WO2011019612A1 - Boron-containing small molecules as antiprotozoal agents - Google Patents

Boron-containing small molecules as antiprotozoal agents Download PDF

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Publication number
WO2011019612A1
WO2011019612A1 PCT/US2010/044727 US2010044727W WO2011019612A1 WO 2011019612 A1 WO2011019612 A1 WO 2011019612A1 US 2010044727 W US2010044727 W US 2010044727W WO 2011019612 A1 WO2011019612 A1 WO 2011019612A1
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exemplary embodiment
compound
unsubstituted
alkyl
salt
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PCT/US2010/044727
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French (fr)
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Matthew Orr
Matthew Jenks
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Anacor Pharmaceuticals, Inc.
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Publication of WO2011019612A1 publication Critical patent/WO2011019612A1/en

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    • 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 System
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis

Definitions

  • oxaboroles useful as antimicrobials have been described previously, such as in U.S. Pat. Pubs. US20060234981 and US20070155699.
  • an oxaborole has the following structure and substituent numbering system:
  • This invention provides, among other things, novel compounds useful for treating protozoa infections, pharmaceutical compositions containing such compounds, as well as combinations of these compounds with at least one additional therapeutically effective agent.
  • FIG. 1 Biological data for exemplary compounds of the invention is provided in FIG. 1.
  • an active agent includes a single active agent as well as two or more different active agents in combination. It is to be understood that present teaching is not limited to the specific dosage forms, carriers, or the like, disclosed herein and as such may vary.
  • Ac is acetyl
  • AcOH is acetic acid
  • ACTBr cetyltrimethylammonium bromide
  • AIBN is azobisisobutyronitrile or 2,2 azobisisobutyronitrile
  • Bn is aqueous; Ar is aryl; B 2 pin 2 is bis(pinacolato)diboron; Bn is, in general, benzyl [see Cbz for one example of an exception]; (BnS) 2 is benzyl disulfide; BnSH is benzyl thiol or benzyl mercaptan; BnBr is benzyl bromide; Boc is tert-butoxy carbonyl; BoC 2 O is dicarbonate; Bz is, in general, benzoyl; BzOOH is benzoyl peroxide; Cbz or Z is benzyloxycarbonyl or carboxybenzyl;
  • Cs 2 C ⁇ 3 is cesium carbonate
  • CSA camphor sulfonic acid
  • CTAB is
  • Ra Ni or Raney Ni is Raney nickel
  • Ph is phenyl
  • PMB is /?-methoxybenzyl
  • PrOH is 1-propanol
  • iPrOH is 2-propanol
  • POCI 3 is phosphorus chloride oxide
  • PTSA is /? ⁇ r ⁇ -toluene sulfonic acid
  • Pyr. or Pyr or Py as used herein means Pyridine; RT or rt or r.t. is room temperature; sat.
  • Si- amine or Si-NH 2 is amino-functionalized silica, available from SiliCycle; Si-pyr is pyridyl-functionalized silica, available from SiliCycle; TEA or Et 3 N is triethylamine; TFA is trifluoroacetic acid; Tf 2 O is trifluoromethanesulfonic anhydride; THF is tetrahydrofuran; TFAA is trifluoroacetic anhydride; THP is tetrahydropyranyl; TMSI is trimethylsilyl iodide; H 2 O is water; diNO 2 PhSO 2 Cl is dinitrophenyl sulfonyl chloride; 3-F-4-NO 2 -PhSO 2 Cl is 3-fluoro-4-nitrophenylsulfonyl chloride; 2-MeO-4- NO 2 -PhSO 2 Cl is 2-methoxy-4-nitrophenylsulfonyl chloride; and
  • (EtO) 2 POCH 2 COOEt is a triethylester of phosphonoacetic acid known as triethyl phosphonoacetate.
  • Compound of the invention refers to the compounds discussed herein, salts (e.g. pharmaceutically acceptable salts), prodrugs, solvates and hydrates of these compounds.
  • Combination of the invention refers to the compounds and antiprotozoals discussed herein as well as acids, bases, salt forms (such as
  • Boon containing compounds refers to the compounds of the invention that contain boron as part of their chemical formula.
  • 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 a radical of a molecule that is attached to the remainder of the molecule.
  • 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 (i.e. Ci-Cio means one to ten carbons).
  • the term “alkyl” means a straight or branched chain, or combinations thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals.
  • 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 (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n- pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3- butynyl, and the higher homologs and isomers.
  • alkylene by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified, but not limited, by
  • alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the invention.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • alkenylene by itself or as part of another substituent means a divalent radical derived from alkene.
  • cycloalkylene by itself or as part of another substituent means a divalent radical derived from cycloalkane.
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkane.
  • heterocycloalkylene by itself or as part of another substituent means a divalent radical derived from heterocycloalkane.
  • arylene by itself or as part of another substituent means a divalent radical derived from aryl.
  • heteroarylene by itself or as part of another substituent means a divalent radical derived from heteroaryl.
  • 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. In some embodiments, the term
  • heteroalkyl by itself or in combination with another term, means a stable straight or branched chain, 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,
  • Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 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 -.
  • heteroalkylene groups heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).
  • no orientation of the linking group is implied by the direction in which the formula of the linking group is written.
  • the formula -C(O) 2 R'- represents both -C(O) 2 R'- and -R 5 C(O) 2 -.
  • 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-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include, but are not limited to, 1 -(1,2,5,6- 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 or halogen
  • haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(Ci-C 4 )alkyl is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 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) that contain from one to four heteroatoms.
  • the heteroatom is selected from B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non- limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3- pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4- oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-
  • aryl when used in combination with other terms (e.g. , aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • 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 alkyl 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).
  • a carbon atom e.g., a methylene group
  • an oxygen atom e.g., phenoxymethyl, 2- pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like.
  • heteroaryl are meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
  • R', 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 arylalkyl groups.
  • each of the R groups is independently selected as are each R', R", R'", R"" and R'"" groups when more than one of these groups is present.
  • R' and R" When 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).
  • haloalkyl e.g., -CF 3 and -CH 2 CF 3
  • 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 generically referred to as "aryl group substituents.”
  • R', R", R'", R" and R'" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
  • each of the R groups is independently selected as are each R', R", R'", R"" and R'"" groups when more than one of these groups is present.
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(0)-(CRR') q -U-, wherein T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer of from 0 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 - (CRR') s -X-(CR"R'")d-, where s and d are independently integers of from O to 3, and X is -0-, -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
  • Ring means a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • a ring includes fused ring moieties. 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. Unless otherwise specified, the ring optionally includes a heteroatom.
  • the term “5- to 7-membered ring” includes, for example phenyl, pyridinyl and piperidinyl.
  • 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).
  • leaving group means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction.
  • representative leaving groups include triflate, chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • 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
  • an effective amount of a drug, formulation, or permeant is meant a sufficient amount of an active agent to provide the desired local or systemic effect.
  • a “Topically 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 either locally at the place of application or systemically as a result of transdermal passage of an active ingredient in the material.
  • pharmaceutically acceptable salt is meant to include a salt of a compound of the invention which is prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • 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 (such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d-lysine, 1-lysine), or magnesium salt, or a similar salt.
  • organic amino such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d-lysine, 1-lysine
  • 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.
  • suitable inert solvent examples include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric,
  • 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 et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)).
  • Certain specific compounds of the 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 invention provides compounds which are in a prodrug form.
  • Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to provide the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment.
  • Certain compounds of the 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 invention. Certain compounds of the invention may exist in multiple crystalline or amorphous forms.
  • Certain compounds of the 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 invention.
  • the graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr, J. Chem. Ed. 1985, 62: 114-120. Solid and broken wedges are used to denote the absolute configuration of a stereocenter unless otherwise noted.
  • the compounds described herein contain olefmic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are included.
  • Compounds of the invention can exist in particular geometric or stereoisomeric forms.
  • the invention contemplates all such compounds, including cis- and trans -isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms can be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • Optically active (R)- and (5)-isomers and d and / isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If, for instance, a particular enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.
  • separation of enantiomers and diastereomers is frequently accomplished using chromatography employing chiral, stationary phases, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).
  • the compounds of the 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 ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • the compounds may also be labeled with stable isotopes such as deuterium. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable vehicle” refers to any formulation or carrier medium that provides the appropriate delivery of an effective amount of an 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” and equivalent terms refer 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.
  • compositions refers to preservatives, antioxidants, fragrances, emulsif ⁇ ers, 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.
  • the terms “enhancement,” “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 skin, nail, hair, claw or hoof using a diffusion cell apparatus.
  • a diffusion cell is described by Merritt et al. Diffusion Apparatus for Skin Penetration, J of Controlled Release, 1 (1984) pp. 161-162.
  • the term “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 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.
  • the 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.
  • an "effective amount” of one active of the combination is the amount of that active that is effective to provide the desired effect when used in combination with the other active of the combination.
  • the amount that is “effective” will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent or agents, and the appropriate “effective” amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • active ingredient means a chemical entity which can be effective in treating a targeted disorder, disease or condition.
  • phrases "pharmaceutically acceptable” means moieties or compounds that are, within the scope of medical judgment, suitable for use in humans without causing undesirable biological effects such as undue toxicity, irritation, allergic response, and the like, for example.
  • oral dosage form means any pharmaceutical composition administered to a subject via the oral cavity.
  • exemplary oral dosage forms include tablets, capsules, films, powders, sachets, granules, solutions, solids, suspensions or as more than one distinct unit (e.g., granules, tablets, and/or capsules containing different actives) packaged together for co-administration, and other formulations known in the art.
  • An oral dosage form can be one, two, three, four, five or six units. When the oral dosage form has multiple units, all of the units are contained within a single package, (e.g. a bottle or other form of packaging such as a blister pack). When the oral dosage form is a single unit, it may or may not be in a single package.
  • the oral dosage form is one, two or three units. In a particularly preferred embodiment, the oral dosage form is one unit.
  • the dosage form includes a compound of the invention in one capsule. This is a single unit. In some embodiments, the dosage form includes a compound of the invention as part of a therapeutically effective dosage of a cream or ointment. This is also a single unit. In some embodiments, the dosage form includes a compound of the invention and another active ingredient contained within one capsule, or as part of a therapeutically effective dosage of a cream or ointment. This is a single unit, whether or not the interior of the capsule includes multiple discrete granules of the active ingredient.
  • the dosage form includes a compound of the invention in one capsule, and the active ingredient in a second capsule.
  • This is a two unit dosage form, such as two capsules or tablets, and so such units are contained in a single package.
  • the term 'unit' refers to the object which is administered to the animal, not to the interior components of the object.
  • prodrug is a derivative of a parent drug molecule that exerts its pharmacological effect only after chemical and/or enzymatic conversion to its active form in vivo.
  • Prodrugs include those designed to circumvent problems associated with delivery of the parent drug. This may be due to poor physicochemical properties, such as poor chemical stability or low aqueous solubility, and may also be due to poor pharmacokinetic properties, such as poor bioavailability or poor half- life. Thus, certain advantages of prodrugs may include improved chemical stability, absorption, and/or PK properties of the parent carboxylic acids.
  • Prodrugs may also be used to make drugs more "patient friendly,” by minimizing the frequency (e.g., once daily) or route of dosing (e.g., oral), or to improve the taste or odor if given orally, or to minimize pain if given parenterally .
  • the prodrugs are chemically more stable than the active drug, thereby improving formulation and delivery of the parent drug, compared to the drug alone.
  • Prodrugs for carboxylic acid analogs of the invention may include a variety of esters.
  • the pharmaceutical compositions of the invention include a carboxylic acid ester.
  • the prodrug is suitable for treatment /prevention of those diseases and conditions that require the drug molecule to cross the blood brain barrier.
  • the prodrug enters the brain, where it is converted into the active form of the drug molecule.
  • a prodrug is used to enable an active drug molecule to reach the inside of the eye after topical application of the prodrug to the eye.
  • a prodrug can be converted to its parent compound by chemical or biochemical methods in an ex vivo environment.
  • a prodrug can be slowly converted to its parent compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Antibiotic is a compound which can kill or inhibit the growth of bacteria.
  • the term antibiotic is broad enough to encompass acids, bases, salt forms (such as pharmaceutically acceptable salts), prodrugs, solvates and hydrates of the antibiotic compound.
  • Antiprotozoal or "antiprotozoa”, as used herein, is a compound which can kill or inhibit the growth of protozoa.
  • the term anti-protozoal or anti-protozoa is broad enough to encompass acids, bases, salt forms (such as pharmaceutically acceptable salts), prodrugs, solvates and hydrates of the antiprotozoal or antiprotozoa compound.
  • microbial infection or "infection by a microorganism” refers to any infection of a host 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 al., eds., 12th ed. 1991); Williams et al, J. of Medicinal Chem. 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.
  • Inhibiting and blocking are used interchangeably herein to refer to the partial or full blockade of an enzyme, such as a beta-lactamase or a leucyl t-RNA synthetase.
  • Boron is able to form additional covalent or dative bonds with oxygen, sulfur or nitrogen under some circumstances in this invention.
  • Embodiments of the invention also encompass compounds that are poly- or multi-valent species, including, for example, species such as dimers, trimers, tetramers and higher homo logs of the compounds of use in the invention or reactive analogues thereof.
  • Salt counterion refers to positively charged ions that associate with a compound of the invention when the boron is fully negatively or partially negatively charged. Examples of salt counterions include H + , H 3 O + , ammonium, potassium, calcium, magnesium, organic amino (such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d-lysine, 1-lysine), and sodium.
  • the compounds comprising a boron bonded to a carbon and three heteroatoms (such as three oxygens described in this section) can optionally contain a fully negatively charged boron or partially negatively charged boron. Due to the negative charge, a positively charged counterion may associate with this compound, thus forming a salt.
  • positively charged counterions include H + , H 3 O + , ammonium, potassium, calcium, magnesium, organic amino (such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d-lysine, 1-lysine), and sodium.
  • the invention provides novel boron compounds.
  • novel compounds, as well as pharmaceutical compositions containing such compounds or combinations of these compounds with at least one additional therapeutically effective agent, can be used for, among other things, treating protozoal infections.
  • the invention provides a compound of the invention.
  • the invention is a compound described herein.
  • the invention is a compound according to a formula described herein.
  • the invention provides a compound having a structure according to the following formula:
  • the compound has a structure according to the following formula:
  • X is phenyl or heteroaryl, in which one substituent on said phenyl or said heteroaryl is halogen or cyano or nitro or unsubstituted Ci or C 2 or C3 or C 4 or C5 or Ce alkyl or unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy or halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl or halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkylthio or unsubstituted phenyl or NR 8 R 9 or -SO 2 (R 7 ) or -SO 2 N(R 7 )(R 8 ), wherein R 7 is H or unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl; R 8 is
  • the compound of the invention has a structure according to the following formula:
  • R 6 are selected from the group consisting of the following table, or a salt thereof.
  • Z is O. In an exemplary embodiment, for any of the entries in the above table, Z is S.
  • the compound of the invention has a structure according to the following formula:
  • R 2 , R 3 , R 4 , R 5 and R 6 are selected from the group consisting of the following table, or a salt thereof.
  • Y 1 is Ci-C 6 unsubstituted alkyl.
  • Y 1 is methyl.
  • Y 1 is ethyl.
  • Y 1 is unsubstituted C3 alkyl.
  • Y 1 is isopropyl.
  • Y 1 is unsubstituted C 4 alkyl.
  • Y 1 is t-butyl.
  • Y 1 is
  • Y 1 is unsubstituted C 6 alkyl.
  • Z is O.
  • Z is S.
  • the compound of the invention has a structure according to the following formula:
  • R 2 , R 3 , R 4 , R 5 and R 6 are selected from the group consisting of the following table, or a salt thereof.
  • Y is unsubstituted alkoxy.
  • Y 2 is unsubstituted Ci alkoxy.
  • Y 2 is unsubstituted C 2 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y 2 is unsubstituted C 3 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y 2 is n-propoxy. In an exemplary embodiment, for any of the entries in the above table, Y 2 is isopropoxy. In an exemplary embodiment, for any of the entries in the above table, Y 2 is unsubstituted C 4 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y 2 is unsubstituted C5 alkoxy.
  • Y 2 is unsubstituted C 6 alkoxy.
  • Z is O.
  • Z is S.
  • the compound of the invention has a structure according to the following formula:
  • R 6 are selected from the group consisting of the following table, or a salt thereof.
  • Y 3 is halosubstituted alkyl.
  • Y is halosubstituted Ci alkyl.
  • Y is halosubstituted C 2 alkyl. In an exemplary embodiment, for any of the entries in the above table, Y is halosubstituted C 3 alkyl. In an exemplary embodiment, for any of the entries in the above table, Y 3 is halosubstituted C 4 alkyl. In an exemplary embodiment, for any of the entries in the above table, Y 3 is halosubstituted C5 alkyl. In an exemplary embodiment, for any of the entries in the above table, Y 3 is halosubstituted C 6 alkyl. In an exemplary embodiment, for any of the entries in the above table, Y 3 is fluorosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl. In an exemplary
  • Y is alkyl substituted with one or two or three halogens.
  • Y 3 is trifluorosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl.
  • Y is
  • Z is O. In an exemplary embodiment, for any of the entries in the above table, Z is S.
  • the compound of the invention has a structure according to the following formula: wherein Z is as described herein, and R 2 , R 3 , R 4 , R 5 and R 6 are selected from the group consisting of the following table, or a salt thereof.
  • Y is halosubstituted alkoxy.
  • Y 4 is halosubstituted Ci alkoxy.
  • Y 4 is halosubstituted C 2 alkoxy.
  • Y 4 is halosubstituted C 3 alkoxy.
  • Y 4 is halosubstituted C 4 alkoxy.
  • Y 4 is halosubstituted C5 alkoxy.
  • Y 4 is halosubstituted C 6 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y 4 is fluorosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy. In an exemplary
  • Y 4 is alkoxy substituted with one or two or three halogens. In an exemplary embodiment, for any of the entries in the above table, Y 4 is trifluoro-substituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y 4 is
  • R 6 are selected from the group consisting of the following table, or a salt thereof.
  • Y 5 is halosubstituted C5 alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y 5 is halosubstituted C 6 alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y 5 is fluoro-substituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y 5 is alkylthio substituted with one or two or three halogens.
  • Y 5 is trifluoro-substituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y 5 is trifluoromethylthio. In an exemplary embodiment, for any of the entries in the above table, Z is O. In an exemplary embodiment, for any of the entries in the above table, Z is S.
  • the compound of the invention has a structure according to the following formula:
  • R 6 are selected from the group consisting of the following table, or a salt thereof.
  • R 8 is H or unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl and R 9 is H or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl or C(O)R 10 , wherein R 10 is unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl.
  • R 8 is unsubstituted Ci or C 2 or C3 or C 4 or C5 or Ce alkyl
  • R 9 is unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl.
  • R 8 is methyl and R 9 is unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl. In an exemplary embodiment, for any of the entries in the above table, R 8 is methyl and R 9 is methyl. In an exemplary embodiment, for any of the entries in the above table, R 8 is H. In an exemplary embodiment, for any of the entries in the above table, R 9 is H. In an exemplary embodiment, for any of the entries in the above table, R 8 is H and R 9 is H. In an exemplary embodiment, for any of the entries in the above table, R 8 is H and R 9 is -C(O)R 10 .
  • R 8 is H and R 9 is -C(O)CH 3 .
  • Z is O.
  • Z is S.
  • the compound of the invention has a structure according to the following formula:
  • R 5 and R 6 are selected from the group consisting of the following table, or a salt thereof.
  • R 7 is unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl.
  • R 7 is methyl.
  • R 7 is ethyl.
  • R 7 is unsubstituted C3 alkyl.
  • R 7 is
  • R 7 is unsubstituted C 4 alkyl.
  • R 7 is unsubstituted C 5 alkyl.
  • R 7 is unsubstituted C 6 alkyl.
  • Z is O.
  • Z is S.
  • the compound of the invention has a structure according to the following formula:
  • R 6 are selected from the group consisting of the following table, or a salt thereof.
  • R 7 is H or unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl and R 8 is H or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl.
  • R 7 is unsubstituted Ci or C 2 or C3 or C 4 or C5 or Ce alkyl and R 8 is unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl.
  • R 7 is methyl and R 8 is unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl.
  • R 7 is methyl and R 8 is methyl.
  • R 7 is H.
  • R 8 is H.
  • R 7 is H and R 8 is H.
  • Z is O.
  • Z is S.
  • Z is as described here and R 6 are selected from the group consisting of the following table, or a salt thereof.
  • Z is O.
  • Z is S.
  • the compound has a structure according to the following formula:
  • R 6 are selected from the group consisting of the following table, or a salt thereof.
  • the compound of the invention has a structure which is selected from the group consisting of:
  • the compound of the invention has a structure which is selected from the group consisting of:
  • the compound of the invention has a structure which is selected from the group consisting of:
  • the compound of the invention has a structure which is selected from the group consisting of:
  • the compound of the invention has a structure which is:
  • the compound of the invention has a structure which is
  • the compound of the invention has a structure which is:
  • the compound of the invention has a structure according to the following formula: wherein Z 6 is halosubstituted pyridazinyl, or a salt thereof.
  • Z 6 is pyridazinyl, substituted with one halogen.
  • Z 6 is pyridazinyl, substituted with two halogens.
  • Z 6 is pyridazinyl, substituted with two chlorines.
  • the compound of the invention has a structure according to the following formula: wherein each R , 14 is chlorine or fluorine, or a salt thereof. In an exemplary embodiment, each R 14 is chlorine.
  • the compound of the invention has a structure according to the following formula:
  • each R 13 are the same or different and are each selected from H or -SH or - OH, or a salt thereof.
  • each R 13 are the same or different and are each selected from -SH or -OH.
  • the compound of the invention has a structure according to the following formula:
  • the compound of the invention is:
  • the compound of the invention has a structure according to the following formula:
  • the compound of the invention has a structure which is:
  • R 15 is unsubstituted alkyl, or a salt thereof.
  • R 15 is unsubstituted Ci alkyl.
  • R 15 is unsubstituted C 2 alkyl.
  • R 15 is unsubstituted C 3 alkyl.
  • R 15 is unsubstituted C 4 alkyl.
  • R 15 is unsubstituted C5 alkyl.
  • R 15 is unsubstituted C 6 alkyl.
  • the compound of the invention has a structure according to the following formula:
  • Z 2 is unsubstituted benzothiophenyl, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 2 is halosubstituted benzothiophenyl, or a salt thereof.
  • Z 2 is benzothiophenyl substituted with chloro.
  • Z 2 is benzothiophenyl substituted with fluoro.
  • Z 2 is benzothiophenyl substituted with one halogen.
  • Z 2 is benzothiophenyl substituted with two halogens.
  • Z 2 is benzothiophenyl substituted with two fluorines.
  • Z 2 is benzothiophenyl substituted with two chlorines.
  • Z 2 is benzothiophenyl substituted with a fluorine and a chlorine.
  • the compound of the invention has a structure which is: wherein R 16 is halogen, R 17 is halogen, or a salt thereof.
  • the compound of the invention has a structure according to the following formula: wherein each R 16 and R 17 are the same or different and are each selected from the group consisting of F, Cl, Br, and I, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • the compound of the invention has a structure which is: or or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • the compound of the invention has a structure which is: wherein R , 18 is unsubstituted alkyl, or a salt thereof.
  • the compound of the invention has a structure according to the following formula: wherein R 18 is unsubstituted alkyl, or a salt thereof.
  • R 18 is Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl.
  • the compound of the invention has a structure according to the following formula:
  • Z 3 is unsubstituted isoxazolyl, or a salt thereof.
  • the compound of the invention is:
  • the compound of the invention has a structure according to the following formula:
  • the compound of the invention has a structure which is:
  • R 19 is unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • R 19 is unsubstituted alkyl, or a salt thereof.
  • R 19 is unsubstituted Ci alkyl. In an exemplary embodiment, R 19 is unsubstituted C 2 alkyl. In an exemplary embodiment, R 19 is unsubstituted C 3 alkyl. In an exemplary embodiment, R 19 is unsubstituted C 4 alkyl. In an exemplary embodiment, R 19 is unsubstituted C5 alkyl. In an exemplary embodiment, R 19 is unsubstituted C 6 alkyl.
  • the compound of the invention has a structure according to the following formula:
  • the compound of the invention has a structure according to the following formula:
  • the compound of the invention has a structure which is:
  • R 20 is unsubstituted alkyl, or a salt thereof.
  • the compound of the invention has a structure which is: is unsubstituted alkyl, or a salt thereof.
  • R 20 is Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl.
  • the compound of the invention has a structure according to the following formula:
  • the compound of the invention has a structure which is:
  • the compound of the invention has a structure according to the following formula:
  • the compound of the invention has a structure according to the following formula: wherein each R 21 are the same or different and are each selected from unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl or phenyl, or a salt thereof.
  • the compound of the invention has a structure which is: or wherein each R .2 Z 1 1 are the same or different and are each selected from unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl or phenyl, or a salt thereof.
  • the compound of the invention has a structure which is: or or a salt thereof.
  • each R 21 is unsubstituted Ci alkyl.
  • R 21 is unsubstituted C 2 alkyl.
  • R 21 is unsubstituted C3 alkyl.
  • R 21 is unsubstituted C 4 alkyl.
  • R 21 is unsubstituted C 5 alkyl. In an exemplary embodiment, R 21 is unsubstituted C 6 alkyl. In an exemplary embodiment, R 21 is unsubstituted phenyl. In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
  • R , 21 is as described herein, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 3 is unsubstituted furanyl, or a salt thereof.
  • the compound is:
  • the compound of the invention has a structure according to the following formula:
  • the compound of the invention is:
  • Y 7 is unsubstituted alkyl, or a salt thereof.
  • Y 7 is unsubstituted Ci alkyl.
  • Y 7 is unsubstituted C 2 alkyl.
  • Y 7 is unsubstituted C 3 alkyl.
  • Y 7 is unsubstituted C 4 alkyl.
  • Y 7 is unsubstituted C5 alkyl.
  • Y 7 is unsubstituted C 6 alkyl.
  • the compound of the invention has a structure according to the following formula:
  • Z 3 is unsubstituted pyrrole, or a salt thereof.
  • the compound is:
  • the compound of the invention has a structure according to the following formula:
  • Z 3 is unsubstituted alkyl pyrrole, or a salt thereof.
  • the compound is:
  • the compound is:
  • R 22 is unsubstituted alkyl, or a salt thereof.
  • R 22 is unsubstituted Ci alkyl.
  • R 22 is unsubstituted C 2 alkyl.
  • R 22 is unsubstituted C 3 alkyl.
  • R 22 is unsubstituted C 4 alkyl.
  • R 22 is unsubstituted C5 alkyl.
  • R 22 is unsubstituted C 6 alkyl.
  • the compound of the invention has a structure which is:
  • the compound of the invention has a structure which is:
  • the compound of the invention has a structure according to the following formula:
  • Z 9 is unsubstituted alkyl, or a salt thereof.
  • Z 9 is unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl.
  • Z 9 is methyl.
  • Z 9 is unsubstituted C 4 alkyl.
  • Z 9 is n-butyl or sec-butyl or isobutyl or tert-butyl.
  • Z 9 is tert-butyl.
  • the compound of the invention has a structure according to the following formula:
  • R 15 is unsubstituted alkyl
  • R 16 is H or phenyl substituted alkyl, or a salt thereof.
  • R 15 is unsubstituted Ci or C 2 or C3 or C 4 or C5 or Ce alkyl.
  • R 15 is unsubstituted C 3 alkyl.
  • R 16 is benzyl.
  • R 16 is H.
  • the compound of the invention has a structure according to the following formula:
  • Z 10 is hydroxy-substituted alkyl, or a salt thereof.
  • Z 10 is hydroxysubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl.
  • the compound of the invention has a
  • the compound of the invention has a
  • R a is unsubstituted alkyl.
  • R a is unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl.
  • R a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl and hexyl.
  • the compound of the invention has a
  • R a is unsubstituted alkyl.
  • R a is unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl.
  • R a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl and hexyl.
  • a compound of the invention essentially does not inhibit a cytochrome P450 enzyme. In an exemplary embodiment, a compound of the invention does not inhibit a cytochrome P450 enzyme.
