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WO2025177123A1 - Monomer subunits for water soluble polymer compounds - Google Patents

Monomer subunits for water soluble polymer compounds

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Publication number
WO2025177123A1
WO2025177123A1 PCT/IB2025/051549 IB2025051549W WO2025177123A1 WO 2025177123 A1 WO2025177123 A1 WO 2025177123A1 IB 2025051549 W IB2025051549 W IB 2025051549W WO 2025177123 A1 WO2025177123 A1 WO 2025177123A1
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Prior art keywords
occurrence
polymer compound
compound
following structures
linker
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PCT/IB2025/051549
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French (fr)
Inventor
Tracy Matray
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Sony Group Corp
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Sony Group Corp
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Publication of WO2025177123A1 publication Critical patent/WO2025177123A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/605—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the macromolecule containing phosphorus in the main chain, e.g. poly-phosphazene
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G79/00—Macromolecular compounds obtained by reactions forming a linkage containing atoms other than silicon, sulfur, nitrogen, oxygen, and carbon with or without the latter elements in the main chain of the macromolecule
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G79/00—Macromolecular compounds obtained by reactions forming a linkage containing atoms other than silicon, sulfur, nitrogen, oxygen, and carbon with or without the latter elements in the main chain of the macromolecule
    • C08G79/02—Macromolecular compounds obtained by reactions forming a linkage containing atoms other than silicon, sulfur, nitrogen, oxygen, and carbon with or without the latter elements in the main chain of the macromolecule a linkage containing phosphorus
    • C08G79/04—Phosphorus linked to oxygen or to oxygen and carbon

Definitions

  • Embodiments of the present disclosure are generally directed to polymeric compounds with cationic monomer subunits and methods for their preparation.
  • ADCs Antibody-drug conjugates
  • ADCs are a simple, but elegant disease therapy.
  • ADCs offer a strategy for cancer therapy whereby a potent cytotoxic agent is delivered to tumor cells with minimal damage to normal cells.
  • this strategy is not without its challenges.
  • these agents come with their share of toxicity. Careful planning with respect to choices of payloads, linkers, and antibodies is needed to develop valuable therapeutic assets.
  • the present disclosure provides compounds that are new therapeutic compounds that include charged moieties to reduce repulsion from a cell surface. Without wishing to be bound by theory, it is thought that by introducing a positive charge into a polymer backbone that links an antibody to payload (drug) there will be a reduction in the likelihood that the resultant ADC will be repulsed from the negatively charged surface of the cell.
  • polymer compounds of the present disclosure e.g., compounds of Structure (I)
  • polymer compounds of the present disclosure can be synthesized in a way that allows precise control of the number of charged moieties per molecule. Additionally, polymer compounds can be made such that there is optimum space and flexibility between moieties.
  • Cyano refers to the -CN group.
  • alkynylene is optionally substituted.
  • Alkylether refers to any alkyl group as defined above, wherein at least one carbon- carbon bond is replaced with a carbon-oxygen bond.
  • the carbon-oxygen bond may be on the terminal end (as in an alkoxy group) or the carbon oxygen bond may be internal (i.e., C-O-C).
  • Alkylethers include at least one carbon oxygen bond but may include more than one.
  • PEG polyethylene glycol
  • an alkylether group is optionally substituted.
  • Heteroalkyl refers to an alkyl group, as defined above, comprising at least one heteroatom (e.g., N, O, P or S) within the alkyl group or at a terminus of the alkyl group.
  • the heteroatom is within the alkyl group (i.e., the heteroalkyl comprises at least one carbon-[heteroatom] x -carbon bond, where x is 1, 2 or 3).
  • the heteroatom is at a terminus of the alkyl group and thus serves to join the alkyl group to the remainder of the molecule (e.g., Ml-H-A), where Ml is a portion of the molecule, H is a heteroatom and A is an alkyl group).
  • a heteroalkyl group is optionally substituted.
  • Exemplary heteroalkyl groups include ethylene oxide (e.g, polyethylene oxide), optionally including phosphorous-oxygen bonds, such as phosphodiester bonds.
  • Heteroalkoxy refers to a group of the formula -ORa where Ra is a heteroalkyl group as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a heteroalkoxy group is optionally substituted.
  • Heteroalkylene refers to an alkylene group, as defined above, comprising at least one heteroatom (e.g, Si, N, O, P or S) within the alkylene chain or at a terminus of the alkylene chain.
  • the heteroatom is within the alkylene chain (i.e., the heteroalkylene comprises at least one carbon-[heteroatom]-carbon bond, where x is 1, 2 or 3).
  • the heteroatom is at a terminus of the alkylene and thus serves to join the alkylene to the remainder of the molecule (e.g, M 1 -H-A-M 2 , where M 1 and M 2 are portions of the molecule, H is a heteroatom and A is an alkylene).
  • heteroalkylene group is optionally substituted.
  • exemplary heteroalkylene groups include ethylene oxide (e.g., polyethylene oxide) and the "C,” “HEG,” and “PEG IK” linking groups illustrated below:
  • Multimers of the above C-linker, HEG linker and/or PEG IK linker are included in various embodiments of heteroalkylene linkers.
  • n ranges from 19-25, for example n is 19, 20, 21, 22, 23, 24, or 25.
  • Multimers may comprise, for example, the following structure: wherein x is 0 or an integer greater than 0, for example, x ranges from 0-100 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10).
  • a “linker” refers to a contiguous chain of at least one atom, such as carbon, oxygen, nitrogen, sulfur, phosphorous, and combinations thereof, which connects a portion of a molecule to another portion of the same molecule or to a different molecule, moiety or solid support (e.g., microparticle). Linkers may connect the molecule via a covalent bond or other means, such as ionic or hydrogen bond interactions.
  • the linker is a heteroatomic linker (e.g., comprising 1-10 Si, N, O, P, or S atoms), a heteroalkylene (e.g., comprising 1-10 Si, N, O, P, or S atoms and an alkylene chain) or an alkylene linker (e.g., comprising 1-12 carbon atoms).
  • a heteroatomic linker e.g., comprising 1-10 Si, N, O, P, or S atoms
  • a heteroalkylene e.g., comprising 1-10 Si, N, O, P, or S atoms and an alkylene chain
  • an alkylene linker e.g., comprising 1-12 carbon atoms
  • Heteroalkenylene is a heteroalkylene, as defined above, comprising at least one carbon- carbon double bond. Unless stated otherwise specifically in the specification, a heteroalkenylene group is optionally substituted.
  • Heteroalkynylene is a heteroalkylene comprising at least one carbon-carbon triple bond. Unless stated otherwise specifically in the specification, a heteroalkynylene group is optionally substituted.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbomyl, decalinyl, 7,7-dimethyl- bicyclo-[2.2.1]heptanyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkyl group is optionally substituted.
  • Aryl refers to a ring system comprising at least one carbocyclic aromatic ring.
  • an aryl comprises from 6 to 18 carbon atoms.
  • the aryl ring may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems.
  • Fused refers to a ring system comprising at least two rings, wherein the two rings share at least one common ring atom, for example two common ring atoms.
  • the fused ring is a heterocyclyl ring or a heteroaryl ring
  • the common ring atom(s) may be carbon or nitrogen.
  • Fused rings include bicyclic, tricyclic, tertracyclic, and the like.
  • substituted means any of the above groups (e.g., alkyl, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, alkoxy, alkylether, phosphoalkyl, phosphoalkylether, thiophosphoalkyl, thiophosphoalkylether, carbocyclic, cycloalkyl, aryl, heterocyclic and/or heteroaryl) wherein at least one hydrogen atom (e.g., 1, 2, 3 or all hydrogen atoms) is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and
  • Substituted further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N- heteroaryl and/or heteroarylalkyl group.
  • each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.
  • Conjugation refers to the overlap of one p-orbital with another p-orbital across an intervening sigma bond. Conjugation may occur in cyclic or acyclic compounds.
  • a “degree of conjugation” refers to the overlap of at least one p-orbital with another p-orbital across an intervening sigma bond. For example, 1, 3-butadine has one degree of conjugation, while benzene and other aromatic compounds typically have multiple degrees of conjugation. Fluorescent and colored compounds typically comprise at least one degree of conjugation.
  • biomolecule refers to any of a variety of biological materials, including nucleic acids, carbohydrates, amino acids, polypeptides, glycoproteins, hormones, aptamers and mixtures thereof. More specifically, the term is intended to include, without limitation, RNA, DNA, oligonucleotides, modified or derivatized nucleotides, enzymes, receptors, prions, receptor ligands (including hormones), antibodies, antigens, and toxins, as well as bacteria, viruses, blood cells, and tissue cells.
  • the visually detectable biomolecules of the disclosure are prepared, as further described herein, by contacting a biomolecule with a compound having a reactive group that enables attachment of the biomolecule to the compound via any available atom or functional group, such as an amino, hydroxy, carboxyl, or sulfhydryl group on the biomolecule.
  • a “reactive group” is a moiety capable of reacting with a second reactive groups (e.g., a “complementary reactive group”) to form one or more covalent bonds, for example by a displacement, oxidation, reduction, addition, or cycloaddition reaction.
  • Such visually detectable substances absorb and emit light in a region of the spectrum ranging from about 300 to about 900 nm.
  • such substances are intensely colored, preferably having a molar extinction coefficient of at least about 40,000, more preferably at least about 50,000, still more preferably at least about 60,000, yet still more preferably at least about 70,000, and most preferably at least about 80,000 M -1 cm -1 .
  • the compounds of the disclosure may be detected by observation with the naked eye, or with the aid of an optically based detection device, including, without limitation, absorption spectrophotometers, transmission light microscopes, digital cameras, and scanners.
  • Visually detectable substances are not limited to those which emit and/or absorb light in the visible spectrum.
  • UV ultraviolet
  • IR infrared
  • the term "photostable visible dye” refers to a chemical moiety that is visually detectable, as defined hereinabove, and is not significantly altered or decomposed upon exposure to light.
  • the photostable visible dye does not exhibit significant bleaching or decomposition after being exposed to light for at least one hour. More preferably, the visible dye is stable after exposure to light for at least 12 hours, still more preferably at least 24 hours, still yet more preferably at least one week, and most preferably at least one month.
  • Non-limiting examples of photostable visible dyes suitable for use in the compounds and methods of the disclosure include azo dyes, thioindigo dyes, quinacridone pigments, dioxazine, phthalocyanine, perinone, diketopyrrolopyrrole, quinophthalone, and truarycarbonium.
  • perylene derivative is intended to include any substituted perylene that is visually detectable. However, the term is not intended to include perylene itself.
  • anthracene derivative e.g., perylene, pyrene, anthracene, or naphthalene derivative
  • a derivative is an imide, bisimide or hydrazamimide derivative of perylene, anthracene, naphthalene, or pyrene.
  • the disclosure provides a method for visually detecting a biomolecule, comprising: (a) providing a biological system with a visually detectable biomolecule comprising the polymer compounds of the present disclosure (e.g., compounds of Structure (I)) linked to a biomolecule; and (b) detecting the biomolecule by its visible properties.
  • the phrase "detecting the biomolecule by its visible properties” means that the biomolecule, without illumination or chemical or enzymatic activation, is observed with the naked eye, or with the aid of an optically based detection device, including, without limitation, absorption spectrophotometers, transmission light microscopes, digital cameras and scanners.
  • a densitometer may be used to quantify the amount of visually detectable biomolecule present.
  • the relative quantity of the biomolecule in two samples can be determined by measuring relative optical density. If the stoichiometry of dye molecules per biomolecule is known, and the extinction coefficient of the dye molecule is known, then the absolute concentration of the biomolecule can also be determined from a measurement of optical density.
  • solid support residue refers to the functional group remaining attached to a molecule when the molecule is cleaved from the solid support. Solid support residues are known in the art and can be easily derived based on the structure of the solid support and the group linking the molecule thereto.
  • a “targeting moiety” is a moiety that selectively binds or associates with a particular target, such as an analyte molecule. "Selectively" binding or associating means a targeting moiety preferentially associates or binds with the desired target relative to other targets.
  • the compounds disclosed herein include linkages to targeting moieties for the purpose of selectively binding or associating the compound with an analyte of interest (i.e., the target of the targeting moiety), thus allowing detection of the analyte.
  • Exemplary targeting moieties include, but are not limited to, antibodies, antigens, nucleic acid sequences, enzymes, proteins, cell surface receptor antagonists, and the like.
  • the targeting moiety is a moiety, such as an antibody, that selectively binds or associates with a target feature on or in a cell, for example a target feature on a cell membrane or other cellular structure, thus allowing for detection of cells of interest.
  • Small molecules that selectively bind or associate with a desired analyte are also contemplated as targeting moieties in certain embodiments.
  • Cell surface protein binding moiety refers to a chemical entity (e.g., ligand, antigen, amino acid sequence, peptide, etc.) that has an avidity or binding affinity for a membrane (i.e., a cell membrane) bound protein (e.g., an immunoglobulin and/or a signal transduction moiety).
  • a membrane bound protein e.g., an immunoglobulin and/or a signal transduction moiety.
  • exemplary membrane bound proteins include IgD, IgM, IgA, IgG, or IgE.
  • Cells that include the surface proteins include B-cells.
  • Base pairing moiety refers to a heterocyclic moiety capable of hybridizing with a complementary heterocyclic moiety via hydrogen bonds (e.g., Watson-Crick base pairing).
  • Base pairing moieties include natural and unnatural bases.
