WO2010073126A2 - Composés utiles dans l'administration d'une thérapie antinéoplasique et en imagerie diagnostique de cellules hypoxiques et procédés pour les utiliser - Google Patents

Composés utiles dans l'administration d'une thérapie antinéoplasique et en imagerie diagnostique de cellules hypoxiques et procédés pour les utiliser Download PDF

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WO2010073126A2
WO2010073126A2 PCT/IB2009/007980 IB2009007980W WO2010073126A2 WO 2010073126 A2 WO2010073126 A2 WO 2010073126A2 IB 2009007980 W IB2009007980 W IB 2009007980W WO 2010073126 A2 WO2010073126 A2 WO 2010073126A2
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group
substituted
agent
compound
unsubstituted
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WO2010073126A3 (fr
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Leonard Irving Weibe
Piyush Kumar
Weizhong Zheng
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The Governors Of The University Of Alberta
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
    • 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
    • A61K47/54—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 compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

Definitions

  • Radiosensitizers such as 2-nitroimidaoles (azomycins), quinoxaline 1,4-dioxides and triazine 1,4-dioxides are highly diffusible radiosensitizers that permeate hypoxic tissues, where they are bioreductively activated by single electron transfer and subsequently selectively bound within viable hypoxic cells.
  • the reversibility of this single electron reduction in the presence of oxygen limits binding and toxicity to cells that are pathologically hypoxic (Bigalow, J. E. et al, Biochem Pharmacol 35:77 (1986)).
  • This oxygen-dependent selectivity forms the basis for non- invasive (i.e., imaging) diagnosis of hypoxic tissue with radiolabeled radiosensitizers such as nitroimidazoles (Chapman J. D. et al, Cancer 43:456 (1981); Adams, G. E., Radiat Res 67:9 (1976)).
  • Radiolabeled radiosensitizers such as nitroimidazoles (Chapman J. D. et al, Cancer 43:456 (1981); Adams, G. E., Radiat Res 67:9 (1976)).
  • Nitroimidazole radiosensitizers are also used to overcome the "oxygen effect" through an oxygen mimicking process that results in radiosensitization through selective bioactivation and consequent binding (adduct formation) to hypoxic tissue components (Adams G. E. et al, Int J Radiat Biol 15:457 (1969)).
  • hypoxic tissue is also ischemic. It is therefore equally important that the diagnostic/therapeutic agent is a facile tissue permeant, meaning that the molecules must be moderately lipophilic to diffuse across cell membranes. (Brown J. M. et al, Radiat Res 82:171 (1980)). However, if lipophilicity is too high, they will dissolve in lipoidal structures and also exhibit toxicities (e.g. neuropathies); if they are too hydrophilic, they tend to be cleared very rapidly via the kidney, severely reducing the amount of drug available for bioreductive activation and hypoxia- dependent binding.
  • diagnostic/chemotherapeutic/radiochemotherapeutic agents that are transported into hypoxic cells via cellular mechanisms that are upregulated in response to hypoxia. Upregulation of transporter proteins will assist permeation of the diagnostic/chemotherapeutic/radiochemotherapeutic agents into hypoxic cells where they will be bioactively reduced and ultimately bound to hypoxic tissue macromolecules. This will result in increased concentration and residence time of these diagnostic/therapeutic agents in the hypoxic cells which would be particularly useful in cancer therapy and imaging hypoxic cells and tissues.
  • the compounds and methods described herein possess described features and address the needs.
  • Described herein are compounds that actively permeate cell membranes via specific hypoxia-upregulated transporters in hypoxic cells, get bioactively reduced intracellularly, and bind selectively to subcellular macromolecules. Chemically, these compounds are saccharides coupled to bioreductively activated drugs.
  • the ATTORNEY DOCKET NO.: 24T04.2-130 compounds have numerous applications in diagnostic imaging and the therapeutic management of hypoxic cells and tissues (e.g., cancer).
  • Figure 2 shows the syntheses of (3R,4S,5R,6R)-6-((3-(2-mtio-lH- imidazol-l-yl)-2-(4-nitrophenylsulfonyloxy)propoxy)methyl)tetrahydro- 2H-pyran-2,3,4,5-tetrayl tetraacetate (5) and related precursors.
  • Figure 3 shows the syntheses of (3RAS,5S,6R)-6-((2-hydmxy-3-(2- nitro-lH-imidazol-l-yl)propoxy)methyl) tetrahydro-2H-pyran-2,3,4,5- tetraol (8) and (3#,4S,5S,6#)-6-((2-fluoro-3-(2-nitro-lH-imidazol-l- yl)propoxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetraol (11).
  • Figure 4 shows the synthesis of (3/?,45,55,6/?)-6-(((£T)-3-(2-nitro- lH-imidazol- 1 -yl)allyloxy) methyl)tetrahydro-2H-pyran-2,3 ,4,5-tetraol (13).
  • Figure 5A shows the syntheses of 3-(2-hydroxy-3- (((2tf,3S,4S,5tf,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2- yl)methoxy)propylamino)benzo[e][l,2,4]triazine 1,4-dioxide (29) and 3-(2- hydroxy-3-(((2tf,3S,4S,5tf)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2- yl)methoxy)propylamino)benzo[e][l,2,4]triazine 1,4-dioxide (30).
  • Figure 5B shows the structure of 3-(3-(((3S,4S,5R,6R)-2-((3R,4S,5S,6R)-6- ((3-(l,4-dioxidobenzo[e][l,2,4]triazin-3-ylamino)-2-hydroxypropoxy)methyl)-
  • Figures 6 shows the synthesis of benzo[e]l,2,4-triazine-3-chloro-l-oxide (27).
  • Figure 7 shows the syntheses of 3-(2-hydroxy-2-(2-nitro-lH- imidazol-l-yl)ethylamino)-6-hydroxymethyl)tetrahydro-2H-pyran-2,4,5- triol ( 47) and 3-(2-fluoro-2-(2-nitro-lH-imidazol-l-yl)ethylamino)-6- hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol (50) and related precursors.
  • the synthesis of compound 50 is being materialized.
  • Figure 8 shows the radiosensitization of HeIa (A), EMT-6 (B) and
  • Figure 9a, 9b and 9c show the radiosensitization of EMT-6, HeLa and M006 carcinoma cell lines, respectively by compound 13 (1.0 mM concentration) .
  • Figures 10-12 show the MTT cytotoxicity assays with compounds
  • Figure 13 shows selected examples of the structures of several metal chelating agents coordinated to ligands that can be incorporated into the compounds of the invention.
  • Figures 14-16 show the inhibition of transport (GLUT-I and
  • Ranges may be expressed herein as from “about” one particular value, and/or to "about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
  • X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
  • a weight percent of a component is based on the total weight of the formulation or composition in which the component is included. Variables such as A, B, a, b, c, d, D, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 10 , L, Q, S,
  • T, U, X, X 1 , Y 1 , Y 2 , Z and Z 1 used throughout the application are the same ATTORNEY DOCKET NO.: 24T04.2-130 variables as previously defined, unless stated to the contrary.
  • longer chain alkyl groups include, but are not limited to, an oleate group or a palmitate group.
  • a "lower alkyl” group is an alkyl group containing from one to six carbon atoms.
  • alkyl group' is not limited only to open-chain alkyl group, it also represents all possible substituted or unsubstituted acyclic/homocarbocyclic and hetero-carbocyclic groups, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, oxyranyl groups.
  • substituted alkyl group is a branched or unbranched saturated hydrocarbon group of 1 to 25 carbon atoms, such as methyl, ethyl, H-propyl, isopropyl, H-butyl, isobutyl, /-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like, where one of the hydrogen atoms is replaced with a non-carbon based group, or is replaced with a 'linker, L' as described later in this section which may be further substituted with substituted or unsubstituted alkyl or aryl (or other ) groups.
