Texaphyrin-oligonucleotide conjugates

• US 5,587,371 A
• Filed: 06/02/1995
• Issued: 12/24/1996
• Est. Priority Date: 01/21/1992
• Status: Expired due to Term

• Current Assignee: Pharmacyclics Incorporated (Abbvie Incorporated), Board of Trustees University of TX Systems
• Original Assignee: Pharmacyclics Incorporated (Abbvie Incorporated), Board of Trustees University of TX Systems
• Inventors: Sessler, Jonathan L., Magda, Darren, Mody, Tarak D., Hemmi, Gregory W., Kr al, Vladimir A.
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US08/458,909
• Time in Patent Office: 571 Days
• Field of Search: 514/2, 514/6, 514/28, 514/32, 514/81, 514/185, 514/43, 514/44, 514/46, 534/11, 534/13, 534/15, 534/16, 536/17.1, 536/17.3, 540/145, 540/465, 540/472, 530/345, 530/391.3, 530/391.5, 530/405
• 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 41/0057 Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
• 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: A61K 49/0021 the fluorescent group being a small organic molecule
• CPC Class Codes: A61K 49/0054 Macromolecular compounds, i.e. oligomers, polymers, dendrimers
• CPC Class Codes: A61K 49/085 conjugated systems
• CPC Class Codes: A61K 49/10 Organic compounds
• CPC Class Codes: A61K 49/106 the complex-forming compound being cyclic, e.g. DOTA
• CPC Class Codes: A61K 49/126 Linear polymers, e.g. dextran, inulin, PEG
• CPC Class Codes: A61K 51/0485 Porphyrins, texaphyrins wherein the nitrogen atoms forming the central ring system complex the radioactive metal
• CPC Class Codes: A61L 2/0011 using physical methods
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: B01J 2531/025 Ligands with a porphyrin ring system or analogues thereof, e.g. phthalocyanines, corroles
• CPC Class Codes: B01J 2531/23 Calcium
• CPC Class Codes: B01J 2531/26 Zinc
• CPC Class Codes: B01J 2531/27 Cadmium
• CPC Class Codes: B01J 2531/28 Mercury
• CPC Class Codes: B01J 2531/36 : Yttrium
• CPC Class Codes: B01J 2531/37 : Lanthanum
• CPC Class Codes: B01J 2531/38 : Lanthanides other than lanthanum
• CPC Class Codes: B01J 2531/72 : Manganese
• CPC Class Codes: B01J 2531/842 : Iron
• CPC Class Codes: B01J 2531/845 : Cobalt
• CPC Class Codes: B01J 2531/847 : Nickel
• CPC Class Codes: B01J 2531/96 : Water
• CPC Class Codes: B01J 31/061 : Chiral polymers
• CPC Class Codes: B01J 31/1658 : immobilised by covalent linkages, i.e. pendant complexes with optional linking groups, e.g. on Wang or Merrifield resins
• CPC Class Codes: B01J 31/1805 : the ligands containing nitrogen
• CPC Class Codes: B01J 31/1815 : with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
• 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

Texaphyrins are provided for use as radiation sensitizers. Advantageous properties of texaphyrins for use as a radiation sensitizer include: i) a low redox potential which allows radiation-induced hydrated electrons to flow to texaphyrin rather than neutralizing hydroxyl radicals, allowing hydroxyl radicals to cause cellular damage, ii) a relatively stable texaphyrin radical that reacts readily to covalently modify neighboring molecules causing further cellular damage, iii) intrinsic biolocalization, and iv) indifference to the presence or absence of O₂. These properties allow texaphyrins to be particularly effective for treating the hypoxic areas of solid neoplasms. Methods of treatment for an individual having a neoplasm or atheroma include the use of a texaphyrin as a radiation sensitizer and as an agent for photodynamic tumor therapy, or the use of a texaphyrin for internal and for external ionizing radiation. Novel texaphyrins are provided.

Claims

1. A texaphyrin having the structure:

##STR5## wherein, M is H, a divalent metal cation or a trivalent metal cation;

each of R₁, R₂, R₃, R₄, R₇, and R₈ is independently hydrogen, hydroxyl, alkyl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, saccharide, oxyaminoalkyl, carboxy, carboxyalkyl, carboxyamidealkyl, an oligonucleotide or a couple to an oligonucleotide, where at least one of R₁, R₂, R₃, R₄, R₇ and R₈ is an oligonucleotide or a couple to an oligonucleotide; and

N is zero, 1 or 2.

2. The texaphyrin of claim 1 where the metal cation is a divalent metal cation selected from the group consisting of Ca(II), Mn(II), Co(II), Ni(II), Zn(II), Cd(II), Hg(II), Fe(II), Sm(II) and UO₂ (II), or a trivalent metal cation selected from the group consisting of Mn(III), Co(III), Ni(III), Fe(III), Ho(III), Ce(III), Y(III), In(III), Pr(III), Nd)III), Sc(III), Sm(III), Eu(III), Gd(III), Tb(III), Dy(III), Er(III), Tm(III), Yb(III), Lu(III), La(III), and U(III).

3. The texaphyrin of claim 1 where the oligonucleotide is an oligodeoxyribonucleotide.

4. The texaphyrin of claim 1 where the oligonucleotide is an oligoribonucleotide.

5. The texaphyrin of claim 1 where the oligonucleotide is a derivatized oligonucleotide or an oligonucleotide analog.

6. The texaphyrin of claim 5 where the derivatized oligonucleotide is selected from the group consisting of methylphosphonates, phosphotriesters, phosphorothioates, and phosphoramidates.

