WO2002017908A1 - Nouveaux derives de metallotexaphyrine - Google Patents

Nouveaux derives de metallotexaphyrine Download PDF

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Publication number
WO2002017908A1
WO2002017908A1 PCT/US2001/026885 US0126885W WO0217908A1 WO 2002017908 A1 WO2002017908 A1 WO 2002017908A1 US 0126885 W US0126885 W US 0126885W WO 0217908 A1 WO0217908 A1 WO 0217908A1
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acid
iii
optionally substituted
bis
alkyl
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PCT/US2001/026885
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English (en)
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Tarak D. Mody
Joshua Galanter
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Pharmacyclics, Inc.
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Priority to CA002434744A priority Critical patent/CA2434744A1/fr
Priority to AU2001288484A priority patent/AU2001288484A1/en
Priority to EP01968223A priority patent/EP1408955A4/fr
Publication of WO2002017908A1 publication Critical patent/WO2002017908A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero 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
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0076—PDT with expanded (metallo)porphyrins, i.e. having more than 20 ring atoms, e.g. texaphyrins, sapphyrins, hexaphyrins, pentaphyrins, porphocyanines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to methods for modifying metallotexaphyrins to provide metallotexaphyrin derivatives (MTDs) having a wide range of physicochemical properties.
  • the methods involve modifying the apical ligands associated with the central metal component of metallotexaphyrins.
  • the invention also relates to the novel MTDs prepared by these methods, and their uses, and pharmaceutical compositions containing such compounds.
  • Porphyrins the so-called “expanded porphyrins”, and related polypyrrole structures are members of a class of macrocycles capable of forming stable complexes with metals.
  • the metal is constrained (as its cation) within a central binding cavity of the macrocycle (the "core”).
  • the anions associated with the metal cation are found above and below the core; and are called apical ligands.
  • Examples of this class of macrocycles are porphyrins, porphyrm isomers, porphyrin-like macrocycles, benzoporphyrins , texaphyrins, alaskaphyrins, sapphyrins, rubyrins, porphycenes, chlorins, benzochlorins, and purpurins.
  • Texaphyrins are aromatic pentadentate macrocyclic compounds that have the ability to integrate metals within their core to form complexes known as "metallotexaphyrins".
  • Texaphyrins and metallotexaphyrins have been described as being useful as MRI contrast agents, fluorescent imaging agents for cancer, plaque, and retinal diseases, as radiosensitizers and as chemosensitizers in both oncology and atherosclerosis, and as photosensitizers in photodynamic therapy in oncology, atherosclerosis, and ophthamology.
  • Texaphyrins are aromatic benzannulene compounds containing both 18 ⁇ - and 22 ⁇ -electron delocalization pathways. Texaphyrin molecules absorb light strongly in the tissue-transparent 700-900 nm range, and they exhibit selective uptake (or biolocahzation) in certain tissues, particularly regions such as liver, atheroma or tumor tissue, and neovascularized regions. Such selectivity can be detected by magnetic resonance imaging (for example with paramagnetic metal complexes) and by fluorescence.
  • advantage may be taken of this property to provide a means for selectively treating tumors, plaque caused by atherosclerosis, retinal diseases, and the like, as disclosed in the publications incorporated by reference below in the detailed description of the invention. Notwithstanding these properties, it has remained desired to provide new MTDs having a range of physicochemical properties, such as improved solubility and/or lipophilicity, lower toxicity, and improved stability, but still retaining the basic attribute of selective localization.
  • One method of accomplishing these goals would be to change the properties of existing metallotexaphyrins by modifying the functional groups covalently attached to the macrocycle, and/or by changing the core metal.
  • the present invention provides such a method by modifying the apical ligands associated with the metal component of existing metallotexaphyrins to provide a library of MTDs having a wide range of physicochemical properties.
  • the invention relates to compounds having the Formula I:
  • M is a metal cation
  • AL is an apical ligand; with the proviso that AL is not derived from acetic acid, nitric acid, or hydrochloric acid
  • n is an integer of 1-5;
  • R 1 , R 2 , R 3 , R 4 , R ⁇ , R 7 , R 8 , and R 9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group -X- Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chem
  • R 5 , R 10 , R 11 , and R 12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl; with the proviso that: halogen is other than iodide and haloalkyl is other than iodoalkyl.
  • Substituents R 1 - R 12 are further described in U.S. Patents, PCT publications and allowed and pending patent applications, incorporated by reference in the Detailed Description.
  • M can be monovalent, divalent, trivalent, or tetravalent.
  • Examples of monovalent metal cations are tellurium and technetium; an example of an appropriate tetravalent metal is thorium.
  • Preferred trivalent metal cations are Mn(III), Co(III), Ni(III), Fe(III), Ho(III), Ce(III), Y(III), In(i ⁇ ), Pr(i ⁇ ), Nd(III), Sm(III), Eu(III), Gd(i ⁇ ), Tb(III), Dy(III), Er(III), Tm(III), Yb(III), Lu(III), La(III), or U(III). More preferred trivalent metal cations are Lu(III) or Gd(III).
  • the metal in particular for use in neutron capture therapy, the metal can be present as a pure isotope of the metal, or be enriched in one or more of its isotopes.
  • gadolinium may be present as its 155 Gd or 157 Gd isotope, or "natural" gadolinium may be optionally enriched in the isotopes 155 Gd and/or 157 Gd.
  • cadmium may be present as the cadmium isotope U3 Cd, or "natural” cadmium enriched in II3 Cd;
  • europium may be present as the europium isotope 151 Eu , or "natural” europium enriched in 151 Eu;
  • mercury may be present as the mercury isotope 199 Hg, or “natural” mercury enriched in 199 Hg; and samarium may be present as the samarium isotope 149 Sm.
  • neutron capture therapy is the 157 Gd isotope of gadolinium, or "natural” gadolinium enriched in the isotope 157 Gd.
  • M or one of groups R 1 to R 12 can be radioactive, and are as described in the U.S.
  • Preferred apical ligands are formed, for example, from carboxylates of sugar derivatives, such as gluconic acid or glucoronic acid, cholesterol derivatives such as cholic acid and deoxycholic acid, polyethylene glycol (PEG) acids, or carboxylic acid derivatives, such as formic acid, propionic acid, butyric acid, pentanoic acid, methylvaleric acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, 3,6,9-trioxodecanoic acid, 3,6- dioxoheptanoic acid, 2,5-dioxoheptanoic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid.
  • sugar derivatives such as gluconic acid or glucoronic acid
  • cholesterol derivatives such as cholic acid and deoxycholic acid
  • Suitable acids for forming apical ligands include methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, organophosphates, such as methylphosphonic acid and phenylphosphonic acid, phosphoric acid and the like.
  • a second aspect of the present invention relates to a preferred process for synthesizing MTDs of Formula I, comprising the steps of contacting the desired apical ligand with an quartenary amine resin (e.g., Ambersep 900(OH), Amberlite IRA904), contacting the apical ligand/amino acid resin complex thus produced with a metallotexaphyrin, preferably a metallotexaphyrin acetate, and isolating the MTD of Formula I having the desired novel apical ligand.
  • an quartenary amine resin e.g., Ambersep 900(OH), Amberlite IRA904
  • a third aspect of the present invention relates to an alternative process for synthesizing MTDs of Formula I, comprising the steps of contacting a metallotexaphyrin, preferably as an acetate, with a large excess of the chosen apical ligand, optionally heating the mixture, and isolating the MTD of Formula I containing the novel apical ligand.
  • a fourth aspect of the present invention relates to a process for synthesizing MTDs having a mixture of apical ligands, comprising the steps of contacting a metallotexaphyrin, preferably a metallotexaphyrin acetate, with a mixture of apical ligands, optionally heating the mixture, and isolating the MTD of Formula I containing a mixture of apical ligands. Alternatively, the reaction can be carried out in a biphasic fashion (for example, in a methylene chloride/water mixture).
  • a fifth aspect of this invention relates to pharmaceutical formulations, comprising a therapeutically effective amount of an MTD of Formula I and at least one pharmaceutically acceptable excipient.
  • a sixth aspect of this invention relates to a method of using the MTDs of Formula I in the treatment of a disease or condition in a mammal that results from the presence of neoplastic tissue, which method comprises administering to a such a mammal a therapeutically effective amount of an MTD of Formula I, and optionally treating further with a chemotherapeutic compound, or preferably treating the area in proximity to the neoplastic tissue with a therapeutic energy means.
  • Preferred therapeutic energies include photoirradiation, ionizing radiation, ultrasound, and neutron bombardment.