  • non- carbon based groups include, but are not limited to, hydroxyl, alkoxy, amino, thiol, thioalkyl, halogen, aryl, and the like.
  • examples of a 'linker' include 1,4-substituted or unsubstituted piperazine, but are not limited to this moiety, and cover all possible acyclic, homocarbocyclic and hetero-carbocyclic linkers.
  • cycloalkyl group is a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • heterocycloalkyl group is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulphur, or phosphorus.
  • the cycloalkyl group can be unsubstituted or substituted with groups such as, for example, alkyl, aryl, ester, keto, and the like.
  • aryl group as used herein is any carbon-based aromatic group including, but not limited to, benzene, naphthalene, etc.
  • aryl group also includes "heteroaryl group,” which is defined as an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus.
  • the aryl group can be substituted with one or more groups including, but not limited to, alkyl, alicyclic, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, alkoxy, thiol, or thioalkyl or be unsubstituted.
  • the 'aryl' group can also be linked to the point of substitution through a 'linker' which is defined later in this section.
  • halide as used herein is defined as F, Cl, Br, I, or At.
  • substituted thiol as used herein is defined as a thiol group (SH) with the hydrogen atom replaced with a substituted or unsubstituted alkyl group, homo/heteroalicyclic group or an aryl group, and the substituted 'alkyl' groups may be linked to sulfur atom or via a linker.
  • amino group as used herein is defined as an unsubstituted amino group (-NH 2 ) or a mono- or disubstituted amino group, where the amino group can be substituted with a substituted or unsubstituted alkyl group or an aryl ATTORNEY DOCKET NO.: 24T04.2-130 group and the substituted 'alkyl' groups may be linked to the nitrogen atom directly or via a linker.
  • aryl sulfonate as used herein is defined by the formula
  • saccharide as used herein is defined as a polyhydric aliphatic, homocarbocyclic or heterocarbocyclic moiety containing polyhydroxy substitutions.
  • the saccharide may be unsubstituted or substituted.
  • Substituted saccharides may have one or more of the hydroxyl groups replaced with other atoms/groups (e.g., halogen, O-alkoxy/aryloxy, thiol, S-alkyl/arylthiol, amino, or
  • a residue of a chemical species refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species.
  • a monosaccharide that contains at least one -COOH group can be represented by the formula Y-COOH, where Y is the remainder (i.e., residue) of the monosaccharide molecule.
  • VII-Xa and XII-XIV is a substituted or unsubstituted acyclic, homocarbocyclic or heterocarbocyclic moiety such as 1 ,4-piperazines that may be used to link the saccharide with the 'X', and/or to link the 'X' with the side chain 'Q', and/or to link any other 'aryl' or 'alkyl' groups in the formulae with the saccharides or the ATTORNEY DOCKET NO.: 24T04.2-130 substituents on the side chain 'Q', and/or to link any two carbons in the 'Q' as described in the coming pages of this invention.
  • Examples of a 'linker' include 1,4- substituted or unsubstituted piperazines, but are not limited to this moiety, and cover all possible linkers.
  • 'Q' as used herein is a branched or unbranched functional chain that contains a 'bioreductive arm' and is linked to the saccharide (transporter arm) via 'X' in the saccharide, directly or through a linker, contains multiple functional substituents and the 'therapeutic drug' (e.g., anti-neoplastic drug(s)) and/or the 'diagnostic functionality' (a radionuclide or a ligand containing the radionuclide).
  • the 'therapeutic drug' e.g., anti-neoplastic drug(s)
  • the 'diagnostic functionality' a radionuclide or a ligand containing the radionuclide.
  • Q is represented below in the formulae I, Ia, II, Ha, and is part of the formulae VI-XIV.
  • Y 1 and Y 2 are, independently, hydrogen, a substituted or unsubstituted alkyl group, an alkoxy group, an aryl group, or Y 1 and Y 2 collectively form an oxo group or a substituted or unsubstituted vinyl group; or Y 1 and Y 2 collectively forms a susbstituted or unsubstituted cycloalkyl group;
  • Z comprises hydrogen, a halide, a hydroxyl group, a substituted or unsubstituted alkyl group, an alkyl sulfonate, an aryl sulfonate, a thiol, an alkyl ATTORNEY DOCKET NO.: 24T04.2-130 halide, a substituted thiol, a carboxy group, a substituted carboxy group, an amino group, an azide group, an ester, a chromophore, a fluorescent group, a radionuclide, diagnostic agent, chemotherapy (CT) agent, radiochemotherapy (XRCT) agent, or molecular radiotherapy (MRT) agent, where Z is directly bonded to carbon-a or Z is bonded to carbon-a via a linker as defined above;
  • CT chemotherapy
  • XRCT radiochemotherapy
  • MRT molecular radiotherapy
  • Z 1 comprises hydrogen, a halide, a hydroxyl group, an alkyl sulfonate, an aryl sulfonate, a thiol, an alkyl halide, a substituted thiol, a carboxy group, a substituted carboxy group, an amino group, an azide group, an ester, a fluorescent group, a radionuclide, diagnostic agent, CT agent, XRCT agent, or MRT agent, where Z 1 is directly bonded to carbon-d as defined above.
  • D comprises O, S, a substituted or unsubstituted imino group, a substituted or unsubstituted phosphino group, or a substituted or unsubstituted ylide;
  • T comprises a substituted or unsubstituted cycloalkyl group; n is from 0 to 10; B comprises a residue of a bioreductively activated agent; bond-b may or may not be present, wherein when bond-b is not present, the stereochemistry at carbon-a is substantially R, substantially S, or racemic; bond-c is syn or anti with respect to the saccharide; when b is not present, carbon-d is optionally asymmetric, wherein when carbon-d is asymmetric, the stereochemistry at carbon-d is substantially R, s bstantially S, or racemic.
  • saccharides that are chemically coupled to "bioreductively activated agents" that can be delivered into hypoxic cells that are useful as hypoxia imaging agents, chemo therapeutic agents, and/or radiochemotherapeutic agents.
  • the compounds have the formula III.
  • a linker 'L' can be present between A (the saccharide) and Q (e.g., formula VII), between X and the side chain Q (e.g., formula VIII), or between any two carbon atoms in the side chain Q.
  • the compounds have one saccharide A unit with two or more side chain Q attached to the saccharide A directly or via a linker L as represented by the formulae IX and X.
  • the linker L can be located anywhere in the molecule (e.g., between A and X or between X and Q or anywhere in the side chain Q) as shown below.
  • the order of linkage in two side chains for the formulae IX and X may be same or different, for example Q-X-L-A-L-X-Q or Q-X-L-A-X-L-Q.
  • the compounds have two saccharide units linked to each other and the side chain Q' is attached via X, with or without a linker to each saccharide unit.
  • These kinds of compounds represent formulae XI, XII, XIII and are shown above.
  • An example of formula XI is depicted in Figure 5B, where two saccharide units A are joined by a Ci-Ci glycosidic linkage and the C6 positions of both saccharide units are substituted with the side chain 'Q'.
  • 'A' is the 'transporter arm' and is a residue of a saccharide that has one of its -OH group replaced with a group 'X' , and the 'X' is bonded to any C-position of the saccharide.
  • the saccharide facilitates the selective transport-assisted uptake of the compounds having the formulae VI-XIV.
  • the saccharide helps increase the concentration of the compounds in the hypoxic cells.
  • the saccharide can be a monosaccharide.
  • monosaccharides useful herein include, but are not limited to, ribose, arabinose, deoxyribose, xylose, lyxose, ribulose, xylulose, glucose, galactose, mannose, gulose, idose, talose, allose, altrose, fructose, sorbose, tagatose, psicose, fucose, rhamnose, or carbocyclic or thio- substituted pentoses and hexoses.
