The University of Texas System

Pharmacyclics, Inc.

Board of Regents, University of Tx

Gregory W Hemmi

Jonathan L Sessler

Tarak D Mody

Darren Magda

Toshiaki Murai

Vladimir A Kral

Vladimir A Kr Al

Richard A Miller

Anthony M Harriman

Brent L Iverson

Meredith Wright

Miguel Rosingana

Murai Toshiaki

Petra L Jansen

The invention relates to the field of radiation sensitizers and the use of texaphyrins for radiation sensitization and other conditions for which X-ray radiation has proven to be therapeutic.

Conjugates of texaphyrins

Texaphyrins are provided for use as radiation sensitizers. Advantageous properties of texaphyrins for use as a radiation sensitizer include: i) a low redox potential which allows radiation-induced hydrated electrons to flow to texaphyrin rather than neutralizing hydroxyl radicals, allowing hydroxyl radicals to cause cellular damage, ii) a relatively stable texaphyrin radical that reacts readily to covalently modify neighboring molecules causing further cellular damage, iii) intrinsic biolocalization, and iv) indifference to the presence or absence of O.sub.2. These properties allow texaphyrins to be particularly effective for treating the hypoxic areas of solid neoplasms. Methods of treatment for an individual having a neoplasm or atheroma include the use of a texaphyrin as a radiation sensitizer and as an agent for photodynamic tumor therapy, or the use of a texaphyrin for internal and for external ionizing radiation. Novel texaphyrins are provided.

Pharmaceutical compositions comprising texaphyrins

The present invention is directed to methods for synthesizing water soluble hydroxy-substituted texaphyrins retaining lipophilicity. The synthesis comprises condensing a diformyltripyrrole with an ortho-phenylenediamine to give a nonaromatic texaphyrin having at least one hydroxy substituent, and oxidizing the condensation product to form an aromatic texaphyrin metal complex having at least one hydroxy substituent. These expanded porphyrin-like macrocycles may be used for magnetic resonance imaging and for photodynamic therapy in the treatment of atheroma and tumors.

Water soluble texaphyrin metal complex preparation

Texaphyrins substituted with imidazda are provided.

Texaphyrins substituted with imidazole are provided

Radiation sensitization using texaphyrins

A method has been developed which utilizes a metal-2,4-dicarbonyl complex as an organic solvent soluble metal ion source in the metallation of polyazamacrocycles including porphyrins, expanded porphyrins and porphyrinoid compounds. Use of a metal ion source which is soluble in the metallation reaction medium produces significantly higher yields of a measurably purer product than is achieved using an insoluble or only sparingly soluble metal salt as in the prior art. Additionally, because the metallation can be performed in relatively concentrated mixtures, the reaction times are dramatically shorter and the amount of waste produced is less than when simple metal salts serve as the metal ion source. Further, use of the soluble metal-2,4-dicarbonyl complex simplifies the purification protocol required for the metallated expanded porphyrin.

Metallation of macrocycles with 2,4-dicarbonyl-metal complexes

Metal complexes of texaphyrins

Novel texaphyrin compounds having improved functionalization are described. Metal complexes of these compounds are active as photosensitizers for the generation of singlet oxygen and thus are potentially useful for treatments performed with singlet oxygen. Several of the metallotexaphyrin complexes absorb light in the physiologically important range of 690-880 nm. The complexes form long-lived triplet states and thus may act as efficient photosensitizers for generation of singlet oxygen.

Methods of producing singlet oxygen using compounds having improved

The present invention relates to the use of water-soluble texaphyrin-diamagnetic metal complexes retaining lipophilicity as photosensitizers in the treatment of benign and malignant neoplastic tissue.

Treatment of neoplastic tissue by water-soluble texaphyrine metal

Texaphyrins are provided for use as radiation sensitizers. Advantageous properties of texaphyrins for use as a radiation sensitizer include: i) a low redox potential which allows radiation-induced hydrated electrons to flow to texaphyrin rather than neutralizing hydroxyl radicals, allowing hydroxyl radicals to cause cellular damage, ii) a relatively stable texaphyrin radical that reacts readily to covalently modify neighboring molecules causing further cellular damage, iii) intrinsic biolocatization, and iv) indifference to the presence or absence of O.sub.2. These properties allow texaphyrins to be particularly effective for treating the hypoxic areas of solid neoplasms. Methods of treatment for an individual having a neoplasm or atheroma include the use of a texaphyrin as a radiation sensitizer and as an agent for photodynamic tumor therapy, or the use of a texaphyrin for internal and for external ionizing radiation. Novel texaphyrins are provided.