  • the cytochrome P450 enzyme is a member selected from CP1A2, 2C9, 2D6 and 3A4. In an exemplary embodiment, the cytochrome P450 enzyme is
  • a compound of the invention is essentially not a substrate for the P-gp transporter. In an exemplary embodiment, a compound of the invention is not a substrate for the P-gp transporter.
  • the invention provides a compound described herein, or a salt, hydrate or solvate thereof, or a combination thereof.
  • the invention provides a compound described herein, or a salt, hydrate or solvate thereof.
  • the invention provides a compound described herein, or a salt thereof.
  • the salt is a pharmaceutically acceptable salt.
  • the invention provides a compound described herein, or a hydrate thereof.
  • the invention provides a compound described herein, or a solvate thereof.
  • the invention provides a compound described herein, or a prodrug thereof.
  • the invention provides a salt of a compound described herein. In an exemplary embodiment, the invention provides a pharmaceutically acceptable salt of a compound described herein. In an exemplary embodiment, the invention provides a hydrate of a compound described herein. In an exemplary embodiment, the invention provides a solvate of a compound described herein. In an exemplary embodiment, the invention provides a prodrug of a compound described herein.
  • alkyl is linear alkyl. In another exemplary embodiment, alkyl is branched alkyl. [0123] In an exemplary embodiment, heteroalkyl is linear heteroalkyl. In another exemplary embodiment, heteroalkyl is branched heteroalkyl. HLb) Compositions involving stereoisomers
  • first compound and a second compound are present in a composition, and the first compound is a non-superimposable mirror image of the second compound, and the first compound is present in the composition in a greater amount than the second compound, then the first compound is referred to herein as being present in "enantiomeric excess".
  • enantiomeric excess is related to the older term “optical purity” in that both are measures of the same phenomenon.
  • the value of ee will be a number from 0 to 100, zero being racemic and 100 being enantiomerically pure.
  • a composition which in the past might have been called 98% optically pure is now more precisely characterized by 96% ee.
  • a 90% ee reflects the presence of 95% of one enantiomer and 5% of the other(s) in the material in question.
  • the value of de will likewise be a number from 0 to 100, zero being an equal mixture of a first diastereomer and the remaining diastereomer(s), and 100 being 100% of a single diastereomer and zero% of the other(s) - i.e.
  • the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has only one stereocenter, and an enantiomer of the first compound of the invention.
  • the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has two stereocenters, and an enantiomer of the first compound of the invention.
  • the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has two stereocenters, and at least one diastereomer of the first compound of the invention.
  • the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has two stereocenters, and only one diastereomer of the first compound of the invention.
  • Enantiomeric or diastereomeric excess can be determined relative to exactly one other stereoisomer, or can be determined relative to the sum of at least two other stereoisomers. In an exemplary embodiment, enantiomeric or
  • diastereomeric excess is determined relative to all other detectable stereoisomers, which are present in the mixture.
  • Stereoisomers are detectable if a concentration of such stereoisomer in the analyzed mixture can be determined using common analytical methods, such as chiral HPLC.
  • substantially free of a compound means that the composition contains less than about 20% by weight, or less than about 15% by weight, or less than about 10% by weight, or less than about 5% by weight, or less than about 3% by weight, or less than about 2% by weight, or less than about 1% by weight of the compound.
  • the term "substantially free of the (or its) enantiomer” means that a composition contains a significantly greater proportion of a first compound of the invention than a second compound of the invention, wherein the first compound is a non-superimposable mirror image of the second compound.
  • the term “substantially free of the enantiomer” means that the composition is made up of at least about 90% by weight of a first compound of the invention, and about 10% by weight or less of a second compound of the invention, wherein the first compound is a non-superimposable mirror image of the second compound.
  • the term "substantially free of the (R) enantiomer” means that the composition is made up of at least about 90% by weight of a first compound of the invention which has only one stereocenter and the stereocenter is in an (S) configuration, and about 10% by weight or less of a second compound of the invention, wherein the second compound is the enantiomer of the first compound.
  • the term “substantially free of the enantiomer” means that the composition is made up of at least about 95% by weight of a first compound of the invention, and about 5% by weight or less of a second compound of the invention, wherein the first compound is a non- superimposable mirror image of the second compound.
  • the term "substantially free of the (R) enantiomer” means that the composition is made up of at least about 95% by weight of a first compound of the invention which has only one stereocenter and the stereocenter is in an (S) configuration, and about 5% by weight or less of a second compound of the invention, wherein the second compound is the enantiomer of the first compound.
  • the term “substantially free of the enantiomer” means that the composition is made up of at least about 98% by weight of a first compound of the invention, and about 2% by weight or less of a second compound of the invention, wherein the first compound is a non-superimposable mirror image of the second compound.
  • the term "substantially free of the (R) enantiomer” means that the composition is made up of at least about 99% by weight of a first compound of the invention which has only one stereocenter and the stereocenter is in an (S) configuration, and about 1% by weight or less of a second compound of the invention, wherein the second compound is the enantiomer of the first compound.
  • the invention provides a composition comprising a) first compound described herein ; and b) the enantiomer of the first compound, wherein the first compound described herein is present in an enantiomeric excess of at least 80%. In an exemplary embodiment, the enantiomeric excess is at least 92%.
  • the compounds of the invention may also be used in combination with additional therapeutic agents.
  • the invention thus provides, in a further aspect, a combination comprising a compound described herein or a pharmaceutically acceptable salt thereof together with at least one additional therapeutic agent.
  • the additional therapeutic agent is a compound of the invention.
  • the additional therapeutic agent includes a boron atom.
  • the additional therapeutic agent does not contain a boron atom.
  • the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian.
  • the additional therapeutic agent is berenil.
  • the additional therapeutic agent is berenil.
  • the additional therapeutic agent is diminazene.
  • the additional therapeutic agent is an antiprotozoa.
  • the additional therapeutic agent is selected from the group consisting of benznidazole, buparvaquone, carbarsone, clioquinol, disulf ⁇ ram, eflornithine, emetine, etofamide, furazolidone, meglumine antimoniate, melarsoprol, metronidazole, miltefosine, nifurtimox, nimorazole, nitazoxanide, ornidazole, paromomycin sulfate, pentamidine, pyrimethamine, secnidazole and tinidazole.
  • benznidazole buparvaquone
  • carbarsone clioquinol
  • disulf ⁇ ram eflornithine
  • emetine etofamide
  • furazolidone meglumine antimoniate
  • the additional therapeutic agent is pentamidine. In an exemplary embodiment, the additional therapeutic agent is suramin. In an exemplary
  • the additional therapeutic agent is an antiparasitic.
  • the additional therapeutic agent is selected from the group consisting of amitraz, avermectin, carbadox,
  • the additional therapeutic agent is selected from the group consisting of antimony, meglumine antimoniate, sodium stibogluconate,
  • amphotericin miltefosine and paromomycin.
  • the compounds of the invention, or pharmaceutical formulations thereof may also be used in combination with other therapeutic agents, for example immune therapies [e.g. interferon, such as interferon alfa-2a (ROFERONd)-A; Hoffmann-La Roche), interferon alpha-2b (INTRONd)-A; Schering-Plough), interferon alfacon-1 (INFERGEN®; Intermune), peginterferon alpha-2b (PEGINTRONTM; Schering- Plough) or peginterferon alpha-2a (PEGASYSd); Hoffmann-La Roche)], therapeutic vaccines, antifibrotic agents, anti-inflammatory agents [such as corticosteroids or NSAIDs], bronchodilators [such as beta-2 adrenergic agonists and xanthines (e.g.
  • interferon such as interferon alfa-2a (ROFERONd)-A; Hoffmann-La Roche), interferon alpha-2b (INTRONd)-A; Schering-Plough
  • compositions according to the invention may also be used in combination with gene replacement therapy.
  • the individual components of such combinations may be administered either simultaneously or sequentially in a unit dosage form.
  • the unit dosage form may be a single or multiple unit dosage forms.
  • the invention provides a combination in a single unit dosage form.
  • An example of a single unit dosage form is a capsule wherein both the compound of the invention and the additional therapeutic agent are contained within the same capsule.
  • the invention provides a combination in a two unit dosage form.
  • An example of a two unit dosage form is a first capsule which contains the compound of the invention and a second capsule which contains the additional therapeutic agent.
  • the term 'single unit' or 'two unit' or 'multiple unit' refers to the object which the patient ingests, not to the interior components of the object. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.
  • an exemplary embodiment of the invention is a pharmaceutical formulation comprising a) a compound of the invention; b) an additional therapeutic agent and c) a pharmaceutically acceptable excipient.
  • the pharmaceutical formulation is a unit dosage form.
  • the pharmaceutical formulation is a single unit dosage form.
  • the pharmaceutical formulation is a two unit dosage form.
  • the pharmaceutical formulation is a two unit dosage form comprising a first unit dosage form and a second unit dosage form, wherein the first unit dosage form includes a) a compound of the invention and b) a first pharmaceutically acceptable excipient; and the second unit dosage form includes c) an additional therapeutic agent and d) a second pharmaceutically acceptable excipient.
  • the compound of the invention can be synthesized according to the following scheme:
  • B is commercially available from, for example, Combi-Blocks (San Diego, CA, USA) and A is commercially available from, for example, Sigma- Aldrich (St. Louis, MO, USA).
  • a and B can be contacted under addition conditions stirred for an appropriate period of time at an appropriate temperature to form the product.
  • the compound of the invention can be synthesized according to the following scheme:
  • B is commercially available from, for example, Combi-Blocks (San Diego,
  • the compound of the invention can be synthesized according to the following scheme:
  • R a is as described herein, k conditions are K2CO3, DMF; 1 conditions are bis(pinacol-diboron), PdCl2(dppf)2, KOAc, dioxane; m conditions are NaBH 4 , MeOH; n conditions are aq. HCl; p conditions are PhCOCl, Et 3 N, CH 2 Cl 2 .
  • the compounds of the invention exhibit potency against microorganisms, such as protozoa, and therefore have the potential to kill and/or inhibit the growth of microorganisms .
  • the invention provides a method of killing and/or inhibiting the growth of a microorganism, said method comprising: contacting said microorganism with an effective amount of a compound of the invention, thereby killing and/or inhibiting the growth of the microorganism.
  • the microorganism is a protozoa.
  • the microorganism is a kinetoplastid.
  • the protozoa is a Trypanosoma.
  • the Trypanosoma is a member selected from T.
  • the protozoa is a Trypanosoma brucei.
  • the protozoa is a member selected from Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. In another exemplary embodiment, the protozoa is a member selected from Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. In another exemplary embodiment, the protozoa is Trypanosoma cruzi. In another exemplary embodiment, the protozoa is a member of the genus Leishmania. In another exemplary embodiment, the protozoa is a member of Leishmania Viannia.
  • the protozoa is a member selected from L. donovani, L. infantum, L. chagasi; L. mexicana, L. amazonensis, L. venezuelensis, L. tropica, L. major, L. aethiopica, L. (V.) braziliensis, L. (V.) guyanensis, L. (V.) panamensis, and L. (V.) peruviana.
  • the protozoa is L. donovani.
  • the protozoa is L.
  • the compound is described herein, or a salt, prodrug, hydrate or solvate thereof, or a combination thereof.
  • the invention provides a compound described herein, or a salt, hydrate or solvate thereof.
  • the invention provides a compound described herein, or a prodrug thereof.
  • the invention provides a compound described herein, or a salt thereof.
  • the compound of the invention is a compound described herein, or a pharmaceutically acceptable salt thereof.
  • the compound is described by a formula listed herein, or a pharmaceutically acceptable salt thereof.
  • the compound is part of a pharmaceutical formulation described herein.
  • the contacting occurs under conditions which permit entry of the compound into the organism. Such conditions are known to one skilled in the art and specific conditions are set forth in the Examples appended hereto.
  • 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 killed or its growth is inhibited through oral administration of the compound of the invention. In an exemplary embodiment, the microorganism is killed or its growth is inhibited through intravenous administration of the compound of the invention. In an exemplary embodiment, the microorganism is killed or its growth is inhibited through topical administration of the compound of the invention. In an exemplary embodiment, the microorganism is killed or its growth is inhibited through intraperitoneal
  • the compound of the invention is administered in a topically effective amount.
  • the compound is administered in a cosmetically effective amount.
  • the pharmaceutical formulation is administered in an orally effective amount.
  • the compounds of the invention exhibit potency against microorganisms, such as protozoa, and therefore have the potential to achieve therapeutic efficacy in the animals described herein.
  • the invention provides a method of treating and/or preventing a disease.
  • the method includes administering to the animal a
  • the compound of the invention can be used in human or veterinary medical therapy, particularly in the treatment or prophylaxis of kinetoplastid- associated disease.
  • the disease is associated with a
  • the Trypanosoma is a member selected from T. avium, T. boissoni, T. brucei, T. carassii, T. cruzi, T. congolense, T equinum, T equiperdum, T evansi, T hosei, T levisi, T melophagium, T parroti, T percae, T rangeli, T rotatorium, T rugosae, T sergenti, T simiae, T sinipercae, T suis, T theileri, T triglae and T. vivax.
  • the disease is associated with a Trypanosoma brucei.
  • the disease is associated with a member selected from Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense.
  • a member selected from Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense is associated with a member selected from Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense.
  • the disease is associated with Trypanosoma brucei rhodesiense. In an exemplary embodiment, the disease is associated with Trypanosoma brucei gambiense. In an exemplary embodiment, the disease is associated with
  • the disease is a trypanosomiasis.
  • the disease is a human trypanosomiasis.
  • the disease is an animal trypanosomiasis.
  • the disease is a member selected from nagana, surra, mal de caderas, murrina de caderas, dourine, cachexial fevers, Gambian horse sickness, baleri, kaodzera, tahaga, galziekte or galzietzke and peste-boba.
  • nagana surra
  • mal de caderas murrina de caderas
  • dourine cachexial fevers
  • Gambian horse sickness baleri, kaodzera, tahaga, galziekte or galzietzke and peste-boba.
  • the disease is a member selected from Chagas disease (or Human American trypanosomiasis), nagana, surra, Covering sickness (or dourine) and sleeping sickness (or African sleeping sickness or Human African trypanosomiasis).
  • the disease is Chagas disease.
  • the disease is sleeping sickness (or African sleeping sickness).
  • the disease is acute phase sleeping sickness.
  • the disease is chronic phase sleeping sickness.
  • the disease is an acute phase of a trypanosomiasis.
  • the disease is a chronic phase of a trypanosomiasis.
  • the disease is the non-CNS form of a trypanosomiasis. In an exemplary embodiment, the disease is the CNS form of a trypanosomiasis. In an exemplary embodiment, the disease is the non-CNS form of sleeping sickness. In an exemplary embodiment, the disease is the CNS form of sleeping sickness. In an exemplary embodiment, the disease is early stage Human African trypanosomiasis. In an exemplary embodiment, the disease is late stage Human African trypanosomiasis. In another exemplary embodiment, the disease is associated with a member of the genus Leishmania. In another exemplary embodiment, the disease is associated with a member of Leishmania Viannia. In an exemplary embodiment, the disease is associated with a member selected from L.
  • the disease is associated with L. donovani. In an exemplary embodiment, the disease is associated with L. infantum. In an exemplary embodiment, the disease is associated with L. infantum. In an exemplary
  • the disease is leishmaniasis. In an exemplary embodiment, the disease is visceral leishmaniasis. In an exemplary embodiment, the disease is cutaneous leishmaniasis. In an exemplary embodiment, the disease is diffuse cutaneous leishmaniasis and/or mucocutaneous leishmaniasis.
  • the compound is described herein, or a salt, prodrug, hydrate or solvate thereof, or a combination thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt, hydrate or solvate thereof. In an exemplary embodiment, the invention provides a compound described herein, or a prodrug thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt thereof.
  • the compound of the invention is a compound described herein, or a pharmaceutically acceptable salt thereof.
  • the compound is described by a formula listed herein, or a pharmaceutically acceptable salt thereof.
  • the compound is part of a pharmaceutical formulation described herein.
  • the contacting occurs under conditions which permit entry of the compound into the organism. Such conditions are known to one skilled in the art and specific conditions are set forth in the Examples appended hereto.
  • 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 animal is a mouse.
  • 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 animal is a human.
  • the disease is treated through oral administration of the compound of the invention. In an exemplary embodiment, the disease is treated through intravenous administration of the compound of the invention. In an exemplary embodiment, the disease is treated through topical administration of the compound of the invention. In an exemplary embodiment, the disease is treated through intraperitoneal administration of the compound of the invention. In an exemplary embodiment, the compound is administered in a topically effective amount. In an exemplary embodiment, the compound is administered in a cosmetically effective amount. In an exemplary embodiment, the pharmaceutical formulation is administered in an orally effective amount. [0158] In an exemplary embodiment, the disease is associated with an infection by a microorganism described herein. In an exemplary embodiment, the disease is associated with an infection by a protozoa described herein. VI.
  • the invention is a pharmaceutical formulation which includes: (a) a pharmaceutically acceptable excipient; and (b) a compound of the invention.
  • the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound according to a formula described herein.
  • the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound described herein, or a salt, prodrug, hydrate or solvate thereof, or a combination thereof.
  • the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound described herein, or a salt, hydrate or solvate thereof, or a combination thereof.
  • the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound described herein, or a salt, hydrate or solvate thereof.
  • the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a salt of a compound described herein.
  • the salt is a pharmaceutically acceptable salt.
  • the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a prodrug of a compound described herein.
  • the pharmaceutical formulation includes: (a) a) a
  • the pharmaceutical formulation is a unit dosage form. In an exemplary embodiment, the pharmaceutical formulation is a single unit dosage form.
  • 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). [0161] The pharmaceutical formulation of the invention may be administered orally, topically, intraperitoneally, parenterally, by inhalation or spray or rectally in unit dosage forms containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • 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.
  • the pharmaceutical formulation is administered orally.
  • the pharmaceutical formulation is administered intravenously.
  • the pharmaceutical formulation is administered in a topically effective dose.
  • the pharmaceutical formulation is administered in a cosmetically effective dose.
  • the pharmaceutical formulation is administered in an orally effective dose.
  • the pharmaceutical formulations containing compounds of the invention are preferably in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • 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 excipients 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 distearate 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 carboxymethylcellulose, methylcellulose, 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, for example polyethylene sorbitan monooleate.
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example 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. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • Pharmaceutical formulations 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 non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • the acceptable 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.
  • 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.
  • Such materials are cocoa butter and polyethylene glycols.
  • the 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. [0173] Dosage levels of the order of from about 5 mg to about 250 mg per kilogram of body weight per day and more preferably from about 25 mg to about 150 mg per kilogram of body weight per day, are useful in the treatment of the above- indicated conditions. The amount of active ingredient that may be combined with the carrier materials to produce a unit dosage form will vary depending upon the condition being treated and the particular mode of administration. Unit dosage 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.
  • the unit dosage form contains from about 1 mg to about 800 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 1 mg to about 500 mg of an active ingredient. In an exemplary embodiment, the unit dosage form contains from about 100 mg to about 800 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 200 mg to about 500 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 500 mg to about 800 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 1 mg to about 100 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 10 mg to about 100 mg of a compound of the invention.
  • the unit dosage form contains from about 50 mg to about 100 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 25 mg to about 75 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 40 mg to about 60 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 75 mg to about 200 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 1 mg to about 5 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 10 mg to about 25 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 50 mg to about 350 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 200 mg to about 400 mg of a compound of the invention.
  • the daily dosage contains from about 1 mg to about 800 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 1 mg to about 500 mg of an active ingredient. In an exemplary embodiment, the daily dosage contains from about 100 mg to about 800 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 200 mg to about 500 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 500 mg to about 800 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 1 mg to about 100 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 10 mg to about 100 mg of a compound of the invention.
  • the daily dosage contains from about 50 mg to about 100 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 75 mg to about 200 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 1 mg to about 5 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 10 mg to about 25 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 50 mg to about 350 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 200 mg to about 400 mg of a compound of the invention.
  • 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. [0178] 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 hepatocytes 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
  • 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 1120-1127).
  • 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.
  • Preferred compounds for use in the pharmaceutical formulations described herein 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 Oravcova 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 1120-1127).
  • 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 LD50 and ED50.
  • Compounds that exhibit high therapeutic indices are preferred.
  • the data obtained from these cell culture assays and animal studies can be used in 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 ED50 with little or no toxicity.
  • the dosage can vary within this range depending upon the unit dosage form employed and the route of administration utilized.
  • 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 protozoa cell growth.
  • EC50 effective dose for 50% increase
  • concentration of the test compound which achieves a half-maximal inhibition of protozoa 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 protozoa 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 0.01-10 wt% of the drug 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%.
  • the invention provides a compound having a structure according to the following formula:
  • Z is a member selected from S or O;
  • X is a member selected from substituted phenyl, substituted or unsubstituted heteroaryl and unsubstituted cycloalkyl, or a salt thereof.
  • the compound has a structure according to the following formula:
  • X is phenyl or heteroaryl, in which one substituent on said phenyl or said heteroaryl is a member selected from halogen or cyano or nitro or unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl or unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy or halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl or halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy or unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkylthio or unsubstituted phenyl or NR 8 R 9 or -SO 2 (R 7 ) or -SO 2 N(R 7 )(R 8 ), wherein R 7 is a member selected from H and unsubstituted Ci or C 2 or C 3 or C 4 or C
  • the compound has a structure according to the following formula:
  • X is phenyl or heteroaryl, in which one substituent on said phenyl or said heteroaryl is a member selected from F, Cl, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , OCH 3 , OCH 2 CH 3 , OCF 3 and N(CH 3 ) 2 .
  • the compound has a structure according to the following formula:
  • X is phenyl or heteroaryl, in which two substituents on said phenyl or said heteroaryl are each the same or different and are each selected from: halogen or cyano or nitro or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl or unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkoxy or halosubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkyl or halosubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkoxy or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkylthio or unsubstituted phenyl or NR 8 R 9 or -SO 2 (R 7 ) or -SO 2 N(R 7 )(R 8 ) wherein R 7 is a member selected from H and unsubstituted Ci or C 2 or C
  • the compound has a structure according to the following formula:
  • X is phenyl or heteroaryl, in which one substituent on said phenyl or said heteroaryl is a member selected from F, Cl, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , OCH 3 , OCH 2 CH 3 , OCF 3 and N(CH 3 ) 2 .
  • the compound has a structure according to the following formula:
  • R 2 , R 3 , R 4 , R 5 and R 6 are each the same or different and are each selected from H or halogen or cyano or nitro or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy or halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl or halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkylthio or unsubstituted phenyl or NR 8 R 9 or -SO 2 (R 7 ) or -SO 2 N(R 7 )(R 8 ) wherein R 7 is a member selected from H and unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 al
  • the compound has a structure according to the following formula:
  • R 2 , R 3 , R 4 , R 5 and R 6 are each the same or different and are each selected from H, F, Cl, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , OCH 3 , OCH 2 CH 3 , OCF 3 and N(CH 3 ) 2 , with the proviso that R 2 , R 3 , R 4 , R 5 and R 6 cannot all be H.
  • the compound has a structure according to the following formula:
  • one member selected is halogen or cyano or nitro or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl or unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkoxy or halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl or halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy or unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkylthio or unsubstituted phenyl or NR 8 R 9 or -SO 2 (R 7 ) or - SO 2 N(R 7 )(R 8 ); wherein R 7 is a member selected from H and unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl; R 8 is a member selected from H and unsubstituted Ci or C 2 or C 3
  • R 6 is F, Cl, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , OCH 3 , OCH 2 CH 3 , OCF 3 and N(CH 3 ) 2 , and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure wherein one member selected from R 2 , R 3 , R 4 , R 5 and R 6 is halogen or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl or halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure wherein one member selected from R 2 , R 3 , R 4 , R 5 and R 6 is a member selected from F, Cl, CH 3 , CF 3 and OCH 3 ; and the remaining members of
  • R 2 , R 3 , R 4 R 5 and R 6 are H.
  • the compound has a structure wherein one member selected from R 2 , R 3 , R 4 , R 5 and R 6 is F or Cl or CH 3 or CF 3 ; and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure wherein two members selected from R 2 , R 3 , R 4 , R 5 and R 6 are each the same or different and are each selected from halogen; and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure wherein one member selected from R 2 , R 3 , R 4 , R 5 and R 6 is halogen; one member selected from R 2 , R 3 , R 4 , R 5 and R 6 is halogen or unsubstituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkyl or halosubstituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkyl; and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure wherein one member selected from R 2 , R 3 , R 4 , R 5 and R 6 is halogen; one member selected from R 2 , R 3 , R 4 , R 5 and R 6 is F or Cl or CH 3 or CF 3 or OCH 3 ; and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure wherein one member selected from R 2 , R 3 , R 4 , R 5 and R 6 is F; one member selected from R 2 , R 3 , R 4 , R 5 and R 6 is halogen or unsubstituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkyl or halosubstituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkyl; and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure wherein one member selected from R 2 , R 3 , R 4 , R 5 and R 6 is F; and one member selected from R 2 , R 3 , R 4 , R 5 and R 6 is Cl or CH 3 or CF 3 ; and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has having a structure according to the following formula:
  • R is a member selected from halogen or cyano or nitro or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy or halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl or halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy or unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkylthio or unsubstituted phenyl or NR 8 R 9 or -SO 2 (R 7 ) or -SO 2 N(R 7 )(R 8 ) wherein R 7 is a member selected from H and unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl; R 8 is a member selected from H and unsubstituted Ci or C 3
  • the compound has a structure wherein R 2 is a member selected from F, Cl, CH 3 , OCH 3 and CF 3 .
  • the compound has a structure according to the following formula:
  • R is a member selected from halogen, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl and halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl.
  • the compound has a structure wherein R is a member selected from F, Cl, CH 3 and CF 3 .
  • the compound has a structure wherein having a structure according to the following formula: wherein R 3 is a member selected from halogen or cyano or nitro or unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl or unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy or halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl or halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkylthio or unsubstituted phenyl or NR 8 R 9 or -SO 2 (R 7 ) or -SO 2 N(R 7 )(R 8 ) wherein R 7 is a member selected from H and unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl
  • the compound has a structure wherein R 3 is a member selected from halogen,
  • Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl
  • halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy
  • halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl
  • R 3 is a member selected from F, Cl, CH 3 , OCH 3 and CF 3 .
  • the compound has a structure according to the following formula:
  • R is a member selected from halogen or cyano or nitro or unsubstituted C or C 2 or C 3 or C 4 or C 5 or C 6 alkyl or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy or halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl or halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkylthio or unsubstituted phenyl or NR 8 R 9 or -SO 2 (R 7 ) or -SO 2 N(R 7 )(R 8 ) wherein R 7 is a member selected from H and unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl; R 8 is a member selected from H and unsubstituted Ci or C 3
  • Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl
  • halosubstituted Ci or C 2 or C3 or C 4 or C 5 or C 6 alkyl unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy
  • halosubstituted Ci or C 2 or C3 or C 4 or C 5 or C 6 alkoxy unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl
  • the compound has a structure wherein R 4 is a member selected from F, Cl, CH 3 , CH 2 CH 3 , CH(CHs) 2 , C(CHs) 3 , CF 3 , OCH 3 , OCH 2 CH 3 , OCF 3 and N(CH 3 ) 2 .
  • the compound has a structure according to the following formula:
  • R is halogen; and R is a member selected from F, Cl, CH 3 , CH 2 CH 3 ,
  • the compound has a structure according to the following formula:
  • R is halogen; and R is a member selected from halogen or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy or halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl or halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy or NR 7 R 8 wherein R 7 is a member selected from H and unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl and R 8 is a member selected from H and unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl.
  • the compound has a structure according to the following formula:
  • R 4 is halogen; and R 3 is a member selected from F, Cl, CH 3 , CH 2 CH 3 , CH(CHs) 2 , C(CHs) 3 , CF 3 , OCH 3 , OCH 2 CH 3 , OCF 3 and N(CH 3 ) 2 .
  • the compound has a structure according to the following formula:
  • R 2 is a member selected from halogen, unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkyl, halosubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkyl, unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkoxy, halosubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkoxy and NR 7 R 8 wherein R 7 is a member selected from H and unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkyl and R 8 is a member selected from H and unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkyl.
