, methyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenylalkyloxy substituted or unsubstituted phenylthio, and substituted or unsubstituted phenylalkylthio. In another exemplary embodiment, Rlb is a selected element of a negative charge, H and a counterion of a salt. In another exemplary embodiment, R10b and RUb are H. In another exemplary embodiment, one element selected from R10 and Rllb is H and the other element selected from R10b and Rllb is an element selected from halo, methyl, cyano, methoxy, hydroxyl and -cyanophenyloxy. In another exemplary embodiment, R10b and Rllb are independently selected from fluoro, chloro, methyl, cyano, methoxy, hydroxymethyl, and p-cyanophenyl. In another particular embodiment, Rlb is a selected element of a negative charge, H and a counterion of the salt; Rb is H; R10b is F and Rllb is H. In another exemplary embodiment, Rllb and R12b, in the company of the atoms to which they are attached, are linked to form a phenyl group. In another exemplary embodiment, Rlb is a selected element of a negative charge, H and a counterion of the salt; R7b is H; R10b is 4-cyanophenoxy, and Rllb is H. In another exemplary embodiment, the compound has a structure according to Formula (lie):
wherein R 10b is a selected element of H, halogen, CN and substituted or unsubstituted C 1-4 alkyl. In another exemplary embodiment, the compound has a formulation that is an element selected from:
In another exemplary embodiment, the pharmaceutical formulation has a compound with a structure according to Formula (lid):
where B is boron. R x is a member selected from substituted or unsubstituted C 1 -C 5 alkyl and substituted or unsubstituted C 1 -C 5 heteroalkyl. Ry2 and Rz2 are elements 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. The pharmaceutical formulations of the invention may take a variety of forms adapted to the chosen route of administration of the invention. Those skilled in the art will recognize various synthetic methodologies that can be employed to accumulate the non-toxic pharmaceutical formulations incorporating the compounds described herein. Those skilled in the art will recognize a wide variety of pharmaceutically acceptable, non-toxic solvents, which can be used to prepare the solvates of the compounds of the invention, such as water, ethanol, propylene glycol, mineral oil, vegetable oil and dimethyl sulfoxide. (DMSO) (for its acronym in English). The compositions of the invention may be administered orally, topically, parenterally, by inhalation or spraying, or rectally in unit dosage formulations containing conventional, non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. It is further understood that the best method of administration may be a combination of methods. Oral administration in the form of a pill, capsule, elixir, syrup, lozenge, troche, or the like, is particularly preferred. The term "parenteral" as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal injections, intrathecal injection or a similar injection or infusion techniques. The pharmaceutical formulations containing the compounds of the invention are preferably in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersed powders or granules, an emulsion, soft or hard capsules, or syrups or elixirs. The compositions proposed for oral use can be prepared according to any method known in the art, for the manufacture of pharmaceutical formulations, and such compositions can have one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives to provide good taste and pharmaceutically elegant preparations. The tablets may contain the active ingredient mixed with pharmaceutically acceptable, non-toxic excipients, which are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate.; granulating and disintegrating agents, for example, corn starch, or alginic acid; agglutination agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets can be uncoated! or they can be coated by known techniques to retard disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the ingredient Active is mixed with water or a medium of oil, for example, peanut oil, liquid paraffin or olive oil. The aqueous suspensions contain the active materials mixed with excipients suitable for the manufacture of the aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and acacia gum; and wetting and dispersing agents, which can be a phosphatide which is naturally present, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene with long chain aliphatic alcohols, for example heptadecaethylene oxyketanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hydrogenated paraffin or cetyl alcohol. Sweetening agents such as those described above, and flavoring agents, can be added to provide palatable oral preparations. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for the preparation of an aqueous suspension provide the active ingredient mixed with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical formulations of the invention may also be in the form of oil-in-water emulsions and water-in-oil emulsions. The oily phase can be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents can be gums that are naturally present, for example, acacia gum or tragacanth gum; phosphatides that are naturally present, for example from soybean, lecithin, and esters or partial esters derived from fatty acids and hexitol; anhydrides, for example sorbitan monooleate; and condensation products of the partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. The syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. The pharmaceutical formulations may be in the form of an injectable, sterile aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable wetting or dispersing agents and suitable suspending agents, which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension, in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, fixed, sterile oils are conventionally employed as a solvent or suspension medium. For this purpose, any mixture of non-hydrogenated fixed oils can be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectable substances. The composition of the invention can also be administered in the form of suppositories, for example, for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. Alternatively, the compositions may be administered parenterally in a sterile medium. The drug, depending on the vehicle and the concentration used, can be either suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. For administration to non-human animals, the composition containing the therapeutic compound can be added to the animal's feed or water for drinking. Also, it will be convenient to formulate the feeding of the animal and the drinking water products of the animal so that the animal itself takes an appropriate amount of the compound in its diet. Additionally it will be convenient to present the compound in the composition as a premix for addition to the feed or to the drinking water. The composition can also be added as a food supplement or a drink for humans. The dosage levels of the order from about 5 mg to about 250 mg per kilogram of body weight per day and more preferably from about 25 mg to about 150 mg per kilogram of body weight per day, are useful in the treatment of the conditions indicated above. . The amount of the active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the condition being treated and the particular mode of administration. Dosage unit forms will generally contain from about 1 mg to about 500 mg of an active ingredient. The frequency of the dosage can also vary depending on the compound used and the particular disease treated. However, for the treatment of most disorders, a dosing regimen of 4 times daily or less is preferred. It will be understood, however, that the specific dosage level for any particular patient will depend on a variety of factors including the activity of the specific compound employed.XID
, age, body weight, general health, sex, diet, time of administration, route of administration and rate of excretion, the combination of drugs and the severity of the particular disease that is being submitted to the therapy. Preferred compounds of the invention will have desirable pharmacological properties including, but not limited to, oral bioavailability, low toxicity, low agglutination of serum protein and desirable in vitro and in vivo half-lives. Penetration of the blood-brain barrier for compounds used to treat CNS disorders is necessary, while low levels in the brain of compounds used to treat peripheral disorders are frequently preferred. . The assays can be used to predict these desirable pharmacological properties. Assays to predict bioavailability include transport through monolayers of human intestinal cells, including monolayers of Caco-2 cells. The toxicity for cultured hepatocytes can be used to predict the toxicity of the compound. Penetration of the blood-brain barrier of a compound in humans can be predicted from levels in the brain of laboratory animals that receive the compound intravenously. Agglutination of serum protein can be predicted from albumin agglutination assays. Such assays are described in a review by Oravcova, et al., (Journal of Chromatography B (1996) volume 677, pages 1-27). The half-life of the compound is inversely proportional to the frequency of dosage of a compound. The in vitro half-lives of the compounds can be predicted from the microsomal half-life assays as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127). The amount of the composition required for use in the treatment will vary not only with the particular compound selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the patient. doctor or medical specialist who provides the care. VII. a) Topical Formulations In a preferred embodiment, the methods of the invention can be used by means of topical application of the compounds described herein. The compositions of the present invention comprise fluid or semi-solid vehicles which may include but are not limited to polymers, thickening agents, buffers, neutralizers, chelating agents, preservatives, surfactants or emulsifiers, antionts, waxes or oils, emollients, sunscreens, and a solvent or system of mixed solvents. The solvent or mixed solvent system is important for the formation because it is mainly responsible for the dissolution of the drug. The best solvent or the best mixed solvent systems are also capable of maintaining clinically relevant levels of the drug in the solution despite the addition of a poor solvent to the formulation. Topical compositions useful in the subject invention can be made in a wide variety of product types. These include, but are not limited to, lotions, creams, gels, bars, spray solutions, ointments, pastes, foams, foaming creams, and cleaning agents. These types of products may comprise various types of carrier systems including, but not limited to, particles, nanoparticles, and liposomes. If desired, disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate. The techniques for formulation and administration can be found in Remington: The Science and Practice of Pharmacy, supra. The formulation can be selected to maximize delivery to a desired target site in the body. Lotions, which are preparations that are to be applied to the skin, to the surface of the skin, nails, hair, claws or hooves without friction, are typically liquid or semi-liquid preparations in which a finely divided solid, a wax, or a liquid, they are dispersed. The lotions will typically contain suspending agents to produce better suspensions as well as compounds useful for locating and maintaining the active agent in contact with the skin, nails, hair, claws or hooves, for example, methylcellulose, sodium carboxymethyl cellulose, or the like. The creams containing the active ingredient for delivery according to the present invention are liquid or semisolid, viscous emulsions, either oil in water or water in oil. The bases of the cream are washable in water, and contain an oily phase, an emulsifier and an aqueous phase. The oily phase is generally comprised of petrolatum or a fatty alcohol, such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oily phase by volume, and generally contains a humectant. The emulsifier in a cream formulation, as explained in Remington: The Science and Practice of Pharmacy, supra, is generally a nonionic, anionic, cationic or amphoteric surfactant. Gel formulations can also be used in relation to the present invention. As will be appreciated by those who work in the field of the formulation of a topical drug, the gels are semi-solid. The single-phase gels contain organic macromolecules distributed substantially uniformly from start to finish of the carrier liquid, which is typically aqueous, but which can also be a solvent or solvent mixtures. Ointments, which are semi-solid preparations, are typically based on petrolatum or other petroleum derivatives. As will be appreciated by the artisan with ordinary experience, the specific ointment base to be used is one that provides the optimum supply for the active agent for a given formulation, and, preferably, also provides the other desirable characteristics, for example , emolience or similar. As with other carriers or vehicles, an ointment base must be inert, stable, non-irritating and not cause sensitization. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton, Pa .: Mack Publishing Co., 1995), on pages 1399-1404, ointment bases can be grouped into four classes: oil bases , emulsifiable bases, emulsion bases; and water soluble bases. The bases of the oily ointment include, for example, vegetable oils, fats obtained from animals, and semi-solid hydrocarbons obtained from carbon. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum. The emulsion ointment bases are either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, and include, for example , cetyl alcohol, glyceryl monostearate, lanolin and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of variable molecular weight, again, reference can be made to Remington: The Science and Practice of Pharmacy, supra, for additional information. Useful formulations of the invention also encompass spray solutions. The spray solutions generally provide the active agent in an aqueous and / or alcoholic solution which can be applied as a mist to the skin, nails, hair, claws or hooves for delivery. Such spray solutions include those formulated to provide the concentration of the active agent solution at the site of administration after delivery, for example, the spray solution may be composed primarily of alcohol or other similar volatile liquid in which the drug or Active agent can be dissolved. During the supply to the skin, nails, hair, claws or hooves. The carrier evaporates, leaving the active agent concentrated in the administration site. Topical pharmaceutical compositions may also comprise suitable solid or gel-phase carriers. Examples of such carriers include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