  • a seventh aspect of this invention relates to a method of using the MTDs of Formula I in the treatment of a disease or condition in a mammal that results from the presence of atherosclerosis, which method comprises administering to a such a mammal a therapeutically effective amount of an MTD of Formula I, and treating the area in proximity to the plaque caused by atherosclerosis with a therapeutic energy means.
  • Preferred therapeutic energies include photoirradiation, ionizing radiation, ultrasound, and neutron bombardment.
  • An eighth aspect of this invention relates to a method of using the MTDs of Formula I in the treatment of a disease or condition in a mammal that results from areas of neovascularization , in particular age-related ocular degeneration, which method comprises administering to a such a mammal a therapeutically effective amount of an MTD of Formula I, and treating the area in proximity to the neovascularization with a therapeutic energy means.
  • a therapeutic energy means include photoirradiation, ionizing radiation, ultrasound, and neutron bombardment.
  • This invention provides novel metallotexaphyrin derivatives (MTDs) having a wide range of physicochemical and biological properties, and methods of making them.
  • the invention provides a method of exchanging the existing apical ligands of a metallotexaphyrin with one or more different apical ligands.
  • the apical ligand exchange modifies the properties of the metallotexaphyrin by altering, for example, its solubility, solution pH, partition coefficient, or other physicochemical properties.
  • Changing the pharmacokinetics and/or the biodistribution of the complex in this fashion may result in, for example, better clearance and/or selective uptake in various tissues, such as tumor tissue, or atheromatous plaque.
  • greater solubility of the MTD when placed in a physiologically compatible buffer can be expected to give greater serum concentration that can be obtained in vivo.
  • This is useful, for example, in delivering the MTD directly to the area of plaque by intra-arterial injection, in which case higher uptake can be achieved.
  • higher solubility leads to lower aggregation effects, which provides lower in-vivo toxicity.
  • gluconate or glucoronate apical ligands render the MTDs very soluble, and are consequently useful for indications that call for higher plasma concentrations of the MTD.
  • the higher solubility of such compounds provides greater potential for tumor uptake of the compounds of the invention.
  • cholate or deoxycholate ligands decrease the compound's solubility and impart hydrophobicity.
  • Hydrophobic compounds when enclosed in a lipid vacuole, are useful for alternative delivery routes such as oral and topical administration.
  • amphiphilic apical ligands such as PEG acids, the MTDs of the invention can be made soluble in a wide variety of solvents.
  • apical ligands of a metallotexaphyrin can be exchanged for a wide range of different apical ligands, including mono or polyanionic ligands, such as carboxylates of sugar derivatives and cholesterol derivatives, PEG acids, organic acids, organosulfates, organophosphates, or phosphates or other inorganic ligands.
  • mono or polyanionic ligands such as carboxylates of sugar derivatives and cholesterol derivatives, PEG acids, organic acids, organosulfates, organophosphates, or phosphates or other inorganic ligands.
  • metallomacrocycles other than metallotexaphyrins can be modified in the same manner as summarized above. That is, metallomacrocycle derivatives can be prepared from metallomacrocycles in a manner similar to those disclosed herein.
  • macrocycles from which metallomacrocyclee derivative can be made are porphyrins, porphyrin isomers, po hyrin-like macrocycles, benzoporphyrins , alaskaphyrins, sapphyrins, rubyrins, porphycenes, chlorins, benzochlorins, and purpurins.
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain preferably having from 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms, and even more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, n-decyl, tetradecyl, and the like.
  • substituted alkyl refers to 1) an alkyl group as defined above, having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino
  • One preferred alkyl substituent is hydroxy, exemplified by hydroxyalkyl groups, such as 2-hydroxyethyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, and the like; dihydroxyalkyl groups (glycols), such as 2,3-dihydroxypropyl, 3,4-dihydroxybutyl, 2,4- dihydroxybutyl, and the like; and those compounds known as polyethylene glycols, polypropylene glycols and polybutylene glycols, and the like.
  • hydroxyalkyl groups such as 2-hydroxyethyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, and the like
  • dihydroxyalkyl groups such as 2,3-dihydroxypropyl, 3,4-dihydroxybutyl, 2,4- dihydroxybutyl, and the like
  • polyethylene glycols polypropylene glycols and polybutylene glycols, and the like.
  • alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-6 carbon atoms. This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and - CH(CH 3 )CH 2 -) and the like.
  • substituted alkylene refers to:
  • an alkylene group as defined above having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, thioaryloxy, heteroaryl, heteroaryloxy, thioheteroaryloxy, heterocyclic, heterocyclooxy, thioheterocyclooxy, nitro, and -NR a R b , wherein R a and R b may be the same or different and are chosen from hydrogen, optionally substituted alkyl,
  • substituted alkylene groups include those where two substituents on the alkylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group; or
  • an alkylene group as defined above that is interrupted by 1-20 atoms independently chosen from oxygen, sulfur and NR a -, where R a is chosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic, or groups selected from carbonyl, carboxyester, carboxyamide and sulfonyl; or (3) an alkylene group as defined above that has both from 1 to 5 substituents as defined above and is also interrupted by 1-20 atoms as defined above.
  • substituted alkylenes are chloromethylene (-CH(Cl)-), aminoethylene (-CH(NH 2 )CH 2 -), methylaminoethylene ((-CH(NHMe)CH 2 -), 2-carboxypropylene isomers (-CH 2 CH(CO 2 H)CH 2 -), ethoxyethyl (-CH 2 CH 2 O-CH 2 CH 2 -), ethylmethylaminoethyl (-CH 2 CH 2 N(CH 3 )CH 2 CH 2 -), 1 -ethoxy-2-(2-ethoxy-ethoxy)ethane (-CH 2 CH 2 O-CH 2 CH 2 -OCH 2 CH 2 - OCH 2 CH 2 -), and the like.
  • alkaryl refers to the groups -optionally substituted alkylene-optionally substituted aryl, where alkylene, substituted alkylene, aryl and substituted aryl are defined herein. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.
  • alkoxy refers to the groups alkyl-O-, alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O-, where alkyl, alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.
  • Preferred alkoxy groups are alkyl-O- and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
  • substituted alkoxy refers to the groups substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O- where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein.
  • One preferred substituted alkoxy group is substituted alkyl-O, and includes groups such as -OCH 2 CH 2 OCH 3 , PEG groups such as -O(CH 2 CH 2 O) x CH 3 , where x is an integer of 2-20, preferably 2-10, and more preferably 2-5.
  • Another preferred substituted alkoxy group is -O-CH 2 -(CH 2 ) y -OH, where y is an integer of 1-10, preferably 1-4.
  • alkylalkoxy refers to the groups -alkylene-O-alkyl, alkylene-O- substituted alkyl, substituted alkylene-O-alkyl and substituted alkylene-O-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.
  • Preferred alkylalkoxy groups are alkylene-O-alkyl and include, by way of example, methylenemethoxy (-CH 2 OCH 3 ), ethylenemethoxy (-CH 2 CH 2 OCH 3 ), n- propylene-iso-propoxy (-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 ), methylene-t-butoxy (-CH 2 -O-C(CH 3 ) 3 ) and the like.
  • alkylthioalkoxy refers to the group -alkylene-S-alkyl, alkylene-S- substituted alkyl, substituted alkylene-S-alkyl and substituted alkylene-S-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.
  • Preferred alkylthioalkoxy groups are alkylene-S-alkyl and include, by way of example, methylenethiomethoxy (-CH 2 SCH 3 ), ethylenethiomethoxy (-CH 2 CH 2 SCH 3 ), n-propylene-iso-thiopropoxy (-CH 2 CH 2 CH 2 SCH(CH 3 ) 2 ), methylene-t-thiobutoxy (-CH 2 SC(CH 3 ) 3 ) and the like.
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of vinyl unsaturation.
  • substituted alkenyl refers to an alkenyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino
  • alkenylene refers to a diradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of vinyl unsaturation.
  • substituted alkenylene refers to an alkenylene group as defined above having from 1 to 5 substituents, and preferably from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamin
  • substituted alkenylene groups include those where 2 substituents on the alkenylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkenylene group.
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation.
  • Preferred alkynyl groups include ethynyl, (- C ⁇ CH), propargyl (or propynyl, -C ⁇ CCH 3 ), and the like.
  • substituted alkynyl refers to an alkynyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxya
  • alkynylene refers to a diradical of an unsaturated hydrocarbon preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation.
  • Preferred alkynylene groups include ethynylene (-C ⁇ C-), propargylene (-CH 2 -C ⁇ C-) and the like.
