Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
  • C07F5/02—Boron compounds
  • C07F5/025—Boronic and borinic acid compounds

Definitions

• the invention provides a compound described herein.
• the compound is a salt of a compound of the invention.
• the compound is a pharmaceutically acceptable salt of a compound of the invention.
• the compound has a structure according to the following formula:
• Y is a member selected from substituted or unsubstituted vinyl and substituted or unsubstituted aryl.
• Z, R ⁇ R , R c and R are members independently selected from members independently selected from H, OR*, NR*R**, SR*, -S(O)R*.
• R b and R c together with the atoms to which they are attached, are optionally joined to form a 4- to 8-membered ring.
• R d and R e together with the atoms to which they are attached, are optionally joined to form a 4- to 8-membered ring.
• Y and Z together with the atoms to which they are attached, are optionally joined to form a member selected from a 4- to 8- membered ring and a 6- to 12-membered bicyclic ring.
• Each R* and R** are members independently selected from H, nitro, halogen, cyano, substituted or unsubstituted aikyi, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted heterocycloaikyi, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
• said compound has a structure which is a member selected from:
• said compound has a structure according to the following formula:
• said Z is substituted or unsubstituted vinyl.
• said compound is a member selected from
• said compound is a member selected from
• said compound is a member selected from
• said compound is a member selected from
• said Z is substituted or unsubstituted alkyl, and wherein said substituted or unsubstituted alkyl is substituted or unsubstituted alkenyl.
• said Z is substituted or unsubstituted vinyl.
• said Z is substituted or unsubstituted aryl.
• said Z is substituted aryl, and has a structure according to the following formula:
• R is a member selected from H, nitro, halogen, cyano, 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.
• said R 1 is a member selected from nitro, halogen, cyano and substituted or unsubstituted alkyl.
• said R 1 is a member selected from fluorine, chlorine and bromine.
• said Z is F . In an exemplary embodiment, said
• said compound is F XJT H 2 N- .
• said Z is substituted or unsubstituted heteroaryl, In an exemplary embodiment, said Z is a member selected from substituted or unsubstituted 2-pyridinyl, substituted or unsubstituted 3-pyridinyl and substituted or unsubstituted 4-pyridinyI. In an exemplary embodiment, said Z is substituted or unsubstituted 3-pyridinyl. In an exemplary embodiment, said compound is
• R b and R c together with the atoms to which they are attached, are joined to form a substituted or unsubstituted 4- to 6-membered
• said compound i tsc In an exemplary embodiment, said compound is a member selected from
• said compound is a member selected from
• said compound is a member selected from
• said compound is a member selected from exemplary embodiment, Y and Z, together with the atoms to which they are attached, are joined to form a member selected from a 4- to 8- membered ring and a 6- to 12-membered bicyclic ring.
• Y and Z, together with the atoms to which they are attached, are joined to form an 8-membered bicyclic ring.
• wherein said 8-membered bicyclic ring is unsubstituted.
• the compound has a structure which is a
• the compound has a structure which is a member selected from an j.
• the compound has a structure which is a member selected from and In an exemplary embodiment, the compound has a structure which is a member selected from
• the invention provides a method of inhibiting the growth of, or killing, a fungus, said method comprising: contacting said fungus with a compound of the invention, in an amount sufficient to inhibit or kill said fungus.
• the compound is a salt of a compound of the invention.
• the compound is a pharmaceutically acceptable salt of a compound of the invention.
• said fungus is a member selected from a dermatophyte, Trichophyton species, Microsporium species, Candida species, Aspergillus species and yeast-like fungus.
• the compound is described above.
• said fungus is a member selected from Candida albicans, Candida neoformans, Aspergillus fumigatus, Trichophyton mentagrophytes (T. mentagrophytes) and Trichophyton rubrum (T. rubrum).
• there is a proviso that the molecular weight of said compound is not greater than about 200.
• there is a proviso that the c log P of said compound is between about -2 and about 2.
• there is a proviso that the efficacy coefficient of said compound is greater than about 10.
• the compound has a structure described in section HA '"Boron- Containing Compounds * '.
• the compound has a structure described from paragraph 58 to paragraph 79. In an exemplary embodiment, the compound has a structure described from paragraph 58 to paragraph 72. In an exemplary embodiment, the compound has a structure described in section HB ''Acyclic Boronic Acids". In an exemplary embodiment, the compound has a structure described from paragraph 80 to paragraph 83, In an exemplary embodiment, the compound has a structure described in paragraph 80. In an exemplary embodiment, the compound has a structure described in section OC ''Low MW Pyridone/Pyrithione derivatives". In an exemplary embodiment, the compound has a structure described from paragraph 84 to paragraph 87. In an exemplary embodiment, the compound has a structure described in paragraph 84.
• the compound has a structure described in section HD "Low MW fungicide moiety F. In an exemplary embodiment, the compound has a structure described from paragraph 88 to paragraph 91. In an exemplary embodiment, the compound has a structure described in paragraph 88. In an exemplary embodiment, the compound has a structure described in section HE "Low MW fungicide moiety II". In an exemplary embodiment, the compound has a structure described from paragraph 92 to paragraph 95. In an exemplary embodiment, the compound has a structure described in paragraph 92. In an exemplary embodiment, the compound has a structure described in section HF "Low MW fungicide moiety III”. In an exemplary embodiment, the compound has a structure described from paragraph 96 to paragraph 115.
• the compound has a structure described in paragraph 96. In an exemplary embodiment, the compound has a structure described in section HG "Commercial Fungicides * '. In an exemplary embodiment, the compound has a structure described from paragraph 116 to paragraph 1 17. In an exemplary embodiment, the compound has a structure described in paragraph 1 16.
• the invention provides a method of treating a disease in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound, thereby treating said disease.
• the disease is an ungual, periungual or subungual infection
• the compound is described herein.
• the compound is a salt of a compound of the invention.
• the compound is a pharmaceutically acceptable salt of a compound of the invention.
• the compound is described above.
• the disease is caused by, or involves a fungus is a member selected from Candida albicans, Candida neoformans, Aspergillus fumigatus, Trichophyton mentagrophytes ⁇ T. mentagrophytes) and Trichophyton rubrum (T. rubrum).
• said disease is onychomycosis.
• there is a proviso that the molecular weight of said compound is not greater than about 200.
• there is a proviso that the c log P of said compound is between about -2 and about 2.
• there is a proviso that the efficacy coefficient of said compound is greater than about 10.
• the compound has a structure described in section HA '"Boron-Containing Compounds".
• the compound has a structure described from paragraph 58 to paragraph 79.
• the compound has a structure described from paragraph 58 to paragraph 72.
• the compound has a structure described in section OB "Acyclic Boronic Acids”.
• the compound has a structure described from paragraph 80 to paragraph 83.
• the compound has a structure described in paragraph 80.
• the compound has a structure described in section HC "Low MW Pyridone/Pyrithione derivatives".
• the compound has a structure described from paragraph 84 to paragraph 87. In an exemplary embodiment, the compound has a structure described in paragraph 84. In an exemplary embodiment, the compound has a structure described in section HD "Low MW fungicide moiety F'. In an exemplary embodiment, the compound has a structure described from paragraph 88 to paragraph 91. In an exemplary embodiment, the compound has a structure described in paragraph 88. In an exemplary embodiment, the compound has a structure described in section HE "Low MW fungicide moiety II". In an exemplary embodiment, the compound has a structure described from paragraph 92 to paragraph 95. In an exemplary embodiment, the compound has a structure described in paragraph 92.
• the compound has a structure described in section HF "Low MW fungicide moiety III". In an exemplary embodiment, the compound has a structure described from paragraph 96 to paragraph 1 15. In an exemplary embodiment, the compound has a structure described in paragraph 96. In an exemplary embodiment, the compound has a structure described in section HG "Commercial Fungicides”. In an exemplary embodiment, the compound has a structure described from paragraph 116 to paragraph 117. In an exemplary embodiment, the compound has a structure described in paragraph 1 16.
• the invention provides a pharmaceutical formulation comprising: a) a pharmaceutically acceptable excipient; and b) a compound of the invention.
• the compound is described above.
• the compound is a salt of a compound of the invention.
• the compound is a pharmaceutically acceptable salt of a compound of the invention,
• there is the proviso that the molecular weight of said compound is not greater than about 200.
• there is the proviso that the c log P of said compound is between about -2 and about 2.
• there is the proviso that the efficacy coefficient of said compound is greater than about 10.
• the compound has a structure described in section HA '"Boron-Containing Compounds " '.
• the compound has a structure described from paragraph 58 to paragraph 79.
• the compound has a structure described from paragraph 58 to paragraph 72.
• the compound has a structure described in section HB "Acyclic Boronic Acids' * .
• the compound has a structure described from paragraph 80 to paragraph 83.
• the compound has a structure described in paragraph 80.
• the compound has a structure described in section HC "Low MW Pyridone/Pyrithione derivatives".
• the compound has a structure described from paragraph 84 to paragraph 87. In an exemplary embodiment, the compound has a structure described in paragraph 84. In an exemplary embodiment, the compound has a structure described in section HD "Low MW fungicide moiety I". In an exemplary embodiment, the compound has a structure described from paragraph 88 Io paragraph 91. In an exemplary embodiment, the compound has a structure described in paragraph 88. In an exemplary embodiment, the compound has a structure described in section HE "Low MW fungicide moiety II”. In an exemplary embodiment, the compound has a structure described from paragraph 92 to paragraph 95. In an exemplary embodiment, the compound has a structure described in paragraph 92.
• the compound has a structure described in section HF '"Low MW fungicide moiety III". In an exemplary embodiment, the compound has a structure described from paragraph 96 to paragraph 115. In an exemplary embodiment, the compound has a structure described in paragraph 96. In an exemplary embodiment, the compound has a structure described in section HG "Commercial Fungicides”. In an exemplary embodiment, the compound has a structure described from paragraph 116 to paragraph 117, In an exemplary embodiment, the compound has a structure described in paragraph 1 16.
• the invention provides a formulation comprising: (a) a keratin containing component which is a member selected from a human nail unit, skin and hair; (b) a compound having a structure described herein.
• the compound has a structure described above.
• the compound is a salt of a compound of the invention.
• the compound is a pharmaceutically acceptable salt of a compound of the invention.
• the compound has a structure described in section HA "Boron-Containing Compounds".
• the compound has a structure described from paragraph 58 to paragraph 79.
• the compound has a structure described from paragraph 58 to paragraph 72, In an exemplary embodiment, the compound has a structure described in section IIB "Acyclic Boronic Acids". In an exemplary embodiment, the compound has a structure described from paragraph 80 to paragraph 83, In an exemplary embodiment, the compound has a structure described in paragraph 80. In an exemplary embodiment, the compound has a structure described in section HC "Low MW Pyridone/Pyrithione derivatives". In an exemplary embodiment, the compound has a structure described from paragraph 84 to paragraph 87. In an exemplary embodiment, the compound has a structure described in paragraph 84. In an exemplary embodiment, the compound has a structure described in section IID "Low MW fungicide moiety I".
• the compound has a structure described from paragraph 88 to paragraph 91. In an exemplary embodiment, the compound has a structure described in paragraph 88. In an exemplary embodiment, the compound has a structure described in section HE "Low MW fungicide moiety II " '. In an exemplary embodiment, the compound has a structure described from paragraph 92 to paragraph 95, In an exemplary embodiment, the compound has a structure described in paragraph 92. In an exemplary embodiment. the compound has a structure described in section HF "'Low MW fungicide moiety III”. In an exemplary embodiment, the compound has a structure described from paragraph 96 to paragraph 1 15. In an exemplary embodiment, the compound has a structure described in paragraph 96.
