WO2001032211A2 - Compose conjugue pour le traitement d'atheromes, de tumeurs et d'autres tissus neoplasiques - Google Patents

Compose conjugue pour le traitement d'atheromes, de tumeurs et d'autres tissus neoplasiques Download PDF

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Publication number
WO2001032211A2
WO2001032211A2 PCT/US2000/029524 US0029524W WO0132211A2 WO 2001032211 A2 WO2001032211 A2 WO 2001032211A2 US 0029524 W US0029524 W US 0029524W WO 0132211 A2 WO0132211 A2 WO 0132211A2
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compound
group
substituted
tumor
atheroma
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PCT/US2000/029524
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English (en)
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WO2001032211A3 (fr
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Jonathan L. Sessler
Darren Madga
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Pharmacyclics, Inc.
The Board Of Regents Of The University Of Texas System
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Priority to AU12340/01A priority Critical patent/AU1234001A/en
Priority to EP00973891A priority patent/EP1223982A2/fr
Publication of WO2001032211A2 publication Critical patent/WO2001032211A2/fr
Publication of WO2001032211A3 publication Critical patent/WO2001032211A3/fr
Priority to US10/160,205 priority patent/US20030031676A1/en
Priority to HK03100643.8A priority patent/HK1050315A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • 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

Definitions

  • This invention relates to compounds that are useful for treating atheroma, tumors and other neoplastic tissue. More specifically, this invention provides compounds that are conjugates of (a) a moiety capable of localizing in the cells of a tumor or atheroma and (b) a moiety capable of catalyzing the production of one or more reactive oxygen species from a cellular metabolite.
  • the treatment of solid mammalian tumors with ionizing radiation involves the in situ generation of hydroxyl radicals and other reactive oxygen species which, due to the focusability of the ionizing radiation are primarily located in the tumor, i.e., in tumor cells.
  • Tumor treatment via the use of ionizing radiation can be enhanced by increasing the radiosensitivity of the tumor cells.
  • One method suggested for enhancing radiosensitivity has been the external administration of a compound having a high affinity for electrons, which ideally localizes in the tumor.
  • Proposed radiation sensitizers include compounds such as halogenated pyrimidines, nitroimidazoles and gadolinium (III) complexes of the pentadentate O 01/32211 - 3 -
  • Motexafin gadolinium (a gadolinium (III) texaphyrin complex) is currently in Phase III clinical trials for the treatment of brain metastheses. 4
  • Phthalocyanine and naphthalocyanine polydentate ligands of the transition metals cobalt and iron have been described as suppressing the growth of tumor cells when administered in combination with a biogenic reductant such as ascorbic acid. 7
  • Patent Application Serial No. 60/ the disclosure of which is incorporated herein by reference in its entirety, it has now been discovered that the known radiation sensitizer motexafin gadolium acts to catalyze the oxidation of NADH, NADPH, ascorbate and other reducing agents under approximate physiological conditions, to generate reactive oxygen species, such as superoxide and hydrogen peroxide.
  • reactive oxygen species such as superoxide and hydrogen peroxide.
  • Metallotexaphrins are known to localize in atheroma, tumor cells and other neoplastic tissue. The generation of reactive oxygen species in situ facilitates oxidative attack on the tumor or other tissue, leading to targeted oxidative stress and effecting treatment and/or sensitization to radiation where such a reactive oxygen species is generated.
  • texaphyrins with other active agents has been described, for example, with chemosensitizers 9 , and various texaphyrin conjugates have also been described, for example, including: with biomolecules, 9 with chemotherapeutic moieties (e.g., cisplatin) 10 and in texaphyrin-lipophiiic molecule-vessicle complexes 11 .
  • chemotherapeutic moieties e.g., cisplatin
  • texaphyrin-lipophiiic molecule-vessicle complexes 11 WO 01/32211 - 4 - PCT/USOO/29524
  • the above-referenced discovery concerning radiation sensitization has further provided the ability to evaluate the radiation sensitization potential of other known and new compounds, as a function of their ability to catalyze the generation of reactive oxygen species from cellular metabolites under approximate physiologic conditions. While some of the compounds found to have radiation sensitization potential will have the inherent ability to localize in atheroma, tumors or other neoplastic tissues, other such reactive oxygen species catalysts may not be useful for treatment in and of themselves due to an inability to selectively localize.
  • the present invention is addressed to facilitating the selective localization of such reactive oxygen species catalysts to provide a new class therapeutic agents for treating conditions responsive to the induction of targeted oxidative stress.
  • This invention is directed to compounds which localize in tumor or atheroma cells and which catalyze the in situ production of reactive oxygen species from cellular metabolites. Accordingly, when administered to a mammalian host having a tumor or atheroma or other condition responsive to targeted cellular oxidative stress, the compounds of this invention selectively catalyze the production of reactive oxygen species in the targeted cells thereby killing or treating the tumor, atheroma or other condition, or rendering it more susceptible to treatment with ionizing radiation.
  • this invention is directed to a compound comprising a conjugate of (a) a moiety capable of localizing in the cells of a tumor or atheroma or other neoplastic tissue, and (b) a moiety capable of catalyzing the production of hydrogen peroxide from a cellular metabolite having a standard biochemical reduction potential more negative than the standard biochemical reduction potential of oxygen/hydrogen peroxide (but, typically, not capable of localizing in the cells of a tumor or atheroma), or a pharmaceutically acceptable salt thereof.