The topical pharmaceutical compositions may also comprise a suitable emulsifier which relates to an agent that improves or facilitates the mixing and suspension of the oil in water or water in oil. The emulsifying agent used herein may consist of a single emulsifying agent or may be a nonionic, anionic, cationic or amphoteric surfactant or a mixture of two or more such surfactants. Preferred for use herein are nonionic or anionic emulsifiers. Such surface active agents are described in "McCutcheon's Detergent and Emulsifiers," North American Edition, 1980 Annual published by the McCutcheon Division, MC Publishing Company, 175 Rock Road, Glen Rock, N.J. 07452, EÜA. High molecular weight alcohols such as cetearyl alcohol, cetyl alcohol, stearyl alcohol, emulsifying wax, glyceryl monostearate are preferred for use herein. Other examples are ethylene glycol distearate, sorbitan tristearate, propylene glycol monostearate, sorbitan monooleate, sorbitan monostearate (SPAN 60), diethylene glycol monolaurate, sorbitan monopalmitate, sucrose dioleate, sucrose stearate (CRODESTA F-160), polyoxyethylene lauryl ether (BRIJ 30), polyoxyethylene stearyl ether (2) (BRIJ 72), polyoxyethylene stearyl ether (21) (BRIJ 721), polyoxyethylene monostearate (Myrj 45), polyoxyethylene sorbitan monostearate (T EEN 60) , polyoxyethylene sorbitan monooleate (TWEEN 80), polyoxyethylene sorbitan monolaurate (TWEEN 20) and sodium oleate. Cholesterol and cholesterol derivatives can also be used in externally used emulsions and promoters of W / O (water / oil) emulsions. Especially suitable nonionic emulsifying agents are those with hydrophilic-lipophilic balances (HLB) of about 3 to 6 for the W / O system and 8 to 18 for the O / W system ( by its acronym in English) as determined by the method described by Paul L. Lindner in "Emulsions and Emulsion", edited by Kenneth Lissant, published by Dekker, New York, NY, 1974, page 188-190. More preferred for use herein is one or more nonionic surfactants that produce a system having an HLB of about 8 to about 18. Examples of such nonionic emulsifiers include, but are not limited to, "BRIJ 72", the registered name for a stearyl ether of polyoxyethylene (2) having an HLB of 4.9; "BRIJ 721", the registered name for a polyoxyethylene stearyl ether (21) having an HLB of 15.5, "Brij 30", the registered name for the polyoxyethylene lauryl ether having an HLB of 9.7; "Polowax", the registered name for the emulsifying wax that has an HLB of 8.0; "Span 60", the registered name for sorbitan monostearate having an HLB of 4.7; "Crodesta F-160", the registered name for sucrose stearate "having a HLB of 14.5, all of these materials are available from Ruger Chemicals Inc., Croda, ICI Americas, Inc., Spectrum Chemicals, and BASF. When the topical formulations of the present invention contain at least one emulsifying agent, each emulsifying agent is presented in an amount of from about 0.5 to about 2.5% by weight, preferably 0.5 to 2.0%, more preferably 1.0% or 1.8%. emulsifying agent comprises a mixture of steareth 21 (about 1.8%) and steareth 2 (about 1.0%). Topical pharmaceutical compositions can also comprise suitable emollients.The emollients are materials used for the prevention or relief of dryness, as for the protection of skin, nails, hair, claws or hooves Useful emollients include, but are not limited to, cetyl alcohol, isopropyl myristate, stearyl alcohol and the like. A wide variety of suitable emollients are already known and can be used here. See for example, Sagarin, Cosmetics, Science and Technology, second edition, volume 1, pp. 32-43 (1972), and U.S. Pat. No. 4,919,934, in favor of Deckner et al., Issued April 24, 1990, both of which are hereby incorporated by reference in their entirety. These materials are available from Ruger Chemical Co, (Irvington, NJ). When the topical formulations of the present invention contain at least one emollient, each emollient is present in at least 0.1 to 15%, preferably 0.1 to about 3.0, more preferably 0.5, 1.0, or 2.5% by weight. Preferably the emollient is a mixture of cetyl alcohol, isopropyl myristate and stearyl alcohol in a 1/5/2 ratio. The emollient can also be a mixture of cetyl alcohol and stearyl alcohol in a 1/2 ratio. Topical pharmaceutical compositions may also comprise suitable antioxidants, substances known to inhibit oxidation. Suitable antioxidants for use in accordance with the present invention include, but are not limited to, butylated hydroxytoluene, ascorbic acid, sodium ascorbate, calcium ascorbate, ascorbic palmitate, butylated hydroxyanisole, 2,4,5-trihydroxybutyrophenone, 4- hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, guaiac gum, propyl gallate, t-iodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone and tocopherols such as vitamin E, and the like, including salts and esters pharmaceutically acceptable of these compounds. Preferably, the antioxidant is butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid, pharmaceutically acceptable salts or esters thereof, or mixtures thereof. Even more preferably, the antioxidant is butylated hydroxytoluene. These materials are available from Ruger Chemical Co. , (Irvington, NJ). When the topical formulations of the present invention contain at least one antioxidant, the total amount of antioxidant present is from about 0.001 to 0.5% by weight, preferably 0.05 to about 0.5% by weight, more preferably 0.1%. Topical pharmaceutical compositions may also comprise suitable preservatives. The preservatives are compounds added to a pharmaceutical formulation to act as an antimicrobial agent. Among the preservatives known in the art to be effective and acceptable in parenteral formulations are benzalkonium chloride, benzethonium, chlorhexidine, phenol, m-cresol, benzyl alcohol, methylparaben, propylparaben, chlorobutanol, o-cresol, p-cresol, chlorocresol, phenylmercuric nitrate, thimerosal, benzoic acid, and various mixtures thereof. See, for example, Wallhausser, K.-H., Develop. Biol. Standard, 24: 9-28 (1974) (S. Krager, Basel). Preferably, the preservative is selected from methylparaben, propylparaben and mixtures thereof. These materials are available from Inolex Chemical Co (Philadephia, PA) or Sprectrum Chemicals. When the topical formulations of the present invention contain at least one preservative, the total amount of the preservative present is from about 0.01 to about 0.5% by weight, preferably from about 0.1 to 0.5%, more preferably from about 0.03 to about 0.15. Preferably, the preservative is a mixture of methylparaben and propylparaben in a 5/1 ratio. When alcohol is used as a preservative, the amount is usually 15 to 20%. Topical pharmaceutical compositions may also comprise chelating agents suitable for forming complexes with metal cations that cross a lipid layer. Examples of suitable chelating agents include ethylenediaminetetraacetic acid (EDTA), ethylene glycol bis (beta-aminoethyl ether) -?,?,? ,? '- tetracetic (EGTA) (for its acronym in English) and 8-amino-2- [(2-amino-5-methylphenoxy) methyl] -6-methoxyquinoline-N,, ', N' -tetraacetic, tetrapotasium salt (QUIN-2) (for its acronym in English). Preferably, the chelating agents are EDTA and citric acid. These materials are available from Spectrum Chemical. When the topical formulations of the present invention contain at least one chelating agent, the total amount of the chelating agent present is from about 0.005% to 2.0% by weight, preferably from about 0.05% to about 0.5% by weight, more preferably roughly 0.1% by weight. Topical pharmaceutical compositions may also comprise suitable neutralization agents used to adjust the pH of the formulation within a pharmaceutically acceptable range. Examples of the neutralizing agents include but are not limited to trolamine, tromethamine, sodium hydroxide, hydrochloric acid, citric acid, and acetic acid. Such materials are available from Spectrum Chemical (Gardena, CA). When the topical formulations of the present invention contain at least one neutralizing agent, the total amount of the neutralizing agent present is from about 0.1 wt.% To about 10 wt.%, Preferably 0.1 wt.% To about 5.0 wt. , and more preferably approximately 1.0% by weight. The neutralizing agent is generally added in any amount that is required to bring the formulation to the desired pH. Topical pharmaceutical compositions may also comprise suitable viscosity-increasing agents. These components are compounds that can diffuse, capable of increasing the viscosity of a solution containing the polymer by means of the interaction of the agent with the polymer. CARBOPOL ULTREZ 10 can be used as an agent for increasing viscosity. These materials are available from Noveon Chemicals, Cleveland, OH. When the topical formulations of the present invention contain at least one viscosity enhancing agent, the total amount of the total viscosity increase agent present is from about 0.25% to about 5.0% by weight, preferably from about 0.25% to about 1.0% by weight, and more preferably from about 0.4% to about 0.6% by weight. Topical pharmaceutical compositions may also comprise suitable improvers for the penetration of the nails. Examples of nail penetration enhancers include mercaptan, sulfite and bisulfite compounds, keratolytic agents and surfactants. Nail penetration enhancers suitable for use in the invention are described in greater detail in Malhotra et al., J. Pharm. Sci. , 91: 2, 312-323 (2002), which is incorporated herein by reference in its entirety. Topical pharmaceutical compositions may also comprise one or more suitable solvents. The capacity of any solid substance (solute) for dissolution in any liquid substance (solvent) depends on the physical properties of the solute and the solvent. When solutes and solvents have similar physical properties, the solubility of the solute in the solvent will be greater. This causes the traditional understanding that "similar substances dissolve similar substances". Solvents can be characterized at one extreme as lipophilic, non-polar oils, while at the other end as polar hydrophilic solvents. Oily solvents dissolve other non-polar substances by Van Der Walls interactions while water and other hydrophilic solvents dissolve polar substances by ionic, bipolar, or hydrogen bonding interactions. All solvents can be listed along a continuous section from the least polar 1, ie, hydrocarbons such as the decane, to the more polar solvent that is water. A solute will have its greatest solubility in solvents that have an equivalent polarity. Therefore, for drugs that have minimal solubility in water, less polar solvents will provide an improved solubility with the solvent having a polarity almost equivalent to the solute that provides maximum solubility. Most drugs have intermediate polarity, and therefore experience maximum solubility in solvents such as propylene glycol or ethanol, which are significantly less polar than water. If the drug has a greater solubility in propylene glycol (for example (8% (w / w)) than in water (for example, 0.1% (w / w)), then the addition of water to propylene glycol should reduce the maximum amount of solubility of the drug from a mixture of solvents compared to pure propylene glycol The addition of a lean solvent to an excellent solvent will reduce the maximum solubility for the mixture compared to the maximum solubility in the excellent solvent. Topical formulations, the concentration of the active ingredient in the formulation may be limited by the solubility of the active ingredient in the solvent and / or carrier chosen.Non-lipophilic drugs typically exhibit very low solubility in pharmaceutically acceptable solvents and / or carriers. example, the solubility of some compounds of the invention in water, is less than 0.00025% w / w.The solubility of the same compounds of the invention may be less than about 2% w / w in either propylene glycol or isopropyl myristate. In one embodiment of the present invention, the diethylene glycol monoethyl ether (DGME) is the solvent used to dissolve the compounds of the formula (I) or the formula (II). The compounds in the invention, useful in the present formulation, are believed to have a solubility from about 10% w / w to about 25% w / w in DGME. In another embodiment, a water / DGME cosolvent system is used to dissolve the compounds of formula (I) and formula (II). The DGME solvent capacity is reduced when the water is added; however, the DGME / water cosolvent system can be designed to maintain the desired concentration from about 0.1% to about 5% w / w of the active ingredient. Preferably, the active ingredient is present from about 0.5% to about 3% w / w, and more preferably at about 1% w / w, in the topical formulations as applied. Because DGME is less volatile than water, when the topical formulation evaporates during application, the active agent becomes more soluble in the cream formulation. This increased solubility reduces the likelihood of reduced bioavailability, caused by the precipitation of the drug on the surface of the skin, nail, hair, claw or hoof.
Liquid formulations, such as lotions suitable for topical administration or suitable for cosmetic application, may include a suitable aqueous or non-aqueous vehicle with the buffers, suspending and dispersing agents, thickening agents, penetration enhancers and the like. Solid forms such as creams or pastes or the like can include, for example, any of the following ingredients, water, oil, alcohol or fat as a substrate with the surfactant, polymers such as polyethylene glycol, thickening agents, solids and the like . Liquid or solid formulations can include improved delivery technologies such as liposomes, microsomes, microsponges and the like. Additionally, the compounds can be delivered using a system, sustained release, such as the semipermeable matrices of the solid hydrophobic polymers containing the therapeutic agent. Various sustained release materials have been established and are well known to those skilled in the art. Topical treatment regimens according to the practice of this invention comprise the application of the composition directly to the skin, nails, hair, claws or hooves at the site of application, from one to several times daily. The formulations of the present invention can be used to treat, ameliorate or prevent the conditions or symptoms associated with bacterial infections, acne, inflammation and the like. In an exemplary embodiment, the pharmaceutical formulation includes a simple solution. In an exemplary embodiment, the simple solution includes an alcohol. In an exemplary embodiment, the simple solution includes alcohol and water. In an exemplary embodiment, the alcohol is ethanol, ethylene glycol, propanol, propylene glycol, isopropanol or butanol. In another exemplary embodiment, the simple solution is a selected element of about 10% polypropylene glycol and about 90% ethanol; about 20% polypropylene glycol and about 80% ethanol; about 30% polypropylene glycol and about 70% ethanol; about 40% polypropylene glycol and about 60% ethanol; about 50% polypropylene glycol and about 50% ethanol; about 60% polypropylene glycol and about 40% ethanol; about 70% polypropylene glycol and about 30% ethanol; about 80% polypropylene glycol and about 20% ethanol; about 90% polypropylene glycol and about 10% ethanol.
In an exemplary embodiment, the pharmaceutical formulation is a lacquer. See Remington's, supra, for more information on lacquer production. In an exemplary embodiment, the compound is present in said pharmaceutical formulation in a concentration of about 0.5% to about 15%. In an exemplary embodiment, the compound is present in the pharmaceutical formulation in a concentration from about 0.1% to about 12.5%. In an exemplary embodiment, the compound is present in the pharmaceutical formulation in a concentration of from about 1% to about 10%. In an exemplary embodiment, the compound is present in the pharmaceutical formulation in a concentration of from about 1% to about 5%. In an exemplary embodiment, the compound is present in the pharmaceutical formulation in a concentration from about 2% to about 8%. In an exemplary embodiment, the compound is present in the pharmaceutical formulation in a concentration of from about 4% to about 9%. VII. b) Additional Active Agents The following are examples of the cosmetic and pharmaceutical agents that can be added to the topical pharmaceutical formulations of the present invention.
The following agents are known compounds and are readily available commercially. Anti-inflammatory agents include, but are not limited to, bisabolol, mentolato, dapsone, aloe, hydrocortisone, and the like. Vitamins include, but are not limited to, vitamin B, vitamin E, vitamin A, vitamin D, and the like and derivatives of vitamins such as tazarotene, calcipotriene, tretinoin, adapalene and the like. Anti-aging agents include, but are not limited to, niacinamide, retinol and retinoid derivatives, AHA, ascorbic acid, lipoic acid, coenzyme Q 10, beta hydroxy acids, salicylic acid, copper agglutination peptides, and dimethylaminoethyl γ (DAEA) ( by its acronym in English), and similar. Sunscreens and / or sunburn relief agents include, but are not limited to, PABA, jojoba, aloe, padimato-O, methoxycinnamates, proxamine HC1, lidocaine and the like. Agents for sunless tanning include, but are not limited to, dihydroxyacetone (DHA) (for its acronym in English). Agents for the treatment of psoriasis and / or agents for the treatment of acne include, but are not limited to, salicylic acid, benzoyl peroxide, tar pitch, selenium sulfide, zinc oxide, pyrithione (zinc and or sodium), tazarotene, calcipotriene, tretinoin, adapalene and the like. Agents that are effective in controlling or modifying keratinization include, without limitation: tretinoin, tazarotene, and adapalene. Compositions comprising a compound / active agent of Formula (I) and Formula (II), and optionally at least one of these additional agents, are to be administered topically. In a primary application, this leads to the compounds of the invention and any other active agent that works during the treatment of the skin, nails, hair, claws or hooves. Alternatively, one of the active agents applied topically can also be delivered systemically by the transdermal routes. In such compositions, an additional cosmetic or pharmaceutically effective agent, such as an anti-inflammatory agent, vitamin, anti-aging agent, sunscreen, and / or acne treatment agent, for example, is usually a minor component (from about 0.001% about 20% by weight or preferably from about 0.01% to about 10% by weight), with the remainder being several carriers or carriers and processing aids useful for shaping in the desired dosage form.