  • Non-limiting examples of base pairing moieties are RNA and DNA bases such adenosine, guanosine, thymidine, cytosine and uridine and analogues thereof.
  • “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds of the present disclosure e.g., compounds of Structure (A), (I), or (B)
  • the compounds of the present disclosure are limited to only stable compounds.
  • compounds of the present disclosure e.g., compounds of Structure (A), (I), or (B)
  • the compounds of the present disclosure do not include any diphosphate moieties.
  • Acid addition salt refers to those salts which are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic
  • Base addition salt refers to those salts which are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • Particularly preferred organic bases are isoprop
  • Crystallizations may produce a solvate of the compounds described herein.
  • Embodiments of the present disclosure include all solvates of the described compounds.
  • the term "solvate" refers to an aggregate that comprises one or more molecules of a compound of the disclosure with one or more molecules of solvent.
  • the solvent may be water, in which case the solvate may be a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the present disclosure may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms.
  • the compounds of the disclosure may be true solvates, while in other cases the compounds of the disclosure may merely retain adventitious water or another solvent or be a mixture of water plus some adventitious solvent.
  • Embodiments of the compounds of the disclosure may contain one or more stereocenters and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
  • Embodiments of the present disclosure are meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.
  • R 1 , R 2 , R 3 , R la ', R lb ', and R lc ' are, at each occurrence independently hydrogen or C 1 -C 6 alkyl;
  • R 4 is a covalent bond to the remainder of the backbone, -OH, or has the following structure: wherein R 4a ' is hydrogen or a covalent bond to the remainder of the backbone;
  • R 6a' and R 6b ' are each independently hydrogen or C 1 -C 6 alkyl
  • R 7a , R 7b ', R 8a ', and R 8b ' are each independently hydrogen or C 1 -C 6 alkyl, provided that at least one of R 7a ', R 7b ', R 8a ', and R 8b ' is C 1 -C 6 alkyl;
  • the ⁇ of Structures (A), (B), (C), (D), (E), and (F) represent a connection to the backbone.
  • At least one occurrence of Structure (A) has the following structure:
  • At least one occurrence of Structure (E) has one of the following structures:
  • L has the following structure: wherein: v is an integer ranging from 0 to 50, provided that at least one occurrence of v is 1 or greater;
  • the polymer compound has the following Structure (la):
  • L 1 comprises one or more alkylene or alkylene oxide moieties.
  • the alkylene oxide moieties comprise polyethylene oxide moieties.
  • L 1 at each occurrence, comprises the following structure: wherein: z is an integer from 1 to 100; and
  • * indicates a bond to the adjacent phosphorous atom.
  • each occurrence of L 1 comprises one of the following structures:
  • each occurrence of L 1 comprises one of the following structures: wherein: each occurrence of x is an integer ranging from 20 to 30.
  • the polymer compound has the following Structure (lb):
  • the polymer compound has one the following structures:
  • L 2 and L 4 are, at each occurrence, independently a direct bond or C 1 -C 6 alkylene.
  • each occurrence of L 3 and L b independently have one of the following structures: In certain embodiments, each occurrence of L 3 and L b independently have one of the following structures:
  • each occurrence of L 3 and L b independently have the following structure:
  • each occurrence of L 3 independently has one of the following structures:
  • each occurrence of L 3 has the following structure:
  • L a is, at each occurrence independently an optionally substituted 5-7 membered heteroarylene linker. In some embodiments, L a has one of the following structures: In some embodiments, at least one occurrence of L b comprises a triazolyl ring. In certain embodiments, at least one occurrence of -L b -M 2 comprises one of the following structures: wherein L c and L d are, at each occurrence independently a direct bond, alkylene, or heteroalkylene.
  • each occurrence of L c , L d , or both are direct bonds. In some embodiments, each occurrence of L c , L d , or both are independently alkylene or heteroalkylene. In certain embodiments, each occurrence of L c , L d , or both have one of the following structures:
  • each occurrence of -L b -M 2 has one of the following structures:
  • At least one occurrence of L 7 has the following structure:
  • R 1 is, at each occurrence, hydrogen.
  • Q comprises a sulfhydryl, disulfide, activated ester, isothiocyanate, azide, alkyne, alkene, diene, dienophile, acid halide, sulfonyl halide, phosphine, a-haloamide, biotin, amino, or maleimide functional group.
  • the activated ester is an N-succinimide ester, imidoester or polyflourophenyl ester.
  • Q comprises one of the following structures:
  • G 1 is halo
  • R 1 or R 2 has one of the following structures:
  • R 1 or R 2 has one of the following structures:
  • R 1 or R 2 has one of the following structures:
  • At least one occurrence of M 1 or M 2 is selected from the group consisting of a pyrene, perylene, perylene monoimide, and 6-FAM moiety. In certain embodiments, at least one occurrence of M 1 or M 2 has one of the following structures:
  • one or more occurrences of M 1 , M 2 , or both have one of the following structures:
  • M 1 , M 2 , or both are anti-cancer drugs. In certain specific embodiments, M 1 , M 2 , or both are at each occurrence, independently an anti-cancer drug, and the antibody specific for a tumor cell antigen.
  • Anti-cancer drug includes derivatives (e.g., compounds with added linkers covalently binding the drug to the compounds of Structure (I)). For example, maytansine is a cancer drug and maytansinoids are cancer drug derivatives.
  • the anti-cancer drug is an epidermal growth factor receptor (EGFR) inhibitor, phosphatidylinositol kinase (PI3K) inhibitor, insulin-like growth factor receptor (IGF1R) inhibitor, Janus kinase (JAK) inhibitor, a Met kinase inhibitor, a SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular-signal- regulated kinase (ERK) inhibitor, a topoisomerase inhibitors (such as irinotecan, or such as etoposide, or such asdoxorubicin), taxanes (such as anti -microtubule agents including paclitaxel and docetaxel), anti-metabolite agents (such as 5-FU or such as gemcitabine), alkylating agents (such as cisplatin or such as cyclophosphamide), or a taxane.
  • EGFR epidermal growth factor
  • One embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising the polymer compound of any one of the embodiments disclosed herein, or a stereoisomer, tautomer, or salt thereof and a pharmaceutically acceptable excipient.
  • Q is, at each occurrence, independently a moiety comprising a reactive group capable of forming a covalent bond with an analyte molecule or a solid support.
  • Q is, at each occurrence, independently a moiety comprising a reactive group capable of forming a covalent bond with a complementary reactive group Q'.
  • Q' is present on a further compound of Structure (I), (e.g., in the R 1 or R 2 position), and Q and Q' comprise complementary reactive groups such that reaction of the compound of Structure (I) and the further compound of Structure (I) results in covalently bound dimer of the compound of Structure (I).
  • Multimer compounds of Structure (I) can also be prepared in an analogous manner and are included within the scope of embodiments of the disclosure.
  • Q comprises a nucleophilic reactive group, an electrophilic reactive group or a cycloaddition reactive group.
  • Q comprises a sulfhydryl, disulfide, activated ester, isothiocyanate, azide, alkyne, alkene, diene, dienophile, acid halide, sulfonyl halide, phosphine, oc-haloamide, biotin, amino or maleimide functional group.
  • the activated ester is an N-succinimide ester, imidoester or polyflourophenyl ester.
  • the alkyne is an alkyl azide or acyl azide.
  • the SH moiety will tend to form disulfide bonds with another sulfhydryl group, for example on another compound of Structure (I). Accordingly, some embodiments include compounds of Structure (I), which are in the form of disulfide dimers, the disulfide bond being derived from SH Q groups.
  • M 2 is the same at each occurrence; however, it is important to note that each occurrence of M 2 need not be an identical M 2 , and certain embodiments include compounds wherein M 2 is not the same at each occurrence. For example, in some embodiments each M 2 is not the same and the different M 2 moiety is selected to have different antineoplastic agents.
  • q is, at each occurrence, an integer of zero or greater. In some embodiments, each occurrence of q independently ranges from 2 to 20. In some more specific embodiments, q is from 0 to 10. In some embodiments, q is from 0 to 5. For example, in some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5. In some other embodiments, q is 1.
  • R 5 is hydrogen or has the following structure:
  • R 7c , R 7d ', R 8c , and R 8d ' are each independently hydrogen or C 1 -C 6 alkyl, or
  • R 7C ' and R 8C ' each represent an electron pair, the nitrogen to which they are each attached are uncharged, and R 7d ' and R 8d ' each independently have the following structure: wherein R 9a ', R 9b ', and R 9c ' are each independently hydrogen or C 1 -C 6 alkyl
  • L 1 ' is an alkylene or heteroalkylene linker
  • L 4 is an alkylene linker or a heteroalkylene linker
  • L 4 ' is C 1 -C 4 alkylene. In some embodiments, L 4 ' comprises 2-4 carbon atoms and one oxygen atom. In some embodiments, L 4 ' is unsubstituted.
  • the compound of Structure (A-l) has one of the following structures:
  • the compound of Structure (B-1) has one of the following structures:
  • the compound of Structure (C-1) has one of the following structures:
  • the compound of Structure (D-l) has one of the following
  • the compound of Structure (E-l) has one of the following structures:
  • the compound of Structure (F-l) has one of the following
  • One embodiment provides a composition comprising the compound according to any one of the embodiments disclosed herein (e.g., a compound of Structure (I) and a pharmaceutically acceptable carrier).
  • the pharmaceutical composition comprises one (or more) of the polymer compounds of the present disclosure (e.g., compounds of Structure (I)) and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is formulated for oral administration.
  • the pharmaceutical composition is formulated for injection.
  • the pharmaceutical compositions comprise a polymer compound of the present disclosure (e.g., compounds of Structure (I)) and an additional therapeutic agent (e.g., anticancer agent).
  • additional therapeutic agent e.g., anticancer agent
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • a polymer compounds of the present disclosure is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation.
  • long-acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ.
  • the polymer compound of the present disclosure e.g., compound of Structure (I)
  • the polymer compound of the present disclosure is provided in the form of a rapid release formulation, in the form of an extended-release formulation, or in the form of an intermediate release formulation.
  • the compound of Structure (I) is administered topically.
  • the polymer compounds of the present disclosure are effective over a wide dosage range.
  • dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that are used in some embodiments.
  • An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
  • a polymer compound of the present disclosure is administered in a single dose.
  • such administration will be by injection, e.g, intravenous injection, to introduce the agent quickly.
  • a single dose of a polymer compound of the present disclosure may also be used for treatment of an acute condition.
  • a polymer compound of the present disclosure is administered in multiple doses. In some embodiments, dosing is about once, twice, three times, four times, five times, six times, or more than six times per day.
  • a polymer compound of the present disclosure is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days.
  • a polymer compound of the present disclosure e.g., compound of Structure (I)
  • a polymer compound of the present disclosure e.g., compound of Structure (I)
  • the polymer compound of the present disclosure (e.g., compound of Structure (I)) is administered in dosages. It is known in the art that due to inter-subject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the disclosure may be found by routine experimentation considering the instant disclosure.
  • compositions comprising a polymer compound of the present disclosure (e.g., compound of Structure (I)) and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s).
  • the compounds described are administered as pharmaceutical compositions in which polymer compounds of the present disclosure (e.g., compounds of Structure (I)) are mixed with other active ingredients, as in combination therapy.
  • the pharmaceutical compositions include one or more polymer compounds of the present disclosure (e.g., compounds of Structure (I))-
  • one or more polymer compound of the present disclosure is formulated in an aqueous solution.
  • the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • one or more polymer compound of the present disclosure is/are formulated for transmucosal administration.
  • transmucosal formulations include penetrants that are appropriate to the barrier to be permeated.
  • appropriate formulations include aqueous or non-aqueous solutions.
  • such solutions include physiologically compatible buffers and/or excipients.
  • therapeutically effective amounts of at least one of the compounds described herein are formulated for buccal or sublingual administration.
  • Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels.
  • the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion.
  • formulations suitable for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations.
  • the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles.
  • aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the polymer compound of the present disclosure (e.g., compound of Structure (I)) is administered topically.
  • the compounds described herein are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments.
  • Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives.
  • transdermal patches provide controlled delivery of the polymer compound of the present disclosure (e.g., compound of Structure (I)).
  • the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel.
  • absorption enhancers are used to increase absorption.
  • Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that assist passage through the skin.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period and means to secure the device to the skin.
  • the polymer compound of the present disclosure (e.g., compound of Structure (I)) is formulated for administration by inhalation.
  • Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists, or powders.
  • Pharmaceutical compositions of any of polymer compound of the present disclosure (e.g., compound of Structure (I)) are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas).
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the polymer compound of the present disclosure is formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like.
  • rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas
  • conventional suppository bases such as cocoa butter or other glycerides
  • synthetic polymers such as polyvinylpyrrolidone, PEG, and the like.
  • a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with melted cocoa butter.
  • compositions include at least one pharmaceutically acceptable carrier, diluent, or excipient and at least one polymer compound of the present disclosure (e.g., compound of Structure (I)), described herein as an active ingredient.
  • the active ingredient is in free-acid or free-base form, or in a pharmaceutically acceptable salt form.
  • the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances.
  • adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances.
  • compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.
  • useful aqueous suspensions contain one or more polymers as suspending agents.
  • Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers.
  • Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.
  • Useful pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a polymer compound of the present disclosure (e.g., compound of Structure (I)).
  • solubilizing agent generally includes agents that result in formation of a micellar solution or a true solution of the agent.