  • the saccharide is a disaccharide. Disaccharides are composed of two monosaccharide units bound together by a covalent glycosidic bond.
  • disaccharides useful herein include, but are not limited to, sucrose, lactose, trehalose, or maltose.
  • the saccharide includes an oligosaccharide or polysaccharide. Oligosaccharides and polysaccharides are composed of longer chains of monosaccharide units bound together by glycosidic bonds. The distinction between the two is based upon the number of monosaccharide units present in the chain. Oligosaccharides typically contain between two and nine monosaccharide units, and polysaccharides contain ten or more monosaccharide units.
  • polysaccharides include, but are not limited to, glycogen, starch, cellulose, chitin, amylase, amylopectin, stachyose, inulin, dextrin or cyclodextrin.
  • Polysaccharides also include glycosaminoglycans (GAGs) such as, for example, heparin, chondroitin sulfate, hyaluronan, heparan sulfate, dermatan sulfate, or keratan ATTORNEY DOCKET NO.: 24T04.2-130 sulfate.
  • GAGs glycosaminoglycans
  • Each 'A' in formulae VI-XIV can be composed of the same or different saccharide units.
  • 'A' in formula VI can be composed of glucose and galactose units. If two or more saccharide units are present in 'A', they can be coupled to one another via a glycosidic linkage at any position in the saccharide. The glycosidic bond between two saccharide residues can be either axial or equatorial.
  • saccharide is halogenated.
  • the hydroxyl group at the 2, 3, or 4 position can be substituted with a halide (F, Cl, Br, I).
  • the saccharide is 2-fluorodeoxy glucose, where coupling with additional components can occur at the 6-hydroxyl group.
  • the group 'X' is part of the saccharide and is located at any carbon of the saccharide skeleton.
  • 'X' normally represents the 'O' in saccharide 'A', but can be replaced with S, C, NR 1 , or PR 1 (a phosphorous group), wherein R 1 can be hydrogen, an alkyl group or a substituted alkyl group, a substituted carbonyl group, a substituted thiocarbonyl, a susbstituted imino group, or substituted or unsubstituted aryl group, or a ligand for coordinating an imaging or radiotherapeutic agent.
  • R 1 can be hydrogen, an alkyl group or a substituted alkyl group, a substituted carbonyl group, a substituted thiocarbonyl, a susbstituted imino group, or substituted or unsubstituted aryl group, or a ligand for coordinating an imaging or radiotherapeutic agent.
  • R 1
  • N and P can be linked to R 1 via an acyclic, homocarbocyclic or hetero-carbocyclic linker, e.g. susbstituted piperazines but not limited to piperazines only as described in previous section.
  • an acyclic, homocarbocyclic or hetero-carbocyclic linker e.g. susbstituted piperazines but not limited to piperazines only as described in previous section.
  • R 1 can be an imaging agent, a therapeutic agent, or a ATTORNEY DOCKET NO.: 24T04.2-130 ligand for coordinating the imaging agent or therapeutic agent.
  • imaging agent is defined herein as any agent or compound that increases or enhances the ability of cells or tissue to be imaged or viewed using imaging techniques known in the art when compared to visualizing the cells or tissue without the imaging agent. Imaging agents known in the art can be used herein.
  • the imaging agent comprises a chromophore, fluorophore, a denoptical dye, a MRI contrast agent, a PET probe, a SPECT probe, a CT contrast agent, a radiodiagnostic agent, or an ultrasound contrast agent.
  • imaging agents useful in magnetic resonance imaging include Gd +3 , Eu +3 , Tm +3 , Dy +3 , Yb +3 , Mn +2 , or Fe +3 ions or complexes.
  • imaging agents useful in PET and SPECT imaging include 55 Co, 64 Cu, 67 Cu, 47 Sc, 66 Ga, 68 Ga, 90 Y, 97 Ru, 99m Tc, 111 In, 109 Pd, 153 Sm, 177 Lu, 186 Re, 188 Re.
  • the imaging agent is a radioisotope of a halide including, but not limited to, 18 F, 124 1, 12 1, 131 1, 7 Br, 7 Br, 77 Br, 82 Br, or 211 At.
  • the complexing of the imaging agent to the ligand can be performed using known techniques.
  • therapeutic agent is defined herein as any agent or compound that kills tumor cells or reduces and/or prevents the growth of a tumor.
  • therapeutic agents include, but are not limited to, a chemotherapeutic (CT, e.g., carboplatin, cisplatin), a radiochemotherapeutic (XRCT, e.g. MISO, tirapazamine) agent or a molecular radiotherapy (MRT, e.g., [ 131 I]-IAZA and [ 131 I]-InIBG) agent.
  • CT chemotherapeutic
  • XRCT radiochemotherapeutic
  • MRT molecular radiotherapy
  • a single compound can act as an imaging agent and a therapeutic agent.
  • the imaging agent can be covalently or non-covalently attached to 'X'.
  • 'X' is oxygen, nitrogen, or sulfur
  • the lone pair electrons can form a dative bond with a radiolabel. This is depicted as O ⁇ R 10 , S ⁇ R 10 , N(R : ) ⁇ R 10 , where the arrow indicates the dative bond between O, S, or N and the imaging agent or therapeutic agent R 10 .
  • an imaging agent is coordinated to the compounds described herein as shown in formula IV and IVa, ATTORNEY DOCKET NO.: 24T04.2-130
  • 'M' is chelating metal (e.g., a radiolabel such as Re, Lu, Tc but not limited to these metals)
  • X -NR 1 , O, P or S
  • Z -NH 2 , -NHR, -OH, -SH, - NH, -NR, -O or -S).
  • X -NR 1 , O, P or S
  • Z -NH 2 , -NHR, -OH, -SH, - NH, -NR, -O or -S.
  • 'T' as indicated in the formula IVa and used herein the side chain 'Q' denotes a substituted or unsubstituted acyclic, homocarbocyclic or hetero-carbocyclic moiety e.g, susbstituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, but is not limited to these descriptions in this application.
  • 'Z 1 ' represents an H, substituted or unsubstituted alkyl, aryl, -OH, -NH, -NR 1 , SH, SR 1 but is not limited to these moieties.
  • Few examples of chelating metal agents that can be bonded to compounds having the formulae III, IV and IVa are shown in Figure 13.
  • R 1 in formulae VI-XIV can be a ligand for coordinating the imaging agent or therapeutic agent.
  • the ligand is any agent that can form non- covalent bond (e.g., complexation, electrostatic, ionic, dipole-dipole, Lewis acid/base interaction) with the imaging agent or therapeutic agent.
  • the ligand can possess a group that can form a covalent bond with the imaging agent or therapeutic agent.
  • 'X' is NH
  • the amino group can react with a carboxylic group on the ligand to produce an amide bond.
  • the ligand comprises an acyclic or cyclic compound comprising at least one ATTORNEY DOCKET NO.: 24T04.2-130 heteroatom (e.g., oxygen, nitrogen, sulfur, phosphorous) that has lone -pair electrons capable of coordinating with the imaging agent.
  • heteroatom e.g., oxygen, nitrogen, sulfur, phosphorous
  • An example of an acyclic ligand includes ethylenediamine.