  • this invention is directed to a compound of formula I:
  • a in formula I is preferably a metallotexaphyrin.
  • A is a porphyrin, metalloporphyrin, antibody, low density lipoprotein, saccharide, or a lipophilic hydrocarbyl moiety capable of association with a liposome.
  • each X in the compound of formula I is independently selected from the group consisting of alloxan, phenazonium salts, a quinone and derivatives and/or salts thereof.
  • Each L in the compounds of formula I is preferably independently selected from the group consisting of a covalent bond, an alkylene group and a poly(oxyalkylene) group, optionally including an amidocarboxy or carboxamide functionality.
  • n 1 or 2.
  • Another embodiment of this invention provides conjugates of (a) a moiety that localizes in the cells of a tumor or atheroma and which is capable of catalyzing the production of reactive oxygen species from a cellular metabolite, and (b) a ligand that binds to NADH or NADPH.
  • binding of the ligand to NADH or NADPH improves the activity of the moiety that catalyzes the production of reactive oxygen species.
  • this invention provides compounds of formula II:
  • B is a moiety capable of localizing in the cells of a tumor or atheroma and which is capable of catalyzing the production of reactive oxygen species from a cellular metabolite having a standard biochemical reduction potential more negative than the standard biochemical reduction potential of oxygen/hydrogen peroxide; each Y is independently a ligand capable of binding to NADH or NADPH; each L is independently a linking group covalently attaching Y to B; and n is an integer ranging from 1 to 5; and pharmaceutically acceptable salts thereof.
  • B in formula II is preferably a metallotexaphyrin.
  • B is a porphyrin, metalloporphyrin, antibody, low density lipoprotein, saccharide, or a lipophilic hydrocarbyl moiety capable of association with a liposome.
  • each Y in the compound of formula II is thymine or a derivative thereof.
  • Each L in the compounds of formula II is preferably independently selected from the group consisting of a covalent bond, an alkylene group and a poly(oxyalkylene) group, optionally including an amidocarboxy or carboxamide functionality.
  • n 1 or 2.
  • this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound comprising a conjugate of (a) a moiety capable of localizing in the cells of a tumor or atheroma or other neoplastic tissue and (b) a moiety capable of catalyzing the production of reactive oxygen species from a cellular metabolite having a standard biochemical reduction potential more negative than the standard biochemical reduction potential of oxygen/hydrogen peroxide, or a pharmaceutically acceptable salt thereof.
  • This invention is also directed to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound a compound of formula I or II.
  • this invention is directed to the use of a compound of this invention, including compounds of formula I and formula II above, in the manufacture of a WO 01/32211 - - PCT/USOO/29524
  • this invention provides a method of treating a mammalian host having a tumor or atheroma or other neoplastic tissue, the method comprising:
  • A administering to a mammalian host having a tumor or atheroma an effective amount of a compound comprising a conjugate of (a) a moiety capable of localizing in the cells of a tumor or atheroma and (b) a moiety capable of catalyzing the production of reactive oxygen species from a cellular metabolite having a standard biochemical reduction potential more negative than the standard biochemical reduction potential of oxygen/hydrogen peroxide, or a pharmaceutically acceptable salt thereof.
  • This invention is further provides methods of treating a mammalian host having a tumor or atheroma or other neoplastic tissue, the method comprising: (A) administering to a mammalian host having a tumor or atheroma an effective amount of a compound of formula I or II.
  • either the above methods further comprises the step of:
  • Figure 1 illustrates the chemical structure of texaphyrin compounds.
  • Figure 2 illustrates the chemical structure of various cellular redox mediators.
  • Figures 3-5 show the preparation of conjugate compounds of this invention.
  • Figure 6 shows the binding of a compound of formula II to NADH and NADPH.
  • This invention is directed to compounds which localize in tumor or atheroma or neoplastic tissue cells and which catalyze the production of reactive oxygen species from cellular metabolites; and to pharmaceutical compositions and methods employing such compounds.
  • the following terms have the following meanings, unless otherwise indicated.
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain preferably having from 1 to 40 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, /so-propyl, n-butyl, /so-butyl, n-hexyl, n-decyl, tetradecyl, and the like.
  • substituted alkyl refers to 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, acyiamino, 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
  • alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms. This term is exemplified by groups such as 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, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acyiamino, 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 alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl WO 01/32211 - 9 - PCT/USOO/29524
  • fused groups fused to the alkylene group.
  • fused groups contain from 1 to 3 fused ring structures.
  • alkoxy refers to the groups alkyl-O-, alkenyl-O-, cycloalkyl-O- and cycloalkenyl-O-, where alkyl, alkenyl, cycloalkyl, and cycloalkenyl are as defined herein.
  • Preferred alkoxy groups are alkyl-O- and include, by way of example, methoxy, ethoxy, n- propoxy, /so-propoxy, n-butoxy, terf-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- and substituted cycloalkenyl-O-, where substituted alkyl, substituted alkenyl, substituted cycloalkyl, and substituted cycloalkenyl are as defined herein.
  • a preferred class of substituted alkoxy are polyoxyalkylene groups represented by the formula -0(R'0) q R" where R' is an alkylene group or a substituted alkylene group, R" is selected from the group consisting of hydrogen, alkyl or substituted alkyl and q is an integer from 1 to 10.