• the compound has a structure described in section HG "'Commercial Fungicides''. In an exemplary embodiment, the compound has a structure described from paragraph 1 16 to paragraph 117. In an exemplary embodiment, the compound has a structure described in paragraph 116.
• the invention provides a method of inhibiting the growth of, or killing, a microorganism present in a human nail unit, wherein said human nail unit comprises a nail plate, comprising: contacting a dorsal layer of the nail plate with a compound capable of penetrating the nail plate, traveling through the nail plate to a nail bed underlying said nail plate, and contacting said microorganism, under conditions sufficient for said compound to penetrate said nail plate, wherein said compound has a structure described herein.
• the compound has a structure described above.
• the compound is a salt of a compound of the invention.
• the compound is a pharmaceutically acceptable salt of a compound of the invention.
• said microorganism is a member selected from a bacteria, a fungus, a virus, a parasite, and a yeast.
• said microorganism is a fungus, and said fungus is a member selected from a dermatophyte, Trichophyton species.
• said fungus is a member selected from Candida albicans, Candida neoformans, Aspergillus fumigatus. Trichophyton mentagrophytes (T. mentagrophyles) and Trichophyton rubrwn (T rubruni).
• the compound has a structure described in section HA "Boron-Containing Compounds", In an exemplary embodiment, the compound has a structure described from paragraph 58 to paragraph 79. In an exemplary embodiment, the compound has a structure described from paragraph 58 to paragraph 72. In an exemplary embodiment, the compound has a structure described in section HB "Acyclic Boronic Acids".
• the compound has a structure described from paragraph 80 to paragraph 83. In an exemplary embodiment, the compound has a structure described in paragraph 80. In an exemplary embodiment, the compound has a structure described in section OC "Low MW Pyridone/Pyrithione derivatives". In an exemplary embodiment, the compound has a structure described from paragraph 84 to paragraph 87. In an exemplary embodiment, the compound has a structure described in paragraph 84. In an exemplary embodiment, the compound has a structure described in section IID "Low MW fungicide moiety I”. In an exemplary embodiment, the compound has a structure described from paragraph 88 to paragraph 91. In an exemplary embodiment, the compound has a structure described in paragraph 88.
• the compound has a structure described in section OE "Low MW fungicide moiety II " '. In an exemplary embodiment, the compound has a structure described from paragraph 92 to paragraph 95. In an exemplary embodiment, the compound has a structure described in paragraph 92. In an exemplary embodiment, the compound has a structure described in section IfF "Low MW fungicide moiety IH' ' . In an exemplary embodiment, the compound has a structure described from paragraph 96 to paragraph 1 15. In an exemplary embodiment, the compound has a structure described in paragraph 96. In an exemplary embodiment, the compound has a structure described in section HG "Commercial Fungicides". In an exemplary embodiment, the compound has a structure described from paragraph 116 to paragraph 1 17. In an exemplary embodiment, the compound has a structure described in paragraph 1 16.
• the invention provides a method of inhibiting the growth of, or killing, a fungus, said method comprising: contacting said fungus with a compound in an amount sufficient to inhibit or kill said fungus, wherein said fungus is a member selected from a dermatophyte, Trichophyton species, Microsporhtm species, Candida species, Aspergillus species and yeast-like fungus.
• the compound is described herein.
• the compound is a salt of a compound of the invention.
• the compound is a pharmaceutically acceptable salt of a compound of the invention.
• the compound is provided above.
• the compound has a structure described in section ⁇ IA "Boron-Containing Compounds". In an exemplary embodiment, the compound has a structure described from paragraph 58 to paragraph 79. In an exemplary embodiment, the compound has a structure described from paragraph 58 to paragraph 72. In an exemplary embodiment, the compound has a structure described in section HB "Acyclic Boronic Acids". In an exemplary embodiment, the compound has a structure described from paragraph 80 to paragraph 83. In an exemplary embodiment, the compound has a structure described in paragraph 80. In an exemplary embodiment, the compound has a structure described in section HC "Low MW Pyridone/Pyrithione derivatives".
• the compound has a structure described from paragraph 84 to paragraph 87. In an exemplary embodiment, the compound has a structure described in paragraph 84. In an exemplary embodiment, the compound has a structure described in section HD "Low MW fungicide moiety I' ⁇ In an exemplary embodiment, the compound has a structure described from paragraph 88 to paragraph 91. In an exemplary embodiment, the compound has a structure described in paragraph 88. In an exemplary embodiment, the compound has a structure described in section HE ''Low MW fungicide moiety II". In an exemplary embodiment, the compound has a structure described from paragraph 92 to paragraph 95.
• the compound has a structure described in paragraph 92, In an exemplary embodiment, the compound has a structure described in section IIP ''Low MW fungicide moiety HI", In an exemplary embodiment, the compound has a structure described from paragraph 96 to paragraph 1 15. In an exemplary embodiment, the compound has a structure described in paragraph 96. In an exemplary embodiment, the compound has a structure described in section HG "Commercial Fungicides”. In an exemplary embodiment, the compound has a structure described from paragraph 1 16 to paragraph 1 17. In an exemplary embodiment, the compound has a structure described in paragraph 1 16.
• the invention provides a method of treating a disease in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound, thereby treating said disease; wherein said disease is an ungual. periungual or subungual infection.
• the compound is described herein.
• the compound is a salt of a compound of the invention.
• the compound is a pharmaceutically acceptable salt of a compound of the invention.
• the compound is provided above.
• the compound has a structure described in section HA "Boron- Containing Compounds".
• the compound has a structure described from paragraph 58 to paragraph 79.
• the compound has a structure described from paragraph 58 to paragraph 72. In an exemplary embodiment, the compound has a structure described in section HB "Acyclic Boronic Acids". In an exemplary embodiment, the compound has a structure described from paragraph 80 to paragraph 83. 3n an exemplary embodiment, the compound has a structure described in paragraph 80. In an exemplary embodiment, the compound has a structure described in section HC "Low MW Pyridone/Pyrithione derivatives". In an exemplary embodiment, the compound has a structure described from paragraph 84 to paragraph 87. In an exemplary embodiment, the compound has a structure described in paragraph 84. In an exemplary embodiment, the compound has a structure described in section HD '"Low MW fungicide moiety I".
• the compound has a structure described from paragraph 88 to paragraph 91. In an exemplary embodiment, the compound has a structure described in paragraph 88. In an exemplary embodiment, the compound has a structure described in section HE "Low MW fungicide moiety II". In an exemplary embodiment, the compound has a structure described from paragraph 92 to paragraph 95. In an exemplary embodiment, the compound has a structure described in paragraph 92. In an exemplary embodiment, the compound has a structure described in section HF "Low MW fungicide moiety III " . In an exemplary embodiment, the compound has a structure described from paragraph 96 to paragraph 1 15. In an exemplary embodiment, the compound has a structure described in paragraph 96.
• the compound has a structure described in section HG '"Commercial Fungicides". In an exemplary embodiment, the compound has a structure described from paragraph 116 to paragraph 1 17. In an exemplary embodiment, the compound has a structure described in paragraph 1 16.
• the invention provides a pharmaceutical formulation comprising: a) a pharmaceutically acceptable excipient; and b) a compound of the invention.
• the compound is a salt of a compound of the invention.
• the compound is a pharmaceutically acceptable salt of a compound of the invention.
• the compound has a structure described in section HA "Boron- Containing Compounds", In an exemplary embodiment, the compound has a structure described in section HA "Boron-Containing Compounds".
• the compound has a structure described from paragraph 58 to paragraph 79. In an exemplary embodiment, the compound has a structure described from paragraph 58 to paragraph 72.
• the compound has a structure described in section HB "Acyclic Boronic Acids". In an exemplary embodiment, the compound has a structure described from paragraph 80 to paragraph 83. In an exemplary embodiment, the compound has a structure described in paragraph 80. In an exemplary embodiment, the compound has a structure described in section HC "Low MW Pyridone/Pyrithione derivatives". In an exemplary embodiment, the compound has a structure described from paragraph 84 to paragraph 87. In an exemplary embodiment, the compound has a structure described in paragraph 84. In an exemplary embodiment, the compound has a structure described in section UD “Low MW fungicide moiety I”. In an exemplary embodiment, the compound has a structure described from paragraph 88 to paragraph 91.
• the compound has a structure described in paragraph 88. In an exemplary embodiment, the compound has a structure described in section HE "Low MW fungicide moiety II". In an exemplary embodiment, the compound has a structure described from paragraph 92 to paragraph 95, In an exemplary embodiment, the compound has a structure described in paragraph 92. In an exemplary embodiment, the compound has a structure described in section OF '"Low MW fungicide moiety III". In an exemplary embodiment, the compound has a structure described from paragraph 96 to paragraph 1 15. In an exemplary embodiment, the compound has a structure described in paragraph 96. In an exemplary embodiment, the compound has a structure described in section HG "Commercial Fungicides". In an exemplary embodiment, the compound has a structure described from paragraph 116 to paragraph 1 17. In an exemplary embodiment, the compound has a structure described in paragraph 1 16.
• the invention provides a formulation comprising: (a) a keratin containing component which is a member selected from a human nail unit, skin and hair; (b) a compound of the invention.
• the compound is a salt of a compound of the invention.
• the compound is a pharmaceutically acceptable salt of a compound of the invention.
• the compound has a structure described in section HA "Boron-Containing Compounds".
• the compound has a structure described from paragraph 58 to paragraph 79.
• the compound has a structure described from paragraph 58 to paragraph 72.
• the compound has a structure described in section HB "Acyclic Boronic Acids * '. In an exemplary embodiment, the compound has a structure described from paragraph 80 to paragraph 83. In an exemplary embodiment, the compound has a structure described in paragraph 80. In an exemplary embodiment, the compound has a structure described in section HC "Low MW Pyridone/Pyrithione derivatives". In an exemplary embodiment, the compound has a structure described from paragraph 84 to paragraph 87. In an exemplary embodiment, the compound has a structure described in paragraph 84. In an exemplary embodiment, the compound has a structure described in section HD "Low MW fungicide moiety I". In an exemplary embodiment, the compound has a structure described from paragraph 88 to paragraph 91.
• the compound has a structure described in paragraph 88. In an exemplary embodiment, the compound has a structure described in section HE "Low MW fungicide moiety II". In an exemplary embodiment, the compound has a structure described from paragraph 92 to paragraph 95. In an exemplar ⁇ ' embodiment, the compound has a structure described in paragraph 92. In an exemplary embodiment, the compound has a structure described in section HF '"Low MW fungicide moiety IH''. In an exemplary embodiment, the compound has a structure described from paragraph 96 to paragraph 1 15. In an exemplary embodiment, the compound has a structure described in paragraph 96. In an exemplary embodiment, the compound has a structure described in section HG "Commercial Fungicides". In an exemplary embodiment, the compound has a structure described from paragraph 1 16 to paragraph 117. In an exemplary embodiment, the compound has a structure described in paragraph 1 16.
• the invention provides a method of inhibiting the growth of, or killing, a microorganism present in a human nail unit, wherein said human nail unit comprises a nail plate, comprising: contacting a dorsal layer of the nail plate with a compound capable of penetrating the nail plate, traveling through the nail plate to a nail bed underlying said nail plate, and contacting said microorganism, under conditions sufficient for said compound to penetrate said nail plate.