VII. c) Test The preferred compounds for use in the present topical formulations will have certain pharmacological properties. Such properties include, but are not limited to, low toxicity, low agglutination to serum protein and desirable in vitro and in vivo half-lives. The assays can be used to predict these desired pharmacological properties. The assays used to predict bioavailability include transport through the monolayers of human intestinal cells, including monolayers of Caco-2 cells. Agglutination to serum protein can be predicted from albumin agglutination assays. Such trials are described in a review by Oravcova et al. (1996 J. Chromat, B677: 1-27). The half-life of the compound is inversely proportional to the frequency of dosage of a compound. The in vitro half-lives of the compounds can be predicted from the microsomal half-life assays as described by Kuhnz and Gleschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127). The toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or in experimental animals, for example, for the determination of LD50 (the lethal dose for 50% of the population) and the ED5o ( the therapeutically effective dose in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio between LD50 and ED50. Compounds that exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in the formulation of a dosing interval for use in humans. The dosage of such compounds preferably lies within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending on the dosage form employed and the route of administration used. The exact formulation, route of administration and dosage can be chosen by individual physicians in view of the patient's condition (see, for example, Fingí et al., 1975, in "The Pharmacological Basis of Therapeutics", Chap. 1, p.1). VII d) administration For any component used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays as described herein. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the EC50 (effective dose for 50% increase) as determined in the cell culture, i.e., the concentration of the test compound which achieves an inhibition of the half-life of bacterial cell growth. Such information can be used to more accurately determine the useful doses in humans. In general, the compounds prepared by the methods, and from the intermediates, described herein, will be administered in an amount therapeutically or cosmetically effective by any of the accepted modes of administration for the agents serving the like utilities. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, the route of administration, and the rate of excretion, the combination of drugs, the severity of the particular disease that the therapy is suffering, and the judgment of the prescribing physician. The drug can be supplied once or twice a day, or up to 3 or 4 times a day. The amount and dosage ranges can be adjusted individually to provide levels in the plasma of the active portion that are sufficient to maintain the inhibitory effects of bacterial cell growth. The usual dosages for a patient, for systemic administration, vary from 0.1 to 1000 mg / day, preferably, 1-500 mg / day, more preferably 10-200 mg / day, even more preferably 100-200 mg / day. Established in terms of the surface areas of the patient's body, the usual dosages range from 50-91 mg / m2 / day. The amount of the compound in the formulation can vary within a complete range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent basis (% weight), from about 0.01-10% by weight of the drug based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 0.1-3.0% by weight, more preferably, about 1.0% by weight. The invention is further illustrated by the following examples. The examples are not proposed to define or limit the scope of the invention. EXAMPLES Proton NMRs are recorded on a Varian AS 300 spectrometer and chemical changes are reported in d (ppm) downfield of tetramet ilsilane. The mass spectra are determined on a Micromass Quattro II device. EXAMPLE 1 Preparation of 3 from 1 1.1 Reduction of carboxylic acid To a solution of 1 (23.3 mmol) in anhydrous THF (70 ml) under nitrogen is added dropwise a solution of BH3 THF (1.0 M, 55 ml, 55 mmol) ) at 0 ° C and the reaction mixture is stirred overnight at room temperature. Then the mixture is again cooled with an ice bath and MeOH (20 ml) is added dropwise to decompose excess BH3. The resulting mixture is stirred until no bubbles were released and then 10% NaOH (10 mL) is added. The mixture is concentrated and the residue is mixed with water (200 ml) and extracted with EtOAc. The residue of the rotary evaporation was purified by flash column chromatography on silica gel to give 20.7 mmol of 3. 1.2 Resulted The exemplary compounds of structure 3 prepared by the above method are provided below. 1.2.a 2-bromo-5-chlorobenzyl alcohol 1 H NMR (300 MHz, DMSO-d6): d 7.57 (d, J = 8.7 Hz, 1H), 7.50-7.49 (m, 1H), 7.28-7.24 (m, 1H), 5.59 (t, J = 6.0 Hz, 1H) and 4.46 (d, J = 6.0 Hz, 2H) ppm. 1.2.b alcohol 2-bromo-5-methoxybenzyl XH NMR (300 MHz, SO-D6 D): d 7.42 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.77 (dd) , Ji = 3 Hz, J2 = 3 Hz, 1H), 5.43 (t, J = 5.7 Hz, 1H), 4.44 (d, J = 5.1 Hz, 2H), 3.76 (s, 3H). EXAMPLE 2 Preparation of 3 from 2 2.1 Reduction of the aldehyde To a solution of 2 (Z = H, 10.7 mmol) in methanol (30 ml) is added sodium borohydride (5.40 mol) and the mixture is stirred at room temperature for 1 hour. Water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with brine and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to give 9.9 mmol of 3. 2.2 Results The exemplary compounds of structure 3, prepared by the above method, are provided below. 2.2.a 2-bromo-5- (4-cyanophenoxy) benzyl alcohol 1 H-NMR (300 MHz, CDC13) d (ppm) 2.00 (s a, 1H), 4.75
(s, 2H), 6.88 (dd, J = 8.5, 2.9 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 2.6 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H). 2.2.b 2-bromo-4- (4-cyanophenoxy) benzyl alcohol XH NMR (300 MHz, DMSO-d6): d 7.83 (d, 2H), 7.58 (d, 1H), 7.39 (d, 1H), 7.18 (dd, 1H), 7.11 (d, 2H), 5.48 (t, 1H) and 4.50 (d, 2H) ppm. 2.2. c 5- (4-cyanophenoxy) -1-indanol P.f. 50-53 ° C. MS (ESI +): m / z = 252 (M + 1). HPLC: 99.7% purity at 254 nm and 99.0% at 220 nm. 1 NMR (300 MHz,
DMSO-d6): d 7.80 (d, 2H), 7.37 (d, 1H), 7.04 (d, 2H), 6.98-6.93 (m, 2H), 5.27 (d, 1H), 5.03 (c, 1H), 2.95-2.85 (m, 1H),
2. 75-2.64 (m, 1H), 2.39-2.29 (m, 1H) and 1.85-1.74 (m, 1H) ppm.
2. 2.d 2-bromo-5- (tert-butyldimethylsiloxy) benzyl alcohol XH-NMR (300 MHz, CDC13): d (ppm) 0.20 (s, 6H), 0.98
(s, 9H), 4.67 (s a, 1H), 6.65 (dd, J = 8.2, 2.6 Hz, 1H), 6.98
(d, J = 2.9 Hz, 1H), 7.36m (d, J = 8.8 Hz, 1H). Additional examples of compounds that can be produced by this method include 2-bromo-4- (3-cyanophenoxy) benzyl alcohol; 2-bromo-4- (4-chlorophenoxy) benzyl alcohol; 2-bromo-4-phenoxybenzyl alcohol; 2-bromo-5- (3,4-dicyanophenoxy) benzyl alcohol; 2- (2-bromo-5-fluorophenyl) ethyl alcohol; 2-bromo-5-fluorobenzyl alcohol; and l-bromo-2-naphthalenemethanol. EXAMPLE 3 Preparation of 4 from 3 3.1 Protective alkylation Compound 3 (20.7 mmol) is dissolved in CH2C12 (150 mL) and cooled to 0 ° C with an ice bath. To this solution under nitrogen were consecutively added N, N-diisopropylethylamine (5.4 ml, 31.02 mmol, 1.5 equivalents) and methyl chloromethyl ether (2 ml, 25.85 mmol, 1.25 equivalents). The reaction mixture is stirred overnight at room temperature and washed with water saturated with NaHCO 3 and then with water saturated with NaCl. The residue after rotary evaporation was purified by flash column chromatography on silica gel to give 17.6 mmol of 4. 3.2 Results The exemplary compounds of structure 4 prepared by the above method are provided below. 3.2.a 2-bromo-5-chloro-1 - (methoxymethoxymethyl) benzene XH NMR (300 MHz, DMSO-d6): d 7.63 (d, J = 8.7 Hz, 1H), 7.50 (dd, J = 2.4 & 0.6 Hz, 1H), 7.32 (dd, J = 8. &2.4 Hz, 1H), 4.71 (s, 2H), 4.53 (s, 2H) and 3.30 (s, 3H) ppm. 3.2.b 2-bromo-5-fluoro-l- [l- (methoxymethoxy) ethyl] benzene 1H-NMR (300.058 MHz, CDC13) d ppm 1.43 (d, J = 6.5 Hz, 3H), 3.38 (s, 3H ), 4.55 (d, J = 6.5 Hz, 1H), 4.63 (d, J = 6.5 Hz, 1H), 5.07 (c, J = 6.5 Hz, 1H), 6.85 (m, 1H), 7.25 (dd, J) = 9.7, 2.6 Hz, 1H), 7.46 (dd, J = 8.8, 5.3Hz, 1H). 3.2. c 2-bromo-5-fluoro-l - [2- (methoxymethoxy) ethyl] benzene XH-NMR (300.058 MHz, CDC13) d ppm 3.04 (t, J = 6.7 Hz, 2H), 3.31 (s, 3H), 3.77 (t, J = 6.7 Hz, 2H), 4.62 (s, 2H), 6.82 (td, J = 8.2, 3.2 Hz, 1H), 7.04 (dd, J = 9.4, 2.9 Hz, 1H), 7.48 (dd) , J = 8.8, 5.3 Hz, 1H).
3. 2. d 2-bromo-4,5-difluoro-l- (methoxymethoxymethyl) benzene XH-NMR (300.058 MHz, CDC13) d ppm 3.42 (s, 3H), 4.57 (d, J = 1.2 Hz, 2H), 4.76 (s, 2H), 7.3-7.5 (m, 2H). 3.2. e 2-bromo-5-cyano-l- (methoxymethoxymethyl) benzene 1H-NMR (300.058 Hz, CDC13) d ppm 3.43 (s, 3H), 4.65 (s,
2H), 4.80 (s, 2H), 7.43 (dd, J = 8.2, 4.1 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.82 (d, J = .1 Hz, 1H). 3.2. f 2-bromo-5-methoxy-l- (methoxymethoxymethyl) benzene 1 H NMR (300 MHz, DMSO-d 6): d 7.48 (dd, J 2 = 1. 2 Hz, 1H), 7.05 (d, J = 2.7 Hz, 1H), 6.83 (dd, Hz, 1H), 4.69 (d, J = 1.2 Hz, 2H), 4.5 (s, 2H), 3.74 (d, J = 1.5 Hz, 3H), 3.32 (d, J = 2.1 Hz, 3H) ppm. 3.2. g 1-benzyl-1 - (2-bromophenyl) -1- (methoxymethoxy) ethane 1 H NMR (300 Hz, SOSO-d 6): d 7.70-7.67 (m, 1H), 7.25-7.09 (m, 6H), 6.96-6.93 (m, 2H), 4.61 (d, 1H), 4.48 (d, 1H), 3.36-3.26 (m, 2H), 3.22 (s, 3H) and 1.63 (s, 3H) ppm. 3.2. h 2-bromo-6-fluoro-l- (methoxymethylmethyl) benzene 1H-NMR (300 MHz, CDC13) d (ppm) 3.43 (s, 3H), 4.74 (s, 2H), 4.76 (d, J = 2.1 Hz , 2H), 7.05 (t, J = 9.1 Hz, 1H), 7.18 (td, J = 8.2, 5.9 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H). 3.2.Í 2-bromo-4- (4-cyanophenoxy) -1 - (methoxymethoxymethyl) benzene
1 H NMR (300 MHz, DMSO-d 6): d 7.84 (d, 2 H), 7.56 (d, 1 H), 7.44 (d, 1 H), 7.19-7.12 (m, 3 H), 4.69 (s, 2 H), 4.56 (s, 2H) and 3.31 (s 3H) ppm.