  • substituted alkynylene refers to an alkynylene group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxya
  • acyl refers to the groups HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)- and heterocyclic-C(O)- where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • acylamino or “aminocarbonyl” refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic or where both R groups are joined to form a heterocyclic group (e.g., morpholino) wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • aminoacyl refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • aminoacyloxy or “alkoxycarbonylamino” refers to the group -NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • acyloxy refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclic-C(O)O- wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
  • aryl refers to an unsaturated aromatic carbocyclic group of from 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.
  • such aryl groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryl
  • aryloxy refers to the group aryl-O- wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.
  • arylene refers to the diradical derived from aryl (including substituted aryl) as defined above and is exemplified by 1,2-phenylene, 1,3-phenylene, 1,4- phenylene, 1,2-naphthylene and the like.
  • amino refers to the group -NH 2 .
  • substituted amino refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic provided that both R's are not hydrogen.
  • carboxyalkyl or “alkoxycarbonyl” refers to the groups
  • cycloalkyl refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.l
  • substituted cycloalkyl refers to cycloalkyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino
  • cycloalkylene refers to the diradical derived from cycloalkyl as defined above and is exemplified by 1,1-cyclopropylene, 1,2-cyclobutylene, 1,4- cyclohexylene and the like.
  • substituted cycloalkylene refers to the diradical derived from substituted cycloalkyl as defined above.
  • cycloalkenyl refers to cyclic alkenyl groups of from 4 to 20 carbon atoms having a single cyclic ring and at least one point of internal unsaturation.
  • suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.
  • cycloalkenylene refers to the diradical derived from cycloalkenyl as defined above and is exemplified by 1,2-cyclobut-l-enylene, l,4-cyclohex-2-enylene and the like.
  • substituted cycloalkenyl refers to cycloalkenyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxya
  • substituted cycloalkenylene refers to the diradical derived from substituted cycloalkenyl as defined above.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • heteroaryl refers to an aromatic group comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring.
  • heteroaryl groups can be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy
  • Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
  • Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl).
  • Preferred heteroaryls include pyridyl, pyrrolyl and furyl.
  • heteroaryloxy refers to the group heteroaryl-O-.
  • heteroarylene refers to the diradical group derived from heteroaryl (including substituted heteroaryl), as defined above, and is exemplified by the groups 2,6- pyridylene, 2,4-pyridiylene, 1,2-quinolinylene, 1,8-quinolinylene, 1,4-benzofuranylene, 2,5-pyridnylene, 2,5-indolenyl and the like.
  • heterocycle or “heterocyclic” refers to a monoradical saturated or unsaturated group having a single ring or multiple condensed rings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring.
  • heterocyclic groups can be optionally substituted with 1 to 5, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro
  • nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenantlrroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tefrahydrofuranyl, and the like as well as N-alkoxy-
  • heterocyclooxy refers to the group heterocyclic-O-.
  • thioheterocyclooxy refers to the group heterocyclic-S-.
  • heterocyclene refers to the diradical group formed from a heterocycle, as defined herein, and is exemplified by the groups 2,6-morpholino, 2,5-morpholino and the like.
  • oxyacylamino or “aminocarbonyloxy” refers to the group -OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • spiro-attached cycloalkyl group refers to a cycloalkyl group attached to another ring via one carbon atom common to both rings.
  • thiol refers to the group -SH.
  • thioalkoxy refers to the group -S-alkyl.
  • substituted thioalkoxy refers to the group -S-substituted alkyl.
  • thioaryloxy refers to the group aryl-S- wherein the aryl group is as defined above including optionally substituted aryl groups also defined above.
  • heteroaryloxy refers to the group heteroaryl-S- wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.
  • carboxyamides include primary carboxyamides (CONHj), secondary carboxyamides (CONHR') and tertiary carboxyamides (CONR'R”), where R' and R" are the same or different substituent groups chosen from alkyl, alkenyl, alkynyl, alkoxy, aryl, a heterocyclic group, a functional group as defined herein, and the like, which themselves may be substituted or unsubstituted.
  • Carboxyamidealkyl means a carboxyamide as defined above attached to an optionally substituted alkylene group as defined above.
  • saccharide includes oxidized, reduced or substituted saccharides, including hexoses such as D-glucose, D-mannose or D-galactose; pentoses such as D- ribose or D-arabinose; ketoses such as D-ribulose or D-fructose; disaccharides such as sucrose, lactose, or maltose; derivatives such as acetals, amines, and phosphorylated sugars; oligosaccharides; as well as open chain forms of sugars, and the like.
  • amine-derivatized sugars are galactosamine, glucosamine, and sialic acid.
  • site-directing molecule refers to a molecule having an affinity for a biological receptor or for a nucleic acid sequence.
  • site-directing molecules useful herein include, but are not limited to, polydeoxyribonucleotides, oligodeoxyribonucleotides, polyribonucleotide analogs, oligoribonucleotide analogs, polyamides including peptides having affinity for a biological receptor and proteins such as antibodies, steroids and steroid derivatives, hormones such as estradiol or histamine, hormone mimics such as morphine, and further macrocycles such as sapphyrins and rubyrins.
  • the oligonucleotides may be derivatized at the bases, the sugars, the ends of the chains, or at the phosphate groups of the backbone to promote in vivo stability. Modifications of the phosphate groups are preferred in one embodiment since phosphate linkages are sensitive to nuclease activity. Presently preferred derivatives are the methylphosphonates, phosphotriesters, phosphorothioates, and phosphoramidates.
  • phosphate linkages may be completely substituted with non-phosphate linkages such as amide linkages. Appendages to the ends of the oligonucleotide chains also provide exonuclease resistance.
  • Sugar modifications may include groups, such as halo, alkyl, alkenyl or alkoxy groups, attached to an oxygen of a ribose moiety in a ribonucleotide. In a preferred embodiment, the group will be attached to the 2' oxygen of the ribose. In particular, halogen moieties such as fluoro may be used.
  • the alkoxy group may be methoxy, ethoxy or propoxy.
  • the alkenyl group is preferably allyl.
  • the alkyl group is preferably a methyl group and the methyl group is attached to the 2' oxygen of the ribose.
  • Other alkyl groups may be ethyl or propyl.
  • texaphyrin- oligonucleotide conjugate means that an oligonucleotide is attached to the texaphyrin in a 5' or a 3' linkage, or in both types of linkages to allow the texaphyrin to be an internal residue in the conjugate. It can also refer to a texaphyrin that is linked to an internal base of the oligonucleotide.
  • the oligonucleotide or other site-directing molecule may be attached either directly to the texaphyrin or to the texaphyrin via a linker or a couple of variable length.
  • catalytic group means a chemical functional group that assists catalysis by acting as a general acid, Br ⁇ nsted acid, general base, Br ⁇ nsted base, nucleophile, or any other means by which the activation barrier to reaction is lowered.
  • exemplary catalytic groups contemplated include, but are not limited to, imidazole; guanidine; substituted saccharides such as D-glucosamine, D-mannosamine, D- galactosamine, D-glucamine and the like; amino acids such as L-histidine and L-arginine; derivatives of amino acids such as histamine; polymers of amino acids such as poly-L- lysine, (LysAla), (LysLeuAla) n where n is from 1-30 or preferably 1-10 or more preferably 2-7 and the like; derivatives thereof; and metallotexaphyrin complexes.
  • a "chemotherapeutic agent” may be, but is not limited to, one of the following: an alkylating agent such as a nitrogen mustard, an ethyleneimine or a methylmelamine, an alkyl sulfonate, a nitrosourea, or a triazene; an antimetabolite such as a folic acid analog, a pyrimidine analog, or a purine analog; a natural product such as a vinca alkaloid, an epipodophyllotoxin, an antibiotic, an enzyme, taxane, or a biological response modifier; miscellaneous agents such as a platinum coordination complex, an anthracenedione, an anthracycline, a substituted urea, a methyl hydrazine derivative, or an adrenocortical suppressant; or a hormone or an antagonist such as an adrenocorticosteroid, a progestin, an estrogen, an antiestrogen, an androgen, an antiandrog
  • Chemotherapeutic agents are used in the treatment of cancer and other neoplastic tissue.
  • the chemotherapeutic agent is a nitrogen mustard, an epipodophyllotoxin, an antibiotic, or a platinum coordination complex.
  • a more preferred chemotherapeutic agent is bleomycin, doxorubicin, taxol, taxotere, etoposide, 4-OH cyclophosphamide, cisplatin, or platinum coordination complexes analogous to cisplatin.
