QUINONES FOR PROTECTION AGAINST RADIATION EXPOSURE

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.

62/102,541, filed January 12, 2015, the entire contents of which is incorporated by reference in its entirety.

TECHNICAL FIELD

[0002] The application discloses compositions and methods useful for treating or for protecting organisms against damage caused by exposure to radiation.

BACKGROUND

[0003] Exposure to radiation is a well-known cause of damage to cells, tissues, and organisms. Ionizing radiation such as high-frequency ultraviolet radiation, X-rays, gamma rays, alpha radiation, and beta radiation can break chemical bonds, leading to damage to biological molecules in cells. Damage to DNA is particularly deleterious, and is known to cause cancer and other pathologies. Further discussion of these effects can be found in, for example, International Patent Publication WO 2010/045220.

[0004] Exposure to ionizing radiation may occur during medical procedures, such as radiography, fluoroscopy, dental X-rays, and CT scans. People who routinely work with radiation or radioactive materials, such as X-ray technicians or nuclear medicine specialists, may also be inadvertently exposed to radiation. Exposure to radiation may also occur due to accidental release of radioactive materials into the environment, such as the 2011 Fukushima disaster or the 1979 Three Mile Island accident, or deliberate release of radioactive materials such as a "dirty bomb."

[0005] There is thus a need for radioprotective agents that can mitigate the adverse effects of exposure to radiation.

DISCLOSURE OF THE INVENTION

[0006] The present invention provides, in some embodiments, compounds and compositions for use in treating or protecting against injury or damage caused by radiation exposure, and methods of using such compounds for treating or for protecting against injury or damage caused by radiation exposure.

[0007] The present invention provides, in some embodiments, methods of using one or more compounds or compositions of Formula I, Formula I-Unsat, Formula I-Sat, Formula II, Formula II-Unsat, Formula II-Sat, Formula III, Formula III-Unsat, Formula Ill-Sat, Formula IV, Formula IV-Unsat, Formula IV-Unsat-R, Formula IV-Unsat-S, Formula IV-Sat, Formula IV-Sat-R, Formula IV-Sat-S, Formula V, Formula V-Unsat, Formula V-Sat, Formula VI, Formula Vl-Unsat, Formula VI-Unsat-R, Formula Vl-Unsat-S, Formula Vl-Sat, Formula VI- Sat-R, and Formula Vl-Sat-S, or a hydroquinone of any of those formulas, and tocotrienol quinones, tocotrienol hydroquinones, tocopherol quinones, and tocopherol hydroquinones disclosed herein, or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, non-crystalline form, isotopologue, deuterated form, hydrate, or solvate thereof, for treating or for protecting against injury or damage caused by radiation exposure, comprising administering to a cell or cells, a tissue or tissues, or a subject in need thereof, a therapeutically effective amount or a prophylactically effective amount of a compound or composition disclosed herein. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure. In another embodiment, the one or more compounds are used prophylactically prior to radiation exposure. In another embodiment, the one or more compounds are administered concurrently with radiation exposure. In another embodiment, the one or more compounds are

administered after radiation exposure.

[0008] The present invention provides, in some embodiments, methods of using one or more compounds or compositions of Formula I, Formula I-Unsat, Formula I-Sat, Formula II, Formula II-Unsat, Formula II-Sat, Formula III, Formula III-Unsat, Formula Ill-Sat, Formula IV, Formula IV-Unsat, Formula IV-Unsat-R, Formula IV-Unsat-S, Formula IV-Sat, Formula IV-Sat-R, Formula IV-Sat-S, Formula V, Formula V-Unsat, Formula V-Sat, Formula VI, Formula Vl-Unsat, Formula VI-Unsat-R, Formula Vl-Unsat-S, Formula Vl-Sat, Formula VI- Sat-R, and Formula Vl-Sat-S, or a hydroquinone of any of those formulas, and tocotrienol quinones, tocotrienol hydroquinones, tocopherol quinones, and tocopherol hydroquinones disclosed herein, or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, non-crystalline form, isotopologue, deuterated form, hydrate, or solvate thereof, for treating or for protecting against injury or damage from radiation exposure, comprising administering a therapeutically effective amount or a prophylactically effective amount of a compound or composition disclosed herein to a subject in need or potential need thereof. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure. In another embodiment, the one or more compounds are used prophylactically prior to radiation exposure. In another embodiment, the one or more compounds are administered concurrently with radiation exposure.

[0009] In another embodiment, the invention embraces a method of reducing the effect of ionizing radiation on normal cells in a subject exposed to or at risk of incurring exposure to ionizing radiation comprising administering to said subject prior to, concurrently with, or after the exposure to radiation, a therapeutically effective amount or a prophylactically effective amount of a compound or composition of Formula I, Formula I-Unsat, Formula I- Sat, Formula II, Formula II-Unsat, Formula II-Sat, Formula III, Formula III-Unsat, Formula

III- Sat, Formula IV, Formula IV-Unsat, Formula IV-Unsat-R, Formula IV-Unsat-S, Formula

IV- Sat, Formula IV-Sat-R, Formula IV-Sat-S, Formula V, Formula V-Unsat, Formula V-Sat, Formula VI, Formula Vl-Unsat, Formula VI-Unsat-R, Formula Vl-Unsat-S, Formula Vl-Sat, Formula VI-Sat-R, and Formula Vl-Sat-S, or a hydroquinone of any of those formulas, and tocotrienol quinones, tocotrienol hydroquinones, tocopherol quinones, and tocopherol hydroquinones disclosed herein, or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, non-crystalline form, isotopologue, deuterated form, hydrate, or solvate thereof.

[0010] In another embodiment, the invention embraces a method of treating, reducing, or preventing radiation injury or radiation damage to normal cells in a subject exposed to or at risk of incurring exposure to ionizing radiation comprising administering to said subject prior to, concurrently with, or after the exposure to radiation, a therapeutically effective amount or a prophylactically effective amount of a compound or composition of Formula I, Formula I- Unsat, Formula I-Sat, Formula II, Formula II-Unsat, Formula II-Sat, Formula III, Formula

III- Unsat, Formula Ill-Sat, Formula IV, Formula IV-Unsat, Formula IV-Unsat-R, Formula

IV- Unsat-S, Formula IV-Sat, Formula IV-Sat-R, Formula IV-Sat-S, Formula V, Formula V- Unsat, Formula V-Sat, Formula VI, Formula Vl-Unsat, Formula VI-Unsat-R, Formula VI- Unsat-S, Formula Vl-Sat, Formula VI-Sat-R, and Formula Vl-Sat-S, or a hydroquinone of any of those formulas, and tocotrienol quinones, tocotrienol hydroquinones, tocopherol quinones, and tocopherol hydroquinones disclosed herein, or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, noncrystalline form, isotopologue, deuterated form, hydrate, or solvate thereof. In some embodiments, the compound is administered prior to a radiation exposure. In some embodiments, the compound is administered subsequent to an accidental or intentional release of radioactive materials.

[0011] In another embodiment, the invention embraces a method of preventing death of radiation-damaged or radiation-injured non-cancerous cells with a therapeutically effective amount or a prophylactically effective amount of a compound or composition of Formula I, Formula I-Unsat, Formula I-Sat, Formula II, Formula Il-Unsat, Formula Il-Sat, Formula III, Formula III-Unsat, Formula Ill-Sat, Formula IV, Formula IV-Unsat, Formula IV-Unsat-R, Formula IV-Unsat-S, Formula IV-Sat, Formula IV-Sat-R, Formula IV-Sat-S, Formula V, Formula V-Unsat, Formula V-Sat, Formula VI, Formula Vl-Unsat, Formula VI-Unsat-R, Formula Vl-Unsat-S, Formula Vl-Sat, Formula VI-Sat-R, and Formula Vl-Sat-S, or a hydroquinone of any of those formulas, and tocotrienol quinones, tocotrienol hydroquinones, tocopherol quinones, and tocopherol hydroquinones disclosed herein, or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, non-crystalline form, isotopologue, deuterated form, hydrate, or solvate thereof.

[0012] In another embodiment, the invention embraces radiotherapy methods for treatment of cancer, comprising administering to a subject a therapeutically effective amount or a prophylactically effective amount of a compound or composition of Formula I, Formula I-Unsat, Formula I-Sat, Formula II, Formula Il-Unsat, Formula Il-Sat, Formula III, Formula

III- Unsat, Formula Ill-Sat, Formula IV, Formula IV-Unsat, Formula IV-Unsat-R, Formula

IV- Unsat-S, Formula IV-Sat, Formula IV-Sat-R, Formula IV-Sat-S, Formula V, Formula V- Unsat, Formula V-Sat, Formula VI, Formula Vl-Unsat, Formula VI-Unsat-R, Formula VI- Unsat-S, Formula Vl-Sat, Formula VI-Sat-R, and Formula Vl-Sat-S, or a hydroquinone of any of those formulas, and tocotrienol quinones, tocotrienol hydroquinones, tocopherol quinones, and tocopherol hydroquinones disclosed herein, or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, noncrystalline form, isotopologue, deuterated form, hydrate, or solvate thereof, and then administering to the subject an effective amount of radiation, such that radiation injury to normal cells is decreased or eliminated.