  • cyclic ligands include diethylenetriaminepentaacetate (DTPA) or its derivatives, 1,4,7,10- tetraazadodecanetetraacetate (DOTA) and its derivatives, 1,4,7,10- tetraazadodecane-l,4,7-triacetate (D03A) and its derivatives, ethylenediaminetetraacetate (EDTA) and its derivatives, 1,4,7,10- tetraazacyclotridecanetetraacetic acid (TRITA) and its derivatives, 1,4,8,11- tetraazacyclotetradecane-l,4,8,ll-tetraacetic acid (TETA) and its derivatives, 1,4,7,10-tetraazadodecanetetramethylacetate (DOTMA) and its derivatives,
  • DTPA diethylenetriaminepentaacetate
  • D03A 1,4,7,10- tetraazadodecanetetraacetate
  • EDTA ethylene
  • D03MA 1,4,7, 10-tetraazadodecane-l,4,7-trimethylacetate
  • D03MA N,N',N",N'"-tetraphosphonatomethyl-l,4,7,10-tetraazacyclododecane
  • Y 1 and Y 2 are, independently, hydrogen, a substituted or unsubstituted alkyl group, an alkoxy group, an aryl group, or Y 1 and Y 2 collectively form an oxo group or a substituted or unsubstituted vinyl group; or Y 1 and Y 2 collectively forms a susbstituted or unsubstituted cycloalkyl group.
  • Y 1 and Y 2 each are hydrogen. In another aspect, Y 1 and Y 2 form a susbstituted or unsubstituted vinyl group or an oxo group. In the case of the substituted vinyl group, one or both vinyl hydrogen atoms can be replaced with an alkyl group, an alkoxy group, or an aryl group.
  • Y 1 and Y 2 form a substituted or unsubstituted vinyl group the vinyl linkage can further be reacted to obtain corresponding susbstituted or unsubstituted 'cycloaddition products', e.g., substituted or unsubstituted cyclopropyl and ATTORNEY DOCKET NO.: 24T04.2-130 cyclohexyl products, and is extended to unlimited cycloaddition products.
  • Z can be hydrogen, a halide, a hydroxyl group, an aryl sulfonate, a thiol, a substituted thiol, an amino group, an azide group, an ester, or a fluorescent group, where Z is directly bonded to carbon-a or Z is bonded to carbon- a via a linker.
  • the group Z can serve numerous roles depending upon the identity of the group.
  • Z can be an imaging agent or therapeutic agent as defined herein.
  • Z can be replaced with a radioisotope of a halide to produce a radiolabeled or radiotherapy (MRT) compound.
  • MRT radiolabeled or radiotherapy
  • radioisotopes examples include, but are not limited to, 18 F, 124 1, 125 I, 131 1, 75 Br, 76 Br, 77 Br, 82 Br, or 211 At.
  • Z can include functional groups that can be readily substituted with a radioisotope; for example, when Z is a sulphonyl ester with an electron-withdrawing group (e.g., a nitro group), Z can be replaced with a radiohalogen. Techniques for replacing Z or groups present on Z with radioisotopes are known in the art.
  • Z can be used to attach a ligand as described above for coordinating imaging agents or therapeutic agents.
  • Z may be directly bonded to carbon-a as shown in formulae I, Ia, II and Ha or, in the alternative, can be indirectly bonded to carbon-a via a linker as defined above.
  • the linker or linking group has functional groups that are capable of forming covalent bonds.
  • Z when Z is a halide directly bonded to carbon-a, the compound can be reacted with a diol such as ethylene glycol, where the halide is replaced with one of the hydroxyl group.
  • the linker is ZCH 2 CH 2 O-, where Z is a hydroxyl group derived from ethylene glycol.
  • Examples of functional groups on the linker include -NH 2 , -NHNH 2 , -ONH 2 , -NH-C(O)NHNH 2 , -OH,- CO 2 H, or -SH but can be extended to other possibilities.
  • Z 1 can be hydrogen, a halide, a hydroxyl group, an aryl sulfonate, a thiol, a substituted thiol, an amino group, an azide group, an ester, or a fluorescent group, where Z 1 is directly bonded to carbon-d. Further, depending on the chemical nature of Z 1 , it can have numerous roles. In other aspects, Z 1 can be an imaging agent or therapeutic agent as defined ATTORNEY DOCKET NO.: 24T04.2-130 herein. For example, Z 1 can be replaced with a radioisotope of a halide to produce a radiolabeled compound for imaging and MRT.
  • Z 1 can include functional groups that can be readily substituted with a radioisotope; for example, when Z 1 is a sulphonyl ester with an electron- withdrawing group (e.g., a nitro group), Z 1 can be replaced with a radiohalogen. Techniques for replacing Z 1 or groups present on Z 1 with radioisotopes are known in the art. In other aspects, Z 1 can also be used to attach a ligand as described above for coordinating imaging agents to compounds as shown in the formulae Ia and Ha.
  • Z 1 is directly bonded to carbon-d as shown in the formulae I, Ia, Ha, and Ha but, in the alternative, can be extended via coupling to a linker as defined herein.
  • the linker or linking group has functional groups that are capable of forming covalent bonds.
  • Z 1 is a halide directly bonded to carbon-d
  • the compound can be reacted with a diol such as ethylene glycol, where the halide is replaced with one of the hydroxyl group.
  • the linker can be Z 1 CH 2 CH 2 O-, where Z 1 is a hydroxyl group derived from ethylene glycol.
  • Examples of functional groups on the linker include -NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -OH 5 -CO 2 H, or - SH but can be extended to other possibilities.
  • Bond-b (i.e., —dashed line) may be present formulae I and Ia.
  • bond-b When bond- b is present, a carbon-carbon double bond is present. In the case when bond-b is not present, a potential stereocenter is present at carbon-a.
  • the stereochemistry at carbon-a can be substantially R, substantially S, or racemic, depending upon the reaction sequence and when bond-b is present, the E or Z stereoisomers or a mixture in any proportion may be present. In both cases, purification techniques can be used to separate the desired stereomer(s).
  • bond-b is present, and n is from 0 to 10, 0 to 8, 0 to 6, 1 to 5, or 1 to 3.
  • bond-b is not present, and n is from 0 to 10, 0 to 8, 0 to 6, 1 to 5, or 1 to 3.
  • 'B' represents a bioreductively activated ATTORNEY DOCKET NO.: 24T04.2-130 agent that can participate in bioreductive activation and covalent binding of the compound to macromolecules in hypoxic cells, which leads to selective diagnostic/chemotherapeutic/radiochemotherapeutic/radiotherapy actions in hypoxic region e.g., imaging/chemo/radiosensitization/radiotherapy using an anti- neoplastic agent.
  • the agent 'B' is a compound capable of undergoing reduction selectively in the hypoxic cell, which ultimately produces reductively activated species that can cleave or complex with DNA present in the hypoxic cell.
  • reduction can be induced by irradiating the compound within the hypoxic cells.
  • bioreductively activated agents include, but are not limited to, chemotherapeutic agents, radioisotopic agents, radiochemotherapeutic (MRT), RT, and chelating agents that, in some embodiments, carry a radioisotope or other metal agent or, in other embodiments, bind to an essential metal ion in the cancer cell.
  • radionuclides useful as anti-neoplastic agents include, but are not limited to, Ytrium-90, Iodine-125, Iodine-131, and Phosphorous-32. In other aspects, the radionuclide can include iodoaryl groups bearing an Iodine-131.
  • Other preferred anti-neoplastic agents include hydroxyurea and other ribonucleotide reductase inhibitors based on iron chelation such as Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarabazone) and 5-HP (5-hydroxypyridine-2-carboxaldehyde thiosemicarbazone) .
  • the bioreductively activated agent is a substituted or unsubstituted heterocyclic nucleus with optimal reduction potential necessary for bioreductive activation in hypoxic microenvironment e.g, optimally substituted or unsubstituted nitroimidazoles which not wishing to be bound by theory, radio- or chemosensitizing a nitroimidazole produces radical anions in the hypoxic cell, or an anti-neoplastic drug e.g., substituted or unsubstituted benzamides, acridines, anthracyclins, nitrosoureas, taxanes, semicarbazone, thiosemicarbazone, DNA alkylating agents, propylene amine oxime (PnAO) ligands, diaminodithiol (DADT) ligands, MAG3 ligands, copper and platinum complexes of the ATTORNEY DOCKET NO.: 24T04.2-130 semicarba
  • the compounds described herein have the formulae V and Va:
  • the chelating metal M is a radiotherapeutic agent (e.g., a radiolabel such as Re, Lu) bonded to the molecule via X 1 and Z or a diagnostic agent (e.g., Tc).