  • a presently preferred chemotherapeutic agent is doxorubicm, taxol, taxotere, cisplatin, or Pt complexes analogous to cisplatin.
  • chemotherapeutic agents their target diseases, and treatment protocols are presented in, for example, Goodman and Gilman's The Pharmacological Basis of Therapeutics, Ninth Ed., Pergamon Press, Inc., 1990; and Remington: The Science and Practice of Pharmacy, Mack Publishing Co., Easton, PA, 1995; both of which are incorporated by reference herein.
  • a site directing molecule, or a group having or catalytic or chemotherapeutic activity, identified above by the symbol Y, may be covalently coupled to any position on a metallotexaphyrin by a covalent bond or by a linker (identified above by the symbol X).
  • linker as used herein means a group that covalently connects Y to a metallotexaphyrin, and may be, for example, alkylene, alkenylene, alkynylene, arylene, ethers, PEG moieties, and the like, all of which may be optionally substituted.
  • reactions to form a covalent link include reaction between an amine (on either the molecule Y or X) with a carboxylic acid (on the corresponding X or Y) to form an amide link. Similar reactions well known in the art are described in standard organic chemistry texts such as J. March, “Advanced Organic Chemistry", 4 th Edition, (Wiley-Interscience (New York), 1992.
  • macrocycle refers to a class of polypyrrole macrocycles that are capable of forming stable complexes with metals by incorporating a metal (as its cation) within a central binding cavity (core) of the macrocycle, and the anions associated with the metal cation are found above and below the core; these anions are known as apical ligands.
  • This class of macrocycles includes porphyrins, the so-called “expanded porphyrins”, and similar structures.
  • porphyrins examples are porphyrins, porphyrin isomers, porphyrin-like macrocycles, benzophyrins, texaphyrins, alaskaphyrins, sapphyrins, rubyrins, porphycenes, chlorins, benzochlorins, and purpurins.
  • apical ligand refers to an anion that binds to the core metal of the MTD with de-localized electrostatic bonds.
  • the number of apical ligands (n) is defined as an integer of 1-5. It should be noted that the apical ligands act to neutralize the charge on the metallotexaphyrin. Thus, typically n is 1 when M is a divalent cation, and n is 2 when M is a trivalent cation (because the core itself neutralizes one unit charge).
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R", and R 12 is capable of forming an acid addition salt, for example a carboxylate or a phosphate, then n will decrease appropriately.
  • the apical ligands could have two functionalities capable of forming an anion, for example a dicarboxylic acid, and such ligands are intended to be within the scope of the invention.
  • any molecule containing a carboxylic acid or phosphate may be used as an apical ligand, for example biomolecules, including lipoproteins, estradiol and amino acids, carboxylates of sugar derivatives, such as gluconic acid or glucoronic acid, cholesterol derivatives such as cholic acid and deoxycholic acid, PEG acids, organophosphates, such as methylphosphonic acid and phenylphosphonic acid, and phosphoric acid or other inorganic acids, and the like, or sulfonic acid derivatives such as methanesulfo ic acid, ethanesulfonic acid, or "carboxylic acid derivatives", which term refers to compounds of the formula R-CO 2 H, in which R is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted aryl, as defined above.
  • gluconic and glucuronic acid and those carboxylic acid derivatives where R is optionally substituted alkyl, for example acids of 1-20 carbon atoms, such as formic acid, acetic acid, propio ic acid, butyric acid, pentanoic acid, 3,6,9- trioxodecanoic acid, 3,6-dioxoheptanoic acid, methylvaleric acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, and the like.
  • acids of 1-20 carbon atoms such as formic acid, acetic acid, propio ic acid, butyric acid, pentanoic acid, 3,6,9- trioxodecanoic acid, 3,6-dioxoheptanoic acid, methylvaleric acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, mal
  • R is aryl, in particular where R is optionally substituted phenyl, for example benzoic acid, salicylic acid, 3-fluorobenzoic acid, 4-aminobenzoic acid, cinnamic acid, mandelic acid, p-toluene-sulfonic acid, 2-[4-[2-[(3,5-dimethylphenyl)amino]-2- oxoethyl]phenoxy]-2-methyl-propanoic acid, and the like.
  • R is aryl, in particular where R is optionally substituted phenyl, for example benzoic acid, salicylic acid, 3-fluorobenzoic acid, 4-aminobenzoic acid, cinnamic acid, mandelic acid, p-toluene-sulfonic acid, 2-[4-[2-[(3,5-dimethylphenyl)amino]-2- oxoethyl]phenoxy]-2-methyl-propanoic acid, and the
  • any of the above groups that contain one or more substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
  • the compounds of this invention include all stereochemical isomers arising from the substitution of these compounds.
  • compound of Formula I is intended to encompass the metallotexaphyrins of the invention as disclosed, coordination complexes of the compounds of Formula I, and/or the pharmaceutically acceptable salts of such compounds.
  • therapeutically effective amount refers to that amount of an MTD of Formula I that is sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment.
  • the therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will provide an image for detection by any one of the imaging methods described herein. The specific dose will vary depending on the particular compound of Formula I chosen, the dosing regimen to be followed, timing of administration, the tissue to be imaged, and the physical delivery system in which it is carried.
  • Texaphyrin means an aromatic pentadentate macrocyclic expanded porphyrins, also described as an aromatic benzannulene containing both 18 ⁇ - and 22 ⁇ -electron delocalization pathways. Texaphyrins and water-soluble texaphyrins, method of preparation and various uses have been described in U.S. Patents Nos.
  • Texaphyrins are illustrated as a compound of Formula I above. Two positions on the compound of Formula I are designated as R 1 , and two positions are designated as R 4 . This is because, in general, the disclosed methods of synthesis of texaphyrins leads to the same substituent at R 1 , and the same substituents at R 4 . However, it should be noted that methods of synthesis of texaphyrins in which these positions are the same or different are described in U.S. Patent Application Serial No. 60/229,247, filed on August 30, 2000, the complete disclosure of which is hereby incorporated by reference in its entirety.
  • Water soluble means soluble in an aqueous medium to about 1 mM or more.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • treatment means any treatment of a disease in a mammal, including:
  • pharmaceutically acceptable salt refers to salts which retain the biological effectiveness and properties of the MTDs of this invention and which are not biologically or otherwise undesirable.
  • the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkeny
  • amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group.
  • suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, argi ine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N- alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N- ethylpiperidine, and the like.
  • Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids include acetic acid, propionic acid, gly colic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
  • Formula IA This compound can be named in a variety of ways (e.g. depending on the origination of the numbering). Examples of alternative names for this compound are: The lutetium (III) complex of: 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxy propyl)- 16, 17-bis[2-[2-(2 methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1 3 ' 6 .
  • solvent inert under the conditions of the reaction being described in conjunction therewith [including, for example, benzene, toluene, acetonitrile, tefrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like].
  • solvents used in the reactions of the present invention are inert organic solvents.
  • q.s means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).
  • the reactions described herein take place at atmospheric pressure within a temperature range from 5° C to 100° C (preferably from 10°C to 50° C; most preferably at about "room” or “ambient” temperature, e.g., about
  • reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about 5°C to about 100°C (preferably from about 10°C to about 50°C; most preferably about 20°C) over a period of about 1 to about 10 hours (preferably about 5 hours). Parameters given in the Examples are intended to be specific, not approximate.
  • Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure, such as crystallization, distillation, filtration, extraction, column chromatography, solvent evaporation under reduced pressure; thin layer chromatography, thick layer chromatography, preparative low or high pressure liquid chromatography, or a combination of these procedures.
  • suitable separation and isolation procedures can be had by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can, of course, also be used.
  • a texaphyrin with the desired apical ligand(s) (a compound of Formula I) is obtained by an exchange reaction between a metallotexaphyrin having displaceable apical ligands, preferably acetate, and an appropriately charged ion exchange resin.
  • a metallotexaphyrin having displaceable apical ligands preferably acetate
  • an appropriately charged ion exchange resin e.g., a metallotexaphyrin having displaceable apical ligands, preferably acetate
  • AL a metallotexaphyrin having displaceable apical ligands
  • a ion exchange resin complex thus obtained is reacted with the starting metallotexaphyrin having displaceable apical ligands.
  • the product is separated and purified conventionally.
  • Formula I utilizing an in-situ exchange of apical ligands.
  • T is the texaphyrin illustrated as the compound of Formula IA
  • AL represents the desired apical ligand that replaces (AL,)
  • n is an integer of 1-5.
