Water soluble texaphyrin metal complexes for singlet oxygen production

• US 5,439,570 A
• Filed: 08/25/1993
• Issued: 08/08/1995
• Est. Priority Date: 03/06/1989
• Status: Expired due to Term

• Current Assignee: Pharmacyclics LLC (Abbvie Incorporated)
• Original Assignee: 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): Niebling, John
• Assistant Examiner(s): DELACROIX MUIRHEI, CYBILLE
• Application Number:
  US08/112,871
• Time in Patent Office: 713 Days
• Field of Search: 204/157.5, 204/157.15, 604/4
• US Class Current: 204/157.15
• 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 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 49/0036 Porphyrins used in photodynamic therapy A61K41/0071 or A61K41/0076; used as targeting group or modifying agent for targeting a therapeutic compound A61K47/546
• CPC Class Codes: A61K 49/0058 Antibodies
• CPC Class Codes: A61K 49/04 X-ray contrast preparations
• CPC Class Codes: A61K 49/106 the complex-forming compound being cyclic, e.g. DOTA
• 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 487/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07H 17/02 Heterocyclic radicals containing only nitrogen as ring hetero atoms
• 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

The present invention involves water soluble hydroxy-substituted texaphyrins retaining lipophilicity, the synthesis of such compounds and their uses. These expanded porphyrin-like macrocycles are efficient chelators of divalent and trivalent metal ions. Various metal (e.g., transition, main group, and lanthanide) complexes of the hydroxy-substituted texaphyrin derivatives of the present invention have unusual water solubility and stability. They absorb light strongly in a physiologically important region (i.e. 690-880 nm). They have enhanced relaxivity and therefore are useful in magnetic resonance imaging. They form long-lived triplet states in high yield and act as photosensitizers for the generation of singlet oxygen. Thus, they are useful for inactivation or destruction of human immunodeficiency virus (HIV-1), mononuclear or other cells infected with such virus as well as tumor cells. They are water soluble, yet they retain sufficient lipophilicity so as to have greater affinity for lipid rich areas such as atheroma and tumors. They may be used for magnetic resonance imaging followed by photodynamic tumor therapy in the treatment of atheroma and tumors. These properties, coupled with their high chemical stability and appreciable solubility in water, add to their usefulness.

Claims

1. A method of light induced singlet oxygen production comprising:

administering to a host a water soluble hydroxy-substituted aromatic pentadentate expanded porphyrin analog metal complex retaining lipophilicity and having intrinsic biolocalization selectivity; and

exposing the host to light in the presence of oxygen to produce singlet oxygen.

2. The method of claim 1 wherein the hydroxy-substituted aromatic pentadentate expanded porphyrin analog metal complex is the In, Lu or La complex of B2T2, 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-(3-hydroxypropyloxy)-13,20,25,26,27-pentaazapentacyclo[20.2.1.1³,6.1⁸,11.0¹4,19 ]heptacosa-1,3,5,7,9,11(27),12,14(19),15,17,20,22(25),23-tridecaene.

3. The method of claim 1 wherein the metal is a diamagnetic metal.

4. The method of claim 3 wherein the metal is La(III), Lu(III) or In(III).

5. A method of light-induced singlet oxygen production comprising

subjecting an hydroxy-substituted aromatic pentadentate expanded porphyrin analog metal complex to light in the presence of oxygen.

6. The method of claim 5 wherein the hydroxy-substituted aromatic pentadentate expanded porphyrin analog metal complex has the structure:

##STR12## wherein;

M is a diamagnetic metal cation;

R₁, R₂, R₃, R₄, and R₅ are independently H, OH, C_n H.sub.(2n+1) O_Y or OC_n H.sub.(2n+1) O_y, where

at least one of R₁, R₂, R₃, R₄, and R₅ is C_n H.sub.(2n+1) O_Y or OC_n H.sub.(2n+1) O_y, having at least one hydroxy substituent;

the molecular weight of any one of R₁, R₂, R₃, R₄, or R₅ is less than or equal to about 1000 daltons;

n is a positive integer from 1 to 10;

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

N is an integer less than or equal to 2.

7. The method of claim 5 wherein the hydroxy-substituted aromatic pentadentate expanded porphyrin analog metal complex has the structure:

##STR13## wherein;

M is a diamagnetic metal cation;

R₁, R₂, R₃, R₄, and R₅ are independently hydrogen, hydroxyl, alkyl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, saccharide, carboxyalkyl or carboxyamidealkyl where at least one of R₁, R₂, R₃, R₄, and R₅ is hydroxyl, oxyhydroxyalkyl, saccharide, oxyalkyl, carboxyalkyl, carboxyamidealkyl or hydroxyalkyl;

the molecular weight of any one of R₁, R₂, R₃, R₄, or R₅ is less than or equal to about 1000 daltons; and

N is an integer less than or equal to 2.

8. The method of claim 7 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).

9. The method of claim 7 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.

10. The method of claim 7 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.

11. The method of claim 7 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.((2+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.

12. The method of claim 7 where R₁ is hydroxyalkyl;

R₂, R₃ and R₄ are alkyl; and

R₅ is oxyalkyl.

13. The method of claim 12 where the hydroxyalkyl of R₁ is CH₂ CH₂ CH₂ OH, the alkyl of R₂ and R₃ is CH₂ CH₃, the alkyl of R₄ is CH₃, and the oxyalkyl of R₅ is O(CH₂ CH₂ O)₂ CH₂ CH₂ OR'"'"', where R'"'"' is H or CH₃.

14. The method of claim 13 where R'"'"' is CH₃.

15. The method of claim 14 where M is Lu(III).

16. The method of claim 5 wherein the light has a wavelength range from about 730 to about 770 nanometers.

17. The method of claim 5 wherein the light is at an intensity up to about 20 joules/cm².

18. The method of claim 5 wherein the hydroxy-substituted aromatic pentadentate expanded porphyrin analog metal complex is the Lu(III) 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[20.2.1.1³,6.1⁸,11.0¹⁴,19 ]heptacosa-1,3,5,7,9,11(27),12,14(19),15,17,20,22(25),23-tridecaene.

19. A method of photosensitization comprising:

administering to a host an hydroxy-substituted aromatic pentadentate expanded porphyrin analog metal complex having an absorption range from about 730 to about 770 nanometers and forming long-lived triplet states in high yield.

20. The method of claim 5 or 19 wherein the hydroxy-substituted aromatic pentadentate expanded porphyrin analog metal complex is a hydroxylated texaphyrin having an oxyalkyl substituent.

22. The method of claim 5, 19 or 21 wherein the metal is a diamagnetic metal.

23. The method of claim 5, 19 or 21 wherein the metal is In(III), Zn(II) or Cd(II).

24. The method of claim 5, 19 or 21 wherein the metal is a lanthanide metal.

25. The method of claim 5, 19 or 21 wherein the metal is Lu(III) or La(III).

21. A method of light-induced singlet oxygen production comprising subjecting a metal complex of B2T2, 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-(3-hydroxypropyloxy)-13,20,25,26,27-pentaazapentacyclo[20.2.1.1³,6.1⁸,11.0¹4,19 ]heptacosa-1,3,5,7,9,11(27),12,14(19),15,17,20,22(25),23-tridecaene, to light in the presence of oxygen.