• the compound is described herein.
• the compound is a salt of a compound of the invention.
• the compound is a pharmaceutical] y acceptable salt of a compound of the invention.
• the compound has a structure described in section HA "Boron-Containing Compounds". In an exemplary embodiment, the compound has a structure described from paragraph 58 to paragraph 79. In an exemplary embodiment, the compound has a structure described from paragraph 58 to paragraph 72. In an exemplary embodiment, the compound has a structure described in section HB "Acyclic Boronic Acids". In an exemplary embodiment, the compound has a structure described from paragraph 80 to paragraph 83. In an exemplary embodiment, the compound has a structure described in paragraph 80. In an exemplary embodiment, the compound has a structure described in section HC "Low MW Pyridone/Pyrithione derivatives".
• the compound has a structure described from paragraph 84 to paragraph 87. In an exemplary embodiment, the compound has a structure described in paragraph 84. In an exemplary embodiment, the compound has a structure described in section HD "Low MW fungicide moiety I". In an exemplary embodiment, the compound has a structure described from paragraph 88 to paragraph 91. In an exemplary embodiment, the compound has a structure described in paragraph 88, In an exemplary embodiment, the compound has a structure described in section HE "Low MW fungicide moiety II'". In an exemplary embodiment, the compound has a structure described from paragraph 92 to paragraph 95. In an exemplary embodiment, the compound has a structure described in paragraph 92.
• the compound has a structure described in section HF "Low MW fungicide moiety III". In an exemplary embodiment, the compound has a structure described from paragraph 96 to paragraph 115. In an exemplary embodiment, the compound has a structure described in paragraph 96. In an exemplary embodiment, the compound has a structure described in section HG "Commercial Fungicides”. In an exemplary embodiment, the compound has a structure described from paragraph 116 to paragraph 1 17. In an exemplary embodiment, the compound has a structure described in paragraph 116,
• FIG. 1 shows selected compounds of the invention and MlC data against various microorganisms.
• substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents, which would result from writing the structure from right to left, e.g., -CH 2 O- is intended to also recite -OCH 2 -.
• poly as used herein means at least 2.
• a polyvalent metal ion is a metal ion having a valency of at least 2,
• Moiety refers to the radical of a molecule that is attached to another moiety.
• alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (Le. C
• 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.
• An unsaturated aikyl group is one having one or more double bonds or triple bonds. Examples of 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 homoiogs and isomers.
• alkyl unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below, such as "heteroaikyl.” Alkyi groups that are limited to hydrocarbon groups are termed "homoalkyl".
• alkyiene 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 described below as “heteroalkylene.”
• an alkyi (or alkyiene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention.
• a “lower alkyl” or “lower alkyiene” is a shorter chain alkyi or alkyiene group, generally having eight or fewer carbon atoms.
• alkoxy alkylamino and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
• heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom.
• the heteroatoms can be selected from the group consisting of B, O, N and S. and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
• the heteroatom(s) B, O. N and S may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
• Examples include, but are not limited to, -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N (CH 3 J-CH 3 , -CH 2 -S- CII 2 -CH 3 , -CH 2 -CH ⁇ -S(O)-CII 3 .
• -CH 2 -CH 2 -S(O) 2 -CH 3 -CH-CH-O-CH 3
• -CH 2 -CH N- OCH 3
• -CH CH-N(CH 3 )-CH 3 .
• heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
• heteroatoms can also occupy either or both of the chain termini (e g , alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediarnino. and the like).
• cycloalkyl and ''heterocycloalkyl. by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1 -cyclohexenyl. 3- cyclohexeny], cycloheptyl, and the like.
• heterocycloalkyl examples include, but are not limited to, 1 ⁇ (l,2.5,6-tetrahydropyridyl), 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- morpholinyl, 3-morpholinyl. tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like.
• * 'halo(Ci-C 4 )alkyr is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyI, 4-chlorobutyl, 3-bromopropyl, and the like.
• aryl means, unless otherwise stated, a polyunsaturated, aromatic, substituent that can be a single ring or multiple rings (preferably from 1 to 3 rings), which are fused together or linked covalently.
• heteroaryl refers to aryl groups (or rings)
• 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 remainder of the molecule through a heteroatom.
• aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl.
• the term "'aryl” when used in combination with other terms includes both aryl and heteroaryl rings as defined above.
• the term ''arylalkyl'' is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alky! groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl. 3-(l- naphthyloxy)propyl, and the like).
• alkyl and heteroalkyl radicals including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyi, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl
• R " , R", R'" and R" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g. , aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalky] groups.
• each of the R groups is independently selected as are each R', R", R" * and R'" " groups when more than one of these groups is present.
• R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.
• -NR ' R" is meant to include, but not be limited to. 1 -pyrrolidinyl and 4-morpholinyl.
• alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl ⁇ e.g., -CF 3 and ⁇ CH 2 CF 3 ) and acyl (e g , -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like).
• substituents for the aryl and heteroaryl groups are generkally referred to as "aryl group substituents.”
• R', R", R'" and R'" are preferably independently selected from hydrogen, substituted or unsubslituted alkyl, substituted or unsubstituted heteroalkyi, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
• R groups are independently selected as are each R', R", R'" and R'"" groups when more than one of these groups is present.
• Two of the substituenls on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CRR ⁇ q -U-, wherein T and U are independently -NR-, -0-, -CRR'- or a single bond, and q is an integer of from O to 3.
• two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 VB-, wherein A and B are independently -CRR'-, -O-, -NR-. -S-, -S(O)-.
• r is an integer of from 1 to 4.
• One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
• two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula - (CRR') s -X-(CR"R"')d-, where s and d are independently integers of from O to 3, and X is -O- , -NR'-. -S-, -S(O)-, -S(O) 2 -. or -S(O) 2 NR ' -.
• the substituents R, R% R" and R'"' are preferably independently selected from hydrogen or substituted or unsubstituted (Q- C 6 )alkyl.
• Ring means a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
• a ring optionally includes fused ring moieties. Substituents on the ring may be optionally joined to form additional ring systems (bicyclic or tricyclic ring systems, for example).
• the number of atoms in a ring is typically defined by the number of members in the ring. For example, a "5- to 7-membered ring" means there are 5 to 7 atoms in the encircling arrangement.
• the ring optionally included a heteroatom.
• the term “5- to 7-membered ring " ' includes, for example pyridinyl and pipcridinyl.
• the term “'ring'' further includes a ring system comprising more than one "'ring", wherein each "ring"' is independently defined as above.
• heteroatom includes atoms other than carbon (C) and hydrogen (H). Examples include oxygen (O). nitrogen (N) sulfur (S), silicon (Si), germanium (Ge), aluminum (Al) and boron (B).
• R is a general abbreviation that represents a substituent group that is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl. substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl groups.
• 'effective amount of a drug, formulation, or permeant is meant a sufficient amount of a active agent to provide the desired local or systemic effect.
• a “Topically effective,” “'Cosmetically effective,” “pharmaceutically effective,” or “therapeutically effective” amount refers to the amount of drug needed to effect the desired therapeutic result.
• Topicically effective refers to a material that, when applied to the skin, nail, hair, claw or hoof produces a desired pharmacological result cither locally at the place of application or systemically as a result of transdermal passage of an active ingredient in the material
• Cosmetically effective refers to a material that, when applied to the skin, nail, hair, claw or hoof, produces a desired cosmetic result locally at the place of application of an active ingredient in the material.
• pharmaceutically acceptable salts is meant to include salts of the compounds of the invention which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
• acid 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 a suitable inert solvent.
• pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic.
• phthalic, benzene sulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like are also included.
• salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge el al.. Journal of Pharmaceutical Science 66: 1-19 (1977)).
• Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
• the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compounds in the conventional manner.
• the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
• the present invention provides compounds which are in a prodrug form.
• Prodrugs of the compounds or complexes described herein readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment.
• Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the 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; the 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 atomic isotopes at one or more of the atoms that constitute such compounds.
• the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 1 H), iodine- 125 ( 123 I) or carbon- 14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
• the term ''pharmaceutically acceptable carrier refers to any formulation or carrier medium that provides the appropriate delivery of an effective amount of a active agent as defined herein, does not interfere with the effectiveness of the biological activity of the active agent, and that is sufficiently non-toxic to the host 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, thickeners, penetration enhancers, and the like. Their formulation is well known to those in the art of cosmetics and topical pharmaceuticals. Additional information concerning carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005) which is incorporated herein by reference.
• “Pharmaceutically acceptable topical carrier” refers to pharmaceutically acceptable carriers, as described herein above, suitable for topical application.
• An inactive liquid or cream vehicle capable of suspending or dissolving the active agent(s), and having the properties of being nontoxic and non-inflammatory when applied to the skin, nail, hair, claw or hoof is an example of a pharmaceutically-acceptable topical carrier. This term is specifically intended to encompass carrier materials approved for use in topical cosmetics as well.
• the term ''pharmaceutically acceptable additive refers to preservatives, antioxidants, fragrances, emulsifiers, dyes and excipients known or used in the field of drug formulation and that do not unduly interfere with the effectiveness of the biological activity of the active agent, and that is sufficiently non-toxic to the host or patient.
• Additives for topical formulations are well-known in the art, and may be added to the topical composition. as long as they are pharmaceutically acceptable and not deleterious to the epithelial cells or their function. Further, they should not cause deterioration in the stability of the composition.
• inert fillers for example, inert fillers, anti- irritants, tackifiers, excipients, fragrances, opacifiers, antioxidants, gelling agents, stabilizers, surfactant, emollients, coloring agents, preservatives, buffering agents, other permeation enhancers, and other conventional components of topical or transdermal delivery formulations as are known in the art.
• penetration enhancement or “permeation enhancement” relate to an increase in the permeability of the skin, nail, hair, claw or hoof to a drug, so as to increase the rate at which the drug permeates through the skin, nail, hair, claw or hoof.
• the enhanced permeation effected through the use of such enhancers can be observed, for example, by measuring the rate of diffusion of the drug through animal or human skin, nail, hair, claw or hoof using a diffusion cell apparatus.
• a diffusion cell is described by Merritt et al, J of Controlled Release, 1 : 161 - 162 ( 1984).
• permeation enhancer or “penetration enhancer” intends an agent or a mixture of agents, which, alone or in combination, act to increase the permeability of the skin, nail, hair or hoof to a drug.
• excipients is conventionally known to mean carriers, diluents and/or vehicles used in formulating drug compositions effective for the desired use.
• Topical administration refers to the application of a pharmaceutical agent to the external surface of the skin, nail, hair, claw or hoof, such that the agent crosses the external surface of the skin, nail, hair, claw or hoof and enters the underlying tissues.
• Topical administration includes application of the composition to intact skin, nail, hair, claw or hoof, or to a broken, raw or open wound of skin, nail, hair, claw or hoof.
• Topical administration of a pharmaceutical agent can result in a limited distribution of the agent to the skin and surrounding tissues or, when the agent is removed from the treatment area by the bloodstream, can result in systemic distribution of the agent.
• Transdermal delivery refers to the diffusion of an agent across the barrier of the skin, nail, hair, claw or hoof resulting from topical administration or other application of a composition.
• stratum corneum acts as a barrier and few pharmaceutical agents are able to penetrate intact skin.