[0013] In some or any embodiments disclosed herein the compound, composition, or radioprotective agent is not a prodrug, metabolite, salt, phosphate substituted form, crystalline form, non-crystalline form, isotopologue, deuterated form, hydrate, or solvate thereof. In some or any embodiments disclosed herein the compound, composition, or radioprotective agent is a salt, a stereoisomer, a mixture of stereoisomers, a hydrate, or solvate thereof. In some or any embodiments disclosed herein the compound, composition, or radioprotective agent is a stereoisomer or a mixture of stereoisomers thereof.

[0014] In another embodiment of the invention, including any of the foregoing embodiments, the radiation is selected from the group consisting of radiation exposure from diagnostic X-rays, dental X-rays, radiotherapy for cancer treatment, CT scans (CAT scans), fluoroscopy, mammograms, radionuclide scans, radiation from ingestion of contaminated food or water, radiation from inhalation of contaminated air or gases, and uncontrolled exposure to ionizing radiation from nuclear weapons, radioactive spills and/or cosmic radiation.

[0015] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula I, and all stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, salts, phosphate substituted forms, crystalline forms, non-crystalline forms, deuterated forms, hydrates and solvates thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula I, and all stereoisomers, mixtures of stereoisomers, phosphate substituted forms, and deuterated forms, thereof; or the hydroquinones form thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula I, and all stereoisomers, and mixtures of stereoisomers thereof; or the hydroquinones form thereof. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used

prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof.

[0016] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula I-Unsat, and all stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, salts, phosphate substituted forms, crystalline forms, non-crystalline forms, deuterated forms, hydrates and solvates thereof; or the hydroquinones form thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula I-Unsat, and all stereoisomers, mixtures of stereoisomers, phosphate substituted forms, and deuterated forms, thereof; or the

hydroquinones form thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula I-Unsat, and all stereoisomers, and mixtures of stereoisomers thereof; or the hydroquinone forms thereof. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof.

[0017] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula I-Sat, and all stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, salts, phosphate substituted forms, crystalline forms, non-crystalline forms, deuterated forms, hydrates and solvates thereof; or the hydroquinones form thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula I-Sat, and all stereoisomers, mixtures of stereoisomers, phosphate substituted forms, and deuterated forms, thereof; or the

hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula I-Sat, and all stereoisomers, and mixtures of stereoisomers thereof; or the hydroquinone forms thereof. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof.

[0018] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula II, and all stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, salts, phosphate substituted forms, crystalline forms, non-crystalline forms, deuterated forms, hydrates and solvates thereof; or the hydroquinones form thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula II, and all stereoisomers, mixtures of stereoisomers, phosphate substituted forms, and deuterated forms, thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula II, and all stereoisomers, and mixtures of stereoisomers thereof; or the hydroquinone forms thereof. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used

prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof.

[0019] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula II-Unsat, and all stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, salts, phosphate substituted forms, crystalline forms, non-crystalline forms, deuterated forms, hydrates and solvates thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula II-Unsat, and all stereoisomers, mixtures of stereoisomers, phosphate substituted forms, and deuterated forms, thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula II-Unsat, and all stereoisomers, and mixtures of stereoisomers thereof; or the hydroquinone forms thereof. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof.

[0020] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula II-Sat, and all stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, salts, phosphate substituted forms, crystalline forms, non-crystalline forms, deuterated forms, hydrates and solvates thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula II-Sat, and all stereoisomers, mixtures of stereoisomers, phosphate substituted forms, and deuterated forms, thereof; or the

hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula II-Sat, and all stereoisomers, and mixtures of stereoisomers thereof; or the hydroquinone forms thereof. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof.

[0021] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula III, and all stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, salts, phosphate substituted forms, crystalline forms, non-crystalline forms, deuterated forms, hydrates and solvates thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula III, and all stereoisomers, mixtures of stereoisomers, phosphate substituted forms, and deuterated forms, thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula III, and all stereoisomers, and mixtures of stereoisomers thereof; or the hydroquinone forms thereof. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used

prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof.

[0022] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula III-Unsat, and all stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, salts, phosphate substituted forms, crystalline forms, non-crystalline forms, deuterated forms, hydrates and solvates thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula III-Unsat, and all stereoisomers, mixtures of stereoisomers, phosphate substituted forms, and deuterated forms, thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula III-Unsat, and all stereoisomers, and mixtures of stereoisomers thereof; or the hydroquinone forms thereof. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof.

[0023] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula Ill-Sat, and all stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, salts, phosphate substituted forms, crystalline forms, non-crystalline forms, deuterated forms, hydrates and solvates thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula Ill-Sat, and all stereoisomers, mixtures of stereoisomers, phosphate substituted forms, and deuterated forms, thereof; or the

hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula Ill-Sat, and all stereoisomers, and mixtures of stereoisomers thereof; or the hydroquinone forms thereof. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof.

[0024] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula IV, and all stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, salts, phosphate substituted forms, crystalline forms, non-crystalline forms, deuterated forms, hydrates and solvates thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula IV, and all stereoisomers, mixtures of stereoisomers, phosphate substituted forms, and deuterated forms, thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula IV, and all stereoisomers, and mixtures of stereoisomers thereof; or the hydroquinone forms thereof. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used

prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof. [0025] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula IV-Unsat, and all stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, salts, phosphate substituted forms, crystalline forms, non-crystalline forms, deuterated forms, hydrates and solvates thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula IV-Unsat, and all stereoisomers, mixtures of stereoisomers, phosphate substituted forms, and deuterated forms, thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula IV-Unsat, and all stereoisomers, and mixtures of stereoisomers thereof; or the hydroquinone forms thereof. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof.

[0026] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula IV-Sat, and all stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, salts, phosphate substituted forms, crystalline forms, non-crystalline forms, deuterated forms, hydrates and solvates thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula IV-Sat, and all stereoisomers, mixtures of stereoisomers, phosphate substituted forms, and deuterated forms, thereof; or the

hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula IV-Sat, and all stereoisomers, and mixtures of stereoisomers thereof; or the hydroquinone forms thereof. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof.

[0027] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula V, and all stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, salts, phosphate substituted forms, crystalline forms, non-crystalline forms, deuterated forms, hydrates and solvates thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula V, and all stereoisomers, mixtures of stereoisomers, phosphate substituted forms, and deuterated forms, thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula V, and all stereoisomers, and mixtures of stereoisomers thereof; or the hydroquinone forms thereof. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used

prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof.

[0028] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula V-Unsat, and all stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, salts, phosphate substituted forms, crystalline forms, non-crystalline forms, deuterated forms, hydrates and solvates thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula V-Unsat, and all stereoisomers, mixtures of stereoisomers, phosphate substituted forms, and deuterated forms, thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula V-Unsat, and all stereoisomers, and mixtures of stereoisomers thereof; or the hydroquinone forms thereof. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof.

[0029] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula V-Sat, and all stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, salts, phosphate substituted forms, crystalline forms, non-crystalline forms, deuterated forms, hydrates and solvates thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula V-Sat, and all stereoisomers, mixtures of stereoisomers, phosphate substituted forms, and deuterated forms, thereof; or the

hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula V-Sat, and all stereoisomers, and mixtures of stereoisomers thereof; or the hydroquinone forms thereof. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof.

[0030] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula VI, and all stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, salts, phosphate substituted forms, crystalline forms, non-crystalline forms, deuterated forms, hydrates and solvates thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula VI, and all stereoisomers, mixtures of stereoisomers, phosphate substituted forms, and deuterated forms, thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula VI, and all stereoisomers, and mixtures of stereoisomers thereof; or the hydroquinone forms thereof. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used

prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof.

[0031] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula Vl-Unsat, and all stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, salts, phosphate substituted forms, crystalline forms, non-crystalline forms, deuterated forms, hydrates and solvates thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula Vl-Unsat, and all stereoisomers, mixtures of stereoisomers, phosphate substituted forms, and deuterated forms, thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula Vl-Unsat, and all stereoisomers, and mixtures of stereoisomers thereof; or the hydroquinone forms thereof. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof.

[0032] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula Vl-Sat, and all stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, salts, phosphate substituted forms, crystalline forms, non-crystalline forms, deuterated forms, hydrates and solvates thereof; or the hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula Vl-Sat, and all stereoisomers, mixtures of stereoisomers, phosphate substituted forms, and deuterated forms, thereof; or the

hydroquinone forms thereof. In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent is selected from one or more compounds of Formula Vl-Sat, and all stereoisomers, and mixtures of stereoisomers thereof; or the hydroquinone forms thereof. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof.

[0033] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent comprises one or more compounds selected from the group consisting of alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, and delta-tocotrienol quinone. In one embodiment, the radioprotective agent comprises alpha-tocotrienol quinone. In one embodiment, the radioprotective agent comprises beta-tocotrienol quinone. In one embodiment, the radioprotective agent comprises gamma-tocotrienol quinone. In one embodiment, the radioprotective agent comprises delta- tocotrienol quinone. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof. In some or any embodiments, the alpha, beta, gamma, and delta-tocotrienol quinones have the naturally- occurring stereochemistry, i.e. 3i?-hydroxy-6E-10E.

