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WO2011063293A1 - Petites molécules contenant du bore en tant qu'agents antihelminthes - Google Patents

Petites molécules contenant du bore en tant qu'agents antihelminthes Download PDF

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Publication number
WO2011063293A1
WO2011063293A1 PCT/US2010/057515 US2010057515W WO2011063293A1 WO 2011063293 A1 WO2011063293 A1 WO 2011063293A1 US 2010057515 W US2010057515 W US 2010057515W WO 2011063293 A1 WO2011063293 A1 WO 2011063293A1
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exemplary embodiment
compound
unsubstituted
substituted
compounds
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PCT/US2010/057515
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English (en)
Inventor
Yong-Kang Zhang
Huchen Zhou
Charles Ding
Jacob J. Plattner
Yvonne Freund
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Anacor Pharmaceuticals, Inc.
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Publication of WO2011063293A1 publication Critical patent/WO2011063293A1/fr

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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 Table
    • 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
    • A61P33/10—Anthelmintics

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 infections by worms, pharmaceutical compositions containing such compounds, as well as combinations of these compounds with at least one additional therapeutically effective agent.
  • FIG. 1 provides a description of in vitro screening of 29 oxaboroles against the adult worms of B. malayi.
  • the chart showed 15 compounds which killed adult worms of B. malayi in 1 to 2 days, compared to 16 to 19 days for the positive control albendazole.
  • FIG. 2 shows that one of the most potent compounds, J15, kills 100% of worms when administered at 0.01 mM in 24 h compared to J13 which loses efficacy at 10 mM.
  • FIG. 3 shows the structure activity relationship of certain oxaboroles against adult B. malayi in vitro.
  • 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.
  • 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 0 is di-tert-butyl dicarbonate; Bz is, in general, benzoyl; BzOOH is benzoyl peroxide; Cbz or Z is benzyloxycarbonyl or carboxybenzyl;
  • Cs 2 C0 3 is cesium carbonate
  • CSA is 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
  • POCl 3 is phosphorus chloride oxide
  • PTSA is /?ara-toluene sulfonic acid
  • Pyr. or Pyr or Py as used herein means Pyridine; RT or rt or r.t. is room temperature; sat.
  • (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 antibiotics discussed herein as well as acids, bases, salt forms (such as pharmaceutically acceptable salts), prodrugs, solvates and hydrates of these compounds and antibiotics.
  • MIC or minimum inhibitory concentration, is the point where the compound stops more than 50% of cell growth, preferably 60%> of cell growth, preferably 70%> of cell growth, preferably 80%> of cell growth, preferably 90%> of cell growth, relative to an untreated control.
  • 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 0- 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).
  • 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 homo logs 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
  • alkylene 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.
  • alkenylene by itself or as part of another substituent means a divalent radical derived from an alkene.
  • cycloalkylene by itself or as part of another substituent means a divalent radical derived from a cycloalkyl.
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from an heteroalkane.
  • heterocycloalkylene by itself or as part of another substituent means a divalent radical derived from an heteroalkane.
  • arylene by itself or as part of another substituent means a divalent radical derived from an 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.
  • 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.
  • 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, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-.
  • 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.
  • 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-C4)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.
  • 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(0)CH 3 , -C(0)CF 3 ,
  • 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-, -0-, -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 -A-(CH 2 ) r -B-, wherein A and B are independently -CRR'-, -0-, -NR-, -S-, -S(O)-, -S(0) 2 -, -S(0) 2 NR'- 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.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula
  • 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).
  • 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.
  • 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.
  • 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, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,
  • 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 stereoisomer ⁇ 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). 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.
  • excipients is conventionally known to mean carriers, diluents and/or vehicles used in formulating drug compositions effective for the desired use.
  • topical administration refers to the application of a
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • Antihelminth is a compound which can kill or inhibit the growth of a helminth.
  • the term antihelminth is broad enough to encompass acids, bases, salt forms (such as pharmaceutically acceptable salts), prodrugs, solvates and hydrates of the antihelminth compound.
  • microbial infection or "infection by a microorganism” refers to any infection of a host by an infectious agent including, but not limited to, bacteria (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).
  • Biological 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.
  • 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.
  • Dative bonds are usually weaker than covalent bonds.
  • a boron is covalently bonded to at least one oxygen, sulfur or nitrogen, and is at the same time datively bonded to an oxygen, sulfur or nitrogen, respectively, the dative bond and covalent bond between the boron and the two identical heteroatoms can interconvert or be in the form of a resonance hybrid.
  • the electrons in such bonds may be partially or fully delocalized.
  • 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 homologs 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.
  • salt counterions include H + , H 3 0 + , ammonium, potassium, calcium, magnesium 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 nature of the dative bond between the boron and one of the oxygens. 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 0 + , calcium, sodium, ammonium and potassium. The salts of these compounds are implicitly contained in descriptions of these compounds.