• the epidermis and dermis are permeable to many solutes and absorption of drugs therefore occurs more readily through skin, nail, hair, claw or hoof that is abraded or otherwise stripped of the stratum corneum to expose the epidermis.
• Transdermal delivery includes injection or other delivery through any portion of the skin, nail, hair, claw or hoof or mucous membrane and absorption or permeation through the remaining portion.
• Absorption through intact skin, nail, hair, claw or hoof can be enhanced by placing the active agent in an appropriate pharmaceutically acceptable vehicle before application to the skin, nail, hair, claw or hoof.
• Passive topical administration may consist of applying the active agent directly to the treatment site in combination with emollients or penetration enhancers.
• transdermal delivery is intended to include delivery by permeation through or past the integument, i.e. skin, nail, hair, claw or hoof.
• microbial infection refers to any infection of a host tissue by an infectious agent including, but not limited to, viruses, bacteria, mycobacteria, fungus and parasites (see, e.g., Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et ah, eds.. 12th ed. 1991 ); Williams et al., J. of Medicinal Chern. 42: 1481 -1485 (1999), herein each incorporated by reference in their entirety).
• Bio medium refers to both in vitro and in vivo biological milieus.
• exemplary in vitro “biological media” include, but are not limited to, cell culture, tissue culture, homogenates, plasma and blood. In vivo applications are generally performed in mammals, preferably humans.
• MIC or minimum inhibitory concentration
• Inhibiting' 1 and “blocking,” are used interchangeably herein to refer to the partial or full blockade of an editing domain of a tRNA synthetase.
• the present invention provides compounds which are capable of inhibiting the growth of, or killing, microorganisms and/or treating diseases in an animal (such as a human) or a plant. These compounds may be included within a pharmaceutical formulation,
• the invention provides a compound which has a structure which is a member selected from the following formulae: wherein Y is a member selected from substituted or unsubstituted vinyl and substituted or unsubstituted aryi, Z, R a , R b , R ⁇ and R d are members independently selected from members independently selected from H, OR*, NR*R**. SR*, -S(O)R*, -S(O) 2 R*, -S(O) 2 NR*R**, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl.
• R b and R c together with the atoms to which they are attached, are optionally joined to form a 4- to 8-membered ring.
• R ⁇ and R e together with the atoms to which they are attached, are optionally joined to form a 4- to 8-membered ring.
• Y and Z together with the atoms to which they are attached, are optionally joined to form a member selected from a 4- to 8- membered ring and a 6- to 12-membered bicyclic ring. Substituents on the ring may be optionally joined to form additional ring systems, for example
• Each R* and R** are members independently selected from H, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl. substituted or unsubstituted heterocycloalkyl. substituted or unsubslituted aryl, and substituted or unsubstituted heteroaryl, and pharmaceutically acceptable salts thereof.
• said compound has a structure according to the following formula:
• R a and R & are H.
• R c and R ⁇ are H.
• R e and R h are H.
• the compound has a structure according to the following formula: and .
• R d and R are H.
• R c and R d are H,
• R g and R h are H.
• said compound has a structure according to the following formula:
• R and are H, In an exemplary embodiment, R a and R are H, In an exemplary embodiment, R c and R d are H. In an exemplary embodiment, R g and R h are H. In an exemplary embodiment, said Z is substituted or unsubstituted vinyl.
• said compound is a member selected from
• R d and R are H.
• R c and R d are H.
• R g and R h are H.
• said compound is a member selected from
• said compound is a
• said compound is a member selected from H 2 N and H 2 N-- / r n m exemplary embodiment, said compound is a member selected from
• said Z is substituted or unsubstituted alkyl, and wherein said substituted or unsubstituted alkyl is substituted or unsubstituted alkenyl.
• said Z is substituted or unsubstituted vinyl.
• said Z is substituted or unsubstituted aryl.
• said Z is substituted aryl, and has a structure according to the following formula:
• R ! is a member selected from H, nitro, halogen, cyano, 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.
• said R 1 is a member selected from nitro, halogen, cyano and substituted or unsubstituted alkyl.
• said R ! is a member selected from fluorine, chlorine and bromine.
• said Z is .
• said compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
• said Z is substituted or unsubstituted heteroaryl.
• said Z is a member selected from substituted or unsubstituted 2- pyridinyL substituted or unsubstituted 3-pyridinyl and substituted or unsubstituted 4- pyridinyl.
• said Z is substituted or unsubstituted 3-pyridiny ⁇ .
• said compound is ( NJ
• said R b and R c together with the atoms to which they axe attached, are joined to form a substituted or unsubstituted 4- to 6-membered ring.
• said compound is [0068] In an exemplary embodiment, said compound is a member selected from
• said compound is a member selected from
• said compound is a member selected from
• said compound is a member selected from
• Y and Z together with the atoms to which they are attached, are joined to form a member selected from a 4- to 8- membered ring and a 6- to 12-membered bicyclic ring.
• Y and Z together with the atoms to which they are attached, are joined to form an 8-membered bicyclic ring
• said 8-membered bicyclic ring is unsubstituted.
• the compound is a salt of the compounds described in this section, In an exemplary embodiment, the compound is a pharmaceutically acceptable salt of the compounds described in this section.
• the compounds are produced according to the following scheme:
• the compounds are produced according to the following scheme:
• 2a and 2b can be contacted in order to produce 2c.
• 2c and 2d can be contacted in order to produce 2e.
• 2e and 2f can be contacted in order to produce 2g.
• the compounds are produced according to the following scheme: THF,
• 3a can be reacted under conditions suitable to produce 3b.
• 3b can be contacted with 3c in order to produce 3d.
• 3d can be reacted under conditions suitable to produce 3e.
• the invention provides a compound which has a structure which is a member selected from the following formulae:
• Each R J is a member independently selected from a negative charge, a salt counterion and H.
• each R in each structure is H.
• at least one of said R 3 is a salt counterion.
• at least one of said R 3 is a negative charge.
• the compound is a salt of the compounds described in this section.
• the compound is a pharmaceutically acceptable salt of the compounds described in this section.
• acyclic boronic acids described in this section can be purchased from sources such as Aldrich (St. Louis, MO). TCI America (Portland, OR), Acros Organics (Belgium), Alfa Aesar (Ward Hill, MA) and Lancaster Synthesis (United Kingdom). Acyclic boronic acids can also be synthesized according to the methods described in Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine, Hall, DG, Ed., Wiley-VCH Verlag GmbH & Co., 2005. In addition, the compounds can be produced according to the following scheme:
• the invention provides a compound which has a structure according to the following formula:
• R and R are members independently selected from H, R*. OR*, NR* R**, SR*, - S(O)R*, -S(O) 2 R*, -S(O) 2 NR*R**, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
• R* and R** are members independently selected from H, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl. substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
• R 3 is a member selected from a negative charge, a salt counterion and H
• X is a member selected from O and S. This aspect has the proviso that the compound is not a member selected from
• R 2 is cyclohexyl.
• R 1 is methyl.
• R 2 is a member selected from H, substituted or unsubstituted alky!.
• R" is a member selected from H, methyl, ethyl and isopropyl.
• R 2 is methyl, ⁇ n an exemplary embodiment, X is S.
• the compound is a salt of the compounds described in this section. In an exemplary embodiment, the compound is a pharmaceutically acceptable salt of the compounds described in this section.
• the compounds described in this section can be purchased from sources such as Aldrich (St. Louis, MO). TCI America (Portland, OR), Acros Organics (Belgium), Alfa Aesar (Ward Hill, MA) and Lancaster Synthesis (United Kingdom). In addition, the compounds can be produced according to the following scheme:
• the invention provides a compound which has a structure according to the following formula:
• R a , R b . R c , R d , R e , R 1 are members independently selected from members independently selected from H, OR*, NR*R**, SR*, -S(O)R*, -S(O) 2 R*, -S(O) 2 NR + R**, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycioalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
• R* and R** are members independently selected from H, nitro. halogen, cyano, substituted or unsubstituted alky], substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycioalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl .
• R 3 is a member selected from a negative charge, a salt counterion and H. In an exemplary embodiment, there is a proviso that said compound is not a member selected from
• R ⁇ R f are H.
• one of said R a . R , R c , R d , R e and R f is a member selected from bromine, chlorine and fluorine and the remainder of said variables is H.
• the compound has a structure according to Cl .
• the compound is a salt of the compounds described in this section.
• the compound is a pharmaceutically acceptable salt of the compounds described in this section.
• the compounds described in this section can be purchased from sources such as Aldrich (St. Louis, MO), TCI America (Portland, OR), Acros Organics (Belgium). Alfa Aesar (Ward Hill, MA) and Lancaster Synthesis (United Kingdom).
• the compounds can be produced according to the Friendlander synthesis, as well as by the following scheme (McNaughlon et al, Org. Lett., 5: 23. 4257-4259 (2003)):
• the invention provides a compound which has a structure which is a member selected from the following formula:
• R a , R b , R c , R d , R c and R f are members independently selected from members independently selected from H, OR*, NR*R**.
• Each R* and R** are members independently selected from H, nitro, halogen, cyano, 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 compound is not a member selected from
• R a , R b , R c , R d , and R e are H.
• R a , R b , R c , R d , and R c are H.
• R 1 is a member selected from H 5 methyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted ⁇ - NH
• R r is a member selected from H
• R g , R h and R 1 are members independently selected from H, OR*, NR*R**, SR*, -S(O)R*, -S(O) 2 R*, -S(O) 2 NR*R**, nitro, halogen, cyano, 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.
• Each R* and R** are members independently selected from H, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
• R d , R , R c , R , and R c are H and R* is the same as described in the previous sentence.
• R 1 is H 3 C .
• R e is wherein R 1 is a member selected from substituted or unsubstituted alkyl and I— NH q substituted or unsubstituted heteroalkyl and R r is R k wherein R k is a member selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl.
• R e is ⁇ H 3
• R f is methyl.
• the compound is a salt of the compounds described in this section.
• the compound is a pharmaceutically acceptable salt of the compounds described in this section.
• the compounds described in this section can be purchased from sources such as Aldrich (St. Louis, MO), TCI America (Portland, OR), Acros Organics (Belgium), Alfa Aesar (Ward Hill, MA) and Lancaster Synthesis (United Kingdom).
• the compounds can be produced according to one of several syntheses which are known to those of skill in the art.
• One synthesis involves coupling phenylenediamines and carboxylic acids (see Grimmet. M. R. In Comprehensive Heterocyclic Chemistry; Katritzky, A.R., Rees C, W., Eds., 1984; Vol. 5, p. 457; Geratz, Arch Biochem. Biophys. 197: 551-559 (1979)).
• the invention provides a compound which has a structure according to the following formula:
• R a , R b , R c and R d are members independently selected from members independently selected from H, OR*, NR*R**, SR*, -S(O)R*, -S(O) 2 R*, -S(O) 2 NR*R**, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryi, and substituted or unsubstituted heteroaryl.
• Each R* and R** are members independently selected from H, nitro.
• X is a member selected from O and S. In an exemplary embodiment, there is a proviso that the compound is not
• X is S.
• R b and R ⁇ are H.
• R a and R ⁇ is a member selected from substituted or unsubstituted alkyl.
• R a and R c are methyl.
• the compound is a salt of the compounds described in this section.
• the compound is a pharmaceutically acceptable salt of the compounds described in this section.