Fluoresence detection using texaphyrins

Texaphyrin metal complexes having improved functionalization include the addition of electron-donating groups to positions 2, 7, 12, 15, 18 and/or 21 and/or the addition of electron-withdrawing groups to positions 15 and/or 18 of the macrocycle. Electron-donating groups at positions 2, 7, 12, 15, 18 and/or 21 contribute electrons to the aromatic .pi. system of the macrocycle which stabilizes the metal complex to demetallation and the imine bonds to hydrolysis. These texaphyrin metal complexes having enhanced stability are useful for localization, magnetic resonance imaging, radiosensitization, radiation therapy, fluorescence imaging, photodynamic therapy, RNA hydrolysis, DNA photocleavage, and applications requiring singlet oxygen production for cytotoxicity. Electron-withdrawing groups at positions 15 and/or 18 render the macrocycle more readily reduced, i.e. the redox potential is lower and the macrocycle more readily gains an electron to form a radical. Such texaphyrins having a low redox potential are useful for radiation sensitization applications.

Methods of MRI enhancement using compounds having improved

Texaphyrin metal complexes having improved functionalization include the addition of electron-donating groups to positions 2, 7, 12, 15, 18 and/or 21 and/or the addition of electron-withdrawing groups to positions 15 and/or 18 of the macrocycle. Electron-donating groups at positions 2, 7, 12, 15, 18 and/or 21 contribute electrons to the aromatic .pi. system of the macrocycle which stabilizes the metal complex to demetallation and the imine bonds to hydrolysis. The addition of substituents to the 12 and 21 positions of the macrocycle offer steric protection for the imine bonds against possible in vivo enzyme hydrolysis. Electron-withdrawing groups at positions 15 and/or 18 render the macrocycle more readily reduced, i.e. the redox potential is lower and the macrocycle more readily gains an electron to form a radical. Such texaphyrins having a low redox potential and imine bond stabilization are useful in a variety of applications.

Texaphyrin compounds having improved functionalization

Texaphyrin metal complexes having improved functionalization including the addition of electron donating groups to positions 12, 15, 18 and/or 21 and/or the addition of electron withdrawing groups to positions 15 or 18 of the macrocycle. Electron donating groups at positions 12, 15, 18 and/or 21 contribute electrons to the aromatic .pi. system of the macrocycle which stabilizes the metal complex to demetallation and the imine bonds to hydrolysis, these texaphyrin metal complexes having enhanced stability are useful for localization, magnetic resonance imaging, radiosensitization, radiation therapy, fluorescence imaging, photodynamic tumor therapy and applications requiring singlet oxygen production for cytotoxicity. Electron withdrawing groups at positions 15 or 18 render the macrocycle more readily reduced, i.e. the redox potential is lower and the macrocycle more readily gains an electron to form a radical. Such texaphyrins having a low redox potential are useful for radiosensitization applications.

Texaphyrin metal complexes having improved functionalization

Texaphyrin metal complexes having improved functionalization include the addition of electron-donating groups to positions 2, 7, 12, 15, 18 and/or 21 and/or the addition of electron-withdrawing groups to positions 15 and/or 18 of the macrocycle. Electron-donating groups at positions 2, 7, 12, 15, 18 and/or 21 contribute electrons to the aromatic .pi. system of the macrocycle which stabilizes the metal complex to demetallation and the imine bonds to hydrolysis. These texaphyrin metal complexes having enhanced stability are useful for localization, radiosensitization and radiation therapy. Electron-withdrawing groups at positions 15 and/or 18 render the macrocycle more readily reduced, i.e. the redox potential is lower and the macrocycle more readily gains an electron to form a radical. Such texaphyrins having a low redox potential are useful for radiation sensitization applications.

Texaphyrin complexes having improved functionalization

The present invention involves a novel tripyrrole dimethine-derived 'expanded porphyrin' (texaphyrin), the synthesis of such compounds, their analogs or derivatives and their uses. These expanded porphyrin-like macrocycles are efficient chelators of divalent and trivalent metal ions. Metal complexes of these compounds are active as photosensitizers for the generation of singlet oxygen and thus potentially for inactivation or destruction of human immunodeficiency virus (HIV-1), mononuclear or other cells infected with such virus and tumor cells as well. A variety of texaphyrin derivatives have been produced and many more are readily obtainable. Various metal (e.g., transition, main group, and lanthanide) complexes with the texaphyrin and texaphyrin derivatives of the present invention have unusual water solubility and stability which render them particularly useful. These metallotexaphyrin complexes have optical properties making them unique as compared to existing porphyrin-like or other macrocycles. For example, they absorb light strongly in a physiologically important region (i.e. 690-880 nm). These complexes also form long-lived triplet states in high yield and act as efficient photosensitizers for the formation of singlet oxygen. These properties, coupled with their high chemical stability and appreciable solubility in polar media such as water, add to their usefulness.

Growing community of inventors

Sunnyvale, CA, United States of America

Gregory W Hemmi