  • Certain acceptable nonionic surfactants for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g, polyethylene glycol 400, and glycol ethers.
  • useful pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric, and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids such as acetic, boric, citric, lactic, phosphoric, and hydrochloric acids
  • bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane
  • buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
  • compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range.
  • salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
  • compositions optionally include one or more preservatives to inhibit microbial activity.
  • Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.
  • compositions include one or more surfactants to enhance physical stability or for other purposes.
  • Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.
  • compositions include one or more antioxidants to enhance chemical stability where required.
  • Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.
  • hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as V-methylpyrrolidone are also employed. In additional embodiments, the compounds described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.
  • the concentration of one or more compounds provided in the pharmaceutical compositions is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v.
  • the autoimmune disease is multiple sclerosis, diabetes, celiacs disease, Graves' disease, myasthenia gravis, Hashimotos encephalomyelitis, Neuromyelitis optica, inflammatory bowel disease, hemaphilia, lupus, autoimmune encephalomyelitis (EAE), or rheumatoid arthritis.
  • Polymer compounds of the present disclosure are safe and offer flexibility in determining the appropriate structure and properties while also allowing efficient carriage of drug and proteins to target cells.
  • the polymer compounds are effective at targeting antigen-presenting cells (APCs), such as dendritic cells and macrophages, due to the inherent ability of these APCs to selectively endocytose.
  • APCs antigen-presenting cells
  • the polymer compound of the present disclosure (e.g., compound of Structure (I)) is co-delivered with a self-antigen (e.g., PLP).
  • the method is a method for treating EAE or multiple sclerosis that includes delivering a polymer compound of the present disclosure (e.g., compound of Structure (I)) that is coupled to an autoantigen, a cell adhesion inhibitory peptide (e.g., LABL), or both and the compound is co- delivered with a self-antigen (e.g., PLP).
  • the disclosure provides a method of treating cancer (e.g., breast cancer).
  • cancer e.g., breast cancer
  • the cancer is HER2+ breast cancer, HR+ breast cancer, or triple negative breast cancer.
  • the disclosure provides a method of treating an autoimmune disease.
  • a compound of the present disclosure can be administered just followed by and any of the agents described above, or vice versa.
  • a compound of the disclosure and any of the agents described above are administered a few minutes apart, or a few hours apart, or a few days apart.

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Abstract

Polymer compounds useful for preparing antibody-drug conjugates are disclosed. The polymer compounds comprise a quaternary ammonium ion. Methods associated with the preparation and the use of such compounds are also provided.

Description

MONOMER SUBUNITS FOR WATER SOLUBLE POLYMER COMPOUNDS
BACKGROUND
Technical Field
Embodiments of the present disclosure are generally directed to polymeric compounds with cationic monomer subunits and methods for their preparation.
Description of the Related Art
Antibody-drug conjugates (ADCs) are a simple, but elegant disease therapy. ADCs offer a strategy for cancer therapy whereby a potent cytotoxic agent is delivered to tumor cells with minimal damage to normal cells. However, this strategy is not without its challenges. Despite their antibody-directed cellular targeting, these agents come with their share of toxicity. Careful planning with respect to choices of payloads, linkers, and antibodies is needed to develop valuable therapeutic assets.
Thus, there exists a need in the art for developing new therapies that function to treat diseases (e.g., cancer) in a targeted manner. The present disclosure fulfills this need and provides further related advantages.
BRIEF SUMMARY
The present disclosure provides compounds that are new therapeutic compounds that include charged moieties to reduce repulsion from a cell surface. Without wishing to be bound by theory, it is thought that by introducing a positive charge into a polymer backbone that links an antibody to payload (drug) there will be a reduction in the likelihood that the resultant ADC will be repulsed from the negatively charged surface of the cell.
One embodiment provides a polymer compound comprising a backbone comprising one or more monomer subunits as defined herein. Polymer compounds of the present disclosure (e.g., polymer compounds of Structure (I)) find utility in several applications, including use as therapeutic agents for various treatment methods.
In another embodiment, a conjugate is provided which comprises a polymer compound covalently bound to an antibody or a toxin.
In another embodiment, compositions are provided which comprise a polymer compound of the present disclosure and a pharmaceutically acceptable carrier or the conjugate comprising a polymer compound of the present disclosure and a pharmaceutically acceptable carrier. In yet another embodiment, a method of treating a disease is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a polymer compound of the present disclosure or a composition comprising a polymer compound of the present disclosure. These and other aspects of the disclosure will be apparent upon reference to the following detailed description.
DETAILED DESCRIPTION
It is important to note that the polymer compounds of the present disclosure (e.g., compounds of Structure (I)) can be synthesized in a way that allows precise control of the number of charged moieties per molecule. Additionally, polymer compounds can be made such that there is optimum space and flexibility between moieties.
In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments of the disclosure. However, one skilled in the art will understand that the disclosure may be practiced without these details.
Unless the context requires otherwise, throughout the present specification and claims, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense, that is, as "including, but not limited to".
Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
"Amino" refers to the -NH2 group.
"Carboxy" refers to the -CO2H group.
"Cyano" refers to the -CN group.
"Hydroxy" or "hydroxyl" refers to the -OH group.
"Nitro" refers to the -NO2 group.
"Oxo" refers to the =O substituent group.
"Sulfhydryl" refers to the -SH group.
"Thioxo" refers to the =S group.
"Alkyl" refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to twelve carbon atoms (C1-C12 alkyl), one to eight carbon atoms (C1-C8 alkyl) or one to six carbon atoms (C1-C6 alkyl), and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl,
1 -methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1 -dimethylethyl (t-butyl), 3 -methylhexyl,
2-methylhexyl, and the like. Unless stated otherwise specifically in the specification, alkyl groups are optionally substituted.
"Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to twelve carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, alkylene is optionally substituted.
"Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms, e.g., ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, alkenylene is optionally substituted.
"Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms, e.g., ethenylene, propenylene, n-butenylene, and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, alkynylene is optionally substituted. "Alkylether" refers to any alkyl group as defined above, wherein at least one carbon- carbon bond is replaced with a carbon-oxygen bond. The carbon-oxygen bond may be on the terminal end (as in an alkoxy group) or the carbon oxygen bond may be internal (i.e., C-O-C). Alkylethers include at least one carbon oxygen bond but may include more than one. For example, polyethylene glycol (PEG) is included within the meaning of alkylether. Unless stated otherwise specifically in the specification, an alkylether group is optionally substituted. For example, in some embodiments an alkylether is substituted with an alcohol or -OP(=Ra)(Rb)Rc, wherein each of Ra, Rb and Rc is as defined for polymer compounds of the present disclosure (e.g., compounds of Structure (I)).
"Alkoxy" refers to a group of the formula -ORa where Ra is an alkyl group as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.
"Alkoxyalkylether" refers to a group of the formula -ORaRb where Ra is an alkylene group as defined above containing one to twelve carbon atoms, and Rb is an alkylether group as defined herein. Unless stated otherwise specifically in the specification, an alkoxyalkylether group is optionally substituted, for example substituted with an alcohol or -OP(=Ra)(Rb)Rc, wherein each of Ra, Rb and Rc is as defined for polymer compounds of the present disclosure (e.g., compounds of Structure (I)).
"Heteroalkyl" refers to an alkyl group, as defined above, comprising at least one heteroatom (e.g., N, O, P or S) within the alkyl group or at a terminus of the alkyl group. In some embodiments, the heteroatom is within the alkyl group (i.e., the heteroalkyl comprises at least one carbon-[heteroatom]x-carbon bond, where x is 1, 2 or 3). In other embodiments, the heteroatom is at a terminus of the alkyl group and thus serves to join the alkyl group to the remainder of the molecule (e.g., Ml-H-A), where Ml is a portion of the molecule, H is a heteroatom and A is an alkyl group). Unless stated otherwise specifically in the specification, a heteroalkyl group is optionally substituted. Exemplary heteroalkyl groups include ethylene oxide (e.g, polyethylene oxide), optionally including phosphorous-oxygen bonds, such as phosphodiester bonds.
"Heteroalkoxy" refers to a group of the formula -ORa where Ra is a heteroalkyl group as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a heteroalkoxy group is optionally substituted.
"Heteroalkylene" refers to an alkylene group, as defined above, comprising at least one heteroatom (e.g, Si, N, O, P or S) within the alkylene chain or at a terminus of the alkylene chain. In some embodiments, the heteroatom is within the alkylene chain (i.e., the heteroalkylene comprises at least one carbon-[heteroatom]-carbon bond, where x is 1, 2 or 3). In other embodiments, the heteroatom is at a terminus of the alkylene and thus serves to join the alkylene to the remainder of the molecule (e.g, M1-H-A-M2, where M1 and M2 are portions of the molecule, H is a heteroatom and A is an alkylene). Unless stated otherwise specifically in the specification, a heteroalkylene group is optionally substituted. Exemplary heteroalkylene groups include ethylene oxide (e.g., polyethylene oxide) and the "C," "HEG," and "PEG IK" linking groups illustrated below:
"PEG IK linker"
Multimers of the above C-linker, HEG linker and/or PEG IK linker are included in various embodiments of heteroalkylene linkers. In some embodiments of the PEG IK linker, n ranges from 19-25, for example n is 19, 20, 21, 22, 23, 24, or 25. Multimers may comprise, for example, the following structure: wherein x is 0 or an integer greater than 0, for example, x ranges from 0-100 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10).
A "linker" refers to a contiguous chain of at least one atom, such as carbon, oxygen, nitrogen, sulfur, phosphorous, and combinations thereof, which connects a portion of a molecule to another portion of the same molecule or to a different molecule, moiety or solid support (e.g., microparticle). Linkers may connect the molecule via a covalent bond or other means, such as ionic or hydrogen bond interactions. In some embodiments, the linker is a heteroatomic linker (e.g., comprising 1-10 Si, N, O, P, or S atoms), a heteroalkylene (e.g., comprising 1-10 Si, N, O, P, or S atoms and an alkylene chain) or an alkylene linker (e.g., comprising 1-12 carbon atoms).
In some embodiments, a heteroalkylene linker comprises the following structure: wherein: x9 and x10 are each independently an integer greater than 0. In some embodiments, the heteroatomic linker is -O-, -S-, or -OP(=O)O--O- In some embodiments, the heteroalkylene linker comprises -OP(=O)O--O- In some embodiments, the heteroalkylene linker comprises at least one S-S bond.
"Heteroalkenylene" is a heteroalkylene, as defined above, comprising at least one carbon- carbon double bond. Unless stated otherwise specifically in the specification, a heteroalkenylene group is optionally substituted.
"Heteroalkynylene" is a heteroalkylene comprising at least one carbon-carbon triple bond. Unless stated otherwise specifically in the specification, a heteroalkynylene group is optionally substituted.
"Heteroatomic" in reference to a "heteroatomic linker" refers to a linker group consisting of one or more heteroatoms. Exemplary heteroatomic linkers include single atoms selected from the group consisting of O, N, P and S, and multiple heteroatoms for example a linker having the formula -P(O-)(=O)O- or -OP(O-)(=O)O- and multimers and combinations thereof.
"Phosphate" refers to the -OP(=O)(Ra)Rb group, wherein Ra is OH, O- or ORc; and Rb is OH, O-, ORc, a thiophosphate group or a further phosphate group, wherein Rc is a counter ion (e.g., Na+ and the like).
"Phosphoalkyl" refers to the -OP(=O)(Ra)Rb group, wherein Ra is OH, O- or ORC; and Rb is -Oalkyl, wherein Rc is a counter ion (e.g., Na+ and the like). Unless stated otherwise specifically in the specification, a phosphoalkyl group is optionally substituted. For example, in certain embodiments, the -Oalkyl moiety in a phosphoalkyl group is optionally substituted with one or more of hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether, thiophosphoalkylether or -OP(=Ra)(Rb)Rc, wherein each of Ra, Rb and Rc is as defined for polymer compounds of the present disclosure (e.g., compounds of Structure (I)).
"Phosphoalkylether" refers to the -OP(=O)(Ra)Rb group, wherein Ra is OH, O- or ORC; and Rb is -Oalkylether, wherein Rc is a counter ion (e.g., Na+ and the like). Unless stated otherwise specifically in the specification, a phosphoalkylether group is optionally substituted. For example, in certain embodiments, the -Oalkylether moiety in a phosphoalkylether group is optionally substituted with one or more of hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether, thiophosphoalkylether or -OP(=Ra)(Rb)Rc, wherein each of Ra, Rb and Rc is as defined for polymer compounds of the present disclosure (e.g., compounds of Structure (I)).
"Thiophosphate" refers to the -OP(=Ra)(Rb)Rc group, wherein Ra is O or S, Rb is OH, O-, S-, ORd or SRa; and Rc is OH, SH, O-, S-, ORd, SRd, a phosphate group or a further thiophosphate group, wherein Rd is a counter ion (e.g., Na+ and the like) and provided that: i) Ra is S; ii) Rb is S- or SRd; iii)Rc is SH, S- or SRd; or iv) a combination of i), ii) and/or iii).
"Thiophosphoalkyl" refers to the -OP(=Ra)(Rb)Rc group, wherein Ra is O or S, Rb is OH, O-, S-, ORd or SRd; and Rc is -Oalkyl, wherein Rd is a counter ion (e.g., Na+ and the like) and provided that: i) Ra is S; ii) Rb is S- or SRd; or iii)Ra is S and Rb is S- or SRd. Unless stated otherwise specifically in the specification, a thiophosphoalkyl group is optionally substituted. For example, in certain embodiments, the -Oalkyl moiety in a thiophosphoalkyl group is optionally substituted with one or more of hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether, thiophosphoalkylether or -OP(=Ra)(Rb)Rc, wherein each of Ra, Rb and Rc is as defined for polymer compounds of the present disclosure (e.g., compounds of Structure (I)).