  • Reaction Scheme 3 shows the preparation of a mixture of compounds of Formula .
  • T-M Reaction Scheme 3
  • This reaction can be carried out as in Reaction Scheme I (using an ion exchange resin), or as shown in Reaction Scheme 2 (using a large excess of a mixture of the apical ligands).
  • the reaction can be carried out in a biphasic mixture, for example in a methylene chloride/water mixture.
  • An alternative method of preparing the compounds of the invention is to first prepare a metal-apical ligand M(Al) n , where M, Al, and n are as defined above, and then reacting this metal complex with a texaphyrin, and an oxidizing agent, for example oxygen, to give a metallated texaphyrin of Formula I.
  • the anion exchange resin is commercially available, e.g., from Rohm and Haas.
  • the desired apical ligands, such as gluconic acid, are likewise commercially available or may be readily prepared by those skilled in the art using commonly employed synthetic methodology.
  • Preferred Compounds Preferred are the compounds of Formula I in which M is a divalent or trivalent metal, R 1 is hydroxyalkyl (in which alkyl preferably has 1-10 carbon atoms), R 2 , R 3 and R 4 are alkyl (preferably of 1-6 carbon atoms), R 7 and R 8 are substituted alkoxy (in which alkoxy preferably has 1-20 carbon atoms), and n is 1-4.
  • R 5 , R 6 , R 9 , R 10 , R 11 and R 12 are hydrogen or alkyl of 1-6 carbon atoms.
  • R 1 is 2-hyrdoxy ethyl or 3-hydroxypropyl
  • R 2 , R 3 and R 4 are methyl or ethyl
  • R 7 and R 8 are 2-[2-(2-methoxyethoxy)ethoxy]ethoxy]
  • n is 2.
  • R 5 , R 6 , R 9 , R 10 , R" and R 12 are preferably hydrogen or methyl.
  • Most preferred are the following compounds:
  • MTDs of the present invention can be prepared according to the following last steps:
  • the MTDs of the present invention are effective in the treatment of conditions known to respond to metallotexaphyrin therapy, including diseases characterized by neoplastic tissue, (e.g. the cancers sarcoma, lymphoma, leukemia, carcinoma, brain metastases, glioma, glioblastoma, cancer of the prostate, melanoma, and the like), cardiovascular diseases (e.g., atherosclerosis, intimal hyperplasia and restenosis) and other activated macrophage-related disorders including autoimmune diseases (e.g., rheumatoid arthritis, Sjogrens, scleroderma, systemic lupus erythematosus, non-specific vasculitis, Kawasaki's disease, psoriasis, Type I diabetes, pemphigus vulgaris, multiple sclerosis), granulomatous diseases (e.g., tuberculosis, sarcoidosis, lymphomatoid granulomato
  • MTDs of Formula I have been shown to have various in vitro and in vivo activity. See e.g. Young et al., Methods for Cancer Chemosensitization, and U.S. Patent No. 5,776,925. Determination of the various physicochemical characteristics of each MTD can be performed, and are apparent to one skilled in the art and are detailed in, for example, Pharmaceutical Dosage Forms: Parenteral Medications vol. 1, Marcel Dekker Inc., New York, NY, 2 nd Edition, 1992. The generally accepted tests performed to determine the MTD's characteristics include, for example: determination of solubility, the partition coefficient, the extinction coefficient, and the solution pH of the MTD.
  • the MTDs of Formula I are usually administered in the form of pharmaceutical compositions.
  • This invention therefore provides pharmaceutical compositions that contain, as the active ingredient, one or more of the MTDs of Formula I, or a pharmaceutically acceptable salt AND/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • the MTDs may be administered alone or in combination with other therapeutic agents.
  • Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17 th Ed. (1985) and "Modern Pharmaceutics", Marcel Dekker, Inc. 3 rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).
  • the MTDs of Formula I may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference above, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer, with parenteral and intra-arterial administration being preferred, and intra-arterial being more preferred.
  • compositions of the present invention are incorporated for administration by injection.
  • forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
  • Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context of the present invention.
  • Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • texaphyrins have a tendency to aggregate in aqueous solution, which potentially decreases their solubility.
  • Aggregation (self-association) of polypyrrolic macrocyclic compounds, including porphyrins, sapphyrins, texaphyrins, and the like, is a common phenomenon in water solution as the result of strong intermolecular van der Waals attractions between these flat aromatic systems. Aggregation may significantly alter the photochemical characteristics of the macrocycles in solution, which is shown by large spectral changes, decrease in extinction coefficient, etc.
  • a carbohydrate, saccharide, polysaccharide, or polyuronide decreases the tendency of the texaphyrin to aggregate, thus increasing the solubility of the texaphyrin in aqueous media.
  • Preferred anti-aggregation agents are sugars, in particular mannitol, dextrose or glucose, preferably mannitol of about 2-8% concentration, more preferably about 5% concentration.
  • These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media that can be employed will be known to those of skill in the art in light of the present disclosure.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • agents delaying absorption for example, aluminum monostearate and gelatin.
  • These particular aqueous solutions are especially suitable for intra-arterial, intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • sterile aqueous media that can be employed will be known to those skilled in the art in light of the present disclosure.
  • Sterile injectable solutions are prepared by incorporating the active MTDs in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • MTDs of Formula I may be impregnated into a stent by diffusion, for example, or coated onto the stent such as in a gel form, for example, using procedures known to one of skill in the art in light of the present disclosure.
  • Oral administration is another route for administration of the MTDs of this invention.
  • Preferred is oral administration via capsule or enteric coated tablets, or the like, which prevent degradation of the MTDs of the invention in the stomach.
  • the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, in can be a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902514; and 5,616,345.
  • Another preferred formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such fransdermal patches may be used to provide continuous or discontinuous infusion of the MTDs of the present invention in controlled amounts.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • compositions are preferably formulated in a unit dosage form.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule).
  • the active MTD is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount.
  • each dosage unit contains from 10 mg to 2 g of an MTD of Formula I, and for parenteral administration, preferably from 10 to 700 mg of an MTD of Formula I, preferably about 350 mg.
  • the amount of the MTD actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of an MTD of the present invention.
  • a pharmaceutical excipient for preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of an MTD of the present invention.
  • these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • the MTDs disclosed herein can be used both diagnostically (e.g. magnetic resonance or fluorescence imaging to detect the presence of a disease) and therapeutically (to treat that disease).
  • Activation Means e.g. magnetic resonance or fluorescence imaging to detect the presence of
  • the compounds of the invention to be used will be administered in a therapeutically effective amount, employing a method of administration and a pharmaceutical formulation as discussed above, and optionally a means of activation of the compound (through a therapeutic energy or agent) as is known in the art.
  • the therapeutic energy or agent to be used includes photodynamic therapy, radiation sensitization, chemotherapy, sonodynamic therapy, and neutron bombardment.
  • the specific dose will vary depending on the particular compound of Formula I chosen, the dosing regimen to be followed, and the particular therapeutic energy or agent with which it is administered. Such dose can be determined by methods known in the art or as described herein.
  • Dosages The specific dose will vary depending on the particular compound of Formula I chosen, the dosing regimen to be followed, and the particular therapeutic energy or agent with which it is administered, employing dosages within the range of about 0.01 mg/kg/treatment up to about 100 mg/kg/treatment, preferably about 0.1 mg/kg/treatment to about 50 mg/kg/treatment. It will be appreciated by one skilled in the art, however, that there are specific differences in the most effective dosimetry depending on the apical ligands chosen, because of the wide range of properties available, such as solubilities, lipophilicity properties, lower toxicity, and improved stability.
  • Administration for Photodynamic Therapy :
  • lutetium texaphyrin may be administered in solution, optionally in 5% mannitol USP. Dosages of about 1.0 - 2.0 mg/kg to about 4.0 - 7.0 mg/kg, preferably 3.0 mg kg, are employed, although in some cases a maximum tolerated dose may be higher, for example about 5 mg/kg.
  • the texaphyrin is administered by intravenous injection, followed by a waiting period of from as short a time as several minutes or about 3 hours to as long as about 72 or 96 hours (depending on the treatment being effected) to facilitate mtracellular uptake and clearance from the plasma and extracellular matrix prior to the administration of photoirradiation.
  • Dose levels for certain uses may range from about 0.05 mgl/kg to about 20 mg/kg administered in single or multiple doses (e.g. before each fraction of radiation).
  • the lower dosage range would be preferred for intra-arterial injection or for impregnated stents.
