Water soluble texaphyrin metal complexes for enhancing relaxivity

• US 5,475,104 A
• Filed: 08/25/1993
• Issued: 12/12/1995
• 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): Shah, Mukund J.
• Assistant Examiner(s): Sripada, Pavanaram K.
• Application Number:
  US08/112,786
• Time in Patent Office: 839 Days
• Field of Search: 540/145, 540/465, 540/472, 540/474, 534/11, 534/15, 536/27.1
• 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 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 imaging comprising:

administering to a subject to be imaged a paramagnetic metal complex of a water soluble hydroxy-substituted texaphyrin retaining lipophilicity; and

imaging the subject using a magnetic resonance device.

2. The method of claim 1 wherein the paramagnetic metal complex is the Gd 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.

3. The method of claim 1 wherein the metal complex of a water soluble hydroxy-substituted texaphyrin has the structure:

##STR12## wherein;

M is a paramagnetic 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.

4. The method of claim 1 wherein the metal complex of a water soluble hydroxy-substituted texaphyrin has the structure:

##STR13## wherein;

M is a paramagnetic metal cation;

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;

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.

5. The method of claim 4 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).

6. The method of claim 4 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) 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.

7. The method of claim 4 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.

8. The method of claim 4 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.

19. The method of claim 4 where R₁ is hydroxyalkyl;

R₂, R₃ and R₄ are alkyl; and

R₅ is oxyalkyl.

20. The method of claim 19 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.

21. The method of claim 20 where R'"'"' is CH₃.

22. The method of claim 21 where M is Gd(III).

23. The method of claim 1 wherein the paramagnetic metal complex is the Gd(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.

9. A method of magnetic resonance image enhancement in a subject comprising:

administering to the subject an effective amount of an hydroxy-substituted texaphyrin-paramagnetic metal complex; and

imaging the subject using a magnetic resonance device.

10. A method of detection of sarcoma or carcinoma in a patient comprising:

administering to a patient an hydroxy-substituted texaphyrin-paramagnetic metal complex in an amount effective to enhance a magnetic resonance image; and

detecting sarcoma or carcinoma by magnetic resonance imaging of said patient.

11. The method of claim 10 wherein the sarcoma is a fibrosarcoma.

15. The method of claim 9, 10, 12, 14 wherein the paramagnetic metal is a trivalent lanthanide metal other than Ln(III), Lu(III) and Pm(III).

16. The method of claim 9, 10, 12 or 14 wherein the paramagnetic metal is Mn(II), Mn(III), Fe(III) or Gd(III).

17. The method of claim 9, 10, 12 or 14 wherein the paramagnetic metal is Gd(III).

18. The method of claim 9, 10, 12 or 14 wherein the paramagnetic metal complex is the Gd 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.

24. The method of claim 10 wherein the paramagnetic metal complex is the Gd(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.

27. The method of claim 10 wherein the carcinoma is an adenocarcinoma.

12. A method of imaging an organ in a patient comprising:

administering to a patient an hydroxy-substituted texaphyrin-paramagnetic metal complex in an amount effective to enhance a magnetic resonance image of the organ; and

detecting the organ by magnetic resonance imaging of said patient.

13. The method of claim 12 wherein the organ is liver, kidney or the upper GI tract.

25. The method of claim 12 wherein the paramagnetic metal complex is the Gd(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.

14. A method of imaging atheroma in a patient comprising:

administering to a patient an hydroxy-substituted texaphyrin-paramagnetic metal complex in an amount effective to enhance a magnetic resonance image of atheroma; and

detecting atheroma by magnetic resonance imaging of said patient.

26. The method of claim 14 wherein the paramagnetic metal complex is the Gd(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.