"Thiophosphoalkylether" refers to the -OP(=Ra)(Rb)Rc group, wherein Ra is O or S, Rb is OH, O-, S-, ORd or SRd; and Rc is -Oalkylether, wherein Rd is a counter ion (e.g., Na+ and the like) and provided that: i) Ra is S; ii) Rb is S- or SRd; or iii)Ra is S and Rb is S- or SRd. Unless stated otherwise specifically in the specification, a thiophosphoalkylether group is optionally substituted. For example, in certain embodiments, the -Oalkylether moiety in a thiophosphoalkyl group is optionally substituted with one or more of hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether, thiophosphoalkylether or -OP(=Ra)(Rb)Rc, wherein each of Ra, Rb and Rc is as defined for polymer compounds of the present disclosure (e.g., compounds of Structure (I)).
"Carbocyclic" refers to a stable 3- to 18-membered aromatic or non-aromatic ring comprising 3 to 18 carbon atoms. Unless stated otherwise specifically in the specification, a carbocyclic ring may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems, and may be partially or fully saturated. Non-aromatic carbocyclyl radicals include cycloalkyl, while aromatic carbocyclyl radicals include aryl. Unless stated otherwise specifically in the specification, a carbocyclic group is optionally substituted.
"Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic carbocyclic ring, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbomyl, decalinyl, 7,7-dimethyl- bicyclo-[2.2.1]heptanyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkyl group is optionally substituted.
"Aryl" refers to a ring system comprising at least one carbocyclic aromatic ring. In some embodiments, an aryl comprises from 6 to 18 carbon atoms. The aryl ring may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryls include, but are not limited to, aryls derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl group is optionally substituted.
"Heterocyclic" refers to a stable 3- to 18-membered aromatic or non-aromatic ring comprising one to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclic ring may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclic ring may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclic ring may be partially or fully saturated. Examples of aromatic heterocyclic rings are listed below in the definition of heteroaryls (i.e., heteroaryl being a subset of heterocyclic). Examples of non-aromatic heterocyclic rings include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, pyrazolopyrimidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trioxanyl, trithianyl, triazinanyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclic group is optionally substituted.
"Heteroaryl" refers to a 5- to 14-membered ring system comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. For purposes of certain embodiments of this disclosure, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzodi oxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotri azolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, benzoxazolinonyl, benzimidazolthionyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1- oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pteridinonyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, pryrimidinonyl, pyridazinyl, pyrrolyl, pyrido[2,3- d]pyrimidinonyl, quinazolinyl, quinazolinonyl, quinoxalinyl, quinoxalinonyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, thieno[3,2-d]pyrimidin-4-onyl, thieno[2,3-d]pyrimidin-4-onyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group is optionally substituted.
The suffix "-ene" refers to a particular structural feature (e.g., alkyl, aryl, heteroalkyl, heteroaryl) attached to the rest of the molecule through a single bond and attached to a radical group through a single bond. In other words, the suffix "-ene" refers to a linker having the structural features of the moiety to which it is attached. The points of attachment of the "-ene" chain to the rest of the molecule and to the radical group can be through one atom of or any two atoms within the chain. For example, a heteroarylene refers to a linker comprising a heteroaryl moiety as defined herein.
"Fused" refers to a ring system comprising at least two rings, wherein the two rings share at least one common ring atom, for example two common ring atoms. When the fused ring is a heterocyclyl ring or a heteroaryl ring, the common ring atom(s) may be carbon or nitrogen. Fused rings include bicyclic, tricyclic, tertracyclic, and the like.
The term "substituted" used herein means any of the above groups (e.g., alkyl, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, alkoxy, alkylether, phosphoalkyl, phosphoalkylether, thiophosphoalkyl, thiophosphoalkylether, carbocyclic, cycloalkyl, aryl, heterocyclic and/or heteroaryl) wherein at least one hydrogen atom (e.g., 1, 2, 3 or all hydrogen atoms) is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, "substituted" includes any of the above groups in which one or more hydrogen atoms are replaced with -NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh, -NRgC(=O)ORh, -NRgSO2Rh, -OC(=O)NRgRh, -ORg, -SRg, -SORg, -SO2Rg, -OSO2Rg, -SO2ORg, =NSO2Rg, and -SO2NRgRh. "Substituted also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)Rg, -C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg, -CH2SO2NR.gR.i1. In the foregoing, Rg and Rh are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl. "Substituted" further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N- heteroaryl and/or heteroarylalkyl group. In addition, each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.
"Conjugation" refers to the overlap of one p-orbital with another p-orbital across an intervening sigma bond. Conjugation may occur in cyclic or acyclic compounds. A "degree of conjugation" refers to the overlap of at least one p-orbital with another p-orbital across an intervening sigma bond. For example, 1, 3-butadine has one degree of conjugation, while benzene and other aromatic compounds typically have multiple degrees of conjugation. Fluorescent and colored compounds typically comprise at least one degree of conjugation.
"Fluorescent" refers to a molecule which is capable of absorbing light of a particular frequency and emitting light of a different frequency. Fluorescence is well-known to those of ordinary skill in the art.
"Colored" refers to a molecule which absorbs light within the colored spectrum (i.e., red, yellow, blue and the like).
The term "biomolecule" refers to any of a variety of biological materials, including nucleic acids, carbohydrates, amino acids, polypeptides, glycoproteins, hormones, aptamers and mixtures thereof. More specifically, the term is intended to include, without limitation, RNA, DNA, oligonucleotides, modified or derivatized nucleotides, enzymes, receptors, prions, receptor ligands (including hormones), antibodies, antigens, and toxins, as well as bacteria, viruses, blood cells, and tissue cells. The visually detectable biomolecules of the disclosure (e.g., compounds of Structure (I) having a biomolecule linked thereto) are prepared, as further described herein, by contacting a biomolecule with a compound having a reactive group that enables attachment of the biomolecule to the compound via any available atom or functional group, such as an amino, hydroxy, carboxyl, or sulfhydryl group on the biomolecule.
A "reactive group" is a moiety capable of reacting with a second reactive groups (e.g., a "complementary reactive group") to form one or more covalent bonds, for example by a displacement, oxidation, reduction, addition, or cycloaddition reaction. Exemplary reactive groups are provided in Table A, and include for example, nucleophiles, electrophiles, dienes, dienophiles, aldehyde, oxime, hydrazone, alkyne, amine, azide, acylazide, acylhalide, nitrile, nitrone, sulfhydryl, disulfide, sulfonyl halide, isothiocyanate, imidoester, activated ester, ketone, α,β-unsaturated carbonyl, alkene, maleimide, a-haloimide, epoxide, aziridine, tetrazine, tetrazole, phosphine, biotin, thiirane and the like.
"Bio-conjugation" or "bio-conjugate" and related variations refer to a chemical reaction strategy for forming a stable covalent bond between two molecules. The term "bio-conjugation" is generally used when one of the molecules is a biomolecule (e.g., an antibody), but can be used to describe forming a covalent bond with a non-biomolecule (e.g., a polymeric resin). The product or compound resulting from such a reaction strategy is a "conjugate," "bio-conjugate" or a grammatical equivalent. The terms "visible" and "visually detectable" are used herein to refer to substances that are observable by visual inspection, without prior illumination, or chemical or enzymatic activation. Such visually detectable substances absorb and emit light in a region of the spectrum ranging from about 300 to about 900 nm. Preferably, such substances are intensely colored, preferably having a molar extinction coefficient of at least about 40,000, more preferably at least about 50,000, still more preferably at least about 60,000, yet still more preferably at least about 70,000, and most preferably at least about 80,000 M-1cm-1. The compounds of the disclosure may be detected by observation with the naked eye, or with the aid of an optically based detection device, including, without limitation, absorption spectrophotometers, transmission light microscopes, digital cameras, and scanners. Visually detectable substances are not limited to those which emit and/or absorb light in the visible spectrum. Substances which emit and/or absorb light in the ultraviolet (UV) region (about 10 nm to about 400 nm), infrared (IR) region (about 700 nm to about 1 mm), and substances emitting and/or absorbing in other regions of the electromagnetic spectrum are also included with the scope of "visually detectable" substances.
For purposes of embodiments of the disclosure, the term "photostable visible dye" refers to a chemical moiety that is visually detectable, as defined hereinabove, and is not significantly altered or decomposed upon exposure to light. Preferably, the photostable visible dye does not exhibit significant bleaching or decomposition after being exposed to light for at least one hour. More preferably, the visible dye is stable after exposure to light for at least 12 hours, still more preferably at least 24 hours, still yet more preferably at least one week, and most preferably at least one month. Non-limiting examples of photostable visible dyes suitable for use in the compounds and methods of the disclosure include azo dyes, thioindigo dyes, quinacridone pigments, dioxazine, phthalocyanine, perinone, diketopyrrolopyrrole, quinophthalone, and truarycarbonium.
As used herein, the term "perylene derivative" is intended to include any substituted perylene that is visually detectable. However, the term is not intended to include perylene itself. The terms "anthracene derivative," "naphthalene derivative," and "pyrene derivative" are used analogously. In some preferred embodiments, a derivative (e.g., perylene, pyrene, anthracene, or naphthalene derivative) is an imide, bisimide or hydrazamimide derivative of perylene, anthracene, naphthalene, or pyrene.
The visually detectable molecules of various embodiments of the disclosure are useful for a wide variety of analytical applications, such as biochemical and biomedical applications, in which there is a need to determine the presence, location, or quantity of a particular analyte e.g., biomolecule). In another aspect, therefore, the disclosure provides a method for visually detecting a biomolecule, comprising: (a) providing a biological system with a visually detectable biomolecule comprising the polymer compounds of the present disclosure (e.g., compounds of Structure (I)) linked to a biomolecule; and (b) detecting the biomolecule by its visible properties. For purposes of the disclosure, the phrase "detecting the biomolecule by its visible properties" means that the biomolecule, without illumination or chemical or enzymatic activation, is observed with the naked eye, or with the aid of an optically based detection device, including, without limitation, absorption spectrophotometers, transmission light microscopes, digital cameras and scanners. A densitometer may be used to quantify the amount of visually detectable biomolecule present. For example, the relative quantity of the biomolecule in two samples can be determined by measuring relative optical density. If the stoichiometry of dye molecules per biomolecule is known, and the extinction coefficient of the dye molecule is known, then the absolute concentration of the biomolecule can also be determined from a measurement of optical density. As used herein, the term "biological system" is used to refer to any solution or mixture comprising one or more biomolecules in addition to the visually detectable biomolecule. Nonlimiting examples of such biological systems include cells, cell extracts, tissue samples, electrophoretic gels, assay mixtures, and hybridization reaction mixtures.
"Solid support" or "solid resin" refers to any solid substrate known in the art for solid- phase support of molecules, for example a "microparticle" refers to any of a number of small particles useful for attachment to compounds of the disclosure, including, but not limited to, glass beads, magnetic beads, polymeric beads, nonpolymeric beads, and the like. In certain embodiments, a microparticle comprises polystyrene beads. In some embodiments, the solid support or solid resin is controlled pore glass or macroporous polystyrene.
A "solid support residue" refers to the functional group remaining attached to a molecule when the molecule is cleaved from the solid support. Solid support residues are known in the art and can be easily derived based on the structure of the solid support and the group linking the molecule thereto.
A "targeting moiety" is a moiety that selectively binds or associates with a particular target, such as an analyte molecule. "Selectively" binding or associating means a targeting moiety preferentially associates or binds with the desired target relative to other targets. In some embodiments the compounds disclosed herein include linkages to targeting moieties for the purpose of selectively binding or associating the compound with an analyte of interest (i.e., the target of the targeting moiety), thus allowing detection of the analyte. Exemplary targeting moieties include, but are not limited to, antibodies, antigens, nucleic acid sequences, enzymes, proteins, cell surface receptor antagonists, and the like. In some embodiments, the targeting moiety is a moiety, such as an antibody, that selectively binds or associates with a target feature on or in a cell, for example a target feature on a cell membrane or other cellular structure, thus allowing for detection of cells of interest. Small molecules that selectively bind or associate with a desired analyte are also contemplated as targeting moieties in certain embodiments. One of skill in the art will understand other analytes, and the corresponding targeting moiety, that will be useful in various embodiments.
"Cell surface protein binding moiety" refers to a chemical entity (e.g., ligand, antigen, amino acid sequence, peptide, etc.) that has an avidity or binding affinity for a membrane (i.e., a cell membrane) bound protein (e.g., an immunoglobulin and/or a signal transduction moiety). Exemplary membrane bound proteins include IgD, IgM, IgA, IgG, or IgE. Cells that include the surface proteins include B-cells.
"Base pairing moiety" refers to a heterocyclic moiety capable of hybridizing with a complementary heterocyclic moiety via hydrogen bonds (e.g., Watson-Crick base pairing). Base pairing moieties include natural and unnatural bases. Non-limiting examples of base pairing moieties are RNA and DNA bases such adenosine, guanosine, thymidine, cytosine and uridine and analogues thereof.
Embodiments of the disclosure disclosed herein are also meant to encompass all compounds being isotopically labelled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I, respectively.