  • q is from 1 to 5 and most preferably 3.
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 40 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, acyiamino, 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
  • acyl refers to the groups HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl- WO 01/32211 - 10 - PCT/USOO/29524
  • alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • acyiamino refers to the group -C(0)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(0)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 refers to the group -NRC(0)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(0)0-, substituted alkyl-C(0)0-, cycloalkyl-C(0)0-, substituted cycloalkyl-C(0)0-, aryl-C(0)0-, heteroaryl-C(0)0-, and heterocyclic-C(0)0- 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, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acyiamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy,
  • aryloxy refers to the group aryl-O- wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.
  • 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, aryl, heteroaryl and heterocyclic provided that both R's are not hydrogen.
  • carboxyalkyl refers to the groups “-C(0)0-alkyl”, “-C(0)0-substituted alkyl”, “-C(0)0-cycloalkyl”, “-C(0)0-substituted cycloalkyl”, “-C(0)0-alkenyl”, and
  • 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.
  • 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, acyiamino, 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
  • 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. Examples of suitable WO 01/32211 - 12 - PCT/USOO/29524
  • cycloalkenyl groups include, for instance, cyclobut-2-enyi, cyciopent-3-enyl, cyclooct-3-enyl 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, acyiamino, 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, alkoxy
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • heteroaryl refers to an aromatic group of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than 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, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acyiamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -
  • 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-. O 01/32211 - 13 - PCT/USOO/29524
  • heterocycle or “heterocyclic” refers to a monoradical saturated unsaturated group having a single ring or multiple condensed rings, 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, acyiamino, 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,
  • 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, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containing
  • heterocyclooxy refers to the group heterocyclic-O-.
  • thioheterocyclooxy refers to the group heterocyclic-S-.
  • oxyacylamino refers to the group -OC(0)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.
  • thiol refers to the group -SH. O 01/32211 - 14 - PCT/USOO/29524
  • 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.
  • poly(oxyalkylene) refers to the group -0(R'0) b R" where R' is an alkylene group or a substituted alkylene group, R' is selected from the group consisting of hydrogen, alkyl or substituted alkyl, and b is an integer ranging from 1 to 10, preferably 1 to 6.
  • R' is an alkylene group or a substituted alkylene group
  • R' is selected from the group consisting of hydrogen, alkyl or substituted alkyl
  • b is an integer ranging from 1 to 10, preferably 1 to 6.
  • One preferred poly(oxyalkylene) has the formula -0-(CH 2 -CH 2 -0) 3 -CH 3 .
  • saccharide refers to oxidized, reduced or substituted saccharides hexoses such as D-glucose, D-mannose, D-xylose, D-galactose, D-glucuronic acid, ⁇ /-acetyl-D- glucosamine, ⁇ /-acetyl-D-galactosamine, sialyic acid, iduronic acid, L-fucose, and the like; 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, acylated, sulfated and phosphorylated sugars; oligosaccharides having from 2 to 10 saccharide units.
  • these saccharides are referenced using conventional three letter nomenclature and the saccharides can be either in
  • 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 and mixtures thereof arising from the substitution of these compounds.
  • pharmaceutically acceptable salt refers to salts which retain the biological effectiveness and properties of the compounds 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.
  • 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, substituted cycloalkyl amines, substituted
  • Suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(/so-propyl) amine, tri( ⁇ -propyl) amine, ethanolamine, 2- dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • carboxylic acid derivatives would be useful in the practice of this invention, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, 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, glycolic 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.
  • Protecting group refers to any group which when bound to one or more hydroxyl, thiol, amino or carboxyl groups of the compounds (including intermediates thereof) prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl, thiol, amino or carboxyl group.
  • removable blocking group employed is not critical and preferred removable hydroxyl blocking groups include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl-diphenylsilyl and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product.
  • substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl-diphenylsilyl and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product.
  • Capable of localizing in the cells of a tumor or atheroma means that following administration a moiety or compound preferentially accumulates in tumor or atheroma cells relative to any accumulation in the cells of surrounding normal tissues.
  • Catalyzing moiety refers to a moiety capable of catalyzing the production of reactive oxygen species from a cellular metabolite.
  • cellular metabolite or "reducing metabolite” refers to a compound found naturally within a living cell.
  • the cellular metabolites that generate reactive oxygen species when acted upon by the compounds disclosed herein have a standard biochemical reduction potential more negative than the standard biochemical reduction potential of oxygen/hydrogen peroxide.
  • Such metabolites include, by way of example only, NAD(P)H (i.e., NADPH and/or NADH), FADH 2 , ascorbate, reduced glutathione, dihydrolipoic acid and the like.