  • a sedative e.g., benzodiazapenes
  • narcotics/analgesics are sometimes recommended prior to light treatment along with topical administration of a local anesthetic, for example Emla cream (lidocaine, 2.5% and prilocaine, 2.5%) under an occlusive dressing.
  • a local anesthetic for example Emla cream (lidocaine, 2.5% and prilocaine, 2.5%) under an occlusive dressing.
  • Other intradermal, subcutaneous and topical anesthetics may also be employed as necessary to reduce discomfort.
  • Subsequent treatments can be provided after approximately 21 days.
  • the optimum length of time following administration of an MTD of Formula I until light treatment can vary depending on the mode of administration, the form of administration, and the type of target tissue.
  • the MTD of Formula I persists for a period of minutes to hours, depending on the compound of Formula I, the formulation, the dose, the infusion rate, as well as the type of tissue and tissue size.
  • a target area is treated with light at about 732 ⁇ 16.5 nm (full width at half max) delivered by an LED device or an equivalent light source (e.g., a Quantum Device QbeamTM Q BMEDXM-728 Solid State Lighting System, which operates at 728 nm) at an intensity of 5-150 mW/cm 2 for a total light dose of 0.5- 600 J/cm 2 , or a solid state diode laser, such as the DioMed 6WW, 15W laser).
  • an LED device or an equivalent light source e.g., a Quantum Device QbeamTM Q BMEDXM-728 Solid State Lighting System, which operates at 728 nm
  • the tissue being treated is photoirradiated at a wavelength similar to the absorbance of the compound of Formula I, usually either about 400-500 nm or about 700-800 nm, more preferably about 450-500 nm or about 710-760 nm, or most preferably about 450-500 nm or about 725-740 nm.
  • the light source may be a laser, a light-emitting diode, or filtered light from, for example, a xenon lamp; and the light may be administered topically, endoscopically, or interstitially (via, e.g., a fiber optic probe), or intraarterially.
  • the light is administered using a slit-lamp delivery system.
  • the fluence and irradiance during the photoirradiating treatment can vary depending on type of tissue, depth of target tissue, and the amount of overlying fluid or blood.
  • a total light energy of about 100 J/cm 2 can be delivered at a power of 200 mW to 250 mW, depending upon the target tissue.
  • MTDs of Formula I may be administered before, at the same time, or after administration of one or more chemotherapeutic drugs.
  • the MTD of Formula I may be administered as a single dose, or it may be administered as two or more doses separated by an interval of time.
  • the MTD of Formula I may be administered concurrently with, or from about one minute to about 12 hours following, administration of a chemotherapeutic drug, preferably from about 5 min to about 5 hr, more preferably about 4 to 5 hr.
  • the dosing protocol may be repeated, from one to three times, for example.
  • a time frame that has been successful in vivo is administration of an MTD of Formula I about 5 min and about 5 hr after administration of a chemotherapeutic agent, with the protocol being performed once per week for three weeks.
  • Administration may be intra-arterial injection, intravenous, intraperitoneal, intramuscular, subcutaneous, oral, topical, or via a device such as a stent, for example, with parenteral and intra-arterial administration being preferred, and intra-arterial being more preferred.
  • Administering an MTD of Formula I and a chemotherapeutic drug to the subject may be prior to, concurrent with, or following vascular intervention.
  • the method may begin at a time roughly accompanying a vascular intervention, such as an angioplastic procedure, for example. Multiple or single treatments prior to, at the time of, or subsequent to the procedure may be used. "Roughly accompanying a vascular intervention” refers to a time period within the ambit of the effects of the vascular intervention.
  • an initial dose of an MTD of Formula I and chemotherapeutic drug will be within 6-12 hours of the vascular intervention, preferably within 6 hours thereafter.
  • Follow-up dosages may be made at weekly, biweekly, or monthly intervals. Design of particular protocols depends on the individual subject, the condition of the subject, the design of dosage levels, and the judgment of the attending practitioner.
  • Administration for Radiation Sensitization is a time roughly accompanying a vascular intervention, such as an angioplastic procedure, for example. Multiple or single treatments prior to, at the time of,
  • MTDs of Formula I where the metal is gadolinium are typically administered in a solution containing 2 mM optionally in 5% mannitol USP/water (sterile and non- pyrogenic solution). Dosages of 0.1 mg/kg up to as high as about 29.0 mg/kg have been delivered, preferably about 3.0 to about 15.0 mg/kg (for volume of about 90 to 450 mL) may be employed, optionally with pre-medication using anti-emetics when dosing above about 6.0 mg/kg.
  • the MTD is administered via intravenous injection over about a 5 to 10 minute period, followed by a waiting period of about 2 to 5 hours to facilitate intracellular uptake and clearance from the plasma and extracellular matrix prior to the administration of radiation.
  • a course of 30 Gy in ten (10) fractions of radiation may be administered over consecutive days excluding weekends and holidays.
  • whole brain megavolt radiation therapy is delivered with 60 Co teletherapy or a >4 MV linear accelerator with isocenter distances of at least 80 cm, using isocentric techniques, opposed lateral fields and exclusion of the eyes.
  • a minimum dose rate at the midplane in the brain on the central axis is about 0.5 Gy/minute.
  • MTDs of Formula I used as radiation sensitizers may be administered before, or at the same time as, or after administration of the ionizing radiation.
  • the MTD of Formula I may be administered as a single dose, as an infusion, or it may be administered as two or more doses separated by an interval of time.
  • the time interval between the MTD of Formula I administrations may be from about one minute to a number of days, preferably from about 5 min to about 1 day, more preferably about 4 to 5 hr.
  • the dosing protocol may be repeated, from one to ten or more times, for example.
  • Dose levels for radiation sensitization may range from about 0.05 mg/kg to about 20 mg/kg administered in single or multiple doses (e.g. before each fraction of radiation).
  • the lower dosage range would be preferred for intra-arterial injection or for impregnated stents.
  • Administration may be intra-arterial injection, intravenous, intraperitoneal, intramuscular, subcutaneous, oral, topical, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer, with intravenous and intra- arterial administration being preferred, and intra-arterial being more preferred.
  • a patient having restenosis or at risk for restenosis is administered a dose of MTD of Formula I at intervals with each dose of radiation.
  • Administering a MTD of Formula I to the subject may be prior to, concurrent with, or following vascular intervention, and the intervention is followed by radiation.
  • the method may begin prior to, such as about 24-48 hours prior to, or at a time roughly accompanying vascular intervention, for example. Multiple or single treatments prior to, at the time of, or subsequent to the procedure may be used. "Roughly accompanying the vascular intervention” refers to a time period within the ambit of the effects of the vascular intervention.
  • an initial dose of MTD of Formula I and radiation will be within 1-24 hours of the vascular intervention, preferably within about 5-24 hours thereafter.
  • Follow-up dosages may be made at weekly, biweekly, or monthly intervals. Design of particular protocols depends on the individual subject, the condition of the subject, the design of dosage levels, and the judgment of the attending practitioner.
  • texaphyrins in sonodynamic therapy is described in U.S. Patent Application Serial No. 09/111,148, which is incorporated herein by reference.
  • Texaphyrin is administered before administration of the ultrasound.
  • the texaphyrin may be administered as a single dose, or it may be administered as two or more doses separated by an interval of time.
  • Parenteral administration is typical, including by intravenous and interarterial injection. Other common routes of administration can also be employed.
  • Ultrasound is generated by a focused array transducer driven by a power amplifier.
  • the transducer can vary in diameter and spherical curvature to allow for variation of the focus of the ultrasonic output.
  • Commercially available therapeutic ultrasound devices may be employed in the practice of the invention.
  • the duration and wave frequency, including the type of wave employed may vary, and the preferred duration of treatment will vary from case to case within the judgment of the treating physician. Both progressive wave mode patterns and standing wave patterns have been successful in producing cavitation of diseased tissue.
  • the second harmonic can advantageously be superimposed onto the fundamental wave.
  • ultrasound of low intensity i.e., ultrasound generated within the wavelengths of about 0.1MHz and 5.0MHz and at intensities between about 3.0 and 5.0 W/cm 2 .
  • Administration for Neutron Capture Therapy i.e., ultrasound generated within the wavelengths of about 0.1MHz and 5.0MHz and at intensities between about 3.0 and 5.0 W/cm 2 .
  • metallotexaphyrins in neutron capture therapy is described in U.S. Patent Application Serial No. 60/229,366, entitled “Agents for Neutron Capture Therapy", filed on August 30, 2000, which is incorporated herein in its entirety by reference.
