Texaphyrin metal complexes having improved functionalization

• US 5,599,923 A
• Filed: 02/15/1994
• Issued: 02/04/1997
• Est. Priority Date: 03/06/1989
• Status: Expired due to Term

• Current Assignee: Pharmacyclics LLC (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:
  US08/196,964
• Time in Patent Office: 1,085 Days
• Field of Search: 540/145, 540/465, 540/472, 540/474
• US Class Current: 540/145
• CPC Class Codes: A61K 2121/00 Preparations for use in therapy
• 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 41/10 Inactivation or decontamination of a medicinal preparation prior to administration to an animal or a person
• CPC Class Codes: A61K 49/0021 the fluorescent group being a small organic molecule
• CPC Class Codes: A61K 49/106 the complex-forming compound being cyclic, e.g. DOTA
• CPC Class Codes: A61K 51/04 Organic compounds
• CPC Class Codes: A61K 51/0485 Porphyrins, texaphyrins wherein the nitrogen atoms forming the central ring system complex the radioactive metal
• CPC Class Codes: A61K 51/1093 conjugates with carriers being antibodies
• CPC Class Codes: A61L 2/0011 using physical methods
• 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
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Abstract

Texaphyrin metal complexes having improved functionalization including the addition of electron donating groups to positions 12, 15, 18 and/or 21 and/or the addition of electron withdrawing groups to positions 15 or 18 of the macrocycle. Electron donating groups at positions 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, magnetic resonance imaging, radiosensitization, radiation therapy, fluorescence imaging, photodynamic tumor therapy and applications requiring singlet oxygen production for cytotoxicity. Electron withdrawing groups at positions 15 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 radiosensitization applications.

Claims

1. A texaphyrin having the structure:

##STR5## 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, Fe⁺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 ;

R₁ -R₄ and R₆ -R₉ are independently hydrogen, halide other than iodide, hydroxyl, alkyl, aryl, haloalkyl other than iodoalkyl, nitro, formyl, acyl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, carboxy, carboxyalkyl, carboxyamidealkyl, a sapphyrin molecule, or a linker to a sapphyrin molecule;

R₅ and R₁₀ are independently hydrogen, alkyl, aryl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, carboxyalkyl, carboxyamidealkyl or a linker to a sapphyrin molecule;

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

N is an integer less than or equal to 2.

2. The texaphyrin of claim 1 wherein:

R₁ -R₄ and R₆ -R₉ are independently hydrogen, hydroxyl, alkyl, aryl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, carboxyalkyl, carboxyamidealkyl, a sapphyrin molecule, or a linker to a sapphyrin molecule; and

R₅ and R₁₀ are independently hydrogen, alkyl, aryl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, carboxyalkyl, carboxyamidealkyl or a linker to a sapphyrin molecule.

3. The texaphyrin of claim 1 wherein:

R₁ -R₄, R₇ and R₈ are independently hydrogen, halide other than iodide, hydroxyl, alkyl, aryl, haloalkyl, nitro, formyl, acyl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, carboxy, carboxyalkyl, carboxyamidealkyl, a sapphyrin molecule, or a linker to a sapphyrin molecule;

R₅ and R₁₀ are independently hydrogen, alkyl, aryl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, carboxyalkyl, carboxyamidealkyl or a linker to a sapphyrin molecule;

R₆ and R₉ are independently halide other than iodide, formyl, acyl, carboxy, or nitro; and

at least one of R₆ and R₉ is other than hydrogen.

4. The texaphyrin of claim 1 further defined as being water soluble.

5. The texaphyrin of claim 1 wherein the halide other than iodide is fluoride, chloride or bromide.

6. The texaphyrin of claim 1 wherein the alkyl, aryl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, carboxyalkyl, carboxyamidealkyl or sapphyrin molecule is covalently bonded to the texaphyrin via a carbon-carbon or a carbon-oxygen bond.

7. The texaphyrin of claim 1 wherein the aryl is a phenyl substituent.

8. The texaphyrin of claim 1 wherein the aryl is phenyl having a nitro, carboxy, sulfonic acid, hydroxy, oxyalkyl or halide other than iodide substituent.