  • the present 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 worm 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 compound has a structure which is:
  • R 5 is H or halogen and R 1 or R 2 is selected from the group consisting of: alkoxy, optionally substituted with a substituted or unsubstituted phenyl; alkoxy, optionally substituted with a substituted or unsubstituted heteroaryl; alkylamino, optionally substituted with a substituted or unsubstituted phenyl;
  • alkylamino optionally substituted with a substituted or unsubstituted heteroaryl; - NHC(0)R n , wherein R 11 is unsubstituted phenyl or unsubstituted heteroaryl; - NHS(0)2R U , wherein R 11 is unsubstituted phenyl or unsubstituted heteroaryl; - NHC(0)R 12 , wherein R 12 is unsubstituted alkyl; -C(0)NHR 12 , wherein R 12 is unsubstituted alkyl, or a hydrate, solvate or salt thereof.
  • the compound has a structure which is: wherein R 5 is H or halogen and R 1 or R 2 is selected from the group consisting of: alkoxy, optionally substituted with a substituted or unsubstituted phenyl; alkoxy, optionally substituted with a substituted or unsubstituted heteroaryl; alkylamino, optionally substituted with a substituted or unsubstituted phenyl; alkylamino, optionally substituted with a substituted or unsubstituted heteroaryl; -NHC(0)R n , wherein R 11 is unsubstituted phenyl or unsubstituted heteroaryl; -NHS(0) 2 R U , wherein R 11 is unsubstituted phenyl or unsubstituted heteroaryl; -NHC(0)R 12 , wherein R 12 is unsubstituted alkyl; -C(0)NHR 12 , wherein R 12
  • the compound has a structure which is:
  • R 5 is H or halogen and R is selected from the group consisting of: alkoxy, optionally substituted with a substituted or unsubstituted phenyl; alkoxy, optionally substituted with a substituted or unsubstituted heteroaryl; alkylamino, optionally substituted with a substituted or unsubstituted phenyl; alkylamino, optionally substituted with a substituted or unsubstituted heteroaryl; -NHC(0)R n , wherein R 11 is unsubstituted phenyl or unsubstituted heteroaryl; -NHS(0) 2 R U , wherein R 11 is unsubstituted phenyl or unsubstituted heteroaryl; -NHC(0)R 12 , wherein R 12 is unsubstituted alkyl; -C(0)NHR 12 , wherein R 12 is unsubstituted alkyl, or a hydrate, solvate or salt thereof
  • the compound has a structure which is: wherein R 5 is H or halogen and R 1 or R 2 is selected from the group consisting of: alkoxy, optionally substituted with a substituted or unsubstituted phenyl; alkoxy, optionally substituted with a substituted or unsubstituted heteroaryl; alkylamino, optionally substituted with a substituted or unsubstituted phenyl; alkylamino, optionally substituted with a substituted or unsubstituted heteroaryl; -NHC(0)R n , wherein R 11 is unsubstituted phenyl or unsubstituted heteroaryl; -NHS(0)2R U , wherein R 11 is unsubstituted phenyl or unsubstituted heteroaryl; -NHC(0)R 12 , wherein R 12 is unsubstituted alkyl; -C(0)NHR 12 , wherein R 12
  • the compound has a structure according to the formula:
  • R 5 is H or halogen and R 1 is alkoxy, substituted with a substituted or unsubstituted heteroaryl.
  • said heteroaryl is selected from the group consisting of pyridinyl, imidazolyl, thiazolyl and pyrimidinyl.
  • R 5 is H or halogen and R 1 is methoxy or ethoxy or propoxy, substituted with pyridinyl, imidazolyl, thiazolyl and pyrimidinyl.
  • R 5 is H or halogen and R 1 is methoxy or ethoxy or propoxy, substituted with a substituted or unsubstituted heteroaryl.
  • R 5 is H or halogen and R 1 is methoxy or ethoxy or propoxy, substituted with a substituted or unsubstituted pyridinyl or substituted or unsubstituted imidazolyl or substituted or unsubstituted thiazolyl or substituted or unsubstituted pyrimidinyl.
  • R 5 is as described herein and R 1 is pyridinylmethoxy.
  • R 5 is as described herein and R 1 is pyridin-2-ylmethoxy.
  • R 5 is as described herein and R 1 is pyridin-3-ylmethoxy.
  • R 5 is as described herein and R 1 is pyridin-4-ylmethoxy. In an exemplary embodiment, R 5 is as described herein and R 1 is imidazolylmethoxy. In an exemplary embodiment, R 5 is as described herein and R 1 is imidazol-2- ylmethoxy. In an exemplary embodiment, R 5 is as described herein and R 1 is thiazolylmethoxy. In an exemplary embodiment, R 5 is as described herein and R 1 is thiazol-2-ylmethoxy. In an exemplary embodiment, R 5 is as described herein and R 1 is pyrimidinylmethoxy.
