Water soluble texaphyrin metal complex preparation

• US 5,569,759 A
• Filed: 07/28/1993
• Issued: 10/29/1996
• 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:
  US08/098,514
• Time in Patent Office: 1,189 Days
• Field of Search: 540/145, 540/465, 540/472, 534/11, 424/9.3, 548/324
• 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 41/0076 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 enveloped viruses, mononuclear or other cells infected with such viruses 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 for synthesizing an aromatic texaphyrin metal complex having at least one hydroxy substituent, the method comprising:

mixing a nonaromatic texaphyrin having at least one hydroxy substituent, a metal cation, a Br.o slashed.nsted base and an oxidant selected from the group consisting of air, oxygen, platinum oxide and 2,3-dichloro-1,4-benzoquinone, in an organic solvent that dissolyes the nonaromatic texaphyrin; and

stirring at ambient temperature or heating the mixture at reflux for at least two hours to form an aromatic texaphyrin metal complex having at least one hydroxy substituent.

2. The method of claim 1 wherein the nonaromatic texaphrin having at least one hydroxy substituent is produced by condensation of a diformyltripyrrole having structure A;

and an ortho-phenylenediamine having structure B;

##STR12## where Rhd 1, R₂, R₃, R₄, and R₅ are independently H, OH, alkyl, oxyalkyl, hydroxyalkyl, oxyhydroxyalkyl, monosaccharide, carboxyalky or carboxyamidealkyl;

where at least one of R₁, R₂, R₃, R₄, and R₅ is oxyhydroxyalky, monosaccharide, oxyalkyl, carboxyalkyl, carboxyamidealkyl or hydroxyalkyl; and

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

3. The method of claim 2 wherein the diformyltripyrrole is 2,5-bis[(5-formyl-3-hydroxyalkyl-4-alkylpyrrol-2-yl)methyl]-3,4-dialkylpyrrole and the ortho-phenylenediamine is 1,2-diamino-4,5-bis(oxyhydroxyalkyl)benzene.

4. The method of claim 2 wherein the diformyltripyrrole is 2,5-bis[(5-formyl-3-hydroxyalkyl-4-alkylpyrrol-2-yl)methyl]-3,4-dialkylpyrrole.

5. The method of claim 2 wherein the orthophenylenediamine is 1,2-diamino-4,5-bis(oxyhydroxyalkyl)benzene.

6. The method of claim 5 wherein the orthophenylenediamine is 1,2-diamino-4,5-bis[(2,3-hydroxypropyl)oxy]benzene.

7. The method of claim 5 wherein the orthobenylenediamine is 1,2-diamino-4,5-bis[(2,3-dihydroxypropyl)oxy]benzene.

8. The method of claim 4 wherein the diformyltripyrrole is 2,5-bis[(5-formyl-3-hydroxypropyl-4-methylpyrrol-2-yl)methyl]-3,4-diethylpyrrole.

9. The method of claim 4 wherein the diformyltripyrrole is 2,5-bis[(3-ethyl-5-formyl-4-methylpyrrol-2-yl)methyl]-3,4-diethylpyrrole.

10. The method of claim 1 wherein the Br.o slashed.nsted base is triethylamine.

11. The method of claim 1 wherein the oxidant is air and the air is saturating the organic solvent.

12. The method of claim 1 wherein the stirring or heating at reflux step is stirring or heating at reflux the mixture for at least 24 hours.

13. The method of claim 1 wherein the organic solvent comprises methanol and chloroform.

14. The method of claim 1 wherein the organic solvent comprises methanol and benzene.

15. The method of claim 2 where

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

and

R₅ is hydroxyl, hydroxyalkyl, oxyhydroxyalkyl, carboxyalkyl or carboxyamidealkyl.

16. The method of claim 2 where

R₁, R₂, R₃, and R₄ are independently hydrogen, hydroxyl, alkyl, hydroxyalkyl, oxyhydroxyalkyl, carboxyalkyl or carboxyamidealkyl, and R₅ is H or C_n H_2n+1 where at least one of R₁, R₂, R₃, and R₄ is hydroxyl, hydroxyalkyl, carboxyaikyl, carboxyamidealkyl or oxyhydroxyalkyl;

and

n is a positive integer from 1 to 10.

17. The method of claim 2 where

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

18. The method of claim 2 where

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

19. The method of claim 2 where

R₁ is (CH₂)₂ CH₂ OH, R₂ and R₃ are CH₂ CH₃, R₄ is CH₃, and R₅ is OCH₂ CH₂ CH₂ OH.