Isotopically labeled compounds and polymer compounds of the present disclosure (e.g., compounds of Structure (I)) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described below and in the following Examples using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.
"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. In some embodiments, the compounds of the present disclosure (e.g., compounds of Structure (A), (I), or (B)) are limited to only stable compounds. In some embodiments, compounds of the present disclosure (e.g., compounds of Structure (A), (I), or (B)) do not include any peroxide moieties (i.e., -O-O-). In some embodiments, the compounds of the present disclosure (e.g., compounds of Structure (A), (I), or (B)) do not include any diphosphate moieties.
"Optional" or "optionally" means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted alkyl" means that the alkyl group may or may not be substituted and that the description includes both substituted alkyl groups and alkyl groups having no substitution.
"Salt" includes both acid and base addition salts.
"Acid addition salt" refers to those salts which are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-l,5-disulfonic acid, naphthal ene-2-sulfonic acid, 1 -hydroxy -2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.
"Base addition salt" refers to those salts which are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
Crystallizations may produce a solvate of the compounds described herein. Embodiments of the present disclosure include all solvates of the described compounds. As used herein, the term "solvate" refers to an aggregate that comprises one or more molecules of a compound of the disclosure with one or more molecules of solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present disclosure may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compounds of the disclosure may be true solvates, while in other cases the compounds of the disclosure may merely retain adventitious water or another solvent or be a mixture of water plus some adventitious solvent.
Embodiments of the compounds of the disclosure (e.g., compounds of structure I), or their salts, tautomers or solvates may contain one or more stereocenters and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. Embodiments of the present disclosure are meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic 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 also intended to be included.
A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.
A "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any said compounds. Various tautomeric forms of the compounds are easily derivable by those of ordinary skill in the art.
The chemical naming protocol and structure diagrams used herein are a modified form of the I.U.P.A.C. nomenclature system, using the ACD/Name Version 9.07 software program and/or ChemDraw Ultra Version 11.0 software naming program (CambridgeSoft). Common names familiar to one of ordinary skill in the art are also used. Compounds
As noted above, in one embodiment of the present disclosure, a water-soluble polymeric compound useful as covalent linker between antibodies and payloads is provided. One embodiment provides a polymer compound comprising a backbone comprising one or more monomer subunits having one of the following Structures (A), (B), (C), (D), (E), or (F):
wherein:
R1 , R2 , R3 , Rla', Rlb', and Rlc' are, at each occurrence independently hydrogen or C1-C6 alkyl;
R4 is a covalent bond to the remainder of the backbone, -OH, or has the following structure: wherein R4a' is hydrogen or a covalent bond to the remainder of the backbone;
R6a' and R6b' are each independently hydrogen or C1-C6 alkyl;
R7a, R7b', R8a', and R8b' are each independently hydrogen or C1-C6 alkyl, provided that at least one of R7a', R7b', R8a', and R8b' is C1-C6 alkyl;
R7c, R7d', R8c, and R8d' are each independently hydrogen or C1-C6 alkyl, or
R7C' and R8C' each represent an electron pair, the nitrogen to which they are each attached are uncharged, and R7d' and R8d' each independently have one of the following structures: wherein R9a', R9b', and R9c' are each independently hydrogen or C1-C6 alkyl
L1 is an alkylene or heteroalkylene linker;
L2 is a direct bond, an alkylene linker, or a heteroalkylene linker;
L3 is an alkylene linker or a heteroalkylene linker;
L4 is an alkylene linker or a heteroalkylene linker; and
Y has one of the following structures:
The < of Structures (A), (B), (C), (D), (E), and (F) represent a connection to the backbone.
In some embodiments, at least one occurrence of Structure (A) has the following structure:
In certain embodiments, at least one occurrence of Structure (B) has one of the following structures: In some embodiments, at least one occurrence of Structure (C) has one of the following structures:
In some embodiments, at least one occurrence of Structure (D) has one of the following structures:
In certain embodiments, at least one occurrence of Structure (E) has one of the following structures:
5
In some embodiments, at least one occurrence of Structure (F) has one of the following structures:
In certain embodiments, the compound has the following Structure (I): or a stereoisomer, tautomer, or salt thereof, wherein: each occurrence of R1 and R2 are independently hydrogen, OH, SH, alkyl, alkoxy, alkylether, heteroalkyl, -OP(=Ra)(Rb)Rc, Q, or L';
Ra is O or S;
Rb is OH, SH, O-, S-, ORd or SRa;
Rc is OH, SH, O-, S-, ORd, OL', SRd, alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkylether, alkoxyalkylether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether or thiophosphoalkylether; Rd is a counter ion; each occurrence of R3 is independently hydrogen or C1-C6 alkyl; each occurrence of R4 is independently OH, SH, O-, S-, ORd or SRd; each occurrence of R5 is independently oxo or thioxo; each occurrence of R6 and R7 are independently hydrogen or halo; each occurrence of L1, L2, L3, L4, L5, and L6 are independently a direct bond, optionally substituted alkylene linker, optionally substituted heteroalkylene linker, a heteroatomic linker, or a combination thereof, provided that at least one occurrence of R1, R2, L1, L2, L4, L5, and L6 includes the monomer subunit of Structure (A), Structure (B), Structure (C), Structure (D), Structure (E), Structure (F), or combinations thereof; each occurrence of La is independently a heteroalkylene or heteroarylene linker; each occurrence of Lb is independently a direct bond, an alkylene linker, a heteroalkylene linker, a heteroatomic linker, or a combination thereof; each occurrence of M1 and M2 are a biologically active moiety, a fluorescent moiety, or a colored moiety; each occurrence of Q is independently a moiety comprising a reactive group, or protected form thereof, capable of forming a covalent bond with a complementary reactive group Q' on a targeting moiety; each occurrence of L' is independently a linker comprising a covalent bond to Q, a targeting moiety, a linker comprising a covalent bond to a targeting moiety, a linker comprising a covalent bond to a solid support, a linker comprising a covalent bond to a solid support residue, a solid support residue, or a linker comprising a covalent bond to a nucleoside; each occurrence of m is an integer ranging from 0 to 50; each occurrence of q and w are each an integer ranging from 0 to 50, provided that the sum of q and w is an integer greater than 1; n is an integer ranging from 1 to 50.
In certain embodiments, the polymer compound has the following Structure (IA):
wherein:
L has the following structure: wherein: v is an integer ranging from 0 to 50, provided that at least one occurrence of v is 1 or greater;
R1, R2, and R3 are, at each occurrence independently hydrogen or C1-C6 alkyl; and
R4 is a covalent bond, -OH, or has the following structure: wherein R4a' is hydrogen or a covalent bond.
In some embodiments, the polymer compound has the following Structure (la): In some embodiments, L1 comprises one or more alkylene or alkylene oxide moieties. In certain embodiments, the alkylene oxide moieties comprise polyethylene oxide moieties. In certain embodiments, L1, at each occurrence, comprises the following structure: wherein: z is an integer from 1 to 100; and
* indicates a bond to the adjacent phosphorous atom.
In some embodiments, each occurrence of L1 comprises one of the following structures:
In certain embodiments, each occurrence of L1 comprises one of the following structures: wherein: each occurrence of x is an integer ranging from 20 to 30.
In some embodiments, the polymer compound has the following Structure (lb):
In certain embodiments, the polymer compound has one the following structures:
In some embodiments, L2 and L4 are, at each occurrence, independently a direct bond or C1-C6 alkylene.
In certain embodiments, each occurrence of L3 is independently selected from the group consisting of optionally substituted alkylene and optionally substituted heteroalkylene.
In some embodiments, each occurrence of L3 and Lb independently have one of the following structures: In certain embodiments, each occurrence of L3 and Lb independently have one of the following structures:
In some embodiments, each occurrence of L3 and Lb independently have the following structure:
In certain embodiments, each occurrence of L3 independently has one of the following structures:
In some embodiments, each occurrence of L3 has the following structure:
In certain embodiments, La is, at each occurrence independently an optionally substituted 5-7 membered heteroarylene linker. In some embodiments, La has one of the following structures: In some embodiments, at least one occurrence of Lb comprises a triazolyl ring. In certain embodiments, at least one occurrence of -Lb-M2 comprises one of the following structures: wherein Lc and Ld are, at each occurrence independently a direct bond, alkylene, or heteroalkylene.
In certain embodiments, each occurrence of Lc, Ld, or both, are direct bonds. In some embodiments, each occurrence of Lc, Ld, or both are independently alkylene or heteroalkylene. In certain embodiments, each occurrence of Lc, Ld, or both have one of the following structures:
In some embodiments, each occurrence of -Lb-M2 has one of the following structures:
In some embodiments, at least one occurrence of L7 has the following structure:
In some embodiments, R1 is, at each occurrence, hydrogen. In certain embodiments, Q comprises a sulfhydryl, disulfide, activated ester, isothiocyanate, azide, alkyne, alkene, diene, dienophile, acid halide, sulfonyl halide, phosphine, a-haloamide, biotin, amino, or maleimide functional group.
In some embodiments, the activated ester is an N-succinimide ester, imidoester or polyflourophenyl ester. In certain embodiments, Q comprises one of the following structures:
wherein:
G1 is halo; and
E is an electronic withdrawing group. In some embodiments, R1 or R2 has one of the following structures:
In certain embodiments, R1 or R2 has one of the following structures:
In some embodiments, R1 or R2 has one of the following structures:
In certain embodiments, n ranges from 1 to 20.
In some embodiments, at least one occurrence of M1 or M2 is selected from the group consisting of a pyrene, perylene, perylene monoimide, and 6-FAM moiety. In certain embodiments, at least one occurrence of M1 or M2 has one of the following structures:
In some embodiments, at least one occurrence of M1 and M2 have one of the following structures:
In certain embodiments, at least one occurrence of M1 or M2 have the following structure:
In some embodiments, one or more occurrences of M1, M2, or both have one of the following structures:
In some embodiments, at least one occurrence of M1, M2, or both have one of the following structures:
In certain embodiments, the targeting moiety is an antibody. In some embodiments, the antibody is trastuzumab, gemtuzumab, brentuximab, vorsetuzumab, lorvotuzumab, cantuzumab, bivatuzumabor inotuzumab, or vadastuximab.
For ease of illustration, various compounds comprising phosphorous moieties (e.g., phosphate and the like) are depicted in the anionic state (e.g., -O-PO-(OH)-O-, -OPO3 2-). One of skill in the art will readily understand that the charge is dependent on pH and the uncharged (e.g., protonated or salt, such as sodium or other cation) forms are also included in the scope of embodiments of the disclosure.
In some embodiments, M1, M2, or both are at each occurrence, independently an NS AID, a kinase inhibitor, an anthracycline, an EGFR inhibitor, or an alkylating agent.
In some embodiments, M1, M2, or both are anti-cancer drugs. In certain specific embodiments, M1, M2, or both are at each occurrence, independently an anti-cancer drug, and the antibody specific for a tumor cell antigen. Anti-cancer drug, as used herein, includes derivatives (e.g., compounds with added linkers covalently binding the drug to the compounds of Structure (I)). For example, maytansine is a cancer drug and maytansinoids are cancer drug derivatives.
In certain embodiments, the anti-cancer drug is an epidermal growth factor receptor (EGFR) inhibitor, phosphatidylinositol kinase (PI3K) inhibitor, insulin-like growth factor receptor (IGF1R) inhibitor, Janus kinase (JAK) inhibitor, a Met kinase inhibitor, a SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular-signal- regulated kinase (ERK) inhibitor, a topoisomerase inhibitors (such as irinotecan, or such as etoposide, or such asdoxorubicin), taxanes (such as anti -microtubule agents including paclitaxel and docetaxel), anti-metabolite agents (such as 5-FU or such as gemcitabine), alkylating agents (such as cisplatin or such as cyclophosphamide), or a taxane.
Anti-cancer drugs that can be modified and incorporated into embodiments of compounds of the present disclosure include, for example, auristatin F; auristatin E; maytansine; calicheamicin; paclitaxel; doxorubicin; cryptophycin; erlotinib; CC-1065; carzelesin; SJG-136; DSB-120; afatinib; Iressa or methotrexate.
Other non-limiting examples of anti-cancer drugs include Gleevec® (Imatinib Mesylate), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), and Adriamycin, alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex®, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5- oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6- azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2- ethylhydrazide; procarbazine; PSK.RTM.; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes, e.g. paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, N.J.) and docetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoic acid; esperamicins or capecitabine. Also included as suitable cancer drugs are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen, (Nolvadex™), raloxifene, aromatase inhibiting 4(5)-imidazoles, 4- hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11); topoisomeRASe inhibitor RFS 2000; difluoromethylornithine (DMFO).
One embodiment provides a pharmaceutical composition comprising the polymer compound of any one of the embodiments disclosed herein, or a stereoisomer, tautomer, or salt thereof and a pharmaceutically acceptable excipient.
In still other embodiments, Q is, at each occurrence, independently a moiety comprising a reactive group capable of forming a covalent bond with an analyte molecule or a solid support. In other embodiments, Q is, at each occurrence, independently a moiety comprising a reactive group capable of forming a covalent bond with a complementary reactive group Q'. For example, in some embodiments, Q' is present on a further compound of Structure (I), (e.g., in the R1 or R2 position), and Q and Q' comprise complementary reactive groups such that reaction of the compound of Structure (I) and the further compound of Structure (I) results in covalently bound dimer of the compound of Structure (I). Multimer compounds of Structure (I) can also be prepared in an analogous manner and are included within the scope of embodiments of the disclosure.