  • a radiotherapeutic agent e.g., a radiolabel such as Re, Lu
  • a diagnostic agent e.g., Tc
  • the chelating metal M can be covalently or non-covalently attached to X 1 and/or Z.
  • the compounds have the formula IIIA:
  • X comprises O, S, NR 1 , O ⁇ R 10 , S ⁇ R 10 , N(R 1 ) ⁇ R 10 ,or a phosphorous group, wherein R 1 comprises hydrogen, a substituted or unsubstituted alkyl group, a keto group, or substituted or unsubstituted aryl group, or a ligand for coordinating an imaging agent, a chemotherapeutic (CT), a radiochemo therapeutic (XRCT) agent, or a molecular radiotherapy (MRT) agent;
  • CT chemotherapeutic
  • XRCT radiochemo therapeutic
  • MRT molecular radiotherapy
  • R 2 -R 5 (or R 6 depending on the location of side chain 'Q' as in example VI) comprises, independently, hydrogen, a substituted or unsubstituted alkyl group, a keto group, a substituted or unsubstituted aryl group, a substituted alkoxy group, a substituted or unsubstituted aryloxy group, or substituted aryl sulphonate;
  • U comprises oxygen, sulfur, an imino, or phosphino group;
  • Z comprises hydrogen, a halide, a hydroxyl group, an alkyl sulfonate, an aryl sulfonate, a thiol, an alkyl halide, a substituted thiol, a substituted or unsubstituted carboxy group, an amino group, an azide group, an ester, a fluorescent group, a radionuclide, diagnostic agent, CT agent, XRCT agent, or MRT agent, where Z is directly bonded to carbon a or Z is bonded to carbon a via a linker; n is from 0 to 10;
  • B comprises a residue of a bioreductively activated agent e.g., an antineoplastic agent; or the pharmaceutically acceptable salt or ester thereof.
  • a bioreductively activated agent e.g., an antineoplastic agent
  • the compound has the formula IIIB :
  • X comprises O, S, NR 1 , O ⁇ R 10 , S ⁇ R 10 , N(R 1 ) ⁇ R 10 ,or a phosphorous group, wherein R 1 comprises hydrogen, a substituted or unsubstituted alkyl group, a keto group, or substituted or unsubstituted aryl group, or a ligand for coordinating an imaging agent, a chemotherapeutic (CT), a radiochemotherapeutic (XRCT) agent, or a molecular radiotherapy (MRT) agent;
  • CT chemotherapeutic
  • XRCT radiochemotherapeutic
  • MRT molecular radiotherapy
  • R 10 comprises an imaging agent, CT, XRCT or a MRT agent
  • R 2 , R 4 , R , and R comprises, independently, hydrogen, a substituted or unsubstituted alkyl group, a keto group, a substituted or unsubstituted aryl group, a substituted alkoxy group, a substituted or unsubstituted aryloxy group, or substituted aryl sulphonate;
  • U comprises oxygen, sulfur, an imino, or phosphino group
  • Z comprises hydrogen, a halide, a hydroxyl group, an alkyl sulfonate, an aryl sulfonate, a thiol, an alkyl halide, a substituted thiol, a substituted or unsubstituted carboxy group, an amino group, an azide group, an ester, a fluorescent group, a radionuclide, diagnostic agent, CT agent, XRCT agent, or MRT agent, where Z is directly bonded to carbon a or Z is bonded to carbon a via a linker; n is from 0 to 10;
  • B comprises a residue of a bioreductively activated anti-neoplastic agent
  • R 2 -R 5 in formula IIIB comprises, independently, hydrogen, acetyl, or benzoyl.
  • Z in formula IIIB is a halide or a hydroxyl group and n is from 1 to 3.
  • B in formula IIIB comprises a nitroimidazole.
  • the compound has the formula IIIC:
  • X comprises O, S, NR 1 , O ⁇ R 10 , S ⁇ R 10 , N(R 1 ) ⁇ R 10 ,or a phosphorous group, wherein R 1 comprises hydrogen, a substituted or unsubstituted alkyl group, a substituted carbonyl group, a substituted thiocarbonyl group, a substituted imino group, or substituted or unsubstituted aryl group, or a ligand for coordinating an imaging agent;
  • R 10 comprises an imaging agent
  • R 2 , R 3 , R 4 , and R comprises, independently, hydrogen, a substituted or unsubstituted alkyl group, a keto group, a substituted or unsubstituted aryl group, a substituted alkoxy group, a substituted or unsubstituted aryloxy group, or substituted aryl sulphonate;
  • Z comprises hydrogen, a halide (diagnostic or radio therapeutic), a hydroxyl group, an aryl sulfonate, a thiol, an alkyl halide, a substituted thiol, a substituted or unsubstituted carboxy group, an amino group, an azide group, an ester, a fluorescent group, a radionuclide, diagnostic agent, CT agent, XRCT agent, or MRT agent, where Z is directly bonded to carbon a or Z is bonded to carbon a via a ATTORNEY DOCKET NO.: 24T04.2-130 linker; n is from 0 to 10; bond b may or may not be present;
  • B comprises a residue of a bioreductively activated agent; and the bond d is syn or anti, or the pharmaceutically acceptable salt or ester thereof.
  • X in formula IIIC is oxygen
  • R 2 , R 3 , R 4 , and R comprises, independently, independently, hydrogen, methyl, or acetyl
  • Z in formula IIIC is fluorine, iodine, bromine, astatine, a hydroxyl group, an alkyl sulfonate, or an aryl sulfonate.
  • B in formula IIIC comprises a residue of a quinazoline-1,4 dioxide, benzotriazin-l,4-dioxide, or quinoxaline, or a nitroimidazole, benzamides, acridines, anthracyclins, nitrosoureas, taxanes, semicarbazone, thiosemicarbazone, DNA alkylating agents, propylene amine oxime (PnAO) ligands, diaminodithiol (DADT) ligands, MAG3 ligands, copper and platinum complexes of the semicarbazones and thiosemicarbazones, and the ligands mentioned here.
  • n is from 0 to 3.
  • the compound has the formula HID:
  • X comprises O, S, NR 1 , O ⁇ R 10 , S ⁇ R 10 , N(R 1 ) ⁇ R 10 ,or a phosphorous group, wherein R 1 comprises hydrogen, a substituted or unsubstituted alkyl group, a keto group, or substituted or unsubstituted aryl group, or a ligand for ATTORNEY DOCKET NO.: 24T04.2-130 coordinating an imaging agent, a MRT agent;
  • R 10 comprises an imaging agent, CT agent, XRCT agent or MRT agent;
  • R 2 , R 3 , R 5 , and R 6 comprises, independently, hydrogen, a substituted or unsubstituted alkyl group, a keto group, a substituted or unsubstituted aryl group, a substituted alkoxy group, a substituted or unsubstituted aryloxy group, or substituted aryl sulphonate;
  • U comprises oxygen, sulfur, an imino, or phosphino group
  • Z comprises hydrogen, a halide (diagnostic or radiotherapeutic), a hydroxyl group, an aryl sulfonate, a thiol, an alkyl halide, a substituted thiol, an amino group, an azide group, an ester, a fluorescent group, a radionuclide, diagnostic agent, CT agent, XRCT agent, or MRT agent, where Z is directly bonded to carbon a or Z is bonded to carbon a via a linker; n is from 0 to 10;
  • B comprises a residue of a bioreductively activated anti-neoplastic agent; and the bond d is syn or anti, or the pharmaceutically acceptable salt or ester thereof.