  • the metallotexaphyrin is administered before administration of the neutron beam. It may be administered as a single dose, or it may be administered as two or more doses separated by an interval of time. Parenteral administration is typical, including by intravenous and interarterial injection. Other common routes of administration can also be employed.
  • MTDs of Formula I and a suitable co-therapeutic agent can also be administered in the context of other medical procedures.
  • allograft transplantation administration may be accomplished by perfusion of the graft prior to implantation.
  • the remaining MTD of Formula I is rinsed from the graft followed by application of the co-therapeutic agent.
  • Administration to selectively treat diseases characterized by circulating macrophages may be accomplished by extracorporeal contact, filtration of non-absorbed MTD of Formula I employing a lipophilic filter, followed by application of the co-therapeutic agent.
  • the following examples are included to demonstrate preferred embodiments of the invention.
  • Ambersep® 900 (OH) anion exchange resin ( ⁇ 100 mL, ⁇ 90 meq) was slurried in 200 mL of deionized water, poured into a Biorad® column and washed with 500 mL of deionized water until the pH of the eluant was approximately 7. The resin was poured out of the column into an Erlenmeyer flask and the excess solvent decanted. 80 g of gluconic acid were dissolved in 200 mL of deionized water. 100 mL of the aqueous solution were added to the flask and stirred for one hour. The resultant mixture was poured onto the Biorad column and the excess solution drained. The remaining 150 mL of gluconic acid solution was then passed through the column followed by 500 mL of water (until the pH ⁇ 4) and methanol (500mL).
  • LuTex diacetate (1.1687g, 1.002mmo ⁇ ) was dissolved in 50 mL of methanol and passed through the Biorad column. The column was washed with 25 mL of methanol. The collected eluant was passed through the column a second time and the column was washed with an additional 100 mL of methanol. The combined solutions from the column were collected and the methanol was evaporated under reduced pressure.
  • EXAMPLE 2 Preparation of metallotexaphyrins via solution phase extraction
  • the metallotexaphyrin complex ( «200 ⁇ mol) is dissolved in 200ml of deionized water. 400-600 mmol of the conjugate base of the apical ligand is added, causing the precipitation of the metallotexaphyrin.
  • Dichloromethane (200 ml) is added, and the biphasic mixture allowed to stir vigorously for several hours. The solutions are allowed to separate and the organic layer collected. The aqueous layer is extracted twice with dichloromethane (50 ml) and the combined organics evaporated under reduced pressure and dried overnight in vacuo.
  • test compound of Formula I between 3mg and 1 lmg
  • solutions and one control sample were diluted to volume.
  • the absorption at 475nm was measured by UV/Vis and recorded for each of the five samples. The extinction coefficient for each sample was determined accordingly.
  • Extinction Coefficient ( ⁇ ) Absorption at 475nmXM.W. of test compound amount of test compound mg/volume: 100ml
  • the extinction coefficient for the test compound at 475nm was determined by averaging the extinction coefficient for the four samples (not including the control). The above steps were repeated (at 733nm) to determine the extinction coefficient for the test compound at 733nm. When determining the extinction coefficient of aggregated test compounds LuTex acetate, cholate or deoxycholate, the extinction coefficient at 733nm is not measured. Instead, the above steps were repeated substituting 4% acetic acid/methanol for methanol. 4B. Solubility in B.O:
  • test compound of Formula I was added to 10 ml of deionized water in increasing mass until some of the test compound was visibly observed not to dissolve. This mixture was then shaken, and 1.5ml of the supernatant removed by a syringe equipped with a 0.22 ⁇ m filter unit. After discarding the first ImL of the filtrate, the remaining 0.5 mL was collected and saved. 0.1ml of the saved filtrate was added to a 25ml flask and diluted with 4% Acetic Acid/Methanol solution to volume. The absorption of the diluted solution at 475nm was measured by UN/Vis at 1, . and 24 hours alter the solutions had been shaken as described above. The concentration of the, compound was determined by the formula: . -;,
  • the sol bility of the test compound is determined by referencing the concentration with the descriptive solubility terra set forth in a table in U.S. Pharmacopeia The National Formulary, United States Pharmacop ⁇ ial Convention, Inc., Rockville, MD., 1997.
  • the partition coefficient was measured using an adaptation of th procedure outlined in Dmg Stability: Principles and Practices (AAI, Inc. Wilmington, North Carolina, 2 nd Edition, 1995).
  • a 10 ml solution of 10 mg/ml of the test compound of Formula I dissolved in deionized water was placed in a separator funnel, to which 10ml of 1 -octanol was added. The combined mixture was stirred. The mixture was left to separate and the absorption of the compound was measured in the water phase and in the octanol phase by UV/Vis at 413-417nm (413-417 offers the closest match in absorbance between the octanol phase and the water phase.
  • the octanol water partition coefficient is determined by the formula:
  • Plasma pK and biodistribution of the different test compounds of Formula I in plaque are determined and compared with the plasma pK and biodistribution in normal arterial walls.
  • Sixteen normal male NZW rabbits, each weighing 3.5-4.0 kg are obtained from R&R Rabbitry in Stanwood Oregon. Each rabbit is given an intramuscular injection of Ketamine/Rompun [(8.4 mg/kg)/(1.2 mg/kg)] and allowed to relax until the anesthetic takes effect. To induce deep anesthesia, the rabbits then receive a second dose of Ketamine/Rompun [(8.4mg/kg)/1.2 mg/kg)] via intravenous injection. To expose the abdomen and back legs, each rabbit is shaved with a size 40 blade. Their eyes are coated with lubricant eye ointment (Artificial Tears).
  • a femoral artery cut down is performed on the right side of the rabbits.
  • Lidocaine (2%) is injected subcutaneously around the femoral artery as a local anesthetic and also applied topically to prevent spasms.
  • a No.4 French Fogarty balloon embolectomy catheter is inserted retrograde 15 cm into the abdominal aorta. The balloon is inflated with 0.5-0.75 ml of hypaque contrast and pulled 3.5cm distally toward the femoral artery six times. The catheter is then withdrawn. The incision line on the underlying muscle is sutured with 3-0 absorbable chromic gut (Ethicon) and the skin is sutured with 2-0 silk (Ethicon). The rabbits are allowed to recover before being placed back into their respective cages and are placed on a 2% cholesterol diet for 6-8 weeks.
  • a 3ml blood sample is taken from each of the rabbits and the cholesterol level for each sample is determined and recorded. Fourteen of the sixteen rabbits are injected with 10 mg/kg of one of the test compounds. One of the remaining rabbits is a pure control and receives neither test compound nor buffer. The other remaining rabbit receives no test compound but does receive 5% mannitol buffer.
  • a 3ml blood sample is drawn from each of the rabbits at 1, 5 and 24 hours post injection. Each 3ml blood sample is handled with minimum exposure to ambient light and spun for 10 minutes in a centrifuge at 2,000rpm within 30 minutes of the blood draw. The supernatant (plasma) is removed by a pipette and put into a 1.8ml cryotube.
  • the plasma is frozen at -70 ⁇ for future analysis (see part B of this example). All of the rabbits are sacrificed 24 hours after injection. At necropsy, the heart and aorta, including the iliac arteries, are harvested in a minimum amount of ambient light. The length of the plaque (cm) in the aorta is measured. The iliac arteries and lower abdominal aortic sections of the above rabbits were subjected to fluorescence spectral bioimaging. Each aorta is excised, cut longitudinally to expose the luminal surface and washed thoroughly with isotonic saline. The luminal surfaces of the iliac arteries and the lower abdominal aorta were compared to the surrounding visually normal aortic surfaces.
  • the aortic samples were illuminated with a Cogent Light illumination system equipped with a coaxial LightWear headlight (Cogent Light Technologies, Inc., Santa Clara, CA) and a 470 nm interference filter (10 nm bandwidth, Oriel Corporation, Stratford, CT). Images were collected with the SD200 spectral bio-imaging system (Applied Spectral Imaging, Carlsbad, CA). A 715 nm long pass filter is utilized (Oriel Corporation, Stratford, CT) with a fluorescence emission range of 650-850 nm being captured. Each signal is averaged over 5 pixels.
  • Cogent Light illumination system equipped with a coaxial LightWear headlight (Cogent Light Technologies, Inc., Santa Clara, CA) and a 470 nm interference filter (10 nm bandwidth, Oriel Corporation, Stratford, CT). Images were collected with the SD200 spectral bio-imaging system (Applied Spectral Imaging, Carlsbad, CA). A 715 nm long pass filter is utilized (Oriel Corporation, Stratford,
  • Each acquired measurement is imaged with a CCD camera coupled to an interferometer, and then the signal Fourier transformed allowing spectral identification at every pixel as described by Garini et al., Spectral Bioimaging, John Wiley and Sons, Inc. New York. 1996; 87-124).