The type of Q group and connectivity of the Q group to the remainder of the compound of Structure (I) is not limited, if Q comprises a moiety having appropriate reactivity for forming the desired bond. In certain embodiments, Q is a moiety which is not susceptible to hydrolysis under aqueous conditions but is sufficiently reactive to form a bond with a corresponding group on an analyte molecule or solid support (e.g., an amine, azide or alkyne).
Certain embodiments of compounds of Structure (I) comprise Q groups commonly employed in the field of bioconjugation. For example, in some embodiments, Q comprises a nucleophilic reactive group, an electrophilic reactive group or a cycloaddition reactive group. In some more specific embodiments, Q comprises a sulfhydryl, disulfide, activated ester, isothiocyanate, azide, alkyne, alkene, diene, dienophile, acid halide, sulfonyl halide, phosphine, oc-haloamide, biotin, amino or maleimide functional group. In some embodiments, the activated ester is an N-succinimide ester, imidoester or polyflourophenyl ester. In other embodiments, the alkyne is an alkyl azide or acyl azide.
The Q groups can be conveniently provided in protected form to increase storage stability or other desired properties, and then the protecting group removed at the appropriate time for conjugation with, for example, a targeting moiety or analyte. Accordingly, Q groups include "protected forms" of a reactive group, including any of the reactive groups described above and in the Table A below. A "protected form" of Q refers to a moiety having lower reactivity under predetermined reaction conditions relative to Q, but which can be converted to Q under conditions, which preferably do not degrade or react with other portions of the compound of Structure (I). One of skill in the art can derive appropriate protected forms of Q based on the Q and desired end use and storage conditions. For example, when Q is SH, a protected form of Q includes a disulfide, which can be reduced to reveal the SH moiety using commonly known techniques and reagents.
Exemplary Q moi eties are provided in Table A below.
Table A. Exemplary Q Moieties
1 In some embodiments, an electron withdrawing group is a halo (e.g., F, Cl, Br, or I), an oxygen containing group (e.g., OH or alkoxy), a nitrogen containing group (e.g., -N(R)2 wherein R is H or alkyl), haloalkyl, nitro, ammonium, cyano, carboxy, -SO3H, and the like.
It should be noted that in some embodiments, wherein Q is SH, the SH moiety will tend to form disulfide bonds with another sulfhydryl group, for example on another compound of Structure (I). Accordingly, some embodiments include compounds of Structure (I), which are in the form of disulfide dimers, the disulfide bond being derived from SH Q groups.
In other embodiments, the Q moiety is conveniently masked (e.g., protected) as a disulfide moiety, which can later be reduced to provide an activated Q moiety for binding to a desired analyte molecule or targeting moiety. For example, the Q moiety may be masked as a disulfide having the following structure: wherein R is an optionally substituted alkyl group. For example, in some embodiments, Q is provided as a disulfide moiety having the following structure: where n is an integer from 1 to 10.
In some embodiments, M2 is the same at each occurrence; however, it is important to note that each occurrence of M2 need not be an identical M2, and certain embodiments include compounds wherein M2 is not the same at each occurrence. For example, in some embodiments each M2 is not the same and the different M2 moiety is selected to have different antineoplastic agents.
In some embodiments, n is an integer of one or greater. In certain embodiments, n is an integer from 1 to 100. In other embodiments, n is an integer from 1 to 20. In other embodiments, n is an integer from 1 to 10. In some embodiments, n is 1, 3, 5, 7, or 10. In some embodiments, n is 1, 2, 3, 4, or 5. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10.
The value for m can control the spacing between neighboring M1 groups and/or M2 groups. In some embodiments, m is an integer of zero or greater. In certain embodiments, m is an integer from 0 to 100. In certain embodiments, m is an integer from 0 to 10. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10. In some certain embodiments, m is 1, 2, 3, 4, or 5.
The value for q can control the efficacy of compounds. In some embodiments, q is, at each occurrence, an integer of zero or greater. In some embodiments, each occurrence of q independently ranges from 2 to 20. In some more specific embodiments, q is from 0 to 10. In some embodiments, q is from 0 to 5. For example, in some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5. In some other embodiments, q is 1.
The value for w can control the efficacy of compounds. In some embodiments, w is, at each occurrence, an integer of zero or greater. In some embodiments, each occurrence of w independently ranges from 2 to 20. In some more specific embodiments, w is from 0 to 10. In some embodiments, w is from 0 to 5. For example, in some embodiments, w is 0. In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4. In some embodiments, w is 5. In some other embodiments, w is 1.
One embodiment provides a compound having one of the following Structures (A-l), (B- 1), (C-1), (D-1), (E-1), or (F-1): wherein:
R1', R2 , R3 , Rla', Rlb', and Rlc' are, at each occurrence independently hydrogen or C1-C6 alkyl;
R4' is hydrogen or has the following structure:
R5 is hydrogen or has the following structure:
R6a' and R6b' are each independently hydrogen or C1-C6 alkyl; R7a, R , R8a', and R8b are each independently hydrogen or C1-C6 alkyl, provided that at least one of R7a', R7b', R8a', and R8b' is C1-C6 alkyl;
R7c, R7d', R8c, and R8d' are each independently hydrogen or C1-C6 alkyl, or
R7C' and R8C' each represent an electron pair, the nitrogen to which they are each attached are uncharged, and R7d' and R8d' each independently have the following structure: wherein R9a', R9b', and R9c' are each independently hydrogen or C1-C6 alkyl
L1' is an alkylene or heteroalkylene linker
L2 is a direct bond, an alkylene linker, or a heteroalkylene linker;
L3 is an alkylene linker or a heteroalkylene linker;
L4 is an alkylene linker or a heteroalkylene linker;
Y has one of the following structures:
In some embodiments, L1' is C1-C4 alkylene. In some embodiments, L1' comprises 2-4 carbon atoms and one oxygen atom. In some embodiments, L1' is unsubstituted.
In some embodiments, L2' is C1-C12 alkylene. In some embodiments, L2' comprises 6-12 carbon atoms and one or more nitrogen atoms. In some embodiments, L1' is substituted with one or more oxo (i.e., =O).
In some embodiments, L3' is C1-C12 alkylene. In some embodiments, L3' comprises 6-12 carbon atoms and one or more nitrogen atoms. In some embodiments, L3' is substituted with one or more oxo (i.e., =O).
In some embodiments, L4' is C1-C4 alkylene. In some embodiments, L4' comprises 2-4 carbon atoms and one oxygen atom. In some embodiments, L4' is unsubstituted.
In some embodiments, the compound of Structure (A-l) has one of the following structures:
In certain embodiments, the compound of Structure (B-1) has one of the following structures:
In certain embodiments, the compound of Structure (C-1) has one of the following structures:
In some embodiments, the compound of Structure (D-l) has one of the following
5 structures:
5 In certain embodiments, the compound of Structure (E-l) has one of the following structures:
In certain embodiments, the compound of Structure (F-l) has one of the following
5 structures:
Pharmaceutical Compositions
One embodiment provides a composition comprising the compound according to any one of the embodiments disclosed herein (e.g., a compound of Structure (I) and a pharmaceutically acceptable carrier).
Some embodiments are directed to pharmaceutical compositions. The pharmaceutical composition comprises one (or more) of the polymer compounds of the present disclosure (e.g., compounds of Structure (I)) and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In still more embodiments, the pharmaceutical compositions comprise a polymer compound of the present disclosure (e.g., compounds of Structure (I)) and an additional therapeutic agent (e.g., anticancer agent). Non- limiting examples of such therapeutic agents are described herein below.
Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
In certain embodiments, a polymer compounds of the present disclosure (e.g., compounds of Structure (I)) is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long-acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the polymer compound of the present disclosure (e.g., compound of Structure (I)) is provided in the form of a rapid release formulation, in the form of an extended-release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the compound of Structure (I) is administered topically.
The polymer compounds of the present disclosure (e.g., compounds of Structure (I)) are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that are used in some embodiments. An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
In some embodiments, a polymer compound of the present disclosure (e.g, compound of Structure (I)) is administered in a single dose. Typically, such administration will be by injection, e.g, intravenous injection, to introduce the agent quickly. However, other routes are used as appropriate. A single dose of a polymer compound of the present disclosure (e.g., compound of Structure (I)) may also be used for treatment of an acute condition. In some embodiments, a polymer compound of the present disclosure (e.g., compound of Structure (I)) is administered in multiple doses. In some embodiments, dosing is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, dosing is about once a month, once every two weeks, once a week, or once every other day. In another embodiment a polymer compound of the present disclosure (e.g., compound of Structure (I)) and another agent are administered together about once per day to about 6 times per day. In another embodiment the administration of a polymer compound of the present disclosure (e.g., compound of Structure (I)) and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.
Administration of the polymer compounds of the present disclosure (e.g., compounds of Structure (I)) may continue as long as necessary. In some embodiments, a polymer compound of the present disclosure (e.g., compound of Structure (I)) is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a polymer compound of the present disclosure (e.g., compound of Structure (I)) is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a polymer compound of the present disclosure (e.g., compound of Structure (I)) is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.
In some embodiments, the polymer compound of the present disclosure (e.g., compound of Structure (I)) is administered in dosages. It is known in the art that due to inter-subject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the disclosure may be found by routine experimentation considering the instant disclosure.
In some embodiments, the polymer compound of the present disclosure (e.g., compound of Structure (I)) is formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).
Provided herein are pharmaceutical compositions comprising a polymer compound of the present disclosure (e.g., compound of Structure (I)) and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). In certain embodiments, the compounds described are administered as pharmaceutical compositions in which polymer compounds of the present disclosure (e.g., compounds of Structure (I)) are mixed with other active ingredients, as in combination therapy. Encompassed herein are all combinations of actives set forth in the combination therapies section below and throughout this disclosure. In specific embodiments, the pharmaceutical compositions include one or more polymer compounds of the present disclosure (e.g., compounds of Structure (I))-
A pharmaceutical composition, as used herein, refers to a mixture of a polymer compound of the present disclosure (e.g., compound of Structure (I)) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, practicing the methods of treatment or use provided herein, therapeutically effective amounts of polymer compounds of the present disclosure (e.g., compounds of Structure (I)) provided herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or medical condition to be treated. In specific embodiments, the mammal is a human. In certain embodiments, therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The polymer compound of the present disclosure (e.g., compound of Structure (I)) is used singly or in combination with one or more therapeutic agents as components of mixtures.
In one embodiment, one or more polymer compound of the present disclosure (e.g., compound of Structure (I)) is formulated in an aqueous solution. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer. In other embodiments, one or more polymer compound of the present disclosure (e.g., compound of Structure (I)) is/are formulated for transmucosal administration. In specific embodiments, transmucosal formulations include penetrants that are appropriate to the barrier to be permeated. In still other embodiments wherein the compounds described herein are formulated for other parenteral injections, appropriate formulations include aqueous or non-aqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and/or excipients.
In other embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In still other embodiments, the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations. In still other embodiments, the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles. Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and/or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In additional embodiments, suspensions of the active compounds (e.g., compounds of Structure (I)) are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
In still other embodiments, the polymer compound of the present disclosure (e.g., compound of Structure (I)) is administered topically. The compounds described herein are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives.
In yet other embodiments, the polymer compound of the present disclosure (e.g., compound of Structure (I)) is formulated for transdermal administration. In specific embodiments, transdermal formulations employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. In various embodiments, such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. In additional embodiments, the transdermal delivery of the polymer compound of the present disclosure (e.g., compound of Structure (I)) is accomplished by means of iontophoretic patches and the like. In certain embodiments, transdermal patches provide controlled delivery of the polymer compound of the present disclosure (e.g., compound of Structure (I)). In specific embodiments, the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to increase absorption. Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that assist passage through the skin. For example, in one embodiment, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period and means to secure the device to the skin.
In other embodiments, the polymer compound of the present disclosure (e.g., compound of Structure (I)) is formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists, or powders. Pharmaceutical compositions of any of polymer compound of the present disclosure (e.g., compound of Structure (I)) are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In specific embodiments, the dosage unit of a pressurized aerosol is determined by providing a valve to deliver a metered amount. In certain embodiments, capsules, and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator is formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
In still other embodiments, the polymer compound of the present disclosure (e.g., compound of Structure (I)) is formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with melted cocoa butter.
In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are optionally used as suitable. Pharmaceutical compositions comprising a polymer compound of the present disclosure (e.g., compound of Structure (I)) are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent, or excipient and at least one polymer compound of the present disclosure (e.g., compound of Structure (I)), described herein as an active ingredient. The active ingredient is in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances.
Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.
In some embodiments, pharmaceutical composition comprising at least one polymer compound of the present disclosure (e.g., compound of Structure (I)) illustratively takes the form of a liquid where the agents are present in solution, in suspension or both. Typically, when the composition is administered as a solution or suspension a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.
In certain embodiments, useful aqueous suspensions contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.
Useful pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a polymer compound of the present disclosure (e.g., compound of Structure (I)). The term "solubilizing agent" generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g, polyethylene glycol 400, and glycol ethers.
Furthermore, useful pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric, and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
Additionally, useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
Other useful pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.
Still other useful compositions include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.
Still other useful compositions include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.
In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.
In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as V-methylpyrrolidone are also employed. In additional embodiments, the compounds described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.
In certain embodiments, the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and/or other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.
In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v.
