WO2024110803A1 - Composés polymères comprenant des agents antinéoplasiques - Google Patents

Composés polymères comprenant des agents antinéoplasiques Download PDF

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WO2024110803A1
WO2024110803A1 PCT/IB2023/061127 IB2023061127W WO2024110803A1 WO 2024110803 A1 WO2024110803 A1 WO 2024110803A1 IB 2023061127 W IB2023061127 W IB 2023061127W WO 2024110803 A1 WO2024110803 A1 WO 2024110803A1
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polymeric compound
compound
occurrence
linker
moiety
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PCT/IB2023/061127
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English (en)
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Tracy Matray
Michael VANBRUNT
John Michael MCCUTCHEON
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Sony Group Corporation
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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
    • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • 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
    • 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
    • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
    • 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
    • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6867—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of a blood cancer
    • 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
    • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
    • A61K49/0043—Fluorescein, used in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0058—Antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Targeted drug conjugates unlike, e.g., chemotherapy, deliver drugs to target cells, with little or no off-target activity.
  • targeted drug conjugates comprise a targeting molecule that is linked to a biologically active payload or drug.
  • ADCs Antibody- drug conjugates
  • ADCs for cancer treatment have been getting more popularity, other uses of ADCs are in its infancy.
  • ADCs for cancer treatment have been getting more popularity, other uses of ADCs are in its infancy.
  • the present disclosure fulfills this need and provides further related advantages.
  • a water soluble polymeric compound which comprises: i) one or more antineoplastic agents; ii) a heteroalkylene backbone comprising negatively charged groups at physiological pH; iii) one or more linear or branched linkers comprising a self- immolative group and an optional spacer group, the linker linking each antineoplastic agent to the heteroalkylene backbone; and iv) a reactive group capable of forming a covalent bond to a targeting moiety.
  • a polymeric compound having the following structure (I) are provided: or a stereoisomer, tautomer, or salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , L 3 , L 4 , L 5 , M 1 , M 2 , p, m, and n are as defined herein.
  • Compounds of structure (I) find utility in a number of applications, including use as therapeutic agents for various treatment methods.
  • a conjugate is provided which comprise a compound of structure (I) covalently bound to a targeting moiety through a bond to the reactive group.
  • compositions which comprise a compound of structure (I) and a pharmaceutically acceptable carrier or the conjugate comprising a compound of structure (I) and a pharmaceutically acceptable carrier.
  • a method of treating a disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structure (I) or a composition comprising a compound of structure (I), wherein each M 2 is independently an antineoplastic agents effective for treating the disease.
  • Amino refers to the ⁇ NH 2 group .
  • Carboxy refers to the ⁇ CO 2 H group.
  • Cyano refers to the ⁇ CN group.
  • Hydroxy or “hydroxyl” refers to the ⁇ OH group.
  • Niro refers to the ⁇ NO 2 group.
  • Sulfhydryl refers to the ⁇ SH 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 (C 1 -C 12 alkyl), one to eight carbon atoms (C 1 -C 8 alkyl) or one to six carbon atoms (C 1 -C 6 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.
  • 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, 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.
  • 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.
  • 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., ethynylene, propynylene, n-butynylene, 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.
  • PEG polyethylene glycol
  • an alkylether group is optionally substituted.
  • Alkoxy refers to a group of the formula -O R a where R a 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.
  • 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., M1-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 -O R a where R a 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'-H-A-M 2 , where M 1 and M 2 are portions of the molecule, H is a heteroatom and A is an alkylene).
  • 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:
  • 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 “heteroalkylene backbone” refers to the following structure:
  • 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 heteroalkylene linker comprises the following structure: wherein: x 9 and x 10 are each independently a integer greater than 0.
  • “Physiologically cleavable linker” refers to a molecular linkage that can be split or separated in a prescribed manner, resulting in two or more separate molecules while in the presence of an in vivo or in vitro environment of an organism or cell system.
  • physiological conditions that induce such a cleavage or scission event may include a temperature ranging from about 20 to 40°C, an atmospheric pressure of about 1 atm (101 kPa or 14.7 psi), a pH of about 4 to 8, a glucose concentration of about 1 to 20 mM, atmospheric oxygen concentration, and earth gravity.
  • physiological conditions include enzymatic conditions (i.e., enzymatic cleavage).