  • the compound has a structure according to the following formula:
  • the compound has a structure according to the following formula: wherein R 3 is a member selected from halogen, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl, halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy, halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy and NR 7 R 8 wherein R 7 is a member selected from H and unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl and R 8 is a member selected from H and unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl
  • the compound has a structure according to the following formula:
  • the compound has a structure according to the following formula:
  • R 2 is a member selected from halogen, unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkyl, halosubstituted Ci or C 2 or C 3 or C 4 or C5 or Ce alkyl, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy, halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy and NR 7 R 8 wherein R 7 is a member selected from H and unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl and R 8 is a member selected from H and unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl.
  • the compound has a structure according to the following formula:
  • the compound has a structure according to the following formula:
  • R 3 is a member selected from F, Cl, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , OCH 3 , OCH 2 CH 3 , OCF 3 and N(CH 3 ) 2 .
  • the compound has a structure according to the following formula:
  • R 4 is halogen
  • R 2 is a member selected from halogen, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl and halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl.
  • R 4 is halogen; and R 2 is a member selected from Cl, CH 3 and CF 3 .
  • R 4 is halogen; and R 2 is a member selected from Cl, CH 3 and CF 3 .
  • R 4 is halogen and R 2 is halogen.
  • the compound has a structure according to the following formula:
  • R is F; and R is a member selected from Cl, CH 3 and CF 3 .
  • the compound is:
  • the compound has a structure according to the following formula:
  • R 4 is halogen
  • the compound has a structure according to the following formula:
  • the compound is: [0237] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
  • the compound has a structure according to the following formula:
  • X 1 is Ci or C 2 or C3 or C 4 or C5 or C 6 or C 7 or Cs or C9 or C 10 alkyl, optionally substituted with substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, hydroxy and phenylalkyloxy.
  • the compound has a structure according to the following formula:
  • X 1 is Ci or C 2 or C3 or C 4 or C5 or C 6 or C 7 or Cs or C9 or C 10 alkyl, substituted with substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl on the carbon adjacent to the carbonyl carbon.
  • the compound has a structure according to the following formula:
  • the compound has a structure according to the following formula:
  • n is 1 or 2 or 3 or 4 or 5 or 6; and one member selected from R 2 , R 3 , R 4 , R 5 and R 6 is F, Cl, CN, NO 2 , -CH 3 , -CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , -OCH 3 , - OCH 2 CH 3 , -OCF 3 , -N(CH 3 ) 2 , -NH(C(O)CH 3 ), -SCH 3 , -S(O) 2 CH 3 , -S(O) 2 N(CH 3 ) 2 and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure according to the following formula:
  • R 6 is halogen; one member selected from R 2 , R 3 , R 4 , R 5 and R 6 is halogen or unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkyl or halosubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkyl; and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure according to the following formula: wherein R 4 is halogen; and R 2 is a member selected from halogen, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl and halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl.
  • n is 1 or n is 2.
  • halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl is trifluorosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl.
  • halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy is trifluorosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy.
  • the invention provides a combination comprising the compound according to any of the above paragraphs, together with at least one other therapeutically active agent.
  • the invention provides a pharmaceutical formulation comprising: a) the compound according to any of the above paragraphs, or a salt thereof; and b) a pharmaceutically acceptable excipient.
  • the invention provides a method of killing and/or preventing the growth of a protozoa, comprising: contacting the protozoa with an effective amount of the compound of the invention, thereby killing and/or preventing the growth of the protozoa.
  • the compound has a structure described herein.
  • the protozoa is a member of the Trypanosome genus.
  • the protozoa is a member of the Leishmania genus.
  • the protozoa is Trypanosoma brucei.
  • the Trypanosoma brucei is a member selected from Trypanosoma brucei brucei, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense.
  • the protozoa is a member selected from Leishmania donovani, Leishmania infantum, Leishmania chagasi, Leishmania mexicana, Leishmania amazonensis, Leishmania venezuelensis, Leishmania tropica, Leishmania major, Leishmania aethiopica.
  • the protozoa is Leishmania donovani.
  • the invention provides a method of treating and/or preventing a disease in an animal, comprising: administering to the animal a therapeutically effective amount of the compound of the invention, thereby treating and/or preventing the disease.
  • the compound has a structure described herein.
  • the disease is African sleeping sickness.
  • the disease is leishmaniasis.
  • the leishmaniasis is a member selected from visceral leishmaniasis, cutaneous leishmaniasis, diffuse cutaneous leishmaniasis and mucocutaneous leishmaniasis.
  • the leishmaniasis is visceral leishmaniasis.
  • the leishmaniasis is cutaneous leishmaniasis.
  • the animal is a human.
  • the invention is a use of a compound of the invention or a combination of the invention in the manufacture of a medicament for the treatment and/or prophylaxis of protozoal infection.
  • HPLC purification was performed using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C 18 column, Dyonex Chromeleon operating system coupled with a Varian Prostar 320 UV-vis detector (254 nm) and a Sedex55 ELS detector.
  • Resazurin (20 uL of 12.5 mg/ml stock) from Sigma- Aldrich was added to each well and plates were incubated for an additional 2-4 hrs. Assay plates were read using an En Vision plate reader at an excitation wavelength of 544 nm and emission of 590 nm. Triplicate data points were averaged to generate sigmoidal dose response curve and determine IC50 values using XLfit curve fitting software from IDBS (Guildford, UK).
  • the kinetic solubilities of compounds were estimated using a nephelometric (light scattering) method. Briefly, compounds of the invention were serially diluted in DMSO, followed by dilution in PBS pH 7.4. After incubation, the amount of light scattered by a compound at each concentration was measured. Clear solutions of soluble compounds do not scatter a light beam passed through the sample well and produce no signal. At concentrations above the solubility limit, the compound precipitates and the precipitant in the well scatters the light, generating a signal. Higher levels of precipitant in a well scatter more light and produce a stronger signal.
  • a stock solution of a compound of the invention (25 mM in DMSO) was prepared, and was serially diluted in DMSO in two-fold increments in a row of a 96 well plate to a lowest concentration of 24 ⁇ M.
  • a duplicate plate was prepared by transfer of half of the volume of each well to a new plate.
  • Each well containing DMSO solution of the test compound was then diluted further (1 : 100) with phosphate buffered saline (pH 7.4) to provide aqueous solutions of compound at the following final concentrations: 250, 125, 62.5, 31.3, 15.6, 7.8, 3.9, 2.0, 1.0, 0.5 and 0.2 ⁇ M. All liquid handling stages were performed on a Beckman Coulter Biomek NX
  • FIG. 1 Biological data for exemplary compounds of the invention is provided in FIG. 1.
  • L929 mouse fibroblast cells were used. Cells were maintained as adherent cultures in T-25 vented cap flasks in a humidified incubator at 37 0 C in the presence of 5% CO 2 . Culture media was D-MEM supplemented with 10% fetal bovine serum and 1%
  • L929 cells were maintained below confluent levels by sub- culturing at 1 :10 dilution twice weekly using 0.05% trypsin for detachment.
  • Sub-confluent L929 cells were trypsinized, resuspended in fresh media and 10 uL was counted using hemocytometer to determine cell concentration.
  • Cells were diluted to 1 x 10 4 /mL in DMEM, dispensed (100 uL) into 96-well plates using a Multidrop 384 dispenser and allowed to attach overnight.
  • Spent media was replaced with 99.5 uL fresh D-MEM and compounds to be tested were serially diluted in DMSO and 0.5 uL added using a Biomek NX liquid handler. Plates were incubated with a compound of the invention for 72 hrs at 37°C with 5% CO 2 .
  • Resazurin (20 uL of 12.5 mg/ml stock) from Sigma- Aldrich was added to each well and plates were incubated for an additional 3-4 hrs. Assay plates were read using an En Vision plate reader at an excitation wavelength of 544 nm and emission of 590 nm. Single data points were used to generate sigmoidal dose response curves and determine IC50 values using XL fit curve fitting software from IDBS (Guildford, UK).
  • Biological data for exemplary compounds of the invention is provided in FIG. 1.
  • mice can be infected with 10,000 parasites of the TREU 667 strain of T. b. brucei. Twenty one days post-infection mice can be treated with a dose of between 6 and 100 mg/kg of the compound of the invention, either BID or QD for 7 days intraperitoneally (IP) or orally (PO). Positive control mice can be treated with Diminazene (10 mg/kg, IP) on Day 4 post-infection. Negative control mice can be treated with Diminazene (10 mg/kg, PO) on Day 21. Since Diminazene is not able to penetrate the CNS, mice treated at Day 21 are not able to cure the infection. Starting 1 week after the end of treatment, mice can be monitored for parasitemia and sacrificed if parasites are detected in the blood. Mice that survive 6 months are considered "cured.”
  • mice weighing approximately 25 g can receive the compound of the invention by either intravenous (IV), oral gavage (OG) or intra-peritoneal (IP) routes.
  • IV group (6-10 animals, 1-2 per time point) received a single bolus injection of approximately 2mg/kg of the compound of the invention.
  • Animals receiving extra- vascular doses can be administered the compound of the invention as either single OG doses (6-10 animals, 1-2 per time point) of approximately 8mg/kg, or as 4 repeat doses (over 2 days) of approximately 25mg/kg or 50mg/kg by the IP route (6-10 animals, 1-2 per time point).
  • All doses can be administered as clear colorless solutions in either: 50% (v/v)PEG400 : 20% (v/v) ethanol : 30% (v/v) carboxymethylcellulose (0.5% w/v in sterile water for injection, WFI), or as in situ sodium salts in 5% (m/v) dextrose : 2% (v/v) ethanol in DWI. All dose solutions can be delivered at 4mL/kg. Animals can be fasted for at least 4 hours before dosing, and for 2 hours after dosing.
  • Blood samples and brain tissue can be sampled from 1 or 2
  • animals/timepoint/group immediately before dosing and approximately 0.17, 0.5, 1, 2, 3, 4, 6, 8, 12, 18 and 24hr after dosing for full pharmacokinetic and tissue analysis, or at 0.5, 2 and 4 hours post dosing to assess early-phase CNS disposition.
  • Bioanalysis for the compound of the invention in whole blood, plasma or brain tissue can be performed by HPLC with tandem mass spectrometry (LC-MSMS).
  • Whole blood and plasma samples can be treated with 3 volumes of either acetonitrile or methanol to precipitate plasma proteins.
  • Treated samples can be centrifuged and supernatants removed for analysis.
  • Brain tissues can be weighed and homogenized mechanically in the presence of 1 volume of phosphate-buffered saline (PBS). The resulting tissue suspensions can be then diluted with a further volume of PBS, and then treated in the same manner as whole blood or plasma.
  • PBS phosphate-buffered saline
  • Extracted samples can be assayed for compound of the invention by means of LC-MSMS employing reversed-phase chromatography coupled to a triple quadrupole mass spectrometer employing electrospray ionization in the positive ion mode.
  • the analytical column can be a Phenomenex Luna 3 ⁇ C8 50 x 2mm, with an online sample purification step performed on a Phenomenex Synergi 4 ⁇ Polar RP 50 x 2mm column.
  • Test articles can be eluted using a binary mobile phase gradient comprising 5mM Ammonium Acetate: 0.1% formic acid in either MeOH or H2O.
  • Non-compartmental analysis of plasma compound of the invention concentration versus time can be performed in Microsoft Excel to generate
  • AUC area under the curve
  • Vdss volume of distribution
  • tl/2 half-life
  • F bioavailability
  • a compound of the invention can receive a compound of the invention as a single oral gavage (OG) dose of approximately 25mg/kg (approximately 10 animals per group).
  • All doses can be administered as clear colorless solutions as in situ sodium salts in 5% (m/v) dextrose : 2% (v/v) ethanol in DWI. All dose solutions can be delivered at 2mL/kg. Animals can be fasted for at least 4 hours before dosing, and for 2 hours after dosing.
  • Blood and CSF samples and brain tissue can be sampled from 1
  • animal/timepoint/group immediately before dosing and approximately 0.5, 1, 2, 3, 4, 6, 8, 12, 18 and 24hr after dosing for full pharmacokinetic (plasma and CSF) and tissue (Brain) analysis.
  • Parasites from the diluted stock were added to each well (50 ⁇ L) using a Multidrop 384 dispenser to give a final concentration of 1.OxlO 5 /ml parasites in 0.5% for DMSO.
  • Amastigotes were incubated with compounds for 72 hrs at 37°C with 5% CO 2 .
  • Resazurin (10 ⁇ L of 12.5 mg/ml stock) from Sigma- Aldrich was added to each well and plates were incubated for an additional 2-3 hrs.
  • Assay plates were read using an En Vision plate reader at an excitation wavelength of 544 nm and emission of 590 nm. Triplicate data points were averaged to generate sigmoidal dose response curve and determine IC50 values using XLfit curve fitting software from IDBS (Guildford, UK).
  • the plates were read with a Spectramax Gemini XS microplate fluorometer (Molecular Devices Cooperation, Sunnyvale, CA, USA) using an excitation wave length of 536 nm and an emission wave length of 588 nm. Data were analyzed using the microplate reader software Softmax Pro (Molecular Devices Cooperation, Sunnyvale, CA, USA).
  • Rat skeletal myoblasts (L-6 cells) were seeded in 96-well microtitre plates at 2000 cells/well in 100 ⁇ L RPMI 1640 medium with 10% FBS and 2 mM 1- glutamine. After 24 h the medium was removed and replaced by 100 ⁇ l per well containing 5000 trypomastigote forms of T. cruzi Tulahuen strain C2C4 containing the ⁇ -galactosidase (Lac Z) gene (Buckner et al. (1996) Efficient technique for screening drugs for activity against Trypanosoma cruzi using parasites expressing beta-galactosidase, p. 2592-2597, vol. 40).
  • Lac Z ⁇ -galactosidase
  • the medium was removed from the wells and replaced by 100 ⁇ l fresh medium with or without a serial drug dilution of seven 3-fold dilution steps covering a range from 90 to 0.123 ⁇ g/ml.
  • the plates were inspected under an inverted microscope to assure growth of the controls and sterility.
  • the substrate CPRG/Nonidet 50 ⁇ l was added to all wells.
  • a color reaction developed within 2-6 h and could be read photometrically at 540 nm. Data were transferred into the graphic programme Softmax Pro (Molecular Devices), which calculated IC50 values.

Abstract

This invention provides, among other things, novel compounds useful for treating protozoal infections, pharmaceutical compositions containing such compounds, as well as combinations of these compounds with at least one additional therapeutically effective agent. The compounds are of formula (I), wherein Z is S or O; and X is selected from the group consisting of substituted phenyl, substituted or unsubstituted heteroaryl, and unsubstituted cycloalkyl, or a salt thereof.

Description

BORON-CONTAINING SMALL MOLECULES AS ANTIPROTOZOAL
AGENTS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Pat. App. No.
61/234,222, filed August 14, 2009, and U.S. Provisional Pat. App. No. 61/308,717, filed February 26, 2010, each of which is incorporated by reference in its entirety for all purposes.
BACKGROUND OF THE INVENTION
[0002] The global rise of protozoa resistant to antimicrobials in general, poses a major threat. Deployment of massive quantities of antimicrobial agents into the ecosphere during the past 60 years has introduced a powerful selective pressure for the emergence and spread of antimicrobial-resistant pathogens. Thus, there is a need to discover new broad spectrum antimicrobials, such as antiprotozoals, useful in combating microorganisms, especially those with multidrug-resistance.
[0003] Boron-containing molecules, such as oxaboroles, useful as antimicrobials have been described previously, such as in U.S. Pat. Pubs. US20060234981 and US20070155699. Generally speaking, an oxaborole has the following structure and substituent numbering system:
Figure imgf000002_0001
It has now been discovered that certain classes of oxaboroles which are surprisingly effective antiprotozoals. This, and other uses of these oxaboroles are described herein.
SUMMARY OF THE INVENTION
[0004] This invention provides, among other things, novel compounds useful for treating protozoa infections, pharmaceutical compositions containing such compounds, as well as combinations of these compounds with at least one additional therapeutically effective agent. BRIEF DESCRIPTION OF THE DRAWINGS
[0005] Biological data for exemplary compounds of the invention is provided in FIG. 1.
DETAILED DESCRIPTION OF THE INVENTION
/. Definitions and Abbreviations
[0006] As used herein, the singular forms "a," "an", and "the" include plural references unless the context clearly dictates otherwise. For example, reference to "an active agent" includes a single active agent as well as two or more different active agents in combination. It is to be understood that present teaching is not limited to the specific dosage forms, carriers, or the like, disclosed herein and as such may vary.
[0007] The abbreviations used herein generally have their conventional meaning within the chemical and biological arts.
[0008] The following abbreviations have been used: Ac is acetyl; AcOH is acetic acid; ACTBr is cetyltrimethylammonium bromide; AIBN is azobisisobutyronitrile or 2,2 azobisisobutyronitrile; aq. is aqueous; Ar is aryl; B2pin2 is bis(pinacolato)diboron; Bn is, in general, benzyl [see Cbz for one example of an exception]; (BnS)2 is benzyl disulfide; BnSH is benzyl thiol or benzyl mercaptan; BnBr is benzyl bromide; Boc is tert-butoxy carbonyl; BoC2O is
Figure imgf000003_0001
dicarbonate; Bz is, in general, benzoyl; BzOOH is benzoyl peroxide; Cbz or Z is benzyloxycarbonyl or carboxybenzyl;
Cs2Cθ3 is cesium carbonate; CSA is camphor sulfonic acid; CTAB is
cetyltrimethylammonium bromide; Cy is cyclohexyl; DABCO is 1,4- diazabicyclo[2.2.2]octane; DCM is dichloromethane or methylene chloride; DHP is dihydropyran; DIAD is diisopropyl azodicarboxylate; DIEA or DIPEA is NJSf- diisopropylethylamine; DMAP is 4-(dimethylamino)pyridine; DME is 1 ,2- dimethoxyethane; DMF is N,N-dimethylformamide; DMSO is dimethylsulfoxide; equiv or eq. is equivalent; EtOAc is ethyl acetate; EtOH is ethanol; Et2O is diethyl ether; EDCI is Λ/-(3-dimethylaminopropyl)-Λ/"-ethylcarbodiimide hydrochloride; ELS is evaporative light scattering; equiv or eq is equivalent; h is hours; HATU is O-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HOBt is JV-hydroxybenzotriazole; HCl is hydrochloric acid; HPLC is high pressure liquid chromatography; ISCO Companion is automated flash chromatography equipment with fraction analysis by UV absorption available from Presearch; KOAc or AcOK is potassium acetate; K2CO3 is potassium carbonate; LiAlH4 or LAH is lithium aluminum hydride; LDA is lithium diisopropylamide; LHMDS is lithium
bis(trimethylsilyl) amide; KHMDS is potassium bis(trimethylsilyl) amide; LiOH is lithium hydroxide; m-CPBA is 3-chloroperoxybenzoic acid; MeCN or ACN is methyl cyanide or cyanomethane or ethanenitrile or acetonitrile which are all names for the same compound; MeOH is methanol; MgSO4 is magnesium sulfate; mins or min is minutes; Mp or MP is melting point; NaCNBH3 is sodium cyanoborohydride; NaOH is sodium hydroxide; Na2SO4 is sodium sulfate; NBS is N-bromosuccinimide; NH4Cl is ammonium chloride; NIS is N-iodosuccinimide; N2 is nitrogen; NMM is N- methylmorpholine; n-BuLi is n-butyllithium; overnight is O/N; PdCl2(pddf) is 1,1'- Bis(diphenylphosphino) ferrocene]dichloropalladium(II); Pd/C is the catalyst known as palladium on carbon; Pd2(dba)3 is an organometallic catalyst known as
tris(dibenzylideneacetone) dipalladium(O); Ra Ni or Raney Ni is Raney nickel; Ph is phenyl; PMB is /?-methoxybenzyl; PrOH is 1-propanol; iPrOH is 2-propanol; POCI3 is phosphorus chloride oxide; PTSA is /?αrα-toluene sulfonic acid; Pyr. or Pyr or Py as used herein means Pyridine; RT or rt or r.t. is room temperature; sat. is saturated; Si- amine or Si-NH2 is amino-functionalized silica, available from SiliCycle; Si-pyr is pyridyl-functionalized silica, available from SiliCycle; TEA or Et3N is triethylamine; TFA is trifluoroacetic acid; Tf2O is trifluoromethanesulfonic anhydride; THF is tetrahydrofuran; TFAA is trifluoroacetic anhydride; THP is tetrahydropyranyl; TMSI is trimethylsilyl iodide; H2O is water; diNO2PhSO2Cl is dinitrophenyl sulfonyl chloride; 3-F-4-NO2-PhSO2Cl is 3-fluoro-4-nitrophenylsulfonyl chloride; 2-MeO-4- NO2-PhSO2Cl is 2-methoxy-4-nitrophenylsulfonyl chloride; and
(EtO)2POCH2COOEt is a triethylester of phosphonoacetic acid known as triethyl phosphonoacetate.
[0009] "Compound of the invention," as used herein refers to the compounds discussed herein, salts (e.g. pharmaceutically acceptable salts), prodrugs, solvates and hydrates of these compounds. [0010] "Combination of the invention," as used herein refers to the compounds and antiprotozoals discussed herein as well as acids, bases, salt forms (such as
pharmaceutically acceptable salts), prodrugs, solvates and hydrates of these compounds and antiprotozoals. [0011] "Boron containing compounds", as used herein, refers to the compounds of the invention that contain boron as part of their chemical formula.
[0012] Where 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. , -CH2O- is intended to also recite -OCH2-.
[0013] The term "poly" as used herein means at least 2. For example, a polyvalent metal ion is a metal ion having a valency of at least 2.
[0014] "Moiety" refers to a radical of a molecule that is attached to the remainder of the molecule.
[0015] The symbol v/wvo ; whether utilized as a bond or displayed perpendicular to a bond, indicates the point at which the displayed moiety is attached to the remainder of the molecule.
[0016] The term "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 (i.e. Ci-Cio means one to ten carbons). In some embodiments, the term "alkyl" means a straight or branched chain, or combinations thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,
(cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n- pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3- butynyl, and the higher homologs and isomers.
[0017] The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified, but not limited, by
-CH2CH2CH2CH2-, and further includes those groups described below as "heteroalkylene." Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. [0018] The term "alkenylene" by itself or as part of another substituent means a divalent radical derived from alkene.
[0019] The term "cycloalkylene" by itself or as part of another substituent means a divalent radical derived from cycloalkane.
[0020] The term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkane.
[0021] The term "heterocycloalkylene" by itself or as part of another substituent means a divalent radical derived from heterocycloalkane.
[0022] The term "arylene" by itself or as part of another substituent means a divalent radical derived from aryl. [0023] The term "heteroarylene" by itself or as part of another substituent means a divalent radical derived from heteroaryl.
[0024] The terms "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. [0025] The term "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. In some embodiments, the term
"heteroalkyl," by itself or in combination with another term, means a stable straight or branched chain, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom. In an exemplary embodiment, 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,
-CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CHs)-CH3, -CH2-S-CH2-CH3, -CH2-CH25-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R5C(O)2-.
[0026] The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively. Additionally, for 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-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1 -(1,2,5,6- 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.
[0027] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(Ci-C4)alkyl" is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. [0028] The term "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. The term "heteroaryl" refers to aryl groups (or rings) that contain from one to four heteroatoms. In an exemplary embodiment, the heteroatom is selected from B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non- limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3- pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4- oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1- isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
[0029] For brevity, the term "aryl" when used in combination with other terms (e.g. , aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, 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 alkyl 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).
[0030] Each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl" and
"heteroaryl") are meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
[0031] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are generically referred to as "alkyl group substituents," and they can be one or more of a variety of groups selected from, but not limited to: -R', -OR', =0, =NR', =N-0R', -NR'R", -SR', -halogen, -SiR'R"R'", -OC(O)R', -C(O)R', -CO2R', -CONR'R",
-OC(O)NR'R", -NR"C(O)R', -NR'-C(0)NR"R"', -NR"C(O)2R',
-NR'""-C(NR'R"R'")=NR"", -NR""-C(NR'R")=NR'", -S(O)R', -S(O)2R',
-S(O)2NR5R", -NR"SO2R', -CN, -NO2, -N3, -CH(Ph)2, fiuoro(Ci-C4)alkoxy, and fluoro(Ci-C4)alkyl, in a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such radical. R', 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 arylalkyl groups. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'", R"" and R'"" groups when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, -NR 'R" is meant to include, but not be limited to, 1- pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, - C(O)CH2OCH3, and the like).
[0032] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are generically referred to as "aryl group substituents." The substituents are selected from, for example: -R', -OR', =0, =NR', =N-0R', -NR'R", -SR', -halogen, -SiR'R"R'", -OC(O)R', -C(O)R', -CO2R', -CONR'R", -0C(0)NR'R", -NR"C(O)R', -NR'-C(0)NR"R"', -NR"C(0)2R',
-NR'""-C(NR'R"R'")=NR"", -NR""-C(NR'R")=NR'", -S(O)R', -S(O)2R',
-S(O)2NR9R", -NR"S02R', -CN, -NO2, -N3, -CH(Ph)2, fiuoro(Ci-C4)alkoxy, and fluoro(Ci-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R", R'", R"" and R'"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'", R"" and R'"" groups when more than one of these groups is present.
[0033] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(0)-(CRR')q-U-, wherein T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, and 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. Alternatively, 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 -0-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R" and R'" are preferably independently selected from hydrogen or substituted or
unsubstituted (Ci-C6)alkyl.
[0034] "Ring" as used herein, means a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. A ring includes fused ring moieties. 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. Unless otherwise specified, the ring optionally includes a heteroatom. Thus, the term "5- to 7-membered ring" includes, for example phenyl, pyridinyl and piperidinyl. The term "5- to 7-membered heterocycloalkyl ring", on the other hand, would include pyridinyl and piperidinyl, but not phenyl. The term "ring" further includes a ring system comprising more than one "ring", wherein each "ring" is independently defined as above.
[0035] As used herein, the term "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).
[0036] The term "leaving group" means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include triflate, chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like. [0037] The symbol "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.
[0038] By "effective" amount of a drug, formulation, or permeant is meant a sufficient amount of an active agent to provide the desired local or systemic effect. A "Topically effective," "pharmaceutically effective," or "therapeutically effective" amount refers to the amount of drug needed to effect the desired therapeutic result. [0039] "Topically effective" refers to a material that, when applied to the skin, nail, hair, claw or hoof produces a desired pharmacological result either locally at the place of application or systemically as a result of transdermal passage of an active ingredient in the material.
[0040] The term "pharmaceutically acceptable salt" is meant to include a salt of a compound of the invention which is prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the 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 (such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d-lysine, 1-lysine), or magnesium salt, or a similar salt. When compounds of the invention contain relatively basic
functionalities, 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. Examples of 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, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are 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 et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
[0041] 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.
[0042] In addition to salt forms, the invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to provide the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment.
[0043] Certain compounds of the 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 invention. Certain compounds of the invention may exist in multiple crystalline or amorphous forms.
[0044] Certain compounds of the 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 invention. The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr, J. Chem. Ed. 1985, 62: 114-120. Solid and broken wedges are used to denote the absolute configuration of a stereocenter unless otherwise noted. When the compounds described herein contain olefmic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are included.
[0045] Compounds of the invention can exist in particular geometric or stereoisomeric forms. The invention contemplates all such compounds, including cis- and trans -isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, as falling within the scope of the invention. Additional asymmetric carbon atoms can be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
[0046] Optically active (R)- and (5)-isomers and d and / isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If, for instance, a particular enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as an amino group, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers. In addition, separation of enantiomers and diastereomers is frequently accomplished using chromatography employing chiral, stationary phases, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).
[0047] The compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). The compounds may also be labeled with stable isotopes such as deuterium. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.
[0048] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable vehicle" refers to any formulation or carrier medium that provides the appropriate delivery of an effective amount of an 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.
[0049] "Pharmaceutically acceptable topical carrier" and equivalent terms refer 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.
[0050] The term "pharmaceutically acceptable additive" refers to preservatives, antioxidants, fragrances, emulsifϊers, 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. 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.
[0051] The terms "enhancement," "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 skin, nail, hair, claw or hoof using a diffusion cell apparatus. A diffusion cell is described by Merritt et al. Diffusion Apparatus for Skin Penetration, J of Controlled Release, 1 (1984) pp. 161-162. The term "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.
[0052] The term "excipients" is conventionally known to mean carriers, diluents and/or vehicles used in formulating drug compositions effective for the desired use.