3. 2. j 2-Bromo-5- (tert-butyldimethylsiloxy) -1- (methoxymethoxymethyl) benzene 1H-RN (300 MHz, CDC13) d (ppm) 0.19 (s, 6H), 0.98 (s, 9H), 3.43 ( s, 3H), 4.59 (s, 2H), 4.75 (s, 2H), 6.64 (dd, J = 8.5, 2.9 Hz, 1H), 6.98 (d, J = 2.9 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H). 3.2.k 2-bromo-5- (2-cyanophenoxy) -1- (methoxymethoxymethyl) benzene
1 H-NMR (300 MHz, CDC13) d (ppm) 3.41 (s, 3H), 4.64 (s, 2H), 4.76 (s, 2H), 6.8-6.9 (m, 2H), 7.16 (td, J = 7.6 , 0.9 Hz, 1H), 7.28 (d, J = 2.9 Hz, 1H), 7.49 (ddd, J = 8.8, 7.6, 1.8 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.67 (dd) , J = 7.9, 1.8 Hz). 3.2.1 2-bromo-5-phenoxy-l- (methoxymethoxymethyl) benzene 1H-NMR (300 MHz, CDC13) d (ppm) 3.40 (s, 3H), 4.62 (s, 2H), 4.74 (s, 2H) , 6.80 (dd, J = 8.8, 2.9 Hz, 1H), 7.01 (d, J = 85 Hz, 2H), 7.12 (t, J = 7.9 Hz, 1H), 7.19 (d, J = 2.9 Hz, 1H) , 7.35 (t, J = 7.6 Hz, 2H), 7.48 (d, J = 8.5 Hz, 1H). Additional examples of compounds that can be produced by this method include 2-bromo-l- (methoxymethoxymethyl) benzene; 2-bromo-5-methyl-l- (methoxymethoxymethyl) -1-benzene; 2-bromo-5- (methoxymethoxymethyl) -1- (methoxymethoxymethyl) benzene, 2-bromo-5-fluoro-1- (methoxymethoxymethyl) benzene; l-bromo-2- (methoxymethoxymethyl) naphthalene; 2-bromo-4-fluoro-1- (methoxymethoxymethyl) benzene; 2-phenyl-1- (2-bromophenyl) -1- (methoxymethoxymethyl) ethane; 2-bromo-5- (4-cyanophenoxy) -1- (methoxymethoxymethyl) benzene; 2-bromo-4- (3-cyanophenoxy) -1- (methoxymethoxymethyl) benzene; 2-bromo-4- (4-chlorophenoxy) -1- (methoxymethoxymethyl) benzene; 2-bromo-4-phenoxy-1- (methoxymethoxymethyl) benzene; 2-bromo-5- (3,4-dicyanophenoxy) -1- (methoxymethoxymethyl) benzene. EXAMPLE 4 Preparation of I from 4 by means of 5 4.1 Metalation and boronylation To a solution of 4 (17.3 mmol) in anhydrous THF (80 ml) at -78 ° C under nitrogen is added dropwise tert-BuLi or n- BuLi (11.7 mi) and the solution turned brown. Then, B (0Me) 3 (1.93 ml, 17.3 mmol) was injected in a portion and the cooling bath was removed. The mixture was gradually heated with stirring for 30 minutes and then stirred with a water bath for 2 hours. After the addition of 6N HC1 (6 ml), the mixture is stirred overnight at room temperature and about 50% of the hydrolysis has been successful as shown by the TLC (for its acronym in English) analysis. The solution was evaporated by centrifugation and the residue was dissolved in MeOH (50 ml) and 6N HC1 (4 ml). The solution is refluxed for 1 h and the hydrolysis was complemented as indicated by the TLC analysis. The rotary evaporation gave a residue which was dissolved in EtOAc, washed with water, dried and then evaporated. The crude product is purified by flash column chromatography on silica gel to provide a solid with a purity of 80%. The solid was further purified by washing with hexane to give 7.2 mmol of I. 4.2 Results The analytical data for the exemplary compounds of structure I are provided later. 4.2.a 5-Chloro-l, 3-dihydro-l-hydroxy-2, 1-benzoxazole (Cl) P.f. 142-150 ° C. MS (ESI): m / z = 169 (M + l, positive) and 167 (M-l, negative). HPLC (220 nm): 99% purity. 1 H NMR (300 MHz, DMSO-d 6): d 9.30 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.38 (d, J = 7.8 Hz, 1H) and 4.96 (s, 2H) ppm. 4.2.b 1, 3-dihydro-l-hydroxy-2, 1-benzoxazole (C2) P.f. 83-86 ° C. MS (ESI): m / z = 135 (M + l), positive) and 133 (M-l, negative). HPLC (220 nm): 95.4% purity. X H NMR (300 MHz, DMSO-d 6): d 9.14 (s, 1 H), 7.71 (d, J = 7.2 Hz, 1 H), 7.45 (t, J = 7.5 Hz, 1 H), 7.38 (d, J = 7.5 Hz, 1H), 7.32 (t, J = 7.1, Hz, 1H), 4.97 (s, 2H) ppm. 4.2. c 5-fluoro-l, 3-dihydro-l-hydroxy-3-methyl-2, 1-benzoxazole (C3) XH-NMR (300 MHz, DMSO-d6) d ppm 1.37 (d, J = 6.4 Hz, 3H ), 5.17 (c, J = 6.4 Hz, 1H), 7.14 (ra, 1H), 7.25 (dd, J = 9.7, 2.3 Hz, 1H), 7.70 (dd, J = 8.2, 5.9 Hz, 1H) and 9.14 (s, 1H). 4.2.d 6-fluoro-l-hydroxy-l, 2,3,4-tetrahydro-2, 1-benzoxazole (C4) ^ -RMN (300 MHz, DMSO-d6) d ppm 2.86 (t, J = 5.9 Hz , 2H), 4.04 (t, J = 5.9 Hz, 2H), 7.0-7.1 (m, 2H), 7.69 (dd, J = 8.2, 7.2 Hz, 1H), 8.47 (s, 1H). 4.2. e 5,6-difluoro-l, 3-dihydro-l-hydroxy-2, 1-benzoxazole
(C5) 1 H-NMR (300 MHz, DMSO-d 6) d ppm 4.94 (s, 2H), 7.50 (dd, J = 10.7, 6.8 Hz, 1H), 7.62 (dd, J = 9.7, 8.2 Hz, 1H) , 9.34 (s, 1H). 4.2.f 5-cyano-l, 3-dihydro-l-hydroxy-2, 1-benzoxazole (C6) 1 H-NMR (300 MHz, DMSO-d6) d ppm 5.03 (s, 2H), 7.76 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.90 (s, 1H), 9.53 (s, 1H). 4.2.g 1, 3-dihydro-l-hydroxy-5-methoxy-2, 1-benzoxazole (C7) P.f. 102-104 ° C. EM ESI: m / z = 165.3 (+ l) and 162.9 (M-1). X H NMR (300 MHz, DMSO-d 6): d 8.95 (s, 1 H), 7.60 (d, J = 8.1 Hz, 1 H), 6.94 (s, 1 H), 6.88 (d, J = 8.1 Hz, 1 H), 4.91 (s, 1H), 3.77 (s, 3H) ppm. 4.2.h 1, 3-dihydro-l-hydroxy-5-methyl-2, 1-benzoxazole (C8) P.f. 124-128 ° C. ESI MS: m / z * 148.9 (M + l) and 146.9 (M-1). 1 H NMR (300 MHz, DMSO-d 6): d 9.05 (s, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.18 (s, 1H), 7.13 (d, J = 7.2 Hz, 2H), 4.91 (s, 2H), 2.33 (s, 3H) ppra.
4. 2.Í 1, 3-dihydro-l-hydroxy-5-hydroxymethyl-2, 1-benzoxazole
(C9) MS: m / z = 163 (M-1, ESI-). 1 H NMR (300 Hz, DMSO-d 6): d 9.08 (s, 1 H), 7.64 (d, 1 H), 7.33 (s, 1 H), 7.27 (d, 1 H), 5.23 (t, 1 H), 4.96 (s) , 2H), 4.53 (d, 2H) ppm. 4.2.j l, 3-Dihydro-5-fluoro-l-hydroxy-2, l-benzoxabole (CIO) P.f. 110-114 ° C. ESI MS: m / z = 150.9 (M-l). 1H RN (300 MHz, DMSO-d6): d 9.20 (s, 1H), 7.73 (dd, Ji = 6 Hz, 1H), 7.21 (m, 1H), 7.14 (m, 1H), 4.95 (s, 2H) ) ppm. 4.2.k 1, 3-dihydro-2-oxa-l-cyclopenta [ot] naphthalene (Cll) P.f. 139-143 ° C. ESI MS: m / z = 184.9 (M + l). 1ti NMR (300 Hz, DMSO-d6): d 9.21 (s, 1H), 8.28 (dd, Jx = 6.9 Hz, J2 = 0.6 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.95 ( d, J = 7.5 Hz, 7.59-7.47 (m, 3H), 5.09 (s, 2H) ppm 4.2.1 l-hydroxy-2, 1-oxaborolane [5, 4-c] pyridine (C12) 1H-NMR (300 MHz, DMSO-d6): d ppm 5.00 (s, 2H), 7.45 (d, J = 5.0 Hz, 1H), 8.57 (d, J = 5.3 Hz, 1H), 8.91 (s, 1H), 9.57 (s, 1H), ESI-MS m / z 134 (MH) ~, C6H6BN02 = 135. 4.2.ml, 3-dihydro-6-fluoro-l-hydroxy-2, l-benzoxazole (C13) Pf 110-117 ° C. MS (ESI): m / z = 151 (Ml, negative), HPLC (220 nm): 100% purity, 1 H NMR (300 MHz, DMSO-d 6): d 9.29 (s, 1H), 7.46- 7.41 (m, 2H), 7.29 (td, 1H), and 4.95 (s, 2H) ppm.
4. 2. n 3-benzyl-l, 3-dihydro-l-hydroxy-3-methyl-2, 1-benzoxazole
(C14) MS (ESI): m / z = 239 (M + l, positive). HPLC: 99.5% purity at 220 nm and 95.9% at 254 nm. 1ti NMR (300 MHz, DMS0-d6): d 8.89 (s, 1H), 7.49-7.40 (m, 3H), 7.25-7.19 (m, 1H), 7.09-7.05 (m, 3H), 6.96-6.64 ( m, 2H), 3.10 (d, 1H), 3.00 (d, 1H) and 1.44 (s, 3H) ppm. 4.2. or 3-benzyl-l, 3-dihydro-l-hydroxy-2, 1-benzoxazole (C15) MS (ESI): m / z = 225 (M + 1). HPLC: 93.4% purity at 220 nm. 1 H NMR (300 MHz, DMSO-d 6): d 9.08 (s, 1H), 7.63 (dd, 1H), 7.43 (t, 1H), 7.35-7.14 (m, 7H), 5.38 (dd, 1H), 3.21 (dd, 1H), and 2.77 (dd, 1H) ppm. 4.2.p 1, 3-dihydro-4-fluoro-l-hydroxy-2, 1-benzoxazole (C16) 1 H-NMR (300 MHz, DMSO-d6) d (ppm) 5.06 (s, 2H), 7.26 (ddd) , J = 9.7, 7.9, 0.6 Hz, 1H), 7.40 (td, J = 8.2, 4.7 Hz, 1H), 7.55 (d, J = 7.0 Hz, 1H), 9.41 (s, 1H). 4.2. q 5- (4-cyanophenoxy) -1,3-dihydro-l-hydroxy-2, Ibenzoxazole (Cl 7) XH-NMR (300 MHz, DMSO-d6) d ppm 4.95 (s, 2H), 7.08 (dd, J = 7.9-2.1 Hz, 1H) 7.14 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 2.1 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 9.1 Hz, 2H), 9.22 (s, 1H). 4.2. r 6- (4-cyanophenoxy) -1,3-dihydro-l-hydroxy-2, 1-benzoxazole (C18) P.f. 148-151 ° C. MS: m / z = 252 (M + 1) (ESI +) and m / z = 250 (M-1) (ESI-). HPLC: 100% purity at 254 nm and 98.7% at 220 nm. 1 NMR (300 MHz, DMSO-d6): d 9.26 (s, 1H), 7.82 (d, 2H), 7.50 (d, 1H), 7.39 (d, 1H), 7.26 (dd, 1H), 7.08 (d , 2H), and 4.99 (s, 2H) ppm. 4.2. s 6- (3-cyanophenoxy) -1,3-dihydro-l-hydroxy-2, 1-benzoxazole (C19) P.f. 146-149 ° C. MS: m / z = 252 (M + 1) (ESI +) and m / z = 250 (M-1) (ESI-). HPLC: 100% purity at 254 nm and 97.9% at 220 nm. 1ti NMR (300 Hz, DMSO-d6): d 9.21 (s, 1H), 7.60-7.54 (m, 2H), 7.50-7.45 (m, 2H), 7.34-7.30 (m, 2H), 7.23 (dd, 1H) and 4.98 (s, 2H) ppm. 4.2. t 6- (4-chlorophenoxy) -1,3-dihydro-l-hydroxy-2, 1-benzoxazole (C20) P.f. 119-130 ° C. MS: m / z = 261 (M + 1) (ESI +) and m / z = 259 (M-1) (ESI-). HPLC: 100% purity at 254 nm and 98.9% at 220 nm. X H NMR (300 MHz, DMSO-d 6): d 9.18 (s, 1 H), 7.45-7.41 (m, 3 H), 7.29 (d, 1 H), 7.01 (d, 2 H) and 4.96 (s, 2 H) ppm. 4.2.u 6-phenoxy-l, 3-dihydro-l-hydroxy-2, 1-benzoxazole (21) P.f. 95-99 ° C. MS: m / z = 227 (M + 1) (ESI +) and m / z = 225 (M-1) (ESI-). HPLC: 100% purity at 254 nm and 98.4% at 220 nm. ?? NMR (300 MHz, DMSO-d6): d 9.I7 (s, 1H), 7.43-7.35 (m, 3H), 7.28 (s, 1H), 7.19-7.09 (m, 2H), 6.99 (d, 2H). ) and 4.96 (s, 2H) ppm.