  • cathepsins are proteases cleaving proteins at a low pH.
  • Cathepsins includes cathepsin A, cathepsin B, cathepsin D, cathepsin K, and cathepsin V.
  • Bond cleavage or scission can be homolytic or heterolytic.
  • “Physiological pH” refers to a pH range about 4 to 8 at a temperature ranging from about 20 to 40°C, an atmospheric pressure of about 1 atm (101 kPa or 14.7 psi).
  • 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.
  • R a is O or S
  • R b is OH, O-, S-, OR a or SR a
  • R c is OH, SH, O-, S
  • 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, norbornyl, 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.
  • 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.
  • 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 quatemized; and the heterocyclic ring may be partially or fully saturated.
  • heteroaryls examples 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, thiazolid
  • 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.
  • 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, benzodioxolyl, benzofuranyl, benzooxazolyl, benzo thiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1 ,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, benzoxazolinonyl, benzimidazolthionyl, carbazolyl,
  • 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.
  • 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.
  • 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.
  • 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” 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.
  • a higher-order bond e.g., a double- or triple-bond
  • nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • R g and R h 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, imino, 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.
  • 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.
  • Cold refers to a molecule which absorbs light within the colored spectrum (i.e., red, yellow, blue and the like).
  • 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.
  • 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, ⁇ , ⁇ -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.
  • 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).
  • 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.
  • 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 -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. 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.
  • 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 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).
  • the disclosure provides a method for visually detecting a biomolecule, comprising: (a) providing a biological system with a visually detectable biomolecule comprising the compound 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 a 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.
  • biological system is used to refer to any solution or mixture comprising one or more biomolecules in addition to the visually detectable biomolecule.
  • biological systems include cells, cell extracts, tissue samples, electrophoretic gels, assay mixtures, and hybridization reaction mixtures.
  • Antineoplastic refers to any molecules blocking the formation of neoplasms where the growth of the neoplasms may become cancer.
  • Antineoplastic agents may include azacitidine, capecitabine, carmofur, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, nelarabine, pentostatin, tegafur, tioguanine, methotrexate, pemetrexed, raltitrexed, hydroxycarbamide, irinotecan, topotecan, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, etoposide, teniposide, cabazitaxel, docetaxel, paclitaxel, vinblastine, vin
  • Self- immolative group refers to a group that undergoes an electronic cascade which results in the release of the group to which it is attached.
  • the self- immolative group comprises one or more groups which can undergo 1,4-elimination, 1,6- elimination, 1,8-elimination, 1,6- cyclization elimination, 1,5-cyclization elimination, 1,3- cyclization elimination, intramolecular 5-exo-trig cyclization, and/or 6-exo-trig cyclization.
  • the self-immolative group comprises valine (Vai) and citrulline (Cit) or valine (Vai) and alanine (Ala).
  • Spacer group refers to a linker covalently bonding between the self-immolative group and an antineoplastic agent.
  • the spacer group is para-aminobenzylcarbamate (PBA).
  • 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.
  • a microparticle comprises polystyrene beads.
  • 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.
  • 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.
  • 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.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively.
  • Isotopically-labeled 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.
  • “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.
  • “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, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, gluco
  • 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
  • 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.
  • a water soluble polymeric compound useful as covalent linkers between biologically active moieties such as antineoplastic agents and targeting moieties are provided.
  • M 1 is, at each occurrence, independently a moiety comprising a fluorescent or colored dye
  • M 2 is, at each occurrence, independently a moiety comprising an antineoplastic agent.
  • M 2 is monomethyl auristatin E and M 1 is fluorescent dye (e.g., fluorescein and the like).
  • antineoplastic agents M 2 that are attached to the heteroalkylene backbone of the polymeric compound and any subsequent targeting moiety
  • spacing between the neighboring antineoplastic agents on the heteroalkylene backbone e.g., how far or close the antineoplastic agents M 2
  • spacing between the heteroalkylene backbone and the antineoplastic agents e.g., the length of linkers off of the polymer backbone
  • the biological active moieties can be attached to the heteroalkylene backbone via linear or branched linkers.
  • the procedures described in the present disclosure provide the ability to selectively install the linear or branched linkers. This allows for synthesizing a compound which has both linear or branched linkers with one or more antineoplastic agents.
  • the antineoplastic agents can be cleaved sequentially depending on physiological conditions.