[0034] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent comprises one or more compounds selected from the group consisting of alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma- tocotrienol hydroquinone, and delta-tocotrienol hydroquinone. In one embodiment, the radioprotective agent comprises alpha-tocotrienol hydroquinone. In one embodiment, the radioprotective agent comprises beta-tocotrienol hydroquinone. In one embodiment, the radioprotective agent comprises gamma-tocotrienol hydroquinone. In one embodiment, the radioprotective agent comprises delta-tocotrienol hydroquinone. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof. In some or any embodiments, the alpha, beta, gamma, and delta- tocotrienol hydroquinones have the naturally-occurring stereochemistry, i.e. 3i?-hydroxy-6E- 10E.

[0035] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent comprises one or more compounds selected from the group consisting of alpha-tocopherol quinone, beta-tocopherol quinone, gamma-tocopherol quinone, and delta-tocopherol quinone. In one embodiment, the radioprotective agent comprises alpha-tocopherol quinone. In one embodiment, the radioprotective agent comprises beta-tocopherol quinone. In one embodiment, the radioprotective agent comprises gamma-tocopherol quinone. In one embodiment, the radioprotective agent comprises delta- tocopherol quinone. In one embodiment, the one or more compounds are used

therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof. In some or any embodiments, the alpha, beta, gamma, and delta-tocopherol quinones have the naturally- occurring stereochemistry, z ^' .e.3(i?)-hydroxy and 7( ?)-methyl and 1 l( ?)-methyl on the tail group.

[0036] In another embodiment of the invention, including any of the foregoing embodiments, the radioprotective agent comprises one or more compounds selected from the group consisting of alpha-tocopherol hydroquinone, beta-tocopherol hydroquinone, gamma- tocopherol hydroquinone, and delta-tocopherol hydroquinone. In one embodiment, the radioprotective agent comprises alpha-tocopherol hydroquinone. In one embodiment, the radioprotective agent comprises beta-tocopherol hydroquinone. In one embodiment, the radioprotective agent comprises gamma-tocopherol hydroquinone. In one embodiment, the radioprotective agent comprises delta-tocopherol hydroquinone. In one embodiment, the one or more compounds are used therapeutically during, after, or during and after radiation exposure, by administering a therapeutically effective amount to a subject in need thereof. In another embodiment, the one or more compounds are used prophylactically prior to radiation exposure, by administering a prophylactically effective amount to a subject in need (or potential need) thereof. In some or any embodiments, the alpha, beta, gamma, and delta- tocopherol hydroquinones have the naturally-occurring stereochemistry, i.e. 3( ?)-hydroxy and 7( ?)-methyl and 1 l( ?)-methyl on the tail group.

[0037] Any one or more of the compounds described herein, including all of the foregoing compounds, can be used in a composition comprising a pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, or pharmaceutically acceptable vehicle. Any one or more of the compounds described herein, including all of the foregoing compounds, can be formulated into a unit dose formulation.

[0038] For all the compounds, compositions, formulations and methods described herein, any compound, composition, or formulation in the quinone form can also be used in its reduced form (hydroquinone) when desired. That is, the compounds recited herein as cyclohexadienedione compounds (oxidized quinone) form can also be used in their benzenediol (reduced hydroquinone) form as desired.

[0039] For all compounds, compositions, and formulations described herein, and all methods using a compound or composition or formulation described herein, the compounds or compositions can either comprise the listed components or steps, or can "consist essentially of the listed components or steps, or can "consist of the listed components or steps. That is, the transitional phrase "comprising" or "comprises" can be replaced by the transitional phrase "consisting essentially of or "consists essentially of." Alternatively, the transitional phrase "comprising" or "comprises" can be replaced, in some or any embodiments, by the transitional phrase "consisting of or "consists of." When a composition is described as "consisting essentially of the listed components, the composition contains the components listed, and may contain other components which do not substantially affect the condition being treated, but do not contain any other components which substantially affect the condition being treated other than those components expressly listed; or, if the composition does contain extra components other than those listed which substantially affect the condition being treated, the composition does not contain a sufficient concentration or amount of the extra components to substantially affect the condition being treated. When a method is described as "consisting essentially of the listed steps, the method contains the steps listed, and may contain other steps that do not substantially affect the condition being treated, but the method does not contain any other steps which substantially affect the condition being treated other than those steps expressly listed. As a non-limiting specific example, when a composition is described as 'consisting essentially of a component, the composition may additionally contain any amount of pharmaceutically acceptable carriers, vehicles, excipients, or diluents and other such components which do not substantially affect the condition being treated.

BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figures 1 A and B show the percent survival and mean weight change, respectively, for CD2F1 mice exposed to LD ₉₀ dose of total body irradiation and treated with (3R)-alpha-tocotrienol quinone or vehicle only.

[0041] Figures 2 A and B show the percent survival and mean weight change, respectively, for CD2F1 mice exposed to LD100 dose of total body irradiation and treated with (3R)-alpha-tocotrienol quinone or vehicle only.

[0042] Figure 3 shows the injection sites after 28 days for mice treated with (3R)-alpha- tocotrienol quinone (Figure 3 A) and delta-tocotrienol (Figures 3 B-E), respectively.

MODES FOR CARRYING OUT THE INVENTION

[0043] The present invention provides compounds and compositions for use in treating or protecting against injury or damage caused by radiation exposure, and methods of using such compounds for treating or for protecting against injury or damage caused by radiation exposure. [0044] The abbreviations used herein have their conventional meaning within the chemical and biological arts, unless otherwise specified.

[0045] Reference to "about" a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to "about X" includes description of "X".

[0046] The terms "a" or "an," as used in herein means one or more, unless the context clearly dictates otherwise.

[0047] By "subject," "individual," or "patient" is meant an individual organism, preferably a vertebrate, more preferably a mammal, most preferably a human.

[0048] By "radiation," as used herein, is meant radiation, including ionizing radiation, capable of causing molecular or cellular damage. Such forms of radiation include ultraviolet radiation, alpha radiation, beta radiation, x-rays, and gamma rays.

[0049] Sources of radiation include, in some embodiments, radioactive isotopes, which may be naturally-occurring or man-made, and cosmic rays. Radiation can be emitted due to the gradual decay of radioactive isotopes, or due to nuclear fission or fusion events (as in an atomic bomb or nuclear reactor). In some embodiments, the radiation is x-ray radiation. In some embodiments, the radiation is gamma radiation. In other embodiments, the radiation is beta radiation. In other embodiments, the radiation is alpha radiation. In other embodiments, the radiation is ultraviolet radiation. In other embodiments, the radiation is radiation due to radiation therapy. In other embodiments, the radiation is radiation due to radioactive fallout or contamination.

[0050] As used herein, the term "preventing radiation damage" means eliminating, ameliorating or decreasing one or more indicia of radiation damage in a cell, tissue, or subject that has received one or more compounds or compositions disclosed herein, compared to a cell, tissue, or subject that has not received one or more compounds or compositions disclosed herein. As used herein, the term "protecting a cell, tissue, or subject against radiation damage" means eliminating, ameliorating or decreasing one or more indicia of radiation damage in the cell, tissue, or subject which has received one or more compounds or compositions disclosed herein, compared to a cell, tissue, or subject which has not received one or more compounds or compositions disclosed herein. In one aspect, treatment or prophylaxis of radiation damage in a cell, tissue, or subject involves decreasing damage to one or more nucleic acid molecules in a cell, tissue, or subject which has received one or more compounds or compositions disclosed herein by at least about 10%, 20%, 30%>, 40%>, 50%, 80%, 90%), or 95%, compared to a cell, tissue, or subject which has not received one or more compounds or compositions disclosed herein.

[0051] "Treating" radiation exposure with the compounds and methods discussed herein is defined as administering one or more of the compounds discussed herein, with or without additional therapeutic agents, in order to reduce or eliminate either the deleterious effects of radiation exposure or one or more symptoms of radiation exposure, or to retard the progression of the deleterious effects of radiation exposure or of one or more symptoms of radiation exposure, or to reduce the severity of the deleterious effects of radiation exposure or of one or more symptoms of radiation exposure, or to suppress the clinical manifestation of radiation exposure, or to suppress the manifestation of adverse symptoms of radiation exposure. "Prophylaxis" against injury or damage caused by radiation exposure with the compounds and methods discussed herein is defined as administering one or more of the compounds discussed herein, with or without additional therapeutic agents, prior to exposure to radiation, in order to reduce or eliminate either the deleterious effects of radiation exposure or one or more symptoms of radiation exposure, or to retard the progression of the deleterious effects of radiation exposure or of one or more symptoms of radiation exposure, or to reduce the severity of the deleterious effects of radiation exposure or of one or more symptoms of radiation exposure, or to suppress the clinical manifestation of radiation exposure, or to suppress the manifestation of adverse symptoms of radiation exposure. Prophylactic use of the compounds and methods of the invention would include, in some embodiments, administering one or more of the compounds described herein to patients undergoing radiotherapy at risk of radiation damage or injury, where the compound or compounds are administered prior to radiotherapy, or to workers in the nuclear industry at risk of exposure to radiation prior to the arrival of the workers at a site where they could be exposed to excessive radiation. "Therapeutic use" of the compounds discussed herein is defined as using one or more of the compounds discussed herein to treat radiation exposure. "Prophylactic use" of the compounds discussed herein is defined as using one or more of the compounds discussed herein as a prophylaxis against radiation exposure (e.g. to suppress the deleterious effects of radiation exposure or one or more symptoms of radiation exposure) prior to radiation exposure. A "therapeutically effective amount" of a compound is an amount of the compound, which, when administered to a subject, is sufficient to reduce or eliminate either the deleterious effects of radiation exposure or one or more symptoms of radiation exposure, or to retard the progression of the deleterious effects of radiation exposure or of one or more symptoms of radiation exposure, or to reduce the severity of the deleterious effects of radiation exposure or of one or more symptoms of radiation exposure, or to suppress the deleterious effects of radiation exposure or of one or more symptoms of radiation exposure. A "prophylactically effective amount" of a compound is an amount of the compound, which, when administered to a subject prior to radiation exposure, is sufficient to suppress the deleterious effects of radiation exposure, or the clinical manifestation of radiation exposure, or to suppress the manifestation of adverse symptoms of radiation exposure. A

therapeutically effective amount or a prophylactically effective amount can be given in one or more administrations.