• the compounds described in this section can be purchased from sources such as Aldrich (St. Louis. MO), TCl America (Portland, OR), Acros Organics (Belgium), Alfa Aesar (Ward Hill, MA) and Lancaster Synthesis (United Kingdom).
• the compounds can be produced according to one of several syntheses which are known to those of skill in the art.
• One synthesis involves the following scheme (Katiyar et a!., Bioorg. Med. Chem., 11:4369-4375 (2003))
• the invention provides a compound which has a structure which is a member selected from the following formulae:
• the fungicide is a sordarin.
• the compound is a salt of the compounds described in this section.
• the compound is a pharmaceutically acceptable salt of the compounds described in this section.
• fungicides described in this section are commercially available from sources such as Aldrich (St, Louis, MO), TCI America (Portland. OR), Acros Organics (Belgium), Alfa Aesar (Ward Hill, MA) and Lancaster Synthesis (United Kingdom). //. H. Formulations with keratin
• a compound of the invention described herein When a compound of the invention described herein is applied to a nail component of a human, the compound absorbs or penetrates into the nail.
• the human nail is primarily composed of keratin (i.e. hair keratin or ⁇ -keratin) as well as trace amounts of lipid components. Therefore, in the process of treating a disease of the nail or killing or inhibiting the growth of a microorganism, a formulation comprising a human nail unit and a compound of the invention is formed.
• the invention provides a formulation comprising: (a) a compound which is a member selected from a compound of the invention; and (b) a keratin containing component which is a member selected from a human nail unit, skin and hair.
• the compound of part (a) contacts the component of part (b).
• the keratin containing component is a nail plate of the human nail unit.
• the keratin containing component is a nail bed of the human nail unit.
• the keratin containing component is a proximal nail fold of the human nail unit.
• the keratin containing component is a lateral nail fold of the human nail unit.
• the human nail unit comprises a member selected from keratin and lipid.
• keratin is a member selected from skin keratin and nail/hair keratin.
• lipid is a member selected from cholesterol sulfate, cerebroside, ceramide, free sterol, free fatty acids, triglycerides, sterol esters, wax esters, and squalene.
• the compound is present in the formulation at a concentration which is a member selected from about 0.001%, about 0.01%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%.
• the keratin is present in said formulation at a concentration which is a member selected from about 99.99%, about 99.95%, about 99.90%, about 99.5%, about 99.0%, about 98.5%, about 98.0%, about 97.5% and about 97%.
• the compound is a compound described herein.
• the invention provides a method of forming this formulation, wherein said method comprises applying said compound to a formulation comprising keratin, thereby forming said formulation.
• the formulation comprising keratin is a human nail unit.
• the formulation comprising keratin is a member selected from a nail plate, nail bed, proximal nail fold, and lateral nail fold. Methods of making these formulations are described herein.
• the invention provides a method for inhibiting the growth, or killing, a microorganism, preferably a bacteria, fungus, virus, yeast or parasite, comprising contacting the microorganism with a compound of the invention, such as a compound described by a formula listed herein, under conditions which permit entry of the compound into the organism. Such conditions are known to one skilled in the art and are also described herein.
• This method involves contacting a microbial cell with a therapeutically-effective amount of an editing domain inhibitor to inhibit tRNA synthetase in vivo or in vitro.
• the invention provides a method of inhibiting the growth of a microorganism, or killing a microorganism, or both, comprising contacting the microorganism with a compound described herein.
• Microorganisms are members selected from fungi, yeast, viruses, bacteria and parasites.
• the microorganism is inside, or on the surface of an animal.
• the animal is a member selected from human, cattle, deer, reindeer, goat, honey bee, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, camel, yak, elephant, ostrich, otter, chicken, duck, goose, guinea fowl, pigeon, swan, and turkey.
• the animal is a human.
• the microorganism is a member selected from a fungus and a yeast.
• the fungus or yeast is a member selected from Candida species, Trichophyton species, Microsporium species, Aspergillus species, Cryptococcus species, Blastomyces species, Cocciodiodes species, Histoplasma species, Paracoccidiodes species, Phycomycetes species, Malassezia species, Fusarium species, Epidermophyton species, Scytalidium species, Scopula ⁇ opsis species, Allernaria species, PenicHlium species. Phialophora species, Rhizopus species, Scedosporium species and Zygomycetes class.
• the fungus or yeast is a member selected from Aspergillus fumigatus ⁇ A. fumigatus), Blastomyces dermatitidis, Candida Albicans (C. albicans, both fluconazole sensitive and resistant strains), Candida glabrata (C. glabrata), Candida krusei (C. knisei), Cryptococcus neoformans (C. neoformans), Candida parapsilosis (C. parapsilosis), Candida tropicalis (C tropicalis), Cocciodiodes immitis, Epidermophyton floccosum (E. floccosum), Fusarium solani (F.
• the fungus or yeast is a member selected from Trichophyton concentricum, T. violaceum, T. schoenleinii, T. verrucosum, T. soudanense, Microsporum gypseum, M, equinum, Candida guilUermondii, Malassezia globosa, M. obtuse, M. restricta, M. slooffiae, and Aspergillus flavus.
• the fungus is a member selected from a dermatophyte, Trichophyton species, Microsporium species, Candida species, Aspergillus species and yeasl-like fungus.
• the fungus or yeast is a member selected from dermatophytes, Trichophyton, Microsporum, Epidermophyton and yeast-like fungi.
• the microorganism is a bacteria.
• the bacteria is a gram-positive bacteria.
• the gram-positive bacteria is a member selected from Staphylococcus species, Streptococcus species, Bacillus species, Mycobacterium species, Corynebaclerium species (Propionibacterium species), Clostridium species, Actinomyces species, Enterococcus species and Streptomyces species.
• the bacteria is a gram- negative bacteria.
• the gram -negative bacteria is a member selected from Acinetobacter species, Neisseria species, Pseudomonas species, Brucella species.
• the bacterium is a member selected from Propionibacterium acnes; Staphylococcus aureus:, Staphylococcus epidermidis.
• Staphylococcus saprophytics Streptococcus pyogenes; Streptococcus agalactiae; Streptococcus pneumoniae; Enterococcus faecalis; Enterococcus faecium; Bacillus anthracis; Mycobacterium avium-intracellular e; Mycobacterium tuberculosis, Acinetobacter baumanii; Corynebacterium diphtheria; Clostridium perfringens; Clostridium botulinum; Clostridium tetani; Clostridium difficile; Neisseria gonorrhoeae; Neisseria meningitidis; Pseudomonas aeruginosa; Legionella pneumophila; Escherichia colt; Yersinia pestis; Haemophilus influenzae; Helicobacter pylori; Campylobacter fetus; Campylobacter je
• the microorganism is a bacteria, which is a member selected from acid-fast bacterium, including Mycobacterium species; bacilli, including Bacillus species, Corynebacterium species (also Propionibacterium) and Clostridium species; filamentous bacteria, including Actinomyces species and Streptomyces species; bacilli, such as Pseudomonas species, Brucella species, Agrobacterium species, Bordetella species. Escherichia species, Shigella species, Yersinia species, Salmonella species, Klebsiella species.
• Enterobacter species Haemophilus species, Pasteurella species, and Streptobacillus species; spirochetal species, Campylobacter species, Vibrio species; and intracellular bacteria including Rickettsiae species and Chlamydia species.
• the microorganism is a virus.
• the virus is a member selected from hepatitis A-B, human rhinoviruses, Yellow fever virus, human respiratory coronaviruses. Severe acute respiratory syndrome (SARS), respiratory syncytial virus, influenza viruses, parainfluenza viruses 1-4.
• human immunodeficiency virus 1 HBV-I
• human immunodeficiency virus 2 HMV-2.
• Herpes simplex virus 1 HSV-I
• Herpes simplex virus 2 HS V-2
• HCMV human cytomegalovirus
• HCMV Varicella zoster virus
• Epstein-Barr (EBV) polioviruses.
• the virus is a member selected from picornaviridae, ⁇ aviviridae, coronaviridae, paramyxoviridae, orthomyxoviridae, retroviridae, herpesviridae and hepadnaviridae.
• the virus is a member selected from a virus included in the following table:
• HCV Human respiratory coronavirus
• SAR Severe acute respiratory syndrome
• Bunyavirm - Bunyamwera BUN
• HTN Hantavirus - Hantaan
• CCHF Bimyaviridae Nairevirus - Crimean-Congo hemorrhagic fever
• Herpes simplex virus 1 Herpes simplex virus 1 (HSV-I)
• Herpes simplex virus 2 Herpes simplex virus 2 (HSV-2)
• HCMV Human cytomegalovirus
• VZV Varicella zoster virus
• EBV Epstein-Barr virus
• HHV ⁇ Human herpes virus 6
• Poxviridae Orthopoxvirus is sub-genus for smallpox Virus Category Pertinent Human Infections
• HBV Hepadnaviridae Hepatitis B virus
• HCV Hepatitis C virus
• the microorganism is a parasite.
• the parasite is a member selected from Plasmodium falciparum, P. vivax, P. ovale P. malar iae, P. berghei, Leishmania 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 histolytica, Trichomonas vaginalis, Pneumocystis carinii, and Cryptosporidium parvum.
• the invention provides a method of inhibiting the growth of, or killing, a fungus, said method comprising: contacting said fungus with a compound in an amount sufficient to inhibit or kill said fungus wherein said fungus is a member selected from a dermatophyte, Trichophyton species, Microsporium species, Candida species, Aspergillus species and yeast-like fungus, and wherein said compound is described herein,
• the fungus is a member selected from Candida albicans, Candida neoformans, Aspergillus fumigatus, Trichophyton mentagrophytes (T. mentagrophytes) and Trichophyton rubrum (T. rubrum).
• the method has the proviso that the molecular weight of said compound is not greater than a member selected from about 300, about 250, about 225, and about 200. In another exemplary embodiment, the method has the proviso that the c log P o ⁇ said compound is between about 0 and about 2. In another exemplary embodiment, the method has the proviso that the c log P of said compound is between about -5 and about 2, In another exemplary embodiment, the method has the proviso that the c log P of said compound is between about -2 and about 2. In another exemplary embodiment, the method has the proviso that the efficacy coefficient of said compound is greater than about 10.
• the invention provides a method of treating or preventing an infection.
• the method includes administering to the animal a therapeutically effective amount of the compound of the invention, sufficient to treat or prevent said infection.
• the compound is a compound described herein,
• the animal is a member selected from human, cattle, deer, reindeer, goat, honey bee, pig, sheep, horse, cow, bull, dog.
• the animal is a human.
• the animal is a member selected from a human, cattle, goat, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil. rabbit, cat, chicken and turkey.
• the infection is a member selected from a systemic infection, a cutaneous infection, and an ungual, periungual or subungual infection.
• the treatment of a disorder or condition occurs through inhibition of an editing domain of an aminoacyl tRNA synthetase.
• the invention provides a method of treating a disease in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound, thereby treating said diseasewherein said disease is an ungual, periungual or subungual infection; wherein said compound is described herein.
• said disease is onychomycosis.
• the method has the proviso that the molecular weight of said compound is not greater than a member selected from about 300, about 250, about 225. and about 200.
• the method has the proviso that the c log P of said compound is between about 0 and about 2.
• the method has the proviso that the c log P of said compound is between about -5 and about 2. In another exemplary embodiment, the method has the proviso that the c log P of said compound is between about - 2 and about 2. In another exemplary embodiment, the method has the proviso that the efficacy coefficient of said compound is greater than about 10.
