Texaphyrin macrocycles and metal complexes thereof

• US 5,587,463 A
• Filed: 03/08/1994
• Issued: 12/24/1996
• 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): Datlow, Philip I.
• Assistant Examiner(s): Sripada, Pavanaram K.
• Application Number:
  US08/207,845
• Time in Patent Office: 1,022 Days
• Field of Search: 540/474, 540/472, 540/145, 534/15
• US Class Current: 534/15
• 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: 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:

##STR16## wherein M is a divalent metal ion and n is 1, or M is a trivalent metal ion and n is 2.

22. A compound according to claim 1 wherein M is a divalent metal ion selected from the group consisting of Cd⁺², Zn⁺², Hg⁺², Mn⁺², Ca⁺², Co⁺², Ni⁺², Sm⁺², and UO₂⁺² ;

and n is 1.

23. A compound according to claim 1 wherein M is a trivalent metal ion selected from the group consisting of Nd⁺³, Sm⁺³, Eu⁺³, Gd⁺³, La⁺³, Lu⁺³, Y⁺³, In⁺³, Mn⁺³, Co⁺³, Ni⁺³, Pr⁺³, Tb⁺³, Dy⁺³, Er⁺³, Tm⁺³, Yb⁺³, and U⁺³ ;

and n is 2.

2. A compound having the structure ##STR17## wherein the substituents R₁, R₂ and R₃ are separately and independently selected from the group consisting of H, alkyl, amino, hydroxy, alkoxy, carboxy, carboxyalkyl, carboxamide, ester, amide, polyether, sulfonato, nitro, halide other than iodide, substituted alkyl, substituted ester, substituted ethers, and substituted amide;

R₄ and R₅ are separately and independently selected from the group consisting of H, alkyl, amino, hydroxy, alkoxy, carboxy, carboxyalkyl, carboxamide, ester, amide, polyether, sulfonato, nitro, halide other than iodide, substituted alkyl, substituted ester, substituted ethers and substituted amide or together form an alkenylene bridge of the formula --C(R₆)═

C(R₇)--CH═

CH--;

where R₆ and R₇ are separately and independently selected from the group consisting of H, alkyl, amino, hydroxy, alkoxy, carboxy, carboxyalkyl, carboxamide, ester, amide, polyether, sulfonato, nitro, halide other than iodide, substituted alkyl, substituted ester, substituted ethers and substituted amide;

M is H, a di- or trivalent metal cation; and

n is between -5 and +5.

4. A compound according to claim 2 wherein at least one of R₁, R₂ and R₃ is other than methyl or au least one of R₄ and R₅ is other than H.

5. A compound according to claim 2 having the following structure ##STR19##

6. A compound according to claim 5 wherein each of R₄ and R₅ is methyl;

or R₄ is H and R₅ is selected from the group consisting of methyl, methoxy, halide other than iodide, nitro, sulfonato, --COOH, and --O(CH₂ CH₂ O)₂ CH₃ ;

or R₄ and R₅ together form an alkenylene bridge of the formula --CH═

CH--CH═

CH-- or --C(SO₃^-)═

CH--CH═

CH--.

7. A compound according to claim 2 having the following structure ##STR20##

8. A compound according to claim 7 wherein each of R₄ and R₅ is independently H or methyl, or R₄ and R₅ together form an alkenylene bridge of the formula --CH═

CH--CH═

CH--.

9. A compound according to claim 2 wherein M is a divalent metal ion selected from the group consisting of Cd⁺², Zn⁺², Hg⁺², Mn⁺², Ca⁺², Co⁺², Ni⁺², Sm⁺², and UO₂⁺² ;

and n is 1.

10. A compound according to claim 2 wherein M is a trivalent metal ion selected from the group consisting of Nd⁺³, Sm⁺³, Eu⁺³, Gd⁺³, La⁺³, Lu⁺³, Y⁺³, In⁺³, Mn⁺³, Co⁺³, Ni⁺³, Pr⁺³, Tb⁺³, Dy⁺³, Er⁺³, Tm⁺³, Yb⁺³, and U⁺³ ;

and n is 2.

11. A compound according to claim 5 wherein M is a divalent metal ion selected from the group consisting of Cd⁺², Zn⁺², Hg⁺², Mn⁺², Ca⁺², Co⁺², Ni⁺², Sm⁺² and UO₂⁺² ;

and n is 1.

12. A compound according to claim 5 wherein M is a trivalent metal ion selected from the group consisting of Nd⁺³, Sm⁺³, Eu⁺³, Gd⁺³, La⁺³, Lu⁺³, Y⁺³, In⁺³, Mn⁺³, Co⁺³, Ni⁺³, Pr⁺³, Tb⁺³, Dy⁺³, Er⁺³, Tm⁺³, Yb⁺³, and U⁺³ ;

and n is 2.

13. A compound according to claim 5 wherein R₄ is hydrogen, R₅ is --COOH, M is In⁺³, and n is 2.

14. A compound according to claim 13 wherein the indium is ¹¹¹ In.

15. A compound according to claim 5 wherein R₄ is hydrogen, R₅ is --O(CH₂ CH₂ O)₂ CH₃, M is Gd⁺³ or Lu⁺³, and n is 2.

16. A compound according to claim 2 wherein M is a paramagnetic ion.

17. A compound according to claim 2 wherein M is a diamagnetic ion.

18. A compound according to claim 5 wherein M is a paramagnetic ion.

19. A compound according to claim 5 wherein M is a diamagnetic ion.

20. A compound according to claim 16 wherein the paramagnetic ion is Gd⁺³.

21. A compound according to claim 17 wherein the diamagnetic ion is In⁺³, Zn⁺², Cd⁺², La⁺³, or Lu⁺³.

3. A compound having the structure:

##STR18##