[0053] The term "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. [0054] The term "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. The stratum corneum acts as a barrier and few pharmaceutical agents are able to penetrate intact skin. In contrast, the epidermis and dermis are permeable to many solutes and 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. As used herein, transdermal delivery is intended to include delivery by permeation through or past the integument, i.e. skin, nail, hair, claw or hoof.
[0055] The terms "effective amount" or a "therapeutically effective amount" of a drug or pharmacologically active agent refers to a nontoxic but sufficient amount of the drug or agent to provide the desired effect. In the oral dosage forms of the present disclosure, an "effective amount" of one active of the combination is the amount of that active that is effective to provide the desired effect when used in combination with the other active of the combination. The amount that is "effective" will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent or agents, and the appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
[0056] The phrases "active ingredient", "therapeutic agent", "active", or "active agent" mean a chemical entity which can be effective in treating a targeted disorder, disease or condition.
[0057] The phrase "pharmaceutically acceptable" means moieties or compounds that are, within the scope of medical judgment, suitable for use in humans without causing undesirable biological effects such as undue toxicity, irritation, allergic response, and the like, for example.
[0058] The phrase "oral dosage form" means any pharmaceutical composition administered to a subject via the oral cavity. Exemplary oral dosage forms include tablets, capsules, films, powders, sachets, granules, solutions, solids, suspensions or as more than one distinct unit (e.g., granules, tablets, and/or capsules containing different actives) packaged together for co-administration, and other formulations known in the art. An oral dosage form can be one, two, three, four, five or six units. When the oral dosage form has multiple units, all of the units are contained within a single package, (e.g. a bottle or other form of packaging such as a blister pack). When the oral dosage form is a single unit, it may or may not be in a single package. In a preferred embodiment, the oral dosage form is one, two or three units. In a particularly preferred embodiment, the oral dosage form is one unit.
[0059] The phrase "unit", as used herein, refers to the number of discrete objects to be administered which comprise the dosage form. In some embodiments, the dosage form includes a compound of the invention in one capsule. This is a single unit. In some embodiments, the dosage form includes a compound of the invention as part of a therapeutically effective dosage of a cream or ointment. This is also a single unit. In some embodiments, the dosage form includes a compound of the invention and another active ingredient contained within one capsule, or as part of a therapeutically effective dosage of a cream or ointment. This is a single unit, whether or not the interior of the capsule includes multiple discrete granules of the active ingredient. In some embodiments, the dosage form includes a compound of the invention in one capsule, and the active ingredient in a second capsule. This is a two unit dosage form, such as two capsules or tablets, and so such units are contained in a single package. Thus the term 'unit' refers to the object which is administered to the animal, not to the interior components of the object.
[0060] The term, "prodrug", as defined herein, is a derivative of a parent drug molecule that exerts its pharmacological effect only after chemical and/or enzymatic conversion to its active form in vivo. Prodrugs include those designed to circumvent problems associated with delivery of the parent drug. This may be due to poor physicochemical properties, such as poor chemical stability or low aqueous solubility, and may also be due to poor pharmacokinetic properties, such as poor bioavailability or poor half- life. Thus, certain advantages of prodrugs may include improved chemical stability, absorption, and/or PK properties of the parent carboxylic acids. Prodrugs may also be used to make drugs more "patient friendly," by minimizing the frequency (e.g., once daily) or route of dosing (e.g., oral), or to improve the taste or odor if given orally, or to minimize pain if given parenterally . [0061] In some embodiments, the prodrugs are chemically more stable than the active drug, thereby improving formulation and delivery of the parent drug, compared to the drug alone.
[0062] Prodrugs for carboxylic acid analogs of the invention may include a variety of esters. In an exemplary embodiment, the pharmaceutical compositions of the invention include a carboxylic acid ester. In an exemplary embodiment, the prodrug is suitable for treatment /prevention of those diseases and conditions that require the drug molecule to cross the blood brain barrier. In an exemplary embodiment, the prodrug enters the brain, where it is converted into the active form of the drug molecule. In one embodiment, a prodrug is used to enable an active drug molecule to reach the inside of the eye after topical application of the prodrug to the eye.
Additionally, a prodrug can be converted to its parent compound by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be slowly converted to its parent compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
[0063] "Antibiotic", as used herein, is a compound which can kill or inhibit the growth of bacteria. The term antibiotic is broad enough to encompass acids, bases, salt forms (such as pharmaceutically acceptable salts), prodrugs, solvates and hydrates of the antibiotic compound.
[0064] "Antiprotozoal" or "antiprotozoa", as used herein, is a compound which can kill or inhibit the growth of protozoa. The term anti-protozoal or anti-protozoa is broad enough to encompass acids, bases, salt forms (such as pharmaceutically acceptable salts), prodrugs, solvates and hydrates of the antiprotozoal or antiprotozoa compound.
[0065] The term "microbial infection" or "infection by a microorganism" refers to any infection of a host 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 al., eds., 12th ed. 1991); Williams et al, J. of Medicinal Chem. 42:1481-1485 (1999), herein each incorporated by reference in their entirety).
[0066] "Biological medium," as used herein 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.
[0067] "Inhibiting" and "blocking," are used interchangeably herein to refer to the partial or full blockade of an enzyme, such as a beta-lactamase or a leucyl t-RNA synthetase. [0068] Boron is able to form additional covalent or dative bonds with oxygen, sulfur or nitrogen under some circumstances in this invention.
[0069] Embodiments of the invention also encompass compounds that are poly- or multi-valent species, including, for example, species such as dimers, trimers, tetramers and higher homo logs of the compounds of use in the invention or reactive analogues thereof. [0070] "Salt counterion", as used herein, refers to positively charged ions that associate with a compound of the invention when the boron is fully negatively or partially negatively charged. Examples of salt counterions include H+, H3O+, ammonium, potassium, calcium, magnesium, organic amino (such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d-lysine, 1-lysine), and sodium.
[0071] The compounds comprising a boron bonded to a carbon and three heteroatoms (such as three oxygens described in this section) can optionally contain a fully negatively charged boron or partially negatively charged boron. Due to the negative charge, a positively charged counterion may associate with this compound, thus forming a salt. Examples of positively charged counterions include H+, H3O+, ammonium, potassium, calcium, magnesium, organic amino (such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d-lysine, 1-lysine), and sodium. These salts of the compounds are implicitly contained in descriptions of these compounds.
//. Introduction
[0072] The invention provides novel boron compounds. The novel compounds, as well as pharmaceutical compositions containing such compounds or combinations of these compounds with at least one additional therapeutically effective agent, can be used for, among other things, treating protozoal infections.
///. The Compounds
III. a) Cyclic Boronic Esters
[0073] In one aspect, the invention provides a compound of the invention. In an exemplary embodiment, the invention is a compound described herein. In an exemplary embodiment, the invention is a compound according to a formula described herein.
[0074] In another aspect, the invention provides a compound having a structure according to the following formula:
Figure imgf000019_0001
wherein Z is S or O; X is selected from the group consisting of substituted phenyl, substituted or unsubstituted heteroaryl, and unsubstituted cycloalkyl, or a salt thereof. [0075] In an exemplary embodiment, the compound has a structure according to the following formula:
Figure imgf000020_0001
wherein X is phenyl or heteroaryl, in which one substituent on said phenyl or said heteroaryl is halogen or cyano or nitro or unsubstituted Ci or C2 or C3 or C4 or C5 or Ce alkyl or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkylthio or unsubstituted phenyl or NR8R9 or -SO2(R7) or -SO2N(R7)(R8), wherein R7 is H or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl; R8 is H or unsubstituted Ci or C2 or C3 or C4 or C5 or Ce alkyl; and R9 is selected from the group consisting of H, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and -C(O)R10, wherein R10 is unsubstituted Ci or C2 or C3 or C4 or C 5 or C6 alkyl.
[0076] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
wherein Z is as described here
Figure imgf000020_0002
and R6 are selected from the group consisting of the following table, or a salt thereof.
Figure imgf000020_0003
Figure imgf000021_0002
In an exemplary embodiment, for any of the entries in the above table, Z is O. In an exemplary embodiment, for any of the entries in the above table, Z is S.
[0077] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000021_0001
wherein Z is as described herein, and R2, R3, R4, R5 and R6 are selected from the group consisting of the following table, or a salt thereof.
Figure imgf000021_0003
wherein Y1 is Ci-C6 unsubstituted alkyl. In an exemplary embodiment, for any of the entries in the above table, Y1 is methyl. In an exemplary embodiment, for any of the entries in the above table, Y1 is ethyl. In an exemplary embodiment, for any of the entries in the above table, Y1 is unsubstituted C3 alkyl. In an exemplary embodiment, for any of the entries in the above table, Y1 is isopropyl. In an exemplary embodiment, for any of the entries in the above table, Y1 is unsubstituted C4 alkyl. In an exemplary embodiment, for any of the entries in the above table, Y1 is t-butyl. In an exemplary embodiment, for any of the entries in the above table, Y1 is
unsubstituted C5 alkyl. In an exemplary embodiment, for any of the entries in the above table, Y1 is unsubstituted C6 alkyl. In an exemplary embodiment, for any of the entries in the above table, Z is O. In an exemplary embodiment, for any of the entries in the above table, Z is S.
[0078] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000022_0001
wherein Z is as described herein, and R2, R3, R4, R5 and R6 are selected from the group consisting of the following table, or a salt thereof.
Figure imgf000022_0002
wherein Y is unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y2 is unsubstituted Ci alkoxy. In an exemplary
embodiment, for any of the entries in the above table, Y2 is unsubstituted C2 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y2 is unsubstituted C3 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y2 is n-propoxy. In an exemplary embodiment, for any of the entries in the above table, Y2 is isopropoxy. In an exemplary embodiment, for any of the entries in the above table, Y2 is unsubstituted C4 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y2 is unsubstituted C5 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y2 is unsubstituted C6 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Z is O. In an exemplary embodiment, for any of the entries in the above table, Z is S. [0079] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
wherein Z is as described here
Figure imgf000023_0001
and R6 are selected from the group consisting of the following table, or a salt thereof.
Figure imgf000023_0003
wherein Y3 is halosubstituted alkyl. In an exemplary embodiment, for any of the entries in the above table, Y is halosubstituted Ci alkyl. In an exemplary
embodiment, for any of the entries in the above table, Y is halosubstituted C2 alkyl. In an exemplary embodiment, for any of the entries in the above table, Y is halosubstituted C3 alkyl. In an exemplary embodiment, for any of the entries in the above table, Y3 is halosubstituted C4 alkyl. In an exemplary embodiment, for any of the entries in the above table, Y3 is halosubstituted C5 alkyl. In an exemplary embodiment, for any of the entries in the above table, Y3 is halosubstituted C6 alkyl. In an exemplary embodiment, for any of the entries in the above table, Y3 is fluorosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl. In an exemplary
embodiment, for any of the entries in the above table, Y is alkyl substituted with one or two or three halogens. In an exemplary embodiment, for any of the entries in the above table, Y3 is trifluorosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl. In an exemplary embodiment, for any of the entries in the above table, Y is
trifluoromethyl. In an exemplary embodiment, for any of the entries in the above table, Z is O. In an exemplary embodiment, for any of the entries in the above table, Z is S.
[0080] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000023_0002
wherein Z is as described herein, and R2, R3, R4, R5 and R6 are selected from the group consisting of the following table, or a salt thereof.
Figure imgf000024_0002
wherein Y is halosubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y4 is halosubstituted Ci alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y4 is halosubstituted C2 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y4 is halosubstituted C3 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y4 is halosubstituted C4 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y4 is halosubstituted C5 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y4 is halosubstituted C6 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y4 is fluorosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy. In an exemplary
embodiment, for any of the entries in the above table, Y4 is alkoxy substituted with one or two or three halogens. In an exemplary embodiment, for any of the entries in the above table, Y4 is trifluoro-substituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y4 is
trifluoromethoxy. In an exemplary embodiment, for any of the entries in the above table, Z is O. In an exemplary embodiment, for any of the entries in the above table, Z is S. [0081] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
wherein Z is as described here
Figure imgf000024_0001
and R6 are selected from the group consisting of the following table, or a salt thereof.
Figure imgf000024_0003
Figure imgf000025_0002
wherein Y is halosubstituted alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y5 is halosubstituted Ci alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y5 is halosubstituted C2 alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y5 is halosubstituted C3 alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y5 is halosubstituted C4 alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y5 is halosubstituted C5 alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y5 is halosubstituted C6 alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y5 is fluoro-substituted Ci or C2 or C3 or C4 or C5 or C6 alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y5 is alkylthio substituted with one or two or three halogens. In an exemplary embodiment, for any of the entries in the above table, Y5 is trifluoro-substituted Ci or C2 or C3 or C4 or C5 or C6 alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y5 is trifluoromethylthio. In an exemplary embodiment, for any of the entries in the above table, Z is O. In an exemplary embodiment, for any of the entries in the above table, Z is S.
[0082] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
wherein Z is as described here
Figure imgf000025_0001
and R6 are selected from the group consisting of the following table, or a salt thereof.
Figure imgf000025_0003
wherein R8 is H or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and R9 is H or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or C(O)R10, wherein R10 is unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl. In an exemplary embodiment, for any of the entries in the above table, R8 is unsubstituted Ci or C2 or C3 or C4 or C5 or Ce alkyl and R9 is unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl. In an exemplary embodiment, for any of the entries in the above table, R8 is methyl and R9 is unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl. In an exemplary embodiment, for any of the entries in the above table, R8 is methyl and R9 is methyl. In an exemplary embodiment, for any of the entries in the above table, R8 is H. In an exemplary embodiment, for any of the entries in the above table, R9 is H. In an exemplary embodiment, for any of the entries in the above table, R8 is H and R9 is H. In an exemplary embodiment, for any of the entries in the above table, R8 is H and R9 is -C(O)R10. In an exemplary embodiment, for any of the entries in the above table, R8 is H and R9 is -C(O)CH3. In an exemplary embodiment, for any of the entries in the above table, Z is O. In an exemplary embodiment, for any of the entries in the above table, Z is S.
[0083] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
wherein Z is as described here
Figure imgf000026_0001
R5 and R6 are selected from the group consisting of the following table, or a salt thereof.
Figure imgf000026_0002
wherein R7 is unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl. In an exemplary embodiment, for any of the entries in the above table, R7 is methyl. In an exemplary embodiment, for any of the entries in the above table, R7 is ethyl. In an exemplary embodiment, for any of the entries in the above table, R7 is unsubstituted C3 alkyl. In an exemplary embodiment, for any of the entries in the above table, R7 is
unsubstituted C4 alkyl. In an exemplary embodiment, for any of the entries in the above table, R7 is unsubstituted C5 alkyl. In an exemplary embodiment, for any of the entries in the above table, R7 is unsubstituted C6 alkyl. In an exemplary embodiment, for any of the entries in the above table, Z is O. In an exemplary embodiment, for any of the entries in the above table, Z is S.
[0084] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
wherein Z is as described here
Figure imgf000027_0001
and R6 are selected from the group consisting of the following table, or a salt thereof.
Figure imgf000027_0003
wherein R7 is H or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and R8 is H or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl. In an exemplary embodiment, for any of the entries in the above table, R7 is unsubstituted Ci or C2 or C3 or C4 or C5 or Ce alkyl and R8 is unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl. In an exemplary embodiment, for any of the entries in the above table, R7 is methyl and R8 is unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl. In an exemplary embodiment, for any of the entries in the above table, R7 is methyl and R8 is methyl. In an exemplary embodiment, for any of the entries in the above table, R7 is H. In an exemplary embodiment, for any of the entries in the above table, R8 is H. In an exemplary embodiment, for any of the entries in the above table, R7 is H and R8 is H. In an exemplary embodiment, for any of the entries in the above table, Z is O. In an exemplary embodiment, for any of the entries in the above table, Z is S. [0085] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
wherein Z is as described here
Figure imgf000027_0002
and R6 are selected from the group consisting of the following table, or a salt thereof.
Figure imgf000028_0001
In an exemplary embodiment, for any of the entries in the above table, Z is O. In an exemplary embodiment, for any of the entries in the above table, Z is S.
[0086] In an exemplary embodiment, the compound has a structure according to the following formula:
wherein Z is as described here
Figure imgf000029_0001
and R6 are selected from the group consisting of the following table, or a salt thereof.
Figure imgf000029_0002
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0004
[0087] In an exemplary embodiment, the compound of the invention has a structure which is selected from the group consisting of:
Figure imgf000034_0001
are as described herein.
[0088] In an exemplary embodiment, the compound of the invention has a structure which is selected from the group consisting of:
wherein
Figure imgf000034_0002
[0089] In an exemplary embodiment, the compound of the invention has a structure which is selected from the group consisting of:
Figure imgf000034_0003
wherein R , R , R , R and R are as described herein. [0090] In an exemplary embodiment, the compound of the invention has a structure which is selected from the group consisting of:
wherein R2,
Figure imgf000035_0001
[0091] In an exemplary embodiment, the compound of the invention has a structure which is:
Figure imgf000035_0002
thereof.
[0092] In an exemplary embodiment, the compound of the invention has a structure which is
Figure imgf000035_0003
wherein Z5 is unsubstituted pyrimidinyl or unsubstituted pyrazinyl or unsubstituted pyridazinyl, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:
Figure imgf000035_0004
or a salt thereof.
[0093] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000035_0005
wherein Z6 is halosubstituted pyridazinyl, or a salt thereof. In an exemplary embodiment, Z6 is pyridazinyl, substituted with one halogen. In an exemplary embodiment, Z6 is pyridazinyl, substituted with two halogens. In an exemplary embodiment, Z6 is pyridazinyl, substituted with two chlorines. In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000036_0001
wherein each R , 14 is chlorine or fluorine, or a salt thereof. In an exemplary embodiment, each R 14 is chlorine.
[0094] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000036_0002
wherein each R13 are the same or different and are each selected from H or -SH or - OH, or a salt thereof. In an exemplary embodiment, each R13 are the same or different and are each selected from -SH or -OH. [0095] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000036_0003
wherein Z is thiophenyl, or a salt thereof. In an exemplary embodiment, the compound of the invention is:
Figure imgf000036_0004
or a salt thereof.
[0096] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000036_0005
wherein Z1 is unsubstituted alkylthiophenyl, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:
Figure imgf000037_0001
wherein R15 is unsubstituted alkyl, or a salt thereof. In an exemplary embodiment, R15 is unsubstituted Ci alkyl. In an exemplary embodiment, R15 is unsubstituted C2 alkyl. In an exemplary embodiment, R15 is unsubstituted C3 alkyl. In an exemplary embodiment, R15 is unsubstituted C4 alkyl. In an exemplary embodiment, R15 is unsubstituted C5 alkyl. In an exemplary embodiment, R15 is unsubstituted C6 alkyl.
[0097] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000037_0002
wherein Z2 is unsubstituted benzothiophenyl, or a salt thereof.
[0098] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000037_0003
wherein Z2 is halosubstituted benzothiophenyl, or a salt thereof. In an exemplary embodiment, Z2 is benzothiophenyl substituted with chloro. In an exemplary embodiment, Z2 is benzothiophenyl substituted with fluoro. In an exemplary embodiment, Z2 is benzothiophenyl substituted with one halogen. In an exemplary embodiment, Z2 is benzothiophenyl substituted with two halogens. In an exemplary embodiment, Z2 is benzothiophenyl substituted with two fluorines. In an exemplary embodiment, Z2 is benzothiophenyl substituted with two chlorines. In an exemplary embodiment, Z2 is benzothiophenyl substituted with a fluorine and a chlorine. In an exemplary embodiment, the compound of the invention has a structure which is:
Figure imgf000037_0004
wherein R16 is halogen, R17 is halogen, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000037_0005
wherein each R16 and R17 are the same or different and are each selected from the group consisting of F, Cl, Br, and I, or a salt thereof.
[0099] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000038_0001
wherein Z is unsubstituted oxazolyl, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:
Figure imgf000038_0002
or or a salt thereof.
[0100] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000038_0003
wherein Z is unsubstituted alkyl oxazolyl, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:
Figure imgf000038_0004
wherein R , 18 is unsubstituted alkyl, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000038_0005
wherein R18 is unsubstituted alkyl, or a salt thereof. In an exemplary embodiment, R18 is Ci or C2 or C3 or C4 or C5 or C6 alkyl.
[0101] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000038_0006
wherein Z3 is unsubstituted isoxazolyl, or a salt thereof. In an exemplary
embodiment, the compound of the invention is:
Figure imgf000038_0007
or a salt thereof. [0102] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000039_0001
wherein Z3 is unsubstituted alkyl isoxazolyl, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:
Figure imgf000039_0002
wherein R19 is unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000039_0003
wherein R19 is unsubstituted alkyl, or a salt thereof. In an exemplary embodiment,
R19 is unsubstituted Ci alkyl. In an exemplary embodiment, R19 is unsubstituted C2 alkyl. In an exemplary embodiment, R19 is unsubstituted C3 alkyl. In an exemplary embodiment, R19 is unsubstituted C4 alkyl. In an exemplary embodiment, R19 is unsubstituted C5 alkyl. In an exemplary embodiment, R19 is unsubstituted C6 alkyl.
[0103] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000039_0004
wherein Z3 is unsubstituted thiazolyl, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:
Figure imgf000039_0005
or a salt thereof.
[0104] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000039_0006
wherein Z is unsubstituted alkyl thiazolyl, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:
Figure imgf000040_0001
wherein R20 is unsubstituted alkyl, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:
Figure imgf000040_0002
is unsubstituted alkyl, or a salt thereof. In an exemplary embodiment, R20 is Ci or C2 or C3 or C4 or C5 or C6 alkyl.
[0105] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000040_0003
wherein Z3 is unsubstituted pyrazolyl, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:
Figure imgf000040_0004
or a salt thereof.
[0106] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
3
Figure imgf000040_0005
wherein Z is unsubstituted alkyl pyrrolyl or unsubstituted phenyl pyrrolyl or unsubstituted phenyl (unsubstituted alkyl) pyrrolyl, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000040_0006
wherein each R21 are the same or different and are each selected from unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or phenyl, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:
Figure imgf000041_0001
or wherein each R .2Z11 are the same or different and are each selected from unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or phenyl, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:
Figure imgf000041_0002
or or a salt thereof. In an exemplary embodiment, each R21 is unsubstituted Ci alkyl. In an exemplary embodiment, R21 is unsubstituted C2 alkyl. In an exemplary embodiment, R21 is unsubstituted C3 alkyl. In an exemplary embodiment, R21 is unsubstituted C4 alkyl. In an exemplary embodiment, R21 is unsubstituted C5 alkyl. In an exemplary embodiment, R21 is unsubstituted C6 alkyl. In an exemplary embodiment, R21 is unsubstituted phenyl. In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000041_0003
wherein R , 21 is as described herein, or a salt thereof.
[0107] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000041_0004
wherein Z3 is unsubstituted furanyl, or a salt thereof. In an exemplary embodiment, the compound is:
Figure imgf000041_0005
or a salt thereof. [0108] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000042_0001
wherein Z3 is unsubstituted alkylfuranyl, or a salt thereof. In an exemplary embodiment, the compound of the invention is:
Figure imgf000042_0002
wherein Y7 is unsubstituted alkyl, or a salt thereof. In an exemplary embodiment, Y7 is unsubstituted Ci alkyl. In an exemplary embodiment, Y7 is unsubstituted C2 alkyl. In an exemplary embodiment, Y7 is unsubstituted C3 alkyl. In an exemplary embodiment, Y7 is unsubstituted C4 alkyl. In an exemplary embodiment, Y7 is unsubstituted C5 alkyl. In an exemplary embodiment, Y7 is unsubstituted C6 alkyl.
[0109] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000042_0003
wherein Z3 is unsubstituted pyrrole, or a salt thereof. In an exemplary embodiment, the compound is:
Figure imgf000042_0004
or a salt thereof.
[0110] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000042_0005
wherein Z3 is unsubstituted alkyl pyrrole, or a salt thereof. In an exemplary embodiment, the compound is:
Figure imgf000042_0006
salt thereof. In an exemplary embodiment, the compound is:
Figure imgf000043_0001
wherein R22 is unsubstituted alkyl, or a salt thereof. In an exemplary embodiment, R22 is unsubstituted Ci alkyl. In an exemplary embodiment, R22 is unsubstituted C2 alkyl. In an exemplary embodiment, R22 is unsubstituted C3 alkyl. In an exemplary embodiment, R22 is unsubstituted C4 alkyl. In an exemplary embodiment, R22 is unsubstituted C5 alkyl. In an exemplary embodiment, R22 is unsubstituted C6 alkyl.
[0111] In an exemplary embodiment, the compound of the invention has a structure which is:
Figure imgf000043_0002
or a salt thereof.
[0112] In an exemplary embodiment, the compound of the invention has a structure which is:
Figure imgf000043_0003
or a salt thereof.
[0113] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000043_0004
wherein Z9 is unsubstituted alkyl, or a salt thereof. In an exemplary embodiment, Z9 is unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl. In an exemplary embodiment, Z9 is methyl. In an exemplary embodiment, Z9 is unsubstituted C4 alkyl. In an exemplary embodiment, Z9 is n-butyl or sec-butyl or isobutyl or tert-butyl. In an exemplary embodiment, Z9 is tert-butyl. [0114] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000044_0001
wherein R15 is unsubstituted alkyl, R16 is H or phenyl substituted alkyl, or a salt thereof. In an exemplary embodiment, R15 is unsubstituted Ci or C2 or C3 or C4 or C5 or Ce alkyl. In an exemplary embodiment, R15 is unsubstituted C3 alkyl. In an exemplary embodiment, R16 is benzyl. In an exemplary embodiment, R16 is H.
[0115] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:
Figure imgf000044_0002
wherein Z10 is hydroxy-substituted alkyl, or a salt thereof. In an exemplary embodiment, Z10 is hydroxysubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl.
[0116] In an exemplary embodiment, the compound of the invention has a
structure which is selected from the group consisting of
Figure imgf000044_0003
Figure imgf000044_0004
[0117] In an exemplary embodiment, the compound of the invention has a
structure which is
Figure imgf000044_0005
; wherein Ra is unsubstituted alkyl. In an exemplary embodiment, Ra is unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl. In an exemplary embodiment, Ra is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl and hexyl.
[0118] In an exemplary embodiment, the compound of the invention has a
structure which is
Figure imgf000044_0006
; wherein Ra is unsubstituted alkyl. In an exemplary embodiment, Ra is unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl. In an exemplary embodiment, Ra is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl and hexyl.
[0119] In an exemplary embodiment, a compound of the invention essentially does not inhibit a cytochrome P450 enzyme. In an exemplary embodiment, a compound of the invention does not inhibit a cytochrome P450 enzyme. In an exemplary embodiment, the cytochrome P450 enzyme is a member selected from CP1A2, 2C9, 2D6 and 3A4. In an exemplary embodiment, the cytochrome P450 enzyme is
CYP2C19.
[0120] In an exemplary embodiment, a compound of the invention is essentially not a substrate for the P-gp transporter. In an exemplary embodiment, a compound of the invention is not a substrate for the P-gp transporter.
[0121] In an exemplary embodiment, the invention provides a compound described herein, or a salt, hydrate or solvate thereof, or a combination thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt, hydrate or solvate thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt thereof. In an exemplary embodiment, the salt is a pharmaceutically acceptable salt. In an exemplary embodiment, the invention provides a compound described herein, or a hydrate thereof. In an exemplary embodiment, the invention provides a compound described herein, or a solvate thereof. In an exemplary embodiment, the invention provides a compound described herein, or a prodrug thereof. In an exemplary embodiment, the invention provides a salt of a compound described herein. In an exemplary embodiment, the invention provides a pharmaceutically acceptable salt of a compound described herein. In an exemplary embodiment, the invention provides a hydrate of a compound described herein. In an exemplary embodiment, the invention provides a solvate of a compound described herein. In an exemplary embodiment, the invention provides a prodrug of a compound described herein.
[0122] In an exemplary embodiment, alkyl is linear alkyl. In another exemplary embodiment, alkyl is branched alkyl. [0123] In an exemplary embodiment, heteroalkyl is linear heteroalkyl. In another exemplary embodiment, heteroalkyl is branched heteroalkyl. HLb) Compositions involving stereoisomers
[0124] As used herein, the term "chiral", "enantiomerically enriched" or
"diastereomerically enriched" refers to a composition having an enantiomeric excess (ee) or a diastereomeric excess (de) of greater than about 50%, preferably greater than about 70% and more preferably greater than about 90%. In general, higher than about 90% enantiomeric or diastereomeric excess is particularly preferred, e.g., those compositions with greater than about 95%, greater than about 97% and greater than about 99% ee or de.