• the invention provides a method of treating or preventing an ungual and/or periungual infection.
• the method includes administering to the animal a therapeutically effective amount of a compound or pharmaceutical formulation of the invention, sufficient to treat or prevent said infection.
• the method includes administering the compound or pharmaceutical formulation of the invention at a site which is a member selected from the skin, nail, hair, hoof, claw and the skin surrounding the nail, hair, hoof and claw.
• Onychomycosis is a disease of the nail caused by yeast, dermatophytes, or other molds, and represents approximately 50% of all nail disorders. Toenail infection accounts for approximately 80% of onychomycosis incidence, while fingernails are affected in about 20% of the cases. Dermatophytes are the most frequent cause of nail plate invasion, particularly in toenail onychomycosis. Onychomycosis caused by a dermatophyte is termed 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 site of entry through the hyponychium (the thickened epidermis underneath the free distal end of a nail) progressing in time to involve the nail bed and the nail plate.
• Discoloration, onycholysis, and accumulation of subungual debris and nail plate dystrophy characterize the disease.
• the disease adversely affects the quality of life of its victims, with subject complaints ranging from unsightly nails and discomfort with footwear, to more serious complications including secondary bacterial infections.
• antibiotics e.g., nystatin and amphotericin B
• imidazole anti-fungal agents such as miconazole, clotrimazole, fluconazole, econazole and sulconazole
• non- imidazole fungal agents such as the allylamine derivatives terbinafme and naftifine, and the benzylamine butenafine
• onychomycosis has proven to be resistant to most treatments.
• Nail fungal infections reside in an area difficult to access by conventional topical treatment and anti-fungal drugs cannot readily penetrate the nail plate to reach the infection sites under the nail. Therefore, onychomycosis has traditionally been treated by oral administration of antifungal drugs; however, clearly this is undesirable due to the potential for side effects of such drugs, in particular those caused by the more potent anti-fungal drugs such as itraconazole and ketoconazole.
• An alternative method of treatment of onychomycosis is by removal of the nail before treating with a topically active anti-fungal agent; such a method of treatment is equally undesirable.
• Systemic antimycotic agents require prolonged use and have the potential for significant side effects.
• Topical agents have usually been of little benefit, primarily because of poor penetration of the anti-fungal agents into and through the nail mass.
• the invention provides a method of treating or preventing onychomycosis.
• the method includes administering to a human or an animal a therapeutically effective amount of a compound of the invention, or a pharmaceutical formulation of the invention, sufficient to treat or prevent onychomycosis.
• the method includes administering the pharmaceutical formulation of the invention at a site which is a member selected from the skin, nail, hair, hoof, claw and the skin surrounding the nail, hair, hoof and claw,
• the pharmaceutical formulation includes a compound described herein.
• the invention provides a method of treating or preventing an ungual or periungual infection in an animal (such as a human) or a plant. This method comprising administering to the animal (human) a therapeutically effective amount of a compound of the invention, thereby treating or preventing the ungual or periungual infection.
• the ungual or periungual infection is onychomycosis.
• the ungual or periungual infection is a member selected from: onychomycosis, chloronychia, paronychias, erysipeloid, onychorrhexis, gonorrhea, swimming-pool granuloma, larva migrans, leprosy, Orf nodule, milkers' nodules, herpetic whitlow, acute bacterial perionyxis, chronic perionyxis, sporotrichosis, syphilis, tuberculosis verrucosa cutis, tularemia, tungiasis, peri- and subungual warts, zona, nail dystrophy (trachyonychia), and dermatological diseases with an effect on the nails, such as psoriasis, pustular psoriasis, alopecia aerata, parakeratosis pustulosa, contact dermatosis, Reiter's syndrome,
• the compounds and pharmaceutical formulations of the invention useful for ungual and periungual applications also find application in the cosmetics field, in particular for the treatment of irregularities of the nails, koilonychias, Beau's lines, longitudinal ridging, ingrown nails.
• the infection is of the skin, nail, hair, claw or hoof, hair, ear and eye and is a member selected from Sporotrichosis, Mycotic keratitis, Extension oculomycosis, Endogenous oculomycosis, Lobomycosis, Mycetoma, Piedra, Pityriasis versicolor, Tinea corporis, Tinea cruris, Tinea pedis, Tinea barbae, Tinea capitis, Tinea nigra, Otomycosis, Tinea favosa, Chromomycosis, and Tinea Imbricata.
• the invention provides a method of treating a systemic disease.
• the method involves contacting an animal (human) with a compound of the invention.
• the method of delivery for treatment of systemic disesases can be oral, intravenous, transdermal, inhalation, intraperitoneal, and subcutaneous,
• the infection is systemic and is a member selected from candidiasis, aspergillosis, coccidioidomycosis, cryptococcosis, histoplasmosis, blastomycosis, paracoccidioidomycosis, zygomycosis, phaeohyphomycosis and rhinosporidiosis.
• the compounds of the invention are useful for the treatment of diseases of animals, such as humans, involving viruses
• the disease is a member selected from hepatitis A - B - C, yellow fever, respiratory syncytial, influenza, AIDS, herpes simplex, chicken pox, varicella zoster, and Epstein-Barr disease.
• the compounds of the invention are useful for the treatment of diseases of animals, such as humans, involving parasites.
• the disease is a member selected from malaria, Chagas' disease, Leishmaniasis, African sleeping sickness
• the invention provides a method of killing or inhibiting growth of a microorganism present in a human nail unit, wherein said human nail unit comprises a nail plate.
• the method comprising contacting a dorsal layer of the nail plate with a compound capable of penetrating the nail plate, traveling through the nail plate to a nail bed underlying said nail plate, and contacting said microorganism, under conditions sufficient for said compound to penetrate said nail plate.
• the compound has a molecular weight of between about 100 Da and about 300 Da, a log P value of between about 1.0 and about 2.6, a water solubility greater than about 0.1 mg/mL octanol/saturated water, and an MIC of less than 16 ⁇ g/mL against said microorganism, thereby killing or inhibiting the growth of said microorganism.
• the compound is described herein.
• the invention provides a method of treating a disease caused by a microorganism present in a human nail unit, wherein said human nail unit comprises a nail plate, said method comprising: contacting a dorsal layer of the nail plate with a compound capable of penetrating the nail plate, traveling through the nail plate to a nail bed underlying said nail plate, and contacting said microorganism, under conditions sufficient for said compound to penetrate said nail plate and to treat said disease.
• the compound has a molecular weight of between about 100 Da and about 300 Da; a log P value of between about 1.0 and about 2.6; a water solubility greater than about 0.] mg/mL octanol/saturated water, and an MIC of less than 16 ⁇ g/mL against said microorganism, thereby treating said disease.
• the compound is described herein.
• 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 300 Da.
• the compound also has a log P value of between about 1.0 and about 2.6.
• the compound additionally has a water solubility between about 0.1 mg/mL and 1 g/mL octanol/saturated water, thereby delivering said compound.
• the compound is described herein.
• the physicochemical properties of the compound of the invention described by quantities predictive for migration of the compound through the nail plate, including, but not limited to. molecular weight, log P and solubility in water, and the like, are effective to provide substantial penetration of the nail plate.
• the compound has a molecular weight of between about 100 Da and about 250 Da. In an exemplary embodiment, the compound has a molecular weight of between about 100 Da and about 225 Da. In an exemplary embodiment, the compound has a molecular weight of between about 100 Da and about 200 Da. 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 210 Da.
• 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 of 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 of from about 145 to about 170 Da. In yet another embodiment the molecular weight is either 151.93 or 168.39 Da.
• the compound has a log P value of between about -3.5 to about 2.5. In another exemplary embodiment, the compound has a log P value of from about -1.0 to about 2.5. In another exemplary embodiment, the compound has a log P value of from about -1.0 to about 2,0. In another exemplary embodiment, the compound has a log P value of from about -0.5 to about 2.5. In another exemplary embodiment, the compound has a log P value of from about -0.5 to about 1.5. In another exemplary embodiment, the compound has a log P value of from about 0.5 to about 2.5. In another exemplary embodiment, the compound has a log P value of from about 1.0 to about 2,5. In yet another exemplary embodiment, the compound has a log P value of 1.9 or 2.3.
• Also contemplated by the present invention is a compound with a log P value less then 2.5, with a molecular weight less than 200 Da, that are still able to penetrate the nail plate.
• the compound has a water solubility between about 0.1 mg/mL to 1 g/mL in octanol saturated water. In one embodiment of the present invention the compound has a water solubility of between 0.1 mg/mL and 100 mg/mL. In another embodiment of this invention, the compound has a water solubility of from about 0.1 mg/mL and 10 mg/mL. In another embodiment of this invention, the compound has a water solubility of from about 0.1 mg/mL and 1 mg/mL. In another embodiment of this invention, the compound has a water solubility of from about 5 mg/mL and 1 g/mL. In another embodiment of this invention, the compound has a water solubility of from about 10 mg/mL and 500 g/mL. In another embodiment of this invention, the compound has a water solubility of from about 80 mg/mL and 250 mg/mL.
• the present invention provides a compound with a log P value selected from a range above, with a molecular weight selected from a range above, that are still able to penetrate the nail plate.
• the present invention provides compounds with a molecular weight selected from a range above, with a water solubility selected from a range above, that are still able to penetrate the nail plate.
• the present invention provides compounds with a log P selected from a range above, with a water solubility selected from a range above, that are still able to penetrate the nail plate.
• the present invention provides compounds with a molecular weight selected from a range above, with a log P selected from a range above, and with a water solubility selected from a range above, that are still able to penetrate the nail plate.
• Penetration of the nail by the active ingredient may be effected by the polarity of the formulation.
• the polarity of the formulation is not expected have as much influence on nail penetration as some of the other factors, such as the molecular weight or the log P of the active ingredient.
• the presence of penetration enhancing agents in the formulation is likely to increase penetration of the active agent when compared to similar formulations containing no penetration enhancing agent.
• Compound 3 below is an example of a compound similar in molecular weight to ciclopirox, and like ciclopirox, penetrates the nail plate poorly.
• the topical formulations including a compound described herein has a total molecular weight of less than 200 Da, has a Log P of less than 2.5, and a minimum inhibitory concentration against Trichophyton ruhrum that is substantially unchanged in the presence of 5% keratin.
• the efficacy coefficient (defined as flux over MIC) of a compound also informs one of skill regarding whether the compound may be effective in killing a microorganism, inhibiting the growth of a microorganism, or treating a disease which is caused by a microorganism present in a human nail unit, wherein said human nail unit comprises a nail plate.
• the method comprises: contacting a dorsal layer of the nail plate with a compound capable of penetrating the nail plate, traveling through the nail plate to a nail bed underlying said nail plate, and contacting said microorganism, under conditions sufficient for said compound to penetrate said nail pjate and to treat said disease, wherein the compound has an efficacy coefficient above 10.
• the compound has an efficacy coefficient between about 10 and about 1000. In an exemplary embodiment, the compound has an efficacy coefficient between about 30 and about 100. In an exemplary embodiment, the compound has an efficacy coefficient between about 100 and about 500. In an exemplary embodiment the compound has an efficacy coefficient between about 25 and about 200.
• This invention is still further directed to methods for treating a fungal infection mediated at least in part by dermatophytes, Trichophyton, Microsporum or Epidermophyion species, or a yeast-like fungi including Candida species, in an animal (such as a human) or a plant, which methods comprise administering to an animal (such as a human) or a plant, that has been diagnosed with said fungal infection or is at risk of developing said fungal 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.