4. 2. v 5- (4-Cyanobenzyloxy) -1,3-dihydro-l-hydroxy-2, 1-benzoxazole (C22) 1 H-NMR (300 MHz, DMSO-d 6) d (ppm) 4.90 (s, 2H) , 5.25 (s, 2H), 6.98 (dd, J = 7.9, 2.1 Hz, 1H), 7.03 (d, J = 1. 8 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.64 ( d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.5 Hz, 1H), 9.01 (s, 1H). 4.2. w 5- (2-cyanophenoxy) -1,3-dihydro-l-hydroxy-2,1-benzoxazole (C23) 1 H-NMR (300 Hz, DMSO-d 6) d (ppm) 4.95 (s, 2H), 7.0 -7.2 (m, 3H), 7.32 (td, 3 = 1.6-1.2 Hz, 1H), 7.68 (ddd, J = 9.1, 7.6, 1.8 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.91 (dd, J = 7.9, 1.8 Hz, 1H). 4.2.x 5-phenoxy-l, 3-dihydro-l-hydroxy-2, 1-benzoxazole (C24) 1 H-NMR (300 MHz, DMSO-d6) d (ppm) 4.91 (s, 2H), 6.94 (s) , 1H), 6.96 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 7.6 Hz, 2H), 7.17 (t, J = 7.3 Hz, 1H), 7.41 (t, J = 7.3 Hz, 2H ), 7.70 (d, J = 8.5 Hz, 1H), 9.11 (s, 1H). 4.2. and 5- [4- (?,? - diethylcarbamoyl) phenoxy] -1,3-dihydro-l-hydroxy-2, 1-benzoxazole (C25) 1H-NMR (300 MHz, DMSO-d6) d (ppm ) 1.08 (sa, 6H), 3.1-3.5
(m, 4H), 4.93 (s, 2H), 7.0-7.1 (m, 4H), 7.37 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 7.9 Hz, 1H), 9.15 (s, 1 HOUR) . 4.2. z 1, 3-dihydro-l-hydroxy -5- [4- (morpholinocarbonyl) phenoxy] -2, 1-benzoxazole (C26) XH-NMR (300 MHz, DMSO-d6) d (ppm) 3.3-3.7 (m , 8H), 4.93 (s, 2H), 7.0-7.1 (m, 4H), 7.44 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 7.9 Hz, 1H), 9.16 (s, 1H) . 4.2.a to 5- (3,4-dicyanophenoxy) -1,3-dihydro-l-hydroxy-2, 1-benzoxazole (C27) 1 H-NMR (300 MHz, DMSO-d 6) d (ppm) 4.97 (s, 2H), 7.13 (dd,
J = 7.9, 2.1 Hz, 1H), 7.21 (d, J = 1. 5 Hz, 1H), 7.43 (d, J = 8.8, 2.6 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 2.6 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 9.26 (s, 1H). 4.2. ab 6-phenylthio-l, 3-dihydro-l-hydroxy-2, 1-benzoxazole (C28) P.f. 121-124 ° C. MS: m / z = 243 (M + 1) (ESI +) and m / z = 241 (M-1) (ESI-). HPLC: 99.6% purity at 254 nm and 99.6% at 220 nm. X H NMR (300 MHz, DMSO-d 6): d 9.25 (s, 1 H), 7.72 (dd, 1 H), 7.48 (dd, 1 H), 7.43 (dd, 1 H), 7.37-7.31 (m, 2 H), 7.29 -7.23 (m, 3H), and 4.98 (s, 2H) ppm. 4.2. ac 6- (4-trifluoromethoxyphenoxy) -1,3-dihydro-l-hydroxy-2, 1-benzoxazole (C29) P.f. 97-101 ° C. MS: m / z = 311 (M + 1) (ESI +) and m / z = 309 (M-1) (ESI-). HPLC: 100% purity at 254 nm and 100% at 220 nm. ?? NMR (300 MHz, DMSO-d6): d 9.20 (s, 1H), 7.45 (d, 1H), 7.37 (d, 2H), 7.33 (d, 1H), 7.21 (dd, 1H), 7.08 (d, 2H), and 4.97 (s, 2H) ppm. .2. ad 5- (N-methyl-N-f'enylsulfoni lamino) -1,3-dihydro-l-hydroxy-2, 1-benzoxazole (C30) P.f. 85-95 ° C. MS: m / z = 304 (M + 1) (ESI +) and m / z = 302 (M-1) (ESI-). HPLC: 96.6% purity at 254 nm and 89.8% at 220 nm. X H NMR (300 MHz, DMSO-d 6): d 9.23 (s, 1 H), 7.72-7.63 (m, 2 H), 7.56 (t, 2 H), 7.50 (d, 2 H), 7.16 (s, 1 H), 7.03 (d, 1H), 4.91 (s, 2H), and 3.14 (s, 3H) ppm. 4.2. ae 6- (4-methoxyphenoxy) -1,3-dihydro-l-hydroxy-2, 1-benzoxazole (C31) P.f. 126-129 ° C. MS: m / z = 257 (M + 1) (ESI +) and m / z = 255 (M-1) (ESI-). HPLC: 98.4% purity at 254 nm and 98.4% at 220 nm. X H NMR (300 MHz, DMSO-d 6): d 9.14 (s, 1 H), 7.36 (d, 1 H), 7.19 (s, 1 H), 7.12 (d, 1 H), 6.98 (d, 2 H), 6.95 (d , 2H), 4.93 (s, 2H) and 3.73 (s, 3H) ppm. 4.2.af 6- (4-methoxyphenylthio) -1,3-dihydro-l-hydroxy-2, 1-benzoxazole (C32) P.f. 95-100 ° C. MS: m / z = 272 (M +), 273 (M + 1) (ESI +) and m / z = 271 (M-1) (ESI-). HPLC: 100% purity at 254 nm and 99.2% at 220 nm. X H NMR (300 MHz, DMSO-d 6): d 9.20 (s, 1H), 7.51 (d, 1H), 7.39-7.28 (m, 4H), 6.98 (d, 2H), 4.93 (s, 2H) and 3.76 (s, 3H) ppm. 4.2.ag (6- (4-methoxyphenylsulfonyl) -1,3-dihydro-l-hydroxy-2, 1-benzoxazole (C33) Mp 180-192 ° C MS: m / z = 305 (M + l) ( ESI +) and m / z = 303 (Ml) (ESI-) CLAR: 96.8% purity at 254 nm and 95.5% at 220 nm 1 H NMR (300 MHz, DMSO-d6): d 9.46 (s, 1H), 8.28 (s, 1H), 7.99 (d, 1H), 7.85 (d, 2H), 7.61 (d, 1H), 7.11 (d, 2H), 5.02 (s, 2H), and 3.80 (s, 3H) ppm .
4. 2.ah 6- (4-methoxyphenylsulfinyl) -1,3-dihydro-l-hydroxy-2, 1-benzoxazole (C34) 1 H-NMR (300 MHz, DMSO-d 6): d 9.37 (s, 1H), 8.02 (d, 1H), 7.71 (dd, 1H), 7.59 (d, 2H), 7.53 (d, 1H), 7.07 (d, 2H), 5.00 (s, 2H) and 3.76 (s), 3H) ppm. 4.2.ai 5-trifluoromethyl-l, 3-dihydro-l-hydroxy-2, 1-benzoxazole (C35) P.f. 113-118 ° C. MS: m / z = 203 (M + 1) (ESI +) and m / z = 201 (M-1) (ESI-). HPLC: 100% purity at 254 nm and 100% at 220 nm. XH-NMR (300 MHz, DMSO-d6): d 9.48 (s, 1H), 7.92 (d, 1H), 7.78 (s, 1H) 7.67 (d, 1H), and 5.06 (s, 2H) ppm. 4.2.aj 4 - (4-cyanophenoxy) -1,3-dihydro-1-hydroxy-2, 1-benzoxazole (C36) For the linking reaction between 4-fluorobenzonitrile and the substituted phenol to provide raw material 2, see Igarashi, S.; et al. Chemical & Pharmaceutical Bulletin (2000), 48 (11), 1689-1697. 1 H NMR (300 MHz, DMSO-d 6) (ppm) 4.84 (s, 2 H), 7.08 (d, J = 8.2 Hz, 2 H), 7.18 (d, J = 7.9 Hz, 1 H), 7.45 (t, J = 7.3 Hz, 1H), 7.63 (d, J = 7.3 Hz, 1H), 7.63 (d, J = 7.3 Hz, 1H), 7.82 (d, J = 8.5 Hz, 2H). 4.2.ak 5- (3-cyanophenoxy) -1,3-dihydro-l-hydroxy-2, 1-benzoxazole (C37) For the union between 3-fluorobenzonitrile and the substituted phenol to give the raw material 2: Li, F. et al., Organic Letters (2003), 5 (12), 2169-2171. 1ti NMR (300 MHz, DMSO-d6) (ppm) 4.93 (s, 2H), 7.0-7.1 (m, 2H), 7.3-7.4 (m, 1H), 7.5-7.7 (m, 3H), 7.75 (d , J = 8.2 Hz, 1H). 4.2.al to 5- (4-carboxyphenoxy) -l-hydroxy-2, 1-benzoxazole (C38) To a solution of 5- (4-cyanophenoxy) -l-hydroxy-2, 1-benzoxabole obtained in C17 (430 mg , 1.71 mmol) in ethanol (10 mL) is added 6 mol / 1 of sodium hydroxide (2 mL), and the mixture is refluxed for 3 hours. Hydrochloric acid (6 mol / 1, 3 ml) is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with brine and dried over anhydrous sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate) followed by trituration with diisopropyl ether to give the objective compound (37 mg, 8%). ?? NMR (300 Hz, DMSO-d6) d (ppm) 4.94 (s, 2H), 7.0-7.1 (m, 4H), 7.76 (d, J = 7.9 Hz, 1H), 7.94 (d, J = 8.8 Hz, 2H), 9.19 (s, 1H), 12.8 (sa, 1H). 4.2. am 1-hydroxy-5- [4 - (tetrazol-1-yl) phenoxy] -2,1-benzoxazole (C39) A mixture of 5- (4-cyano-phenoxy) -l-hydroxy-2, 1-benzoxazole (200 mg, 0.797 mmol), sodium acid (103 mg, 1.59 mmol), and ammonium chloride (85 mg, 1.6 mmol) in N, N-dimethylformamide (5 mL) was stirred at 80 ° C for two days. Water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by chromatography on silica gel (ethyl acetate) followed by trituration with ethyl acetate to give the objective compound (55 mg, 23%). ^ -RMN (300 MHz, DMSO-d6) d (ppm) 4.95 (s, 2H), 7.0-7.1 (m, 2H), 7.23 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 7.9 Hz, 1H), 8.05 (d, J = 8.5 Hz, 2H), 9.18 (sa, 1H). EXAMPLE 5 Preparation of I from 2 by Medium 6 5.1 Catalytic boronilation, reduction and cyclization A mixture of 2 (10.0 mmol), bis (pinacolato) diboro (2.79 g, 11.0 mmol), PdCl2 (dppf) (250 mg, 3% in mol), and potassium acetate (2.94 g, 30.0 mmol) in 1,4-dioxane (40 ml) and stirred at 80 ° C overnight. Water is added and the mixture is extracted with ethyl acetate. The organic layer is washed with brine and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure. The crude product is dissolved in tetrahydrofuran (80 ml), then sodium periodate (5.56 g, 26.0 mmol) is added. After stirring at room temperature for 30 minutes, 2N HC1 (10 mL) is added, and the mixture is stirred at room temperature overnight. Water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with brine and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure, and the residue is treated with ether to give 6.3 mmol of the corresponding boronic acid. To the solution of the boronic acid obtained (0.595 mmol) in methanol (5 ml) is added sodium borohydride (11 mg, 0.30 mmol) and the mixture is stirred at room temperature for 1 h. Water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel to give 0.217 mmol of I. 5.2 Results The analytical data for the exemplary compounds of structure I are provided later. 5.2.a l, 3-dihydro-5-fluoro-l-hydroxy-2, l-benzoxazole (CIO) The analytical data for this compound are listed in 4.2.j. EXAMPLE 6 Preparation of I from 3 Cyclization and boronylation in a vessel To a solution of 3 (4.88 mmol) and triisopropyl borate (1.35 ml, 5.86 mmol) in tetrahydrofuran (10 ml) is added n-butyllithium (1.6 mol / 1 in hexanes; 6.7 ml, 10.7 mmol) was dripped for 15 minutes at -78 ° C under nitrogen atmosphere, and the mixture was stirred for 2 h while allowing heating at room temperature. The reaction is quenched with 2N HC1, and extracted with ethyl acetate. The organic layer is washed with brine and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure, and the residue is purified by silica gel column chromatography and treated with pentane to give 0.41 mmol of I. 6.2 Results The analytical data for the exemplary compounds of structure I are provided below. 6.2.a, 3-dihydro-5-fluoro-l-hydroxy-2, l-benzoxazole (CIO) Analytical data for this compound are listed in 4.2.j. EXAMPLE 7 Preparation of I from 3 7.1 Boronylation and cyclization in a vessel with distillation To a solution of 3 (4.88 mmol) in toluene (20 ml) is added triisopropyl borate (2.2 ml, 9.8 mmol), and the mixture is mixed. heat at reflux for 1 h. The solvent, the isopropyl alcohol generated and the excess triisopropyl borate were removed under reduced pressure. The residue is dissolved in tetrahydrofuran (10 ml) and cooled to -78 ° C. N-butyl lithium (3.2 ml, 5.1 mmol) is added dropwise over 10 minutes, and the mixture is stirred for 1 h while it is allowed to warm to room temperature. The reaction is quenched with HC1 2 N, and extracted with ethyl acetate. The organic layer is washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give 1.54 mmol of I. 1.2 results The analytical data for the exemplary compounds of structure I are provided below. 7.2.a l, 3-dihydro-5-fluoro-l-hydroxy-2, l-benzoxazole (CIO) The analytical data for this compound are listed in 4.2. j. EXAMPLE 8 Preparation of 8 from 7 8.1 Bromination To a solution of 7 (49.5 mmol) in carbon tetrachloride (200 ml) were added N-bromosuccinimide (8.81 g, 49.5 mmol) and N, N-azobisobutyl ilonitrile (414 mg. , 5 mol%), and the mixture is refluxed for 3 h. Water is added, and the mixture is extracted with chloroform. The organic layer is washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the crude methyl brominated intermediate 8.