  • X is NR 1 , where R 1 comprises hydrogen, an alkyl group or a substituted alkyl group, a substituted carbonyl group, a substituted thiocarbonyl group, a substituted imino group, or substituted or unsubstituted aryl group, a ligand for coordinating an imaging agent; and R 2 -R 6 comprises, independently, hydrogen or acetyl.
  • X is NR 1
  • R 1 comprises hydrogen, an alkyl group or a substituted alkyl group, a substituted carbonyl group, a substituted thiocarbonyl group, a substituted imino group, or substituted or unsubstituted aryl group, a ligand for coordinating an imaging agent
  • R 2 -R 5 comprises, independently, hydrogen or acetyl
  • Z is a halide, a hydroxyl group, or a fluorescent group and n is from 1 to 3.
  • B comprises a residue of a nitroimidazole, and bond c is syn or anti.
  • the compound is represented by the formulae: ATTORNEY DOCKET NO.: 24T04.2-130
  • X comprises O, S, NR 1 , O ⁇ R 10 , S ⁇ R 10 , N(R 1 ) ⁇ R 10 ,or a phosphorous group, wherein R 1 comprises hydrogen, a substituted or unsubstituted alkyl group, an alkoxy group, a substituted carbonyl group, a substituted thiocarbonyl group, a substituted imino group, or substituted or unsubstituted aryl group, or a ligand for coordinating an imaging or therapeutic agent;
  • R 10 comprises an imaging agent, CT agent, XRCT agent, or MRT agent;
  • L comprises a substituted or unsubstituted an acyclic group, homocarbocyclic group or heterocarbocyclic group
  • Y 1 and Y 2 are, independently, hydrogen, a substituted or unsubstituted alkyl group, an alkoxy group, an aryl group, or Y 1 and Y 2 collectively form an oxo group or a substituted or unsubstituted vinyl group; or Y 1 and Y 2 collectively forms a susbstituted or unsubstituted cycloalkyl group;
  • D comprises O, S, a substituted or unsubstituted imino group, a substituted or unsubstituted phosphino group, or a substituted or unsubstituted ylide;
  • Z comprises hydrogen, a halide, a hydroxyl group, an aryl sulfonate, a thiol, a substituted thiol, an alkyl halide, an amino group, an azide group, an ester, a fluorescent group or a fluorophore, a diagnostic radionuclide, a radiotherapeutic radionuclide, where Z is directly bonded to carbon-a or Z is bonded to carbon-a via a linker; ATTORNEY DOCKET NO.: 24T04.2-130 n is from 0 to 10;
  • B comprises a residue of a bioreductively activated agent; bond-b may or may not be present, wherein when bond-b is not present, the stereochemistry at carbon-a is substantially R, substantially S, or racemic, or the pharmaceutically acceptable salt or ester thereof.
  • the compound is
  • Representative pharmaceutically acceptable bases are ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, aluminum hydroxide, ferric hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2- ATTORNEY DOCKET NO.: 24T04.2-130 dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, histidine, and the like.
  • the pharmaceutically acceptable salts are prepared by treating the free base with an appropriate amount of a pharmaceutically acceptable acid such as, for example, HCl and AcOH.
  • the reaction is conducted in water, alone or in combination with an inert, water-miscible organic solvent, at a temperature of from about 0 0 C to about 100 0 C such as at room temperature.
  • the molar ratio of compound to base used is chosen to provide the ratio desired for any particular salts.
  • the starting material can be treated with approximately one equivalent of pharmaceutically acceptable base to yield a neutral salt.
  • Ester derivatives are typically prepared as precursors to the acid form of the compounds-as illustrated in the examples below-and accordingly can serve as prodrugs. Generally, these derivatives will be lower alkyl esters such as methyl, ethyl, and the like.
  • Amide derivatives -(CO)NH 2 , -(CO)NHR and -(CO)NR 2 , where R is an alkyl group defined above, can be prepared by reaction of the carboxylic acid-containing compound with ammonia or a substituted amine.
  • Methods for producing the compounds having the formula I are provided in the Examples and Figures 2-6.
  • the methods involve techniques known in the art. Standard techniques for purifying the compounds can be used and are described in the Examples below.
  • the methods described in the Examples and Figures 2-6 provide a convenient approach to producing the compounds having the formula I and precursors thereof in high yields.
  • any of the compounds having the formula I can be combined with at least one pharmaceutically-acceptable carrier to produce a pharmaceutical composition.
  • the pharmaceutical compositions can be prepared using techniques known in the art.
  • the composition is prepared by admixing the compound having the formula I with a pharmaceutically-acceptable carrier.
  • admixing is defined as mixing the two components together so that there is no chemical reaction or physical interaction.
  • admixing also includes the chemical reaction or physical interaction between the compound having the ATTORNEY DOCKET NO.: 24T04.2-130 formula I and the pharmaceutically-acceptable carrier.
  • Pharmaceutically-acceptable carriers are known to those skilled in the art. These most typically would be standard carriers for administration to humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH.
  • Molecules intended for pharmaceutical delivery may be formulated in a pharmaceutical composition.
  • Pharmaceutical compositions may include carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice.
  • Pharmaceutical compositions may also include one or more active ingredients such as antimicrobial agents, antiinflammatory agents, anesthetics, and the like.
  • the pharmaceutical composition may be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated. Administration may be topically (including ophthalmically, vaginally, rectally, intranasally).
  • Preparations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles if needed for collateral use of the disclosed compositions and methods, include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
  • Intravenous vehicles if needed for collateral use of the disclosed compositions and methods, include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.
  • Formulations for topical administration may include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • active compound ATTORNEY DOCKET NO.: 24T04.2-130 in a specified case will vary according to the specific compound being utilized, the particular compositions formulated, the mode of application, the intended use (i.e., therapeutic (RT, MRT) or diagnostic (MRI or PET); etc) and the particular situs and mammal being treated. Dosages for a given host can be determined using conventional considerations, e.g. by customary comparison of the differential activities of the subject compounds and of a known agent, e.g., by means of an appropriate conventional pharmacological protocol. Physicians and formulators, skilled in the art of determining doses of pharmaceutical compounds, will have no problems determining dose according to standard recommendations (Physicians Desk Reference, Barnhart Publishing (1999).
  • hypoxic cells are generally more resistant to cell death by radiation as compared to oxic cells.
  • Oxic cells possess molecular oxygen that is able to interact with radiation- induced radicals in DNA, leading to irreversible fixation of the damage. Since hypoxic cells do not possess sufficient molecular oxygen levels to compete effectively with reducing species, much of the radiation- induced damage in hypoxic cells is repaired.
  • Hypoxic cells are also resistant to a range of chemotherapeutic drugs and imaging agents, which limits the detection and treatment of tumors. Hypoxic cells effectively upregulate transport mechanisms for the compounds described herein. This results in an increase in the concentration and residence time of the anti-neoplastic agent, MRT agent and/or imaging agent in the hypoxic cells.
  • the compounds described herein are effective in treating a tumor present in a subject.
  • the term "treat” as used herein includes reducing the size of an existing tumor as well as preventing the growth and/or metastasis of an existing tumor.
  • a variety of different squamous and non-squamous cancer cells and tissues can be treated with the compounds described herein including, but not limited to, acute lymphocytic leukemia, adult acute myeloid leukemia, adult non-Hodgkin's lymphoma, brain tumors, cervical cancers, childhood cancers, childhood sarcoma, chronic lymphocytic leukemia, chronic myeloid leukemia, esophageal cancer, ATTORNEY DOCKET NO.: 24T04.2-130 hairy cell leukemia, kidney cancer, liver cancer, multiple myeloma, neuroblastoma, oral cancer, pancreatic cancer, primary central nervous system lymphoma, skin cancer, head and neck cancers, and small-cell and non-small-cell lung cancer
  • Childhood cancers amenable to compounds and methods described herein include but are not limited to brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma, ependymoma, Ewing's sarcoma and family of tumors, germ cell tumor— extracranial, Hodgkin's disease, ALL, AML, liver cancer, medulloblastoma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, malignant fibrous histiocytoma of bone, retinoblastoma, rhabdomyosarcoma, soft tissue sarcoma, supratentorial primitive neuroectodermal and pineal tumors, unusual childhood cancers, visual pathway and hypothalamic glioma, and Wilms's tumor and other childhood kidney tumors.