• the infection is onychomycosis.
• 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 invention is a pharmaceutical formulation which includes:
• the invention is a pharmaceutical formulation which includes: (a) a pharmaceutically acceptable excipient; and (b) a compound described herein.
• the invention is a pharmaceutical formulation which includes: (a) a pharmaceutically acceptable excipient; and (b) a compound which is a member selected from a boron containing compound described in this document, a Sow molecular weight ciclopirox derivative described in this document, and a fungicide described in this document.
• the invention is a pharmaceutical formulation which includes: (a) a pharmaceutically acceptable excipient; and
• the pharmaceutical formulations of the invention can take a variety of forms adapted to the chosen route of administration. Those skilled in the art will recognize various synthetic methodologies that may be employed to prepare non-toxic pharmaceutical formulations incorporating the compounds described herein. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable solvents that may be used to prepare solvates of the compounds of the invention, such as water, ethanol, propylene glycol, mineral oil, vegetable oil and dimethylsulfoxide (DMSO).
• DMSO dimethylsulfoxide
• compositions of the invention may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles, ⁇ t 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.
• parenteral as used herein includes subcutaneous injections, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intrathecal injection or like injection or infusion techniques.
• compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical formulations, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
• Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipicnts that are suitable for the manufacture of tablets.
• excipients may 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; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
• the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monostearate or glyceryl distearatc may be employed.
• Formulations for oral use may 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 active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
• an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
• water or an oil medium for example peanut oil, liquid paraffin or olive oil.
• Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
• excipients are suspending agents, for example sodium carboxymethylcelluiose, methylceliulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; and dispersing or wetting agents, which may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, 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
• 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 arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
• the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
• Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
• a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
• compositions of the invention may also be in the form of oil-in- water emulsions and water-in-oil emulsions.
• the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
• Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth; naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol; anhydrides, for example sorbitan monooleate; and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
• the emulsions may also contain sweetening and flavoring agents.
• Syrups and elixirs may 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 a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol.
• Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides,
• fatty acids such as oleic acid find use in the preparation of injectables.
• composition of the invention may also be administered in the form of suppositories, e.g., for rectal administration of the drug.
• suppositories e.g., for rectal administration of the drug.
• These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• suitable non-irritating excipient that 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.
• compositions can be administered parenterally in a sterile medium.
• the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
• adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
• the composition containing the therapeutic compound may be added to the animal's feed or drinking water. Also, it will be convenient to formulate animal feed and drinking water products so that the animal takes in an appropriate quantity of the compound in its diet. It will further be convenient to present the compound in a composition as a premix for addition to the feed or drinking water. The composition can also added as a food or drink supplement for humans.
• the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the condition being treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
• Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration and rate of excretion, drug combination and the severity of the particular disease undergoing therapy. [0185] Preferred compounds of the invention will have desirable pharmacological properties that include, but are not limited to, oral bioavailability, low toxicity, low serum protein binding 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 brain levels of compounds used to treat peripheral disorders are often preferred.
• Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocyctes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of laboratory animals that receive the compound intravenously.
• Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcova, et al. (Journal of Chromatography B (1996) volume 677, pages 1 -27).
• Compound half-life is inversely proportional to the frequency of dosage of a compound.
• In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1 120-1 127).
• compositions required for use in 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 attendant physician or clinician.
• the pharmaceutical formulation excipient comprises ethanol and the pharmaceutical formulation compound is a compound described herein.
• the pharmaceutical formulation excipient comprises propylene glycol and the pharmaceutical formulation compound is a compound described herein.
• the pharmaceutical formulation comprises: about 20% propylene glycol; about 70% elhanol; about 10% of a compound described herein.
• the pharmaceutical formulation comprises: about 70% ethanoh about 20% poly(vinyl methyl ether-alt-maleic acid monobutyl ester); about 10% of a compound described herein.
• the pharmaceutical ibrmulalion comprises: about 56% ethanol; about 14% water; about 15% poly(2-hydroxyethyl methacrylate); about 5% di butyl sebacate; about 10% of a compound described herein.
• the pharmaceutical formulation comprises: about 55% ethanol; about 15% ethyl acetate; about 15% polyvinyl acetate); about 5% dibutyl sebacate; about 10% of a compound described herein.
• a compound described herein is present in a pharmaceutical formulation in a concentration which is a member selected from 1 %. 2.5%, 5%, 7.5%, 10% and 15% w/v.
• the pharmaceutical formulation is a lacquer.
• the methods of the invention can be used employed through the topical application of the compounds described herein.
• compositions of the present invention comprises fluid or semi-solid vehicles that may include but are not limited to polymers, thickeners, buffers, neutralizers, chelating agents, preservatives, surfactants or emulsifiers, antioxidants, waxes or oils, emollients, sunscreens, and a solvent or mixed solvent system.
• the solvent or mixed solvent system is important to the formation because it is primarily responsible for dissolving the drug.
• the best solvent or mixed solvent systems are also capable of maintaining clinically relevant levels of the drug in solution despite the addition of a poor solvent to the formulation.
• the topical compositions useful in the subject invention can be made into a wide variety of product types.
• These include, but are not limited to, lotions, creams, gels, sticks, sprays, ointments, pastes, foams, mousses, and cleansers.
• These product types can comprise several types of carrier systems including, but not limited to particles, nanoparticles, and liposomes, if desired, disintegrating agents can be added, such as the cross-linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate. 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, nail, hair, claw or hoof surface without friction, are typically liquid or semi-liquid preparations in which finely divided solid, waxy, or liquid are dispersed. Lotions will typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, nail, hair, claw or hoof, e.g.. methylcellulose, sodium carboxymethyl-cellulose, or the like.
• Creams containing the active agent for delivery according to the present invention are viscous liquid or semisolid emulsions, either oil-in- water or water-in-oil.
• Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase.
• the oil 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 oil phase in volume, and generally contains a humectant.
• the emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant.
• Gel formulations can also be used in connection with the present invention, As will be appreciated by those working in the field of topical drug formulation, gels are semisolid. Single-phase gels contain organic macromolecules distributed substantialiy uniformly throughout the carrier liquid, which is typically aqueous, but also may be a solvent or solvent blend,
• Ointments which are semisolid preparations, are typically based on petrolatum or other petroleum derivatives.
• the specific ointment base to be used is one that provides for optimum delivery for the active agent chosen for a given formulation, and, preferably, provides for other desired characteristics as well, e.g., emolliency or the like.
• an ointment base should be inert, stable, nonirritating and non-sensitizing. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed.
• ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emuision bases; and water-soluble bases.
• Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum.
• Emulsifiable ointment bases also known as absorbent ointment bases, contain little or no water and include, for example, hydroxy stearin sulfate, anhydrous lanolin and hydrophilic petrolatum.
• Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in- water (OfW) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid.
• W/O water-in-oil
• OfW oil-in- water
• Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight; again, reference may be had to Remington: The Science and Practice of Pharmacy, supra, for further information.
• Sprays generally provide the active agent in an aqueous and/or alcoholic solution which can be misted onto the skin, nail, hair, claw or hoof for delivery.
• Such sprays include those formulated to provide for concentration of the active agent solution at the site of administration following delivery, e.g., the spray solution can be primarily composed of alcohol or other like volatile liquid in which the drug or active agent can be dissolved.
• the carrier evaporates, leaving concentrated active agent at the site of administration.
• the topical pharmaceutical compositions may also comprise suitable solid or gel phase carriers.
• suitable solid or gel phase 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 refers to an agent that enhances or facilitates mixing and suspending oil-in-water or watcr-in-oil.
• a suitable emulsifier which refers to an agent that enhances or facilitates mixing and suspending oil-in-water or watcr-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 blend 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, USA.
• Preferred for use herein are high molecular weight alcohols such as cetearyl alcohol, cetyl alcohol, stearyl alcohol, emulsifying wax, glyceryl monostearate.
• high molecular weight alcohols such as cetearyl alcohol, cetyl alcohol, stearyl alcohol, emulsifying wax, glyceryl monostearate.
• Other examples are ethylene glycol distearate, sorbitan tristearate.
• nonionic emulsifying agents are those with hydrophile- lipophile balances (HLB) of about 3 to 6 for w/o system and 8 to 18 for o/w system as determined by the method described by Paul L. Lindner in “Emulsions and Emulsion' " , edited by Kenneth Lissant, published by Dekker, New York. N.Y., 1974. pages 188-190. More preferred for use herein are one or more nonionic surfactants that produce a system having FILB of about 8 to about 18.
• HLB hydrophile- lipophile balances
• nonionic emulsifiers include but are not limited to "BRIJ 72". the trade name for a polyoxyethylene (2) stearyl ether having an HLB of 4,9; "BRIJ 721 ", the trade name for a polyoxyelhylene (21) stearyl ether having an HLB of 15.5, “Brij 30", the trade name for polyoxyethylene lauryl ether having an HLB of 9.7; "Polawax”, the trade name for emulsifying wax having an HLB of 8.0; "Span 60”, the trade name for sorbitan monostearate having an HLB of 4.7; “Crodesta F- 160”, the trade name for sucrose stearate” having an HLB of 14.5.
• BRIJ 72 the trade name for a polyoxyethylene (2) stearyl ether having an HLB of 4,9
• Brij 30 the trade name for polyoxyethylene lauryl ether having an HLB of 9.7
• Polyawax the trade name for emulsifying wax having an HLB of
• each emulsifying agent is present in amount from about 0.5 to about 2.5 wt%, preferably 0.5 to 2.0%, more preferably 1.0% or 1 ,8%.
• the emulsifying agent comprises a mixture of steareth 21 (at about 1.8 %) and steareth 2 (at about 1.0%).
• the topical pharmaceutical compositions may also comprise suitable emollients.
• Emollients are materials used for the prevention or relief of dryness, as well as for the protection of the skin, nail, hair, claw or hoof.
• Useful emollients include, but are not limited to, cetyl alcohol, isopropyl myristate, stearyl alcohol, and the like.
• suitable emollients are known and can be used herein. See e.g., Sagarin, Cosmetics, Science and Technology, 2nd Edition, Vol. 1 , pp. 32-43 (1972), and U.S. Pat. No. 4,919,934, to Deckner et al., issued Apr. 24, 1990, both of which are incorporated herein by reference in their entirety.
• These materials are available from Ruger Chemical Co, (Irvington, NJ).
• each emollient is present in an amount from about 0.1 to 15%, preferably 0.1 to about 3.0, more preferably 0.5, 1.0, or 2.5 wt%.
• the emollient is a mixture of cetyl alcohol, isopropyl myristate and stearyl alcohol in a 1/5/2 ratio.
• the emollient may also be a mixture of cetyl alcohol and stearyl alcohol in a 1 /2 ratio.
• the topical pharmaceutical compositions may also comprise suitable antioxidants, substances known to inhibit oxidation.
• Antioxidants suitable for use in accordance with the present invention include, but are not limited to, butylated hydroxy toluene, ascorbic acid, sodium ascorbate, calcium ascorbate. ascorbic palmitate, butylated hydroxyanisole, 2,4,5- trihydroxybutyrophenone. 4-hydroxymethyl-2,6-di-fer/-butylphenol, erythorbic acid, gum guaiac, propyl gallate.