In some embodiments, the concentration of one or more compounds is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%,
15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%,
12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%,
9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125% , 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v.
In some embodiments, the concentration of one or more compounds is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40 %, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/v. In some embodiments, the concentration of one or more compounds is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v.
In some embodiments, the amount of one or more compounds is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.
In some embodiments, the amount of one or more compounds is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, , 0.15 g, 0.2 g, , 0.25 g, 0.3 g, , 0.35 g, 0.4 g, , 0.45 g, 0.5 g, 0.55 g, 0.6 g, , 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5g, 7 g, 7.5g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.
In some embodiments, the amount of one or more compounds ranges from 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g, 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g-
Method of Treatment
The polymer compounds of the present disclosure can be administered for treatment of various diseases and disorders while conjugated to a targeting protein (e.g., an antibody). Accordingly, one embodiment provides a method of treating a disease or disorder comprising administering a conjugate comprising (i) an antibody and (ii) a polymer compound as disclosed herein, wherein the antibody is covalently bound to the polymer compound. In some embodiments, the disease or disorder is cancer. In some embodiments, the treatment is for a cancerous tumor. In some embodiments, the autoimmune disease is multiple sclerosis, diabetes, celiacs disease, Graves' disease, myasthenia gravis, Hashimotos encephalomyelitis, Neuromyelitis optica, inflammatory bowel disease, hemaphilia, lupus, autoimmune encephalomyelitis (EAE), or rheumatoid arthritis.
Polymer compounds of the present disclosure (e.g., compounds of Structure (I)) are safe and offer flexibility in determining the appropriate structure and properties while also allowing efficient carriage of drug and proteins to target cells. In addition, the polymer compounds are effective at targeting antigen-presenting cells (APCs), such as dendritic cells and macrophages, due to the inherent ability of these APCs to selectively endocytose.
In some embodiments, the polymer compound of the present disclosure (e.g., compound of Structure (I)) is co-delivered with a self-antigen (e.g., PLP). In some embodiments, the method is a method for treating EAE or multiple sclerosis that includes delivering a polymer compound of the present disclosure (e.g., compound of Structure (I)) that is coupled to an autoantigen, a cell adhesion inhibitory peptide (e.g., LABL), or both and the compound is co- delivered with a self-antigen (e.g., PLP).
For example, in certain embodiments the disclosure provides a method of treating cancer (e.g., breast cancer). In some embodiments, the cancer is HER2+ breast cancer, HR+ breast cancer, or triple negative breast cancer. In some embodiments, the disclosure provides a method of treating an autoimmune disease.
Further therapeutic agents that can be combined with a compound of the disclosure are found in Goodman and Gilman's "The Pharmacological Basis of Therapeutics" Tenth Edition edited by Hardman, Limbird and Gilman or the Physician's Desk Reference, both of which are incorporated herein by reference in their entirety.
The polymer compound of the present disclosure (e.g., compound of Structure (I)) described herein can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Hence, in some embodiments the one or more compounds of the disclosure will be co-administered with other agents as described above. When used in combination therapy, the compounds described herein are administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the disclosure and any of the agents described above can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, a compound of the present disclosure can be administered just followed by and any of the agents described above, or vice versa. In some embodiments of the separate administration protocol, a compound of the disclosure and any of the agents described above are administered a few minutes apart, or a few hours apart, or a few days apart.
The examples and preparations provided below further illustrate and exemplify the polymer compounds of the present disclosure and methods of preparing such compounds. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations. In the following examples, and throughout the specification and claims, molecules, and moieties with a single stereocenter, unless otherwise noted, exist as a racemic mixture. Those molecules and moieties with two or more stereocenters, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.
A Representative DNA Synthesis Cycle
Oligomerization is initiated, typically, through the removal of a protecting group (e.g., a dimethoxytrityl group, DMTr) to reveal a free -OH (hydroxyl) group (Step 1, DETRIT YLATION). In a subsequent coupling step, a phosphoramidite monomer is introduced that reacts with the free OH group making a new covalent bond to phosphorus, with concomitant loss of the diisopropyl amine group (Step 2, COUPLING). The resultant, phosphite triester is oxidized (e.g., with I2 and pyridine) to the more stable phosphate ester (Step 3, OXIDATION) and a capping step renders unreactive any remaining free OH groups (Step 4, CAPPING). The new product, phosphate oligomer, contains a DMTr protected OH group that can be deprotected to reinitiate the synthetic cycle so another phosphoramidite monomer can be appended to the oligomer.
Customization occurs at step 2 through the choice of phosphoramidite monomer. The nature of L (i.e., a linker group) and M (e.g., a cell surface protein binding moiety or a fluorescent or colored moiety) in the scheme above are selected such that a desired polymer compound of the present disclosure (e.g., compound of Structure (I)) is synthesized. M can be optionally absent to incorporate desired spacing between M moieties. A person of ordinary skill in the art can select multiple monomer types to arrive at compounds of the disclosure containing multiple therapeutic agents and/or other moieties (e.g., fluorophores or chromophores) with concurrent variability in linker groups.
EXAMPLES
General Methods
Mass spectral analysis is performed on a Waters/Micromass Quattro micro MS/MS system (in MS only mode) using MassLynx 4.1 acquisition software. Mobile phase used for LC/MS on dyes is 100 mM l,l,l,3,3,3-hexafluoro-2-propanol (HFIP), 8.6 mM triethylamine (TEA), pH 8. Phosphoramidites and precursor molecules are also analyzed using a Waters Acquity UHPLC system with a 2.1 mm x 50 mm Acquity BEH-C18 column held at 45 °C, employing an acetonitrile / water mobile phase gradient. Molecular weights for monomer intermediates are obtained using tropylium cation infusion enhanced ionization on a Waters/Micromass Quattro micro MS/MS system (in MS only mode). Excitation and emission profiles experiments are recorded on a Cary Eclipse spectra photometer.
All reactions are carried out in oven dried glassware under a nitrogen atmosphere unless otherwise stated. Commercially available DNA synthesis reagents are purchased from Glen Research (Sterling, VA). Anhydrous pyridine, toluene, dichloromethane, diisopropylethyl amine, triethylamine, acetic acid, pyridine, and THF are purchased from Aldrich. All other chemicals are purchase from Aldrich or TCI and are used as is with no additional purification. EXAMPLE 1
SYNTHESIS OF COMPOUNDS OF STRUCTURE (I)
Stock Solution Preparation
Borate buffer prepared at 250 mM, pH 10
M1-NHS or M2-NHS solution prepared at 350 mM (300 mg in 1.35 mL DMSO: acetonitrile at 25:75)
Solid Phase Synthesis
Compounds of Structure (I) are prepared on the DNA synthesizer via solid support using standard DNA synthesis techniques (i.e., DMT protected 2-cyanoethyl phosphoramidite). The polymer is removed from the solid support with ammonium hydroxide and lyophilized to a paste. 250 mg aliquots are reconstituted in water. A small aliquot is removed, and serial dilutions are prepared in 100 mM NaCO3 at pH 9 to determine concentration (A 263 a = 10,000). Final stock concentration is found to be 14.5 mM.
Coupling Reaction
In 50 mL centrifuge tube equipped with magnetic stir bar is placed water (1.110 pL), borate buffer (1.800 pL), compound of Structure (I) in final stock solution (466 pL), acetonitrile (137.5 pL), triethylamine (313 pL) and M1-NHS or M2-NHS solution (675 pL). The tube is wrapped in aluminum foil and the mixture stirred overnight at room temperature.
Size Exclusion Filtration
To an Amicon Ultra-15 Centrifugal filter (Millipore UFC900324, MW cutoff = 3000) is added 1 mL of water. The crude reaction from the coupling reaction (4.5 mL) is added to the filtration setup. The reaction vessel is rinsed 2 x with 4 mL of 100 mM NaOH and the rinseates are transferred to the filtration setup. The filtration setup is centrifuged at max speed (3220 g, swing bucket, 30 minutes). The filtrate is removed and the retentate treated with an additional 10 mL of 100 mM NaOH. The filtration setup is centrifuged as before. Again, the filtrate is removed and a third 10 mL 100 mM NaOH aliquot is added to the retentate. The setup is centrifuged as before, and the filtrate removed. A fourth 10 mL 100 mM NaOH aliquot is added to the retentate and centrifuged as before. The filtrate is removed, and 10 mL of water are added to the filtration setup. The mixture is centrifuged as before. The retentate is removed, the filtration vessel is washed with water and the rinesates are added to the final volume (3.5 mL). The desired product is confirmed by LC-MS and absorbance is used to determine concentration.
EXAMPLE 2
ACTIVATION AND ANTIBODY CONJUGATION OF COMPOUND OF STRUCTURE (I)
The maleimide functionalized compound of Structure (I) is prepared according to the method described herein. In parallel, an UCHT-1 antibody is treated to reduce disulfide bonds. The reduced antibody is reacted with a compound of Structure (I) in a 5: 1 molar ratio (polymer to antibody). The reaction results in a final product having a polymer to antibody ratio of 1 : 1 as detected by size exclusion chromatography.
Alternatively, the reduced antibody is treated with bis-maleimidoethane ("BMOE"). The resultant product is then reacted with a compound of Structure (I) having a terminal -SH group. Again, the compound of Structure (I) is reacted with the antibody in a 5: 1 molar ratio (polymer to antibody) and results in a final product having a polymer to antibody ratio of 1 : 1 as detected by size exclusion chromatography.
In some embodiments, anti-CD33, anti-CD70, or anti-CD123 is used in place of the UCHT-1 antibody. EXAMPLE 3
SYNTHESIS OF COMPOUND OF STRUCTURE (A-l)
Molecular Weight: 242.23 Molecular Weight: 544.60
Thymidine starting material (3.0 g, 12.4 mmol) and pyridine (125 mL) were placed in a 250 mL round bottomed flask with magnetic stir bar. Dimethoxytrityl chloride (DMTr-Cl, 3.8 g, 11.2 mmol) was added as a single portion. The reaction was stirred overnight.
The mixture was concentrated in vacuo. The oily mixture was treated water (100 mL) and ethyl acetate (100 mL) and partitioned. The aqueous layer was extracted with ethyl acetate (100 mL x 2). Organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (Hexane-ethyl acetate gradient). Desired product was obtained at a yield of 4.12g, 60% and confirmed by LC/MS (m/z = 566.8 [M+Na]+)
Molecular Weight: 544.60 Molecular Weight: 672.84
Thymidine derivative (1.0 g, 1.8 mmol) was placed into a 200 mL round bottomed flask with magnetic stir bar. DMF (18 mL) and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.3 mL, 2.0 mmol) were added and the mixture stirred to homogeneity. 5-bromo-A,A,A-trimethylpentan-l- aminium (0.6 mg, 2.0 mmol) was added in a single portion and the mixture was stirred overnight.
The reaction was concentrated in vacuo, and the resultant oil was treated with water (50 mL) and ethyl acetate (50 mL) and partitioned. Layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL x 2). Organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. Desired product was obtained at a yield of 1.1 g and confirmed by LC/MS (m/z = 672.2 [M]+).
Molecular Weight: 873.06 Thymidine starting material (1.0 g, 1.5 mmol) was placed into a 100 mL round bottomed flask with magnetic stir bar. Dichloromethane (15 mL) and a few 4 A molecular sieves were added, the mixture was stirred, the flask was sealed with a rubber septum and a nitrogen line was added via a needle. 2-cyanoethyl-N,N-diisopropylchlorophosphoramidite (0.5 mL, 2.2 mmol) and diisopropylethylamine (1.0 mL, 5.6 mmol) were added via syringe in a back and forth manner. The mixture was stirred for 2 hours.
The reaction mixture was diluted with dichloromethane (50 mL), transferred to an extraction funnel, and washed with 100 mM sodium bicarbonate solution (50 mL x 1). The organic layer was retained, dried over sodium sulfate, filtered, and concentrated in vacuo. Desired product was verified by LC/MS (m/z = 872.2 [M]+). EXAMPLE 4
SYNTHESIS OF COMPOUNDS OF STRUCTURE (B-l) Fmoc Fmoc
Phosphoramidite Conversion The reaction scheme above can be used to synthesize compounds of Structure (B-l) as disclosed herein. The starting material shown is commercially available and the reaction steps are carried out using appropriate reaction conditions.
The starting material shown above can be substituted with a commercially available compound having the following structure to yield another compound of Structure (B-l): The reaction scheme above can be used to synthesize phosphoramidite compounds of the present disclosure. The starting materials shown (i.e., Amine-diol) are either commercially available or readily synthesized from commercially available starting materials (e.g., performing an Fmoc protecting step) and the reaction steps are carried out using appropriate reaction conditions. Additionally, the amine-diol can be substituted with any one of the following compounds to yield a desired compound:
Alternatively, other phosphoramidite compounds can be synthesized with a minor modification to the scheme shown above. Namely, the scheme above can be modified following the Fmoc deprotection step as follows:
EXAMPLE 6
EXEMPLARY SYNTHESIS OF PHOSPHORAMIDITE COMPOUNDS
Fmoc Protection
Amine-diol
Acid Starting Material Coupling Fmoc
Phosphoramidite Conversion
The reaction scheme above can be used to synthesize phosphoramidite compounds of the present disclosure. The starting materials shown (i.e., Acid Starting Materials, Amine-diol) are commercially available and the reaction steps are carried out using appropriate reaction conditions.