  • the compounds described herein can be activated to produce radicals once imported via upregulated transporters by the hypoxic cells.
  • the anti-neoplastic agent is a nitroimidazole
  • radio- or chemosensitization of the nitroimidazole produces radical anions in the cell.
  • the radicals can permanently damage DNA present in the hypoxic cells, which can help reduce or prevent tumor growth.
  • the cells can be exposed to irradiation by external beam radiotherapy (XRT) to generate radical species within the cell causing its death.
  • XRT external beam radiotherapy
  • the specific dose and duration of radiation will depend upon the compound chosen, and the species being treated.
  • the radiation should be applied at a sufficient wavelength, dose and duration to maximize tumor damage, and, at the same time, to minimize the damage to the bone marrow and blood cells and/or other surrounding normoxic tissues.
  • Sources of radiation useful herein include, but are not limited to, ultraviolet, infrared (IR), gamma-irradiation, x-ray and visible light.
  • the radiation can be applied from about five minutes to about 48 hours after administering the compound to the subject in one single dose or fractionated doses as used by those experienced in the art.
  • one or more quenchers can be administered ATTORNEY DOCKET NO.: 24T04.2-130 before, during or after the administration of the compounds described herein but prior to irradiation.
  • Suitable quenchers include, but are not limited to, amifostine, glutathione, trolox, flavonoids, vitamin C, vitamin E, cysteine and ergothioneine and other non-toxic quenchers, and preferably vitamin E.
  • the amount of the quencher administered will depend upon the specific quencher(s) chosen and can be determined by one skilled in the art. Administering one or more of the aforementioned quenchers is optional, and is complimentary to administering the compounds described herein.
  • the compounds described herein can be co-administered in combination with other anti-cancer and anti-neoplastic agents.
  • the dosages of the additional agent are either the standard dosages employed for those agents or are adjusted downward or upward from levels employed when that agent is used alone.
  • the administration of a compound described herein permits the physician to treat tumors with existing drugs, but at a lower concentration or dose than is currently used, thus ameliorating the toxic side effects of such drugs, or at a higher concentration, due to the fact that the conjugate is less toxic than its un-conjugated counterpart.
  • the compounds described herein can be used to MRT hypoxic tissue.
  • the method comprises contacting the hypoxic tissue with a compound described herein, and (2) analyzing the MRT effects of hypoxic tissues.
  • the compounds described herein can be labeled with therapeutic radioisotopes, for example but not limited to, 131 I- to deliver the therapeutic doses of radiations to the tumor cells.
  • MRT molecular radioisotope therapy
  • the radiation should be applied at a sufficient wavelength, dose and duration to maximize tumor damage, and, at the same time, to minimize the damage to the bone marrow and blood cells and/or other surrounding normoxic tissues.
  • Sources of radiation useful herein include, but are not limited to, ultraviolet, infrared (IR), gamma-irradiation, x-ray and visible light.
  • the radiation can be applied from about five minutes to about 48 hours after administering the compound to the subject in one single dose or fractionated doses as used by those experienced in the art.
  • the MRT effects can be analyzed by positron emission tomography, (PET), single photon computer tomography (SPECT), autoradiography, identification of molecular biomarkers, or planar imaging.
  • the compounds described herein can be used to image/diagnose hypoxic tissue.
  • the method involves
  • the compounds described herein can be labeled with an imaging agent that is readily detectable using techniques known in the art.
  • an imaging agent that is readily detectable using techniques known in the art.
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • MRS nuclear magnetic resonance spectroscopy
  • ATTORNEY DOCKET NO.: 24T04.2-130 magnetic resonance imaging (MRI) can also be used to detect the compounds when they are used in therapeutic concentrations.
  • the imaging agent when the imaging agent is a fluorescent group, the fluorescent group can be detected by optical imaging, autoradiography, or fluorescence-based histology.
  • the diagnostic method includes waiting a period of time such that a substantial amount of the labeled compound has been cleared from the less hypoxic or oxic cells such that a detectable amount of the labeled compound remains within the hypoxic cells.
  • One skilled in the art will be capable of determining the appropriate amount of time with observation and as a function of administered dose, patient weight, patient age, patient sex, and suspected hypoxic cell location in the body.
  • the amount and location of the hypoxic cells throughout the population of lesser hypoxic or oxic cells is determined by detecting the labeled compound.
  • the determination of the extent and location of the compound in the cells provides for or permits the monitoring of regions of hypoxia, which correlates with the presence of a collection of cancerous cells or tumors.
  • the compounds described herein may be administered orally, parenterally
  • compositions may be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, or the like, preferably in unit dosage form suitable for single administration of a precise dosage.
  • the compositions will include, as noted above, ATTORNEY DOCKET NO.: 24T04.2-130 an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, etc.
  • reaction conditions e.g., component concentrations, desired solvents, solvent mixtures, temperatures, pressures and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions.
  • the resultant solution was treated with Amberlyst A26 (OH " , 12 g) to adjust the pH of the solution to a value of 8.
  • the ion-exchange resin was filtered off and the filtrate was liophilized to provide 3.6 g of a red solid, which was subjected to dry chromatography (Silica Gel for TLC, 5% MeOH - CHCl 3 ⁇ 30% MeOH - CHCl 3 ) to afford 30 as a red solid.
  • 2-N-acryloyl-D-glucosamine (1.0 g, 4.29 mmol) was dissolve in 16 mL of pyridine-acetate anhydride (1:1) at 0 0 C, and than, the mixture was stirred under room temperature for 2 days. All solvents were removed in vacuo, the residue was purified by column chromatography on SiO 2 using hexane-ethyl acetate as eluents. Evaporation of the appropriate fraction yielded a white solid (1.6 g, 97%).
  • Radiochemistry Procedures include the development of the radiolabeled compounds claimed, for example 3 H-, 14 C, 35 S, radiohalogenated (e.g., 18 F, 123/124/125/131 i but not limited to these radiohalogens), and metal chelated products of the compounds described in the application.
  • the radiochemistry process development and isotopic labeling include substitution or exchange -based chemistries using conventional thermal radiolabeling techniques, microwave-assisted radiolabeling techniques, solid phase immobilized precursor-based radiochemistry techniques, and immobilized superparamagnetic precursor based radiochemistry development. These processes and the techniques used for the isotopic radiolabeling are claimed.
  • radiolableing processes may vary with the structure of the target compound and the radionuclide to be incorporated in the molecule, and all future variations are also claimed.
  • the radiohalogenation of compound 5 has been chosen as an example of radiochemistry development of these classes of compounds, and is described.
  • EXAMPLE Radiohalogenation This process is exemplified by the development of F- 18 labeling process to synthesize 18 F-Il, but is not limited to the development of the compounds labeled only with F- 18 radionuclide. The process in its current form or with modified reaction parameters and process may be used to radiohalogenate other compounds described in this application, and is part of the radiochemistry process claims.
  • a ATTORNEY DOCKET NO.: 24T04.2-130 typical (unoptimized) radiohalogenation procedure is exemplified below by the description of the synthesis of radiofluorinated 18 F-Il.