[0125] When a first compound and a second compound are present in a composition, and the first compound is a non-superimposable mirror image of the second compound, and the first compound is present in the composition in a greater amount than the second compound, then the first compound is referred to herein as being present in "enantiomeric excess".
[0126] The term "enantiomeric excess" of a compound z, as used herein, is defined as: ee, = { ycCoOnncC.- o °ff z Z + ' C c°onnCe-, ° off A y) x WO wherein z is a first compound in a composition, y is a second compound in the composition, and the first compound is a non-superimposable mirror image of the second compound.
[0127] The term "enantiomeric excess" is related to the older term "optical purity" in that both are measures of the same phenomenon. The value of ee will be a number from 0 to 100, zero being racemic and 100 being enantiomerically pure. A composition which in the past might have been called 98% optically pure is now more precisely characterized by 96% ee. A 90% ee reflects the presence of 95% of one enantiomer and 5% of the other(s) in the material in question.
[0128] When a first compound and at least one additional compound are present in a composition, and the first compound and each of the additional compounds are stereoisomers, but not mirror images, of one another, and the first compound is present in the composition in a greater amount than each of the additional
compounds, then the first compound is referred to herein as being present in
"diastereomeric excess". [0129] When dealing with mixtures of diastereomers, the term "diastereomeric excess" or "de" is defined analagously to enantiomeric excess. Thus:
( cone, of major diastereomer - cone, of minor diastereomer (s) \ , _ _ dew = : — : — x 100
\conc. of major diastereomer + cone, of nun or diastereomer \s) J wherein the major diastereomer is a first compound in a composition, and the minor diastereomer(s) is at least one additional compound in the composition, and the major diastereomer and minor diastereomer(s) are stereoisomers, but not mirror images, of one another.
[0130] The value of de will likewise be a number from 0 to 100, zero being an equal mixture of a first diastereomer and the remaining diastereomer(s), and 100 being 100% of a single diastereomer and zero% of the other(s) - i.e.
diastereomerically pure. Thus, 90% de reflects the presence of 95% of one diastereomer and 5% of the other diastereomer(s) in the material in question.
[0131] Hence, in one embodiment, the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has at least one stereocenter, and at least one stereoisomer of the first compound of the invention. In another embodiment, the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has at least one stereocenter, and a second compound of the invention, wherein the first compound of the invention is a stereoisomer of the second compound of the invention. In another embodiment, the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has at least one stereocenter, and only one stereoisomer of the first compound of the invention.
[0132] In another embodiment, the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has only one stereocenter, and an enantiomer of the first compound of the invention. In another embodiment, the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has two stereocenters, and an enantiomer of the first compound of the invention. In another embodiment, the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has two stereocenters, and at least one diastereomer of the first compound of the invention. In another embodiment, the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has two stereocenters, and only one diastereomer of the first compound of the invention.
[0133] In situations where the first compound of the invention and its enantiomer are present in a composition, the first compound of the invention can be present in an enantiomeric excess of at least about 80%, or at least about 90%, or at least about 92% or at least about 95%. In another embodiment, where the first compound of the invention and its enantiomer are present in a composition, the first compound of the invention can be present in an enantiomeric excess of at least about 96%, at least about 97%, at least about 98%, at least about 99% or at least about 99.5%. In another embodiment, the first compound of the invention has at least one stereocenter and is enantiomerically pure (enantiomeric excess is about 100%).
[0134] In situations where the first compound of the invention and at least one diastereomer of the first compound of the invention are present in a composition, the first compound of the invention can be present in a diastereomeric excess of at least about 80%, or at least about 90%, or at least about 92% or at least about 95%. In situations where the first compound of the invention and at least one diastereomer of the first compound of the invention are present in a composition, the first compound of the invention can be present in a diastereomeric excess of at least about 96%, at least about 97%, at least about 98%, at least about 99% or at least about 99.5%. In another embodiment, the first compound of the invention has at least two
stereocenters and is diastereomerically pure (diastereomeric excess is about 100%).
[0135] Enantiomeric or diastereomeric excess can be determined relative to exactly one other stereoisomer, or can be determined relative to the sum of at least two other stereoisomers. In an exemplary embodiment, enantiomeric or
diastereomeric excess is determined relative to all other detectable stereoisomers, which are present in the mixture. Stereoisomers are detectable if a concentration of such stereoisomer in the analyzed mixture can be determined using common analytical methods, such as chiral HPLC.
[0136] As used herein, and unless otherwise indicated, a composition that is
"substantially free" of a compound means that the composition contains less than about 20% by weight, or less than about 15% by weight, or less than about 10% by weight, or less than about 5% by weight, or less than about 3% by weight, or less than about 2% by weight, or less than about 1% by weight of the compound.
[0137] As used herein, the term "substantially free of the (or its) enantiomer" means that a composition contains a significantly greater proportion of a first compound of the invention than a second compound of the invention, wherein the first compound is a non-superimposable mirror image of the second compound. In one embodiment of the invention, the term "substantially free of the enantiomer" means that the composition is made up of at least about 90% by weight of a first compound of the invention, and about 10% by weight or less of a second compound of the invention, wherein the first compound is a non-superimposable mirror image of the second compound. In one embodiment of the invention, the term "substantially free of the (R) enantiomer" means that the composition is made up of at least about 90% by weight of a first compound of the invention which has only one stereocenter and the stereocenter is in an (S) configuration, and about 10% by weight or less of a second compound of the invention, wherein the second compound is the enantiomer of the first compound. In one embodiment of the invention, the term "substantially free of the enantiomer" means that the composition is made up of at least about 95% by weight of a first compound of the invention, and about 5% by weight or less of a second compound of the invention, wherein the first compound is a non- superimposable mirror image of the second compound. In one embodiment of the invention, the term "substantially free of the (R) enantiomer" means that the composition is made up of at least about 95% by weight of a first compound of the invention which has only one stereocenter and the stereocenter is in an (S) configuration, and about 5% by weight or less of a second compound of the invention, wherein the second compound is the enantiomer of the first compound. In one embodiment of the invention, the term "substantially free of the enantiomer" means that the composition is made up of at least about 98% by weight of a first compound of the invention, and about 2% by weight or less of a second compound of the invention, wherein the first compound is a non-superimposable mirror image of the second compound. In one embodiment of the invention, the term "substantially free of the (R) enantiomer" means that the composition is made up of at least about 98% by weight of a first compound of the invention which has only one stereocenter and the stereocenter is in an (S) configuration, and about 2% by weight or less of a second compound of the invention, wherein the second compound is the enantiomer of the first compound. In one embodiment of the invention, the term "substantially free of the enantiomer" means that the composition is made up of at least about 99% by weight of a first compound of the invention, and about 1% by weight or less of a second compound of the invention, wherein the first compound is a non- superimposable mirror image of the second compound. In one embodiment of the invention, the term "substantially free of the (R) enantiomer" means that the composition is made up of at least about 99% by weight of a first compound of the invention which has only one stereocenter and the stereocenter is in an (S) configuration, and about 1% by weight or less of a second compound of the invention, wherein the second compound is the enantiomer of the first compound.
[0138] In an exemplary embodiment, the invention provides a composition comprising a) first compound described herein ; and b) the enantiomer of the first compound, wherein the first compound described herein is present in an enantiomeric excess of at least 80%. In an exemplary embodiment, the enantiomeric excess is at least 92%.
II Lb) Combinations comprising additional therapeutic agents
[0139] The compounds of the invention may also be used in combination with additional therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound described herein or a pharmaceutically acceptable salt thereof together with at least one additional therapeutic agent. In an exemplary embodiment, the additional therapeutic agent is a compound of the invention. In an exemplary embodiment, the additional therapeutic agent includes a boron atom. In an exemplary embodiment, the additional therapeutic agent does not contain a boron atom.
[0140] When a compound of the invention is used in combination with a second therapeutic agent active against the same disease state, the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In an exemplary embodiment, the additional therapeutic agent is berenil. In an exemplary
embodiment, the additional therapeutic agent is diminazene. In an exemplary embodiment, the additional therapeutic agent is an antiprotozoa. In an exemplary embodiment, the additional therapeutic agent is selected from the group consisting of benznidazole, buparvaquone, carbarsone, clioquinol, disulfϊram, eflornithine, emetine, etofamide, furazolidone, meglumine antimoniate, melarsoprol, metronidazole, miltefosine, nifurtimox, nimorazole, nitazoxanide, ornidazole, paromomycin sulfate, pentamidine, pyrimethamine, secnidazole and tinidazole. In an exemplary
embodiment, the additional therapeutic agent is pentamidine. In an exemplary embodiment, the additional therapeutic agent is suramin. In an exemplary
embodiment, the additional therapeutic agent is eflornithine. In an exemplary embodiment, the additional therapeutic agent is melarsoprol. In an exemplary embodiment, the additional therapeutic agent is nifurtimox. In an exemplary embodiment, the additional therapeutic agent contains a 5-nitrofuran moiety. In an exemplary embodiment, the additional therapeutic agent contains a 5-nitroimidazolyl moiety. In an exemplary embodiment, the additional therapeutic agent is
fexinidazole. In an exemplary embodiment, the additional therapeutic agent is an antiparasitic. In an exemplary embodiment, the additional therapeutic agent is selected from the group consisting of amitraz, avermectin, carbadox,
diethylcarbamazine, dimetridazole, diminazene, ivermectin, macrofilaricide, malathion, mitaban, organophosphate, oxamniquine, permethrin, praziquantel, pyrantel pamoate, selamectin, sodium stibogluconate and thiabendazole. In an exemplary embodiment, the additional therapeutic agent is selected from the group consisting of antimony, meglumine antimoniate, sodium stibogluconate,
amphotericin, miltefosine and paromomycin.
[0141] The compounds of the invention, or pharmaceutical formulations thereof may also be used in combination with other therapeutic agents, for example immune therapies [e.g. interferon, such as interferon alfa-2a (ROFERONd)-A; Hoffmann-La Roche), interferon alpha-2b (INTRONd)-A; Schering-Plough), interferon alfacon-1 (INFERGEN®; Intermune), peginterferon alpha-2b (PEGINTRON™; Schering- Plough) or peginterferon alpha-2a (PEGASYSd); Hoffmann-La Roche)], therapeutic vaccines, antifibrotic agents, anti-inflammatory agents [such as corticosteroids or NSAIDs], bronchodilators [such as beta-2 adrenergic agonists and xanthines (e.g. theophylline)], mucolytic agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion [e.g. ICAM antagonists], anti-oxidants [e.g. N-acetylcysteine], cytokine agonists, cytokine antagonists, lung surfactants and/or antimicrobial. The
compositions according to the invention may also be used in combination with gene replacement therapy.
[0142] The individual components of such combinations may be administered either simultaneously or sequentially in a unit dosage form. The unit dosage form may be a single or multiple unit dosage forms. In an exemplary embodiment, the invention provides a combination in a single unit dosage form. An example of a single unit dosage form is a capsule wherein both the compound of the invention and the additional therapeutic agent are contained within the same capsule. In an exemplary embodiment, the invention provides a combination in a two unit dosage form. An example of a two unit dosage form is a first capsule which contains the compound of the invention and a second capsule which contains the additional therapeutic agent. Thus the term 'single unit' or 'two unit' or 'multiple unit' refers to the object which the patient ingests, not to the interior components of the object. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.
[0143] The combinations referred to herein may conveniently be presented for use in the form of a pharmaceutical formulation. Thus, an exemplary embodiment of the invention is a pharmaceutical formulation comprising a) a compound of the invention; b) an additional therapeutic agent and c) a pharmaceutically acceptable excipient. In an exemplary embodiment, the pharmaceutical formulation is a unit dosage form. In an exemplary embodiment, the pharmaceutical formulation is a single unit dosage form. In an exemplary embodiment, the pharmaceutical formulation is a two unit dosage form. In an exemplary embodiment, the pharmaceutical formulation is a two unit dosage form comprising a first unit dosage form and a second unit dosage form, wherein the first unit dosage form includes a) a compound of the invention and b) a first pharmaceutically acceptable excipient; and the second unit dosage form includes c) an additional therapeutic agent and d) a second pharmaceutically acceptable excipient. [0144] It is to be understood that the invention covers all combinations of aspects and/or embodiments, as well as suitable, convenient and preferred groups described herein.
HLc) Preparation of Boron-Containing Compounds
[0145] Compounds of use in the invention can be prepared using commercially available starting materials, known intermediates, or by using the synthetic methods described herein, or published in references described and incorporated by reference herein, such as PCT Pub. No. WO2008157726 and U.S. Pat. Pubs. US20060234981, US20070155699 and US20070293457.
[0146] In one embodiment, the compound of the invention can be synthesized according to the following scheme:
Addition
X- Conditions
Figure imgf000053_0001
Figure imgf000053_0002
wherein B is commercially available from, for example, Combi-Blocks (San Diego, CA, USA) and A is commercially available from, for example, Sigma- Aldrich (St. Louis, MO, USA). A and B can be contacted under addition conditions stirred for an appropriate period of time at an appropriate temperature to form the product.
[0147] In an alternative embodiment, the compound of the invention can be synthesized according to the following scheme:
Figure imgf000053_0003
wherein B is commercially available from, for example, Combi-Blocks (San Diego,
CA, USA) and D and F are commercially available from, for example, Sigma- Aldrich (St. Louis, MO, USA). B and D can be contacted under addition conditions stirred for an appropriate period of time at an appropriate temperature to form the activated intermediate E, which is may or may not be isolated. Intermediate E can be contacted with F under appropriate conditions, stirred for an appropriate period of time at an appropriate temperature to form the product. [0148] In an embodiment, the compound of the invention can be synthesized according to the following scheme:
Figure imgf000054_0001
wherein Ra is as described herein, k conditions are K2CO3, DMF; 1 conditions are bis(pinacol-diboron), PdCl2(dppf)2, KOAc, dioxane; m conditions are NaBH4, MeOH; n conditions are aq. HCl; p conditions are PhCOCl, Et3N, CH2Cl2.
[0149] Compounds described herein can be converted into hydrates and solvates by methods similar to those described herein. IV. Methods of Inhibiting Microorganism Growth or Killing Microorganisms
[0150] The compounds of the invention exhibit potency against microorganisms, such as protozoa, and therefore have the potential to kill and/or inhibit the growth of microorganisms .
[0151] In a further aspect, the invention provides a method of killing and/or inhibiting the growth of a microorganism, said method comprising: contacting said microorganism with an effective amount of a compound of the invention, thereby killing and/or inhibiting the growth of the microorganism. In an exemplary embodiment, the microorganism is a protozoa. In an exemplary embodiment, the microorganism is a kinetoplastid. In another exemplary embodiment, the protozoa is a Trypanosoma. In an exemplary embodiment, the Trypanosoma is a member selected from T. avium, T boissoni, T brucei, T carassii, T cruzi, T congolense, T equinum, T equiperdum, T evansi, T hosei, T levisi, T melophagium, T parroti, T percae, T rangeli, T rotatorium, T. rugosae, T sergenti, T simiae, T sinipercae, T suis, T theileri, T triglae and T. vivax. In another exemplary embodiment, the protozoa is a Trypanosoma brucei. In another exemplary embodiment, the protozoa is a member selected from Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. In another exemplary embodiment, the protozoa is a member selected from Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. In another exemplary embodiment, the protozoa is Trypanosoma cruzi. In another exemplary embodiment, the protozoa is a member of the genus Leishmania. In another exemplary embodiment, the protozoa is a member of Leishmania Viannia. In an exemplary embodiment, the protozoa is a member selected from L. donovani, L. infantum, L. chagasi; L. mexicana, L. amazonensis, L. venezuelensis, L. tropica, L. major, L. aethiopica, L. (V.) braziliensis, L. (V.) guyanensis, L. (V.) panamensis, and L. (V.) peruviana. In an exemplary embodiment, the protozoa is L. donovani. In an exemplary embodiment, the protozoa is L.
infantum. In an exemplary embodiment, the compound is described herein, or a salt, prodrug, hydrate or solvate thereof, or a combination thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt, hydrate or solvate thereof. In an exemplary embodiment, the invention provides a compound described herein, or a prodrug thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt thereof. In another exemplary embodiment, the compound of the invention is a compound described herein, or a pharmaceutically acceptable salt thereof. In another exemplary embodiment, the compound is described by a formula listed herein, or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is part of a pharmaceutical formulation described herein. In another exemplary embodiment, the contacting occurs under conditions which permit entry of the compound into the organism. Such conditions are known to one skilled in the art and specific conditions are set forth in the Examples appended hereto.
[0152] In another aspect, the microorganism is inside, or on the surface of an animal. In an exemplary embodiment, 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. In another exemplary embodiment, the animal is a human.
[0153] In an exemplary embodiment, the microorganism is killed or its growth is inhibited through oral administration of the compound of the invention. In an exemplary embodiment, the microorganism is killed or its growth is inhibited through intravenous administration of the compound of the invention. In an exemplary embodiment, the microorganism is killed or its growth is inhibited through topical administration of the compound of the invention. In an exemplary embodiment, the microorganism is killed or its growth is inhibited through intraperitoneal
administration of the compound of the invention. In an exemplary embodiment, the compound is administered in a topically effective amount. In an exemplary embodiment, the compound is administered in a cosmetically effective amount. In an exemplary embodiment, the pharmaceutical formulation is administered in an orally effective amount.
V. Methods of Treating and/or Preventing Disease
[0154] The compounds of the invention exhibit potency against microorganisms, such as protozoa, and therefore have the potential to achieve therapeutic efficacy in the animals described herein.
[0155] In another aspect, the invention provides a method of treating and/or preventing a disease. The method includes administering to the animal a
therapeutically effective amount of the compound of the invention, sufficient to treat and/or prevent the disease. In an exemplary embodiment, the compound of the invention can be used in human or veterinary medical therapy, particularly in the treatment or prophylaxis of protozoa-associated disease. In an exemplary
embodiment, the compound of the invention can be used in human or veterinary medical therapy, particularly in the treatment or prophylaxis of kinetoplastid- associated disease. In an exemplary embodiment, the disease is associated with a
Trypanosoma. In an exemplary embodiment, the Trypanosoma is a member selected from T. avium, T. boissoni, T. brucei, T. carassii, T. cruzi, T. congolense, T equinum, T equiperdum, T evansi, T hosei, T levisi, T melophagium, T parroti, T percae, T rangeli, T rotatorium, T rugosae, T sergenti, T simiae, T sinipercae, T suis, T theileri, T triglae and T. vivax. In an exemplary embodiment, the disease is associated with a Trypanosoma brucei. In an exemplary embodiment, the disease is associated with a member selected from Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. In an exemplary
embodiment, the disease is associated with Trypanosoma brucei rhodesiense. In an exemplary embodiment, the disease is associated with Trypanosoma brucei gambiense. In an exemplary embodiment, the disease is associated with
Trypanosoma cruzi. In an exemplary embodiment, the disease is a trypanosomiasis. In an exemplary embodiment, the disease is a human trypanosomiasis. In an exemplary embodiment, the disease is an animal trypanosomiasis. In an exemplary embodiment, the disease is a member selected from nagana, surra, mal de caderas, murrina de caderas, dourine, cachexial fevers, Gambian horse sickness, baleri, kaodzera, tahaga, galziekte or galzietzke and peste-boba. In an exemplary
embodiment, the disease is a member selected from Chagas disease (or Human American trypanosomiasis), nagana, surra, Covering sickness (or dourine) and sleeping sickness (or African sleeping sickness or Human African trypanosomiasis). In an exemplary embodiment, the disease is Chagas disease. In an exemplary embodiment, the disease is sleeping sickness (or African sleeping sickness). In an exemplary embodiment, the disease is acute phase sleeping sickness. In an exemplary embodiment, the disease is chronic phase sleeping sickness. In an exemplary embodiment, the disease is an acute phase of a trypanosomiasis. In an exemplary embodiment, the disease is a chronic phase of a trypanosomiasis. In an exemplary embodiment, the disease is the non-CNS form of a trypanosomiasis. In an exemplary embodiment, the disease is the CNS form of a trypanosomiasis. In an exemplary embodiment, the disease is the non-CNS form of sleeping sickness. In an exemplary embodiment, the disease is the CNS form of sleeping sickness. In an exemplary embodiment, the disease is early stage Human African trypanosomiasis. In an exemplary embodiment, the disease is late stage Human African trypanosomiasis. In another exemplary embodiment, the disease is associated with a member of the genus Leishmania. In another exemplary embodiment, the disease is associated with a member of Leishmania Viannia. In an exemplary embodiment, the disease is associated with a member selected from L. donovani, L. infantum, L. chagasi; L. mexicana, L. amazonensis, L. venezuelensis, L. tropica, L. major, L. aethiopica, L. (V.) braziliensis, L. (V.) guyanensis, L. (V.) panamensis, and L. (V.) peruviana. In an exemplary embodiment, the disease is associated with L. donovani. In an exemplary embodiment, the disease is associated with L. infantum. In an exemplary
embodiment, the disease is leishmaniasis. In an exemplary embodiment, the disease is visceral leishmaniasis. In an exemplary embodiment, the disease is cutaneous leishmaniasis. In an exemplary embodiment, the disease is diffuse cutaneous leishmaniasis and/or mucocutaneous leishmaniasis. In an exemplary embodiment, the compound is described herein, or a salt, prodrug, hydrate or solvate thereof, or a combination thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt, hydrate or solvate thereof. In an exemplary embodiment, the invention provides a compound described herein, or a prodrug thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt thereof. In another exemplary embodiment, the compound of the invention is a compound described herein, or a pharmaceutically acceptable salt thereof. In another exemplary embodiment, the compound is described by a formula listed herein, or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is part of a pharmaceutical formulation described herein. In another exemplary embodiment, the contacting occurs under conditions which permit entry of the compound into the organism. Such conditions are known to one skilled in the art and specific conditions are set forth in the Examples appended hereto.
[0156] In another exemplary embodiment, 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. In another exemplary embodiment, the animal is a human. In another exemplary embodiment, the animal is a mouse. In another exemplary embodiment, 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. In another exemplary embodiment, the animal is a human. [0157] In an exemplary embodiment, the disease is treated through oral administration of the compound of the invention. In an exemplary embodiment, the disease is treated through intravenous administration of the compound of the invention. In an exemplary embodiment, the disease is treated through topical administration of the compound of the invention. In an exemplary embodiment, the disease is treated through intraperitoneal administration of the compound of the invention. In an exemplary embodiment, the compound is administered in a topically effective amount. In an exemplary embodiment, the compound is administered in a cosmetically effective amount. In an exemplary embodiment, the pharmaceutical formulation is administered in an orally effective amount. [0158] In an exemplary embodiment, the disease is associated with an infection by a microorganism described herein. In an exemplary embodiment, the disease is associated with an infection by a protozoa described herein. VI. Pharmaceutical Formulations
[0159] In another aspect, the invention is a pharmaceutical formulation which includes: (a) a pharmaceutically acceptable excipient; and (b) a compound of the invention. In another aspect, the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound according to a formula described herein. In another aspect, the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound described herein, or a salt, prodrug, hydrate or solvate thereof, or a combination thereof. In another aspect, the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound described herein, or a salt, hydrate or solvate thereof, or a combination thereof. In another aspect, the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound described herein, or a salt, hydrate or solvate thereof. In another aspect, the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a salt of a compound described herein. In an exemplary embodiment, the salt is a pharmaceutically acceptable salt. In another aspect, the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a prodrug of a compound described herein. In another aspect, the pharmaceutical formulation includes: (a) a
pharmaceutically acceptable excipient; and (b) a compound described herein. In an exemplary embodiment, the pharmaceutical formulation is a unit dosage form. In an exemplary embodiment, the pharmaceutical formulation is a single unit dosage form.
[0160] 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). [0161] The pharmaceutical formulation of the invention may be administered orally, topically, intraperitoneally, parenterally, by inhalation or spray or rectally in unit dosage forms containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. It is further understood that the best method of administration may be a combination of methods. Oral administration in the form of a pill, capsule, elixir, syrup, lozenge, troche, or the like is particularly preferred. The term parenteral as used herein includes subcutaneous injections, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intrathecal injection or like injection or infusion techniques. In an exemplary embodiment, the pharmaceutical formulation is administered orally. In an exemplary embodiment, the pharmaceutical formulation is administered intravenously. In an exemplary embodiment, the pharmaceutical formulation is administered in a topically effective dose. In an exemplary embodiment, the pharmaceutical formulation is administered in a cosmetically effective dose. In an exemplary embodiment, the pharmaceutical formulation is administered in an orally effective dose.
[0162] The pharmaceutical formulations containing compounds of the invention are preferably in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
[0163] 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 excipients that are suitable for the manufacture of tablets. These 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. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
[0164] 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.
[0165] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, 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, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. [0166] 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.
[0167] 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. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. [0168] Pharmaceutical formulations 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. [0169] 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 non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
[0170] The composition of the invention may also be administered in the form of 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. Such materials are cocoa butter and polyethylene glycols. [0171] Alternatively, the 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. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
[0172] For administration to non-human animals, 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. [0173] Dosage levels of the order of from about 5 mg to about 250 mg per kilogram of body weight per day and more preferably from about 25 mg to about 150 mg per kilogram of body weight per day, are useful in the treatment of the above- indicated conditions. The amount of active ingredient that may be combined with the carrier materials to produce a unit dosage form will vary depending upon the condition being treated and the particular mode of administration. Unit dosage forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
[0174] 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.
[0175] In an exemplary embodiment, the unit dosage form contains from about 1 mg to about 800 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 1 mg to about 500 mg of an active ingredient. In an exemplary embodiment, the unit dosage form contains from about 100 mg to about 800 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 200 mg to about 500 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 500 mg to about 800 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 1 mg to about 100 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 10 mg to about 100 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 50 mg to about 100 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 25 mg to about 75 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 40 mg to about 60 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 75 mg to about 200 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 1 mg to about 5 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 10 mg to about 25 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 50 mg to about 350 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 200 mg to about 400 mg of a compound of the invention.
[0176] In an exemplary embodiment, the daily dosage contains from about 1 mg to about 800 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 1 mg to about 500 mg of an active ingredient. In an exemplary embodiment, the daily dosage contains from about 100 mg to about 800 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 200 mg to about 500 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 500 mg to about 800 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 1 mg to about 100 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 10 mg to about 100 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 50 mg to about 100 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 75 mg to about 200 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 1 mg to about 5 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 10 mg to about 25 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 50 mg to about 350 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 200 mg to about 400 mg of a compound of the invention. [0177] 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. [0178] 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 hepatocytes 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.
[0179] 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).
[0180] 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 1120-1127).
[0181] The amount of the composition 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.
VI. a) Testine
[0182] Preferred compounds for use in the pharmaceutical formulations described herein 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 Oravcova 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 1120-1127).
[0183] 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 ED50 (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 LD50 and ED50. Compounds that exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in 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 ED50 with little or no toxicity. The dosage can vary within this range depending upon the unit 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 et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1, p. 1).
VI. b) Administration
[0184] For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays, as disclosed herein. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the EC50 (effective dose for 50% increase) as determined in cell culture, i.e., the concentration of the test compound which achieves a half-maximal inhibition of protozoa cell growth. Such information can be used to more accurately determine useful doses in humans.
[0185] In general, 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.
[0186] Dosage amount and interval can be adjusted individually to provide plasma levels of the active moiety that are sufficient to maintain protozoa 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/m2/day. [0187] The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt%) basis, from about 0.01-10 wt% of the drug based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 0.1-3.0 wt%, more preferably, about 1.0 wt%.
[0188] Exemplary embodiments are summarized herein below.
[0189] In an exemplary embodiment, the invention provides a compound having a structure according to the following formula:
Figure imgf000067_0001
wherein Z is a member selected from S or O; X is a member selected from substituted phenyl, substituted or unsubstituted heteroaryl and unsubstituted cycloalkyl, or a salt thereof.