7. The texaphyrin of claim 5 where the derivatized oligonucleotide is 2'"'"'-O-alkyl oligoribonucleotide.

8. The texaphyrin of claim 1 where the oligonucleotide has binding specificity for localization to a treatment site.

9. The texaphyrin of claim 1 where the oligonucleotide has complementary binding affinity for oncogenes.

10. The texaphyrin of claim 1 where the oligonucleotide has complementary binding affinity for DNA.

11. The texaphyrin of claim 1 where the oligonucleotide has complementary binding affinity for RNA.

12. The texaphyrin of claim 1 where the oligonucleotide has complementary binding affinity for a targeted intracellular mRNA.

13. The texaphyrin of claim 1 where the oligonucleotide is an antisense oligonucleotide.

14. The texaphyrin of claim 1 wherein R₁ alkyl or hydroxyalkyl, and each of R₂, R₃ and R₄ is alkyl.

15. The texaphyrin of claim 1 where one of R₃, R₇ and R₈ is an oligonucleotide or a couple to an oligonucleotide.

16. The texaphyrin of claim 1 wherein the oligonucleotide or couple to oligonucleotide is O(CH₂)_n CO-oligonucleotide where n is 1 to 7.

17. The texaphyrin of claim 1 where the texaphyrin is attached to the 5'"'"' end of the oligonucleotide.

18. The texaphyrin of claim 1 where the texaphyrin is attached to the 3'"'"' end of the olignucleotide.

19. The texaphyrin of claim 1 where the texaphyrin is attached to the oligonucleotide at an internal position.

20. The texaphyrin of claim 5 where the derivatized oligonucleotide is a phosphorothioate.

21. The texaphyrin of claim 5 where the derivatized oligonucleotide is a phosphoramidate.

22. The texaphyrin of claim 5 where the derivatized oligonucleotide is 2'"'"'-O-substituted oligoribonucleotide.

23. The texaphyrin of claim 7 where the derivatized oligonucleotide is 2'"'"'-O-methyl oligoribonucleotide.

24. The texaphyrin of claim 1 where the oligonucleotide has complementary binding affinity for viral RNA.

25. The texaphyrin of claim 1 where the oligonucleotide has complementary binding affinity for retroviral RNA.

26. The texaphyrin of claim 1 where the oligonucleotide has complementary binding affinity for bacterial nucleic acids.

27. The texaphyrin of claim 1 where the oligonucleotide has complementary binding affinity for bacterial ribosomal RNA.

28. The texaphyrin of claim 5 where the derivatized oligonucleotide is a peptide nucleic acid.

29. The texaphyrin of claim 1 where two of R₁, R₂, R₃, R₄, R₇, and R₈ are oligonucleotides or couples to oligonucleotides.

30. The texaphyrin of claim 29 where R₃ is an oligonucleotide or a couple to an oligonucleotide, and R₈ is an oligonucleotide or a couple to an oligonucleotide.

31. The texaphyrin of claim 1 where R₁ is CH₂ CH₂ CH₂ OH, each of R₂ and R₃ is CH₂ CH₃, and R₄ is CH₃.

32. The texaphyrin of claim 31 where R₇ is OCH₂ CH₂ CH₂ OH and R₈ is an oligonucleotide or a couple to an oligonucleotide.

33. The texaphyrin of claim 31 where R₇ is O(CH₂ CH₂ O)₂ CH₂ CH₂ OCH₃ and R₈ is an oligonucleotide or a couple to an oligonucleotide.

34. The texaphyrin of claim 1 where 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).

35. The texaphyrin of claim 1 where the oxyhydroxyalkyl or saccharide 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 or equal to ((2n+1)-q);

q is zero or a positive integer less than or equal to (2n+1); and

R^a is independently H, alkyl, hydroxyalkyl, saccharide, 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), and

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 H, alkyl, hydroxyalkyl, or saccharide.

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

n is a positive integer from 1 to 10;

R^a is independently H, alkyl, hydroxyalkyl, saccharide, 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), and

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 H, alkyl, hydroxyalkyl, or saccharide.

37. The texaphyrin of claim 1 where 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 or equal to ((2n+1)-q);

q is zero or a positive integer less than or equal to (2n+1); and

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, and

R^d is H, alkyl, hydroxyalkyl, saccharide, 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),

and

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 H, alkyl, hydroxyalkyl, or saccharide.

38. The texaphyrin of claim 1 where the metal cation is a lanthanide metal.

39. The texaphyrin of claim 1 where the metal cation is a paramagnetic ion.

40. The texaphyrin of claim 1 where the metal cation is a diamagnetic ion.

41. The texaphyrin of claim 1 wherein R₁ is CH₂ CH₃ or CH₂ CH₂ CH₂ OH;

each of R₂ and R₃ is CH₂ CH₃ ;

R₄ is CH₃ ;

R₇ is H, OCH₃, OCH₂ CH₂ CH₂ OH or O(CH₂ CH₂ O)_n CH₃ where n is 1-7; and

R₈ is an oligonucleotide or a couple to an oligonucleotide.

42. A pharmaceutical perparation comprising the texaphyrin of claim 1.