9. The texaphyrin of claim 1 wherein the oxyhydroxyalkyl is alkyl having independently hydroxy substituents and ether branches.

10. The texaphyrin of claim 1 wherein the oxyhydroxyalkyl is C.sub.(n-x) H.sub.((2n+1)-2x) O_x O_y or OC.sub.(n-x) H.sub.((2n+1)-2x) O_x O_y where

n is a positive integer from 1 to 10;

x is zero or a positive integer less than or equal to n; and

y is zero or a positive integer less than or equal to ((2n+1)-2x).

11. The texaphyrin of claim 1 wherein the oxyhydroxyalkyl is C_n H.sub.((2n+1)-q) O_y R^a_q, OC_n H.sub.((2n+1)-q) O_y R^a_q or (CH₂)_n CO₂ R^a where

n is a positive integer from 1 to 10,

y is zero or a positive integer less than ((2n+1)-q),

q is zero or a positive integer less than or equal to 2n+1,

R^a is independently H, alkyl, hydroxyalkyl, C.sub.(m-w) H.sub.((2m+1)-2w) O_w O_z, O₂ CC.sub.(m-w) H.sub.((2m+1)-2w) O_w O_z or N(R)OCC.sub.(m-w) H.sub.((2m+1)-2w) O_w O_z, where

m is a positive integer from 1 to 10,

w is zero or a positive integer less than or equal to m,

z is zero or a positive integer less than or equal to ((2m+1)-2w),

R is H, alkyl, hydroxyalkyl, or C_m H.sub.(( 2m+1)-r)O_z R^b_r where

m is a positive integer from 1 to 10,

z is zero or a positive integer less than ((2m+1)-r),

r is zero or a positive integer less than or equal to 2m+1, and

R^b is independently H, alkyl or hydroxyalkyl.

12. The texaphyrin of claim 1 wherein the carboxyamidealkyl is alkyl having secondary or tertiary amide linkages.

13. The texaphyrin of claim 1 wherein the carboxyamidealkyl is (CH₂)_n CONHR^a, O(CH₂)_n CONHR^a, (CH₂)_n CON(R^a)₂, or O(CH₂)_a CON(R^a)₂ where

n is a positive integer from 1 to 10,

R^a is independently H, alkyl, hydroxyalkyl, C.sub.(m-w) H.sub.((2m+1)-2w) O_w O_z,

O₂ CC.sub.(m-w) H.sub.((2m+1)-2w) O_w O_z or N(R)OCC.sub.(m-w) H.sub.((2m+1)-2w) O_w O_z, where

m is a positive integer from 1 to 10,

w is zero or a positive integer less than or equal to m,

z is zero or a positive integer less than or equal to ((2m+1)-2w),

R is H, alkyl, hydroxyalkyl, or C_m H.sub.(2m+1)-r) O_z R^b_r where

m is a positive integer from 1 to 10,

z is zero or a positive integer less than ((2m+1)-r),

r is zero or a positive integer less than or equal to 2m+1, and

R^b is independently H, alkyl or hydroxyalkyl.

14. The texaphyrin of claim 1 wherein the carboxyalkyl is alkyl having a carboxyl substituted ether, an amide substituted ether or a tertiary amide removed from an ether.

15. The texaphyrin of claim 1 wherein the carboxyalkyl is C_n H.sub.((2n+1)-q) O_y R^c_q or OC_n H.sub.((2n+1)-q) O_y R^c_q where

n is a positive integer from 1 to 10;

y is zero or a positive integer less than ((2n+1)-q),

q is zero or a positive integer less than or equal to 2n+1,

R^c is (CH₂)_n CO₂ R^d, (CH₂)_n CONHR^d or (CH₂)_n CON(R^d)₂ where

n is a positive integer from 1 to 10;

R^d is independently H, alkyl, hydroxyalkyl, C.sub.(m-w) H.sub.((2m+1)-2w) O_w O_z,