  • a compound with both multiple antineoplastic agents and a fluorescent moiety attached by linkers can be synthesized.
  • Some embodiments of the present disclosure provide combinations of antineoplastic agents, targeting moieties, and dye moieties (e.g., chromophores or fluorophores) that can be used for simultaneous targeting, treatment, and detection.
  • dye moieties e.g., chromophores or fluorophores
  • M 1 is a fluorophore (e.g., FITC, 5-FAM, 6-FAM, and the like) or colored moiety.
  • the compounds of certain embodiments also provide other desirable properties, including enhanced permeability and retention effects.
  • the chemical features of embodiments of the present compounds can be adjusted to modulate the compound’s ability to permeate diseased cells/tissue and be retained within the same. These features allow effective delivery of the antineoplastic agents by increasing permeation and increasing efficacy by enhancing retention.
  • one embodiment provides a water soluble polymeric compound comprising: i) one or more antineoplastic agents; ii) a heteroalkylene backbone comprising negatively charged groups at physiological pH; iii) one or more linear or branched linkers comprising a self- immolative group and an optional spacer group, the linker linking each antineoplastic agent to the heteroalkylene backbone; and iv) a reactive group capable of forming a covalent bond to a targeting moiety.
  • the polymeric compound further comprises i) at least one fluorescent or colored moiety; and ii) one or more linker, each linker linking a fluorescent or colored moiety to the heteroalkylene backbone.
  • polymeric compound having the following structure (I): or stereoisomer, or tautomer thereof, wherein
  • M 1 is, at each occurrence, independently a moiety comprising the fluorescent or colored moiety
  • M 2 is, at each occurrence, independently a moiety comprising the antineoplastic agent
  • L 1 is at each occurrence, independently the linear or branched linkers
  • L 2 and L 3 are, at each occurrence, independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene or heteroatomic linker;
  • L 4 is, at each occurrence, independently a heteroalkylene linker;
  • L 5 is, at each occurrence, independently the linker
  • R 1 is, at each occurrence, independently H, alkyl or alkoxy
  • R 4 is, at each occurrence, independently OH, SH, O-, S-, OR d or SR d ;
  • R 5 is, at each occurrence, independently oxo, thioxo or absent;
  • R a is O or S
  • R b is OH, SH, O , S', OR d or SR d ;
  • R c is OH, SH, O', S', OR d , OL', SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkylether, alkoxyalkylether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether or thiophosphoalkylether;
  • R d is a counter ion
  • Q is, at each occurrence, 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;
  • L' is, at each occurrence, 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 linker comprising a covalent bond to a nucleoside or a linker comprising a covalent bond to a further compound of structure (I); m is, at each occurrence, independently an integer of m is from 1 to 5; p is an integer of zero or greater; and n is an integer of one or greater.
  • the various linkers and substituents e.g., R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , L 3 , L 4 , L 5 , M 1 , M 2 , and Q
  • the optional substituent is selected to optimize the water solubility or other property of the compound of structure (I).
  • each chromophore, alkyl, alkoxy, alkylether, heteroarylene, heteroalkyl, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, alkoxyalkylether, phosphoalkyl, thiophosphoalkyl, phosphoalkylether and thiophosphoalkylether in the compound of structure (I) is optionally substituted with one more substituent selected from the group consisting of hydroxyl, alkoxy, alkylether , alkoxyalkylether, sulfhydryl, amino, alkylamino, carboxyl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether and thiophosphoalkylether.
  • the at least one fluorescent or colored moiety M 1 is a fluorescent moiety.
  • the fluorescent or colored moiety M 1 is, at each occurrence, independently selected from the group consisting of a pyrene, perylene, perylene monoimide, and 6-FAM moiety.
  • the fluorescent or colored moiety M 1 is, at each occurrence, independently has one of the following structures: wherein indicates a point of attachment to the fluorescent compound.
  • the fluorescent or colored moiety M 1 has the one of the following structures: In some other specific embodiments, wherein the fluorescent or colored moiety M 1 has the following structure:
  • the polymeric compound comprises 1-10 fluorescent or colored moieties. In some other embodiments, the polymeric compound comprises 1-5 fluorescent or colored moieties. In some specific embodiments, the polymeric compound comprises 1 fluorescent or colored moiety.