EXAMPLE 9 Preparation of 3 from 8 9.1 Hydroxylation To unrefined compound 8 (49.5 mmol) is added dimethylformamide (150 ml) and sodium acetate (20.5 g, 250 mmol), and the mixture is stirred at 80 ° C throughout. the night. Water is added, and the mixture is extracted with ether. The organic layer is washed with water and brine, and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure. Ethanol (150 ml) and 1N sodium hydroxide (50 ml) are added to the residue, and the mixture is stirred at room temperature for 1 h. The reaction mixture is concentrated to approximately one third of the volume under reduced pressure. Water and hydrochloric acid are added, and the mixture is extracted with ethyl acetate. The aqueous layer is washed with water and brine, and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure, and the residue is purified by column chromatography with silica gel followed by trituration with dichloromethane to give 21.8 mmol of 3. 9.2 Results The exemplary compounds of structure 3 prepared by the above method are subsequently provided. . 9.2.a 2-bromo-5-cyanobenzyl alcohol 1 H NMR (300 MHz, DMSO-d 6) d (ppm) 4.51 (d, J = 5.9 Hz, 2H), 5.67 (t, J = 5.6 Hz, 1H), 7.67 (dd, J = 8.2, 2.0 Hz, 1H), 7.80 (s, J = 8.2 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H). Additional examples of the compounds that can be produced by this method include the alcohol 2-bromo-5- (4-cyanophenoxy) benzyl EXAMPLE 10 Preparation of 9 from 2 10.1 Reaction A mixture of 2 (20.0 mmol), (methoxymethyl) triphenylphosphonium (8.49 g, 24.0 mmol), and tere. Potassium-butoxide (2.83 g, 24.0 mol) in N, N-dimethylformamide (50 ml) is stirred at room temperature overnight. The reaction is quenched with HC1 6 N, and the mixture is extracted with ethyl acetate. The organic layer is washed with water (2x) and brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue was added tetrahydrofuran (60 ml) and HC1 6 N, and the mixture was refluxed for 8 h. Water is added, and the mixture is extracted with ether. The organic layer is washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 16.6 mmol of 9. EXAMPLE 11 Preparation Method of Step 13 11.1 Reaction A solution of I in an appropriate alcohol solvent (R1-OH) is refluxed under a nitrogen atmosphere and then Distillate to remove the alcohol to give the corresponding ester. EXAMPLE 12 Preparation of Ib from 12.1 Reaction To a solution of the in toluene an amino alcohol is added and the participated solid was collected to give Ib.
12. 2 Results (500 mg, 3.3 mmol) are dissolved in toluene (37 ml) at
80 ° C and ethanolamine (0.20 ml, 3.3 mmol) was added. The mixture is cooled to room temperature, then cooled in an ice bath, and filtered to give C40 as a white powder (600.5 mg, 94%). 12.2a (CAO) * H NMR (300 MHz, DMSO-d6) d (ppm) 2.88 (t, J = 6.2 Hz, 2H), 3.75 (t, J = 6.3Hz, 2H), 4.66 (s, 2H) , 5.77 (amp., 2H), 6.85-6.91 (m, 2H), 7.31 (td, J = 7.2, 1.2 Hz, 1H). EXAMPLE 13 Formulations The compounds of the present invention can be administered to a patient using a therapeutically effective amount of the compound of Formulas (I) or (II) in any of the following three lacquer formulations and a solvent formulation. The lacquer formulation provides good durability while the solvent formulation provides good ease of use. These compounds can also be applied using a spray formulation, a paint spray, drops, or others. 1. 20% propylene glycol; 70% ethanol, 10% of the compound of the invention; 2. 70% ethanol; 20% poly (vinyl methyl ether-salt mono-maleic acid ester of maleic acid) compound of the invention; 3. 56% ethanol; 14% water; 15% poly (2-hydroxyethyl methacrylate); 5% dibutyl sebacate; 10% of the compound of the invention; 4. 55% ethanol; 15% ethyl acetate; 15% poly (vinyl acetate); 5% dibutyl sebacate; 10% of the compound of the invention. The preparation of these formulations is well known in the art and is found in references such as Remington: The Science and Practice of Pharmacy, supra. Example 14 Antifungal MIC Test All MIC tests followed by the National Committee for Clinical Laboratory Standards (NCCLS) guidelines for antimicrobial testing of yeasts and filamentous fungi ( Pfaller et al; publication M38-A - by NCCLS Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filaraentous Fungi; Approved Standard, Wayne, PA: NCCLS; 2002 (Vol. 22, No. 16) except Malassezia species that were incubated in a urea broth (Nakamura et al., Antimicrobial Agents and Chemotheraphy, 2000, 44 (8) pp. 2185-2186) The results of the MIC test are provided in Figure 1. EXAMPLE 15 Keratin test Many antifungal agents they agglutinate strongly to keratin which not only reduces their antifungal potency but also may restrict their penetration into the nails.The affinities of the compounds for keratin potency were determined by a method described in Tatsumi, Antimicrobial Agents and Chemotheraphy, 46 (12): 3797-3801 (2002). A comparison of MIC data for various compounds of the invention against T. rubrum, with and without the presence of 5% keratin, is given in Figure 1. EXAMPLE 16 (CIO) Antifungal Activity Spectrum (CIO) is a novel compound in development for use as a topical antifungal treatment. The purpose of this study was to determine the minimum inhibitory concentration (MIC) for (CIO) against 19 test strains of fungi including: Aspergillus fumigatus (A. fumigatus), Candida Albicans (C. Albicans, strains both resistant and sensitive to fluconazole); Candida glabrata (C. glabrata), Candida krusei (C. krusei), Cryptococcus neoformans (C. neoformans), Candida parapsilosis
(C. parapsilosis), Candida tropicalis (C. troplicalis), Epidermophyton floccosum. { E. floccosum), Fusarium solani (F. solani), Malasseiza fúrfur. { M. fúrfur), Malassezia pachydermatis. { M. pachydermatis), Malassezia sympodialis. { M. sympodialis), Microsporum audouinii (. Audouinii), Microsporum canis. { M. canis), Microsporum gypseum. { M. gypseum), Trichophyton mentagrophytes (G. mentagrophytes), Trichophyton rubrum (G. rubrum), Trichophyton tonsurans (G. tonsurans). Fungus growth was evaluated after exposure to different concentrations of (CIO). In addition, the MIC for (CIO) against T. rubrum in the presence of 5% keratin and the minimum fungicidal concentration (MFC) for (CIO) against T. rubrum and T. mentagrophytes were also determined . Cyclopirox and / or terbinafine and / or fluconazole and / or itraconazole were used as comparators and tested in a similar manner. These studies were carried out at NAEJA Pharmaceutical, Inc. Materials and methods (CIO) was obtained from Anacor Pharmaceuticals, Inc.
(Palo Alto, CA, USA). Strains of ATTC were obtained from ATCC (Manassas, VA, USA). Cyclopiroxolamin was obtained from Sigma-Aldrich Co. (St. Louis, MO, USA). Terbinafine, fluconazole and itraconazole were synthesized in NAEJA Pharmaceutical, Inc. (Edmonton, AB, Canada), experimental procedures and analytical data for these standards are stored in the NAEJA archives. All MIC tests followed by National Commitee guidelines by Clinical Laboratory Standards (NCCLS) for antimicrobial testing of yeasts and filamentous fungi (Pfaller et al., 2002) except for Malasaezia species that were incubated in a urea broth (Nakamura et al, 2000). The microcalde dilution method was used to test the in vitro activity of (CIO) against 19 fungal test strains. Briefly, the compounds were dissolved in DMSO and diluted in sterile water to give a storage, working material. Serial dilutions twice of the material in work storage were prepared in 96-well plates and the medium was added. The medium was RPMI, RPMI + MOPS, modified RPMI, or modified urea broth. The plates were inoculated with the fungal suspensions to give a final inoculum size of 0.5-2.5 x 103 cells / ml for the yeasts or 0.4-5.104 CFU / ml for the filamentous fungi and then incubated for 24-168 ha. ° C. The final concentration of DMSO did not exceed 5%. MIC (for its acronym in English) was defined as the lowest concentration that led above 90% reduction in growth, when compared to the free control of the drug. The MFC was defined as the lowest concentration that exterminated over 90% of the fungi, when compared to a free control of the drug. Results and Conclusions The results for the MIC of (CIO) and reference compounds against 19 strains of the fungi are shown in figure 2. The results for the MFC of AN2690 against 2 fungal strains are shown in table 2. ( CIO) had MIC values that vary from 0.25-2 g / ml against all the fungi tested. The addition of 5% keratin powder to the medium does not affect the MIC against G. rubrum. (CIO) had a fungicidal activity against T. rubrum and T. mentagrophytes with CFM values of 8 and 16 g / ml, respectively. The reference compounds had MIC values in the range defined by NCCLS (for its acronym in English). EXAMPLE 17 The Solubility, Stability and T Log Determination of the Compounds of the Present Invention. by LC / MS / MS The solubility, the stability at room temperature and the P log value of CIO was determined by the following methodology.
Reagents and standards Ethanol: ACS 200 proof grade (E Science, Gibbstown, NJ, USA); octanol: octyl alcohol (EM Science, Gibbstown, NJ, USA); Acetonitrile: CLAR grade (Burdick &; Jackson, Muskegon, MI, USA); Ammonium acetate: lot 3272X49621 (Mallinckrodt, Phillipsburg, NJ, USA); CIO: lot A032-103 (Anacor Pharmaceuticals, Palo Alto, CA, USA); p-nitrophenol (PNP): OGNOl batch (TC1 America, Portland, OR, USA); water: deionized water (from Millipore systems, Billerica, MA, USA). Solubility The N-octanol and water were pre-saturated with each other by vigorous stirring of a mixture of both solvents for up to 12 h and the mixture allowed to separate. The solubility in each solvent was determined by adding 10 μ? of 20, 40, 200, 1000 and 5000 pg / ml of CIO in DMSO to the pre-saturated n-octanol or water. After the sample was shaken for 10 seconds, the sample was centrifuged for 10 minutes at ca. 3000 rpm. A visual inspection was performed to determine if the sample was clear or if a pellet had formed on the bottom of the tube. P Log CIO value (10 μ? Of 5000 μ / ml) at 2X of the final concentration was added to 0.5 ml of pre-saturated n-octanol and mixed. An equal volume of pre-saturated water (0.5 ml) was added, mixed as a whirlpool and then mixed on a rotary shaker for 1 hour and 24 h in triplicate in ca. 25 ° C. The organic and aqueous layers were separated by centrifugation for 5 minutes at ca. 2000 rpm. Twenty-five μ? of the octanol layer (upper part) were removed and placed in the pre-labeled tube. Twenty-five μ? of the aqueous layer (bottom) were removed, taking care to avoid ethanol contamination, and placed in a pre-labeled tube. Stability at CIO Ambient Temperature (10 μg of 5000 g / ml) was added to both 0.5 ml of n-octanol and 0.5 ml of water in triplicate. The samples were mixed. At 0 h and 24 h the samples were stored at ca. -20 ° C. Twenty-five μ? of the sample were used for the analysis. CIO Extraction Procedure For the octanol sample, 25 μ? of ethanol, 25 μ? of water and 300 μ? of acetonitrile containing the internal standard were added. For the water sample, 25 μ? of ethanol, 25 μ? of octanol and 300 μ? of acetonitrile containing the internal standard [60 ml of acetonitrile are added to 6 μ? of PNP (1000 ^ q / ml)] were added. For the calibrators, 25 μ? of octanol, 25 μ? of water and 300 μl of acetonitrile containing an internal standard. The sample was swirled for 10 seconds. Two hundred μ? of the organic layer were transferred into a deactivated, clean autosampler vial. Calculations A linear regression weighted with 1 / concentration was used for the quantification of CIO. All the integration was done with the peak areas using version 1.3 of Analyst, Applied Biosystems. For CIO, the ratios of the analyte peak area with respect to PNP of the internal standard were used for all the quantification. The distribution coefficient (P) was calculated according to the equation described below: P = [sample concentration] octanoi / [sample concentration] water P value Log = logio (distribution coefficient). Results: As shown in Table 17A the solubility of CIO in both octanol and water is very good over the tested concentration range. Table 17A. Solubility of CIO in water and octanol
Table 17B shows the results determination of the P Log value after 1 h and 24 h for CIO. The average P Log value was 1.97 (n = 3). After 24 h the concentrations in the layer of both methanol and water remained identical. The average P Log value after 24 h was 1.93 (n = 3). Table 17B. CIO P Log Value
A stability study for CIO was initiated at room temperature for 24 h without continuous mixing. Table 17C shows that CIO in pure water and octanol is stable for 24 h. Table 17C. Stability in water and in octanol for CIO at room temperature after 24 h.
Example 18 Determination of the penetration of IOC in human nails Two nail penetration studies were performed based on the protocol of Hui et al., Journal of Pharmaceutical Sciences, 91 (1): 189-195 (2002) (" Hui Protocol "). The purpose of this study was to determine and compare the penetration and distribution of CIO in the vehicle in the human nail plate in vitrc in relation to ciclopirox at 8% w / w in a commercial lacquer (Penlac®). Materials and methods Test article and dosage formulation Cyclopirox at 8% w / w in commercial lacquer was manufactured by Dermick (Berwyn, PA). The radiochemical purity and the specific activity of the chemical substance was determined as > 95% and 12.5 mCi / mmol, respectively. The study was composed of two groups. The compositions (% by weight) of the dosage formulations are as follows: The radioactive compound active in four groups.