  • the p ⁇ of the resulting solution was adjusted to 5-7 by using an appropriate buffer, for example citrate or phosphate but not limited to these, the impure 18 F-Il was loaded on a C-18 reverse phase ⁇ PLC column (25 cm X 0.9 cm) and eluted with 8% ethanol in sterile water (mobile phase). The pure product was collected at a retention time of -23 ( ⁇ 5%) min using a flow rate of 1.5 mlVmin. The standard product appeared at the same retention time using the described ⁇ PLC conditions, and was detected by a UV signal at 318 nm. The purity of the radiochemical product was found to be >98%.
  • an appropriate buffer for example citrate or phosphate but not limited to these
  • the impure 18 F-Il was loaded on a C-18 reverse phase ⁇ PLC column (25 cm X 0.9 cm) and eluted with 8% ethanol in sterile water (mobile phase).
  • the pure product was collected at a retention time of -23 ( ⁇ 5%)
  • Radiosensitization Studies Procedure Cell radiosensitization was determined using a 60 Co x-ray source together with a clonogenic survival assay (22). Radiosensitization potential of the compounds was studied against ⁇ ela, EMT-6 and M006X cancer cell lines.
  • Carcinoma cells 300,000 cells in 3 mL DMEM/F12 medium per T60 petri dish) were individually incubated under 5% CO 2 in air at 37 0 C for 24 h. The dishes were assigned to either the control (normoxic) or hypoxic groups, the test substance (stock solution 10 mM in 95 % ethanol) was added to these groups to achieve a concentration of 100 ⁇ M and the incubation was allowed for 30 min.
  • hypoxic group Those in the hypoxic group were de-gassed to hypoxia by 6 consecutive vacuum and nitrogen fill cycles in a vacuum chamber.
  • the Petri dishes (hypoxic and normoxic controls) were incubated for 30 min on an oscillating shaker at R/T X 60 ATTORNEY DOCKET NO.: 24T04.2-130 cycles per min and then irradiated in a 60 Co ⁇ -irradiator at 0 (control), 4, 8, 12, 16 and 20 Gy in N 2 (hypoxic sub-group) and air chambers (normoxic sub-group).
  • the cells were then recovered from each dish by two consecutive washes with PBS followed by the addition of trypsin (500 ⁇ L) and quenching with fresh medium (4.5 mL).
  • Cells were trypsinized, centrifuged, and suspended in growth medium and the cell counts were readjusted to 8 x 10 3 cells/mL.
  • the cells were seeded into 96- well plates at a count of 8xlO 2 cells/well and incubated in 37 0 C, 5%CU 2 for 24hours.
  • the test compounds (stock solution 2 mM in 95 % ethanol) were added to the growth medium and exposed to the cells in 96-well plates at a final volume of 300 ⁇ L to produce the required dilution of the experimental design. Control wells were filled with 100 ⁇ L of medium. These plate groups were incubated for 3 days at 37 0 C in a humidified atmosphere containing 95% air and 5% CO 2 .
  • test compounds to GLUT 1 and GLUT 2 transporters was measured by monitoring the abilities of test compounds to drive sugars across the membrane, potentially against its concentration gradient.
  • plasmids containing each of the wild type GLUT isoform were linearized with Nhe I and transcribed in vitro with T7 polymerase mMESSAGE mMACHINETM (Ambion).
  • T7 polymerase mMESSAGE mMACHINETM Ambion
  • Adult female Xenopus laevis oocytes were injected with 10-50 nL ( ⁇ 20ng) GLUTl synthetic mRNA transcript and incubated for 3 - 5 days at 16-18 0 C prior to functional uptake assays.
  • the concentration of RNA was determined using Bio- Rad SmartSpecTM3000machine.
  • the influx experiments were performed at 20 0 C using 10-12 oocytes for each condition and 14 C labelled hexose at a specific activity of 4 ⁇ Ci/mL.
  • Oocytes were washed with ice cold MBM to stop the incubation and then individual oocytes were placed in vials and dissolved in 0.5 mL 5% SDS for 30 min. Finally, scintillation fluid (5 mL) was added to each vial and radio activity measured using a Beckman LS6500 liquid scintillation counter. In all experiments the results were compared to the influx values obtained with water-injected oocytes as a control.
  • a sterile saline solution of compound 11 (GAZ-F) was injected in increasing experimental doses (75 mg/kg, 150 mg/kg, 300 mg/kg and 900 mg/kg) in Balb/c mice (5 per group) intraperitoneally in order to determine the MTD of ATTORNEY DOCKET NO.: 24T04.2-130 compound 11, and the animals were evaluated for manifestations of acute toxicity using the M 102 Acute Toxicity Study Criteria outlined by Stanford Research Institute. The animals were weighed weekly and observed for clinical signs of toxicity and death for 2 weeks after the treatment. Tissue necropsy was performed at the end of the study and the data were recorded. MTD for the compound 11 was found to be >900 mg/kg in this experimental model.

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Abstract

L'invention concerne des composés qui traversent les membranes cellulaires au moyen de transporteurs spécifiques positivement régulés par l'hypoxie dans des cellules hypoxiques, sont activés par bioréduction dans le milieu intracellulaire, et se lient sélectivement aux macromolécules subcellulaires pour présenter une accumulation spécifique de l'hypoxie dans des cellules hypoxiques. Du point de vie chimique, ces composés sont des saccharides couplés à des médicaments activés par bioréduction. Les composés ont de nombreuses applications en imagerie diagnostique et dans la prose en charge thérapeutique des cellules et des tissus hypoxiques (par exemple, en cas de cancer).
PCT/IB2009/007980 2008-12-22 2009-12-22 Composés utiles dans l'administration d'une thérapie antinéoplasique et en imagerie diagnostique de cellules hypoxiques et procédés pour les utiliser WO2010073126A2 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016164921A1 (fr) * 2015-04-10 2016-10-13 The Regents Of The University Of California Traceur d'imagerie pet pour l'imagerie du cancer de la prostate
CN110551226A (zh) * 2019-07-30 2019-12-10 大连理工大学 一种亲/疏水性可控转换的叔胺型含氮聚糖衍生物及其制备方法和应用
EP3684781A4 (fr) * 2017-09-19 2022-06-29 The Governors of the University of Alberta Composés activés par bioréduction, leurs promédicaments, produits radiopharmaceutiques, les compositions et leurs applications dans la gestion théranostique multimodale de l'hypoxie, dont le cancer
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds
US12030903B2 (en) 2021-02-17 2024-07-09 Gilead Sciences, Inc. Antiviral compounds

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CA2520000A1 (fr) * 2003-03-28 2004-10-14 Threshold Pharmaceuticals, Inc. Compositions et methodes de traitement du cancer
CA2581450A1 (fr) * 2004-09-24 2006-03-30 Angiogene Pharmaceuticals Limited Promedicaments actives par une bioreduction

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YAO, S-P. ET AL.: 'A single-enzyme, two-step, one-pot synthesis of N-substituted imidazole derivatives containing a glucose branch via combined acylation/Michael addition reaction' CHEM. COMM. vol. 17, 2004, pages 2006 - 2007 *
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016164921A1 (fr) * 2015-04-10 2016-10-13 The Regents Of The University Of California Traceur d'imagerie pet pour l'imagerie du cancer de la prostate
EP3684781A4 (fr) * 2017-09-19 2022-06-29 The Governors of the University of Alberta Composés activés par bioréduction, leurs promédicaments, produits radiopharmaceutiques, les compositions et leurs applications dans la gestion théranostique multimodale de l'hypoxie, dont le cancer
CN110551226A (zh) * 2019-07-30 2019-12-10 大连理工大学 一种亲/疏水性可控转换的叔胺型含氮聚糖衍生物及其制备方法和应用
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds
US12030903B2 (en) 2021-02-17 2024-07-09 Gilead Sciences, Inc. Antiviral compounds
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides

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