  • the antineoplastic agent M 2 is, at each occurrence, independently selected from the group consisting of a paclitaxel, camptonthecin, doxorubicin, monomethyl auristatin E, monomethyl auristatin F and PF-06380101.
  • the antineoplastic agent M 2 at each occurrence, independently has one of the following structures:
  • the antineoplastic agent M 2 is monomethyl auristatin E.
  • the antineoplastic agent M 2 has the following structure:
  • the polymeric compound comprises 1-20 antineoplastic agents. In some other embodiments, the polymeric compound comprises 1-10 antineoplastic agents. In some specific embodiments, the polymeric compound comprises 1 antineoplastic agent. In some other specific embodiments, the polymeric compound comprises 3 antineoplastic agents. In some other specific embodiments, the polymeric compound comprises 5 antineoplastic agents. In some other specific embodiments, the polymeric compound comprises 7 antineoplastic agents. In some other specific embodiments, the polymeric compound comprises 10 antineoplastic agents.
  • the heteroalkylene linker L 4 comprises one or more alkylene or alkylene oxide moieties.
  • the alkylene oxide of L 4 is ethylene oxide.
  • the ethylene oxide is polyethylene oxide.
  • L 4 at each occurrence, has the following structure: wherein: z is an integer from 1 to 100; and
  • * indicates a bond to the adjacent phosphorous atom.
  • z is an integer from 3 to 8. In some embodiments, z is 3. In some embodiments, z is 4. In some embodiments, z is 5. In some embodiments, z is 6. In some embodiments, z is 7. In some embodiments, z is 8.
  • z is an integer from 22 to 26. In some embodiments, z is 22. In some embodiments, z is 23. In some embodiments, z is 24. In some embodiments, z is 25. In some embodiments, z is 26.
  • z ranges from 19 to 28. In certain embodiments, the average z is 23. In some embodiments, the average z is 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28.
  • At least one occurrence of compounds of structure (I) comprising one of the following structures:
  • z is an integer from 1 to 100. In some embodiments, z is an integer from 3 to 8. In some other embodiments, z is an integer from 22 to 26. In some other embodiments, z ranges from 19 to 28. In some embodiments, at each occurrence in compounds of structure (I) comprises one of the following structures:
  • the heteroalkylene linker L 4 comprises one of the following structures: In some more specific embodiments, wherein the heteroalkylene linker L 4 comprises the following structure:
  • heteroalkylene linker L 4 comprises the following structure:
  • R 4 is O' or S'. In some other embodiments, R 4 is O'. In some embodiments, at least one occurrence of R 4 is O'. In some embodiments, at least one occurrence of R 4 is S'. In certain embodiments, each occurrence of R 4 is O'.
  • Some embodiments provide a compound having the following structure (IA) or (IB):
  • L 2 and L 3 are, at each occurrence, independently either i) absent or ii) C 1 -C 6 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene.
  • Some embodiments provide a compound having the following structure (IC) or (ID): wherein x 1 , x 2 , x 3 and x 4 are, at each occurrence, independently an integer from 0 to 6.
  • x 1 , x 2 , x 3 and x 4 are, at each occurrence, an integer 0 (i.e.. L 5 is a direct bond). In some embodiments, x 1 , x 2 , x 3 and x 4 are, at each occurrence, an integer 1. In some embodiments, x 1 , x 2 , x 3 and x 4 are, at each occurrence, an integer 2. In some embodiments, x 1 , x 2 , x 3 and x 4 are, at each occurrence, an integer 3. In some embodiments, x 1 , x 2 , x 3 and x 4 are, at each occurrence, an integer 4.
  • x 1 , x 2 , x 3 and x 4 are, at each occurrence, an integer 5. In some embodiments, x 1 , x 2 , x 3 and x 4 are, at each occurrence, an integer 6. In some more specific embodiments, x 1 , x 2 , x 3 and x 4 are each o or 1 at each occurrence.
  • the self-immolative group comprises two or more amino acids.
  • the two amino acids are selected from the group consisting of valine, citrulline, glucine, and alanine.
  • the self-immolative group comprises one of the following structures:
  • the self-immolative group comprises one of the following structures (or combinations thereof):
  • the self-immolative group has the following structure:
  • the optional spacer group can be used as a point of attachment of the M 2 and each antineoplastic agent.