[0190] In an exemplary embodiment, according to the above paragraph, the compound has a structure according to the following formula:
Figure imgf000068_0001
wherein X is phenyl or heteroaryl, in which one substituent on said phenyl or said heteroaryl is a member selected from halogen or cyano or nitro or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkylthio or unsubstituted phenyl or NR8R9 or -SO2(R7) or -SO2N(R7)(R8), wherein R7 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl; R8 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl; and R9 is a member selected from H, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and -C(O)R10, wherein R10 is unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl.
[0191] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000068_0002
wherein X is phenyl or heteroaryl, in which one substituent on said phenyl or said heteroaryl is a member selected from F, Cl, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF3, OCH3, OCH2CH3, OCF3 and N(CH3)2.
[0192] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000068_0003
wherein X is phenyl or heteroaryl, in which two substituents on said phenyl or said heteroaryl are each the same or different and are each selected from: halogen or cyano or nitro or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkylthio or unsubstituted phenyl or NR8R9 or -SO2(R7) or -SO2N(R7)(R8) wherein R7 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl; R8 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl; and R9 is a member selected from H, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and -C(O)R10 wherein R10 is unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl.
[0193] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000069_0001
wherein X is phenyl or heteroaryl, in which one substituent on said phenyl or said heteroaryl is a member selected from F, Cl, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF3, OCH3, OCH2CH3, OCF3 and N(CH3)2.
[0194] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000069_0002
wherein R2, R3, R4, R5 and R6 are each the same or different and are each selected from H or halogen or cyano or nitro or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkylthio or unsubstituted phenyl or NR8R9 or -SO2(R7) or -SO2N(R7)(R8) wherein R7 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl; R8 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl; and R9 is a member selected from H, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and - C(O)R10 wherein R10 is unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl, with the proviso that R2, R3, R4, R5 and R6 cannot all be H.
[0195] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000069_0003
wherein R2, R3, R4, R5 and R6 are each the same or different and are each selected from H, F, Cl, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF3, OCH3, OCH2CH3, OCF3 and N(CH3)2, with the proviso that R2, R3, R4, R5 and R6 cannot all be H. [0196] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
wherein one member selected
Figure imgf000070_0001
is halogen or cyano or nitro or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkylthio or unsubstituted phenyl or NR8R9 or -SO2(R7) or - SO2N(R7)(R8); wherein R7 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl; R8 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl; and R9 is a member selected from H, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and -C(O)R10 wherein R10 is unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and the remaining members of R2, R3, R4, R5 and R6 are H. [0197] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
wherein one member selected
Figure imgf000070_0002
R6 is F, Cl, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF3, OCH3, OCH2CH3, OCF3 and N(CH3)2, and the remaining members of R2, R3, R4, R5 and R6 are H.
[0198] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein one member selected from R2, R3, R4, R5 and R6 is halogen or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl, and the remaining members of R2, R3, R4, R5 and R6 are H.
[0199] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein one member selected from R2, R3, R4, R5 and R6 is a member selected from F, Cl, CH3, CF3 and OCH3; and the remaining members of
R2, R3, R4 R5 and R6 are H. [0200] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein one member selected from R2, R3, R4, R5 and R6 is F or Cl or CH3 or CF3; and the remaining members of R2, R3, R4, R5 and R6 are H.
[0201] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein two members selected from R2, R3, R4, R5 and R6 are each the same or different and are each selected from halogen; and the remaining members of R2, R3, R4, R5 and R6 are H.
[0202] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein one member selected from R2, R3, R4, R5 and R6 is halogen; one member selected from R2, R3, R4, R5 and R6 is halogen or unsubstituted Ci or C2 or C3 or C4 or Cs or C6 alkyl or halosubstituted Ci or C2 or C3 or C4 or Cs or C6 alkyl; and the remaining members of R2, R3, R4, R5 and R6 are H.
[0203] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein one member selected from R2, R3, R4, R5 and R6 is halogen; one member selected from R2, R3, R4, R5 and R6 is F or Cl or CH3 or CF3 or OCH3; and the remaining members of R2, R3, R4, R5 and R6 are H.
[0204] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein one member selected from R2, R3, R4, R5 and R6 is F; one member selected from R2, R3, R4, R5 and R6 is halogen or unsubstituted Ci or C2 or C3 or C4 or Cs or C6 alkyl or halosubstituted Ci or C2 or C3 or C4 or Cs or C6 alkyl; and the remaining members of R2, R3, R4, R5 and R6 are H.
[0205] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein one member selected from R2, R3, R4, R5 and R6 is F; and one member selected from R2, R3, R4, R5 and R6 is Cl or CH3 or CF3; and the remaining members of R2, R3, R4, R5 and R6 are H.
[0206] In an exemplary embodiment, according to any of the above paragraphs, the compound has having a structure according to the following formula:
Figure imgf000071_0001
wherein R is a member selected from halogen or cyano or nitro or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkylthio or unsubstituted phenyl or NR8R9 or -SO2(R7) or -SO2N(R7)(R8) wherein R7 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl; R8 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl; and R9 is a member selected from H, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and -C(O)R10 wherein R10 is unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl.
[0207] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein R2 is a member selected from halogen,
unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy and halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl.
[0208] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein R2 is a member selected from F, Cl, CH3, OCH3 and CF3.
[0209] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000072_0001
wherein R is a member selected from halogen, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl.
[0210] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein R is a member selected from F, Cl, CH3 and CF3.
[0211] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein having a structure according to the following formula:
Figure imgf000072_0002
wherein R3 is a member selected from halogen or cyano or nitro or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkylthio or unsubstituted phenyl or NR8R9 or -SO2(R7) or -SO2N(R7)(R8) wherein R7 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl; R8 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl; and R9 is a member selected from H, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and -C(O)R10 wherein R10 is unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl.
[0212] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein R3 is a member selected from halogen,
unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl, halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy, halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy.
[0213] In an exemplary embodiment, according to any of the above paragraphs, wherein R3 is a member selected from F, Cl, CH3, OCH3 and CF3.
[0214] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000073_0001
wherein R is a member selected from halogen or cyano or nitro or unsubstituted C or C2 or C3 or C4 or C5 or C6 alkyl or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkylthio or unsubstituted phenyl or NR8R9 or -SO2(R7) or -SO2N(R7)(R8) wherein R7 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl; R8 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl; and R9 is a member selected from H, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and -C(O)R10, wherein R10 is unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl. [0215] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein R4 is a member selected from halogen,
unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl, halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy, halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy.
[0216] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein R4 is a member selected from F, Cl, CH3, CH2CH3, CH(CHs)2, C(CHs)3, CF3, OCH3, OCH2CH3, OCF3 and N(CH3)2.
[0217] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000074_0001
wherein R4 is halogen; and R2 is a member selected from halogen or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or NR7R8 wherein R7 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and R8 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl.
[0218] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000074_0002
wherein R is halogen; and R is a member selected from F, Cl, CH3, CH2CH3,
CH(CH3)2, C(CH3)3, CF3, OCH3, OCH2CH3, OCF3 and N(CH3)2.
[0219] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000074_0003
wherein R is halogen; and R is a member selected from halogen or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or NR7R8 wherein R7 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and R8 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl.
[0220] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000075_0001
wherein R4 is halogen; and R3 is a member selected from F, Cl, CH3, CH2CH3, CH(CHs)2, C(CHs)3, CF3, OCH3, OCH2CH3, OCF3 and N(CH3)2.
[0221] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000075_0002
wherein R2 is a member selected from halogen, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl, halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy, halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy and NR7R8 wherein R7 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and R8 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl.
[0222] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000075_0003
wherein R2 is a member selected from F, Cl, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF3,
OCH3, OCH2CH3, OCF3 and N(CH3)2.
[0223] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000075_0004
wherein R3 is a member selected from halogen, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl, halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy, halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy and NR7R8 wherein R7 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and R8 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl
[0224] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000076_0001
wherein R3 is a member selected from F, Cl, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF3, OCH3, OCH2CH3, OCF3 and N(CH3)2.
[0225] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000076_0002
wherein R2 is a member selected from halogen, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl, halosubstituted Ci or C2 or C3 or C4 or C5 or Ce alkyl, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy, halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy and NR7R8 wherein R7 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and R8 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl.
[0226] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000076_0003
wherein R2 is a member selected from F, Cl, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF3, OCH3, OCH2CH3, OCF3 and N(CH3)2. [0227] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000077_0001
wherein R3 is a member selected from halogen, unsubstituted Ci or C2 or C3 or C4 or C5 or Ce alkyl, halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy, halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy and NR7R8 wherein R7 is H or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and R8 is H or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl.
[0228] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000077_0002
wherein R3 is a member selected from F, Cl, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF3, OCH3, OCH2CH3, OCF3 and N(CH3)2.
[0229] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000077_0003
wherein R4 is halogen; and R2 is a member selected from halogen, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl. [0230] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000077_0004
wherein R4 is halogen; and R2 is a member selected from Cl, CH3 and CF3. [0231] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000078_0001
wherein R4 is halogen and R2 is halogen.
[0232] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000078_0002
wherein R is F; and R is a member selected from Cl, CH3 and CF3.
[0233] In an exemplary embodiment, according to any of the above paragraphs, the compound is:
Figure imgf000078_0003
[0234] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000078_0004
wherein R4 is halogen.
[0235] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000078_0005
wherein R is halogen. [0236] In an exemplary embodiment, according to any of the above paragraphs, the compound is:
Figure imgf000078_0006
[0237] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000079_0001
[0238] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000079_0002
wherein X1 is a member selected from substituted and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 or C7 or Cg or C9 or C10 alkyl; Z is a member selected from S or O; or a salt thereof. [0239] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000079_0003
wherein X1 is Ci or C2 or C3 or C4 or C5 or C6 or C7 or Cs or C9 or C10 alkyl, optionally substituted with substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, hydroxy and phenylalkyloxy.
[0240] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000079_0004
wherein X1 is Ci or C2 or C3 or C4 or C5 or C6 or C7 or Cs or C9 or C10 alkyl, substituted with substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl on the carbon adjacent to the carbonyl carbon.
[0241] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000079_0005
wherein n 1 or 2 or 3 or 4 or 5 or 6; at least one member selected from R2, R3, R4, R5 and R6 is halogen or cyano or nitro or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkylthio or unsubstituted phenyl or NR8R9 or -SO2(R7) or -SO2N(R7)(R8) wherein R7 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl; and R8 is a member selected from H and unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl; R9 is a member selected from H, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and - C(O)R10 wherein R10 is unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and the remaining members of R2, R3, R4, R5 and R6 are H.
[0242] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000080_0001
wherein n is 1 or 2 or 3 or 4 or 5 or 6; and one member selected from R2, R3, R4, R5 and R6 is F, Cl, CN, NO2, -CH3, -CH2CH3, CH(CH3)2, C(CH3)3, CF3, -OCH3, - OCH2CH3, -OCF3, -N(CH3)2, -NH(C(O)CH3), -SCH3, -S(O)2CH3, -S(O)2N(CH3)2 and the remaining members of R2, R3, R4, R5 and R6 are H.
[0243] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
wherein one member selecte
Figure imgf000080_0002
R6 is halogen; one member selected from R2, R3, R4, R5 and R6 is halogen or unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl or halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl; and the remaining members of R2, R3, R4, R5 and R6 are H.
[0244] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
Figure imgf000080_0003
wherein R4 is halogen; and R2 is a member selected from halogen, unsubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl and halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl.
[0245] In an exemplary embodiment, according to any of the above paragraphs, n is 1 or n is 2.
[0246] In an exemplary embodiment, according to any of the above paragraphs, halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl is trifluorosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkyl.
[0247] In an exemplary embodiment, according to any of the above paragraphs, halosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy is trifluorosubstituted Ci or C2 or C3 or C4 or C5 or C6 alkoxy.
[0248] In an exemplary embodiment, the invention provides a combination comprising the compound according to any of the above paragraphs, together with at least one other therapeutically active agent. [0249] In an exemplary embodiment, the invention provides a pharmaceutical formulation comprising: a) the compound according to any of the above paragraphs, or a salt thereof; and b) a pharmaceutically acceptable excipient.
[0250] In an exemplary embodiment, according to any of the above paragraphs, the pharmaceutical formulation is a unit dosage form. [0251] In an exemplary embodiment, according to any of the above paragraphs, the salt of the compound according to any of the above paragraphs is a
pharmaceutically acceptable salt.
[0252] In an exemplary embodiment, the invention provides a method of killing and/or preventing the growth of a protozoa, comprising: contacting the protozoa with an effective amount of the compound of the invention, thereby killing and/or preventing the growth of the protozoa.
[0253] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure described herein.
[0254] In an exemplary embodiment, according to any of the above paragraphs, the protozoa is a member of the Trypanosome genus. [0255] In an exemplary embodiment, according to any of the above paragraphs, the protozoa is a member of the Leishmania genus.
[0256] In an exemplary embodiment, according to any of the above paragraphs, the protozoa is Trypanosoma brucei. [0257] In an exemplary embodiment, according to any of the above paragraphs, the Trypanosoma brucei is a member selected from Trypanosoma brucei brucei, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense.
[0258] In an exemplary embodiment, according to any of the above paragraphs, the protozoa is a member selected from Leishmania donovani, Leishmania infantum, Leishmania chagasi, Leishmania mexicana, Leishmania amazonensis, Leishmania venezuelensis, Leishmania tropica, Leishmania major, Leishmania aethiopica.
[0259] In an exemplary embodiment, according to any of the above paragraphs, the protozoa is Leishmania donovani.
[0260] In an exemplary embodiment, the invention provides a method of treating and/or preventing a disease in an animal, comprising: administering to the animal a therapeutically effective amount of the compound of the invention, thereby treating and/or preventing the disease.
[0261] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure described herein. [0262] In an exemplary embodiment, according to any of the above paragraphs, the disease is African sleeping sickness.
[0263] In an exemplary embodiment, according to any of the above paragraphs, the disease is leishmaniasis.
[0264] In an exemplary embodiment, according to any of the above paragraphs, the leishmaniasis is a member selected from visceral leishmaniasis, cutaneous leishmaniasis, diffuse cutaneous leishmaniasis and mucocutaneous leishmaniasis.
[0265] In an exemplary embodiment, according to any of the above paragraphs, the leishmaniasis is visceral leishmaniasis. [0266] In an exemplary embodiment, according to any of the above paragraphs, the leishmaniasis is cutaneous leishmaniasis.
[0267] In an exemplary embodiment, according to any of the above paragraphs, the animal is a human. [0268] In an exemplary embodiment, according to any of the above paragraphs, the invention is a use of a compound of the invention or a combination of the invention in the manufacture of a medicament for the treatment and/or prophylaxis of protozoal infection.
[0269] The invention is further illustrated by the Examples that follow. The Examples are not intended to define or limit the scope of the invention.
EXAMPLES
[0270] The following Examples illustrate the synthesis of representative compounds used in the invention and the following Reference Examples illustrate the synthesis of intermediates in their preparation. These examples are not intended, nor are they to be construed, as limiting the scope of the invention. It will be clear that the invention may be practiced otherwise than as particularly described herein.
Numerous modifications and variations of the invention are possible in view of the teachings herein and, therefore, are within the scope of the invention.
[0271] All temperatures are given in degrees Centigrade. Room temperature means 20 to 250C. Reagents were purchased from commercial sources or prepared following standard literature procedures. Unless otherwise noted, reactions were carried out under a positive pressure of nitrogen. Reaction vessels were sealed with either rubber septa or Teflon screw caps. Nitrogen was introduced through Tygon tubing, fitted with a large bore syringe needle. Concentration under vacuum refers to the removal of solvent on a Bϋchi Rotary Evaporator.
[0272] Analytical HPLC was performed using a Supelco discovery C18 15 cm x 4.6 mm / 5 μm column coupled with an Agilent 1050 series VWD UV detector at 210 nm. Conditions: Solvent A: H2O/1% acetonitrile/0.1% HCO2H; Solvent B:
methanol. [0273] Proton magnetic resonance (1H NMR) spectra were recorded on a Varian INOVA NMR spectrometer [400 MHz (1H) or 500 MHz (1H)]. AU spectra were determined in the solvents indicated. Although chemical shifts are reported in ppm downfield of tetramethylsilane, they are referenced to the residual proton peak of the respective solvent peak for 1H NMR. Interproton coupling constants are reported in Hertz (Hz).
[0274] LCMS spectra were obtained using a ThermoFinnigan AQA MS ESI instrument utilizing a Phenomenex Aqua 5 micron C18 125 A 50 x 4.60 mm column. The spray setting for the MS probe was at 350 μL/min with a cone voltage at 25 mV and a probe temperature at 450 0C. The spectra were recorded using ELS and UV (254 nm) detection. Alternatively, LCMS spectra were obtained using an Agilent 1200SL HPLC equipped with a 6130 mass spectrometer operating with electrospray ionization.
[0275] Silica gel chromatography was carried out on either a Teledyne ISCO CombiFlash Companion or Companion Rf Flash Chromatography System with a variable flow rate from 5-100 mL/min. The columns used were Teledyne ISCO RediSep Disposable Flash Columns (4, 12, 40, 80, or 120 g prepacked silica gel), which were run with a maximum capacity of 1 g crude sample per 1O g silica gel. Samples were preloaded on Celite in Analogix Sample Loading Cartridges with frits ( 1 /in, 1 /out) . The eluent was 0- 100% EtOAc in heptane or 0- 10% MeOH in CH2Cl2 as a linear gradient over the length of the run (14-20 minutes). Peaks were detected by variable wavelength UV absorption (200-360 nm). The resulting fractions were analyzed, combined as appropriate, and evaporated under reduced pressure to provide purified material. [0276] HPLC purification was performed using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C18 column, Dyonex Chromeleon operating system coupled with a Varian Prostar 320 UV-vis detector (254 nm) and a Sedex55 ELS detector. Conditions: Solvent A: H2O/1% acetonitrile/0.1% HCO2H; Solvent B: MeOH. The appropriate solvent gradient for purification was determined based on the results of analytical HPLC experiments. The resulting fractions were analyzed, combined as appropriate, and evaporated under reduced pressure to provide purified material. [0277] The following experimental sections illustrate procedures for the preparation of intermediates and methods for the preparation of products according to this invention. It should be evident to those skilled in the art that appropriate substitution of both the materials and methods disclosed herein will produce the examples illustrated below and those encompassed by the scope of the invention.
[0278] All solvents used were commercially available and were used without further purification. Reactions were typically run using anhydrous solvents under an inert atmosphere of N2.
[0279] Compounds are named using the AutoNom 2000 add-on for MDL ISIS™ Draw 2.5 SP2 or their catalogue name if commercially available.
[0280] Starting materials used were either available from commercial sources or prepared according to literature procedures and had experimental data in accordance with those reported. 6-aminobenzo[c][l,2]oxaborol-l(3H)-ol (C50), for example, can be synthesized according to the methods described in U.S. Pat. Pubs. US20060234981 and US20070155699.
EXAMPLE 1
1 l-(l-Hydroxy-l,3-dihydro-benzo fell 1,2 }oxaborol-6-yl)-3-phenyl urea
Figure imgf000085_0001
[0281] In a 40 mL scintillation vial 6-aminobenzo[c][l,2]oxaborol-l(3H)-ol (78.8 mg, 0.529 mmol) (purchased from Combi-Blocks (San Diego, CA)) was taken up in 10 mL of dry acetonitrile. To this was added phenyl isocyanate (63.0 mg, 0.529 mmol). The reaction was allowed to stir overnight at room temperature. Solvent was removed under reduced pressure, and the resultant white solid was washed sparingly with 30 mL of acetonitrile followed by 30 mL of diethyl ether to yield 1 as an off- white solid. LCMS (m/z): 269 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.93 (s, 2 H) 6.96 (t, J=7.3 Hz, IH) 7.30 (dd, J=9.7, 8.2 Hz, 3 H) 7.46 (d, J=7.9 Hz, 3 H) 7.50 - 7.61 (m, 1 H) 7.83 (d, J=I.4 Hz, 1 H) 8.85 (br. s., 2 H) 9.17 (s, 1 H). Amount obtained: 53.4 mg, 37.6% yield. [0282] By proceeding in a similar manner, the following compounds were prepared from 6-aminobenzo[c][l,2]oxaborol-l(3H)-ol and the appropriate isocyanate or thioisocyanate:
2 l-(l-Hydroxy-l,3-dihydro-benzof elf l,21oxaborol-6-yl)-3-j)-tolyl urea
Figure imgf000086_0001
[0283] Compound 2 was prepared using a procedure similar to that of 1 with 4- methylphenyl isocyanate replacing phenyl isocyanate. Data for 2: LCMS (m/z): 283 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 2.24 (s, 3 H) 4.93 (s, 2 H) 7.08 (d, J=8.3 Hz, 2 H) 7.30 (d, J=8.3 Hz, 1 H) 7.34 (d, J=8.3 Hz, 2 H) 7.52 (dd, J=S.2, 2.0 Hz, 1 H) 7.82 (d, J=1.6 Hz, 1 H) 8.53 (s, 1 H) 8.62 (s, 1 H) 9.15 (s, 1 H).
3 l-(l-Hydroxy-l,3-dihydro-benzo fell 1,2 }oxaborol-6-yl)-3-m-tolyl urea
Figure imgf000086_0002
[0284] Compound 3 was prepared using a procedure similar to that of 1 with 3- methylphenyl isocyanate replacing phenyl isocyanate. Data for 3: LCMS (m/z): 283 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 2.28 (s, 3 H) 4.93 (s, 2 H) 6.78 (d, J=7.4 Hz, IH) 7.15 (t, J=7.7 Hz, 1 H) 7.19 - 7.27 (m, 1 H) 7.27 - 7.37 (m, 2 H) 7.52 (dd, J=8.2, 2.0 Hz, 1 H) 7.83 (d, J=I.6 Hz, 1 H) 8.56 (s, 1 H) 8.56 (s, 1 H) 8.65 (s, 1 H) 9.15 (s, I H).
4 l-(l-Hvdwxy-l,3-dihydro-benzo fell 1,2 loxaborol-6-yl)-3-o-tolyl urea
Figure imgf000086_0003
[0285] Compound 4 was prepared using a procedure similar to that of 1 with 2- methylphenyl isocyanate replacing phenyl isocyanate. Data for 4: LCMS (m/z): 283 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 2.25 (s, 3 H) 4.93 (s, 2 H) 6.94 (d, J=14.7 Hz, 1 H) 7.10 - 7.22 (m, 2 H) 7.32 (d, J=8.2 Hz, 1 H) 7.53 (dd, J=S.2, 1.9 Hz, 1 H) 7.79 - 7.88 (m, 2 H) 7.90 (s, 1 H) 9.02 (s, 1 H) 9.17 (s, 1 H). 5 l-(l-Hvdroxy-l,3-dihvdro-benzotcltl,21oxaborol-6-yl)-3-(4-methoxy-t)henyl) urea
Figure imgf000087_0001
[0286] Compound 5 was prepared using a procedure similar to that of 1 with A- methoxyphenyl isocyanate replacing phenyl isocyanate. Data for 5: LCMS (m/z): 299 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 3.72 (s, 3 H) 4.93 (s, 2 H) 6.87 (d, J=9.0 Hz, 2 H) 7.30 (d, J=8.2 Hz, 1 H) 7.36 (d, J=9.0 Hz, 2 H) 7.52 (dd, J=S.2, 2.0 Hz, 1 H) 7.81 (d, J=1.6 Hz, 1 H) 8.45 (s, 1 H) 8.58 (s, 1 H) 9.15 (s, 1 H).
6 l-(l-Hvdroxy-l,3-dihvdro-benzofcJfl,2Joxaborol-6-yl)-3-(4-ethoxy-phenyl) urea
Figure imgf000087_0002
[0287] Compound 6 was prepared using a procedure similar to that of 1 with 4- ethoxyphenyl isocyanate replacing phenyl isocyanate. Data for 6: LCMS (m/z): 313 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 1.31 (q, J=7.0 Hz, 2 H) 4.93 (s, 2 H) 6.85 (d, J=8.9 Hz, 2 H) 7.30 (d, J=8.2 Hz, 1 H) 7.35 (d, J=8.2 Hz, 1 H) 7.35 (d, J=8.9 Hz, 2 H) 7.52 (dd, J=S.2, 2.0 Hz, 1 H) 7.81 (d, J+1.6 Hz, 1 H) 8.43 (s, 1 H) 8.58 (s, 1 H) 9.15 (s, 1 H).
7 l-(l-Hvdroxy-l,3-dihvdro-benzofcJfl,2Joxaborol-6-yl)-3-(3-methoxy-phenyl) urea
Figure imgf000087_0003
[0288] Compound 7 was prepared using a procedure similar to that of 1 with 3- methoxyphenyl isocyanate replacing phenyl isocyanate. Data for 7: LCMS (m/z): 299 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 3.73 (s, 3 H) 4.93 (s, 2 H) 6.55 (dd, J=8.1,2.1 Hz, 1 H) 6.92 (dd, J=8.1, 1.0 Hz, 1 H) 7.17 (t, J=8.1 Hz, 1 H) 7.21 (t, J=2.0 Hz, 1 H) 7.31 (d, J=8.2 Hz, 1 H) 7.51 (dd, J=S.2, 2.0 Hz, 1 H) 7.84 (d, J=I.6 Hz, 1 H) 8.66 (s, 2 H) 9.17 (s, 1 H). Amount obtained: 87.5 mg, 63.8% yield. 8 l-(l-Hvdmxy-l,3-dihvdro-benzofcl[l,21oxaborol-6-yl)-3-(2-methoxy-phenyl) urea
Figure imgf000088_0001
[0289] Compound 8 was prepared using a procedure similar to that of 1 with 2- methoxyphenyl isocyanate replacing phenyl isocyanate. Data for 8: LCMS (m/z): 299 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 3.88 (s, 3 H) 4.93 (s, 2 H) 6.83 - 6.98 (m, 2 H) 7.01 (d, J=1.0 Hz, 1 H) 7.31 (d, J=8.2 Hz, 1 H) 7.53 (dd, J=8.3, 1.9 Hz, 1 H) 7.85 (d, J=1.6 Hz, 1 H) 8.14 (dd, J=7.8, 1.6 Hz, 1 H) 8.22 (s, 1 H) 9.17 (s, 1 H) 9.32 (s, 1 H).
9 l-(l-Hvdroxy-l,3-dihvdro-benzofcJfl,2Joxaborol-6-yl)-3-(4-trifluoromethyl phenyl) urea
Figure imgf000088_0002
[0290] Compound 9 was prepared using a procedure similar to that of 1 with 4- trifluoromethylphenyl isocyanate replacing phenyl isocyanate. Data for 9: LCMS (m/z): 337 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.94 (s, 2 H) 7.33 (d,
J=8.2 Hz, 1 H) 7.54 (dd, J=8.2, 1.9 Hz, 1 H) 7.58-7.72 (m, 4 H) 7.84 (d, J=I.6 Hz, 1 H) 8.82 (s, 1 H) 9.08 (s, 1 H) 9.18 (s, 1 H).
10 l-(Hvdroxy-l,3-dihvdro-benzo[cni,21oxaborol-6-yl)-3-(3-trifluoromethyl phenyl) urea
Figure imgf000088_0003
[0291] Compound 10 was prepared using a procedure similar to that of 1 with 3- trifluoromethylphenyl isocyanate replacing phenyl isocyanate. Data for 10: LCMS (m/z): 337 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.94 (s, 2 H) 7.32 (t, J=8.4 Hz, 2 H) 7.53 (quin, J=7.7 Hz, 3 H) 7.88 (d, J=I.6 Hz, IH) 8.06 (s, 1 H) 8.80 (s, 1 H) 9.03 (s, 1 H) 9.17 (s, I H). 11 l-(l-Hvdroxy-l,3-dihvdro-benzofcUl,21oxaborol-6-yl)-3-(2-triβuoromethyl phenyl) urea
Figure imgf000089_0001
[0292] Compound 11 was prepared using a procedure similar to that of 1 with 2- trifluoromethylphenyl isocyanate replacing phenyl isocyanate. Data for 11: LCMS (m/z): 337 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.94 (s, 2 H) 7.27 (t, J=7.6 Hz, 1 H) 7.33 (d, J=8.2 Hz, 1 H) 7.53 (dd, J=8.2, 2.0 Hz, 1 H) 7.59 - 7.67 (m, 1 H) 7.68 (d, J=7.9 Hz, 1 H) 7.85 (d, J=I.6 Hz, 1 H) 7.96 (d, J=8.2 Hz, 1 H) 8.06 (s, 1 H) 9.18 (s, 1 H) 9.39 (s, I H). 12 l-(l-Hvdroxy-l,3-dihvdro-benzofcIfl,2Ioxaborol-6-yl)-3-(4-trifluoromethoxy phenyl) urea
Figure imgf000089_0002
[0293] Compound 12 was prepared using a procedure similar to that of 1 with 4- trifluoromethoxyphenyl isocyanate replacing phenyl isocyanate. Data for 12: LCMS (m/z): 353 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.93 (s, 2 H) 7.30 (dd, J=14.0, 8.5 Hz, 3 H) 7.53 (dd, J=8.3, 2.0 Hz, 3 H) 7.83 (d, J=1.6 Hz, 1 H) 8.73 (s, 1 H) 8.86 (s, 1 H) 9.17 (s, I H).