  • R 5 is as described herein and R 1 is pyrimidin-6-ylmethoxy. In an exemplary embodiment, R 5 is as described herein and R 1 is methoxy substituted with a substituted or unsubstituted heteroaryl. In an exemplary embodiment, R 5 is as described herein and R 1 is ethoxy substituted with a substituted or unsubstituted phenyl. In an exemplary embodiment, R 5 is as described herein and R 1 is propoxy substituted with a substituted or unsubstituted phenyl. In an exemplary embodiment, R 5 is as described herein and R 1 is butoxy substituted with a substituted or unsubstituted phenyl. In an exemplary embodiment, R 1 is as described herein and R 5 is H. In an exemplary embodiment, R 1 is as described herein and R 5 is F.
  • the compound has a structure according to the formula:
  • R 5 is H or halogen and R 1 is alkoxy, substituted with a substituted or unsubstituted phenyl.
  • R 5 is as described herein and R 1 is benzoxy.
  • R 5 is as described herein and R 1 is methoxy substituted with a substituted phenyl.
  • R 5 is as described herein and R 1 is ethoxy substituted with a substituted or unsubstituted phenyl.
  • R 5 is as described herein and R 1 is propoxy substituted with a substituted or unsubstituted phenyl.
  • R 5 is as described herein and R 1 is butoxy substituted with a substituted or unsubstituted phenyl. In an exemplary embodiment, R 5 is as described herein and R 1 is alkoxy, substituted with an aminomethylsubstituted phenyl. In an exemplary embodiment, R 5 is as described herein and R 1 is alkoxy, substituted with a phenyl which is substituted with a mono-unsubstituted alkylaminomethyl moiety. In an exemplary embodiment, R 5 is as described herein and R 1 is alkoxy, substituted with a phenyl with is substituted with a di-unsubstituted alkylaminomethyl moiety. In an exemplary embodiment, R 1 is as described herein and R 5 is H. In an exemplary embodiment, R 1 is as described herein and R 5 is F.
  • the compound has a structure according to the formula:
  • R 5 is H or halogen and R 4a is alkylene
  • R 21 and R 22 are each
  • R 5 is H or halogen and R 4a is methylene or ethylene or propylene
  • R 21 and R 22 are each independently selected from H or methyl or ethyl or unsubstituted C 3 alkyl or unsubstituted C 4 alkyl or unsubstituted C 5 alkyl or unsubstituted C 6 alkyl.
  • R 5 is H or halogen and R 4a is methylene or ethylene or propylene
  • R 21 is H and R 22 is H.
  • R 5 is H or halogen and R 4a is methylene or ethylene or propylene
  • R 21 is H and R 22 is H or methyl or ethyl or unsubstituted C 3 alkyl or unsubstituted C 4 alkyl or unsubstituted C 5 alkyl or unsubstituted C 6 alkyl.
  • R 5 is H or halogen and R 4a is methylene or ethylene or propylene
  • R 21 is H and R 22 is H or methyl or ethyl or unsubstituted C 3 alkyl.
  • R 5 is H or F and R 4a is methylene
  • R 21 and R 22 are each
  • R 5 is H or F and R 4a is methylene
  • R 21 and R 22 are each independently selected from H or methyl or ethyl or unsubstituted C 3 alkyl
  • R 5 is H or F and R 4a is methylene
  • R 21 is H and R 22 are each independently selected from H or methyl or ethyl or unsubstituted C 3 alkyl.
  • R 5 is H or F and R 4a is methylene
  • R 21 and R 22 are each independently selected from methyl or ethyl or unsubstituted C 3 alkyl.
  • the compound has a structure according to the formula:
  • R 1 is halogen and R 5 is H or halogen.
  • R 5 when R 1 is CI, R 5 is not H.
  • R 5 is as described herein and R 1 is F.
  • R 5 is as described herein and R 1 is CI.
  • R 5 is as described herein and R 1 is Br.
  • R 5 is as described herein and R 1 is I.
  • R 1 is as described herein and R 5 is H.
  • R 1 is as described herein and R 5 is F.
  • the compound has a structure according to the formula:
  • R 3 is H or unsubstitute ogen.
  • R 5 when R 3 is methyl, R 5 is not H.
  • R 5 is as described herein and R 3 is unsubstituted Ci-C 6 alkyl.
  • R 5 is as described herein and R 3 is H.
  • R 5 is as described herein and R 3 is methyl.
  • R 5 is as described herein and R 3 is ethyl.
  • R 5 is as described herein and R 3 is unsubstituted C 3 alkyl.
  • R 5 is as described herein and R 3 is is isopropyl.
  • R 5 is as described herein and R 3 is unsubstituted C 4 alkyl. In an exemplary embodiment, R 5 is as described herein and R 3 is t-butyl. In an exemplary embodiment, R 5 is as described herein and R 3 is unsubstituted C 5 alkyl. In an exemplary embodiment, R 5 is as described herein and R 3 is unsubstituted C 6 alkyl. In an exemplary embodiment, R 3 is as described herein and R 5 is H. In an exemplary embodiment, R 3 is as described herein and R 5 is F.