  • a synthetic precursor to the compound of structure (I)-(ID) is prepared, and the M 2 moieties are attached to the synthetic precursor using any number of coupling methods known in the art.
  • at least one occurrence of the optional spacer group comprises an amide bond, an ester bond, an ether bond, or combinations thereof.
  • the functional group of the optional spacer group comprises an amide, an ester, an ether, or combinations thereof.
  • the optional spacer group has one of the following structures:
  • the optional spacer group has the following structure:
  • the linker L 5 can be used as a point of attachment of the M 1 moieties to the remainder of the compound (i.e., heteroalkylene backbone).
  • a synthetic precursor to the compound of structure (I) is prepared, and the M 1 moieties are attached to the synthetic precursor using any number of coupling methods known in the art.
  • at least one occurrence of L 5 comprises an amide bond, an ester bond, a phosphodiester bond, a disulfide bond, a double bond, a triple bond, an ether bond, a hydrazone, an amino acid sequence comprising one or more amino acid residues, a ketone, a diol, a cyano, a nitro, or combinations thereof.
  • the functional group comprises an amide or an ester.
  • at least one occurrence of L 5 comprises one of the following structures:
  • each occurrence of the linker L 5 comprises one of the following structures:
  • the linker L 5 has the following structure:
  • At least one occurrence of R 1 is H. In some embodiments, at least one occurrence of R 1 is alkyl. In some embodiments, at least one occurrence of R 1 is alkoxy. In certain embodiments, each occurrence of R 1 is H.
  • the other of R 2 or R 3 is Q or a linker comprising a covalent bond to Q.
  • R c is OL'.
  • the linker L' can be any linker suitable for attaching Q, a targeting moiety, an analyte (e.g., analyte molecule), a solid support, a solid support residue, a nucleoside or a further compound of structure (I)-(ID) to the compound of structure (I)-(ID).
  • analyte e.g., analyte molecule
  • solid support e.g., analyte molecule
  • R 2 or R 3 is L'.
  • L' is a linker to a targeting moiety.
  • R 2 or R 3 is -NH 2 .
  • one of R 2 or R 3 is L' and L' is a linker comprising a covalent bond to a solid support.
  • the solid support is a polymeric bead or non-polymeric bead.
  • L' is a linker to a targeting moiety, the linker comprising an alkylene oxide or phosphodiester moiety, or combinations thereof.
  • L' has one of the following structures: wherein: x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 and x 8 are independently an integer from 1 to 10;
  • R b is H, an electron pair or a counter ion
  • L" is the targeting moiety or a linkage to the targeting moiety.
  • x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 and x 8 are independently an integer 1. In some embodiments, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 and x 8 are independently an integer 2. In some embodiments, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 and x 8 are independently an integer 3. In some embodiments, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 and x 8 are independently an integer 4.
  • x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 and x 8 are independently an integer 5. In some embodiments, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 and x 8 are independently an integer 6. In some embodiments, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 and x 8 are independently an integer 7. In some embodiments, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 and x 8 are independently an integer 8.
  • x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 and x 8 are independently an integer 9. In some embodiments, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 and x 8 are independently an integer 10.
  • R b is H. In some embodiments, R b is a counter ion. For example, in some embodiments, R b is Na + . In some embodiments, R b is K + .
  • L" is the targeting moiety. In some other embodiments, L" is a linkage to the targeting moiety.
  • the targeting moiety is an antibody.
  • the targeting moiety is cell surface receptor antagonist.
  • the antibody or cell surface receptor antagonist is an epidermal growth factor receptor (EGFR) inhibitor, a hepatocyte growth factor receptor (HGFR) inhibitor, an insulin-like growth factor receptor (IGFR) inhibitor, a folate, or a MET inhibitor.
  • the targeting moiety is a monoclonal antibody.
  • the monoclonal antibody is Abciximab, Adalimumab, Alemtuzumab, Alirocumab, Avibactam, Basiliximab, Benralizumab, Bezlotoxumab, Blinatumomab, Brodalumab, Burosumab, Canakinumab, Caplacizumab, Certolizumab pegol, Daclizumab, Denosumab, Dupilumab, Eculizumab, Emicizumab, Erenumab, Evolocumab, Fremanezumab, Galcanezumab, Golimumab, Guselkumab, Ibalizumab, Idarucizumab, Infliximab, Itolizumab, Ixekizumab, Lanadelumab, Lokivetmab, Mepolizumab, Natalizumab, Obiltoxaximab
  • R 2 or R 3 has one of the following structures:
  • R 2 or R 3 has the following structure:
  • the analyte molecule is a nucleic acid, amino acid or a polymer thereof. In some embodiments, the analyte molecule is an enzyme, receptor, receptor ligand, antibody, glycoprotein, aptamer or prion. In some embodiments, the targeting moiety is an antibody or cell surface receptor antagonist. In further some embodiments, the solid support is a polymeric bead or non-poly meric bead.
