Multi DTPA conjugated tetrapyrollic compounds for phototherapeutic contrast agents

• US 7,897,140 B2
• Filed: 06/30/2006
• Issued: 03/01/2011
• Est. Priority Date: 12/23/1999
• Status: Active Grant

• Current Assignee: Health Research Incorporated
• Original Assignee: Health Research Incorporated
• Inventors: Pandey, Ravindra K., Kanter, Peter, Goswami, Lalit, Mazurchuk, Richard, Spernyak, Joseph
• Primary Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US11/479,524
• Publication Number:
  US 20070053840A1
• Time in Patent Office: 1,705 Days
• Field of Search: 424/1.11, 424/1.45, 424/1.49, 424/1.65, 424/1.73, 424/9.1, 424/9.2, 424/9.3, 424/9.36, 424/9.361, 424/9.362, 424/9.364, 424/9.365, 424/1.69, 534/7, 534 10- 16, 534/550, 540/1, 540/121, 540/400, 540/450
• US Class Current: 424/9.362
• CPC Class Codes: A61K 41/0071 PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
• 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 49/124 dendrimers, dendrons, hyperbranched compounds
• CPC Class Codes: C07D 487/22 in which the condensed system contains four or more hetero rings

Abstract

Novel tetrapyrollic water soluble photosensitizing and imaging compounds and the methods of treating and imaging hyperproliferative tissue, e.g. tumors and hypervacularized tissue such as found in macular degeneration. Broadly, the compounds are tetrapyrollic photosensitizer compounds where the tetrapyrollic compound is a chlorin, bacteriochlorin, porphyrin, pyropheophorbide, purpurinimide, or bacteriopurpurinimide having 3 to 6 —CH₂CONHphenylCH₂CH(N(CH₂COOH)₂))(CH₂N(CH₂COOH)(CH₂CH₂N(CH₂COOH)₂)) groups or esters thereof or complexes thereof with gadolinium(III).

Claims

1. A tetrapyrollic photosensitizer compound said tetrapyrollic compound being a chlorin, bacteriochlorin, porphyrin, pyropheophorbide, purpurinimide, or bacteriopurpurinimide having 3 to 6 —

CH₂CONHphenylCH₂CH(N(CH₂COOH)₂)(CH₂N(CH₂COOH)(CH₂CH₂N(CH₂COOH)₂)) groups or esters thereof or complexes thereof with gadolinium(III).

2. The compound of claim 1 having at least one pendant —

CH₂CH₂CONHC(CH₂CH₂CONHphenylCH₂CH(N(CH₂COOH)₂(CH₂N(CH₂COOH)—

(CH₂CH₂N(CH₂COOH)₂)))₃ group or esters thereof or complexes thereof with gadolinium(III).

7. A compound according to claim 2 having the formula:

13. A pharmaceutical composition, comprising a compound of claim 1 in a pharmaceutically acceptable carrier.

15. An article of manufacture, comprising packaging material and a compound of claim 1 contained within the packaging material, and the packaging material includes a label that indicates that the compound is used in a photodynamic therapy treatment for hyperproliferative tissue.

17. A method for administering a therapy to hyperproliferative tissue, comprising:

(i) administering to a subject the compound of claim 1 that selectively interacts with the hyperproliferative tissue relative to normal tissue, and

(ii) irradiating the hyperproliferative tissue with light of a wavelength to kill or impair hyperproliferative tissue.

18. The method of claim 17, wherein the hyperproliferatve tissue is selected from the group consisting of:

a vascular endothelial tissue, a neovasculature tissue, a neovasculature tissue present in an eye, an abnormal vascular wall of a tumor, a solid tumor, a tumor of a head, a tumor of a neck, a tumor of an eye, a tumor of a gastrointestinal tract, a tumor of a liver, a tumor of a breast, a tumor of a prostate, a tumors of a lung, a nonsolid tumor, and malignant cells of one of a hematopoietic tissue and a lymphoid tissue.

21. The method of claim 17, further comprising the step of allowing time for any of the compound that is not selectively interacted with the hyperproliferative tissue to clear from normal tissue of the subject prior to the step of irradiating.

22. A method of photodynamic therapy for treating hyperproliferative tissue in a subject, comprising:

(i) administering to the subject the compound of claim 1 that selectively interacts with the hyperproliferative tissue relative to normal tissue, and

(ii) irradiating the subject with light of a wavelength to activate the compound, whereby the hyperproliferative tissue is destroyed or impaired.

24. A method for detecting the presence of a hyperproliferative tissue in a subject comprising:

(i) administering to the subject an effective quantity of the compound of claim 1, said compound being fluorescent and that selectively interacts with the hyperproliferative tissue relative to normal tissue; and

(ii) visualizing the compound within the patient by fluorescent spectroscopy.

26. A method for detecting the presence of a hyperproliferative tissue in a subject comprising:

(i) administering to the subject an effective quantity of the compound of claim 1, said compound being magnetically resonant and that selectively interacts with the hyperproliferative tissue; and

(ii) visualizing the compound within the patient by MRI imaging.

3. A compound of the formula:

4. The compound of claim 3 where R₉ is —

CH₂CH₂CONHC(CH₂CH₂CONHphenylCH₂CH(N(CH₂COOH)₂)(CH₂N(CH₂COOH)(CH₂CH₂N(CH₂COOH)₂)))₃

group or esters thereof or complexes thereof with gadolinium(III).