  • the compound has a structure according to the formula: wherein R 5 is H or halogen. In an exemplary embodiment, R 5 is H. In an exemplary embodiment, R 5 is F.
  • the compound has a structure according to the formula:
  • R 5 is H or halogen. In an exemplary embodiment, R 5 is H. In an exemplary embodiment, R 5 is F.
  • the compound has a structure according to the formula:
  • R 5 is H or halogen. In an exemplary embodiment, R 5 is H. In an exemplary embodiment, R 5 is F.
  • the compound has a structure according to the formula:
  • R 5 is H or halogen. In an exemplary embodiment, R 5 is halogen. In an exemplary embodiment, R 5 is F.
  • the compound has a structure according to the formula:
  • R 1 is halogen and R 5 is H or halogen.
  • R 5 when R 1 is CI, R 5 is not H.
  • R 5 is as described herein and R 1 is F.
  • R 5 is as described herein and R 1 is CI.
  • R 5 is as described herein and R 1 is Br.
  • R 5 is as described herein and R 1 is I.
  • R 1 is as described herein and R 5 is H.
  • R 1 is as described herein and R 5 is F.
  • the compound has a structure according to the formula:
  • R 3 is H or unsubstituted alkyl and R 5 is H or halogen.
  • R 5 is as described herein and R 3 is unsubstituted Ci-C 6 alkyl.
  • R 3 is methyl, R 5 is not H.
  • R 5 is as described herein and R 3 is H. In an exemplary embodiment, R 5 is as described herein and R 3 is methyl. In an exemplary embodiment, R 5 is as described herein and R 3 is ethyl. In an exemplary embodiment, R 5 is as described herein and R 3 is unsubstituted C 3 alkyl. In an exemplary embodiment, R 5 is as described herein and R 3 is unsubstituted C 4 alkyl. In an exemplary embodiment, R 5 is as described herein and R 3 is unsubstituted C 5 alkyl. In an exemplary embodiment, R 5 is as described herein and R 3 is unsubstituted C 6 alkyl. In an exemplary embodiment, R 3 is as described herein and R 5 is H. In an exemplary embodiment, R 3 is as described herein and R 5 is F.
  • the compound has a structure according to the formula:
  • R 8 is unsubstituted alkyl alogen.
  • R 5 is not H.
  • R 5 is as described herein and R 8 is unsubstituted Ci-C 6 alkylene.
  • R 5 is as described herein and R 8 is methylene. In an exemplary embodiment, R 5 is as described herein and R 8 is ethylene. In an exemplary embodiment, R 5 is as described herein and R 8 is propylene. In an exemplary embodiment, R 5 is as described herein and R 8 is butylene. In an exemplary embodiment, R 5 is as described herein and R 8 is pentylene. In an exemplary embodiment, R 5 is as described herein and R 8 is hexylene. In an exemplary embodiment, R 8 is as described herein and R 5 is H. In an exemplary embodiment, R 8 is as described herein and R 5 is F.
  • the compound has a structure according to the formula:
  • R 8 is unsubstituted alky logen.
  • R 5 is not H.
  • R 5 is as described herein and R 8 is unsubstituted Ci-C 6 alkylene.
  • R 5 is as described herein and R 8 is not ethylene. In an exemplary embodiment, R 5 is as described herein and R 8 is not methylene, ethylene, and propylene. In an exemplary embodiment, R 5 is as described herein and R 8 is methylene. In an exemplary embodiment, R 5 is as described herein and R 8 is ethylene. In an exemplary embodiment, R 5 is as described herein and R 8 is propylene. In an exemplary embodiment, R 5 is as described herein and R 8 is butylene. In an exemplary embodiment, R 5 is as described herein and R 8 is pentylene. In an exemplary embodiment, R 5 is as described herein and R 8 is hexylene. In an exemplary embodiment, R 8 is as described herein and R 5 is H. In an exemplary embodiment, R 8 is as described herein and R 5 is F.
  • the compound has a structure according to the formula:
  • R 1 is selected from the group consisting of F, Br and I, R 8 is as described herein, and R 5 is H or halogen. In an exemplary embodiment, R 1 and R 8 are as described herein and R 5 is H. In an exemplary embodiment, R 1 and R 8 are as described herein and R 5 is F.
  • the compound has a structure according to the formula: wherein R 8 is as described h .
  • R 5 is not H.
  • R 8 is unsubstituted alkylene.
  • R 8 is as described herein and R 5 is H.
  • R 8 is as described herein and R 5 is F.
  • the compound has a structure according to the formula:
  • R 3 is H or unsubstitute ogen.
  • R 5 is not H.
  • R 3 is as described herein.
  • R 3 is as described herein and R 5 is H.
  • R 3 is as described herein and R 5 is F.
  • the compound has a structure which is selected from the group consisting of:
  • R 9 and R 5 as described herein, and R 3a is S.
  • R 3a and R 9 are as described herein, and R 5 is F.
  • R 3a and R 9 are as described herein, and R 5 is H.