13 l-tf-ChlorophenvD-S-fl-hydroxy-U-dihydrobenzofcIfl^Ioxaborol-ό-yl) urea
Figure imgf000089_0003
[0294] Compound 13 was prepared using a procedure similar to that of 1 with 4- chlorophenyl isocyanate replacing phenyl isocyanate. Data for 13: LCMS (m/z): 303 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.93 (s, 2 H) 7.26 - 7.37 (m, 3 H) 7.49 (d, J=8.8 Hz, 2 H) 7.52 (dd, J=8.3, 2.0 Hz, 1 H) 7.82 (d, J=1.5 Hz, 1 H) 8.71 (s, I H) 8.79 (s, I H), 9.16 (s, 1 H). 14 l-β-ChlorophenvDS-tt-hvdroxy-U-dihvdrobenzotcimioxaborol-ό-yl) urea
Figure imgf000090_0001
[0295] Compound 14 was prepared using a procedure similar to that of 1 with 3- chlorophenyl isocyanate replacing phenyl isocyanate. Data for 14: LCMS (m/z): 303 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.94 (s, 2 H) 7.01 (d, J=7.4 Hz, 1 H) 7.29 (dd, J=I 1.9, 4.3 Hz, 3 H) 7.52 (dd, J=8.2, 2.0 Hz, 1 H) 7.69-7.77 (m, 1 H) 7.84 (d, J=1.6 Hz, 1 H) 8.76 (s, 1 H) 8.86 (s, 1 H) 9.17 (s, 1 H).
15 l-G-ChlorophenvDS-tt-hvdroxy-U-dihvdrobenzotcimioxaborol-ό-yl) urea
Figure imgf000090_0002
[0296] Compound 15 was prepared using a procedure similar to that of 1 with 2- chlorophenyl isocyanate replacing phenyl isocyanate. Data for 15: LCMS (m/z): 303 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.94 (s, 2 H) 6.98-7.08 (m, 1 H) 7.27-7.32 (m, 1 H) 7.34 (d, J=8.3 Hz, 1 H) 7.46 (dd, J=8.0, 1.2 Hz, 1 H) 7.54 (dd,
J=8.2, 2.0 Hz, 1 H) 7.86 (d, J=1.7 Hz, 1 H) 8.19 (dd, J=8.3, 1.2 Hz, 1 H) 8.30 (s, 1 H) 9.19 (s, 1 H) 9.43 (s, I H).
16 l-(4-Fluorophenyl)-3-(l-hvdroxy-l,3-dihydrobenzofcJfl,2Joxaborol-6-yl) urea
Figure imgf000090_0003
[0297] Compound 16 was prepared using a procedure similar to that of 1 with 4- fluorophenyl isocyanate replacing phenyl isocyanate. Data for 16: LCMS (m/z): 287 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.93 (s, 2 H) 7.12 (t, J=8.9 Hz, 2 H) 7.31 (d, J=8.2 Hz, 1 H) 7.47 (dd, J=9.0, 4.9 Hz, 2 H) 7.52 (dd, J=8.2, 2.0 Hz, 1 H) 7.82 (d, J=1.6 Hz, 1 H) 8.66 (br. s., 1 H) 8.67 (br.s., 1 H) 9.16 (s, 1 H). 17 l-β-FluorophenvD-S-d-hvdroxy-U-dihvdrobenzofcUUloxaborol-ό-yl) urea
Figure imgf000091_0001
[0298] Compound 17 was prepared using a procedure similar to that of 1 with 3- fluorophenyl isocyanate replacing phenyl isocyanate. Data for 17: LCMS (m/z): 287 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.93 (s, 2 H) 6.78 (td, J=8.4, 2.2 Hz, 1 H) 7.12 (d, J=8.1 Hz, 1 H) 7.23 - 7.38 (m, 2 H) 7.42 - 7.60 (m, 1 H) 7.83 (d, J=I.6 Hz, 1 H) 8.74 (s, 1 H) 8.88 (s, 1 H) 9.17 (s, 1 H).
18 l-(2-Fluorophenyl)-3-(l-hvdroxy-l,3-dihvdrobenzofclfl,21oxaborol-6-yl) urea
Figure imgf000091_0002
[0299] Compound 18 was prepared using a procedure similar to that of 1 with 2- fluorophenyl isocyanate replacing phenyl isocyanate. Data for 18: LCMS (m/z): 287 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.94 (s, 2 H) 6.94 - 7.07 (m, 1 H) 7.14 (t, J=7.8 Hz, 1 H) 7.24 (dd, J=19.8, 0.7 Hz, 1 H) 7.33 (d, J=8.2 Hz, 1 H) 7.53 (dd, J=8.2, 1.9 Hz, 1 H) 7.84 (d, J=1.6 Hz, 1 H) 8.17 (td, J=8.2, 1.2 Hz, 1 H) 8.53 (d, J=2.0 Hz, 1 H) 9.08 (s, 1 H) 9.18 (s, 1 H).
19 l-(4-Ethylphenyl)-3-(l-hvdroxy-l,3-dihydrobenzofcJfl,2Joxaborol-6-yl) urea
Figure imgf000091_0003
[0300] Compound 19 was prepared using a procedure similar to that of 1 with 4- ethylphenyl isocyanate replacing phenyl isocyanate. Data for 19: LCMS (m/z): 297 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 1.16 (t, J=7.6 Hz, 3 H) 2.54 (d, J=7.6 Hz, 2 H) 4.93 (s, 2 H) 7.11 (d, J=8.3 Hz, 2 H) 7.30 (d, J=8.2 Hz, 1 H) 7.36 (d, J=8.4 Hz, 2 H) 7.52 (dd, J=8.2, 1.9 Hz, 1 H) 7.82 (d, J=I.6 Hz, 1 H) 8.54 (s, 1 H) 8.62 (s, 1 H) 9.16 (s, 1 H). 20 l-(l-Hvdmxy-l,3-dihvdrobenzofcl[l,21oxaborol-6-yl)-3-(4-isopmpylphenyl) urea
Figure imgf000092_0001
[0301] Compound 20 was prepared using a procedure similar to that of 1 with 4- isopropylphenyl isocyanate replacing phenyl isocyanate. Data for 20: LCMS (m/z): 311 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 1.17 (s, 3 H) 1.19 (s, 3 H) 2.83 (dt, J=13.8, 6.9 Hz, 1 H) 4.93 (s, 2 H) 7.15 (d, J=8.4 Hz, 2 H) 7.30 (d, J=8.2 Hz, 1 H) 7.36 (d, J=8.5 Hz, 2 H) 7.52 (dd, J=8.2, 2.0 Hz, 1 H) 7.83 (d, J=I.6 Hz, 1 H) 8.54 (s, I H) 8.62 (s, I H) 9.16 (s, 1 H). 21 l-(4-tert-Butylphenyl)-3-(l-hvdroxy-l,3-dihydrobenzofcIfl,2Joxaborol-6-yl) urea
Figure imgf000092_0002
[0302] Compound 21 was prepared using a procedure similar to that of 1 with 4-t- butylphenyl isocyanate replacing phenyl isocyanate. Data for 21: LCMS (m/z): 325 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 1.26 (s, 9 H) 4.93 (s, 2 H) 7.23 - 7.34 (m, 3 H) 7.34 - 7.43 (m, 2 H) 7.51 (dd, J=8.2, 1.9 Hz, 1 H) 7.83 (d, J=I.5 Hz, 1 H) 8.55 (s, 1 H) 8.62 (s, 1 H) 9.16 (br. s., 1 H).
22 l-(4-Dimethylaminophenyl)-3-(l-hvdroxy-l,3-dihvdrobenzofclfl,21
oxaborol-6-yl) urea
Figure imgf000092_0003
[0303] Compound 22 was prepared using a procedure similar to that of 1 with dimethylaminophenyl isocyanate replacing phenyl isocyanate. Data for 22: LCMS (m/z): 312 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 2.83 (s, 6 H) 4.92 (s, 2 H) 6.71 (d, J=8.7 Hz, 2 H) 7.27 (d, J=8.6 Hz, 3 H) 7.51 (dd, J=8.2, 1.9 Hz, 1 H) 7.81 (d, J=1.4 Hz, 1 H) 8.28 (s, 1 H) 8.52 (s, 1 H) 9.15 (s, 1 H). 23 (2,4-Difluorophenyl)-3-(l-hvdroxy-l,3-dihvdrobenzofclfl,2]oxaborol-6-yl)- urea
Figure imgf000093_0001
[0304] Compound 23 was prepared using a procedure similar to that of 1, but using 2,4-difluorophenyl isocyanate in place of phenyl isocyanate. Data for 23: LCMS (ml Q): 305 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.93 (s, 2 H) 7.05 (t, J=8.7 Hz, 1 H) 7.32 (d, J=8.2 Hz, 2 H) 7.53 (dd, J=8.2, 2.0 Hz, 1 H) 7.82 (d, J=I.6 Hz, 1 H) 8.10 (td, J=9.2, 6.2 Hz, 1 H) 8.49 (d, J=1.4 Hz, 1 H) 9.04 (s, 1 H) 9.17 (s, 1 H).
24 l-(2,6-Difluorophenyl)-3-(l-hvdroxy-l,3-dihvdrobenzofc]fl,2]oxaborol-6- vD-urea
Figure imgf000093_0002
[0305] Compound 24 was prepared using a procedure similar to that of 1, but using 2,6-difluorophenyl isocyanate in place of phenyl isocyanate. Data for 24: LCMS (m/e): 305 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.93 (s, 2 H) 7.15 (t, J=8.1 Hz, 2 H) 7.31 (d, J=8.2 Hz, 2 H) 7.52 (dd, J=8.2, 2.0 Hz, 1 H) 7.81 (d, J=I.6 Hz, 1 H) 8.09 (s, 1 H) 8.93 (s, 1 H) 9.15 (s, 1 H).
25 l-GJ-DichlorophenvD-S-d-hvdroxy-U-dihvdrobenzofcπUloxaborol-ό- vD-urea
Figure imgf000093_0003
[0306] Compound 25 was prepared using a procedure similar to that of 1, but using 2,3-dichlorophenyl isocyanate in place of phenyl isocyanate. Data for 25: LCMS (m/e): 335 (M-H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.94 (s, 2 H) 7.25 - 7.32 (m, 1 H) 7.34 (d, J=9.4 Hz, 2 H) 7.54 (dd, J=8.2, 1.9 Hz, 1 H) 7.86 (d, J=I.5 Hz, 1 H) 8.19 (dd, J=8.1, 1.5 Hz, 1 H) 8.47 (s, 1 H) 9.19 (s, 1 H) 9.51 (s, 1 H). 26 l-(2,5-Difluorophenyl)-3-(l-hvdroxy-l,3-dihvdrobenzo[cUl,21oxaborol-6- yl)-urea
Figure imgf000094_0001
[0307] Compound 26 was prepared using a procedure similar to that of 1, but using 2,5-difluorophenyl isocyanate in place of phenylisocyanate. Data for 26: LCMS (m/e): 305 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.94 (s, 2 H) 6.81 (t, J=8.5 Hz, 1 H) 7.29 (td, J=5.4, 4.0 Hz, 1 H) 7.34 (d, J=8.3 Hz, 1 H) 7.53 (dd, J=8.2, 2.0 Hz, 1 H) 7.85 (d, J=I.6 Hz, 1 H) 8.06 (ddd, J=I 1.1, 6.5, 3.2 Hz, 1 H) 8.75 (br. s., I H) 9.17 (s, I H) 9.19 (s, I H). 27 l-(4-Bromo-2-fluorophenyl)-3-(l-hvdroxy-l,3-dihvdrobenzo[cl[l,21
oxaborol-6-vD-urea
Figure imgf000094_0002
[0308] Compound 27 was prepared using a procedure similar to that of 1, but using 4-bromo-2-fluorophenyl isocyanate in place of phenylisocyanate. Data for 27:
LCMS (m/e): 365 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.94 (s, 2 H) 7.34 (t, J=8.9 Hz, 2 H) 7.54 (dd, J=14.4, 2.0 Hz, 2 H) 7.82 (d, J=1.6 Hz, 1 H) 8.15 (t, J=8.8 Hz, 1 H) 8.64 (s, 1 H) 9.10 (s, 1 H) 9.18 (s, 1 H).
28 l-GΛ-DichlorophenvD-S-d-hvdroxy-U-dihvdrobenzofcπUloxaborol-ό- vD-urea
Figure imgf000094_0003
[0309] Compound 28 was prepared using a procedure similar to that of 1, but using 2,4-dichlorophenyl isocyanate in place of phenylisocyanate. Data for 28: LCMS (m/e): 335 (M-H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.94 (s, 2 H) 7.34 (d, J=8.2 Hz, 1 H) 7.39 (dd, J=9.0, 2.4 Hz, 1 H) 7.54 (dd, J=8.2, 2.0 Hz, 1 H) 7.62 (d, J=2.4 Hz, 1 H) 7.85 (d, J=1.6 Hz, 1 H) 8.22 (d, J=9.0 Hz, 1 H) 8.39 (s, 1 H) 9.19 (s, 1 H) 9.47 (s, 1 H). 29 l-(2-Fluoro-3-trifluoromethylphenyl)-3-(l-hydroxy-l,3- dihvdrobenzotcltl,21oxaborol-6-yl)-urea
Figure imgf000095_0001
[0310] Compound 29 was prepared using a procedure similar to that of 1, but using 2-fluoro-3-(trifluoromethyl) phenyl isocyanate. Data for 29: LCMS (m/e): 355
(M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.94 (s, 2 H) 7.36 (d, J=5.4 Hz, 3 H) 7.54 (dd, J=8.2, 1.9 Hz, 1 H) 7.85 (d, J=I.4 Hz, 1 H) 8.47 (td, J=7.0, 3.4 Hz, 1 H) 8.81 (d, J=I.8 Hz, 1 H) 9.15 (s, 1 H) 9.19 (s, I H).
30 l-(2-Fluoro-5-trifluoromethylphenyl)-3-(l-hvdroxy-l,3-dihydrobenzofcJfl,2J oxaborol-6-vD-urea
Figure imgf000095_0002
[0311] Compound 30 was prepared using a procedure similar to that of 1, but using 2-fluoro-5-(trifluoromethyl) phenyl isocyanate. Data for 30: LCMS (m/e): 355 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.94 (s, 2 H) 7.38 (dd, J=6.5, 2.1 Hz, 2 H) 7.44 - 7.56 (m, 2 H) 7.92 (d, J=1.6 Hz, 1 H) 8.66 (dd, J=7.2, 1.8 Hz, 1 H) 8.89 (d, J=2.4 Hz, 1 H) 9.19 (d, J=3.0 Hz, 2 H).
31 l-(2-Fluoro-6-trifluoromethylphenyl)-3-(l-hvdroxy-l,3-dihydrobenzofclH,21 oxaborol-6-yl)-urea
Figure imgf000095_0003
[0312] Compound 31 was prepared using a procedure similar to that of 1, but using 2-fluoro-6-(trifluoromethyl) phenyl isocyanate. Data for 31: LCMS (m/e):
355(M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.93 (s, 2 H) 7.31 (d, J=8.3 Hz, 1 H) 7.51 (dd, J=8.2, 1.9 Hz, 2 H) 7.57 - 7.70 (m, 2 H) 7.82 (d, J=1.6 Hz, 1 H) 8.02 (s, I H) 9.00 (s, I H) 9.15 (s, 1 H). 32 l-(l-Hvdroxy-l,3-dihvdrobenzoIc]Il,2]oxaborol-6-yl)-3-Ohenyl thiourea
Figure imgf000096_0001
[0313] Compound 32 was prepared using a procedure similar to that of 1 with phenyl isothiocyanate replacing phenyl isocyanate. Data for 32: LCMS (m/z): 285 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.97 (s, 2 H) 7.12 (t, J=7.4 Hz, 1 H) 7.33 (t, J=7.9, 3 H) 7.46-7.57 (m, 3 H) 7.76 (d, J=I.4 Hz, 1 H) 9.21 (s, 1 H) 9.74 (s, 1 H), 9.80 (s, 1 H).
33 l-Benzyl-3-(l-hvdroxy-l,3-dihvdrobenzofcJfl,2Joxabowl-6-yl) urea
Figure imgf000096_0002
[0314] Compound 33 was prepared using a procedure similar to that of 1 with phenylmethyl isocyanate replacing phenyl isocyanate. Data for 33: LCMS (m/z): 283 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 4.30 (d, J=5.9 Hz, 2 H) 4.90 (s, 2 H) 6.69 (br.s., 1 H) 7.25 (d, J=8.3 Hz, 2 H) 7.28-7.39 (m, 4 H) 7.49 (dd, J=8.2, 1.8 Hz, 1 H) 7.77 (d, J=1.5 Hz, 1 H) 8.66 (br.s., 1 H) 9.12 (s, 1 H). 34 l-(l-Hvdroxy-l,3-dihvdrobenzoIc]Il,2]oxaborol-6-yl)-3-Ohenethyl urea
Figure imgf000096_0003
[0315] Compound 34 was prepared using a procedure similar to that of 1 with phenylethyl isocyanate replacing phenyl isocyanate. Data for 34: LCMS (m/z): 297 (M+H); 1H NMR (400 MHz, DMSO-J6) δ ppm 2.75 (t, J=7.2 Hz, 2 H) 3.34 (d, J=6.7 Hz, 2 H) 4.89 (s, 2 H) 6.09 (t, J=5.6 Hz, 1 H) 7.24 (d, J=8.3 Hz, 4 H) 7.30 (d, J=7.4 Hz, 2 H) 7.45 (dd, J=8.2, 2.0 Hz, 1 H) 7.74 (d, J=1.6 Hz, 1 H) 8.46 (s, 1 H) 9.10 (s, 1 H).
A. N-Methyl-6-(benzylamino)-l,3-dihvdro-l-hydroxy-2,l-benzoxaborole (48)
Figure imgf000096_0004
N-Methyl-4-benzylamino-2-bromobenzaldehvde (46)
[0316] A solution of 2-bromo-4-fluorobenzaldehyde (6.09 g, 30 mmol), N- methylbenzylamine (3.58 g, 30 mmol) and K2CO3 (8.48 g, 60 mmol) in DMF (100 niL) was heated to 100 0C overnight, then was cooled to room temperature and filtered. The filtrate was evaporated and purified by flash chromatography eluting with an EtO Ac/heptanes gradient (0:100 to 100:0) to afford compound 46 (8.1O g, 88.8%) as a light yellow solid. 1U NMR (400 MHz, CDCl3): 10.03-10.10 (m, 6H), 7.76 (dd, J= 8.9, 0.1 Hz, 6H), 7.23-7.35 (m, 23H), 7.15 (td, J= 1.2, 0.7 Hz, 7H),
7.05-7.14 (m, J= 1.4, 0.9, 0.6, 0.5, 0.5 Hz, 6H), 6.85 (d, J= 2.5 Hz, 7H), 6.67 (ddd, J = 8.9, 2.1, 0.5 Hz, 6H), 6.67 (d, J= 8.9 Hz, 3H), 4.61 (s, 15H), 3.11 (d, J= 0.1 Hz, 21H).
N-Methyl-4-benzylamino-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- vDbenzaldehvde (47)
[0317] To a solution of compound 46 (0.91 g, 3.0 mmol) in 1,4-dioxane (25 mL) was added bis-pinacol-diboron (0.84 g, 3.3 mmol), KOAc (0.88 g, 9.0 mmol) and PdCl2(dppf)2 (66 mg, 0.09 mmol). The mixture was degassed with N2, heated at 90 0C overnight, then was cooled to room temperature and filtered though a short pack of diatomaceous earth. The filtrate was concentrated, and the residue was purified by flash chromatography eluting with an EtO Ac/heptanes gradient (0:100 to 100:0) to give compound 47 (1.07 g, 99%) as a yellow oil. 1U NMR (400 MHz, CDCl3): δ 10.03-10.10 (m, 6H), 7.76 (dd, J= 8.9, 0.1 Hz, 6H), 7.23-7.35 (m, 23H), 7.15 (td, J = 1.2, 0.7 Hz, 7H), 7.05-7.14 (m, J= 1.4, 0.9, 0.6, 0.5, 0.5 Hz, 6H), 6.85 (d, J= 2.5 Hz, 7H), 6.67 (ddd, J= 8.9, 2.1, 0.5 Hz, 6H), 6.67 (d, J= 8.9 Hz, 3H), 4.61 (s, 15H), 3.11 (d, J= 0.1 Hz, 21H).
N-Methyl-6-(benzylamino)-l,3-dihvdro-l-hvdroxy-2,l-benzoxaborole (48)
[0318] To a suspension of compound 47 (3.5 g, 10.0 mmol, 1.0 eq.) in EtOH (60 mL) at 0 0C was added NaBH4 (378.3 mg, 10.0 mmol, 1.0 eq.) in small portions. The mixture was stirred at 0 0C for 20 minutes and allowed to warm to room temperature in another 1 h. After cooling to 0 0C, the clear solution was carefully treated with H2O (1 mL), followed by slow addition of HCl (30 mL, 3N). The resulting yellow suspension was allowed to warm to room temperature gradually and stirred for 2 h. The mixture was then treated with sat. NaHCO3 drop wise until pH reaching 7. The precipitate was collected by filtration and washed with water to give compound 48 ( 1.7Og, 67.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.95 (s, IH), 7.28- 7.34 (m, 2H), 7.20 (q, J= 8.9 Hz, 4H), 7.07 (d, J= 2.4 Hz, IH), 6.90 (dd, J= 8.4, 2.5 Hz, IH), 4.86 (s, 2H), 4.58 (s, 2H), 3.01 (s, 3H). B. N-(l,3-dihvdro-l-hvdroxy-2,l-benzoxaborol-6-yl)-N-methylbenzamide
(50)
Figure imgf000098_0001
6-Methylamino-l,3-dihvdro-l-hvdroxy-2, 1-benzoxaborole (49)
[0319] To a solution of compound 48 (253.1 mg, 1.0 mmol, 1.0 eq.) in EtOH (15 niL) was added ammonium formate (630.6 mg, 10.0 mmol, 10.0 eq.) and 5% (w/w) Pd/C (40 mg). The mixture was heated in a preheated 65 0C oil bath under N2. Upon complete consumption of the starting material (TLC), the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give compound 49 as a light yellow solid (160 mg). The yellow solid was used to next step immediately. 1H NMR (400 MHz, acetone-d6): δ 7.80 (s, IH), 7.09-7.14 (m, IH), 6.90 (d, J= 2.2 Hz, IH), 6.73-6.78 (m, IH), 4.87 (s, 2H), 3.79 (s, IH), 2.77 (s, 3H).
N-(l,3-dihvdro-l-hvdroxy-2,l-benzoxaborol-6-yl)-N-methylbenzamide (50)
[0320] To a 20 mL scintillation vial containing compound 49 (160 mg, 1.0 mmol) in DCM (10.0 mL) was added triethylamine (290 μL, 2.0 mmol, 2.0 eq.), followed by benzoyl chloride (160 μL, 1.4 mmol, 1.4 eq.). The resulting white suspension was stirred at room temperature for 8 hours, then was concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a
MeOH/DCM gradient (0:100 to 10: 90) to give compound 50 (123.0 mg, 46.1% over 2 steps) as a white solid. IH NMR (400 MHz, DMSO-d6): δ 9.13 (s, IH), 7.41 (s, IH), 7.16-7.27 (m, 7H), 4.87 (s, 2H), 3.33 (s, 3H); LCMS (m/z) 268 (M+H).
C. (l,3-Dihvdw-l-hvdwxy-2,l-benzoxabowl-6-yl)-phenyl-carbamic acid t- butvl ester (59)
Figure imgf000098_0002
(3-Bromo-4-methyl-phenyl)-phenyl-amine (54)
[0321] To a mixture of iodobenzene (4.4 g, 21.56 mmol), 3-bromo-4- methylbenzamine (4.0 g, 21.56 mmol) and DMSO (50 mL) were added in sequence copper (I) iodide (0.82 g, 4.31 mmol), L-proline (0.99 g, 8.61 mmol) and NaOBu-t (4.14 g, 43.13 mmol) under N2. The mixture was stirred at 50 0C for 48 hbefore poured onto ice (100 g) and extracted with EtOAc (100 mL x 3). The extracts were dried over Na2SO4 and the residue after rotary evaporation was purified by column chromatography to give 1.2 g of compound 54 (21.2%). 1HNMR (300 MHz, DMSO): δ 8.19 (s, 1 H), 7.27-7.15 (m, 4 H), 7.05-7.01 (m, 2 H), 6.97 (dd, Ji = 8.4, J2 = 2.4 Hz, 1 H), 6.85 (m, 1 H) and 2.23 (s, 3 H) ppm.
(3-Bromo-4-methyl-phenyl)-phenyl-carbamic acid t-butyl ester (55)
[0322] To a solution of compound 54 (3.26 g, 12.44 mmol) in THF (60 mL) was added dropwise LiHMDS (27.4 mL, 27.4 mmol) at -80 0C over 30 min. After stirring for another 30 min, BoC2O (6.0 g, 27.4 mmol) was added dropwise over 10 min. The reaction was carried out for 14 h at room temperature. The mixture was evaporated to get the crude product which was purified by column chromatography to give 4.3 g of compound 55 (95%). 1HNMR (300 MHz, DMSO): δ 7.44 (d, J= 2.1 Hz, 1 H), 7.39- 7.30 (m, 3 H), 7.26-7.20 (m, 3 H), 7.11 (dd, Ji = 8.4, J2 = 2.4 Hz, 1 H), 2.31 (s, 3 H) and 1.37 (s, 9 H) ppm.
2-Bromo-4-(t-butoxycarbonyl-phenyl-amino)-benzyl alcohol (56)
[0323] To a solution of compound 55 (4.3 g, 11.88 mmol) in tetrachloromethane (300 mL) was added NBS (2.54 g, 14.25 mmol) and Bz2O2 (0.28 g, 1.19 mmol). The reaction was refluxed for 20 h. The mixture was cooled to room temperature and filtered, and the filtrate was evaporated under vacuum to get the crude product which was purified by column chromatography to give 2.65 g of (3-Bromo-4-bromomethyl- phenyl)-phenyl-carbamic acid f-butyl ester (50.6%). 1HNMR (400 MHz, CDCl3): δ 7.47 (d, J= 2.4 Hz, 1 H), 7.37-7.33 (m, 3 H), 7.19-7.17 (m, 3 H), 7.13 (dd, Ji = 8.4, J2 = 2.4 Hz, 1 H), 4.57 (s, 2 H) and 1.44 (s, 9 H) ppm. To a solution of (3-Bromo-4- bromomethyl-phenyl)-phenyl-carbamic acid t-butyl ester (2.65 g, 6.0 mmol) in DMF (50 mL) was added sodium acetate (2.46 g, 30 mmol). The mixture was stirred at 70 0C for 5 h. The mixture was poured onto ice (100 g) and extracted with EtOAc (100 mL x 3). The combined extracts were dried over Na2SO4 and evaporated to give 2.5 g of acetate intermediate (99%). To a solution of this acetate intermediate (2.5 g, 5.95 mmol) in MeOH (50 mL) was added NaOH (1.2 g, 29.76 mmol) in water (15 mL). The mixture was refluxed for 1 h. The residue after evaporation was extracted with EtOAc (40 mL x 3). The combined extracts were washed with water (40 mL x 2) and brine and dried over Na2SO4, and the solvent was evaporated to give 2.1 g of compound 56 (93.4%). 1HNMR (300 MHz, CDCl3): δ 7.44 (d, J= 2.1 Hz, 1 H), 7.40- 7.30 (m, 3 H), 7.23-7.14 (m, 4 H), 4.71 (s, 2 H) and 1.44 (s, 9 H) ppm. β-Bromo-4- (tetrahvdro-pyran^-yloxymethvD-phenylJ-phenyl-carbamic acid t-butyl ester (57)
[0324] To a solution of compound 56 (2.1 g, 5.55 mmol) in dichloromethane (50 niL) were added in sequence 3, 4-dihydro-2H-pyran (0.93 g, 11.11 mmol), pyridine (28 mg, 0.35 mmol), and p-toluenesulfonic acid monohydrate (53 mg, 0.28 mmol). The reaction was carried out for 48 h at room temperature. The mixture was washed with water and brine, and dried over Na2SO4. The residue after evaporation was purified by column chromatography to give 2.2 g of compound 57 (85.7%). 1HNMR (300 MHz, CDCl3): δ 7.44-7.42 (m, 2 H), 7.35-7.30 (m, 2 H), 7.23-7.13 (m, 4 H), 4.82-4.75 (m, 2 H), 4.54 (d, J= 13.2 Hz, 1 H), 3.94-3.87 (m, 1 H), 3.59-3.52 (m, 1 H), 1.94-1.50 (m, 6 H) and 1.45 (s, 9 H) ppm.