5. A compound according to claim 3 having the formula:

6. A compound according to claim 3 having the formula:

8. The compound of claim 3, wherein:

R₁ is substituted or unsubstituted alkyl;

R₂ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or —

C(O)R_a,

where R_a is substituted or unsubstituted alkyl;

R_1a and R_2a together form a covalent bond;

R₃ and R₄ are each independently substituted or unsubstituted alkyl;

R_3a and R_4a are each independently hydrogen, or together form a covalent bond;

R₅ is substituted or unsubstituted alkyl;

R₆ and R_6a together form ═

O;

R₇ is azaalkyl, or azaaralkyl;

R₈ and R_8a together form ═

O;

R₉ and R₁₀ are each independently substituted or unsubstituted alkyl;

each of R₁-R₁₀, when substituted, is substituted with one or more substituents each independently selected from Q, where Q is halo, haloalkyl, COOR_b where R_b is hydrogen or alkyl, OR_c where R_c is alkyl or aralkyl, NR_fR_g where R_f and R_g are each independently hydrogen, alkyl or aralkyl, or ═

NR_h where R_h is aralkyl;

each Q is independently unsubstituted or is substituted with one or more substituents each independently selected from Q₁, where Q₁ is halo, or haloalkyl.

9. The compound of claim 3, wherein:

R₁ is unsubstituted alkyl;

R₂ is substituted or unsubstituted alkyl, unsubstituted alkenyl, or —

C(O)R_a, where R_a is unsubstituted alkyl;

R_1a and R_2a together form a covalent bond;

R₃ and R₄ are each independently unsubstituted alkyl;

R_3a and R_4a are each independently hydrogen, or together form a covalent bond;

R₅ is unsubstituted alkyl;

R₆ and R_6a together form ═

O;

R₇ is azaalkyl, or azaaralkyl;

R₈ and R_8a together form ═

O;

R₁₀ is unsubstituted alkyl;

each of R₁-R₁₀, when substituted, is substituted with one or more substituents each independently selected from Q, where Q is halo, haloalkyl, COOR_b where R_b is hydrogen or alkyl, OR_c where R_c is alkyl or aralkyl, NR_fR_g where R_f and R_g are each independently hydrogen, alkyl or aralkyl, or ═

NR_h where R_h is aralkyl;

each Q is independently unsubstituted or is substituted with one or more substituents each independently selected from Q₁, where Q₁ is halo, or haloalkyl.

10. The compound of claim 3, wherein:

R₁ is methyl;

R_1a and R_2a together form a covalent bond;

R₃ is methyl;

R₄ is ethyl;

R_3a and R_4a are each independently hydrogen, or together form a covalent bond;

R₅ is methyl; and

R₁₀ is methyl.

11. The compound claim 3, wherein:

R₂ is CH═

CH₂, CH(OR₂₀)CH₃, C(O)Me, C(═

NR₂₁)CH₃ or CH(NHR₂₁)CH₃;

where R₂₀ is methyl, butyl, heptyl, dodecyl or 3,5-bis(trifluoromethyl)-benzyl; and

R₂₁ is 3,5-bis(trifluoromethyl)benzyl.

12. The compound of claim 3, wherein:

R₇ is ═

NR₂₀, where R₂₀ is methyl, butyl, heptyl, dodecyl or 3,5-bis(trifluoromethyl)-benzyl.

14. A pharmaceutical composition, comprising a compound of claim 3 in a pharmaceutically acceptable carrier.

16. An article of manufacture, comprising packaging material and a compound of claim 3 contained within the packaging material, and the packaging material includes a label that indicates that the compound is used in a photodynamic therapy treatment for hyperproliferative tissue.

19. A method for administering a therapy to a hyperproliferative tissue, comprising:

(i) administering to a subject the compound of claim 3 that selectively interacts with hyperproliferative tissue relative to normal tissue, and

(ii) irradiating the subject with light of a wavelength to kill or impair hyperproliferative tissue.

20. The method of claim 19, wherein the hyperproliferative tissue is selected from the group consisting of:

a vascular endothelial tissue, a neovasculature tissue, a neovasculature tissue present in an eye, an abnormal vascular wall of a tumor, a solid tumor, a tumor of a head, a tumor of a neck, a tumor of an eye, a tumor of a gastrointestinal tract, a tumor of a liver, a tumor of a breast, a tumor of a prostate, a tumors of a lung, a nonsolid tumor, and malignant cells of one of a hematopoietic tissue and a lymphoid tissue.

23. A method of photodynamic therapy for treating hyperproliferative tissue in a subject, comprising:

(i) administering to the subject the compound of claim 3 that selectively interacts with the hyperproliferative tissue relative to normal tissue, and

(ii) irradiating the subject with light of a wavelength to activate the compound, whereby the hyperproliferative tissue is destroyed or impaired.

25. A method for detecting the presence of a hyperproliferative tissue in a subject comprising:

(i) administering to the subject an effective quantity of the compound of claim 3, said compound being fluorescent and that selectively interacts with the hyperproliferative tissue relative to normal tissue; and

(ii) visualizing the compound within the patient by fluorescent spectroscopy.

27. A method for detecting the presence of a hyperproliferative tissue in a subject comprising:

(i) administering to the subject an effective quantity of the compound of claim 3, said compound being magnetically resonant and that selectively interacts with the hyperproliferative tissue relative to normal tissue; and

(ii) visualizing the compound within the patient by MRI imaging.