  • the results of the fluorescence signal measurements in plaque vs. normal tissue are plotted.
  • the clearance rate of the test compound is also particularly important to measure.
  • Plasma samples from each of the test compounds are mixed with 10 mM Triton X-100 and the fluorescence optimum is measured at 745nm by scanning between 700-800nm using a 450nm excitation. A standard curve is ran to insure that the fluorescence of the samples lies on the linear portion of the curve. The entire fluorescence emission spectrum is observed by using both a monochromator and CCD array. This permits differentiating between the peak at 745 nm and any possible extraneous fluorescence that might have a different optimum, and tail off into the 745 nm region. Test compound accumulation is expressed as ⁇ g drug/g tissue (wet weight) or ⁇ g/ml in plasma. Results Plasma Concentration in ⁇ g/ml
  • test compounds are compared for efficacy as phototherapeutic agents in cancer.
  • each of the test compounds is used as a photodynamic (PDT) agent using the murine EMT6 sarcoma model.
  • PDT photodynamic
  • the EMT6 tumor cell line, urine mammary sarcoma, (Stanford University, Stanford, CA) is maintained through in vivo/in vitro propagation according to the established procedure of Rockwell and Kallman, found in, "Growth and cell Population Kinetics of Single and Multiple KHT Sarcomas" Cell Tissue Kinetics, 1972, 1, pp.449-457.
  • the EMT6 cells (1 x 10 6 ) are grown in 50 ⁇ l Waymouth's Medium (MB752/1, GIBCO, Grand Island NY), supplemented with 15% fetal bovine serum (GIBCO, Grand Island NY) and penicillin/streptomycin (Sigma, St. Louis, MO).
  • MB752/1, GIBCO, Grand Island NY fetal bovine serum
  • penicillin/streptomycin Sigma, St. Louis, MO.
  • Thirty Two female Balb/c mice weighing 18-22g and between 10 to 12 weeks old, are obtained from Simonsen Laboratories, Gilroy CA. The right flanks of the mice are shaved and depiled the day prior to tumor inoculation.
  • the tumor cells (lxlO 6 in 0.05 ml Waymouth's Medium) are injected subcutaneously into the right flanks of the recipient mice.
  • mice are entered into PDT studies when their tumors reached surface diameters of between 5-7 mm and depths of 3-5 mm. The tumors are measured for 40 days post PDT treatment.
  • Each test compound (10 mg/kg) is administered to eight mice by tail-vein injection, and the tumor is irradiated 5 hours later by localized laser irradiation using a ALGaAs diode laser (Diomed Cambridge, UK) at 732nm.
  • Eight mice used as controls are injected with 10 mg/kg of 5% mannitol but no test compound, and are also irradiated 5 hours post injection by localized laser irradiation at 732nm. During the laser irradiation, each mouse is restrained with laboratory tape.
  • a 400 ⁇ m diameter fiberoptic cable couples the laser to the microlens which produces uniform light intensity in the treatment field.
  • the light fluences are 100 J/cm 2
  • the power density is set to 75mW/cm 2 .
  • Power measurements are made with a power meter (Scientech Boulder, CO).
  • mice When each mouse appears moribund or when the tumor appears to grow to four times the prestudy volume, it is removed from the study. As illustrated in Figure 3, the number of mice remaining in the study (percent survival) is plotted against the number of days after treatment. The mice are euthanized by either carbon dioxide or methane inhalation.
  • test compounds The different test compounds, number of mice treated and treatment regiments are outlined below.
  • Hard gelatin capsules containing the following ingredients are prepared:
  • Quantity Ingredient (mg/capsule ' )
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below
  • the components are blended and compressed to form tablets, each weighing 240 mg.
  • a dry powder inhaler formulation is prepared containing the following components:
  • the active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
  • EXAMPLE 9 Tablets each containing 30 mg of active ingredient, are prepared as follows:
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvmylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50 °C to 60 °C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • Capsules each containing 40 mg of medicament are made as follows:
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • Suspensions each containing 50 mg of active ingredient per 5.0 mL dose are as follows:
  • a subcutaneous formulation may be prepared as follows: Ingredient Quantity
  • Indirect techniques usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drags into lipid-soluble drags.
  • Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drag more lipid soluble and amenable to transportation across the blood-brain barrier.
  • the delivery of hydrophilic drags may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
  • EXAMPLE 14 An injectable preparation is prepared having the following composition: Ingredients Amount
  • EXAMPLE 15 A topical preparation is prepared having the following composition: Ingredients grams Lu Tex bis benzoate 0.2- 10
  • Example 1 can be used as the active compound in the preparation of the topical formulations of this example

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Abstract

La présente invention concerne de nouveaux dérivés de métallotexaphyrines, préparés par modification des ligands apicaux qui sont associés au composant métallique central d'une métallotexaphyrine.
PCT/US2001/026885 2000-08-30 2001-08-28 Nouveaux derives de metallotexaphyrine WO2002017908A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002434744A CA2434744A1 (fr) 2000-08-30 2001-08-28 Nouveaux derives de metallotexaphyrine
AU2001288484A AU2001288484A1 (en) 2000-08-30 2001-08-28 Novel metallotexaphyrin derivatives
EP01968223A EP1408955A4 (fr) 2000-08-30 2001-08-28 Nouveaux derives de metallotexaphyrine

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US22925500P 2000-08-30 2000-08-30
US60/229,255 2000-08-30

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Publication number Priority date Publication date Assignee Title
EP1345606A2 (fr) * 2000-11-17 2003-09-24 Pharmacyclics, Inc. Composes de coordination de texaphyrine et leurs utilisations
EP1408955A1 (fr) * 2000-08-30 2004-04-21 Pharmacyclics, Inc. Nouveaux derives de metallotexaphyrine
US7449454B2 (en) 2000-08-30 2008-11-11 Pharmacyclics, Inc. Metallotexaphyrin derivatives
US8410263B2 (en) 2005-09-26 2013-04-02 Pharmacyclics, Inc. High-purity texaphyrin metal complexes

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US4935498A (en) * 1989-03-06 1990-06-19 Board Of Regents, The University Of Texas System Expanded porphyrins: large porphyrin-like tripyrroledimethine-derived macrocycles
US5457183A (en) * 1989-03-06 1995-10-10 Board Of Regents, The University Of Texas System Hydroxylated texaphyrins
US5567687A (en) * 1989-03-06 1996-10-22 University Of Texas Texaphyrins and uses thereof
US5955586A (en) * 1996-03-22 1999-09-21 Sessler; Jonathan L. Highly boronated derivatives of texaphyrins

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WO2002017908A1 (fr) * 2000-08-30 2002-03-07 Pharmacyclics, Inc. Nouveaux derives de metallotexaphyrine
CA2429411A1 (fr) * 2000-11-17 2002-05-23 Pharmacyclics, Inc. Composes de coordination de texaphyrine et leurs utilisations

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US5457183A (en) * 1989-03-06 1995-10-10 Board Of Regents, The University Of Texas System Hydroxylated texaphyrins
US5567687A (en) * 1989-03-06 1996-10-22 University Of Texas Texaphyrins and uses thereof
US5801229A (en) * 1992-01-21 1998-09-01 The Board Of Regents, University Of Texas System Metal complexes of texaphyrins
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1408955A1 (fr) * 2000-08-30 2004-04-21 Pharmacyclics, Inc. Nouveaux derives de metallotexaphyrine
EP1408955A4 (fr) * 2000-08-30 2006-09-06 Pharmacyclics Inc Nouveaux derives de metallotexaphyrine
US7449454B2 (en) 2000-08-30 2008-11-11 Pharmacyclics, Inc. Metallotexaphyrin derivatives
EP1345606A2 (fr) * 2000-11-17 2003-09-24 Pharmacyclics, Inc. Composes de coordination de texaphyrine et leurs utilisations
EP1345606A4 (fr) * 2000-11-17 2005-02-09 Pharmacyclics Inc Composes de coordination de texaphyrine et leurs utilisations
US8410263B2 (en) 2005-09-26 2013-04-02 Pharmacyclics, Inc. High-purity texaphyrin metal complexes

Also Published As

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EP1408955A1 (fr) 2004-04-21
EP1408955A4 (fr) 2006-09-06
AU2001288484A1 (en) 2002-03-13
CA2434744A1 (fr) 2002-03-07

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