  • standard biochemical reduction potential refers to the reduction potential of a metabolite measured at pH 7 and 25 C in an aqueous solution. At these conditions, oxygen and hydrogen peroxide have a reduction potential of approximately 0.273 mV. See, for example, Stryer, L. Biochem. 3 rd Ed. W. H. Freeman & Co., New York (1988) and The Handbook of Chemistry and Physics, CRC Press, Cleveland, Ohio. The production of reactive oxygen species, such as hydrogen peroxide, can be measured using conventional procedures, O 01/3
  • Conjugate refers to two or more compounds or moieties covalently bound together.
  • redox cycling agents refers to compounds which may exist in two or more oxidation states, are able to lower the activation barrier for electron transfer between two compounds, and may therefore be suitable moieties for generating reactive oxygen species.
  • suitable redox cycling agents include, for instance, alloxan, phenazine methosulfate, menadione, copper/putrescine/pyridine, methylene blue, paraquat, doxorubicin, bleomycin, and ruthenium (II) tris-(1 ,10-phenanthroline-5,6-dione).
  • FAD refers to the oxidized form of flavin adenine dinucieotide
  • FAD 2 refers to the reduced form of flavin adenine dinucieotide
  • ionizing radiation refers to radiation conventionally employed in the treatment of tumors which radiation, either as a large single dosage or as repeated smaller dosages, will initiate ionization of water thereby forming reactive oxygen species
  • ionizing radiation includes, by way of example, x-rays, electron beams, ⁇ -rays, and the like.
  • Localizing moiety refers to a moiety capable of localizing in the cells or tissue of a tumor or atheroma or other neoplasia. Suitable localizing moieties include, by way of example, metallotexaphyrins, metalloporphyrins, monoclonal antibodies, polypeptides and like.
  • NADH refers to the reduced form of nicotinamide adenine dinucieotide
  • NAD + refers to the oxidized form of nicotinamide adenine dinucieotide.
  • NADPH refers to the reduced form of nicotinamide adenine dinucieotide phosphate
  • NADP + refers to the oxidized form of nicotinamide adenine dinucieotide phosphate
  • the term "effective amount” means a dosage sufficient to provide treatment for the disease state being treated. This will vary depending on the patient, the disease and the treatment being effected.
  • Treatment refers to any treatment of a pathologic condition in a mammal, particularly a human, and includes: (i) preventing the pathologic condition from occurring in a subject which may be predisposed to the condition but has not yet been diagnosed with the condition and, accordingly, the treatment constitutes prophylactic treatment for the disease condition; (ii) inhibiting the pathologic condition, i.e., arresting its development; (iii) relieving the pathologic condition, i.e., causing regression of the pathologic condition; or
  • the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • the compounds of this invention comprise a conjugate of (a) a moiety capable of localizing in the cells of a tumor or atheroma and (b) one or more moieties capable of catalyzing the production of reactive oxygen species from cellular metabolites.
  • Any moiety capable of localizing in the cells of a tumor or atheroma may be used in this invention.
  • Suitable localizing moieties include, by way of example, metallotexaphyrins, porphyrins, metalloporphyrins, antibodies, low density lipoproteins, saccharides, lipophilic hydrocarbyl moieties capable of association with a liposome, and the like.
  • Such moieties are well-known in the art including derivatives thereof having functional groups suitable for use in covalently coupling a moiety capable of catalyzing the production of reactive oxygen species from a cellular metabolite to the localizing moiety.
  • Such functional groups include, by way of example, amino, hydroxyl, thio, halo, sulfonyl and carboxyl groups and the like.
  • polypeptides which localize in tumor tissue are described in U.S. Patent No. 5,762,909, the disclosure of which is incorporated herein by reference in its entirety.
  • monoclonal antibodies which localize in tumor tissue are described, for example, in U.S. Patent Nos. 5,965,132; 5,928,641 ; 5,911 ,969; and 5,889,157, the disclosures of which are incorporated herein by reference in their entirety.
  • Porphyrin derivatives and, in particular, iron(lll) porphyrin may be used as the localizing moiety.
  • Such derivatives are known to accumulate in tumor tissue and iron(lll) porphyrin has been disclosed as generating hydrogen peroxide from ascorbate and oxygen. See, for example, Lin, et al., Analytical Biochemistry, The Cytotoxic Activity of Hematoheme: Evidence for Two Different Mechanisms, 161:323-331 (1987).
  • Texaphyrin compounds may be employed as the localizing moiety in this invention.
  • Texaphyrin compounds and methods for their preparation are described in U.S. Patent Nos. 4,935,498; 5, 162,509; 5,252,720; 5,272,142, 5,256,399, 5,457,183, 5,567,687, 5,583,220 and 5,599,923; and in PCT Publication No. WO 95/21845, the disclosures of which are incorporated herein by reference in their entirety.
  • Texaphyrin refers to an "expanded porphyrin" pentadentate macrocyclic ligand as shown by way of example in Figure 1.
  • Such compounds are capable of existing in both a free-base form and in a 1 :1 complex form with a variety of metal cations, including divalent metal cations such as Ca(ll), Cd(ll), Mn(ll), Co(ll), Ni(ll), Zn(ll), Hg(ll), Fe(ll), Sm(ll) and U0 2 (ll); and trivalent metal cations such as Mn(lll), Co(lll), Ni(lll), Fe(lll), Ho(lll), Ce(lll), Y(lll), ln(ill), Pr(lll), Nd(lll), Sm(lll), Eu(lll), Gd(lll), Tb(lll), Dy(lll), Er(lll), Tm(lll), Yb(lll), Lu(lll), La(lll) and U(lll); and other cations.
  • Particularly preferred texaphyrins include those represented by formula
  • M is a divalent metal cation or a trivalent metal cation
  • R 1 to R 4 as well as R 7 and R 8 are independently selected from the group consisting of hydrogen, carboxyl, carboxylalkyl, acyl, acyiamino, aminoacyl, alkyl, substituted alky (particularly hydroxyalkyl or aminoalkyl, and especially where R 1 is hydroxypropyl or aminopropyl), alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, aryl, heteroaryl, heterocyclic, halo, hydroxyl, nitro, and a saccharide;