* A = CIO group, C = Ciclopirox group Human nails The plates of healthy human fingernails were collected from cadavers of human adults and stored in a closed container at 0-4 ° C. Before the experiment, the nail plates were gently washed with a normal saline solution to remove any contamination, then rehydrated by placing them for three hours on a cloth moistened with normal saline. Nail samples were randomly selected into four groups. Dosage and surface washing procedures Preparation of the dose: The radioactivity of each group is approximately 0.19 + 0.01 and 0.22 + 0.03 Ci / 10 μ? of the solutions, respectively, for 1C-C10 (group A), and 14C-cyclopirox (group C). Experimental procedure:
w once per day before dosing (9 10
AM) D once per day (9 - 10 AM). C change / sampling of cotton ball after surface washing before topical dosing. N = nail sampling. Washing procedure The washing of the surface was started in the morning 10 minutes before the next dosage, the surface of the nail was washed with cotton tip applicators in a cycle, as follows: a cotton-tipped applicator moistened with ethanol pure, then a cotton-tipped applicator moistened with pure ethanol, then a cotton-tipped applicator moistened with 50% YVORI liquid soap, then a cotton-tipped applicator moistened with distilled water, then a cotton-tipped applicator, final, moistened with distilled water. The samples for the washing of each cycle of each nail were grouped and collected by the rupture of the applicator with cotton tip in glass vials for the scintillation count. Aliquots of 3.0 ml of methanol were added in each vial to extract the test material. The radioactivity of each sample was measured in a liquid scintillation counter. Incubation system A diffusion chamber of a chamber, Teflon
(PermeGear, Inc., Hellertown, PA) was used to hold each nail. To approximate physiological conditions, a small cotton ball moistened with 0.1 ml of normal saline was placed in the chamber to serve as a bed for the nail and to provide moisture for the nail plate. Every 3 days, 0.1 ml of the normal saline solution was injected through the inlet into the chamber to keep the cotton ball moist. The nail plate was placed on a ledge inside the receiver (1.0 cm in diameter and 0.5 cm in height). The ventral (internal) surface of the nail was placed downward and rests on the wet cotton ball. The cells were placed on a platform in a large glass containment tank, filled with the saturated sodium phosphate solution to keep the cells at a constant humidity of 40%. Sampling instrument The instrument for sampling the nails had two parts, a sampling plate for the nail and an auger. The nail sampling stage consists of a nail clamp, copper, three adjusters, and a fingernail dust capture device. Three adjustments allow movement in the vertical direction. The first approximate fit (above the top) was to load the copper cell and take the powder from the samples from the capture apparatus. The other two (lower) settings were for the sampling process. The second approximate adjustment allowed the movement of 25 mm and the fine adjustment provides movement of 0.20 mm. The nail dust capture device was located between the copper cell and the cutter. The internal shape of the capture device was an inverted funnel and the end of the funnel is connected to a vacuum. By placing a circular filter paper inside the funnel, the samples of the nail dust were captured on the filter paper during the sampling process. Sampling procedure After the complement of the incubation phase, the nail plate was transferred from the diffusion cell to a clean, copper nail clip for the sampling process. The nail plate was inverted so that the ventral surface (the nail bed) now turned upwards and the dorsal (outer) dosed surface is turned downward. The nail clamp, copper, has an opening when it sits on the top of the plate. When the sampling process is started, the approximate adjustment was adjusted to move the position of the platen until the nail plate was just touching the tip of the cutter. Then the bit was turned on and the fine adjustment was flipped to push the stage closer to the bit, removing a sample from the nail core. After the previous process, the powdered samples of the nail of approximately 0.40-0.50 ram depth and 7.9 mm diameter were collected from the center of the ventral surface (nail bed) of the nail. The samples of the powdered nail were collected in a vial for scintillation, glass, and weighed. The 5.0 ml aliquots of soluene-350 from Packard (Packard Instrument Company, Meriden, CI), were added to the vial for scintillations to dissolve the powder. The upper part, the intermediate and dorsal layers of the center of the nail, including the area of application of the dose, were cut of the same diameter as the sampled area and were then placed in a vial for the counting of the scintillations, of glass , with 5.0 mi of solueno-350 of Packard. The rest of the nail was also placed in a vial for the glass scintillation counting, with 5.0 ml of soluene-350 from Packard. The amount of the removed nail sample was measured by verifying the difference in the weight of the nail plate before and after perforation, and the collection of the powder core.
Measurement of radioactivity All measurements of radioactivity were carried out with a liquid scintillation meter Model 1500 (Packard Instrument Company, Downer Grove, IL). The meter was audited to verify accuracy using sealed samples of the off and un-switched standards as detailed in the instrument manual. The counting efficiency of 1 C is equal to or greater than 95%. All the samples of the nail pre-treated with soluene-350 from Packard were incubated at 40 ° C for 48 hours followed by the addition of the cocktail to measure the 10 ml scintillations (HIONIC-FLUOR, Packard Instument company, Meriden, CT) . Other samples (standard dose, surface wash, and packaging material) were mixed directly with the Universal ES scintillation cocktail (ICN Biomedicals, Costa Mesa, CA). The test and control samples of the bottom were verified by counting for 3 minutes each to evaluate the radioactivity. Analysis of the data All sample counts (expressed as dpm) were transcribed by hand into a computerized spreadsheet (Microsoft Excel). The individual and average quantities (+ SD) of the equivalent test chemical in the nail samples, the packing material, and the wash samples, are presented as dpm, pCi, the percentage of the dose administered, and the mg equivalents at each moment of time. The concentration of the test chemicals labeled as 1 C were calculated from the value based on the specific activity of each of the test chemical substances- [1 C]. Information on the concentration of the test chemical not labeled in the topical formulation was obtained from the manufacturers. The total concentration of the test chemical equivalent is the sum of the concentration of the test chemical labeled with 14C and the concentration of the unlabeled test chemical. The value of the total amount of the test chemical equivalent in each sample of the nail was calculated from those values based on the radioactivity of the sample and the ratio of the total mg of the test chemical equivalent and the radioactivity of the chemical test. The data were further normalized by the division between the weight of the sample. Significant statistical data from the nail samples from each two groups were analyzed by Student's t-test. Thermonilogy Center intermediate / ventral: The sample of the powdered nail, drilled from the center of the inner surface (turned towards the nail bed) of approximately 0.3-0.5 mm in depth with respect to the surface. The area is below the dosed site of the nail site but does not include the dosed surface (dorsal nail surface). Intermediate / dorsal center: Intermediate area of the dosed site. Remaining nail: The remaining part of the nail that has not been dosed. Support bed: The cotton ball placed inside the Teflon chamber of the diffusion cell to provide moisture to the nail plate and also to receive chemicals that penetrate through the nail plate. Surface washing: Washing with ethanol (or other organic solvents) and soap / water on the surface of the dosed site. Ring: a plastic ring placed on top of the nail plate to prevent leakage from the dosing site onto the rest of the nail plate or inside the cell chamber. Cell washing: Washing with ethanol (or other organic solvents) and with soap / water from the inside of the diffusion cell. Results Characteristics of the nail samples For both groups (group A and group C), the thickness of the entire nail plate, the depth of the core sample of the ventral surface removed by the cutter, the percentage of the thickness of the the entire nail, and the actual weight of the powdered nail sample were collected. No statistical difference is found between the two groups (P >; 0.05). Normalized weight of CIO and the equivalent of ciclopirox in the nail Figure 3 shows the equivalents of the normalized drug, summarized, in each part (layer) of the nail samples. After normalization of the weight, the concentration of the IOC equivalent in the intermediate / dorsal center, the intermediate / ventral center, and the samples of the remaining nails, was significantly higher than that of the ciclopirox equivalent (p <0.002). . CIO and cyclopirox equivalent in the cotton ball nail support bed Figure 4 shows the cyclopirox and CIO equivalents summarized in the samples of the cotton ball of the support bed. Similar to the IOC equivalent normalized in weight, in the samples of the nail plate, the absolute amount of the IOC equivalent per sample of the cotton ball in group A (after the 14-day dosing) was significantly higher than that of ciclopirox in group C (p <0.004). The difference of these two test chemicals was 250 times. Mass balance of the radioactivity of [1 C] -C10 and [14C] -cyclopirox after a 14 day treatment Table 5 shows the radioactive recovery summary of the wash, the samples of the nails, and the samples of the ball of cotton bedding support. Recoveries of cumulative radioactivity of carbon 14 were 88 + 9.21, and 89 + 1.56 percent of the dose applied in group A, and group C, respectively. 88% of the radiolabelling material was taken into account. Conclusion In this study, the penetration velocity of [14C] -C10 in the topical formulation of Anacor and [14C] -cyclopirox (8% w / w in a commercial lacquer) in the human nail with four washing and dosing methods different, it was studied. The results show that a much larger amount of [14C] -C10 penetrates the deeper parts of the nail when compared to [14C] -cyclopirox. Tables 3 and 4 show that the amount of the [14 C] -CIO equivalent in the ventral / intermediate center of the nail layer and of the cotton ball support bed in group A was statistically higher (p < 0.002) than group C after a dosing period of 14 days. Example 19 Determination of IOC penetration in the human nail The objective of the present study was to evaluate and compare the periungular absorption of CIO in a single vehicle using the MedPharm TurChub® model see http: / / www. medpharm co.uk; specifically http: // www.
Medpharm.co.uk/downloads/Skin%20and20nail%20dec%202003.pdf; revised on February 14, 2006, in a full-scale experiment. Six duplicates involving IOC were carried out and the Formulations Y (8% ciclopirox p / p in a commercial lacquer) and Z (Loceryl, 5% amorolfine p / v in a commercial lacquer) were used as the reference formulations . The following materials were used in these experiments. These materials were used without any modification. A dose of 40 μl / cm2 of the CIO test compound in 50:50 of propylene glycol: ethyl acetate was applied to the full thickness nail sample every day for a total period of 5 days. Both of the reference formulations were also applied at the same dose. TurChub® zone of the inhibition experiment The placebo, the CIO test article in the vehicle and the reference formulations Y and Z were tested to verify their inhibition of Trichophyton rubrum (T. rubrum) in their growth after penetration through of a human fingernail of full thickness using a zone of measurement of inhibition. Testing the effectiveness of the formulation Figures 5-9 show the results obtained from the TurChub zone of the inhibition tests. It can be observed that CIO is a potent antifungal agent, which can penetrate through a full thickness nail to produce its effect against the target organism of G. rubrum. No zone of inhibition was observed with reference formulations Y and Z or with placebo for CIO. The experiment using CIO was repeated a second time to confirm the result and it can be observed from figures 6 and 7 that CIO shows inhibition zones of 100%, 67%, 46%, 57%, 38% and 71% in the first experiment and 74%, 86%, 100%, 82%, 100%, and 84% in the second experiment. The measurement was taken from the nail to the first observed growth point. Of the results obtained using the zone of
TurPhub MedPharm of the inhibition assay as a test system, the CIO test article was found to be a powerful antifungal agent and demonstrated superior results against commercial Y and Z reference formulations. From these experiments it appears that the compound is permeating through the total thickness of the nail barrier to exhibit antifungal activity. Example 20 Determination of the penetration of IOC in the human nail: Response to the dose The optimal dose-response interval for penetration into the human nail was determined to be between 1% and 15%. Experiments to determine the response-optimal dose were carried out as follows. The tests at different concentrations of the test compound were carried out on the nails derived from the same corpse. The cadaver's nails were hydrated overnight, cut into 4 squares of equal size and placed on individual poloxamer supports. The test articles were formulated in 1%, 2.5%, 5%, 7.5%, 10% and 15% w / v lacquer. A dose of 40 μ? / Cm2 is applied to the center of the nail piece and the nails are left at rest for 24 hours. The nails were removed from the poloxamer support. The poloxamer support is analyzed to verify the amount of the compound using LC / MS / S (for its acronym in English). It is to be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in view thereof will be suggested to those skilled in the art and to be included within the spirit and scope of this application. and the scope of the appended claims. All publications, patents, and patent applications cited herein, are hereby incorporated by reference in their entirety for all purposes. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (39)
1. A compound having a structure in accordance with Formula I: characterized in that: B is boron; Rla is a selected element of a negative charge, a counterion of a salt, H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and heteroaryl substituted or unsubstituted MI is a selected element of oxygen, sulfur and NR2a; wherein R2a is a selected element of 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 an element selected from (CR3aR4a) ni and CR5a wherein R3a, R and R5a are elements 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 neither is a whole number selected from 0 to 2; W1 is a selected element of C = 0 (carbonyl), (CR6aR7a) mi and CR8a; R6a, R7a, and R8a are elements 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; mi is an integer selected from 0 and 1; Al is a selected element of CR9a and N; Di is a selected element of CR10a and N; He is a selected element of CRlla and N; Gl is a selected element of CR12a and N; wherein: R9a, R10a, Rlla and R12a are elements independently selected from H, OH, NH2, SH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted aryl or unsubstituted, and substituted or unsubstituted heteroaryl; the combination of nitrogens (Al + DI + El + Gl) is an integer selected from 0 to 3; wherein a selected element of R3a, R4a, and R5a and a selected element of R6a, R7a and R8a, together with the atoms to which they are attached, are optionally bonded to form a ring of 4 to 7 elements; R3a and R4a, together with the atoms to which they are attached, are optionally linked to form a ring of 4 to 7 elements; R6a and R7a, together with the atoms to which they are attached, are optionally linked to form a ring of 4 to 7 elements; R9a and R10a together with the atoms to which they are attached are optionally attached to form a ring of 4 to 7 elements; R10a and Rlla, together with the atoms to which they are attached, are optionally bonded to form a ring of 4 to 7 elements; Rlla and R12a, together with the atoms to which they are attached, are optionally linked to form a ring of 4 to 7 elements; with the proviso that when Mi is oxygen, Wl is a selected element of (CR3aR4a) ni, where neither is 0, Jl is a selected element of (CR6aR7a) mi where mi is 1, Al is CR9a, DI is CR10a , Is Rlla, Gl is CR12a, then R9a is not halogen, methyl, ethyl, or is optionally linked with R10 to form a phenyl ring; R10a is not unsubstituted phenoxy, C (CH3) 3, halogen, CF3, methoxy, ethoxy, or optionally linked with R9a to form a phenyl ring; Rlla is not halogen, or is optionally linked with R10a to form a phenyl ring, and R12a is not halogen; with the additional condition that when MI is oxygen, Wl is an element selected from (CR3aR4a) ni, where ni is 0, Jl is an element selected from (CR6aR7a) mi, where mi is 1, Al is CR9a, DI is CR10a, He is CRlla, Gl is CR12a, then neither R6a nor R7a are halophenyl; with the additional condition that when MI is oxygen, Wl is an element selected from (CR3aR4a) ni, where nl is 0, Jl is a selected element of (CR6aR7a) mi, where mi is 1, Al is CR9a, DI is CR10a, He is CRUa, Gl is CR12a, and R9a, R10a and Rlla are then R7a and R12a nQ SQn R. with the additional proviso that when MI is oxygen, neither is 1, Jl is a selected element of (CRaRa) mi, where mi is 0, Al is CR9a, DI is CR10a, He is CRlla, Gl is CR12a, R9a is H, R10a is H, Rlla is H, R6a is H, R7a is H, R12a is H, then W1 is not C = 0 (carbonyl); with the additional condition that when MI is oxygen, Wl is CRba, nor is 1, Jl is CR, mi is 1, Al is CR, 39aa, DI is CR10a, He is CRlla, Gl is CR12a, R6a, R7a, R9a, R10a, Rlla and R12a are H, then R5a and R8a, together with the atoms to which they are attached, do not form a phenyl ring.