[0052] A "radioprotective agent" is a compound suitable for therapeutic use for radiation exposure, or suitable for prophylactic use against radiation exposure. In some or any embodiments, the radioprotective agent is one or more compounds or compositions of Formula I, Formula I-Unsat, Formula I-Sat, Formula II, Formula II-Unsat, Formula II-Sat, Formula III, Formula III-Unsat, Formula Ill-Sat, Formula IV, Formula IV-Unsat, Formula IV-Unsat-R, Formula IV-Unsat-S, Formula IV-Sat, Formula IV-Sat-R, Formula IV-Sat-S, Formula V, Formula V-Unsat, Formula V-Sat, Formula VI, Formula Vl-Unsat, Formula VI- Unsat-R, Formula Vl-Unsat-S, Formula Vl-Sat, Formula VI-Sat-R, and Formula Vl-Sat-S, or a hydroquinone of any of those formulas, and tocotrienol quinones, tocotrienol

hydroquinones, tocopherol quinones, and tocopherol hydroquinones disclosed herein, or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, non-crystalline form, isotopologue, deuterated form, hydrate, or solvate thereof.

[0053] A subject in "potential need" of a compound, composition, or formulation of the invention, or a method of the invention, is a subject who may be exposed to excessive radiation, in some embodiments, who has a about a 0.001% chance, about a 0.01% chance, about a 0.1% chance, about a 1% chance, about a 5% chance, about a 10% chance, about a 25%o chance, or about a 50%> chance of being exposed to excessive radiation, or at least about a 0.001% chance, at least about a 0.01% chance, at least about a 0.1% chance, at least about a 1% chance, at least about a 5% chance, at least about a 10% chance, at least about a 25% chance, or at least about a 50% chance of being exposed to excessive radiation. In some embodiments, excessive radiation can be more than about 1 mSv in one year, more than about 2 mSv in one year, more than about 5 mSv in one year, more than about 10 mSv in one year, more than about 20 mSv in one year, or more than about 50 mSv in one year. In some embodiments, excessive radiation can be more than about 1 mGray in one year, more than about 2 mGray in one year, more than about 5 mGray in one year, more than about 10 mGray in one year, more than about 20 mGray in one year, or more than about 50 mGray in one year. A subject in need or potential need of a compound, composition, or formulation of the invention, or a method of the invention, can also be a subject who desires protection against exposure to routine radiation, such as natural background radiation, such as ultraviolet light, in order to minimize the effects of routine or background exposure to radiation.

Compounds for Use in the Invention for Treatment or Prophylaxis of Radiation Exposure

[0054] The compounds disclosed below of Formula I, Formula I-Unsat, Formula I-Sat, Formula II, Formula II-Unsat, Formula II-Sat, Formula III, Formula III-Unsat, Formula III- Sat, Formula IV, Formula IV-Unsat, Formula IV-Unsat-R, Formula IV-Unsat-S, Formula IV- Sat, Formula IV-Sat-R, Formula IV-Sat-S, Formula V, Formula V-Unsat, Formula V-Sat, Formula VI, Formula Vl-Unsat, Formula VI-Unsat-R, Formula Vl-Unsat-S, Formula Vl-Sat, Formula VI-Sat-R, and Formula Vl-Sat-S, or a hydroquinone of any of those formulas, and the various tocotrienol quinones, tocotrienol hydroquinones, tocopherol quinones, and tocopherol hydroquinones described below, can be used as radioprotective agents for treatment of radiation exposure or prophylaxis against radiation exposure, according to the invention.

[0055] Compounds for use in the invention include one or more compounds of Formula I:

Formula I

wherein:

each bond indicated with a dashed line, independently of the other bonds indicated with a dashed line, can be a single bond or a double bond;

R 1 , R2 , and R 3 are independently selected from H, (Ci-C ₄ )-alkyl, (Ci-C ₄ )-haloalkyl, -CN, -F, -CI, -Br, and -I; and

R ⁴ and R ⁵ are independently selected from hydroxy and (Ci-C ₄ )-alkyl, and R ⁶ is hydrogen; or R ⁴ is (Ci-C ₄ )-alkyl, and R ⁵ and R ⁶ are hydrogen; or

R ⁴ is (Ci-C ₄ )-alkyl, and R ⁵ and R ⁶ together form the second bond of a double bond between the carbon atoms to which they are attached; or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, non-crystalline form, isotopologue, deuterated form, hydrate, or solvate thereof;

or the hydroquinone form thereof.

[0056] Compounds for use in the invention also include one or more compounds of Formula I-Unsat:

Formula I-Unsat

where the substituents are as indicated for Formula I; or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, noncrystalline form, isotopologue, deuterated form, hydrate, or solvate thereof;

or the hydroquinone form thereof.

[0057] Compounds for use in the invention also include one or more compounds of Formula I-Sat:

Formula I-Sat

where the substituents are as indicated for Formula I; or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, noncrystalline form, isotopologue, deuterated form, hydrate, or solvate thereof;

or the hydroquinone form thereof.

[0058] Compounds for use in the invention also include one or more compounds of Formula II:

Formula II where the bonds and substituents are as indicated for Formula I; or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, noncrystalline form, isotopologue, deuterated form, hydrate, or solvate thereof;

or the hydroquinone form thereof.

[0059] Compounds for use in the invention also include one or more compounds of Formula II-Unsat:

Formula II-Unsat

where the substituents are as indicated for Formula I; or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, noncrystalline form, isotopologue, deuterated form, hydrate, or solvate thereof;

or the hydroquinone form thereof.

[0060] Compounds for use in the invention also include one or more compounds of Formula II- Sat:

Formula II-Sat

where the substituents are as indicated for Formula I; or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, noncrystalline form, isotopologue, deuterated form, hydrate, or solvate thereof;

or the hydroquinone form thereof.

[0061] Compounds for use in the invention also include one or more compounds of Formula III:

Formula III where the bonds and substituents are as indicated for Formula I; or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, noncrystalline form, isotopologue, deuterated form, hydrate, or solvate thereof;

or the hydroquinone form thereof.

[0062] Compounds for use in the invention also include one or more compounds of Formula III-Unsat:

Formula III-Unsat

where the substituents are as indicated for Formula I; or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, noncrystalline form, isotopologue, deuterated form, hydrate, or solvate thereof;

or the hydroquinone form thereof.

[0063] Compounds for use in the invention also include one or more compounds of Formula III- Sat:

Formula III- Sat

where the substituents are as indicated for Formula I; or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, noncrystalline form, isotopologue, deuterated form, hydrate, or solvate thereof;

or the hydroquinone form thereof.

[0064] Compounds for use in the invention also include one or more compounds of Formula IV:

Formula IV where the bonds and substituents are as indicated for Formula I; or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, noncrystalline form, isotopologue, deuterated form, hydrate, or solvate thereof;

or the hydroquinone form thereof. In some embodiments, the compounds of Formula IV are compounds of Formula I -R:

In some embodiments, the compounds of Formula IV are compounds of Formula IV-S:

[0065] Compounds for use in the invention also include one or more compounds of Formula IV-Unsat:

Formula IV-Unsat

where the substituents are as indicated for Formula I; or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, noncrystalline form, isotopologue, deuterated form, hydrate, or solvate thereof;

or the hydroquinone form thereof. In some embodiments, the compounds of Formula IV- Unsat are compounds of Formula IV-Unsat-R:

In some embodiments, the compounds of Formula IV-Unsat are compounds of Formula IV-

Unsat-S:

[0066] Compounds for use in the invention also include one or more compounds of Formula IV-Sat:

Formula IV-Sat

where the substituents are as indicated for Formula I; or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, noncrystalline form, isotopologue, deuterated form, hydrate, or solvate thereof;

or the hydroquinone form thereof. In some embodiments, the compounds of Formula IV-Sat are compounds of Formula IV-Sat-R:

In some embodiments, the compounds of Formula IV-Sat are compounds of Formula IV-Sat- S:

Compounds for use in the invention also include one or more compounds of

Formula V

where the bonds and substituents are as indicated for Formula I; or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, noncrystalline form, isotopologue, deuterated form, hydrate, or solvate thereof;

or the hydroquinone form thereof. In some embodiments, the compounds of Formula V are compounds of Formula V-R:

[0068] Compounds for use in the invention also include one or more compounds of Formula V-Unsat:

Formula V-Unsat

which is alpha-tocotrienol quinone; or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, non-crystalline form, isotopologue, deuterated form, hydrate, or solvate thereof; or the hydroquinone form thereof. In some embodiments, the compound of Formula V-Unsat is 3R-alpha-tocotrienol quinone. In some embodiments, the compound of Formula V-Unsat is 3S-alpha-tocotrienol quinone.

