Water soluble tetrapyrollic photosensitizers for photodynamic therapy

• US 7,501,509 B2
• Filed: 06/14/2006
• Issued: 03/10/2009
• Est. Priority Date: 06/27/2002
• Status: Expired due to Fees

• Current Assignee: Health Research Incorporated
• Original Assignee: Health Research Incorporated
• Inventors: Pandey, Ravindra K., Goswami, Lalit, Gryshuk, Amy, Oseroff, Allan, Potter, William
• Primary Examiner(s): Eyler; Yvonne
• Assistant Examiner(s): Nwaonicha; Chukwuma O
• Application Number:
  US11/452,511
• Publication Number:
  US 20070149497A1
• Time in Patent Office: 1,000 Days
• Field of Search: 540/140, 540/145, 534/14, 514/185, 514/410, 424/9.362, 424/9.6
• US Class Current: 540/145
• 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: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 471/22 in which the condensed systems contains four or more hetero rings
• CPC Class Codes: C09B 47/00 Porphines; Azaporphines non-dyeing compounds C07D487/22
• CPC Class Codes: C09B 69/108 containing a phthalocyanine dye

Abstract

A tetrapyrollic photosensitizer compound having at least one pendant —CH₂CH₂CON(CH₂CON(CH₂COOH)₂)₂ or —N(CH₂COOH)₂ group or esters thereof said tetrapyrollic compound being a chlorin, bacteriochlorin, porphyrin, pyropheophorbide, purpurinimide, or bacteriopurpurinimide. Desirably the compound has the formula:

or a phamaceutically acceptable derivative thereof, wherein R₁-R₈ and R₁₀ are various substituents and R₉ is substituted or unsubstituted —CH₂CH₂CON(CH₂CON(CH₂COOH)₂)₂; or —N(CH₂COOH)₂. The invention also includes a method of treatment by photodynamic therapy by treatment with light after injecting the compound and a method of imaging by fluorescence after injection of the compound.

Claims

1. A tetrapyrollic photosensitizer compound having at least one pendant —

CH₂CH₂CON(CH₂CON(CH₂COOH)₂)₂ or —

N(CH₂COOH)₂ group or esters thereof said tetrapyrollic compound being a chlorin, bacteriochlorin, porphyrin, pyropheophorbide, purpurinimide, or bacteriopurpurinimide.

11. A pharmaceutical composition, comprising a compound of claim 1 or a pharmaceutically acceptable derivative thereof in a pharmaceutically acceptable carrier.

2. A compound of the formula:

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

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

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

6. The compound of claim 2, 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, pseudohalo, 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, pseudohalo, or haloalkyl.

7. The compound of claim 2, 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, pseudohalo, 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, pseudohalo, or haloalkyl.

8. The compound of claim 2, 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.

9. The compound claim 2, 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.

10. The compound of claim 2, wherein:

R₇ is ═

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

12. A pharmaceutical composition, comprising a compound of claim 2 or a pharmaceutically acceptable derivative thereof in a pharmaceutically acceptable carrier.