  • R 6 and R 9 are independently selected from the group consisting of hydrogen, carboxyl, carboxylalkyl, acyl, acyiamino, aminoacyl, alkyl, substituted alkyl other than iodoalkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, aryl, heteroaryl
  • R 5 and R 10 to R 12 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, carboxyl, carboxylalkyl, acyl and acyiamino; and the charge, Z, is an integer having a value less than or equal to 5.
  • the divalent or trivalent metal M is preferably selected from the group consisting of Ca(ll), Mn(ll), Co(ll), Ni(ll), Zn(ll), Cd(ll), Hg(ll), Fe(ll), Sm(ll), U0 2 (ll), Mn(lll), Co(lll), Ni(lll), Fe(lll), Ho(lll), Ce(lll), Y(lll), ln(lll), Pr(lll), Nd(lll), Sm(lll), Eu(lll), Gd(lll), Tb(lll), Dy(lll), Er(lll), Tm(lll), Yb(lll), Lu(lll), La(lll), and U(lll).
  • hydroxyl groups serve as useful functional groups for covalently attaching linkers and/or catalyzing moieties to the metallotexaphyrin.
  • M is Gd(lll) and Z is +2; M is Dy(lll) and Z is +2; M is Y(lll) and Z is +2; M is Lu(lll) and Z is +2; M is Co(ll) and Z is +1 ; and M is Mn(ll) and Z is +1.
  • M is Gd(lll) or Lu(lll).
  • the localizing moiety employed in this invention is typically coupled to one or more moieties capable of catalyzing the production of reactive oxygen species from cellular metabolites.
  • Any moiety capable of catalyzing the production of reactive oxygen species from a cellular metabolite having a standard biochemical reduction potential more negative than the standard biochemical reduction potential of oxygen/hydrogen peroxide, i.e, about 0.273 mV, may be used in this invention.
  • Suitable catalyzing moieties include, by way of illustration, WO 01/32211 - 22 - PCT/USOO/29524
  • the compounds of this invention typically contain from 1 to about 5 catalyzing moieties, preferably 1 or 2 catalyzing moieties, per localizing moiety.
  • the catalyzing moieties may be the same or different.
  • the catalyzing moiety may be derivatized to improve the solubility and/or biodistribution of the conjugate, i.e., by substitution with one or more poly(oxyalkylene) groups.
  • nitroimidazole Coordination of nitroimidazole with porphyrin has been suggested as a potential targeting approach (Brunner, H. et al., Chem. Ber., 1995, 28:173-181 ; Chem. Ber. 1994, 727:2141-2149).
  • nitroimidazole may subsequently be found to catalyze the production of reactive oxygen species from a cellular metabolite and thereby inherently fall within the mechanism disclosed in in co-pending U.S. Patent Application _/ , filed on even date herewith and entitled "Methods and Compositions for Treating Atheroma, Tumors and Other Neoplastic Tissue" (Attorney Docket No.
  • the catalyzing moiety(s) are covalently bound to the localizing moiety with a linking group.
  • Any linking group which covalently attaches the catalyzing moiety(s) to the localizing moiety may used in the compounds of this invention, including a covalent bond.
  • the linking group can be represented by formula V:
  • p is an integer of from 0 to 20;
  • X a at each separate occurrence is selected from the group consisting of -0-, -S-, -NR-, -C(O)-, -C(0)0-, -C(0)NR-, -C(S), -C(S)0-, -C(S)NR- or a covalent bond where R is as defined below;
  • Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;
  • Y a and Y b at each separate occurrence are selected from the group consisting of:
  • R, R and R at each separate occurrence are 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.
  • linker moiety can be optionally substituted at any atom therein by one or more alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic group.
  • Particularly preferred linking groups are alkylene groups having from 1 to 20 carbon atoms; poly(oxyalkylene) groups having from 2 to 20 carbon atoms and from 1 to 10 oxygen atoms; and a covalent bond.
  • a preferred alkylene linking group has the formula: -(CH 2 ) n - where n is an integer ranging from 1 to about 20, preferably from 2 to 6.
  • the catalyzing moiety(s) may be covalently attached to the localizing moiety via the linking group using conventional coupling procedures well known in the art.
  • Reaction chemistries for forming covalent linkages are well known in the art and involve the use of complementary functional groups on the moieties to be coupled together.
  • the complementary functional groups on each moiety are selected relative to the functional groups available on the other moiety for bonding or which can be introduced onto the other moiety for bonding. Again, such complementary functional groups are well known in the art.
  • reaction between a carboxylic acid on one moiety and a primary or secondary amine of the other moiety in the presence of suitable, well-known activating moieties results in formation of an amide bond covalently linking the two moieties; reaction between an amine group of one moiety and a sulfonyl halide of the other moiety results in formation of a sulfonamide bond covalently linking the two moiety; and reaction between an alcohol or phenol group of one moiety and and an alkyl or aryl halide of the other moiety results in formation of an ether bond covalently linking the two moiety.
  • a wide variety of other complementary chemistries are well known to those skilled in the art.
  • the Mitsunobu reaction is particularly useful for coupling texaphyrin and porphyrin derivatives to various catalyzing moieties.
  • the Mitsunobu reaction is further described in Mitsunobu, O., Synthesis, 1981 , 1-28.
  • Figure 3 illustrates the coupling of a protected alloxan deriviative to the bis- hydroxy metallotexaphyrin using the Mitsunobu reaction.
  • 3-benzoylalloxan is first coupled to the bis-hydroxy metallotexaphyrin under Mitsunobu reaction conditions as described above.
  • the benzoyl protecting groups are then removed using standard deprotection conditions, i.e., treatment with 40% aqueous methylamine at ambient temperature, to afford the coupled product shown in Figure 3.
  • the bis-iodo metallotexaphyrin shown in Figure 4 (prepared by a conventional modification of the Mitsunobu reaction) can be employed to couple a catalyzing moiety to the localizing moiety.
  • the bis-iodo metallotexaphyrin can be reacted with 2.0 to about 2.3 equivalents of phenazine in refluxing acetonitrile to afford the coupled product shown in Figure 4.