[0069] Compounds for use in the invention also include one or more compounds of Formula V-Sat:

Formula V-Sat

which is alpha-tocopherol quinone; or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, non-crystalline form, isotopologue, deuterated form, hydrate, or solvate thereof; or the hydroquinone form thereof. In some embodiments, the compound of Formula V-Sat is (3R,7R,1 lR)-alpha-tocopherol quinone. In some embodiments, the compound of Formula V-Sat is (3S,7R,1 lR)-alpha- tocopherol quinone. In some embodiments, the compound of Formula V-Sat is (3R,7S,11R)- alpha-tocopherol quinone. In some embodiments, the compound of Formula V-Sat is (3S,7S,1 lR)-alpha-tocopherol quinone. In some embodiments, the compound of Formula V- Sat is (3R,7R,11 S)-alpha-tocopherol quinone. In some embodiments, the compound of Formula V-Sat is (3S,7R,11 S)-alpha-tocopherol quinone. In some embodiments, the compound of Formula V-Sat is (3R,7S,11 S)-alpha-tocopherol quinone. In some

embodiments, the compound of Formula V-Sat is (3S,7S,11 S)-alpha-tocopherol quinone.

[0070] Compounds for use in the invention also include one or more compounds of Formula VI:

Formula VI

11 12 13

where R , R , and R ^1J are independently selected from the group consisting of -CH ₃ and -H; or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, non-crystalline form, isotopologue, deuterated form, hydrate, or solvate thereof; or the hydroquinone form thereof. In some embodiments, the compounds of Formula VI are compounds of Formula VI-R:

In some embodiments, the compounds of

Formula VI are compounds of Formula VI-S:

[0071] Compounds for use in the invention also include one or more compounds of Formula Vl-Unsat:

Formula Vl-Unsat

where the substituents are as indicated for formula VI; or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, crystalline form, isotopologue, deuterated form, hydrate, or solvate thereof; or the hydroquinone form thereof. In some embodiments, the compounds of Formula VI- Unsat are com ounds of Formula VI-Unsat-R:

. In some embodiments, the compounds of

F rmula Vl-Unsat are compounds of Formula Vl-Unsat-S:

[0072] Compounds for use in the invention also include one or more compounds of Formula Vl-Sat:

Formula VI- Sat

where the substituents are as indicated for formula VI; or a stereoisomer, mixtures of stereoisomers, prodrug, metabolite, salt, phosphate substituted form, crystalline form, noncrystalline form, isotopologue, deuterated form, hydrate, or solvate thereof;

or the hydroquinone form thereof. In some embodiments, the compounds of Formula Vl-Sat are com ounds of Formula VI-Sat-R:

. In some embodiments, the compounds of

F rmula Vl-Sat are compounds of Formula Vl-Sat-S:

[0073] In other embodiments of the invention, the radioprotective agent comprises one or more compounds selected from the group consisting of alpha-tocotrienol quinone, beta- tocotrienol quinone, gamma-tocotrienol quinone, and delta-tocotrienol quinone. In one embodiment, the radioprotective agent comprises alpha-tocotrienol quinone. In one embodiment, the radioprotective agent comprises beta-tocotrienol quinone. In one embodiment, the radioprotective agent comprises gamma-tocotrienol quinone. In one embodiment, the radioprotective agent comprises delta-tocotrienol quinone.

[0074] In another embodiment of the invention, the radioprotective agent comprises one or more compounds selected from the group consisting of alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma-tocotrienol hydroquinone, and delta-tocotrienol hydroquinone. In one embodiment, the radioprotective agent comprises alpha-tocotrienol hydroquinone. In one embodiment, the radioprotective agent comprises beta-tocotrienol hydroquinone. In one embodiment, the radioprotective agent comprises gamma-tocotrienol hydroquinone. In one embodiment, the radioprotective agent comprises delta-tocotrienol hydroquinone.

[0075] In another embodiment of the invention, the radioprotective agent comprises one or more compounds selected from the group consisting of alpha-tocopherol quinone, beta- tocopherol quinone, gamma-tocopherol quinone, and delta-tocopherol quinone. In one embodiment, the radioprotective agent comprises alpha-tocopherol quinone. In one embodiment, the radioprotective agent comprises beta-tocopherol quinone. In one embodiment, the radioprotective agent comprises gamma-tocopherol quinone. In one embodiment, the radioprotective agent comprises delta-tocopherol quinone.

[0076] In another embodiment of the invention, the radioprotective agent comprises one or more compounds selected from the group consisting of alpha-tocopherol hydroquinone, beta-tocopherol hydroquinone, gamma-tocopherol hydroquinone, and delta-tocopherol hydroquinone. In one embodiment, the radioprotective agent comprises alpha-tocopherol hydroquinone. In one embodiment, the radioprotective agent comprises beta-tocopherol hydroquinone. In one embodiment, the radioprotective agent comprises gamma-tocopherol hydroquinone. In one embodiment, the radioprotective agent comprises delta-tocopherol hydroquinone.

[0077] For all the formulations and methods described herein, any composition in the quinone form can also be used in its reduced form (hydroquinone) when desired. That is, the compounds recited herein as cyclohexadienedione compounds (oxidized quinone) form can also be used in their benzenediol (reduced hydroquinone) form as desired.

[0078] While the compounds described herein can occur and can be used as the neutral (non-salt) compound, the description is intended to embrace all salts of the compounds described herein, as well as methods of using such salts of the compounds. In one embodiment, the salts of the compounds comprise pharmaceutically acceptable salts. Pharmaceutically acceptable salts are those salts which can be administered as drugs or pharmaceuticals to humans and/or animals and which, upon administration, retain at least some of the biological activity of the free compound (neutral compound or non-salt compound). The desired salt of a basic compound may be prepared by methods known to those of skill in the art by treating the compound with an acid. In some embodiments, inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. In some embodiments, organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid. Salts of basic compounds with amino acids, such as aspartate salts and glutamate salts, can also be prepared. The desired salt of an acidic compound can be prepared by methods known to those of skill in the art by treating the compound with a base. In some embodiments, inorganic salts of acid compounds include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, and calcium salts;

ammonium salts; and aluminum salts. In some embodiments, organic salts of acid compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, N,N- dibenzylethylenediamine, and triethylamine salts. Salts of acidic compounds with amino acids, such as lysine salts, can also be prepared.

[0079] The invention also includes all stereoisomers of the compounds, including diastereomers and enantiomers. The invention also includes mixtures of stereoisomers in any ratio, including, but not limited to, racemic mixtures. Unless stereochemistry is explicitly indicated in a structure, the structure is intended to embrace all possible stereoisomers of the compound depicted. If stereochemistry is explicitly indicated for one portion or portions of a molecule, but not for another portion or portions of a molecule, the structure is intended to embrace all possible stereoisomers for the portion or portions where stereochemistry is not explicitly indicated.

[0080] The compounds can be administered in prodrug form. Prodrugs are derivatives of the compounds, which are themselves relatively inactive but which convert into the active compound when introduced into the subject in which they are used by a chemical or biological process in vivo, such as an enzymatic conversion. Suitable prodrug formulations include, but are not limited to, peptide conjugates of the compounds of the invention and esters of compounds of the inventions. Further discussion of suitable prodrugs is provided in H. Bundgaard, Design of Prodrugs, New York: Elsevier, 1985; in R. Silverman, The Organic Chemistry of Drug Design and Drug Action, Boston: Elsevier, 2004; in R.L. Juliano (ed.), Biological Approaches to the Controlled Delivery of Drugs (Annals of the New York Academy of Sciences, v. 507), New York: New York Academy of Sciences, 1987; and in E.B. Roche (ed.), Design of Biopharmaceutical Properties Through Prodrugs and Analogs (Symposium sponsored by Medicinal Chemistry Section, APhA Academy of Pharmaceutical Sciences, November 1976 national meeting, Orlando, Florida), Washington : The Academy, 1977.

[0081] Metabolites of the compounds are also embraced by the invention.

[0082] "C1-C4 alkyl" is intended to embrace a saturated linear, branched, cyclic, or a combination thereof, hydrocarbon of 1 to 4 carbon atoms. In some embodiments of "C ₁ -C ₄ alkyl" are methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, cyclopropyl-methyl, and methyl-cyclopropyl.

[0083] "Halogen" or "halo" designates fluoro, chloro, bromo, and iodo.

[0084] "C1-C4 haloalkyl" is intended to embrace any C ₁ -C ₄ alkyl substituent having at least one halogen substituent, in some embodiments 1 to 6 halogens, in some embodiments, 1 to 3 halogens; the halogen can be attached via any valence on the C1-C4 alkyl group. In some embodiments of C1-C4 haloalkyl is -CF ₃ , -CC1 ₃ , -CHF ₂ , -CHC1 ₂ , -CHBr ₂ , -CH ₂ F, -CH ₂ C1.

[0085] "Deuterated form" means the compound is isotopically enriched for deuterium in at least one atom.