2. The compound in accordance with the claim I, characterized because it has the structure in accordance with the Formula (the :) wherein: Rsa, Riua, Rlia and Rl a are 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 heteroaryl replaced or not replaced; and wherein R9a and R10a together with the atoms to which they are attached, are optionally attached to form a ring of 4 to 7 elements; R10a and Rlla, together with the atoms to which they are attached, are optionally linked to form a ring of 4 to 7 elements; and Rlla and R12a, together with the atoms to which they are attached, are optionally attached to form a ring of 4 to 7 elements; with the proviso that R9a is not halogen, methyl, ethyl, or is optionally linked with R10a to form a ring of 4 to 7 elements; with the proviso that R10a is not unsubstituted phenoxy, C (CH3) 3, halogen, CF3, methoxy, ethoxy, optionally linked with R9a to form a ring of 4 to 7 elements, or optionally linked with Rlla to form a ring of 4 to 7 elements; with the proviso that Rlla is not halogen or is optionally linked with R10a to form a ring of 4 to 7 elements; with the proviso that R12a is not halogen.
3. The compound in accordance with the claim 2, characterized in that it has the structure in accordance with the Formula (Ib) wherein: B is boron; Rxl is a member selected from substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 1 -C 5 heteroalkyl; Ryl and Rzl are selected elements of 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; R6a are elements 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 R9a, R10a, Rlla, and R12a are elements 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 heteroaryl or not replaced; and wherein Rlla and R12a, together with the atoms to which they are attached, are optionally attached to form a ring of 4 to 7 elements; with the proviso that when R9, Rlla and R12a are H, R10a is not H, halogen, unsubstituted phenoxy or t-butyl; with the additional proviso that when R9 is H, R10a and Rlla together with the atoms to which they are fixed, are not joined to form a phenyl ring; with the additional proviso that when Rlla is H, R9a and R10a, together with the atoms to which they are fixed, they are not joined to form a phenyl ring.
4. A pharmaceutical formulation, characterized in that it comprises: (a) a pharmaceutically acceptable excipient; and (b) a compound having a structure according to formula II: where B is boron; Rlb is a selected element of a negative charge, a counterion of a salt, H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and heteroaryl replaced or not replaced; M2 is a selected element of oxygen, sulfur and NR2b wherein R2b is a selected element of 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 an element selected from (CR3bR b) n2 and CR5b wherein R3b, R4b, and R5b are elements independently selected from H, OH, NH2, SH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl substituted, 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 selected element of C = 0 (carbonyl), (CR6bR7b) m2 and CR8b wherein R6b, R7b, and R8b are elements independently selected from H, OH, NH2, SH, substituted or unsubstituted alkyl, substituted heteroalkyl or not substituted, 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 selected element of CR9b and N; D2 is a selected element of CR10 and N; E2 is a selected element of CRll and N; G2 is a selected element of CR12b and N; wherein R9b, R10b, Rllb and R12b are elements 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 substituted, and substituted or unsubstituted heteroaryl; the combination of nitrogens (A2 + D2 + E2 + G2) is an integer selected from 0 to 3; a selected element of R3b, R4, and R5b and a selected element of R6b, R7b and R8b, together with the atoms to which they are attached, are optionally linked to form a ring of 4 to 7 elements; R3b and R4b, together with the atoms to which they are attached, are optionally linked to form a ring of 4 to 7 elements; R6b and R7b, together with the atoms to which they are attached, are optionally linked to form a ring of 4 to 7 elements; R9b and R10b together with the atoms to which they are attached, are optionally linked to form a ring of 4 to 7 elements; R10b and Rllb together with the atoms to which they are attached are optionally attached to form a ring of 4 to 7 elements; Rllb and R12b, together with the atoms to which they are attached, are optionally linked to form a ring of 4 to 7 elements.
5. The pharmaceutical formulation according to claim 4, characterized in that the compound has a structure according to the formula (lia):
6. The pharmaceutical formulation according to claim 4, characterized in that the compound has a structure according to Formula (Ilb): wherein R7b is a selected element of H, methyl, ethyl and phenyl; R10b is a selected element of H, halogen, substituted or unsubstituted phenoxy, substituted or unsubstituted phenylalkyloxy, substituted or unsubstituted phenylthio, and substituted or unsubstituted phenylalkylthio; and Rllb is a selected element of H, OH, methyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenylalkyloxy, substituted or unsubstituted phenylthio, and substituted or unsubstituted phenylalkylthio.
7. The pharmaceutical formulation according to claim 4, characterized in that the compound has a structure according to the formula (lie): wherein R10b is a selected element of H, halogen, CN and substituted or unsubstituted Ci-4 alkyl.
8. The pharmaceutical formulation according to claim 4, characterized in that the compound has a structure that is an element selected from:
9. The pharmaceutical formulation according to claim 6, characterized in that Rlb is a selected element of a negative charge, H and a counterion of a salt.
10. The pharmaceutical formulation according to claim 9, characterized in that R10b and Rllb are H.
11. The pharmaceutical formulation according to claim 6, characterized in that one element selected from R10b and Rllb is H and the other element selected from R10b. and R10b is an element selected from halo, methyl, cyano, methoxy, hydroxymethyl and p-cyanophenyloxy.
12. The pharmaceutical formulation according to claim 6, characterized in that R10b and Rllb are independently selected from fluoro, chloro, methyl, cyano, methoxy, hydroxymethyl and p-cyanophenyl.
13. The pharmaceutical formulation according to claim 6, characterized in that Rlb is a selected element of a negative charge, H and a counterion of a salt; R7b is H; R10b is F and Rllb is H. The pharmaceutical formulation according to claim 6, characterized in that Rlb is a selected element of a negative charge, H and a counterion of a salt; R7b is H; R10b is 4-cyanophenoxy and Rllb is H. 15. The pharmaceutical formulation according to claim 4, characterized in that Rllb and R12b, in the company of the atoms to which they are attached, are bonded to form a phenyl group. 16. The pharmaceutical formulation according to claim 4, characterized in that the compound has a structure according to the Formula (lid): (My where B is boron; Rx2 is a member selected from substituted or unsubstituted C1-C5 alkyl and substituted or unsubstituted C1-C5 heteroalkyl; Ry2 and Rz2 are elements 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 according to claim 4, characterized in that the excipient is a pharmaceutically acceptable topical carrier. 18. The pharmaceutical formulation according to claim 4, characterized in that the compound is present in the pharmaceutical formulation in a concentration from about 1% to 10%. A method for killing a microorganism or for inhibiting the growth of a microorganism, characterized in that it comprises contacting the microorganism with a therapeutically effective amount of a compound according to claim 1. 20. The method according to claim 19 , characterized in that the microorganism is a fungus. The method according to claim 19, characterized in that the fungus is a selected element of the Candida species, of the Trychophyton species, of the Microsporiüm species, of Aspergillus species, Cryptococcus species, Blastomyces species, Cocciodiodes species, Histoplasma species, Paracoccidiodes species, Phycomycetes species, Malassezia species, the Fusarium species, the Epidermophyton species, the Scytalidium species, the Scopulariopsis species, the Alternaria species, the Penicillium species, the Phialophora species, the Rhizopus species, the species of Scedosporium, and of the Zygomicetes class. 22. The method according to claim 19, characterized in that the fungus is a selected element of dermatophytes, Trichophyton, Microsporum, Epidermophyton and fungi similar to yeast. 23. A method for killing a microorganism or inhibiting the growth of a microorganism, characterized in that it comprises contacting the microorganism with a therapeutically effective amount of a pharmaceutical formulation in accordance with claim 4. 24. The method according to claim 23, characterized in that the microorganism is a fungus. 25. The method according to claim 23, characterized in that the fungus is a selected element of the species of Candida, of the species of Trychophyton, of the species of Microsporium, of the species of Aspergillus, of the species of Cryptococcus, of species of Blastomyces, species of Cocciodiodes, species of Histoplasma, species of Paracoccidiodes, species of Phycomycetes, species of Malassezia, species of Fusarium, species of Epidermophyton, species of Scytalidium, of Scopularíopsis species, of Alternaria species, of Penicillium species, of Phialophora species, of Rhizopus species, of Scedosporium species, and of the Zygomicetes class. 26. The method according to claim 23, characterized in that the fungus is a selected element of dermatophytes, Trichophyton, Microsporum, Epidermophyton and fungi similar to yeast. 27. A method of treating or preventing an infection in an animal, characterized in that it comprises administering to the animal a therapeutically effective amount of the compound according to claim 1. 28. The method according to claim 27, characterized in that the infection is a selected element of a systemic infection, a cutaneous infection, and an ungular or periungular infection. 29. The method of compliance with the claim 27, characterized in that the infection is a selected element of chloronychia, paronychias, erysipeloid, onychorhexis, gonorrhea, pool granuloma, larva migrans, leprosy, Orf's nodule, milker's nodules, herpetic whitlow, acute bacterial perionixis, chronic perionixis, sporotrichosis, syphilis, verrucous skin tuberculosis, tularemia, tungiasis, peri-sublingual warts, zone or herpes zoster, nail dystrophy (trachyonychia), dermatological diseases, psoriasis, pustular psoriasis, alopecia areata, pustular parakeratosis, contact dermatosis, Reiter's syndrome, psoriasiform acral dermatitis, lichen planus, idiopathic nail atrophy, clear lichen, striated lichen, inflammatory linear warty epidermal nevus (ILVEN), alopecia, pemphigus, bullous pemphigoid, acquired bullous epidermolysis, Darier's disease, pityriasis pilaris red , palmoplantar keratoderma, contact eczema, polymorphic erythema, scabies, syndrome of Bazex, systemic scleroderma, systemic lupus erythematosus, chronic lupus erythematosus, dermatomyositis, sporotrichosis, fungal keratitis, oculomycosis of extension, endogenous oculomycosis, lobomycosis, mycetoma, black stone, pityriasis versicolor, Tinea corporis, Tinea cruris, Tinea pedis, Tinea barbae, Tinea capitis, Tinea nigra, Otomicosis, Tinea favosa, chromomycosis, and Tinea imbricata. 30. The method of compliance with the claim 27, characterized in that the infection is onychomycosis. 31. The method according to claim 27, characterized in that the animal is a selected element of a human being, cattle, goats, pigs, sheep, horses, cows, bulls, dogs, guinea pigs, gerbils, rabbits, cats, chickens and turkeys. 32. A method of treating or preventing an infection in an animal, characterized in that it comprises administering to the animal a therapeutically effective amount of the pharmaceutical formulation according to claim 4. The method according to claim 32, characterized in that the Infection is a selected element of a systemic infection and an ungular and periungular infection. 34. The method according to claim 32, characterized in that the infection is a selected element of chloronychia, paronychia, erysipeloid, onychorhexis, gonorrhea, granuloma of the pools, larva migrans, leprosy, nodule of Orf, nodules of the milkers, whitlow herpetic, acute bacterial perionixis, chronic perionixis, sporotrichosis, syphilis, verrucous skin tuberculosis, tularemia, tungiasis, peri-sublingual warts, zone or herpes zoster, nail dystrophy (trachyonychia), dermatological diseases, psoriasis, pustular psoriasis, alopecia areata, pustular parakeratosis, contact dermatosis, Reiter's syndrome, psoriasiform acral dermatitis, lichen planus, idiopathic nail atrophy, clear lichen, striated lichen, inflammatory linear warty epidermal nevus (ILVEN), alopecia, pemphigus, bullous pemphigoid, epidermolysis hulosa acquired, Darier's disease, pityriasis pilaris red, palmoplantar keratoderma, eczema by contact, polymorphic erythema, scabies, Bazex syndrome, systemic scleroderma, systemic lupus erythematosus, chronic lupus erythematosus, dermatomyositis, sporotrichosis, fungal keratitis, oculomycosis of extension, endogenous oculomicosis, lobomycosis, mycetoma, black stone, pityriasis versicolor, Tinea corporis, Tinea cruris, Tinea pedis, Tinea barbae, Tinea capitis, Tinea nigra, Otomicosis, Tinea favosa, cromomycosis, and Tinea imbricata. 35. The method according to claim 32, characterized in that the infection is onychomycosis. 36. The method according to claim 32, characterized in that the animal is a selected element of a human being, cattle, goats, pigs, sheep, horses, cows, bulls, dogs, guinea pigs, gerbils, rabbits, cats, chickens and turkeys. 37. A method, characterized in that it is used for the synthesis of the compound according to claim 1. 38. A method, characterized in that it is used for the synthesis of the pharmaceutical formulation according to claim 4. 39. A method for supplying a compound from the dorsal layer of the nail plate to the nail bed, characterized in that it comprises: contacting the cell with a compound capable of penetrating the nail plate; under conditions sufficient to penetrate the nail plate, wherein the compound has a molecular weight of between about 100 and about 200 Da; the compound has a value of P log of between about 1.0 and about 2.6; the compound has a solubility in water greater than about 0.1 mg / ml of water saturated with octanol; by means of which the compound is supplied.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/654,060 | 2005-02-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MX2007009625A true MX2007009625A (en) | 2008-10-03 |
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