• the antioxidant is butylaled hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid, pharmaceutically acceptable salts or esters thereof, or mixtures thereof. Most preferably, the antioxidant is butylated hydroxytoluene. These materials are available from Ruger Chemical Co, (Irvinglon. NJ).
• 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 wt%, preferably 0.05 to about 0.5 wt%, more preferably 0.1%.
• the topical pharmaceutical compositions may also comprise suitable preservatives.
• Preservatives are compounds added to a pharmaceutical formulation to act as an anti-microbial agent.
• preservatives known in the art as being effective and acceptable in parenteral formulations are benzalkonium chloride, benzethonium, chlorohexidine, phenol, m-cresol, benzyl alcohol, methylparaben, propylparaben, chlorobutanol, o-cresol, p-cresol, cbJorocresoI, phenylmercuric nitrate, thimerosal, benzoic acid, and various mixtures thereof. See, e.g., Wall Arbitr, K. -H., Develop.
• the preservative is selected from methylparaben, propylparaben and mixtures thereof. These materials are available from Inolex Chemical Co (Philadelphia, PA) or Spectrum Chemicals.
• the topical formulations of the present invention contain at least one preservative
• the total amount of preservative present is from about 0.01 to about 0.5 wt%, preferably from about 0.1 to 0.5%, more preferably from about 0.03 to about 0.15.
• the preservative is a mixture of methylparaben and proplybarben in a 5/1 ratio.
• the amount is usually 15 to 20%.
• the topical pharmaceutical compositions may also comprise suitable chelating agents to form complexes with metal cations that do not cross a lipid bilayer.
• suitable chelating agents include ethylene diamine tetraacetic acid (EDTA). ethylene glycol- bis(beta-aminoethyl ether)-N,N,N', N '-tetraacetic acid (EGTA) and 8-Amino-2-[(2-amino-5- methylphenoxy)methyl]-6-methoxyquinoline-N,N,N',N'-tetraacetic acid, tetrapotassium salt (QUIN-2).
• the chelating agents are EDTA and citric acid. These materials are available from Spectrum Chemicals.
• the total amount of chelating agent present is from about 0.005% to 2.0% by weight, preferably from about 0.05% to about 0.5 wt%, more preferably about 0.1% by weight.
• the topical pharmaceutical compositions may also comprise suitable neutralizing agents used to adjust the pH of the formulation to within a pharmaceutically acceptable range.
• neutralizing agents include but are not limited to trolamine, tromethamine, sodium hydroxide, hydrochloric acid, citric acid, and acetic acid. Such materials are available from are available from Spectrum Chemicals (Gardena, CA).
• the total amount of 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 about 1.0 wt %.
• the neutralizing agent is generally added in whatever amount is required to bring the formulation to the desired pH.
• the topical pharmaceutical compositions may also comprise suitable viscosity increasing agents. These components are diffusible compounds capable of increasing the viscosity of a polymer-containing solution through the interaction of the agent with the polymer.
• CARBOPOL ULTREZ 10 may be used as a viscosity-increasing agent. These materials are available from Noveon Chemicals. Cleveland, OH.
• the total amount of viscosity increasing agent present is from about 0.25% to about 5.0% by weight, preferably from about 0.25% to about 1.0 wt%, and more preferably from about 0.4% to about 0.6% by weight.
• the topical pharmaceutical compositions may also comprise suitable nail penetration enhancers.
• nail penetration enhancers include mercaptan compounds, sulfites and bisulfites, keratolytic agents and surfactants.
• Nail penetration enhancers suitable for use in the invention are described in greater detail in Malhotra et ai, J, Pharm. ScL, 91 :2, 312-323 (2002), which is incorporated herein by reference in its entirety.
• the topical pharmaceutical compositions may also comprise one or more suitable solvents.
• suitable solvents The ability of any solid substance (solute) to dissolve in any liquid substance (solvent) is dependent upon 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 the greatest. This gives rise to the traditional understanding that "like dissolves like.”
• Solvents can be characterized in one extreme as non-polar, lipophilic oils, while in the other extreme as polar hydrophilic solvents. Oily solvents dissolve other non-polar substances by Van der WaIs interactions while water and other hydrophilic solvents dissolve polar substances by ionic, dipole, or hydrogen bonding interactions.
• solvents can be listed along a continuum from the least polar, i.e. hydrocarbons such as decane, to the most polar solvent being water.
• a solute will have its greatest solubility in solvents having equivalent polarity.
• less polar solvents will provide improved solubility with the solvent having polarity nearly equivalent to the solute providing maximum solubility.
• Most drugs have intermediate polarity, and thus experience maximum solubility in solvents such as propylene glycol or ethanol, which are significantly less polar than water.
• the concentration of active ingredient in the formulation may be limited by the solubility of the active ingredient in the chosen solvent and/or carrier.
• Non-lipophilic drugs typically display very low- solubility in pharmaceutically acceptable solvents and/or carriers.
• the solubility of some compounds in the invention in water is less than 0.00025% wt/wt.
• the solubility of the same compounds in the invention can be less than about 2% wt/wt in either propylene glycol or isopropyl myristate.
• diethylene glycol monoethyl ether (DGME) is the solvent used to dissolve the compounds of the invention.
• the compounds in the invention useful in the present formulation are believed to have a solubility of from about 10% wt/wt to about 25% wt/wt in DGME.
• a DGME water cosolvent system is used to dissolve the compounds of the invention.
• the solvent capacity of DGME drops when water is added; however, the DGME/water cosolvent system can be designed to maintain the desired concentration of from about 0.1 % to about 5% wt/wt active ingredient.
• the active ingredient is present from about 0.5 % to about 3% wt/wt. and more preferably at about 1% wt/wt. in the as-applied topical formulations.
• DGME is less volatile than water, as the topical formulation evaporates upon application, the active agent becomes more soluble in the cream formulation. This increased solubility reduces the likelihood of reduced bioavailability caused by the drug precipitating on the surface of the skin, nail, hair, claw or hoof.
• Liquid forms such as lotions suitable for topical administration or suitable for cosmetic application, may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, thickeners, penetration enhancers, and the like.
• Solid forms such as creams or pastes or the like may include, for example, any of the following ingredients, water, oil, alcohol or grease as a substrate with surfactant, polymers such as polyethylene glycol, thickeners, solids and the like.
• Liquid or solid formulations may include enhanced delivery technologies such as liposomes, microsomes, microsponges and the like.
• the compounds can be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
• sustained-release materials have been established and are well known by those skilled in the art.
• Topical treatment regimens according to the practice of this invention comprise applying the composition directly to the skin, nail, hair, claw or hoof at the application site, from one to several times daily.
• Formulations of the present invention can be used to treat, ameliorate or prevent conditions or symptoms associated with bacterial infections, acne, inflammation and the like.
• the pharmaceutical formulation includes a simple solution.
• the simple solution includes an alcohol.
• the simple solution includes alcohol and water.
• the alcohol is ethanol, ethylene glycol, propanol, polypropylene glycol, isopropanol or butanol
• the simple solution is a member selected from 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.
• the pharmaceutical formulation is a lacquer. Please see Remington's, supra, for more information on the production of lacquers.
• the compound is present in said pharmaceutical formulation in a concentration of from about 0,5% to about 15%. In an exemplary embodiment, the compound is present in said pharmaceutical formulation in a concentration of from about 0.1% to about 12.5%. In an exemplary embodiment, the compound is present in said pharmaceutical formulation in a concentration of from about 1% to about 10%. In an exemplary embodiment, the compound is present in said pharmaceutical formulation in a concentration of from about 1% to about 5%. In an exemplary embodiment, the compound is present in said pharmaceutical formulation in a concentration of from about 0.5% to about 5%.
• the compound is present in said pharmaceutical formulation in a concentration of from about 0.5% to about 7.5%, In an exemplary embodiment, the compound is present in said pharmaceutical formulation in a concentration of from about 5% to about 7.5%. In an exemplary embodiment, the compound is present in said pharmaceutical formulation in a concentration of from about 2% to about 8%. In an exemplary embodiment, the compound is present in said pharmaceutical formulation in a concentration of from about 4% to about 9%.
• Anti-inflammatory agents include, but are not limited to, bisabolol, mentholatum, 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 vitamin derivatives 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 lO, beta hydroxy acids, salicylic acid, copper binding peptides, dimethyl ami noethyl (DAEA), and the like.
• Sunscreens and or sunburn relief agents include, but are not limited to, PABA, jojoba, aloe, padimate-O, methoxycinnamates, proxamine HCl, lidocaine and the like.
• Sunless tanning agents include, but are not limited to, dihydroxyacetone (DHA).
• DHA dihydroxyacetone
• Psoriasis-treating agents and/or acne-treating agents include, but are not limited to, salicylic acid, benzoyl peroxide, coal tar, selenium sulfide, zinc oxide, pyrithione (zinc and/or sodium), tazarotene, calcipotriene, tretinoin, adapalene and the like.
• Agents that are effective to control or modify keratinization including without limitation: tretinoin, tazarotene, and adapalene.
• compositions comprising an compound/active agent of the invention, and optionally at least one of these additional agents, are to be administered topically.
• this leads to the compounds of the invention and any other active agent working upon and treating the skin, nail, hair, claw or hoof.
• any one of the topically applied active agents may also be delivered systemically by transdermal routes.
• an additional cosmetically or pharmaceutically effective agent such as an anti-inflammatory agent, vitamin, anti-aging agent, sunscreen, and/or acne- treating agent, for example, is usually a minor component (from about 0.001 % to about 20% by weight or preferably from about 0.01 % to about 10% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
• 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 serum protein binding and desirable in vitro and in vivo half-lives. Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oavcova et al. (1996, J, Chromat. B677: 1-27). Compound half- life is inversely proportional to the frequency of dosage of a compound. In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gleschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1 127).
• Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
• the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD 50 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 formulating a range of dosage for use in humans.
• the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED S Q with little or no toxicity.
• the dosage can vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See, e.g. Fingl el al., 1975, in "The Pharmacological Basis of Therapeutics", Ch
• the therapeutically effective dose can be estimated initially from cell culture assays, as disclosed herein.
• 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 cell culture, i.e., the concentration of the test compound which achieves a half-maximal inhibition of bacterial cell growth.
• EC50 effective dose for 50% increase
• concentration of the test compound which achieves a half-maximal inhibition of bacterial cell growth Such information can be used to more accurately determine useful doses in humans.
• the compounds prepared by the methods, and from the intermediates, described herein will be administered in a therapeutically or cosmetically effective amount by any of the accepted modes of administration for agents that serve similar utilities. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination, the severity of the particular disease undergoing therapy and the judgment of the prescribing physician.
• the drug can be administered from once or twice a day, or up to 3 or 4 times a day.
• Dosage amount and interval can be adjusted individually to provide plasma levels of the active moiety that are sufficient to maintain bacterial cell growth inhibitory effects.
• Usual patient dosages for systemic administration range 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. Stated in terms of patient body surface areas, usual dosages range from 50-91 mg/m 2 /day.
• the amount of the compound in a formulation can vary within the full range employed by those skilled in the art.
• the formulation will contain, on a weight percent (wt%) basis, from about 0.01-iO wt% of the drag based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
• the compound is present at a level of about 0.1-3.0 wt%, more preferably, about 1,0 wt%.
• This compound can be synthesized according to the method described in Benkovic el at., J. Med. Chern,, 48: 7468-7476 (2005).
• This compound can be synthesized according to the method described in Brown et al., J, Org. Chem,, 51: 4526-4530 (1986).

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