Texaphyrin complexes having improved functionalization

• US 5,591,422 A
• Filed: 06/06/1995
• Issued: 01/07/1997
• Est. Priority Date: 06/02/1995
• Status: Expired due to Fees

• Current Assignee: Pharmacyclics Incorporated (Abbvie Incorporated), Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Pharmacyclics Incorporated (Abbvie Incorporated), Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Sessler, Jonathan L., Mody, Tarak D., Hemmi, Gregory W.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Sripada, Pavanaram K.
• Application Number:
  US08/468,209
• Time in Patent Office: 581 Days
• Field of Search: 424/1.65, 424/9, 424/9.362, 534/10, 534/15, 540/474, 540/472
• US Class Current: 424/9.362
• CPC Class Codes: A61K 41/0038 Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy radiotherapy per se A61N5/10
• CPC Class Codes: A61K 41/0076 PDT with expanded (metallo)porphyrins, i.e. having more than 20 ring atoms, e.g. texaphyrins, sapphyrins, hexaphyrins, pentaphyrins, porphocyanines
• CPC Class Codes: C07D 487/18 Bridged systems
• CPC Class Codes: C07D 487/22 in which the condensed system contains four or more hetero rings

Abstract

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 π 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.

Claims

1. A method of radiation therapy for a host harboring atheroma or neoplastic tissue, the method comprising:

administering to the host a texaphyrin, the texaphyrin having radiosensitization properties; and

administering ionizing radiation to the host in proximity to the atheroma or neoplastic tissue;

wherein the texaphyrin has the structure;

##STR14## wherein M is H, a divalent metal cation, or a trivalent metal cation;

R₁ -R₄, R₇ and R₈ are independently hydrogen, halide, hydroxyl, alkyl, aryl, haloalkyl, nitro, formyl, acyl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, saccharide, carboxy, carboxyalkyl, carboxyamidealkyl, a site-directing molecule, a catalytic group, or a couple to a site-directing molecule or to a catalytic group;

R₆ and R₉ are independently selected from the groups of R₁ -R₄, R₇ and R₈, with the proviso that the halide is other than iodide and the haloalkyl is other than iodoalkyl;

R₅ and R₁₀ -R₁₂ are independently hydrogen, alkyl, aryl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, carboxyalkyl, carboxyamidealkyl or a couple to a saccharide, to a site-directing molecule or to a catalytic group;

at least one of R₅, R₆, R₉, R₁₀, R₁₁ and R₁₂ is other than hydrogen; and

Z is an integer less than or equal to 5.

2. The method of claim 1 further comprising the step of determining localization sites in the host by reference to a detectable texaphyrin.

3. The method of claim 1 where the texaphyrin is complexed with a metal.

4. The method of claim 3 where the metal is a paramagnetic metal, a gamma-emitting metal, or a radioactive metal.

5. The method of claim 3 where M is a paramagnetic metal selected from the group consisting of Mn(III), Mn(III), Fe(III), and all trivalent lanthanides other than La(III), Lu(III) and Pm(III).

6. The method of claim 3 where M is Gd(III).

7. The method of claim 1 where the ionizing radiation is from an external source.

8. The method of claim 3 where the metal is a radioactive metal and the ionizing radiation is from the radioactive metal in combination with radiation from an external source.

9. The method of claim 1 where the catalytic group is selected from the group consisting of imidazole, guanidine, substituted saccharides, amino acids, derivatives of amino acids, polymers of amino acids, and texaphyrin metal complexes.

10. The method of claim 1 where the site-directing molecule has binding specificity for localization to a treatment site.

11. The method of claim 1 where the site-directing molecule is selected from the group consisting of an oligonucleotide, an antibody, a hormone, a hormone mimic, a peptide having affinity for a biological receptor, and a sapphyrin molecule.

12. The method of claim 1 where at least one of R₅ and R₁₀ -R₁₂ is other than hydrogen;

and

when R₅ is other than hydrogen, then R₆ is hydrogen, halide other than iodide, or hydroxyl; and

when R₁₀ is other than hydrogen, then R₉ is hydrogen, halide other than iodide, or hydroxyl.

13. The method of claim 1 where at least one of R₆ and R₉ is other than hydrogen;

and

when R₆ is other than hydrogen, then R₅ is hydrogen or methyl; and

when R₉ is other than hydrogen, then R₁₀ is hydrogen or methyl.

14. The method of claim 1 where R₅ and R₁₀ are aryl having an R₁₃ substituent where R₁₃ is hydrogen, nitro, carboxy, sulfonic acid, hydroxy, oxyalkyl or halide.

15. The method of claim 1 where each of R₁ -R₁₂ is any one of the substituents for R₁ -R₁₂ set out in Tables A and B.

16. The method of claim 1 where R₁ is CH₂ (CH₂)₂ OH, R₂ and R₃ are CH₂ CH₃, R₄, R₅ and R₁₀ are CH₃, R₆ and R₉ are H, and R₇ and R₈ are O(CH₂ CH₂ O)₃ CH₃ or R₇ is H or OCH₃ and R₈ is a site-directing molecule or a couple to a site-directing molecule.

17. The method of claim 16 where R₁₁ and R₁₂ are H or CH₃.

18. The method of claim 1 where the texaphyrin is selected from texaphyrins A1-A56 of Tables A and B.

19. The method of claim 1 where the neoplastic tissue is a tumor.