[0086] "Isotopologue" means a compound which differs, i.e. in the number of neutrons, in its isotopic composition of at least one atom from the parent molecule having a natural isotopic composition. In some or any embodiments, the compound is isotopically enriched.

[0087] The term "isotopic composition," as used herein, and unless otherwise specified, refers to the amount of each isotope present for a given atom, and "natural isotopic composition" refers to the naturally occurring isotopic composition or abundance for a given atom. Atoms containing their natural isotopic composition may also be referred to herein as "non-enriched" atoms. Unless otherwise designated, the atoms of the compounds recited herein are meant to represent any stable isotope of that atom. For example, unless otherwise stated, when a position is designated specifically as "FT or "hydrogen," the position is understood to have hydrogen at its natural isotopic composition.

[0088] The term "isotopic enriched," as used herein, and unless otherwise specified, refers to the percentage of incorporation of an amount of a specific isotope at a given atom in a molecule in the place of that atom's natural isotopic abundance. In certain embodiments, deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0089] The term "isotopically enriched," as used herein, and unless otherwise specified, refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.

[0090] "Phosphate substituted form" means that any unsubstituted hydroxy group of the compound is substituted with a phosphate group, -P(0)(OH)2 or -PO ₃ ^" .

Sources of radiation

[0091] The compounds, compositions, and methods of the invention can be used in any situation where protection against radiation is desired, whether exposure to such radiation is known to be certain to occur (in some embodiments, a patient undergoing a CT scan) or exposure to radiation is possible (in some embodiments, a worker in a nuclear power plant). The compounds, compositions, and methods of the invention can be used to protect against radiation exposure from, in some embodiments, diagnostic X-rays, dental X-rays,

radiotherapy for cancer treatment, CT scans (CAT scans), fluoroscopy, mammograms, radionuclide scans, radiation from ingestion of contaminated food or water, radiation from inhalation of contaminated air or gases, and uncontrolled exposure to ionizing radiation from nuclear weapons, radioactive spills and/or cosmic radiation. The compounds, compositions, and methods of the invention can be used to protect against radiation exposure from ultraviolet light, such as from prolonged exposure to sunlight, or exposure to intense sunlight.

[0092] Subjects who are exposed to radiation include, in some embodiments, patients undergoing diagnostic or therapeutic radiation exposure, such as occurs during medical or dental procedures, such as radiography, fluoroscopy, dental X-rays, and CT scans, and therapeutic radiation treatment. Subjects who are exposed to radiation also include persons who routinely work at high elevation, such as aircraft flight crew members, or who spend a prolonged period at high elevation (greater than about 1 mile or about 1.6 kilometers above sea level), such as mountain climbers, or who travel into outer space, such as astronauts and space tourists. Subjects who are exposed to radiation also include persons who must decontaminate sites which are contaminated with radioactive waste, or with waste containing a high amount of radioactivity such as coal ash, or miners who work in sites with elevated radioactivity. Subjects who are at risk of being exposed to radiation include persons who routinely work with or near radiation or radioactive materials, such as X-ray technicians, nuclear medicine specialists, nuclear power plant workers, and persons who live near a nuclear power plant.

[0093] In one embodiment of the invention, the compounds, compositions, and methods are used to protect against excess radiation; that is, radiation in excess of the natural background radiation. The 2007 recommendation of the International Commission on Radiological Protection (ICRP) for exposure of the general public to radiation is a limit of 1 milliSievert (1 mSv) per year (Wrixon, A.D., J. Radiol. Prot. 28: 161-168 (2008)). Thus, in one embodiment of the invention, the compounds, compositions, and methods can be used for therapeutic or prophylactic use in subjects whose expected or actual dose of radiation exceeds about 1 mSv in one year. The recommended occupational exposure from the ICRP is 20 mSv per year, averaged over five years, with no more than 50 mSv exposure in any one year, and thus, the compounds, compositions, and methods can be used for therapeutic or prophylactic use in subjects whose expected or actual dose of radiation exceeds that level. In further embodiments of the invention, the compounds, compositions, and methods can be used for therapeutic or prophylactic use in subjects whose expected or actual dose of radiation exceeds about 2 mSv in one year, about 5 mSv in one year, about 10 mSv in one year, about 20 mSv in one year, or about 50 mSv in one year. In further embodiments of the invention, the compounds, compositions, and methods can be used for therapeutic or prophylactic use in subjects whose expected or actual dose of radiation exceeds about 2 mGray in one year, about 5 mGray in one year, about 10 mGray in one year, about 20 mGray in one year, or about 50 mGray in one year. In further embodiments of the invention, the compounds, compositions, and methods can be used for therapeutic or prophylactic use in subjects who wish to minimize the effects of exposure to routine or background radiation, such as, in some embodiments, routine or everyday exposure to ultraviolet light.

[0094] In one embodiment of the invention, the compounds, compositions, and methods are used to protect against exposure to extreme amounts of radiation, in some embodiments, radiation at or greater than about the LDio, LD ₂ o, LD ₅₀ , or LDso dose for an organism (where LD is the lethal dose). Exposure to such high amounts of radiation can occur, in some embodiments, due to accidents at nuclear power plants, or accidents in handling extremely radioactive substances such as enriched uranium-235 or plutonium, or by proximity to a nuclear explosion or a bomb designed to spread lethal amounts of radioactivity.

[0095] In one embodiment of the invention, the compounds, compositions, and methods are used to protect against exposure to radiation which damages the skin. Such radiation includes, in some embodiments, ultraviolet radiation. Topical administration of the compounds and compositions as disclosed herein may be used for such protection (in some embodiments, in a lotion, cream, salve, or spray), as well as other routes of administration described below.

[0096] In one embodiment of the invention, the compounds, compositions, and methods are used to protect against exposure to radiation which damages the eyes. Such radiation includes, in some embodiments, ultraviolet radiation. Topical administration of the compounds and compositions as disclosed herein may be used for such protection (in some embodiments, in eyedrops), as well as other routes of administration described below.

Assessment and efficacy of therapy

[0097] The utility of the compounds, compositions, and methods of the present invention for radioprotection may be demonstrated both in vitro and in vivo. For example, the ability of cultured cells to form clones (colonies) may be evaluated as a function of exposure to radiation, such as X-rays. Cells are either not treated or are treated with a compound or composition of the invention at a certain time (in some embodiments, 30 minutes) prior to exposure. The degree of retention of ability to form clones after exposure, in comparison to untreated cells, is directly related to the protective effect of the drug. A typical experiment of this type may be carried out essentially as described by Snyder and Lachmann Radiation Res. (1989) 120: 121-128.

[0098] Alternatively, the utility of the compounds, compositions, and methods of the present invention for radioprotection can be evaluated by measuring the production of DNA strand breaks upon exposure to radiation, such as X-rays. Cells are either not treated or are treated with a compound or composition of the invention at a certain time (in some embodiments, 30 minutes) prior to exposure. The extent of DNA strand breakage after exposure, in comparison to that in untreated cells, is inversely related to the protective effect of the drug. A typical experiment of this type may be carried out essentially as described by Snyder Int. J. Radiat. Biol. (1989) 55:773. [0099] In vivo, the utility of the compounds, compositions, and methods of the present invention for radioprotection may be evaluated by the survivability of mice exposed to whole body irradiation. Animals, either pre-dosed with a compound or composition disclosed herein, or not dosed (i.e., control animals), are exposed to whole body irradiation (such as, in some embodiments, 1500 rads). Control animals are expected to survive about 12-15 days. The degree of survivability of the dosed animals, in comparison to the controls, is directly related to the protective effect of the compound or composition administered. A typical experiment of this type may be carried out essentially as described by Carroll et al. J. Med. Chem. (1990) 33:2501.

[00100] Additionally, the production of DNA strand breaks in lymphocytes taken from treated animals exposed to whole body irradiation may be evaluated in comparison to untreated control animals. Alternatively, the viability and clonogenicity of bone marrow cells taken from treated animals exposed to whole body irradiation may be evaluated in

comparison to cells taken from untreated control animals as described by Pike and Robinson J. Cell Physiol. (1970) 76:77-84.

Pharmaceutical formulations

[00101] The compounds described herein can be formulated as pharmaceutical

compositions by formulation with additives such as pharmaceutically acceptable excipients, pharmaceutically acceptable carriers, and pharmaceutically acceptable vehicles. Suitable pharmaceutically acceptable excipients, carriers and vehicles include processing agents and drug delivery modifiers and enhancers, such as, in some embodiments, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl- -cyclodextrin, polyvinylpyrrolidone, low melting waxes, ion exchange resins, and the like, as well as combinations of any two or more thereof. Other suitable pharmaceutically acceptable excipients are described in "Remington's Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991), and "Remington: The Science and Practice of Pharmacy," Lippincott Williams & Wilkins, Philadelphia, 20th edition (2003) and 21st edition (2005), incorporated herein by reference.

[00102] A pharmaceutical composition can comprise a unit dose formulation, where the unit dose is a dose sufficient to have a therapeutic or prophylactic effect.