  • the bis-iodo metallotexaphyrin shown in Figure 4 is a useful synthon for preparing other compounds of this invention via displacement of the iodo groups.
  • the compounds of formula II can be prepared using procedures similar to those described herein for the compounds of formula I.
  • a localizing moiety capable of catalyzing the production of reactive oxygen species from a cellular metabolite having a standard biochemical reduction potential more negative than the standard biochemical reduction potential of oxygen/hydrogen peroxide is chosen, such as a gadolinium texaphyrin, and one or more ligands capable of binding to NADH or NADPH are covalently attached thereto using conventional reagents and procedures.
  • Any ligand capable of binding to NADH or NADPH may be employed including, by way of illustration, thymine and thymine derivatives.
  • the binding of a compound of formula II to NADH or NADPH is illustrated in Figure 6.
  • the preferred compounds of the present invention include the following:
  • compositions When employed as pharmaceuticals, compounds described herein are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, intravenous, intramuscular, and the like. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • compositions contain, as the active ingredient, one or more of the compounds described herein associated with pharmaceutically acceptable carriers.
  • the active ingredient is usually mixed with an excipient.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • the compositions can be in the form of tablets, pills, elixirs, suspensions, emulsions, solutions, syrups, and the like containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • the active compound In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • 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.
  • the 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. WO 01/32211 - 28 - PCT/USOO/29524
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient.
  • 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.
  • the compound of formula I above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier(s).
  • the active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound 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, 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 a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • 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.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • 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.
  • 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 which 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.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as corn oil, cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • 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 which deliver the formulation in an appropriate manner.
  • Hard gelatin capsules containing the following ingredients are prepared:
  • Quantity Ingredient (mo/capsule .
  • a tablet formula is prepared using the ingredients below:
  • Stearic acid 5.0 The components are blended and compressed to form tablets, each weighing 240 mg.
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone 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 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:
  • Quantity Ingredient (mg/capsule)
  • the active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Suspensions each containing 50 mg of medicament per 5.0 mL dose are made as follows:
  • the active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • Quantity Ingredient (mg/capsule)
  • the active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425.0 mg quantities.
  • composition Example 7 An intravenous formulation may be prepared as follows:
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent 5,023,252, issued June 11 , 1991 , herein incorporated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Indirect techniques which are generally preferred, usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into WO 01/32211 - 33 - PCT/USOO/29524
  • lipid-soluble drugs Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
  • the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
  • the compounds of this invention localize in tumor or atheroma cells and catalyze the in situ production of reactive oxygen species from cellular metabolites. Accordingly, when administered to a mammalian host having a tumor or atheroma, the compounds of this invention selectively catalyze the production of reactive oxygen species in the tumor or atheroma cells thereby killing or treating the tumor or atheroma. Accordingly, the compound of this invention are useful for treating atheroma, tumors and other neoplastic tissues.
  • compositions are administered to a patient already suffering from, for example, atheroma or a tumor in an amount sufficient to at least partially reduce the growth of the atheroma or tumor. Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the type of atheroma or tumor in the patient and its size, the age, weight and general condition of the patient, and the like.
  • the pharmaceutical compositions of this invention may contain more than one compound of the present invention or other active drugs or materials.
  • compositions described herein are suitable for use in a variety of drug delivery systems.
  • the compositions can be administered by different routes including intravenously, intraperitoneally, subcutaneously, intramuscularly, orally, topically, or transmucosally.
  • the amount of compound administered to the patient will vary depending upon what is being administered, the purpose of the administration, the state of the patient, the manner of O 01/32211 " 34 - PCT/USOO/29524
  • a sufficient amount of the compound is administered to the cell or to the patient so as to generate reactive oxygen species in quantities effective to initiate tumor cell death.
  • An amount adequate to accomplish this is defined as "therapeutically effective dose.” Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the degree or severity of the cancer in the patient, the age, weight and general condition of the patient, and the like.
  • the compound is administered at dosages ranging from about 0.1 to about 100 mg/kg/day.