  • R 3a and R 9 are as described herein, and R 5 is F.
  • R 3a and R 5 as described herein, and R 9 is F.
  • R 3a and R 5 as described herein, and R 9 is CI.
  • R 3a and R 5 as described herein, and R 9 is methoxy. In an exemplary embodiment, R 3a and R 5 as described herein, and R 9 is ethoxy. In an exemplary embodiment, R 3a and R 5 as described herein, and R 9 is unsubstituted C 3 alkoxy. In an exemplary embodiment, R 3a and R 5 as described herein, and R 9 is unsubstituted C 4 alkoxy. In an exemplary embodiment, R 3a and R 5 as described herein, and R 9 is unsubstituted C 5 alkoxy. In an exemplary embodiment, R 3a and R 5 as described herein, and R 9 is unsubstituted C 6 alkoxy.
  • R 9 is described herein, R 3a is S, and R 5 is H.
  • R 9 is methoxy
  • R 3a is S
  • R 5 is as described herein.
  • R 3a is described herein, and R 5 is H
  • R 9 is F or CI or methoxy or ethoxy or unsubstituted C 3 alkoxy or unsubstituted C 4 alkoxy or unsubstituted C 5 alkoxy or unsubstituted C 6 alkoxy.
  • R 3a is S
  • R 5 is F
  • R 9 is F or CI or methoxy or ethoxy or unsubstituted C 3 alkoxy or unsubstituted C 4 alkoxy or unsubstituted C 5 alkoxy or unsubstituted C 6 alkoxy.
  • the compound has a structure according to the formula:
  • R 3a , R 9 , and R 5 are as described herein.
  • the compound has a structure which is selected from the roup consisting of:
  • the compound has a structure selected from the group consisti
  • R 3a is selected from the group consisting of S, SO and S0 2 , and R 5 is H or halogen.
  • R 5 as described herein, and R 3a is S.
  • R 3a is as described herein, and R 5 is F.
  • R 3a is as described herein, and R 5 is H.
  • R 5 is as described herein, and R 3a is S.
  • R 3a is S, and R 5 is H.
  • the compound is:
  • 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. [0097] In an exemplary embodiment, alkyl is linear alkyl. In another exemplary embodiment, alkyl is branched alkyl.
  • heteroalkyl is linear heteroalkyl. In another exemplary embodiment, heteroalkyl is branched heteroalkyl.
  • 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.
  • z is a first compound in a composition
  • y is a second compound in the composition
  • the first compound is a non-superimposable mirror image of the second compound
  • 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.
  • 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
  • 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 at least one stereocenter, and at least one stereoisomer 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 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.
  • 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.
  • 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 diasteromer 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 diasteromer of the first compound of the invention.
  • 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%.
  • 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%.
  • the first compound of the invention has at least one stereocenter and is enantiomerically pure (enantiomeric excess is about 100%).
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • enantiomeric or diastereomeric excess can be determined relative to exactly one other stereoisomer, or can be determined relative
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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 comopund, 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.
  • each compound of the invention 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.
  • the additional therapeutic agent is an antiworm agent.
  • the additional therapeutic agent is an antihelmintic agent.
  • the additional therapeutic agent is selected from the group consisting of abamectin, diethylcarbamazine, mebendazole, niclosamide, suramin, thiabendazole, pyrantel pamoate, levamisole, piperazine, piperazine analogs, praziquantel, thiacetarsamide, triclabendazole, flubendazole, fenbendazole, Ooctadepsipeptides, such as emodepside, amino acetonitrile derivatives (such as monepantel).
  • the additional therapeutic agent is albendazole. In an exemplary embodiment, the additional therapeutic agent is ivermectin. In an exemplary embodiment, the additional therapeutic agent is melarsomine. In an exemplary embodiment, the additional therapeutic agent is selected from the group consisting of selamectin, milbemycin, and moxidectin. In an exemplary embodiment, the additional therapeutic agent is selected from the group consisting of tobacco, Moringa oleifera (Moringaceae), black walnut (Juglans nigra), wormwood (Artemisia absynthium), clove (Syzygium aromaticum), tansy tea
  • 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.
  • J4 p-methoxy phenyl
  • J2 p-chlorophenyl
  • J1 m-chlorophenyl
  • J3 m,p-dichlorophenyl
  • J10 p-nitrophenyl
  • J11 p-fluorophenyl
  • J12 2-naphthalenyl IV.
  • the compounds of the present invention exhibit potency against worms, and therefore have the potential to kill and/or inhibit the growth of such worms.
  • the invention therefore provides a method of killing and/or inhibiting the growth of a worm, comprising: contacting the worm with an effective amount of the compound of the invention, thereby killing and/or inhibiting the growth of the worm.
  • the worm is a parasitic worm.
  • the worm is a helminth.
  • the worm is a nematode.
  • the nematode is selected from the group consisting of ascarids, filarids, hookworms, pinworms, and whipworms.
