WO2014007831A1 - Petites molécules contenant du bore - Google Patents

Petites molécules contenant du bore Download PDF

Info

Publication number
WO2014007831A1
WO2014007831A1 PCT/US2012/045842 US2012045842W WO2014007831A1 WO 2014007831 A1 WO2014007831 A1 WO 2014007831A1 US 2012045842 W US2012045842 W US 2012045842W WO 2014007831 A1 WO2014007831 A1 WO 2014007831A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
substituted
unsubstituted
compounds
exemplary embodiment
Prior art date
Application number
PCT/US2012/045842
Other languages
English (en)
Inventor
Jacob J. Plattner
Xianfeng Li
Vincent S. Hernandez
Original Assignee
Anacor Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Anacor Pharmaceuticals, Inc. filed Critical Anacor Pharmaceuticals, Inc.
Priority to PCT/US2012/045842 priority Critical patent/WO2014007831A1/fr
Publication of WO2014007831A1 publication Critical patent/WO2014007831A1/fr

Links

Classifications

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

Definitions

  • This invention provides, among other things, novel compounds useful in boron neutron capture therapy.
  • 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-terf-butyl dicarbonate; Bz is, in general, benzoyl; BzOOH is benzoyl peroxide; Cbz or Z is benzyloxycarbonyl or carboxybenzyl;
  • CS2CO3 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.
  • poly as used herein means at least 2.
  • a polyvalent metal ion is a metal ion having a valency of at least 2.
  • Moiety refers to a radical of a molecule that is attached to the remainder of the molecule.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. Ci-Cio means one to ten carbons).
  • the term “alkyl” means a straight or branched chain, or combinations thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,
  • cyclohexyl (cyclohexyl)methyl, cyclopropylmethyl, homo logs 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
  • 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 heterocycloalkane.
  • 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.
  • 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.
  • the formula -C(0) 2 R'- represents both -C(0) 2 R'- and - R'C(0) 2 -.
  • cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include, but are not limited to, 1 -(1,2,5,6- tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like.
  • halo or halogen
  • haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(Ci-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 or 2 or 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- is
  • aryl when used in combination with other terms (e.g. , aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined herein.
  • arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g. , benzyl, phenethyl, pyridiylethyl 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).
  • heteroaryl when used in combination with other terms (e.g., hetero aryloxy, heteroarylthioxy, heteroarylalkyl) includes those radicals in which a heteroaryl group is attached through the next moiety to the rest of the molecule.
  • heteroarylalkyl is meant to include those radicals in which a heteroaryl group is attached to an alkyl group (e.g., pyridylmethyl and the like).
  • heteroaryloxy is meant to include those radicals in which a heteroaryl group is attached to an oxygen atom.
  • heteroaryloxyalkyl is meant to include those radicals in which an aryl group is attached to an oxygen atom which is then attached to an alkyl group, (e.g., 2-pyridyloxymethyl and the like). [0024] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and
  • heteroaryl are meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
  • 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 or 2 or 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 , -C(0)CH 2 OCH 3 , and the like).
  • substituents for the aryl and heteroaryl groups are generically referred to as "aryl group substituents.”
  • 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 from 0 or 1 or 2 or 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 from 1 or 2 or 3 or 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula - (CRR')s-X-(CR"R'")d-, where s and d are independently integers from 0 or 1 or 2 or 3, and X is -0-, -NR'-, -S-, -S(O)-, -S(0) 2 -, or -S(0) 2 NR'-.
  • the substituents R, R', R" and R'" are preferably independently selected from hydrogen or substituted or unsubstituted (Ci or C 2 or C 3 or C 4 or C 5 or C 6 )alkyl.
  • Ring means a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • a ring 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 or 6 or 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), and boron (B).
  • leaving group means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction.
  • representative leaving groups include triflate, chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • R is a general abbreviation that represents a substituent group that is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl groups.
  • 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 are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino (such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d- lysine, or 1-lysine), or magnesium salt, or a similar salt.
  • organic amino such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d- lysine, or 1-lysine
  • magnesium salt or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • suitable inert solvent examples include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric,
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)).
  • Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compounds in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • the invention provides compounds which are in a prodrug form.
  • Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to provide the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment.
  • Certain compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the invention. Certain compounds of the invention may exist in multiple crystalline or amorphous forms.
  • Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the invention.
  • the graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr, J. Chem. Ed. 1985, 62: 114-120. Solid and broken wedges are used to denote the absolute configuration of a stereocenter unless otherwise noted.
  • the compounds described herein contain olefmic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are included.
  • Compounds of the invention can exist in particular geometric or stereoisomeric forms.
  • the invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms can be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • Optically active (R)- and (5)-isomers and d and / isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If, for instance, a particular enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.
  • separation of enantiomers and diastereomers is frequently accomplished using chromatography employing chiral, stationary phases, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).
  • the compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.
  • 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.
  • Bio medium refers to both in vitro and in vivo biological milieus.
  • exemplary in vitro “biological media” include, but are not limited to, cell culture, tissue culture, homogenates, plasma and blood. In vivo applications are generally performed in mammals, preferably humans.
  • 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, organic amino (such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d-lysine, or 1-lysine) and sodium.