(l,3-Dihvdro-l-hvdroxy-2,l-benzoxaborol-6-yl)-phenyl-carbamic acid t-butyl ester (59)
[0325] To a solution of compound 57 (2.56 g, 5.54 mmol) in anhydrous THF (50 mL) was added dropwise 1.6 M n-BuLi in hexane (3.98 mL, 6.37 mmol) at -80 0C under N2 atmosphere over 20 min. After the mixture was stirred for another 20 min, B(iPrO)3 (1.47 mL, 6.37 mmol) was added dropwise over 10 min. The mixture was allowed to warm to room temperature slowly and stirred overnight before 6 M HCl (10 mL) was added and stirred for another 1 h. After evaporation of THF the residue was extracted with EtOAc (40 mL x 5). The combined extracts were washed with water and brine, and dried over Na2SO4. The residue after evaporation was purified by column chromatography to give 0.64 g of compound 58 (27.0%). To a solution of compound 58 (0.64 g, 1.50 mmol) in EtOH (20 mL) was added pyridine (35 mg, 0.45 mmol) and p-toluenesulfonic acid monohydrate (85 mg, 0.45 mmol). The reaction was carried out at 50 0C for 4 h. The mixture was evaporated and the residue was dissolved in EtOAc (50 mL) and washed with water and brine, and dried over
Na2SO4. After evaporation the residue was purified by column chromatography to give 0.44 g of compound 59 (90.3%). 1HNMR (300 MHz, DMSO): δ 9.18 (s, 1 H), 7.53 (s, 1 H), 7.40-7.32 (m, 4 H), 7.21-7.18 (m, 3 H), 4.97 (s, 2 H) and 1.38 (s, 9 H) ppm. D. 6-Phenylamino-l,3-dihydro-l-hydroxy-2,l-benzoxaborole (60)
Figure imgf000101_0001
[0326] To a solution of compound 59 (150 mg, 0.46 mmol) in dichloromethane (10 niL) was added dropwise TFA (0.4 niL, 5.38 mmol) at 0 0C under N2 atmosphere. The mixture was then slowly warmed to room temperature and stirred for 3 h before neutralization with saturated NaHCO3. The organic phase was separated, washed with brine and dried over Na2SO4. The residue after evaporation was purified by column chromatography and recrystallization to 13.2 mg of compound 60 (12.7%). 1H NMR (300 MHz, DMSO-de): δ 9.07 (s, IH), 8.12 (s, IH), 7.50 (s, IH), 7.22 (m, 4H), 7.05 (d, J= 8.1 Hz, 2H), 6.80 (d, J= 7.2 Hz, IH) and 4.91 (s, 2H) ppm; 13C NMR
(75 MHz, CDCl3): δ 146.38, 143.45, 142.33, 129.26, 121.74, 120.70, 119.03, 117.34, 71.10; HRMS-EI: Ci3Hi2BNO2 calcd 225.0961, found 225.0955; mp: 108-110 0C.
EXAMPLE 2
Trypanosoma brucei brucei High-Throughput Screening Assay Procedure
[0327] All experiments were conducted with the bloodstream- form trypanosome T. brucei brucei 427 strain obtained from Seattle Biomedical Research Institute (Seattle, WA). Parasites were cultured in T-25 vented cap flasks and kept in humidified incubators at 37°C and 5% CO2. The parasite culture media was complete HMI- 9 medium (c.f. Hirumi, Journal of Parasitology 1989, VoI 75, page 985 et seq) containing 10% FBS, 10% Serum Plus medium and penicillin/streptomycin. To ensure log growth phase, trypanosomes were sub-cultured at appropriate dilutions every 2-3 days.
In Vitro Drug Sensitivity Assays
[0328] Approximately 50 microliters of log phase cultures were diluted 1 : 10 in HMI-9 and 10 uL of the diluted culture was removed and counted using a
hemocytometer to determine parasite concentration. Parasites were diluted by addition of an appropriate volume of HMI-9 to achieve a final parasite concentration of 2 x 105 ImL. Compounds of the invention to be tested were serially diluted in DMSO and 0.5 uL added to 49.5 uL HMI-9 in triplicate 96-well plates using a Biomek NX liquid handler. Parasites from the diluted stock were added to each well (50 uL) using a Multidrop 384 dispenser to give a final concentration of 1.0x105/ml parasites in 0.4% for DMSO. Trypanosomes were incubated with compounds for 72 hrs at 37°C with 5% CO2. Resazurin (20 uL of 12.5 mg/ml stock) from Sigma- Aldrich was added to each well and plates were incubated for an additional 2-4 hrs. Assay plates were read using an En Vision plate reader at an excitation wavelength of 544 nm and emission of 590 nm. Triplicate data points were averaged to generate sigmoidal dose response curve and determine IC50 values using XLfit curve fitting software from IDBS (Guildford, UK).
[0329] Biological data for exemplary compounds of the invention is provided in FIG. 1. EXAMPLE 3
Method for Estimation of Kinetic Solubility of Compounds of the Invention
[0330] The kinetic solubilities of compounds were estimated using a nephelometric (light scattering) method. Briefly, compounds of the invention were serially diluted in DMSO, followed by dilution in PBS pH 7.4. After incubation, the amount of light scattered by a compound at each concentration was measured. Clear solutions of soluble compounds do not scatter a light beam passed through the sample well and produce no signal. At concentrations above the solubility limit, the compound precipitates and the precipitant in the well scatters the light, generating a signal. Higher levels of precipitant in a well scatter more light and produce a stronger signal. [0331] A stock solution of a compound of the invention (25 mM in DMSO) was prepared, and was serially diluted in DMSO in two-fold increments in a row of a 96 well plate to a lowest concentration of 24 μM. A duplicate plate was prepared by transfer of half of the volume of each well to a new plate. Each well containing DMSO solution of the test compound was then diluted further (1 : 100) with phosphate buffered saline (pH 7.4) to provide aqueous solutions of compound at the following final concentrations: 250, 125, 62.5, 31.3, 15.6, 7.8, 3.9, 2.0, 1.0, 0.5 and 0.2 μM. All liquid handling stages were performed on a Beckman Coulter Biomek NX
Laboratory Automation Workstation. Each compound was diluted and tested in duplicate, providing four separate wells at each test concentration. [0332] The test solutions of compound were incubated at room temperature for 90 minutes and then analyzed using a Thermoskan Ascent nephelometric plate reader. The nephelometer protocol included two steps: first, the plate was shaken for 60 seconds at 1200 rpm, then each well of the plate was read in succession with an 800 ms settling delay between measurements. The total measurement time for a single plate was less than 4 minutes. [0333] The four values (in nephelometric units) obtained for each compound at each concentration were averaged and plotted on a log scale versus concentration. The concentration at which the nephelometric signal is > 110% of the value obtained for a DMSO/PBS blank is reported as the limit of solubility .
[0334] Biological data for exemplary compounds of the invention is provided in FIG. 1.
EXAMPLE 4
L929 Cells and Cultivation
[0335] For evaluation of compound effects on mammalian cells, L929 mouse fibroblast cells were used. Cells were maintained as adherent cultures in T-25 vented cap flasks in a humidified incubator at 370C in the presence of 5% CO2. Culture media was D-MEM supplemented with 10% fetal bovine serum and 1%
penicillin/streptomycin. L929 cells were maintained below confluent levels by sub- culturing at 1 :10 dilution twice weekly using 0.05% trypsin for detachment.
Cytotoxicity Evaluation
[0336] Sub-confluent L929 cells were trypsinized, resuspended in fresh media and 10 uL was counted using hemocytometer to determine cell concentration. Cells were diluted to 1 x 104 /mL in DMEM, dispensed (100 uL) into 96-well plates using a Multidrop 384 dispenser and allowed to attach overnight. Spent media was replaced with 99.5 uL fresh D-MEM and compounds to be tested were serially diluted in DMSO and 0.5 uL added using a Biomek NX liquid handler. Plates were incubated with a compound of the invention for 72 hrs at 37°C with 5% CO2. Resazurin (20 uL of 12.5 mg/ml stock) from Sigma- Aldrich was added to each well and plates were incubated for an additional 3-4 hrs. Assay plates were read using an En Vision plate reader at an excitation wavelength of 544 nm and emission of 590 nm. Single data points were used to generate sigmoidal dose response curves and determine IC50 values using XL fit curve fitting software from IDBS (Guildford, UK). [0337] Biological data for exemplary compounds of the invention is provided in FIG. 1.
EXAMPLE 5
Acute Murine Model A
[0338] Female Swiss Webster mice can be inoculated with 250,000 parasites of the LAB 110 Eatro strain of T. b. brucei. 24 hrs post-infection, treatment can be initiated BID for 4 days with 20 mg/kg/dose of a compound of the invention (40 mg/kg/day) intraperitoneally (IP) or orally (PO), 5 mg/kg BID or 10 mg/kg BID orally (PO). N=3 mice/group. Mice can be monitored for 30 days for survival. Pentamidine at 2 mg/kg IP can be used as the positive control.
EXAMPLE 6
Chronic CNS Model
[0339] Mice can be infected with 10,000 parasites of the TREU 667 strain of T. b. brucei. Twenty one days post-infection mice can be treated with a dose of between 6 and 100 mg/kg of the compound of the invention, either BID or QD for 7 days intraperitoneally (IP) or orally (PO). Positive control mice can be treated with Diminazene (10 mg/kg, IP) on Day 4 post-infection. Negative control mice can be treated with Diminazene (10 mg/kg, PO) on Day 21. Since Diminazene is not able to penetrate the CNS, mice treated at Day 21 are not able to cure the infection. Starting 1 week after the end of treatment, mice can be monitored for parasitemia and sacrificed if parasites are detected in the blood. Mice that survive 6 months are considered "cured."
EXAMPLE 7
Pharmacokinetic studies in mice:
[0340] Male CD-I mice weighing approximately 25 g can receive the compound of the invention by either intravenous (IV), oral gavage (OG) or intra-peritoneal (IP) routes. Animals in IV group (6-10 animals, 1-2 per time point) received a single bolus injection of approximately 2mg/kg of the compound of the invention. Animals receiving extra- vascular doses can be administered the compound of the invention as either single OG doses (6-10 animals, 1-2 per time point) of approximately 8mg/kg, or as 4 repeat doses (over 2 days) of approximately 25mg/kg or 50mg/kg by the IP route (6-10 animals, 1-2 per time point).
[0341] All doses can be administered as clear colorless solutions in either: 50% (v/v)PEG400 : 20% (v/v) ethanol : 30% (v/v) carboxymethylcellulose (0.5% w/v in sterile water for injection, WFI), or as in situ sodium salts in 5% (m/v) dextrose : 2% (v/v) ethanol in DWI. All dose solutions can be delivered at 4mL/kg. Animals can be fasted for at least 4 hours before dosing, and for 2 hours after dosing.
[0342] Blood samples and brain tissue can be sampled from 1 or 2
animals/timepoint/group immediately before dosing and approximately 0.17, 0.5, 1, 2, 3, 4, 6, 8, 12, 18 and 24hr after dosing for full pharmacokinetic and tissue analysis, or at 0.5, 2 and 4 hours post dosing to assess early-phase CNS disposition.
[0343] Bioanalysis for the compound of the invention in whole blood, plasma or brain tissue can be performed by HPLC with tandem mass spectrometry (LC-MSMS). Whole blood and plasma samples can be treated with 3 volumes of either acetonitrile or methanol to precipitate plasma proteins. Treated samples can be centrifuged and supernatants removed for analysis. Brain tissues can be weighed and homogenized mechanically in the presence of 1 volume of phosphate-buffered saline (PBS). The resulting tissue suspensions can be then diluted with a further volume of PBS, and then treated in the same manner as whole blood or plasma. [0344] Extracted samples can be assayed for compound of the invention by means of LC-MSMS employing reversed-phase chromatography coupled to a triple quadrupole mass spectrometer employing electrospray ionization in the positive ion mode. The analytical column can be a Phenomenex Luna 3μ C8 50 x 2mm, with an online sample purification step performed on a Phenomenex Synergi 4μ Polar RP 50 x 2mm column.
[0345] Test articles can be eluted using a binary mobile phase gradient comprising 5mM Ammonium Acetate: 0.1% formic acid in either MeOH or H2O.
[0346] Non-compartmental analysis of plasma compound of the invention concentration versus time can be performed in Microsoft Excel to generate
pharmacokinetic parameters including: area under the curve (AUC), clearance (as Cl or Cl/F), volume of distribution (Vdss), half-life (tl/2), and bioavailability (F). Pharmacokinetic studies in rats:
[0347] Male Sprague Dawley rats weighing approximately 20Og can receive a compound of the invention as a single oral gavage (OG) dose of approximately 25mg/kg (approximately 10 animals per group). [0348] All doses can be administered as clear colorless solutions as in situ sodium salts in 5% (m/v) dextrose : 2% (v/v) ethanol in DWI. All dose solutions can be delivered at 2mL/kg. Animals can be fasted for at least 4 hours before dosing, and for 2 hours after dosing.
[0349] Blood and CSF samples and brain tissue can be sampled from 1
animal/timepoint/group immediately before dosing and approximately 0.5, 1, 2, 3, 4, 6, 8, 12, 18 and 24hr after dosing for full pharmacokinetic (plasma and CSF) and tissue (Brain) analysis.
EXAMPLE 8
Leishmania donovani Strain and Cultivation
[0350] All experiments were conducted with the axenic amastigote-form of the following parasite: Leishmania donovani strain 1S-CL2D from Sudan, World Health Organization (WHO) designation: (MHOM/SD/62/1S-CL2D). Parasites were cultured in T-25 vented cap flasks and kept in humidified incubators at 37°C and 5% CO2. The axenic parasite culture media was RPMI- 1640/MES/pH 5.5 formulated and prepared as described by Debrabant et. al. (International Journal for Parasitology 2004, Volume 34, page 205-217). To ensure log growth phase, axenic amastigotes were sub-cultured at appropriate dilutions every 2-3 days.
In Vitro Drug Sensitivity Assays
[0351] Cultures of axenic amastigotes growing in the log phase were passed through a 22 gauge blunt needle to break up the clumps, diluted 1 : 10 in RPMI- 1640/MES medium and counted using hemocytometer to determine parasite concentration. Amastigotes were diluted to 2 x 105 /mL in RPMI- 1640/MES medium to generate a 2-fold working concentration for assay. Compounds to be tested were serially diluted in DMSO and 0.5 μ L added to 50 μL HMI-9 in triplicate 96-well plates using a Biomek NX liquid handler. Parasites from the diluted stock were added to each well (50 μL) using a Multidrop 384 dispenser to give a final concentration of 1.OxlO5/ml parasites in 0.5% for DMSO. Amastigotes were incubated with compounds for 72 hrs at 37°C with 5% CO2. Resazurin (10 μL of 12.5 mg/ml stock) from Sigma- Aldrich was added to each well and plates were incubated for an additional 2-3 hrs. Assay plates were read using an En Vision plate reader at an excitation wavelength of 544 nm and emission of 590 nm. Triplicate data points were averaged to generate sigmoidal dose response curve and determine IC50 values using XLfit curve fitting software from IDBS (Guildford, UK).
[0352] Biological data for exemplary compounds of the invention is provided in FIG. 1. EXAMPLE 9
Activity against Trypanosoma brucei rhodesiense
[0353] This stock was isolated in 1982 from a human patient in Tanzania and after several mouse passages cloned and adapted to axenic culture conditions (Baltz et al (1985) EMBO Journal 4: 1273-1277; Thuita et al (2008) Acta Tropica 108:6-10.) Minimum Essential Medium (50 μl) supplemented with 25 mM HEPES, lg/1 additional glucose, 1% MEM non-essential amino acids (10Ox), 0.2 mM 2- mercaptoethanol, ImM Na-pyruvate and 15% heat inactivated horse serum was added to each well of a 96-well microtiter plate. Serial drug dilutions of seven 3-fold dilution steps covering a range from 90 to 0.123 μg/ml were prepared. Then 104 bloodstream forms of T. b. rhodesiense STIB 900 in 50 μl was added to each well and the plate incubated at 37 0C under a 5 % CO2 atmosphere for 72 h. 10 μl Alamar Blue (resazurin, 12.5 mg in 100 ml double-distilled water) was then added to each well and incubation continued for a further 2-4 h (Raz et al. (1997) Acta Trop 68:139-47). Then the plates were read with a Spectramax Gemini XS microplate fluorometer (Molecular Devices Cooperation, Sunnyvale, CA, USA) using an excitation wave length of 536 nm and an emission wave length of 588 nm. Data were analyzed using the microplate reader software Softmax Pro (Molecular Devices Cooperation, Sunnyvale, CA, USA).
[0354] Biological data for exemplary compounds of the invention is provided in FIG. 1. EXAMPLE 10
Activity against T. cruzi
[0355] Rat skeletal myoblasts (L-6 cells) were seeded in 96-well microtitre plates at 2000 cells/well in 100 μL RPMI 1640 medium with 10% FBS and 2 mM 1- glutamine. After 24 h the medium was removed and replaced by 100 μl per well containing 5000 trypomastigote forms of T. cruzi Tulahuen strain C2C4 containing the β-galactosidase (Lac Z) gene (Buckner et al. (1996) Efficient technique for screening drugs for activity against Trypanosoma cruzi using parasites expressing beta-galactosidase, p. 2592-2597, vol. 40). After 48 h the medium was removed from the wells and replaced by 100 μl fresh medium with or without a serial drug dilution of seven 3-fold dilution steps covering a range from 90 to 0.123 μg/ml. After 96 h of incubation the plates were inspected under an inverted microscope to assure growth of the controls and sterility. Then the substrate CPRG/Nonidet (50 μl) was added to all wells. A color reaction developed within 2-6 h and could be read photometrically at 540 nm. Data were transferred into the graphic programme Softmax Pro (Molecular Devices), which calculated IC50 values.
[0356] Biological data for exemplary compounds of the invention is provided in FIG. 1.
[0357] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

WHAT IS CLAIMED IS:
1. A compound having a structure according to the following formula:
Figure imgf000109_0001
wherein
Z is S or O;
X is selected from the group consisting of substituted phenyl, substituted or unsubstituted heteroaryl, and unsubstituted cycloalkyl or a salt thereof.
2. The compound of claim 1, having a structure according to the following formula:
Figure imgf000109_0002
wherein
R4 is halogen; and
R2 is a member selected from halogen or unsubstituted Ci or C2 or C3 or C4 or Ci or C5 or C6 alkyl or unsubstituted Ci or C2 or C3 or C4 or Ci or C5 or C6 alkoxy or halosubstituted Ci or C2 or C3 or C4 or Ci or C5 or C6 alkyl or halosubstituted Ci or C2 or C3 or C4 or Ci or C5 or C6 alkoxy Or NR7R8
wherein
R7 is H or unsubstituted Ci or C2 or C3 or C4 or Ci or C5 or C6 alkyl and
R8 is H or unsubstituted Ci or C2 or C3 or C4 or Ci or C5 or C6 alkyl.
3. The compound of claim 1, having a structure according to the following formula:
Figure imgf000109_0003
wherein
R4 is halogen; and R2 is a member selected from F, Cl, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF3, OCH3, OCH2CH3, OCF3 and N(CH3)2.
4. The compound of claim 1, having a structure according to the following formula:
Figure imgf000110_0001
wherein
R4 is halogen; and
R2 is a member selected from halogen, unsubstituted Ci or C2 or C3 or C4 or Ci or Cs or C6 alkyl and halosubstituted Ci or C2 or C3 or C4 or Ci or C5 or C6 alkyl.
5. The compound of claim 1, having a structure according to the following formula:
Figure imgf000110_0002
wherein
R4 is halogen; and
R2 is a member selected from Cl, CH3 and CF3.
6. A pharmaceutical formulation comprising:
a) the compound of claim 1, or a salt thereof; and
b) a pharmaceutically acceptable excipient.
7. A method of killing and/or preventing the growth of a protozoa, comprising: contacting the protozoa with an effective amount of the compound of claim 1, thereby killing and/or preventing the growth of the protozoa.
8. A method of treating and/or preventing a disease in an animal, comprising: administering to the animal a therapeutically effective amount of the compound of claim 1, thereby treating and/or preventing the disease.
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011116348A1 (en) * 2010-03-19 2011-09-22 Anacor Pharmaceuticals, Inc. Boron-containing small molecules as anti-protozoal agent
US8716478B2 (en) 2010-01-27 2014-05-06 Anacor Pharmaceuticals, Inc. Boron-containing small molecules
WO2014149793A1 (en) * 2013-03-15 2014-09-25 Eli Lilly And Company 1 -hydroxy-benzooxaboroles as antiparasitic agents
US9138002B2 (en) 2013-01-30 2015-09-22 Agrofresh Inc. Compounds and compositions
WO2016001834A1 (en) 2014-07-01 2016-01-07 Daiichi Sankyo Company, Limited Tricyclic benzoxaboroles as antibacterial agents
US9426996B2 (en) 2013-01-30 2016-08-30 Agrofresh Inc. Use of benzoxaboroles as volatile antimicrobial agents on meats, plants, or plant parts
US9440994B2 (en) 2009-08-14 2016-09-13 Anacor Pharmaceuticals, Inc. Boron containing small molecules as antiprotozoal agents
US9585396B2 (en) 2013-01-30 2017-03-07 Agrofresh Inc. Volatile applications against pathogens
US10070649B2 (en) 2013-01-30 2018-09-11 Agrofresh Inc. Volatile applications against pathogens
WO2020123881A1 (en) * 2018-12-12 2020-06-18 Boragen, Inc. Boron containing compounds and their uses
US10966429B2 (en) 2016-03-07 2021-04-06 Agrofresh Inc. Synergistic methods of using benzoxaborole compounds and preservative gases as an antimicrobial for crops
US11039617B2 (en) 2013-01-30 2021-06-22 Agrofresh Inc. Large scale methods of uniformly coating packaging surfaces with a volatile antimicrobial to preserve food freshness

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006079843A1 (en) * 2005-01-31 2006-08-03 Cambridge Enterprise Limited Sensor molecules incorporating a boronic acid sensor group
US20060234981A1 (en) 2005-02-16 2006-10-19 Anacor Pharmaceuticals Boron-containing small molecules
US20070155699A1 (en) 2005-02-16 2007-07-05 Anacor Pharmaceuticals Boron-containing small molecules
WO2007095638A2 (en) * 2006-02-16 2007-08-23 Anacor Pharmaceuticals, Inc. Boron-containing small molecules as anti-inflammatory agents
US20070286822A1 (en) * 2006-06-12 2007-12-13 Anacor Pharmaceuticals Inc. Compounds for the Treatment of Periodontal Disease
WO2008157726A1 (en) 2007-06-20 2008-12-24 Anacor Pharmaceuticals, Inc. Boron-containing small molecules
WO2010045505A1 (en) * 2008-10-15 2010-04-22 Anacor Pharmaceuticals, Inc Boron-containing small molecules as anti-protozoal agents
WO2010045503A1 (en) * 2008-10-15 2010-04-22 Anacor Pharmaceuticals, Inc. Boron-containing small molecules as anti-protozoal agents

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006079843A1 (en) * 2005-01-31 2006-08-03 Cambridge Enterprise Limited Sensor molecules incorporating a boronic acid sensor group
US20060234981A1 (en) 2005-02-16 2006-10-19 Anacor Pharmaceuticals Boron-containing small molecules
US20070155699A1 (en) 2005-02-16 2007-07-05 Anacor Pharmaceuticals Boron-containing small molecules
WO2007095638A2 (en) * 2006-02-16 2007-08-23 Anacor Pharmaceuticals, Inc. Boron-containing small molecules as anti-inflammatory agents
US20070293457A1 (en) 2006-02-16 2007-12-20 Baker Stephen J Boron-containing small molecules as anti-inflammatory agents
US20070286822A1 (en) * 2006-06-12 2007-12-13 Anacor Pharmaceuticals Inc. Compounds for the Treatment of Periodontal Disease
WO2008157726A1 (en) 2007-06-20 2008-12-24 Anacor Pharmaceuticals, Inc. Boron-containing small molecules
WO2010045505A1 (en) * 2008-10-15 2010-04-22 Anacor Pharmaceuticals, Inc Boron-containing small molecules as anti-protozoal agents
WO2010045503A1 (en) * 2008-10-15 2010-04-22 Anacor Pharmaceuticals, Inc. Boron-containing small molecules as anti-protozoal agents

Non-Patent Citations (18)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy, 21 st Ed", 2005, LIPPINCOTT, WILLIAMS & WILKINS
BALTZ ET AL., EMBO JOURNAL, vol. 4, 1985, pages 1273 - 1277
BERGE ET AL.: "Pharmaceutical Salts", JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1977, pages 1 - 19
BUCKNER ET AL., EFFICIENT TECHNIQUE FOR SCREENING DRUGS FOR ACTIVITY AGAINST TRYPANOSOMA CRUZI USING PARASITES EXPRESSING BETA-GALACTOSIDASE, vol. 40, 1996, pages 2592 - 2597
DEBRABANT, INTERNATIONAL JOURNAL FOR PARASITOLOGY, vol. 34, 2004, pages 205 - 217
FINGL ET AL.: "The Pharmacological Basis of Therapeutics", 1975, pages: 1
HIRUMI, JOURNAL OFPARASITOLOGY, vol. 75, 1989, pages 985
KUHNZ; GIESCHEN, DRUG METABOLISM AND DISPOSITION, vol. 26, 1998, pages 1120 - 1127
KUHNZ; GLESCHEN, DRUG METABOLISM AND DISPOSITION, vol. 26, 1998, pages 1120 - 1127
LENNARZ W J ET AL: "Arylboronic acids. IV. Reactions of boronophthalide", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 82, May 1960 (1960-05-01), pages 2172 - 2175, XP002376014, ISSN: 0002-7863, DOI: 10.1021/JA01494A021 *
MAEHR, J. CHEM. ED., vol. 62, 1985, pages 114 - 120
MERRITT ET AL.: "Diffusion Apparatus for Skin Penetration", J OFCONTROLLED RELEASE, vol. I, 1984, pages 161 - 162
ORAVCOVA ET AL., J. CHROMAT., vol. B677, 1996, pages 1 - 27
ORAVCOVA, JOURNAL OF CHROMATOGRAPHY B, vol. 677, 1996, pages 1 - 27
RAZ ET AL., ACTA TROP, vol. 68, 1997, pages 139 - 47
THUITA ET AL., ACTA TROPICA, vol. 108, 2008, pages 6 - 10
WILLIAMS ET AL., J. OF MEDICINAL CHEM., vol. 42, 1999, pages 1481 - 1485
WILSON ET AL: "Harrison's Principles of Internal Medicine,12th ed", 1991, pages: 93 - 98

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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US8716478B2 (en) 2010-01-27 2014-05-06 Anacor Pharmaceuticals, Inc. Boron-containing small molecules
US9499570B2 (en) 2010-01-27 2016-11-22 Anacor Pharmaceuticals, Inc. Boron containing small molecules
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