  • 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 structures (I)-(ID), (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 structures (I)-(ID) and the further compound of structures (I)-(ID) results in covalently bound dimer of the compound of structures (I)-(ID).
  • Multimer compounds of structures (I)-(ID) 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 structures (I)-(ID) is not limited, provided that Q comprises a moiety having appropriate reactivity for forming the desired bond.
  • 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 structures (I)-(ID) comprise Q groups commonly employed in the field of bioconjugation.
  • 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, ⁇ -haloamide, biotin, amino or maleimide functional group.
  • the activated ester is an N-succinimide ester, imidoester or polyfluorophenyl ester.
  • 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.
  • 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 structures (I)-(ID).
  • 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 moieties are provided in Table A below.
  • 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, -SO 3 H, and the like.
  • 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, -SO 3 H, and the like.
  • the SH moiety will tend to form disulfide bonds with another sulfhydryl group, for example on another compound of structures (I)-(ID). Accordingly, some embodiments include compounds of structures (I)-(ID), which are in the form of disulfide dimers, the disulfide bond being derived from SH Q groups.
  • 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.
  • the Q moiety may be masked as a disulfide having the following structure: wherein R is an optionally substituted alkyl group.
  • Q is provided as a disulfide moiety having the following structure: where n is an integer from 1 to 10.
  • At least one occurrence of -L 5 - M 1 has the following structure:
  • each occurrence of -L 5 - M 1 has the following structure:
  • 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.
  • each M 2 is not the same and the different M 2 moiety is selected to have different antineoplastic agents.
  • the compound is a compound selected from Table 1. The compounds in Table 1 are prepared according to the procedures set forth in the Examples.
  • FAM represents:
  • 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. In some embodiments, n is 2. In some embodiments, n is
  • 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 fluorescence or efficacy toward treating diseases may also be tuned by selection of values for m.
  • the value for m has the ability to control the spacing between neighboring M 1 and M 2 .
  • m is an integer of zero or greater.
  • m is an integer from 0 to 100.
  • m is an integer from 0 to 10.
  • m is 0.
  • m is 1.
  • m is 2.
  • m is 3.
  • m is 4.
  • m is 5.
  • m is 6.
  • m is 7.
  • m is 8.
  • m is 9.
  • m is 10.
  • m is 1, 2,
  • the value for m depends on how hydrophobic M 1 or M 2 are. Hydrophobic M 1 or M 2 may require more spacing units, which increases the value of m. In this regard, less hydrophobic M 1 or M 2 may require less spacing units, which decreases the value of m.
  • the fluorescence intensity may be tuned how many fluorescent dye moieties are attached to the polymeric backbone.
  • the value for p has the ability to control the brightness of compounds.
  • p is, at each occurrence, an integer of zero or greater. In some more specific embodiments, p is from 0 to 10. In some embodiments, p is from 0 to 5. For example, in some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some other embodiments, p is 1.
  • n, p, and m are closely related to provide the ability to control the fluorescence and effectiveness toward diseases.
  • n is 1; p is 1; and m is 3. In some specific embodiments, n is 3; p is 1; and m is 3. In some specific embodiments, n is 5; p is 1; and m is 3. In some specific embodiments, n is 7; p is 1; and m is 3. In some specific embodiments, n is 10; p is 1; and m is 3.
  • n is 1; p is 1; and m is 1. In some other specific embodiments, n is 3; p is 1; and m is 1. In some other specific embodiments, n is 5; p is 1; and m is 1. In some other specific embodiments, n is 7 ; p is 1 ; and m is 1. In some other specific embodiments, n is 10; p is 1; and m is 1.
  • Conjugates of the disclosure may comprise any antibody of the disclosure in combination with any Linker of the disclosure in combination with any Compound of the disclosure.