[00103] Pharmaceutical compositions containing the compounds of the invention may be in any form suitable for the intended method of administration, including, in some embodiments, a solution, a suspension, or an emulsion. Liquid carriers are typically used in preparing solutions, suspensions, and emulsions. Liquid carriers contemplated for use in the practice of the present invention include, in some embodiments, water, saline,

pharmaceutically acceptable organic solvent(s), pharmaceutically acceptable oils or fats, and the like, as well as mixtures of two or more thereof. The liquid carrier may contain other suitable pharmaceutically acceptable additives such as solubilizers, emulsifiers, nutrients, buffers, preservatives, suspending agents, thickening agents, viscosity regulators, stabilizers, and the like. Suitable organic solvents include, in some embodiments, monohydric alcohols, such as ethanol, and polyhydric alcohols, such as glycols. Suitable oils include, in some embodiments, sesame oil, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, and the like. For parenteral administration, the carrier can also be an oily ester such as ethyl oleate, isopropyl myristate, and the like. Compositions of the present invention may also be in the form of microparticles, microcapsules, liposomal encapsulates, and the like, as well as combinations of any two or more thereof.

[00104] Time-release or controlled release delivery systems may be used, such as a diffusion controlled matrix system or an erodible system, as described for example in: Lee, "Diffusion-Controlled Matrix Systems", pp. 155-198 and Ron and Langer, "Erodible

Systems", pp. 199-224, in "Treatise on Controlled Drug Delivery", A. Kydonieus Ed., Marcel Dekker, Inc., New York 1992. The matrix may be, in some embodiments, a biodegradable material that can degrade spontaneously in situ and in vivo, in some embodiments, by hydrolysis or enzymatic cleavage, e.g., by proteases. The delivery system may be, in some embodiments, a naturally occurring or synthetic polymer or copolymer, in some

embodiments, in the form of a hydrogel. Exemplary polymers with cleavable linkages include polyesters, polyorthoesters, polyanhydrides, polysaccharides, poly(phosphoesters), polyamides, polyurethanes, poly(imidocarbonates) and poly(phosphazenes).

[0100] The compounds of the invention may be administered enterally, orally, parenterally, sublingually, by inhalation (e.g. as mists or sprays), rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. In some embodiments, suitable modes of administration include oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intraarterial, intramuscular, intraperitoneal, intranasal (e.g. via nasal mucosa), subdural, rectal, gastrointestinal, and the like, and directly to a specific or affected organ or tissue. For delivery to the central nervous system, spinal and epidural administration, or administration to cerebral ventricles, can be used. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, and intrasternal injection or infusion techniques. The compounds are mixed with

pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for the desired route of administration. Oral administration is a preferred route of administration, and

formulations suitable for oral administration are preferred formulations. The compounds described for use herein can be administered in solid form, in liquid form, in aerosol form, or in the form of tablets, pills, powder mixtures, capsules, granules, injectables, creams, solutions, suppositories, enemas, colonic irrigations, emulsions, dispersions, food premixes, and in other suitable forms. The compounds can also be administered in liposome formulations. The compounds can also be administered as prodrugs, where the prodrug undergoes transformation in the treated subject to a form which is therapeutically effective. Additional methods of administration are known in the art.

[0101] Injectable preparations, in some embodiments, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, in some embodiments, as a solution in propylene glycol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0102] Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

[0103] Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.

[0104] The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.W., p. 33 et seq. (1976).

[0105] The formulations of the present invention may comprise two or more compounds or compositions as described herein.

[0106] The invention also provides articles of manufacture and kits containing materials useful for treatment or prophylaxis of radiation exposure. The invention also provides kits comprising any one or more of the compounds of the invention. In other aspects, the kits may be used for any of the methods described herein, including, in some embodiments, for treatment of or prophylaxis against radiation exposure in a subject.

[0107] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host to which the active ingredient is administered and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, body area, body mass index (BMI), general health, sex, and diet of the patient; time of administration, route of administration, rate of excretion, or drug combination; and the type, progression, and severity of the particular disease undergoing therapy. The

pharmaceutical unit dosage chosen is usually fabricated and administered to provide a defined final concentration of drug in the blood, tissues, organs, or other targeted region of the body. The therapeutically effective amount or prophylactically effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.

[0108] The single or multiple dosages which can be used include an amount independently selected from about 0.1 mg/kg to about 600 mg/kg body weight, or about 1.0 mg/kg to about 500 mg/kg body weight, or about 1.0 mg/kg to about 400 mg/kg body weight, or about 1.0 mg/kg to about 300 mg/kg body weight, or about 1.0 mg/kg to about 200 mg/kg body weight, or about 1.0 mg/kg to about 100 mg/kg body weight, or about 1.0 mg/kg to about 50 mg/kg body weight, or about 1.0 mg/kg to about 30 mg/kg body weight, or about 1.0 mg/kg to about 10 mg/kg body weight, or about 10 mg/kg to about 600 mg/kg body weight, or about 10 mg/kg to about 500 mg/kg body weight, or about 10 mg/kg to about 400 mg/kg body weight, or about 10 mg/kg to about 300 mg/kg body weight, or about 10 mg/kg to about 200 mg/kg body weight, or about 10 mg/kg to about 100 mg/kg body weight, or about 50 mg/kg to about 150 mg/kg body weight, or about 100 mg/kg to about 200 mg/kg body weight, or about 150 mg/kg to about 250 mg/kg body weight, or about 200 mg/kg to about 300 mg/kg body weight, or about 250 mg/kg to about 350 mg/kg body weight, or about 200 mg/kg to about 400 mg/kg body weight, or about 300 mg/kg to about 400 mg/kg body weight, or about 250 mg/kg to about 300 mg/kg body weight, or about 300 mg/kg body weight. Compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided dosage of two, three or four times daily.

[0109] Single or multiple doses can be administered. In some embodiments, the dose is administered once, twice, three times, four times, five times, or six times. In some embodiments, the dose is administered once per day, twice per day, three times per day, or four times per day. In some embodiments, the dose is administered every hour, every two hours, every three hours, every four hours, every 6 hours, every 12 hours, or every 24 hours.

[0110] Single or multiple doses can be administered during or after radiation exposure. In some embodiments, the dose is administered once, twice, three times, four times, five times, or six times during or after radiation exposure. In some embodiments, the dose is administered once per day, twice per day, three times per day, or four times per day during or after radiation exposure. In some embodiments, the dose is administered every hour, every two hours, every three hours, every four hours, every 6 hours, every 12 hours, or every 24 hours during or after radiation exposure.

[0111] Single or multiple doses can be administered before radiation exposure. In some embodiments, the dose is administered once, twice, three times, four times, five times, or six times before radiation exposure. In some embodiments, the dose is administered once per day, twice per day, three times per day, or four times per day before radiation exposure. In some embodiments, the dose is administered every hour, every two hours, every three hours, every four hours, every 6 hours, every 12 hours, or every 24 hours before radiation exposure. In some embodiments, the dose is administered about 30 minutes before radiation exposure, about 1 hour before radiation exposure, about 2 hours before radiation exposure, about 3 hours before radiation exposure, about 4 hours before radiation exposure, about 6 hours before radiation exposure, about 8 hours before radiation exposure, about 10 hours before radiation exposure, about 12 hours before radiation exposure, and/or about 24 hours before radiation exposure. In some embodiments, the dose is administered about 4 hours before radiation exposure. In some embodiments, the dose is administered about 24 hours before radiation exposure. In some embodiments, the dose is administered about 4 hours and about 24 hours before radiation exposure.

[0112] While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more other agents used in the treatment of or prophylaxis against radiation exposure. In some embodiments, the compound(s) of the invention are administered as the sole active pharmaceutical agent that is present in a therapeutically effective amount.

[0113] When additional active agents are used in combination with the compounds of the present invention, the additional active agents may generally be employed in therapeutic amounts as indicated in the Physicians' Desk Reference (PDR) 53rd Edition (1999), or such therapeutically useful amounts as would be known to one of ordinary skill in the art.

[0114] The compounds of the invention and the other therapeutically active agents or prophylactically effective agents can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired response depending on the route of administration, severity of the radiation exposure and the response of the patient. When administered in combination with other therapeutic or prophylactic agents, the therapeutic agents or prophylactic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents or prophylactic agents can be given as a single composition.

[0115] The one or more radioprotective agent can be administered during radiation exposure in single or multiple doses.

[0116] The one or more radioprotective agent can be administered about 0 to about 48 hours after radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 0 to about 24 hours after radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 0 to about 12 hours after radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 0 to about 4 hours after radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 0 to about 1 hour after radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 0 to about 30 minutes after radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 0 to about 15 minutes after radiation exposure in single or multiple doses. The one or more

radioprotective agent can be administered about 0 to about 10 minutes after radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 0 to about 5 minutes after radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 5 minutes to about 48 hours after radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 5 minutes to about 24 hours after radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 5 minutes to about 12 hours after radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 5 minutes to about 4 hours after radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 5 minutes to about 2 hours after radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 5 minutes to about 1 hour after radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 30 minutes to about 48 hours after radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 30 minutes to about 24 hours after radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 30 minutes to about 12 hours after radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 30 minutes to about 4 hours after radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 30 minutes to about 2 hours after radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 30 minutes to about 1 hour after radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, bout 16 hours, about 17 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, and/or about 48 hours after radiation exposure.