  • the compounds of this invention can also be administered in conjunction with radiation treatment.
  • the amount of compound administered to the patient will vary depending upon what is being administered, the purpose of the administration, the state of the patient, the manner of administration, and the like.
  • a sufficient amount of the compound is administered to the cell or to the patient to therapeutically enhance the effect of ionizing radiation on tumor cell death.
  • An amount adequate to accomplish this is defined as "therapeutically effective dose.”
  • Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the degree or severity of the cancer in the patient, the age, weight and general condition of the patient, and the like.
  • compounds used in conjunction with ionizing radiation are administered at dosages ranging from about 0.1 to about 100 mg/kg/day.
  • composition can be administered at short time intervals using a pump to control the time interval or achieve continuously administration.
  • Suitable pumps are commercially available (e.g., the ALZET® pump sold by Alza corporation, and the BARD ambulatory PCA pump sold by Bard MedSystems).
  • Plasma half-life and biodistribution of the drug and metabolites in the plasma, tumors, and major organs can be also be determined to facilitate the selection of drugs most appropriate to inhibit a disorder. Such measurements can be carried out, for example, using HPLC analysis from dissected animals treated with the drug.
  • Compounds that show potent activity in the screening assays, but have poor pharmacokinetic characteristics can be optimized by altering the chemical structure and retesting. In this regard, compounds displaying good pharmacokinetic characteristics can be used as a model.
  • the compounds administered to a patient are in the form of pharmaceutical compositions described herein. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. When aqueous solutions are employed, these may be packaged for use as is, or lyophiiized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 1 1 , more preferably from 5-9 and most preferably from 7 and 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the radiation sensitizer motexafin gadolinium is administered in a solution containing 2 mM optionally in 5% mannitol USP/water (sterile and non-pyrogenic solution).
  • the texaphyrin 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 palliative course of 30 Gy in ten (10) fractions of radiation are typically administered over consecutive days excluding weekends and holidays.
  • whole brain megavolt radiation therapy is delivered with 60Co 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.
  • Radiation sensitizers may be administered before, or at the same time as, or after administration of the ionizing radiation, preferably before.
  • the radiation sensitizer 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 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 using motexafin gadolinium may range from about 0.05 ⁇ mol/kg to about 20 ⁇ mol/kg administered in single or multiple doses (e.g. before each fraction of radiation).
  • a lower dosage range is presently preferred for intra-arterial injection or for impregnated stents.
  • the additional administration of radiation as a co-therapeutic agent is optional.
  • Administering a radiation sensitizer to a mammalian host bearing atheroma cells may be prior to, concurrent with, or following vascular intervention, and the intervention is followed by radiation.
  • the administration 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 the sensitizer 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. The following examples are offered to illustrate this invention and are not to be construed in any way as limiting the scope of this invention.
  • Step 1 To a stirred solution of Compound A as shown in Figure 1 (prepared as described in U.S. Patent No. 5,457,183) (1 mmoi) in methylene chloride (10 mL) under nitrogen is added triphenylphosphine (2.2 mmol) followed by diethylazodicarboxylate (2.2 mmol) at room temperature. 3-Benzoylalloxan (2.2 mmol) is added and stirring is continued. The course of the reaction is followed by HPLC. After reaction is complete, the reaction mixture is concentrated in vacuo and the desired intermediate is obtained by purification of the crude product by use of reverse-phase column chromatography.
  • triphenylphosphine 2.2 mmol
  • diethylazodicarboxylate 2.2 mmol
  • 3-Benzoylalloxan 2.2 mmol
  • Step 2 A solution of the intermediate prepared in Step 1 above, in methylamine (10 mL, 40 wt. % solution in water) is stirred at room temperature. After reaction is complete, the reaction mixture is concentrated to dryness and the crude intermediate is used in the next step without further purification.
  • methylamine 10 mL, 40 wt. % solution in water
  • Step 3 A solution of the intermediate prepared in Step 2 above, in ammonium acetate buffer (10 ml, 1 M solution) is stirred at room temperature. After reaction is complete, the reaction mixture is concentrated to dryness and the desired product shown in Figure 3 is obtained by purification of the crude product by use of HPLC.
  • In vivo tumor inhibition can be measured using a subcutaneous Xenograft model. Mice (BALB/c, nu/nu) are implanted with C6 glioma cells and the ability of compounds of this invention to inhibit tumor growth can be measured.
  • C6 cells are maintained in Ham's F10 supplemented with 10% fetal bovine serum (FBS) and 2 mM glutamine (GLN). Cells are harvested at or near confluence with 0.05% Trypsin-EDTA and pelleted at 450 x g for 10 min. Pellets are resuspended in sterile PBS or media (without FBS) to a particular concentration and the cells are implanted into the hind- flank of mice. Tumor growth is measured over 3 to 6 weeks using venier calipers. Tumor volumes are calculated as a product of length x width x height. The test compounds are solubilized in 50-100 ⁇ L vehicle (DMSO) or dissolved in PBS (pH 7.4).
  • DMSO fetal bovine serum
  • PBS pH 7.4
  • the compounds are delivered by IP injection at 15 mg/kg/day.
  • ionizing radiation is administered after a suitable waiting period when the catalytic moiety is a radiation sensitizer.
  • a reduction in tumor volume compared to untreated controls indicates that tumor growth is inhibited.