O₂ C.sub.(m-w) H.sub.((2m+1)-2w) O_w O_z or N(R)OCC.sub.(m-w) H.sub.((2m+1)-2w) O_w O_z, where m is a positive integer from 1 to 10,

w is zero or a positive integer less than or equal to m,

z is zero or a positive integer less than or equal to ((2m+1)-2w),

R is H, alkyl, hydroxyalkyl, or C_m H.sub.((2m+1)-r) O_z R^b_r where

m is a positive integer from 1 to 10,

z is zero or a positive integer less than ((2m+1)-r),

r is zero or a positive integer less than or equal to 2m+1, and R^b is independently H, alkyl or hydroxyalkyl.

16. The texaphyrin of claim 1 wherein the linker is an amide, thiol, thioether or ether covalent bond.

17. The texaphyrin of claim 1 wherein the sapphyrin has binding specificity for localization to a treatment site.

18. The texaphyrin of claim 1 wherein

R₁ -R₄, R₇ and R₈ are independently hydrogen, halide other than iodide, hydroxyl, alkyl, aryl, haloalkyl other than iodoalkyl, nitro, formyl, acyl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, carboxy, carboxyalkyl, carboxyamidealkyl, a sapphyrin molecule, or a linker to a sapphyrin molecule;

at least one of R₅ and R₁₀ is alkyl, aryl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, carboxyalkyl, carboxyamidealkyl or a linker to a sapphyrin molecule;

where R₅ is other than hydrogen, then R₆ is hydrogen, fluorine or hydroxyl; and

where R₁₀ is other than hydrogen, then R₉ is hydrogen, fluorine or hydroxyl.

19. The texaphyrin of claim 1 wherein

R₁ -R₄, R₇ and R₈ are independently hydrogen, halide other than iodide, hydroxyl, alkyl, aryl, haloalkyl other than iodoalkyl, nitro, formyl, acyl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, carboxy, carboxyalkyl, carboxyamidealkyl, a sapphyrin molecule, or a linker to a sapphyrin molecule;

at least one of R₆ and R₉ is halide other than iodide, hydroxyl, alkyl, aryl, haloalkyl other than iodoalkyl, nitro, formyl, acyl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, carboxy, carboxyalkyl, carboxyamidealkyl, a sapphyrin molecule, or a linker to a sapphyrin molecule;

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

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

20. The texaphyrin of claim 1 where R₂ and R₃ are CH₂ CH₃ and R₄ is CH₃.

21. The texaphyrin of claim 1 where R₅ and R₁₀ are methyl.

22. The texaphyrin of claim 1 where R₅ and R₁₀ are CH₂ (CH₂)₆ OH.

23. The texaphyrin of claim 1 where R₅ and R₁₀ are (CH₂)_n CH₃ where n is 0, 1, 2, 3 or 4.

24. The texaphyrin of claim 1 where R₅ and R₁₀ are phenyl having an R₁₁ substituent where R₁₁ is hydrogen, nitro, carboxy, sulfonic acid, hydroxy, oxyalkyl or halide other than iodide.

25. The texaphyrin of claim 1 where R₆ is carboxy.

26. The texaphyrin of claim 1 where R₆ is alkyl or oxyalkyl.

27. The texaphyrin of claim 1 where R₆ is hydroxyl, halide other than iodide or nitro.

28. The texaphyrin of claim 1 where R₆ is carboxyamidealkyl having a tertiary amide linkage.

29. The texaphyrin of claim 1 wherein R₁ is CH₂ (CH₂)₂ OH.

30. The texaphyrin of claim 1 wherein R₇ or R₈ is O(CH₂ CH₂ O)₃ CH₃.

31. The texaphyrin of claim 1 wherein R₈ is any one of the substituents listed for R₈ in Table A.

32. The texaphyrin of claim 1 wherein R₉ is any one of the substituents listed for R₉ in Table A.

33. The texaphyrin of claim 1 wherein R₁ -₁₀ are as in Table A for texaphyrins A1-A38.

34. The texaphyrin of claim 1 wherein 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.