Radiation sensitization using texaphyrins

• US 5,622,946 A
• Filed: 05/10/1995
• Issued: 04/22/1997
• Est. Priority Date: 10/12/1993
• 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: Harriman, Anthony M., Miller, Richard A., Sessler, Jonathan L.
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US08/437,968
• Time in Patent Office: 713 Days
• Field of Search: 514/2, 514/23, 514/185, 514/410
• 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. An improved method for radiation therapy of a patient with a neoplasm or atheroma employing a radiation sensitizer, wherein the improvement comprises treating said patient with an effective amount of a texaphyrin as the radiation sensitizer.

28. The method of claim 1 wherein the texaphyrin has structure A or B:

##STR6## wherein, M is H, a divalent metal cation or a trivalent metal cation;

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, saccharide, aminoalkyl, oxyaminoalkyl, carboxy, carboxyalkyl, carboxyamidealkyl, a site-directing molecule or a couple to a site-directing molecule;

R₅ and R₁₀ are independently hydrogen, alkyl, aryl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, aminoalkyl, oxyaminoalkyl, carboxyalkyl, carboxyamidealkyl or a couple to a site-directing molecule;

R₁₁ is alkyl, alkenyl, oxyalkyl or hydroxyalkyl having up to about 3 carbon atoms and having rotational flexibility around a first-bound carbon atom;

where R₆ and R₉ are other than hydrogen, then R₅ and R₁₀ are hydrogen or methyl;

where R₅ and R₁₀ are other than hydrogen, then R₆ and R₉ are hydrogen, hydroxyl, or halide other than iodide; and

N is zero, 1 or 2.

2. A method of radiation therapy for a host harboring a neoplasm or atheroma comprising:

administering to the host a texaphyrin, said texaphyrin having radiosensitization properties; and

administering ionizing radiation to the host in proximity to the neoplasm or atheroma.

3. The method of claim 2 further comprising the step of determining localization sites in the host by reference to a detectable texaphyrin.

4. The method of claim 2 wherein the texaphyrin is complexed with a metal.

5. The method of claim 4 wherein the metal is a paramagnetic metal, a gamma-emitting metal, or a radioactive metal.

6. The method of claim 4 wherein the metal is selected from the group consisting of Gd(III), Mn(II), Mn(III), Fe(III), Y(III) and all trivalent lanthanides other than La(III), Lu(III) and Pm(III).

7. The method of claim 3 wherein determining localization sites occurs by observing fluorescence from the texaphyrin.

8. The method of claim 3 wherein the texaphyrin is complexed with a gamma-emitting metal and determining localization sites occurs by gamma camera body imaging.

9. The method of claim 3 wherein the texaphyrin is complexed with a paramagnetic metal and determining localization sites occurs by magnetic resonance imaging.

10. The method of claim 9 wherein the paramagnetic metal is Gd(III).

11. The method of claim 2 wherein the ionizing radiation is from an external source.

12. The method of claim 4 wherein the metal is a radioactive metal and the ionizing radiation is from the radioactive metal in combination with radiation from an external source.

13. The method of claim 2 wherein the texaphyrin is the Gd complex of 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]-13,20,25,26,27-pentaazapentacyclo[20.2.1.1³,6 0.1⁸,11 0.0¹⁴,19 ]-heptacosa-1,3,5,7,9,11(27),12,14(19),15,17,20,22(25),23-tridecaene.

14. The method of claim 3 wherein the texaphyrin is the Gd complex of 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]-13,20,25,26,27-pentaazapentacyclo[20.2.1.1³,6 0.1⁸,11 0.0¹⁴,19 ]-heptacosa-1,3,5,7,9,11(27),12,14(19),15,17,20,22(25),23-tridecaene.

15. The method of claim 2 further comprising the steps of administering to the host as a second agent a photosensitive texaphyrin having essentially identical biolocalization property, and administering photoirradiation in proximity to the neoplasm or atheroma.

16. The method of claim 15, wherein the photosensitive texaphyrin is a texaphyrin complexed to a diamagnetic metal and the diamagnetic metal is selected from the group consisting of Lu(III), La(III) and In(III).

17. The method of claim 2 where the texaphyrin has structure A or B:

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

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, saccharide, aminoalkyl, oxyaminoalkyl, carboxy, carboxyalkyl, carboxyamidealkyl, a site-directing molecule or a couple to a site-directing molecule;

R₅ and R₁₀ are independently hydrogen, alkyl, aryl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, aminoalkyl, oxyaminoalkyl, carboxyalkyl, carboxyamidealkyl or a couple to a site-directing molecule;

R₁₁ is alkyl, alkenyl, oxyalkyl or hydroxyalkyl having up to about 3 carbon atoms and having rotational flexibility around a first-bound carbon atom;

where R₆ and R₉ are other than hydrogen, then R₅ and R₁₀ are hydrogen or methyl;

where R₅ and R₁₀ are other than hydrogen, then R₆ and R₉ are hydrogen, hydroxyl, or halide other than iodide; and

N is 0, 1 or 2.

18. The method of claim 17 where the site-directing molecule is an oligonucleotide, a peptide, protein, steroid, hormone, hormone mimic or macrocycle.

