Expanded porphyrins: large porphyrin-like tripyrroledimethine-derived macrocycles

• US 5,369,101 A
• Filed: 12/16/1993
• Issued: 11/29/1994
• 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): Raymond, Richard L.
• Application Number:
  US08/168,668
• Time in Patent Office: 348 Days
• Field of Search: 534/13, 534/16, 540/145, 540/465, 540/472
• US Class Current: 534/13
• 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: A61K 47/546 Porphyrines; Porphyrine with an expanded ring system, e.g. texaphyrine
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 compound having the structure:

##STR17## wherein;

M is H;

a trivalent metal cation selected from the group consisting of Mn⁺³, Co⁺³, Ni⁺³, Fe⁺³, Ho⁺³, Ce⁺³, Y⁺³, In⁺³, Pr⁺³, Nd⁺³, Sm⁺³, Eu⁺³, Gd⁺³, Tb⁺³, Dy⁺³, Er⁺³, Tm⁺³, Yb⁺³, Lu⁺³, La⁺³, and U⁺³ ;

or a divalent metal cation selected from the group consisting of Ca⁺², Mn⁺², Co⁺², Ni⁺², Zn⁺², Cd⁺², Hg⁺², Sm⁺², and UO₂⁺² ;

R₁, R₂, and R₃ are independently hydrogen, alkyl, carboxy or carboxyalkyl where at least one of R₁, R₂, and R₃ is carboxy or carboxyalkyl;

the molecular weight of any one of R₁, R₂, or R₃ is less than or equal to about 1000 daltons; and

n is an integer less than or equal to 2.

2. The compound of claim 1 wherein R₁ is CH₂ COOH.

3. The compound of claim 1 wherein R₂ or R₃ is COOH.

4. The compound of claim 1 wherein R₁ is CH₂ CH₃, R₂ is H and R₃ is COOH.

5. The compound of claim 1 wherein R₁ is CH₂ COOH, and R₂ and R₃ are H.

6. The compound of claim 1 wherein R₁ is CH₂ COOH, and R₂ and R₃ are alkyl.

7. A compound having the structure:

##STR18## wherein M is a divalent metal ion and n is 1 or M is a traivalent metal ion and n is 2.

8. A compound having the structure:

##STR19## wherein M is H, a divalent metal cation selected from the group consisting of Ca⁺², Mn⁺², Co⁺², Ni⁺², Zn⁺², Cd⁺², Hg⁺², Sm⁺² and UO₂⁺² ;

or a trivalent metal cation selected from the group consisting of Mn⁺³, Co⁺³, Ni⁺³, Fe⁺³, Ho⁺³. Ce⁺³, Y⁺³. In⁺³, Pr⁺³, Nd⁺³, Sm⁺³, Eu⁺³, Gd⁺³, Tb⁺³, Dy⁺³, Er⁺³, Tm⁺³, Yb⁺³, Lu⁺³, La⁺³, and U⁺³ ; and

n is an integer less than or equal to 2.