Hydroxylated texaphyrins

• US 5,457,183 A
• Filed: 10/12/1993
• Issued: 10/10/1995
• 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: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Kral, Vladimir, Sessler, Jonathan L., Mody, Tarak D., Hemmi, Gregory W.
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US08/135,118
• Time in Patent Office: 728 Days
• Field of Search: 534/11, 534/13, 534/15, 534/16, 540/145, 540/465, 540/472, 536/17.1, 536/17.4, 536/17.3, 530/345, 530/391.3, 530/391.5, 530/405
• US Class Current: 534/11
• 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

A method of using texaphyrins as radiosensitizers. Advantageous properties of texaphyrins for use as a radiosensitizer include i) a low redox potential which allows radiation induced solvated electrons to flow to texaphyrin rather than neutralizing hydroxyl radicals, allowing the hydroxyl radicals to cause cellular damage, ii) a relatively stable texaphyrin radical which, nevertheless, reacts readily to covalently modify neighboring molecules causing further cellular damage, and iii) intrinsic biolocalization and indifference to the presence of O₂ which allow texaphyrin to be particularly effective for treating the hypoxic areas of solid tumors. Sensitizer enhancement ratios of 1.62 and 2.2 were achieved at 20 μM and 80 μM gadolinium-texaphyrin, respectively, with a mouse leukemia cell line. Methods of treatment for an individual having a tumor include the use of a texaphyrin as a radiosensitizer and as an agent for photodynamic tumor therapy, or the use of a texaphyrin for internal and for external ionizing radiation. New water soluble hydroxy-substituted texaphyrins are described.

Claims

1. A water soluble compound retaining lipophilicity and 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 ;

R₂ and R₃ are CH₂ CH₃, R₄ is CH₃, R₁, R₅ and R₆ are independently hydrogen, hydroxyl, alkyl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, saccharide, carboxyalkyl, carboxyamidealkyl, antibody, a peptide having affinity for a biological receptor, a sapphyrin molecule, or a couple to an antibody, a peptide having affinity for a biological receptor, or a sapphyrin molecule, where at least one of R₁, R₅, and R₆ is oxyhydroxyalkyl, saccharide, oxyalkyl, carboxyalkyl, carboxyamidealkyl, hydroxyalkyl, an antibody, a peptide having affinity for a biological receptor, a sapphyrin molecule, or a couple to an antibody, a peptide having affinity for a biological receptor, or a sapphyrin molecule, having at least one hydroxy substituent; and

N is 0, 1 or 2.

2. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CONCH(CH₂ OH)₂ and R₅ and R₆ are OCH₃.

3. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CONCH(CH₂ OH)₂ and R₅ and R₆ are OCH₂ CH₂ CH₂ OH.

4. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CONCH(CH₂ OH)₂ and R₅ and R₆ are OCH₂ CH₂ OH.

5. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CONCH(CH₂ OH)₂ and R₅ and R₆ are O(CH₂ CH₂ O)_n CH₂ CH₂ OR'"'"', where n is an integer less than or equal to 10 and R'"'"' is H or CH₃.

6. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CONCH(CH₂ OH)₂ and R₅ and R₆ are independently H or CH₃.

7. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CONCH(CH₂ OH)₂, R₅ is CH₃, and R₆ is H, CH₃, OCH₃, OCH₂ CH₂ OH, OCH₂ CH₂ CH₂ OH, or O(CH₂ CH₂ O)_n CH₂ CH₂ OR'"'"', where n is an integer less than or equal to 10 and R'"'"' is H or CH₃.

8. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CON(CH₂ CH₂ OH)₂ and R₅ and R₆ are OCH₃.

9. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CON(CH₂ CH₂ OH)₂ and R₅ and R₆ are OCH₂ CH₂ CH₂ OH.

10. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CON(CH₂ CH₂ OH)₂ and R₅ and R₆ are OCH₂ CH₂ OH.

11. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CON(CH₂ CH₂ OH)₂ and R₅ and R₆ are O(CH₂ CH₂ O)_n CH₂ CH₂ OR'"'"', where n is an integer less than or equal to 10 and R'"'"' is H or CH₃.

12. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CON(CH₂ CH₂ OH)₂ and R₅ and R₆ are independently H or CH₃.

13. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CON(CH₂ CH₂ OH)₂, R₅ is CH₃, and R₆ is H, CH₃, OCH₃, OCH₂ CH₂ OH, OCH₂ CH₂ CH₂ OH, or O(CH₂ CH₂ O)_n CH₂ CH₂ OR'"'"', where n is an integer less than or equal to 10 and R'"'"' is H or CH₃.

14. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CONHCH₂ CH(OH)CH(OH)CH(OH)CH(OH)CH₂ OH and R₅ and R₆ are OCH₃.

15. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CONHCH₂ CH(OH)CH(OH)CH(OH)CH(OH)CH₂ OH and R₅ and R₆ are OCH₂ CH₂ CH₂ OH.

16. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CONHCH₂ CH(OH)CH(OH)CH(OH)CH(OH)CH₂ OH and R₅ and R₆ are OCH₂ CH₂ OH.

17. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CONHCH₂ CH(OH)CH(OH)CH(OH)CH(OH)CH₂ OH and R₅ and R₆ are O(CH₂ CH₂₀)_n CH₂ CH₂ OR'"'"', where n is an integer less than or equal to 10 and R'"'"' is H or CH₃.

18. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CONHCH₂ CH(OH)CH(OH)CH(OH)CH(OH)CH₂ OH and R₅ and R₆ are independently H or CH₃.

19. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CONHCH₂ CH(OH)CH(OH)CH(OH)CH(OH) CH₂ OH, R₅ is CH₃, and R₆ is H, CH₃, OCH₃, OCH₂ CH₂ OH, OCH₂ CH₂ CH₂ OH, or O(CH₂ CH₂ O)_n CH₂ CH₂ OR'"'"', where n is an integer less than or equal to 10 and R'"'"' is H or CH₃.

20. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CH₂ OH and R₅ and R₆ are OCH₃.

21. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CH₂ OH and R₅ and R₆ are OCH₂ CH₂ CH₂ OH.

22. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CH₂ OH and R₅ and R₆ are OCH₂ CH₂ OH.

23. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CH₂ OH and R₅ and R₆ are O(CH₂ CH₂₀)_n CH₂ CH₂ OR'"'"', where n is an integer less than or equal to 10 and R'"'"' is H or CHB.

24. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CH₂ OH and R₅ and R₆ are independently H or CH₃.

25. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CH₂ OH, R₅ is CH₃, and R₆ is H, CH₃, OCH₃, OCH₂ CH₂ OH, OCH₂ CH₂ CH₂ OH, or O(CH₂ CH₂ O)_n CH₂ CH₂ OR'"'"', where n is an integer less than or equal to 10 and R'"'"' is H or CH₃.

26. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CONHC₆ H₁₁ O₅ and R₅ and R₆ are OCH₃.

27. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CONHC₆ H₁₁ O₅ and R₅ and R₆ are OCH₂ CH₂ CH₂ OH.

28. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CONHC₆ H₁₁ O₅ and R₅ and R₆ are OCH₂ CH₂ OH.

29. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CONHC₆ H₁₁ O₅ and R₅ and R₆ are O(CH₂ CH₂ O)_n CH₂ CH₂ OR'"'"', where n is an integer less than or equal to 10 and R'"'"' is H or CH₃.

30. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CONHC₆ H₁₁ O₅ and R₅ and R₆ are independently H or CH₃.

31. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CONHC₆ H₁₁ O₅, R₅ is CH₃, and R₆ is H, CH₃, OCH₃, OCH₂ CH₂ OH, OCH₂ CH₂ CH₂ OH, or O(CH₂ CH₂ O)_n CH₂ CH₂ OR'"'"', where n is an integer less than or equal to 10 and R'"'"' is H or CH₃.

32. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ COOC₆ H₁₁ O₅ and R₅ and R₆ are OCH₃.

33. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ COOC₆ H₁₁ O₅ and R₅ and R₆ are OCH₂ CH₂ CH₂ OH.

34. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ COOC₆ H₁₁ O₅ and R₅ and R₆ are OCH₂ CH₂ OH.

35. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ COOC₆ H₁₁ O₅ and R₅ and R₆ are O(CH₂ CH₂ O)_n CH₂ CH₂ OR'"'"', where n is an integer less than or equal to 10 and R'"'"' is H or CH₃.

36. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ COOC₆ H₁₁ O₅ and R₅ and R₆ are independently H or CH₃.

37. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ COOC₆ H₁₁ O₅, R₅ is CH₃, and R₆ is H, CH₃, OCH₃, OCH₂ CH₂ OH, OCH₂ CH₂ CH₂ OH, or O(CH₂ CH₂ O)_n CH₂ CH₂ OR'"'"', where n is an integer less than or equal to 10 and R'"'"' is H or CH₃.

38. The water-soluble compound 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).

39. The water soluble compound of claim 1 wherein 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 ((2n+1)-q),

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

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),

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, hydroxyalkyl, or saccharide.