19. The method of claim 17 where R₁ is (CH₂)₂ CH₂ OH;

R₂ and R₃ are CH₂ CH₃ ;

R₄ is CH₃ ;

R₅, R₆, R₉, and R₁₀ are H;

R₇ is H, OCH₃ or O(CH₂ CH₂ O)₂ CH₂ CH₂ OCH₃ ;

R₈ is a site-directing molecule, or a couple to a site-directing molecule; and

R₁₁ is methyl.

20. The method of claim 17 where R₄ is methyl and R₁ -R₃ and R₅ -R₁₀ are as in Table 1 for texaphyrins A1-A38.

21. The method of claim 17 where R₂ and R₃ are ethyl, R₄ is methyl, and R₁ and R₅ -R₁₁ are as in Table 2 for texaphyrins B1-B28.

22. The method of claim 17 where R₁ is (CH₂)₂ CH₂ OH;

R₂ and R₃ are CH₂ CH₃ ;

R₄ is CH₃ ;

R₅, R₆, R₉, and R₁₀ are H;

R₇ and R₈ are OCH₂ CH₂ CH₂ OH; and

R₁₁ is methyl.

23. The method of claim 17 where R₁ is CH₂ CH₂ CH₂ OH;

R₂ and R₃ are CH₂ CH₃ ;

R₄ is CH₃ ;

R₅, R₆, R₉, and R₁₀ are H;

R₇ and R₈ are O(CH₂ CH₂ O)₂ CH₂ CH₂ OCH₃ ; and

R₁₁ is methyl.

24. The method of claim 20 wherein M is a paramagnetic metal cation.

25. The method of claim 20 wherein M is Gd(III).

26. The method of claim 17 wherein the texaphyrin has structure A, where R₁ is (CH₂)₂ CH₂ OH;

R₂ and R₃ are CH₂ CH₃ ;

R₄ is CH₃ ;

R₅, R₆, R₉, and R₁₀ are H;

R₇ and R₈ are OCH₂ CH₂ CH₂ OH, or R₇ and R₈ are O(CH₂ CH₂ O)₂ CH₂ CH₂ OCH₃, or R₇ is H, OCH₃ or O(CH₂ CH₂ O)₂ CH₂ CH₂ OCH₃ and R₈ is a site-directing molecule or a couple to a site-directing molecule; and

M is a paramagnetic ion.

27. The method of claim 26 wherein M is Gd(III).

43. The method of claim 17 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).

44. The method of claim 17 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.

45. The method of claim 17 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.

46. The method of claim 17 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 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.

29. A method of radiation therapy for a host harboring a neoplasm or atheroma comprising:

administering to the host a texaphyrin, said texaphyrin having radiosensitization properties; and

administering ionizing radiation to the host in proximity to the neoplasm or atheroma;

wherein the texaphyrin has the following structure A;

##STR7## where, M is H, a divalent metal cation or a trivalent metal cation;

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, saccharide, aminoalkyl, oxyaminoalkyl, carboxy, carboxyalkyl, carboxyamidealkyl, a site-directing molecule or a couple to a site-directing molecule;

R₅ and R₁₀ are independently hydrogen, alkyl, aryl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, aminoalkyl, oxyaminoalkyl, carboxyalkyl, carboxyamidealkyl or a couple to a site-directing molecule;

where R₆ and R₉ are other than hydrogen, then R₅ and R₁₀ are hydrogen or methyl;

where R₅ and R₁₀ are other than hydrogen, then R₆ and R₉ are hydrogen, hydroxyl, or halide other than iodide; and

N is zero, 1 or 2.

30. The method of claim 29 wherein M is Gd(III).

31. The method of claim 29 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).

32. The method of claim 29 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.

33. The method of claim 29 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.

34. The method of claim 29 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 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.

35. The method of claim 29 wherein the site-directing molecule is an oligonucleotide, a peptide, a protein, asteroid, a hormone, a hormone mimic or a macrocycle.

36. The method of claim 29 wherein the site-directing molecule is an oligonucleotide.

37. The method of claim 29 wherein R₄ is methyl, and R₁ -R₃ and R₅ -R₁₀ are as in Table 1 for texaphyrins A1-A38.

38. The method of claim 29 wherein R₁ is CH₂ CH₃ or (CH₂)₂ CH₂ OH;

R₂ and R₃ are CH₂ CH₃ ;

R₄ is CH₃ ;

R₅, R₆, R₉, and R₁₀ are H; and

R₇ and R₈ are OCH₂ CH₂ CH₂ OH, or R₇ and R₈ are O(CH₂ CH₂ O)₂ CH₂ CH₂ OCH₃, or R₇ is H, OCH₃, OCH₂ CH₂ CH₂ OH or O(CH₂ CH₂ O)₂ CH₂ CH₂ OCH₃ and R₈ is a site-directing molecule or a couple to a site-directing molecule.

39. The method of claim 38 wherein the site-directing molecule is an oligonucleotide, a peptide, a protein, asteroid, a hormone, a hormone mimic or a macrocycle.

40. The method of claim 38 wherein the site-directing molecule is an oligonucleotide.

41. The method of claim 38 wherein M is Gd(III).

42. The method of claim 29 wherein R₁ is (CH₂)₂ CH₂ OH;

R₂ and R₃ are CH₂ CH₃ ;

R₄ is CH₃ ;

R₅, R₆, R₉, and R₁₀ are H;

R₇ and R₈ are O(CH₂ CH₂ O)₂ CH₂ CH₂ OCH₃ ; and

M is Gd(III).