Additionally, the amine-diol can be substituted with any one of the following compounds to yield a desired compound:
The acid starting material shown in the reaction scheme above may also be substituted with one of the following commercially available materials to yield desired compounds:
All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Applicant Data Sheet, including U.S. Provisional Patent Application No. 63/557,187, filed February 23, 2024, are incorporated herein by reference, in their entirety to the extent not inconsistent with the present description. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments. From the foregoing it will be appreciated that, although specific embodiments of the disclosure have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the disclosure. Accordingly, the disclosure is not limited except as by the appended claims.

Claims

1. A polymer compound comprising a backbone comprising one or more monomer subunits having one of the following Structures (A), (B), (C), (D), (E), or (F): wherein:
R1 , R2 , R3 , Rla', Rlb', and Rlc' are, at each occurrence independently hydrogen or C1-C6 alkyl;
R4' is a covalent bond to the remainder of the backbone, -OH, or has the following structure: wherein R4a' is hydrogen or a covalent bond to the remainder of the backbone;
R6a' and R6b' are each independently hydrogen or C1-C6 alkyl;
R7a' R7a', R8a', and R8b' are each indepenciently hydrogen or C1-C6 alkyl, provided that at least one of R7a', R7b', R8a', and R8b' is C1-C6 alkyl;
R7c', R7d', R8c', and R8d' are each independently hydrogen or C1-C6 alkyl, or
R7C' and R8C' each represent an electron pair, the nitrogen to which they are each attached are uncharged, and R7d' and R8d' each independently have one of the following structures: wherein R9a', R9b', and R9c' are each independently hydrogen or C1-C6 alkyl
L1 is an alkylene or heteroalkylene linker;
L2 is a direct bond, an alkylene linker, or a heteroalkylene linker;
L3 is an alkylene linker or a heteroalkylene linker;
L4 is an alkylene linker or a heteroalkylene linker; and
Y has one of the following structures:
2. The polymer compound of claim 1, wherein at least one occurrence of Structure (A) has the following structure:
3. The polymer compound of claim 1, wherein at least one occurrence of Structure (B) has one of the following structures:
4. The polymer compound of claim 1, wherein at least one occurrence of Structure
(C) has one of the following structures:
5. The polymer compound of claim 1, wherein at least one occurrence of Structure
(D) has one of the following structures:
6. The polymer compound of claim 1, wherein at least one occurrence of Structure
(E) has one of the following structures:
7. The polymer compound of claim 1, wherein at least one occurrence of Structure
8. The polymer compound of any one of claims 1-7, wherein the compound has the following Structure (I): or a stereoisomer, tautomer, or salt thereof, wherein: each occurrence of R1 and R2 are independently hydrogen, OH, SH, alkyl, alkoxy, alkylether, heteroalkyl, -OP(=Ra)(Rb)Rc, Q, or L';
Ra is O or S;
Rb is OH, SH, O', S', ORd or SRa;
Rc is OH, SH, O', S', 0Rd, OL', SRd, alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkylether, alkoxyalkylether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether or thiophosphoalkylether;
Rd is a counter ion; each occurrence of R3 is independently hydrogen or C1-C6 alkyl; each occurrence of R4 is independently OH, SH, O', S', 0Rd or SRd; each occurrence of R5 is independently oxo or thioxo; each occurrence of R6 and R7 are independently hydrogen or halo; each occurrence of L1, L2, L3, L4, L5, and L6 are independently a direct bond, optionally substituted alkylene linker, optionally substituted heteroalkylene linker, a heteroatomic linker, or a combination thereof, provided that at least one occurrence of R1, L1, L2, L4, L5, and L6 includes the monomer subunit of Structure (A), Structure (B), Structure (C), Structure (D), Structure (E), Structure (F), or combinations thereof; each occurrence of La is independently a heteroalkylene or heteroarylene linker; each occurrence of Lb is independently a direct bond, an alkylene linker, a heteroalkylene linker, a heteroatomic linker, or a combination thereof; each occurrence of M1 and M2 are a biologically active moiety, a fluorescent moiety, or a colored moiety; each occurrence of Q is independently a moiety comprising a reactive group, or protected form thereof, capable of forming a covalent bond with a complementary reactive group Q' on a targeting moiety; each occurrence of L1 is independently a linker comprising a covalent bond to Q, a targeting moiety, a linker comprising a covalent bond to a targeting moiety, a linker comprising a covalent bond to a solid support, a linker comprising a covalent bond to a solid support residue, a solid support residue, or a linker comprising a covalent bond to a nucleoside; each occurrence of m is an integer ranging from 0 to 50; each occurrence of q and w are each an integer ranging from 0 to 50, provided that the sum of q and w is an integer greater than 1; n is an integer ranging from 1 to 50.
9. The polymer compound of claim 8, wherein the polymer compound has the following Structure (IA): wherein:
L7 has the following structure: wherein: v is an integer ranging from 0 to 50, provided that at least one occurrence of v is 1 or greater;
R1, R2, and R3 are, at each occurrence independently hydrogen or C1-C6 alkyl; and R4' is a covalent bond, -OH, or has the following structure: wherein R4a' is hydrogen or a covalent bond.
10. The polymer compound of any one of claims 8-9, wherein the polymer compound has the following Structure (la):
11. The polymer compound of any one of claims 8-10, wherein L1 comprises one or more alkylene or alkylene oxide moieties.
12. The polymer compound of any one of claims 8-11, wherein the alkylene oxide moieties comprise polyethylene oxide moieties.
13. The polymer compound of any one of claims 8-12, wherein L1, at each occurrence, comprises the following structure: wherein: z is an integer from 1 to 100; and
* indicates a bond to the adjacent phosphorous atom.
14. The polymer compound of any one of claims 8-13, wherein each occurrence of L1 comprises one of the following structures:
15. The polymer compound of any one of claims 8-14, wherein each occurrence of L1 comprises one of the following structures: wherein: each occurrence of x is an integer ranging from 20 to 30.
16. The polymer compound of any one of claims 8-15, wherein the polymer compound has the following Structure (Ib):
17. The polymer compound of any one of claims 8-16, wherein the polymer compound has one the following structures:
18. The polymer compound of any one of claims 8-17, wherein L2 and L4 are, at each occurrence, independently a direct bond or C1-C6 alkylene.
19. The polymer compound of any one of claims 8-18, wherein each occurrence of L3 is independently selected from the group consisting of optionally substituted alkylene and optionally substituted heteroalkylene.
20. The polymer compound of any one of claims 8-19, wherein each occurrence of L3 and Lb independently have one of the following structures:
21. The polymer compound of any one of claims 8-20, wherein each occurrence of L3 and Lb independently have one of the following structures:
22. The polymer compound of any one of claims 8-21, wherein each occurrence of L3 and Lb independently have the following structure:
23. The polymer compound of any one of claims 8-22, wherein each occurrence of L3 independently has one of the following structures:
24. The polymer compound of any one of claims 8-23, wherein each occurrence of L3 has the following structure:
25. The polymer compound of any one of claims 8-24, wherein La is, at each occurrence independently an optionally substituted 5-7 membered heteroarylene linker.
26. The polymer compound of any one of claims 8-25, wherein La has one of the following structures:
27. The polymer compound of any one of claims 8-26, wherein at least one occurrence ofLb comprises a triazolyl ring.
28. The polymer compound of any one of claims 8-27, wherein at least one occurrence of -Lb-M2 comprises one of the following structures: wherein Lc and Ld are, at each occurrence independently a direct bond, alkylene, or heteroalkylene.
29. The polymer compound of claim 28, wherein each occurrence of Lc, Ld, or both, are direct bonds.
30. The polymer compound of claim 28, wherein each occurrence of Lc, Ld, or both are independently alkylene or heteroalkylene.
31. The polymer compound of claim 28, wherein each occurrence of Lc, Ld, or both have one of the following structures:
32. The polymer compound of any one of claims 8-31, wherein each occurrence of - Lb-M2 has one of the following structures:
33. The polymer compound of any one of 8-32, wherein at least one occurrence of L7 has the following structure:
34. The polymer compound of any one of claims 8-33, wherein R1 is, at each occurrence, hydrogen.
35. The polymer compound of any one of claims 8-34, wherein Q comprises a sulfhydryl, disulfide, activated ester, isothiocyanate, azide, alkyne, alkene, diene, dienophile, acid halide, sulfonyl halide, phosphine, a-haloamide, biotin, amino, or maleimide functional group.
36. The polymer compound of claim 35, wherein the activated ester is an N- succinimide ester, imidoester or polyflourophenyl ester.
37. The polymer compound of any one of claims 8-36, wherein Q comprises one of the following structures:
wherein:
G1 is halo; and
E is an electronic withdrawing group.
38. The polymer compound of any one of claims 8-37, wherein R1 or R2 has one of the following structures:
39. The polymer compound of any one of claims 8-38, wherein R1 or R2 has one of the following structures:
40. The polymer compound of any one of claims 8-39, wherein R1 or R2 has one of the following structures:
41. The polymer compound of any one of claims 8-40, wherein n ranges from 1 to 20.
42. The polymer compound of any one of claims 8-41, wherein n ranges from 1 to 10.
43. The polymer compound of any one of claims 8-42, wherein each occurrence of m independently is 1, 2, 3, 4, or 5.
44. The polymer compound of any one of claims 8-43, wherein each occurrence of q independently ranges from 2 to 20.
45. The polymer compound of any one of claims 8-44, wherein each occurrence of w independently ranges from 2 to 20.
46. The polymer compound of any one of claims 8-45, wherein at least one occurrence of M1 or M2 is selected from the group consisting of a pyrene, perylene, perylene monoimide, and 6-FAM moiety.
47. The polymer compound of any one of claims 8-46, wherein at least one occurrence of M1 or M2 has one of the following structures:
48. The polymer compound of any one of claims 8-47, wherein at least one occurrence of M1 and M2 have one of the following structures:
49. The polymer compound of any one of claims 8-48, wherein at least one occurrence of M1 or M2 have the following structure:
50. The polymer compound of any one of claims 8-49, wherein one or more occurrences of M1, M2, or both have one of the following structures:
51. The compound of any one of claims 8-50, wherein at least one occurrence of M1, M2, or both have one of the following structures:
52. The polymer compound of any one of claims 8-51, wherein the targeting moiety is an antibody.
53. The polymer compound of any one of claims 8-52, wherein the antibody is trastuzumab, gemtuzumab, brentuximab, vorsetuzumab, lorvotuzumab, cantuzumab, bivatuzumabor inotuzumab, or vadastuximab.
54. A pharmaceutical composition comprising the polymer compound of any one of claims 1-53, or a stereoisomer, tautomer, or salt thereof and a pharmaceutically acceptable excipient.
55. A method for treating a disease in a subject, the method comprising administering the polymer compound of any one of claims 1-53, or a stereoisomer, tautomer, or salt thereof to the subject.
56. The method of any one of claims 55, wherein the disease is cancer.
57. The method of any one of claims 55, wherein the disease is an autoimmune disease.
58. The method of claim 57, wherein the autoimmune disease is multiple sclerosis, diabetes, celiacs disease, Graves' disease, myasthenia gravis, Hashimotos encephalomyelitis, Neuromyelitis optica, inflammatory bowel disease, hemaphilia, lupus, autoimmune encephalomyelitis (EAE), or rheumatoid arthritis.
59. A compound having one of the following Structures (A-l), (B-l), (C-l), (D-l), (E-l), or (F-l):
(E-1 ) wherein:
R1 , R2 , R3 , Rla', Rlb', and Rlc' are, at each occurrence independently hydrogen or C1-C6 alkyl;
R4' is hydrogen or has the following structure:
R5 is hydrogen or has the following structure:
R6a' and R6b' are each independently hydrogen or C1-C6 alkyl;
R7a' and R8b' are each independently hydrogen or C1-C6 alkyl, provided that at least one of R7a', R71’’, R8a', and R8b' is C1-C6 alkyl;
R7c, R7d', R8c, and R8d' are each independently hydrogen or C1-C6 alkyl, or
R7C' and R8C' each represent an electron pair, the nitrogen to which they are each attached are uncharged, and R7d' and R8d' each independently have the following structure: wherein R9a', R9b', and R9c' are each independently hydrogen or C1-C6 alkyl
L1 is an alkylene or heteroalkylene linker
L2' is a direct bond, an alkylene linker, or a heteroalkylene linker;
L3 is an alkylene linker or a heteroalkylene linker;
L4' is an alkylene linker or a heteroalkylene linker;
Y has one of the following structures:
60. The compound of claim 59, wherein the compound of Structure (A-1) has one of the following structures:
61. The compound of claim 59, wherein the compound of Structure (B-1) has one of the following structures:
62. The compound of claim 59, wherein the compound of Structure (C-1) has one of the following structures:
63. The compound of claim 59, wherein the compound of Structure (D-1) has one of the following structures:
64. The compound of claim 59, wherein the compound of Structure (E-1) has one of the following structures:
65. The compound of claim 59, wherein the compound of Structure (F-1) has one of the following structures:
PCT/IB2025/051549 2024-02-23 2025-02-13 Monomer subunits for water soluble polymer compounds Pending WO2025177123A1 (en)

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Citations (1)

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WO2017214165A1 (en) * 2016-06-06 2017-12-14 Sony Corporation Ionic polymers comprising fluorescent or colored reporter groups

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Publication number Priority date Publication date Assignee Title
WO2017214165A1 (en) * 2016-06-06 2017-12-14 Sony Corporation Ionic polymers comprising fluorescent or colored reporter groups

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