Pyrole nitrogen-substituted texaphyrins

• US 5,583,220 A
• Filed: 05/24/1995
• Issued: 12/10/1996
• Est. Priority Date: 10/12/1993
• 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: Miller, Richard A., Sessler, Jonathan L., Magda, Darren, Mody, Tarak D., Kral, Vladimir A., Hemmi, Gregory W., Harriman, Anthony M.
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US08/449,681
• Time in Patent Office: 566 Days
• Field of Search: 540/145, 540/472
• US Class Current: 540/472
• 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:

##STR6## wherein 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, 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, 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; and

where

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

2. The texaphyrin of claim 1 where the site-directing molecule is an oligonucleotide, a peptide, protein, steroid, hormone, hormone mimic or macrocycle.

3. The texaphyrin of claim 1 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.

4. The texaphyrin of claim 1 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 OCH₂ CH₂ CH₂ OH, or R₇ and R₈ are O(CH₂ CH₂ O)₂ CH₂ CH₂ OCH₃ ; and

R₁₁ is methyl.

5. The texaphyrin of claim 1 where R₂ and R₃ are ethyl;

R₄ is methyl;

R₅, R₆, R₉ and R₁₀ are H; and

R₁, R₇, R₈ and R₁₁ are chosen from the substituents as in Table 2.

6. The texaphyrin of claim 1 chosen from compounds B1-B28 in Table 2.

7. 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).

8. 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.

9. 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.

10. 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.

11. The texaphyrin of claim 3 where the site-directing molecule is an oligonucleotide, a peptide, protein, steroid, hormone, hormone mimic or macrocycle.

12. The texaphyrin of claim 3 where the site-directing molecule is an oligonucleotide.