Compounds containing acyclic N-N bonds for phototherapy

• US 8,731,655 B2
• Filed: 05/12/2010
• Issued: 05/20/2014
• Est. Priority Date: 05/12/2009
• Status: Expired due to Fees

• Current Assignee: SpecGx LLC (Mallinckrodt plc)
• Original Assignee: Mallinckrodt LLC (Mallinckrodt plc)
• Inventors: Rajagopalan, Raghavan
• Primary Examiner(s): Sims, Jason
• Assistant Examiner(s): Bori, Ibrahim D
• Application Number:
  US13/319,761
• Publication Number:
  US 20120053511A1
• Time in Patent Office: 1,469 Days
• Field of Search: 604/20
• US Class Current: 604/20
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 41/0057 Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
• CPC Class Codes: A61K 49/0019 characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
• CPC Class Codes: A61K 49/0026 Acridine dyes
• CPC Class Codes: A61K 49/0056 Peptides, proteins, polyamino acids
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The invention relates generally to optical agents for biomedical applications, including phototherapy. The invention includes optical agents, and related therapeutic methods, comprising compounds with an acyclic N—N bond having at least one aromatic and/or heterocyclic aromatic group providing phototherapeutic agents, including Type 1 phototherapeutic agents. In some embodiments, for example, the invention provides compounds for phototherapeutic methods having one or more photolabile acyclic N—N bonds capable of undergoing photoactivated cleavage to produce reactive species, such as radicals, ions, etc., that achieve a desired therapeutic effect, such as selective and/or localized tissue damage and/or cell death.

Claims

1. A method of performing a phototherapy procedure, the method comprising:

(i) administering to a patient in need thereof, a therapeutically effective amount of a phototherapeutic composition to a target tissue, wherein, the phototherapeutic composition comprises a compound of formula (FX1) or (FX2); and

(ii) exposing the administered phototherapeutic composition to electromagnetic radiation having wavelengths selected over the range of 350 nm and 1300 nm sufficient to result in injury or death to cells at the target tissue

2. The method of claim 1, wherein the compound absorbs the electromagnetic radiation having wavelengths selected over the range of 350 nanometers to 1300 nanometers.

3. The method of claim 1, wherein R¹ is C₅-C₃₀ aryl or C₅-C₃₀ heteroaryl, and R², R³ and R⁴ are independently hydrogen, C₁-C₂₀ alkyl, C₅-C₃₀ aryl, C₅-C₃₀ heteroaryl, a or wherein R² is C₅-C₃₀ aryl or C₅-C₃₀ heteroaryl, and R¹, R³ and R⁴ are independently hydrogen, C₁-C₂₀ alkyl, C₅-C₃₀ aryl, C₅-C₃₀ heteroaryl, or or wherein R³ is C₅-C₃₀ aryl or C₅-C₃₀ heteroaryl, and R¹, R² and R⁴ are independently hydrogen, C₁-C₂₀alkyl, C₅-C₃₀ aryl, C₅-C₃₀ heteroaryl, or wherein R⁴ is C₅-C₃₀ aryl or C₅-C₃₀ heteroaryl, and R¹, R² and R³ are independently hydrogen, C₁-C₂₀ alkyl, C₅-C₃₀ aryl, C₅-C₃₀ heteroaryl.

4. The method of claim 1, wherein at least one of R¹, R², R³ and R⁴ is independently a group corresponding to benzene, naphthalene, naphthoquinone, diphenylmethane, fluorene, anthracene, anthraquinone, phenanthrene, tetracene, naphthacenedione, pyridine, quinoline, isoquinoline, indole, isoindole, pyrrole, imidazole, oxazole, thiazole, pyrazole, pyrazine, pyrimidine, purine, benzimidazole, furan, benzofuran, dibenzofuran, carbazole, acridine, acridone, phenanthridine, thiophene, benzothiophene, dibenzothiophene, xanthene, xanthone, flavone, coumarin, azulene, azaazulene or anthracycline.

5. The method of claim 1,

wherein each of R¹, R², R³, and R⁴ Ar¹, Ar² , Ar³ and Ar⁴ is independently a group corresponding to benzene, naphthalene, naphthoquinone, diphenylmethane, fluorene, anthracene, anthraquinone, phenanthrene, tetracene, naphthacenedione, pyridine, quinoline, isoquinoline, indole, isoindole, pyrrole, imidazole, oxazole, thiazole, pyrazole, pyrazine, pyrimidine, purine, benzimidazole, furan, benzofuran, dibenzofuran, carbazole, acridine, acridone, phenanthridine, thiophene, benzothiophene, dibenzothiophene, xanthene, xanthone, flavone, coumarin, azulene, azaazulene or anthracycline;

and wherein R¹-R⁴ Ar¹-Ar⁴ do not include an azide group.

6. The method of claim 1, wherein at least one of R¹-R⁴ is independently a group corresponding to naphthalene, diphenylmethane, fluorene, anthracene, phenanthrene, tetracene, naphthoquinone, anthraquinone, naphthacenedione, azulene, azaazuleneor anthracycline.

7. The method of claim 1, wherein at least one of R¹-R⁴ is independently a group corresponding to pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, purine, acridine, acridone, or phenanthridine.

8. The method of claim 1, wherein at least one of R¹-R⁴ is independently a group corresponding to pyrrole, pyrazole, indole, isoindole, imidazole, oxazole, thiazole, purine, benzimidazole, or carbazole.

9. The method of claim 1, wherein at least one of R¹-R⁴ is independently a group corresponding to furan, oxazole, benzofuran, dibenzofuran, xanthene, xanthone, flavone, or coumarin.

10. The method of claim 1, wherein at least one of R¹-R⁴ is independently a group corresponding to thiophene, thiazole, benzothiophene, or dibenzothiophene.

11. The method of claim 1, wherein said compound is of the formula (FX21), (FX22), (FX23), (FX24) or (FX25):

12. The method of claim 1, wherein said procedure is a Type 1 phototherapy procedure.

13. The method of claim 1, wherein exposing the administered phototherapeutic agent to the electromagnetic radiation cleaves an N—

N bond of the compound.

14. The method of claim 1, further comprising contacting the target tissue of the subject with the administered phototherapeutic agent.

15. The method of claim 1, wherein the target tissue is a colon, prostate, gastric, esophageal, uterine, endometrial, pancreatic, breast, cervical, brain, skin, gallbladder, lung, throat, kidney, testicular, prostate, gastric, or ovary tissue.

16. The method of claim 1, wherein the target tissue is cancerous tissue or a tumor.

17. The method of claim 1 for use in treatment of cancer, a cancer-associated disorder, inflammation or an inflammation-associated disorder.