20. The method of claim 2 where

R₁, R₂, and R₃ are CH₂ CH₃, R₄ is CH₃, and R₅ is OCH₂ CHOHCH₂ OH.

21. The method of claim 2 where

R₁ is (CH₂)₂ CH₂ OH, R₂ and R₃ are CH₂ CH₃, R₄ is CH₃, and R₅ is OCH₂ CHOHCH₂ OH.

22. The method of claim 2 where

R₁ is (CH₂)₂ CH₂ OH, R₂ is CH₂ CH₂ OH, R₃ is CH₂ CH₃, R₄ is CH₃, and R₅ is OCH₂ CHOHCH₂ OH.

23. The method of claim 2 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).

24. The method of claim 2 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 posimive 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.

25. The method of claim 2 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) 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.

26. The method of claim 2 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 mositive 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 Dositive integer less than or equal to 2m+1, and R^b is independently H, alkyl, hydroxyalkyl, or monosaccharide.

34. The method of claim 1 wherein the metal cation is a trivalent 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.

35. The method of claim 1 wherein the metal cation is a divalent cation selected from the group consisting of Ca⁺², Mn⁺², Co⁺², Ni⁺², Zn⁺², Cd⁺² , Hg⁺², Sm⁺², and UO.sub.⁺².

36. The method of claim 1 wherein the organic solvent comprises methanol.

38. The method of claim 2 where R₁ is hydroxyalkyl;

R₂, R₃ and R₄ are alkyl; and

R₅ is oxyalkyl.

39. The method of claim 38 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.

40. The method of claim 39 where R'"'"' is CH₃.

41. The method of claim 40 where the metal cation is Lu (III) or Gd (III).

27. A method for synthesizing a metal complex of 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-(3-hydroxypropyloxy)-13,20,25,26,27-pentaaza pentacyclo[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, the method comprising:

mixing 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis(3-hydroxypropyloxy)-13,20,25,26,27-pentaazapentacyclo[20.2.1.1³,6.1⁸,11.0.sup.14,19 ]heptacosa-3,5,8,10,12,14(19),15,17,20, 22,24-undecaene, 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, Gd³, Tb⁺³, Dy⁺³, Er³, Tm⁺³, Yb⁺³, Lu⁺³, La⁺³, and U⁺³, a Br.o slashed.nsted base and an oxidant selected from the group consisting of air, oxygen, platinum oxide and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. in an organic solvent that dissolves 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis(3-hydroxypropyloxy)-13,20,25,26,27-pentaaza-pentacyclo[20.2.1.1³,6.1⁸,11.0.sup.14,19 ]heptacosa-3,5,8,10,12,14(19),15,17,20,22,24-undecaene; and

stirring at ambient temperature or heating the mixture at reflux for at least two hours to form a metal complex of 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.

28. The method of claim 27 wherein the Br.o slashed.nsted base is triethylamine.

29. The method of claim 27 wherein the oxidant is air and the air is saturating the organic solvent.

30. The method of claim 27 wherein the stirring or heating at reflux step is stirring or heating at reflux the mixture for at least 24 hours.

31. The method of claim 27 wherein the organic solvent comprises methanol and chloroform.

32. The method of claim 27 wherein the organic solvent comprises methanol and benzene.

33. The method of claim 27 wherein the organic solvent comprises methanol and dimethylformamide.

37. The method of claim 27 wherein the organic solvent comprises methanol.

42. A method for synthesizing a metal 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, the method comprising:

mixing 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-3,5,8,10,12,14,16,18,20,22,24-undecaene, a metal cation, a Br.o slashed.nsted base and an oxidant selected from the group consisting of air, oxygen, platinum oxide and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, in an organic solvent that dissolves 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-3,5,8,10,12,14,16,18,20,22,24-undecaene; and

stirring at ambient temperature or heating the mixture at reflux for at least two hours to form a metal 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),2 3 -tridecaene.

43. The method of claim 42 wherein the Br.o slashed.nsted base triethylamine.

44. The method of claim 42 wherein the oxidant is air and the air is saturating the organic solvent.

45. The method of claim 42 wherein the organic solvent consists of methanol and chloroform, methanol and benzene, methanol and dimethylformamide, or methanol.

46. The method of claim 42 wherein the metal cation is a trivalent 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 or a divalent cation selected from the group consisting of Ca⁺², Mn⁺², Co⁺², Ni⁺², Zn⁺², Cd⁺², Hg⁺², Sm⁺² and UO₂⁺².