  • conjugates of the disclosure may covalently bound to a targeting moiety through a bond to the reactive group.
  • the targeting moiety has affinity for a target analyte.
  • the targeting moiety comprises an antibody.
  • the antibody comprises trastuzumab, gemtuzumab, brentuximab, vorsetuzumab, lorvotuzumab, cantuzumab, bivatuzumabor inotuzumab, or vadastuximab.
  • the antibody comprises bretuximab.
  • the targeting moiety specifically binds to bretuximab.
  • One embodiment provides a composition comprising the compound according to any one of the embodiments disclosed herein (e.g., a compound of Structures (I)-(ID) and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises any one (or more) of the compounds of Structures (I)-(ID) 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 compound of Structures (I)-(ID) and an 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 compound of Structures (I)-(ID) 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 compound of Structures (I)-(ID) 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 Structures (I)-(ID) is administered topically.
  • the compounds of Structures (I)-(ID) 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 compound of Structures (I)-(ID) is administered in a single dose.
  • administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly.
  • injection e.g., intravenous injection
  • other routes are used as appropriate.
  • a single dose of a compound of Structures (I)-(ID) may also be used for treatment of an acute condition.
  • a compound of Structures (I)-(ID) 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 compound of Structures (I)-(ID) and another agent are administered together about once per day to about 6 times per day. In another embodiment the administration of a compound of Structures (I)-(ID) 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.
  • a compound of Structure (I)-(ID) may continue as long as necessary.
  • a compound of Structure (I) is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days.
  • a compound of Structures (I)-(ID) is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day.
  • a compound of Structures (I)-(ID) is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.
  • the compounds of Structures (I)-(ID) are 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 in light of the instant disclosure.
  • the compounds of Structures (I)-(ID) are formulated into pharmaceutical compositions.
  • 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).
  • compositions comprising a compound of Structures (I)-(ID) and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s).
  • the compounds described are administered as pharmaceutical compositions in which compounds of Structures (I)-(ID) are mixed with other active ingredients, as in combination therapy.
  • the pharmaceutical compositions include one or more compounds of Structures (I)-(ID).
  • a pharmaceutical composition refers to a mixture of a compound of Structures (I)-(ID) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • therapeutically effective amounts of compounds of Structures (I)-(ID) provided herein are administered in a pharmaceutical composition to a mammal having a disease, disorder or medical condition to be treated.
  • the mammal is a human.
  • 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 compounds of Structures (I)-(ID) are used singly or in combination with one or more therapeutic agents as components of mixtures.
  • one or more compounds of Structures (I)-(ID) 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 compound of Structures (I)-(ID) 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.
  • compounds described herein are formulated for oral administration.
  • Compounds described herein are formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients.
  • the compounds described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.
  • pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • dosage forms such as dragee cores and tablets, are provided with one or more suitable coating.
  • concentrated sugar solutions are used for coating the dosage form.
  • the sugar solutions optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs and/or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and/or pigments are optionally utilized to characterize different combinations of active compound doses.
  • Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • push-fit capsules contain the active ingredients in admixture with one or more filler.
  • Fillers include, by way of example only, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • soft capsules contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol.
  • stabilizers are optionally added.
  • 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.
  • Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form.
  • suspensions of the active compounds e.g., compounds of Structures (I)-(ID)
  • 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.
  • 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 compounds of Structures (I)-(ID) are 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.
  • the compounds of Structures (I)-(ID) are formulated for transdermal administration.
  • 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.
  • patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • the transdermal delivery of the compounds of Structures (I)-(ID) is accomplished by means of iontophoretic patches and the like.
  • transdermal patches provide controlled delivery of the compounds of structures (I)-(ID).
  • 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 of time, and means to secure the device to the skin.
  • the compounds of Structures (I)-(ID) are 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 compound of Structures (I)-(ID) 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 dosage unit of a pressurized aerosol is determined by providing a valve to deliver a metered amount.
  • 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.
  • the compounds of Structures (I)-(ID) are 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.
  • a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with melted cocoa butter.
  • 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 compound of Structures (I)-(ID) 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.
  • compositions include at least one pharmaceutically acceptable carrier, diluent or excipient and at least one compound of Structures (I)-(ID), 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 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.
  • 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.
  • composition comprising at least one compound of Structures (I)-(ID) illustratively takes the form of a liquid where the agents are present in solution, in suspension or both.
