Reduced sp.sup.3 texaphyrins

• US 5,504,205 A
• Filed: 07/26/1994
• Issued: 04/02/1996
• 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): Shah, Mukund J.
• Assistant Examiner(s): Sripada, Pavanaram K.
• Application Number:
  US08/280,351
• Time in Patent Office: 616 Days
• Field of Search: 540/145, 540/465, 540/472, 540/474
• US Class Current: 540/474
• 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 reduced sp³ texaphyrin having the structure:

##STR12## where R₁, R₂, R₃, R₄, and R₅ are independently hydrogen, hydroxyl, alkyl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, monosaccharide, carboxyalkyl or carboxyamidealkyl where at least one of R₁, R₂, R₃, R₄, and R₅ is hydroxyl, oxyhydroxyalkyl, monosaccharide, oxyalkyl, carboxyalkyl, carboxyamidealkyl or hydroxyalkyl and where at least one of R₁, R₂, R₃, R₄, and R₅ is oxyhydroxyalkyl, monosaccharide, oxyalkyl, carboxyalkyl, carboxyamidealkyl or hydroxyalkyl then at least one of R₁, R₂, R₃, R₄, and R₅ has at least one hydroxy substituent; and

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

2. The reduced sp³ texaphyrin 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).

3. The reduced sp³ texaphyrin of claim 1 wherein the oxyhydroxyalkyl or monosaccharide 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, monosaccharide, 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 monosaccharide.

4. The reduced sp³ texaphyrin 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, monosaccharide, 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 monosaccharide.

5. The reduced sp³ texaphyrin 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, monosaccharide,

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 monosaccharide.

6. The reduced sp³ texaphyrin of claim 1 wherein:

R₁, R₂, R₃, and R₄ are independently C_n H_2n+1 where n is a positive integer from 1 to about 10;

R₅ is hydroxyl, hydroxyalkyl, oxyhydroxyalkyl, carboxyalkyl or carboxyamidealkyl and where R₅ is hydroxyalkyl, oxyhydroxyalkyl, carboxyalkyl or carboxyamidealkyl then R₅ has at least one hydroxy substituent; and

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

7. The reduced sp³ texaphyrin of claim 1 wherein:

R₁, R₂, R₃, and R₄ are independently hydroxyl, alkyl, hydroxyalkyl, oxyhydroxyalkyl, carboxyalkyl or carboxyamidealkyl and at least one of R₁, R₂, R₃, and R₄ is hydroxyalkyl, carboxyalkyl, carboxyamidealkyl or oxyhydroxyalkyl having at least one hydroxy substituent;

R₅ is H or C_n H_2n+1 where n is a positive integer from 1 to 10; and

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

8. The reduced sp³ texaphyrin of claim 1 wherein:

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

R₅ is hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, monosaccharide, carboxyalkyl or carboxyamidealkyl having at least one hydroxy substituent; and

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

9. The reduced sp³ texaphyrin of claim 1 wherein R₅ is OCH₂ CH₂ CH₂ OH.

10. The reduced sp³ texaphyrin of claim 1 wherein:

R₁, R₂, and R₃ are CH₂ CH₃, R₄ is CH₃, and R₅ is OCH₂ CH₂ CH₂ OH.

11. The reduced sp³ texaphyrin of claim 1 wherein R₁ is (CH₂)₂ CH₂ OH.

12. The reduced sp³ texaphyrin of claim 1 wherein:

R₁ is (CH₂)₂ CH₂ OH, R₂ and R₃ are CH₂ CH₃ and R₄ and R₅ are CH₃.

13. The reduced sp³ texaphyrin of claim 1 wherein:

R₁ is (CH₂)₂ CH₂ OH and R₅ is OCH₂ CH₂ CH₂ OH.

14. The reduced sp³ texaphyrin of claim 1 wherein R₅ is OCH₂ CHOHCH₂ OH.

15. The reduced sp³ texaphyrin of claim 1 wherein:

R₁ is (CH₂)₂ CH₂ OH and R₅ is OCH₂ CHOHCH₂ OH.

16. The reduced sp³ texaphyrin of claim 1 wherein R₂ is CH₂ CH₂ OH.

17. The reduced sp³ texaphyrin of claim 1 wherein the oxyalkyl has repeating units of CH₂ CH₂ O.

18. The reduced sp³ texaphyrin of claim 1 wherein R₅ is OH.

19. The reduced sp³ texaphyrin of claim 1 wherein R₅ is OR'"'"' where R'"'"' is monosaccharide.

20. The reduced sp³ texaphyrin of claim 1 wherein R₅ is OR'"'"' where R'"'"' is carboxyalkyl.

21. The reduced sp³ texaphyrin of claim 20 wherein R₁ is hydroxyalkyl or carboxyalkyl.

22. The reduced sp³ texaphyrin of claim 1 wherein R₅ is OR'"'"' where R'"'"' is carboxyamidealkyl.