40. The water soluble compound 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)_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),

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, hydroxyalkyl, or saccharide.

41. The water soluble compound 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, saccharide,

C.sub.(m-w) H.sub.((2m+1)-2w) O_w O_z, O₂ CC.sub.(m-w) H.sub.((2m+1)-2 w) 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, hydroxyalkyl, or saccharide.

42. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CH₂ OH and R₅ and R₆ are O(CH₂ CH₂ O)₂ CH₂ CH₂ OR'"'"', where R'"'"' is H or CH₃.

43. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CH₂ OH and R₅ and R₆ are O(CH₂ CH₂ O)₂ CH₂ CH₂ OCH₃.

44. The water soluble compound of claim 23 wherein n is 2 and R'"'"' is CH₃.

45. The water soluble compound of claim 42, 43 or 44 wherein M is Gd⁺³.

46. The water soluble compound of claim 42, 43 or 44 wherein M is Lu⁺³.

47. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CH₂ OH and R₅ and R₆ are OCH₂ COOH or OCH₂ CH₂ COOH.

48. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CH₂ OH and R₅ and R₆ are OCH₂ CH₂ CONHC(CH₂ OH)₃ ;

OCH₂ CH₂ CH₂ NHCO[CH(OH)]₄ CH₂ OH;

OCH₂ CH₂ C(CH₂ OH)₃ ;

or OCH₂ CH₂ COOCH₂ C(CH₂ OH)₃.

49. The water soluble compound of claim 1 wherein R₁ is CH₂ CH₂ CH₂ OH;

R₅ is (O)_m (CH₂)_n CONHR, where m is zero or 1;

n is zero, 1, 2, or 3; and

R is an aminosugar, a polysaccharide, an oligosaccharide, or an oligopeptide; and

R₆ is H, OH, OCH₃, O(CH₂)₂ OH, O(CH₂)₃ OH, or COOH.

50. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CH₂ OH;

R₅ is (O)_m (CH₂)_n CONHR, where m is zero or 1;

n is zero, 1, 2, or 3; and

R is glucosamine, galactosamine, mannosamine, poly-L-lysine, derivatized poly-L-lysine, (LysAla)_n, (LysLeuAla)_n, polyglutamic acid, polyornithine, or heparin; and

R₆ is H, OH, OCH₃, O(CH₂)₂ OH, O(CH₂)₃ OH, or COOH.

51. The water soluble compound of claim 49 or 50 where R₆ is H.

52. The water soluble compound of claim 1 were R₁ is CH₂ (CH₂ CH₂ O)_n CH₂ CH₂ OR, where n is an integerless than or equal to 10 and R is H or CH₃ ;

and R₅ and R₆ are OCH₃, OCH₂ CH₂ OH;

OCH₂ CH₂ CH₂ OH;

O(CH₂ CH₂ O)_n CH₂ CH₂ OR'"'"', where n is an integer less than or equal to 10 and R'"'"' is H or CH₃ ;

or independently H or CH₃.

53. The water soluble compound of claim 52 where R₅ and R₆ are OCH₂ CH₂ CH₂ OH.

54. The water soluble compound of claim 1 where R₁ is (CH₂)_n CON(R'"'"')R, where n is 1, 2, or 3, R'"'"' is H or CH₃, and R is an aminosugar, a polysaccharide, an oligosaccharide, or an oligopeptide;

and R₅ and R₆ are CH₃, OCH₃, O(CH₂)₂ OH, or O(CH₂)₃ OH.

55. The water soluble compound of claim 1 where R₁ is O(CH₂)_n CON(R'"'"')R, where n is 1, 2, or 3, R'"'"' is H or CH₃, and R is glucosamine, galactosamine, mannosamine, poly-L-lysine, derivatized poly-L-lysine, (LysAla)_n, (LysLeuAla)_n, polyglutamic acid, polyornithine, or heparin;

and R₅ and R₆ are CH₃, OCH₃, O(CH₂)₂ OH, or O(CH₂)₃ OH.

56. The water soluble compound of claim 1 where R₅ and R₆ are OCH₂ CH₂ OHCH₂ OH.

57. The water soluble compound of claim 23 wherein M is Mn⁺² or Mn⁺³.

58. The water soluble compound of claim 43 wherein M is Mn⁺² or Mn⁺³.

59. The water soluble compound of claim 1 where R₁ is CH₂ CH₂ CH₂ OH, R₅ and R₆ are OCH₂ CH₂ CH₂ OH, and M is Mn⁺² or Mn⁺³.