  • the compounds comprising a boron bonded to a carbon and three heteroatoms can optionally contain a fully negatively charged boron or partially negatively charged boron. Due to the negative charge, a positively charged counterion may associate with this compound, thus forming a salt.
  • positively charged counterions include H + , H 3 0 + , ammonium, potassium, calcium, magnesium, organic amino (such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d-lysine, 1-lysine), and sodium.
  • the invention provides novel boron compounds, method of making such compounds, methods of using such compounds to treat diseases, and pharmaceutical formulations including such compounds.
  • the compounds of the invention can be used in combination with boron neutron capture therapy to treat a disease, such as, for example, cancer.
  • BPA /?-Boronophenylalanine
  • BPA Boron Neutron Capture Therapy
  • BPA with fructose or mannitol has been proposed to produce a water soluble form of BPA for BNCT. Mori, Y. et al, Pigment Cell Res. 1989, 2, 273-277. Also, the continued development of new boron delivery agents, including boron-containing amino acids or BPA analogues with water-solubilizing groups, is the subject of extensive research.
  • Benzoxaboroles are boron-containing heterocycles that have emerged as a new class of potential therapeutics.
  • the benzoxaborole core has been shown to have a lower pK» value (pK» 7.2) (Dowlut, M. et al, J. Am. Chem. Soc. 2006, 128, 4226- 4227) compared to that of phenylboronc acid (pK a 8.9), (Westmark, P. R. et al., J. Am. Chem. Soc. 1996, 118, 11093-11100) suggesting that it exists about 50% in anionic tetrahedral form at physiological pH and thus has an enhanced water solubility.
  • the invention provides a compound of the invention.
  • the invention provides a compound described herein.
  • the invention provides a compound having a structure according to the formula which is:
  • R is H or substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
  • R 2 and R 3 are independently selected from H or substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or a salt thereof.
  • R 1 is H and
  • R 2 and R 3 are as defined herein.
  • R 2 is H and R 1 and R 3 are as defined herein.
  • R 1 is H
  • R 3 is H
  • R 2 is as defined herein.
  • the invention provides a compound which is:
  • the invention provides a compound which 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.
  • alkyl is linear alkyl. In another exemplary embodiment, alkyl is branched alkyl.
  • heteroalkyl is linear heteroalkyl. In another exemplary embodiment, heteroalkyl is branched heteroalkyl. IILb) Compositions involving stereoisomers
  • 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.
  • 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.
  • 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 compound, wherein the first compound described herein is present in an enantiomeric excess of at least 80%. In an exemplary embodiment, the enantiomeric excess is at least 92%. III. c) Preparation of Compounds
  • Compounds of use in the invention can be prepared using commercially available starting materials or known intermediates. Compounds of use in the invention can be prepared using synthetic methods known in the art or described herein. Preparation of compounds are as described herein.
  • the compounds of the invention exhibit potency against tumors, especially in conjunction with boron neutron capture therapy.
  • the invention provides a method of treating a tumor through the use of boron neutron capture therapy.
  • the method includes administering to the animal a therapeutically effective amount of the compound of the invention, sufficient to treat and/or prevent the disease.
  • the compound is described herein, or a salt, prodrug, hydrate or solvate thereof, or a combination thereof.
  • the invention provides a compound described herein, or a prodrug 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 compound of the invention is a compound described herein, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound described herein, or a pharmaceutically acceptable salt thereof.
  • the compound is according to a formula described herein, or a pharmaceutically acceptable salt thereof.
  • the compound is part of a pharmaceutical formulation described herein.
  • the animal is selected from the group consisting of 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 selected from the group consisting of a human, cattle, goat, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, chicken and turkey.
  • 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.
  • 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 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 pharmaceutically acceptable excipient; and (b) a compound described herein.
  • the pharmaceutical formulation is a unit dosage form. In an exemplary embodiment, the pharmaceutical formulation is a single unit dosage form.
  • the invention is a compound having a structure which is:
  • R 1 is H or substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
  • R 2 and R 3 are independently selected from H or substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or a salt thereof.
  • the invention provides a pharmaceutical formulation comprising a) the compound according to any of the above paragraphs, or a pharmaceutically acceptable salt thereof, and b) a pharmaceutically acceptable excipient.
  • the invention provides a method of tumor therapy, comprising administering a
  • Reagents and conditions (a) triflate chloride, DMAP, dichloromethane, 0 °C, 1 h, 80%; (b) pinacol diboron, Pd(dppf)Cl 2 , KOAc, dioxane, N 2 , 80 °C, 16 h, 55%; (c) NaBH 4 , MeOH, r.t., 2 h, then 6N HC1, 12 h, 32% for 7, 39% for 8; (d) Pd/C, EtOH, H 2 , 10 h, 89%; (e) LiOH, MeOH, H 2 0, 30 min, r.t., 64%.
  • Hydroxybenzaldehyde 4 was prepared according to Kalesh, K. A. et. al, Chem. Commun., 2010, 46, 589-591. Hydroxybenzaldehyde 4 was converted to its triflate derivative 5 in 80% yield by reaction with triflate chloride in dichloromethane. Without further purification, crude 5 was allowed to react with pinacol diboron in the presence of Pd(dppf)Cl 2 , Nakamura, H. et. al, J. Org. Chem. 1998, 63, 7529-7530, to afford boronate 6 in 55 > yield.
  • benzoxaborole ring formation was accomplished by using a one-pot procedure as previously described in Zhang, Y.-K., et. al, Bioorg. Med. Chem. Lett. 2010, 20, 2270-2274. This included the treatment of 6 with sodium borohydride in methanol to convert the aldehyde to a hydroxylmethyl group. The hydroxylmethyl group simultaneously cyclized to the adjacent boronate and subsequently hydrolyzed to form the corresponding benzoxaborole ring upon addition of aqueous hydrochloric acid. Boc protecting group was also removed in this step resulting in the desired benzyl ester 7 in 32%> yield.
  • BPA 1 has a solubility of 1.7 mg/mL, which is in consistent with the reported value (1.6 mg/mL) (Mori, Y. et. ⁇ , Pigment Cell Res. 1989, 2, 273-277; Nemoto, H., et. al, J. Med. Chem. 1995, 38, 1673-1678).
  • compounds 2 and 3 exhibit improved water solubility of 5.2 mg/mL and 3.6 mg/mL, respectively. Their better solubility could be attributable to the lower pK a since the benzoxaborole would exist in anionic tetrahedral form to a significant extent at physiological pH. Compound 2 is more soluble than 3.
  • One potential explanation is that the presence of the electron-donating oxygen atom para to the benzoxaborole in 3 would increase its pK a value and thus decrease its water solubility.