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Abstract

L'invention concerne des composés étant des conjugués a) d'une fraction capable de se localiser dans les cellules d'une tumeur ou d'un athérome et b) d'une fraction capable de catalyser la production d'espèces oxygène réactives d'un métabolite cellulaire. Les composés de l'invention sont utiles pour le traitement d'athéromes, de tumeurs et d'autres tissus néoplasiques.
PCT/US2000/029524 1999-10-29 2000-10-27 Compose conjugue pour le traitement d'atheromes, de tumeurs et d'autres tissus neoplasiques WO2001032211A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU12340/01A AU1234001A (en) 1999-10-29 2000-10-27 Conjugate compounds for treating atheroma, tumors and other neoplastic tissue
EP00973891A EP1223982A2 (fr) 1999-10-29 2000-10-27 Compose conjugue pour le traitement d'atheromes, de tumeurs et d'autres tissus neoplasiques
US10/160,205 US20030031676A1 (en) 1999-10-29 2002-05-30 Conjugate compounds for treating atheroma and other diseases
HK03100643.8A HK1050315A1 (zh) 1999-10-29 2003-01-24 用於治療粉瘤，腫瘤以及其他新生組織的共扼化合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US43129899A 1999-10-29 1999-10-29
US09/431,298 1999-10-29

Related Child Applications (1)

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US10/160,205 Continuation US20030031676A1 (en) 1999-10-29 2002-05-30 Conjugate compounds for treating atheroma and other diseases

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WO2001032211A2 true WO2001032211A2 (fr) 2001-05-10
WO2001032211A3 WO2001032211A3 (fr) 2002-03-07

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PCT/US2000/029524 WO2001032211A2 (fr) 1999-10-29 2000-10-27 Compose conjugue pour le traitement d'atheromes, de tumeurs et d'autres tissus neoplasiques

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EP (1) EP1223982A2 (fr)
AU (1) AU1234001A (fr)
HK (1) HK1050315A1 (fr)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021102616A (ja) * 2014-06-11 2021-07-15 ボード オブ リージェンツ, ザ ユニバーシティ オブ テキサス システムBoard Of Regents, The University Of Texas System 白金耐性の克服における使用のためのテキサフィリン−白金（ｉｖ）コンジュゲート及び組成物

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5587371A (en) * 1992-01-21 1996-12-24 Pharmacyclics, Inc. Texaphyrin-oligonucleotide conjugates
US5888997A (en) * 1994-04-14 1999-03-30 Pharmacyclics, Inc. Radiation sensitization using texaphyrins
WO1999062551A1 (fr) * 1998-06-05 1999-12-09 Board Of Regents, The University Of Texas System Conjugues de texaphyrine et utilisations associees
WO2001032210A2 (fr) * 1999-10-29 2001-05-10 Pharmacyclics, Inc. Methodes et compositions de traitement d'atheromes, de tumeurs et d'autres tissus neoplasiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5587371A (en) * 1992-01-21 1996-12-24 Pharmacyclics, Inc. Texaphyrin-oligonucleotide conjugates
US5888997A (en) * 1994-04-14 1999-03-30 Pharmacyclics, Inc. Radiation sensitization using texaphyrins
WO1999062551A1 (fr) * 1998-06-05 1999-12-09 Board Of Regents, The University Of Texas System Conjugues de texaphyrine et utilisations associees
WO2001032210A2 (fr) * 1999-10-29 2001-05-10 Pharmacyclics, Inc. Methodes et compositions de traitement d'atheromes, de tumeurs et d'autres tissus neoplasiques

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021102616A (ja) * 2014-06-11 2021-07-15 ボード オブ リージェンツ, ザ ユニバーシティ オブ テキサス システムBoard Of Regents, The University Of Texas System 白金耐性の克服における使用のためのテキサフィリン−白金（ｉｖ）コンジュゲート及び組成物
US11389459B2 (en) 2014-06-11 2022-07-19 Board Of Regents, The University Of Texas System Texaphyrin-Pt(IV) conjugates and compositions for use in overcoming platinum resistance

Also Published As

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WO2001032211A3 (fr) 2002-03-07
AU1234001A (en) 2001-05-14
EP1223982A2 (fr) 2002-07-24
HK1050315A1 (zh) 2003-06-20

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