  • the nematode is a member of Filarioidea.
  • the nematode is a filarid.
  • the nematode is a filarial worm.
  • the nematode is a member of the genus Wuchereria.
  • the nematode is Wuchereria bancrofti. In an exemplary embodiment, the nematode is a member of the genus Brugia. In an exemplary embodiment, the nematode is Brugia malayi. In an exemplary
  • the nematode is Brugia timori.
  • the nematode is a member of the genus Loa. In an exemplary embodiment, the nematode is Loa loa. In an exemplary embodiment, the nematode is a member of the genus Mansonella. In an exemplary embodiment, the nematode is selected from the group consisting of Mansonella streptocerca, Mansonella perstans, and Monsonella ozzardi. In an exemplary embodiment, the nematode is a member of the genus Onchocerca. In an exemplary embodiment, the nematode is Onchocerca volvulus. [0125] In an exemplary embodiment, the nematode is a pinworm.
  • the nematode is Enterobius vermicular is. In an exemplary embodiment, the nematode is a member of the genus Ascaris. In an exemplary embodiment, the nematode is Ascaris lumbricoides. In an exemplary embodiment, the nematode is a member of the genus Dracunculus. In an exemplary embodiment, the nematode is Dracunculus medinensis. In an exemplary embodiment, the nematode is a member of the genus Ancylostoma. In an exemplary embodiment, the nematode is Ancylostoma duodenale.
  • the nematode is selected from the group consisting of Ancylostoma braziliense, Ancylostoma tubaeforme, and Ancylostoma caninum.
  • the nematode is a member of the genus Necator.
  • the nematode is Necator americanus.
  • the nematode is a member of the genus Trichuris.
  • the nematode is selected from the group consisting of Trichuris trichiura, Trichuris vulpis, Trichuris campanula, Trichuris suis, and Trichuris muris.
  • the nematode is a member of the genus Strongyloides.
  • the nematode is selected from the group consisting of Strongyloides stercoralis, Strongyloides canis, Strongyloides fuelleborni, Strongyloides cebus, and Strongyloides kellyi.
  • the nematode is a member of the genus Nematodirus.
  • the nematode is a member of the genus Moniezia.
  • the nematode is a member of the genus Oesophagostomum. In an exemplary embodiment, the nematode is
  • the nematode is
  • the nematode is Oesophagostomum brumpti. In an exemplary embodiment, the nematode is
  • the nematode is Oesophagostomum stephanostomum var thomasi.
  • the nematode is a member of the genus Cooperia.
  • the nematode is Cooperia ostertagi or Cooperia oncophora. In an exemplary
  • the nematode is a member of the genus Haemonchus. In an exemplary embodiment, the nematode is a member of the genus Ostertagia. In an exemplary embodiment, the nematode is Ostertagia ostertagi. In an exemplary embodiment, the nematode is a member of the genus Trichostrongylus. In an exemplary embodiment, the nematode is Trichostrongylus axei.
  • the nematode is a heartworm. In an exemplary embodiment, the nematode is a member of the genus Dirofilaria. In an exemplary embodiment, the nematode is Dirofilaria immitis. In an exemplary embodiment, the nematode is Dirofilaria tenuis or Dirofilaria repens.
  • the worm is a trematode.
  • the trematode is a blood fluke or bilharzia.
  • the trematode is a member of the genus Schistosoma.
  • the trematode is selected from the group consisting of Schistosoma incognitum, Schistosoma ovuncatum, and Schistosoma sinensium.
  • the trematode is a member of the group Schistosoma indicum.
  • the trematode is selected from the group consisting of Schistosoma indicum, Schistosoma nasale, and Schistosoma spindale. In an exemplary embodiment, the trematode is a member of the group Schistosoma japonicam. In an exemplary embodiment, the trematode is selected from the group consisting of Schistosoma japonicum, Schistosoma malayensis, and Schistosoma mekongi. In an exemplary embodiment, the trematode is a member of the group
  • the trematode is selected from the group consisting of Schistosoma bovis, Schistosoma curassoni, Schistosoma guineensis, Schistosoma haematobium, Schistosoma intercalatum, Schistosoma leiperi, Schistosoma margrebowiei, and Schistosoma mattheei.
  • the trematode is a member of the group Schistosoma mansoni.
  • the trematode is selected from the group consisting of Schistosoma edwardiense, Schistosoma hippotami, Schistosoma mansoni, and Schistosoma rodhaini.
  • the trematode is Schistosoma mansoni.
  • the trematode is Schistosoma intercalatum.
  • the trematode is Schistosoma haematobium.
  • the trematode is Schistosoma japonicum.
  • the trematode is Schistosoma mekongi.
  • the trematode is Schistosoma bovis. In an exemplary embodiment, the trematode is Schistosoma mattheei. In an exemplary embodiment, the trematode is Schistosoma margrebowiei. In an exemplary embodiment, the trematode is Schistosoma curassoni. In an exemplary embodiment, the trematode is Schistosoma rodhaini.