Abstract

Cette invention concerne des analogues de phénylalanine contenant du benzoxaborole, utiles dans le cadre d'une thérapie par capture de neutrons par le bore.
PCT/US2012/045842 2012-07-06 2012-07-06 Petites molécules contenant du bore WO2014007831A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/US2012/045842 WO2014007831A1 (fr) 2012-07-06 2012-07-06 Petites molécules contenant du bore

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2012/045842 WO2014007831A1 (fr) 2012-07-06 2012-07-06 Petites molécules contenant du bore

Publications (1)

Publication Number Publication Date
WO2014007831A1 true WO2014007831A1 (fr) 2014-01-09

Family

ID=46579332

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2012/045842 WO2014007831A1 (fr) 2012-07-06 2012-07-06 Petites molécules contenant du bore

Country Status (1)

Country Link
WO (1) WO2014007831A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016001834A1 (fr) 2014-07-01 2016-01-07 Daiichi Sankyo Company, Limited Benzoxaboroles tricycliques en tant qu'agents antibactériens
CN107224675A (zh) * 2016-03-25 2017-10-03 南京中硼联康医疗科技有限公司 硼中子捕获治疗系统
EP3424561A4 (fr) * 2016-03-25 2019-03-20 Neuboron Medtech Ltd. Système de traitement par capture de neutrons de bore et mise en oeuvre d'un trifluorure de bore de type acide alpha-aminé dans la fabrication d'un médicament destiné au traitement de tumeurs

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060234981A1 (en) 2005-02-16 2006-10-19 Anacor Pharmaceuticals Boron-containing small molecules
US20070155699A1 (en) 2005-02-16 2007-07-05 Anacor Pharmaceuticals Boron-containing small molecules

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060234981A1 (en) 2005-02-16 2006-10-19 Anacor Pharmaceuticals Boron-containing small molecules
US20070155699A1 (en) 2005-02-16 2007-07-05 Anacor Pharmaceuticals Boron-containing small molecules