  • a liquid composition includes a gel formulation.
  • the liquid composition is aqueous.
  • 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 compound of Structures (I)-(ID).
  • 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, poly glycols, 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 -hydroxy methylaminomethane; 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 -hydroxy methylaminomethane
  • 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.
  • 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.
  • aqueous suspension compositions are packaged in single-dose non-reclo sable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.
  • hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-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 formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and/or other general stabilizing agents.
  • 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.
  • 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 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%,
  • 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.
  • 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.
  • 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
  • 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.
  • 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-
  • Certain compounds of the present disclosure are useful for treating disease (i.e., compounds of Structures (I)-(ID)). Those compounds disclosed herein offer a targeted approach to drug delivery strategies. Accordingly, one embodiment provides a method of treating a disease (or the symptoms thereof) comprising administering to a mammal (e.g., a human) in need thereof a therapeutically effective amount of a compound of Structures (I)-(ID).
  • a mammal e.g., a human
  • the disclosure provides a method of treating autoimmune diseases such as rheumatoid arthritis juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, pediatric Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, Behcets disease, a spondyloarthropathy, psoriasis, or osteoarthritis.
  • autoimmune diseases such as rheumatoid arthritis juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, pediatric Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, Behcets disease, a spondyloarthropathy, psoriasis, or osteoarthritis.
  • the compounds of Structures (I)-(ID) 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.
  • 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.
  • 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.
  • 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, DETRITYLATION).
  • 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.
  • L i.e., a linker group
  • M i.e., a chemotherapeutic agent
  • L and M i.e., a linker group
  • M i.e., a chemotherapeutic agent
  • 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.
  • 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 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), 8.6 mM triethylamine (TEA), pH 8.
  • HFIP 1,1,1,3,3,3-hexafluoro-2-propanol
  • TAA triethylamine
  • pH 8 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-C 18 column held at 45 °C, employing an acetonitrile / water mobile phase gradient.
  • Compound 1-1 is prepared on the DNA synthesizer via solid support using standard DNA synthesis techniques (i.e., DMT protected 2-cyanoethyl phosphoramidite).
  • 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.
  • the maleimide functionalized Compound 1-2 or 1-7 is prepared according to the method described in Example 1.
  • an brentuximab antibody is treated with bis- maleimidoethane (“BMOE”) to reduce disulfide bonds.
  • the reduced antibody is reacted with Compound 1-2 or 1-7 in a 5: 1 molar ratio of 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.
  • anti-CD33, anti-CD70, or anti-CD123 may be used with bis- maleimidoethane (“BMOE”) to reduce disulfide bonds.

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Abstract

Un composé polymère soluble dans l'eau est divulgué. Le composé comprend : i) un ou plusieurs agents antinéoplasiques ; ii) un squelette hétéroalkylène comprenant des groupes chargés négativement à un pH physiologique ; iii) un ou plusieurs lieurs linéaires ou ramifiés comprenant un groupe auto-immolable et un groupe espaceur facultatif, le lieur liant chaque agent antinéoplasique au squelette hétéroalkylène ; et iv) un groupe réactif permettant de former une liaison covalente à une fraction de ciblage. Le composé polymère soluble dans l'eau trouve une utilité dans un certain nombre d'applications, comprenant l'utilisation en tant qu'agents thérapeutiques pour divers procédés de traitement.
PCT/IB2023/061127 2022-11-22 2023-11-03 Composés polymères comprenant des agents antinéoplasiques WO2024110803A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020210694A1 (fr) * 2019-04-11 2020-10-15 Sony Corporation Médicaments polymères programmables

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020210694A1 (fr) * 2019-04-11 2020-10-15 Sony Corporation Médicaments polymères programmables

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Title
"Pharmaceutical Dosage Forms and Drug Delivery Systems", 1999, LIPPINCOTT WILLIAMS & WILKINS
"Pharmaceutical Dosage Forms", 1980, MARCEL DECKER
GOODMANGILMAN: "the Physician's Desk Reference", article "The Pharmacological Basis of Therapeutics"
HOOVER, JOHN E.: "Remington's Pharmaceutical Sciences", 1975, MACK PUBLISHING CO.
REMINGTON: "The Science and Practice of Pharmacy", 1995, MACK PUBLISHING COMPANY

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