Methods of producing singlet oxygen using compounds having improved functionalization

• US 5,756,726 A
• Filed: 06/06/1995
• Issued: 05/26/1998
• Est. Priority Date: 06/02/1995
• Status: Expired due to Fees

• Current Assignee: Pharmacyclics LLC (Abbvie Incorporated)
• 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:
  US08/468,935
• Time in Patent Office: 1,085 Days
• Field of Search: 540/472, 540/474, 514/185, 534/10, 534/14, 534/15, 204/157.5
• US Class Current: 540/474
• 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

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.

Claims

1. A method of producing light-induced singlet oxygen, the method comprising subjecting a texaphyrin to light in the presence of oxygen, wherein the texaphyrin has the structure:

##STR14## wherein M is a diamagnetic 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 where the paramagnetic metal cation is selected from the group consisting of Cd(II), Zn(II), In(III), Y(III), La(III), and Lu(III).

3. The method of claim 1 where the light has a wavelength range from about 730 to about 770 nm.

4. The method of claim 1 where the couple is an amide, disulfide, thioether or ether covalent bond.

5. 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.

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

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. The method of claim 12 where R₁₁ and R₁₂ are H or CH₃.

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