Expanded porphyrins: large porphyrin-like tripyrroledimethine-derived macrocycles and methods for treating tumors

• US 5,272,142 A
• Filed: 05/07/1992
• Issued: 12/21/1993
• Est. Priority Date: 03/06/1989
• Status: Expired due to Term

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Sessler, Jonathan L., Murai, Toshiaki, Hemmi, Gregory W.
• Primary Examiner(s): Hollrah, Glennon H.
• Assistant Examiner(s): Hollinden, Gary E.
• Application Number:
  US07/880,131
• Time in Patent Office: 593 Days
• Field of Search: 514/185, 514/836, 514/908, 534/15, 540/145, 435/2
• US Class Current: 514/185
• 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 41/0071 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
• 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: A61K 47/546 Porphyrines; Porphyrine with an expanded ring system, e.g. texaphyrine
• CPC Class Codes: C07D 487/22 in which the condensed system contains four or more hetero rings

Abstract

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.

Claims

1. A method of photodynamic tumor therapy for tumors having an affinity for texaphyrin, the method comprising administering a texaphyrin complexed with a metal to a tumor host and irradiating the complex in proximity to the tumor.

2. A method of photodynamic tumor therapy for tumors having an affinity for a texaphyrin metal complex, the method comprising:

administering to a patient a texaphyrin metal complex capable of producing singlet oxygen when irradiated in the presence of oxygen; and

photoirradiating said metal complex in proximity to tumor cells binding said texaphyrin, wherein singlet oxygen is produced in sufficient quantity to be cytotoxic to said tumor cells.

3. The method of claim 2 wherein the metal is a diamagnetic metal.

4. The method of claim 2 wherein the metal is In⁺³, Zn⁺² or Cd⁺².

5. The method of claim 2 wherein the metal is a lanthanide metal.

6. The method of claim 2 wherein the wavelength range of photoirradiation is from about 730 to about 770 nanometers.

7. A method for deactivating a retrovirus or enveloped virus in blood comprising:

mixing with blood in vitro or ex vivo a texaphyrin metal complex capable of producing singlet oxygen when irradiated in the presence of oxygen; and

irradiating the mixture in vitro or ex vivo to produce singlet oxygen in a quantity cytotoxic to said retrovirus or enveloped virus.

8. The method of claim 7 wherein the metal is a diamagnetic metal.

9. The method of claim 7 wherein the metal is In⁺³, Zn⁺² or Cd⁺².

10. The method of claim 7 wherein the metal is a lanthanide metal.

11. The method of claim 7 wherein the wavelength range of photoirradiation is from about 730 to about 770 nanometers.