Diaza heterocyclic compounds for phototherapy
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Publication Number
US-9186349-B2
Publication Date
2015-11-17
Expiration Date
Abstract
The invention relates generally to optical agents, including phototherapeutic agents, for biomedical applications, including phototherapy. The invention includes optical agents, and related therapeutic methods, comprising alicyclic diaza compounds, including 1,2 diaza heterocyclic compounds, having a photolabile N—N bond directly or indirectly linked to at least one carbocyclic aromatic and/or heterocyclic aromatic group. In some embodiments, for example, the invention provides alicyclic diaza compounds for phototherapeutic methods having a photolabile N—N bond that undergoes 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.
Core Innovation
The invention provides phototherapeutic/optical agents containing an alicyclic diaza photolabile N–N bond linked to carbocyclic or heterocyclic aromatic chromophore or antenna groups. Upon exposure to electromagnetic radiation having wavelengths in the range of 350 nm to 1300 nm, the agent undergoes photoactivated cleavage of the N–N bond to form reactive species, including N radicals, that effect injury or death to cells at a target tissue.
The disclosure characterizes the agents as Type 1 phototherapy procedure agents and states that Type 1 phototherapy does not require oxygen. It describes improved performance under hypoxic tumor conditions where Type 1 photosensitizers are needed.
The disclosure further provides photochemical reaction mechanisms for alicyclic diaza photosensitizers, including single photon absorption and multiphoton absorption processes, intramolecular energy transfer from C5–C30 aryl or C5–C30 heteroaryl groups, and reactive species categories such as nitrene, ions, electrophiles, vibrationally excited species, and translationally excited species. It also describes targeting-ligand concepts using a targeting ligand (Bm), including receptor/peptide ligand examples such as bombesin, and carrier and illumination frameworks such as liposome or micelle carriers and endoscope or catheter illumination.
Claims Coverage
The independent claim coverage centers on a Type 1 phototherapy method for treating cancer, cancer-associated disorders, inflammation, or inflammation-associated disorders using a phototherapeutic agent of formula FX38 and exposure to electromagnetic radiation sufficient to cleave an N–N bond and form two N radicals. Dependent claims further refine substituent classes, target tissue selection, wavelength ranges, substituent identities, and a specific FX36 embodiment.
Type 1 phototherapy with N–N bond cleavage to form N radicals
A method of treating cancer, a cancer-associated disorder, inflammation, or an inflammation-associated disorder by administering a therapeutically effective amount of a phototherapeutic agent comprising a compound of formula (FX38) to a target tissue and exposing it to electromagnetic radiation having wavelengths selected over the range of 350 nm to 1300 nm sufficient to result in injury or death to cells, wherein the exposing cleaves the N–N bond forming two N radicals and the method is a Type 1 phototherapy procedure.
Dye-excited substituent selection for R1 and R6
At least one of R1 and R6 is a dye that is excited by electromagnetic radiation having wavelengths selected from 350 nm to 1300 nanometers, chosen from specified dye classes.
Selected target tissue list
The method is applied to a target tissue selected from specified human or organ tissues.
Narrowing electromagnetic radiation wavelengths to about 350 nm–900 nm
The electromagnetic radiation has wavelengths selected over the range of 350 nm to about 900 nm.
Substituent identity limitation for R1 and R6
R1 and R6 are each either t-Bu or H.
Specific formula embodiment FX(36)
The compound being administered is a compound of formula FX(36).
Overall, the claim set centers on Type 1 phototherapy in which a therapeutically effective amount of a defined phototherapeutic compound is administered to target tissue and then exposed to electromagnetic radiation to cleave an N–N bond and form two N radicals, resulting in cell injury or death. Dependent claims further constrain substituent classes, dye identity options, enumerated target tissues, specific substituent identities, and the irradiation wavelength range.
Stated Advantages
Results in injury or death to cells at the target tissue.
Operates as a Type 1 phototherapy procedure characterized in the document as not requiring oxygen.
Targets improved Type 1 photosensitizers under hypoxic tumor conditions.
Documented Applications
Treating cancer.
Treating a cancer-associated disorder.
Treating inflammation.
Treating an inflammation-associated disorder.
Applying the method to selected target tissues including colon, prostate, gastric, esophageal, uterine, endometrial, pancreatic, breast, cervical, brain, skin, gallbladder, lung, throat, kidney, testicular, and ovary.
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