  • the compounds of the invention exhibit potency against bacteria which are associated with worms. In an exemplary embodiment, the compounds of the invention exhibit potency against bacteria which live inside of worms. In an exemplary embodiment, the invention provides a method of killing and/or inhibiting the growth of a bacteria which is associated with a worm, comprising: contacting the bacteria with an effective amount of the compound of the invention, thereby killing and/or inhibiting the growth of the bacteria.
  • the bacteria is of the Wolbachia genus. In an exemplary embodiment, the bacteria is Wolbachia pipientis.
  • 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 worm-associated disease.
  • the compound of the invention can be used in human or veterinary medical therapy, particularly in the treatment or prophylaxis of helminth-associated disease.
  • the disease is associated with a worm described herein.
  • the disease is associated with a nematode.
  • the disease is associated with a nematode described herein.
  • the nematode is Wuchereria bancrofti.
  • the nematode is Brugia malayi. In an exemplary embodiment, the nematode is Brugia timori. In an exemplary embodiment, the nematode is Dirofilaria immitis. In an exemplary embodiment, the disease is associated with a trematode. In an exemplary embodiment, the disease is associated with a trematode described herein. In an exemplary embodiment, the disease is a member selected from enterobiasis, oxyuriasis, ascariasis, dracunculiasis, filariasis, onchocerciasis, schistosomiasis, and trichuriasis. In an exemplary embodiment, the disease is lymphatic filariasis.
  • the disease is subcutaneous filariasis. In an exemplary embodiment, the disease is serious cavity filariasis. In an exemplary embodiment, the disease is elephantiasis. In an exemplary embodiment, the disease is elephantiasis tropica. In an exemplary embodiment, the disease is onchocerciasis.
  • 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 worm. 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 goat, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, chicken and turkey.
  • the disease is treated through oral
  • the disease is treated through intravenous administration of the compound of the invention.
  • the disease is treated through topical administration of the compound of the invention.
  • the disease is treated through intraperitoneal administration of the compound of the invention.
  • the compound 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 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).
  • DMSO dimethylsulfoxide
  • 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.
  • 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.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • composition of the invention may also be administered in the form of suppositories, e.g., for rectal administration of the drug.
  • suppositories e.g., for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • compositions can be administered parenterally in a sterile medium.
  • the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
  • the composition containing the therapeutic compound may be added to the animal's feed or drinking water. Also, it will be convenient to formulate animal feed and drinking water products so that the animal takes in an appropriate quantity of the compound in its diet. It will further be convenient to present the compound in a composition as a premix for addition to the feed or drinking water. The composition can also added as a food or drink supplement for humans.
  • the amount of active ingredient that may be combined with the carrier materials to produce a 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.
  • Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocyctes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of laboratory animals that receive the compound intravenously.
  • Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcova, et al. (Journal of
  • 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.
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD 50 and ED 50 .
  • Compounds that exhibit high therapeutic indices are preferred.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 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
  • 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 EC 50 (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 worm growth.
  • EC 50 effective dose for 50% increase
  • concentration of the test compound which achieves a half-maximal inhibition of worm growth i.e., the concentration of the test compound which achieves a half-maximal inhibition of worm growth.
  • 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 helminth 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 structure which is:
  • R 5 is H or halogen and R 1 or R 2 is selected from the group consisting of alkoxy, optionally substituted with a substituted or unsubstituted phenyl; alkoxy, optionally substituted with a substituted or unsubstituted heteroaryl;
  • alkylamino optionally substituted with a substituted or unsubstituted phenyl
  • alkylamino optionally substituted with a substituted or unsubstituted heteroaryl; - NHC(0)R n , wherein R 11 is unsubstituted phenyl or unsubstituted heteroaryl; - NHS(0)2R U , wherein R 11 is unsubstituted phenyl or unsubstituted heteroaryl; - NHC(0)R 12 , wherein R 12 is unsubstituted alkyl; -C(0)NHR 12 , wherein R 12 is unsubstituted alkyl; or a hydrate, solvate or salt thereof.
  • the invention provides a structure according to the following formula: wherein R 5 is H or halogen and R 1 is alkoxy, substituted with a substituted or unsubstituted phenyl, or a hydrate, solvate or salt thereof.
  • R 5 is F.
  • R 1 is benzoxy
  • 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 pharmaceutical formulation is a unit dosage form.
  • the salt of the compound according to any of the above paragraphs is a
  • the invention provides a method of killing and/or inhibiting the growth of a helminth, comprising: contacting the helminth with an effective amount of the compound of the invention, thereby killing and/or inhibiting the growth of the helminth.
  • the helminth is a nematode or a trematode.
  • the helminth is a nematode, and the nematode is selected from the group consisting of Wuchereria bancrofti, Brugia malayi, and Brugia timori.
  • the compound has a structure described herein.
  • 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 lymphatic filariasis.
  • 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 worm infection.