Non-Patent Citations (16)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacv, 21st Ed.,", 2005, LIPPINCOTT, WILLIAMS & WILKINS
"Remington: The Science and Practice of Pharmacy", 2011, PHARMACEUTICAL PRESS
BARTH, R. F., APPL. RADIAT. ISOT., vol. 67, 2009, pages S3 - S6
BERG ET AL.: "Pharmaceutical Salts", JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1977, pages 1 - 19
DOWLUT, M. ET AL., J. AM. CHEM. SOC., vol. 128, 2006, pages 4226 - 4227
KALESH, K. A., CHEM. COMMUN., vol. 46, 2010, pages 589 - 591
MAEHR, J. CHEM. ED., vol. 62, 1985, pages 114 - 120
MORI, Y. ET AL., PIGMENT CELL RES., vol. 2, 1989, pages 273 - 277
MORI, Y., PIGMENT CELL RES., vol. 2, 1989, pages 273 - 277
NAKAMURA, H., J. ORG. CHEM., vol. 63, 1998, pages 7529 - 7530
NEMOTO, H., J. MED. CHERN., vol. 38, 1995, pages 1673 - 1678
PANDA, G., SYNLETT, vol. 4, 2004, pages 714 - 716
WESTMARK, P. R. ET AL., J. AM. CHEM. SOC., vol. 118, 1996, pages 11093 - 11100
XIANFENG LI ET AL: "Synthesis of novel benzoxaborole-containing phenylalanine analogues", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 52, no. 38, 12 July 2011 (2011-07-12), pages 4924 - 4926, XP028267107, ISSN: 0040-4039, [retrieved on 20110723], DOI: 10.1016/J.TETLET.2011.07.053 *
YANG, W. ET AL.: "Boronic Acids", 2005, WILEY-VCH, article "Biological and Medicinal Applications ofBoronic Acids", pages: 481 - 512
ZHANG, Y.-K., BIOORG. MED. CHEM. LETT., vol. 20, 2010, pages 2270 - 2274

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016001834A1 (fr) 2014-07-01 2016-01-07 Daiichi Sankyo Company, Limited Benzoxaboroles tricycliques en tant qu'agents antibactériens
CN107224675A (zh) * 2016-03-25 2017-10-03 南京中硼联康医疗科技有限公司 硼中子捕获治疗系统
EP3424561A4 (fr) * 2016-03-25 2019-03-20 Neuboron Medtech Ltd. Système de traitement par capture de neutrons de bore et mise en oeuvre d'un trifluorure de bore de type acide alpha-aminé dans la fabrication d'un médicament destiné au traitement de tumeurs

Similar Documents

Publication Publication Date Title
US9493490B1 (en) Boron-containing small molecules
WO2011022337A1 (fr) Petites molécules contenant du bore en tant qu'agents anti-protozoaires
CA2597273C (fr) Inhibiteurs du proteasome et leurs methodes d'utilisation
EP2564857B1 (fr) Petites molécules contenant du bore en tant qu'agents anti-inflammatoires
ES2729936T3 (es) Inhibidores de arginasa y sus aplicaciones terapéuticas
CA2902711A1 (fr) Derives de pyridinyl-6-methoxy-2-hydroxybenzaldehyde substitues et compositions pharmaceutiques de ceux-ci pour utilisation dans la modulation de l'hemoglobine
US8623911B2 (en) Boron-containing small molecules as anti-protozoal agent
US10919916B2 (en) Boron-containing small molecules
WO2011019618A1 (fr) Petites molécules contenant du bore et utilisables en tant qu'agents antiprotozoaires
US11352323B2 (en) Processes for making, and methods of using, glycopyrronium compounds
WO2011019612A1 (fr) Petites molécules contenant du bore en tant qu'agents antiprotozoaires
WO2014007831A1 (fr) Petites molécules contenant du bore
WO2017151492A1 (fr) Petites molécules contenant du bore
WO2015147950A2 (fr) Composés radioiodés
CN111447931B (zh) 抗癌/抗纤维化化合物
US20210070779A1 (en) Boron-containing small molecules as anti-inflammatory agents
WO2016161021A1 (fr) N-méthylpyrazoles
WO2014106606A1 (fr) Nouvelle série phényle/pyridine substituée par hydroxyéthylamino pour le traitement du cancer
WO2023076453A1 (fr) Traitement d'états neuroinflammatoires
US20200230160A1 (en) Boron-containing small molecules
AU2021377857A1 (en) Method for producing 4-borono-l-phenylalanine and intermediate thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12738680

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12738680

Country of ref document: EP

Kind code of ref document: A1