  • LCMS spectra were obtained using a ThermoFinnigan AQA MS ESI instrument utilizing a Phenomenex Aqua 5 micron C 18 125 A 50 x 4.60 mm column.
  • the spray setting for the MS probe was at 350 ⁇ / ⁇ ⁇ with a cone voltage at 25 mV and a probe temperature at 450 °C.
  • the spectra were recorded using ELS and UV (254 nm) detection.
  • LCMS spectra were obtained using an Agilent 1200SL HPLC equipped with a 6130 mass spectrometer operating with electrospray ionization.
  • the eluent was 0-100% EtOAc in heptane or 0-10% MeOH in CH 2 C1 2 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.
  • 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. Conditions: Solvent A: H 2 0/1% acetonitrile/0.1% HC0 2 H; 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.
  • the title compound can be synthesized by using similar methods as described in the Example above with 3-methylbutan-l-amine to replace 2- pheny lethanamine .
  • the title compound can be synthesized according to the following scheme: 5-Fluoro-6 5-(pyridin-4-yloxy)indol4-yl ⁇ 4,3-dihvdro -hvdroxy-2 -benzoxaboro
  • R and R are independently selected unsubstituted alkyl.
  • the title compound can be synthesized according to the following scheme: 5-Fluoro-6 5-(pyrimidin-6-ylmethoxy)indol-l-yl ⁇ 4,3-dihvdro -hydwxy-2,l- benzoxaborole
  • the aqueous was extracted with EA for three times and the organic layer was washed with water, brine and dried over anhydrous Na 2 S0 4 .
  • the mixture was filtered and the filtrate was concentrated.
  • the crude product was purified by silica gel to provide 2.1 g of the desired product. The yield was 48%.

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Abstract

La présente invention porte, entre autres, sur de nouveaux composés utiles pour le traitement des infections par l'helminthe, sur des compositions pharmaceutiques contenant de tels composés, ainsi que sur des combinaisons de ces composés avec au moins un agent thérapeutiquement efficace supplémentaire.
PCT/US2010/057515 2009-11-20 2010-11-19 Petites molécules contenant du bore en tant qu'agents antihelminthes WO2011063293A1 (fr)

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US10301329B2 (en) 2009-08-14 2019-05-28 Anacor Pharmaceuticals, Inc. Boron-containing small molecules as antiprotozoal agents
US9440994B2 (en) 2009-08-14 2016-09-13 Anacor Pharmaceuticals, Inc. Boron containing small molecules as antiprotozoal agents
US9145429B2 (en) 2010-01-27 2015-09-29 Anacor Pharmaceuticals, Inc. Boron-containing small molecules
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
CN104039149B (zh) * 2011-11-21 2016-11-16 安纳考尔医药公司 含硼的小分子
WO2013078070A1 (fr) * 2011-11-21 2013-05-30 Eli Lilly And Company Petites molécules contenant du bore
CN104039149A (zh) * 2011-11-21 2014-09-10 安纳考尔医药公司 含硼的小分子
JP2014534259A (ja) * 2011-11-21 2014-12-18 アナコール ファーマシューティカルズ，インコーポレイテッド ホウ素含有小分子
JP2015517976A (ja) * 2012-02-17 2015-06-25 キネタ フォー エルエルシー アレナウイルス感染症の治療のための抗ウイルス薬
US10070649B2 (en) 2013-01-30 2018-09-11 Agrofresh Inc. Volatile applications against pathogens
US9426996B2 (en) 2013-01-30 2016-08-30 Agrofresh Inc. Use of benzoxaboroles as volatile antimicrobial agents on meats, plants, or plant parts
US9585396B2 (en) 2013-01-30 2017-03-07 Agrofresh Inc. Volatile applications against pathogens
US9138002B2 (en) 2013-01-30 2015-09-22 Agrofresh Inc. Compounds and compositions
US10765117B2 (en) 2013-01-30 2020-09-08 Agrofresh Inc. Volatile applications against pathogens
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
US11202448B2 (en) 2013-01-30 2021-12-21 Agrofresh Inc. Volatile applications against pathogens
US11771089B2 (en) 2013-01-30 2023-10-03 Agrofresh Inc. Large-scale methods of uniformly coating packaging surfaces with a volatile antimicrobial to preserve food freshness
US11917997B2 (en) 2013-01-30 2024-03-05 Agrofresh Inc. Volatile applications against pathogens
WO2016001834A1 (fr) 2014-07-01 2016-01-07 Daiichi Sankyo Company, Limited Benzoxaboroles tricycliques en tant qu'agents antibactériens
CN107108661A (zh) * 2015-01-13 2017-08-29 先正达参股股份有限公司 杀微生物的苯并氧杂硼杂环戊烯
US10314308B2 (en) * 2015-01-13 2019-06-11 Syngenta Participations Ag Microbiocidal benzoxaboroles
US10966429B2 (en) 2016-03-07 2021-04-06 Agrofresh Inc. Synergistic methods of using benzoxaborole compounds and preservative gases as an antimicrobial for crops

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