[0117] The one or more radioprotective agent can be administered about 0 to about 48 hours before radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 0 to about 24 hours before radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 0 to about 12 hours before radiation exposure in single or multiple doses. The one or more

radioprotective agent can be administered about 0 to about 4 hours before radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 0 to about 1 hour before radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 0 to about 30 minutes before radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 0 to about 15 minutes before radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 0 to about 10 minutes before radiation exposure in single or multiple doses. The one or more

radioprotective agent can be administered about 0 to about 5 minutes before radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 5 minutes to about 48 hours before radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 5 minutes to about 24 hours before radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 5 minutes to about 12 hours before radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 5 minutes to about 4 hours before radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 5 minutes to about 2 hours before radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 5 minutes to about 1 hour before radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 30 minutes to about 48 hours before radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 30 minutes to about 24 hours before radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 30 minutes to about 12 hours before radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 30 minutes to about 4 hours before radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 30 minutes to about 2 hours before radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 30 minutes to about 1 hour before radiation exposure in single or multiple doses. The one or more radioprotective agent can be administered about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, bout 16 hours, about 17 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, and/or about 48 hours before radiation exposure.

Preparation of Compounds of the Invention

[0118] In general, the nomenclature used in this Application was generated with the help of naming package within the ChemOffice® . version 11.0 suite of programs by

CambridgeSoft Corp (Cambridge, Mass.).

[0119] The compounds of this invention can be prepared from readily available starting materials using general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0120] Preparation of the compounds disclosed herein is described in co-assigned US

Patent Application Publications No. 2006/0281809 and 2010/0105930.

[0121] Furthermore, the compounds of this invention will typically contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer- enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, in some embodiments, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, in some embodiments, chiral column chromatography, chiral resolving agents and the like. [0122] The invention is further described by the following non-limiting examples and embodiments.

Example 1

Assessment of Radio-Protection Against Exposure to Total Body Irradiation (TBI)

[0123] Compounds described herein were tested to determine their effects on survival following total body irradiation (TBI).

Experimental Design

[0124] Male CD2F1 mice (Charles River Laboratories), aged 6-8 weeks, were randomly and prospectively assigned to receive treatment with either a test compound or vehicle only. On Day 0, the animals were placed in a pie cage and exposed to total body irradiation (TBI) with a dose of 8.75 Gy or 9.75 Gy to achieve an approximate LD ₅ o or LDgo survival outcome, respectively; these doses resulted in LD ₉₀ and LDioo values in the actual experiment. Treatments were administered at 24 hours and 4 hours prior to irradiation.

Animals were monitored for survival twice daily for 30 days, and those that lost greater than 30% of their total starting body weight were euthanized and counted as having died on that day.

Animal Housing and Environment

[0125] The animals were housed in disposable cages with sterile wood chip bedding, food, and water. The mice were acclimated for at least 3 days and given food and tap water ad libitum. The animals were examined prior to initiation of the study to assure adequate health and suitability. Animals that were found to be diseased or unsuitable were not assigned to the study.

[0126] During the course of the study, 12-hour light/12-hour dark cycles were maintained. A nominal temperature range of 20-23 °C with a relative humidity between 30% and 70% were also maintained. LabDiet 5053 -certified PicoLab Rodent Diet and sterile water were provided ad libitum. The animals were not fasted prior to dosing.

Total Body Irradiation (TBI)

[0127] Mice were placed in a pie cage in groups of 9-11 at a time. Radiation was generated with a 160 kilovolt potential (18-ma) source at a focal distance of 25 cm, hardened with a 0.35 mm Al filtration system. The animals were subjected to TBI at a rate of < 100 cGy. Dosimetry (Fluke 3504 dosimeter with farmer type 0.6 cm ion chamber probe) was used with each radiation to ensure that all animals received the correct dose.

Animal Weights

[0128] All animals were weighed daily throughout this study and their survival recorded in order to assess possible differences in animal weight among treatment groups as an indication for radiation-induced toxicity. Group weight change is expressed as a mean percent weight change and mean percent weight change area under the curve. Animals that lost greater than 30% of their total starting body weight were euthanized.

Animals Found Dead or Moribund

[0129] Animal deaths in this model generally occur as a consequence of radiation toxicity. Animals were monitored on a daily basis, and those exhibiting weight loss greater than 30%), were unable to ambulate, achieve food and water, and/or appeared moribund were euthanized. Animals were not replaced during the course of the study.

Statistical Analysis

[0130] Statistical differences between treatment groups were determined using appropriate statistical techniques. A one-way ANOVA or ANOVA on ranks was used to evaluate the area-under the curve for weight gain. A Kaplan-Meier survival curve was provided to assess statistical differences in survival among treatment groups.

Test Article preparation

[0131] Test compound was dissolved in PEG-400/2%> Tween 80 and mixed until visually homogeneous at a concentration of 90 mg/mL. All compound solutions were stored at room temperature, protected from light, and used within 24 hours of preparation.

Test Article Administration

[0132] The animals were each administered with single or multiple subcutaneous

(SC) 300 mg/kg body weight dose(s) of the test compound formulation or vehicle only formulation as described herein. All animals were dosed at approximately the same time on the dosing day (± 1 hour). Subcutaneous doses were administered via bolus injection between the skin and underlying layers of tissue in the scapular region on the back of each animal. The hair was not clipped from the injection site prior to dosing. The injection site was monitored for necrosis and other changes to the skin and hair.

[0133] Figures 1 and 2 show the percent survival and body weight for test compound alpha-tocotrienol quinone compared to vehicle only at LD90 and LD100 radiation doses, respectively.

[0134] Figure 3 shows the injection sites after 28 days for mice treated with test compounds alpha-tocotrienol quinone (Figure 3A) and delta-tocotrienol (Figures 3B-E), respectively. The injection site for mice treated with delta-tocotrienol exhibited necrosis and hair loss, whereas necrosis and hair loss were not observed at the injection site for mice treated with alpha-tocotrienol quinone.

Example 2

Assessment of Radio-Protection Against Exposure to Gamma Radiation

[0135] Compounds described herein are tested to determine their effects on survival and other symptoms of radiation damage following exposure to gamma-radiation.

[0136] Mice are randomly and prospectively assigned to receive treatment with either a test compound or vehicle only. On Day 0, the animals are exposed to gamma-radiation with a dose sufficient to achieve survival outcome between LD ₂ o to LDgo- Treatments are administered at set time points between 48 hours and 1 hour prior to irradiation. Animals are monitored for survival twice daily, and those that lose greater than 30% of their total starting body weight are euthanized and counted as having died on that day. Animals are also monitored for various symptoms of radiation damage.

[0137] Statistical differences between treatment groups are determined using appropriate statistical techniques. A one-way ANOVA or ANOVA on ranks is used to evaluate the area-under the curve for weight gain. A Kaplan-Meier survival curve is provided to assess statistical differences in survival among treatment groups.

[0138] Test compound is dissolved in PEG-400/2% Tween 80 and mixed until visually homogeneous at a concentration of 90 mg/mL. All compound solutions are stored at room temperature, protected from light, and used within 24 hours of preparation.

[0139] The animals are each administered with single or multiple subcutaneous (SC)

300 mg/kg body weight dose(s) of the test compound formulation or vehicle only formulation as described herein. All animals are dosed at approximately the same time on the dosing day (± 1 hour). Subcutaneous doses are administered via bolus injection between the skin and underlying layers of tissue in the scapular region on the back of each animal. The hair is not clipped from the injection site prior to dosing. The injection site is monitored for necrosis and other changes to the skin and hair.

[0140] Compounds are evaluated for their ability to increase survival rates and/or reduce or prevent symptoms of radiation damage.

Example 3

Assessment of Radio-Protection Against Exposure to Ultraviolet Radiation

[0141] Compounds described herein are tested to determine their effects on survival and other symptoms of radiation damage following exposure to ultraviolet radiation.

[0142] Mice are randomly and prospectively assigned to receive treatment with either a test compound or vehicle only. On Day 0, the animals are exposed to ultraviolet radiation (UVA and/or UVB) with doses sufficient to achieve an LD ₂ o to LDso survival outcome. Treatments are administered at set time points between 48 hours and 1 hour prior to irradiation. Animals are monitored for survival twice daily, and those that lose greater than 30% of their total starting body weight are euthanized and counted as having died on that day. Animals are also monitored for various symptoms of radiation damage.

[0143] Statistical differences between treatment groups are determined using appropriate statistical techniques. A one-way ANOVA or ANOVA on ranks is used to evaluate the area-under the curve for weight gain. A Kaplan-Meier survival curve is provided to assess statistical differences in survival among treatment groups.

[0144] Test compound is dissolved in PEG-400/2% Tween 80 and mixed until visually homogeneous at a concentration of 90 mg/mL. All compound solutions are stored at room temperature, protected from light, and used within 24 hours of preparation.

[0145] The animals are each administered with single or multiple subcutaneous (SC)

300 mg/kg body weight dose(s) of the test compound formulation or vehicle only formulation as described herein. All animals are dosed at approximately the same time on the dosing day (± 1 hour). Subcutaneous doses are administered via bolus injection between the skin and underlying layers of tissue in the scapular region on the back of each animal. The hair is not clipped from the injection site prior to dosing. The injection site is monitored for necrosis and other changes to the skin and hair.

[0146] Compounds are evaluated for their ability to increase survival rates and/or reduce or prevent symptoms of radiation damage. [0147] The disclosures of all publications, patents, patent applications and published patent applications referred to herein by an identifying citation are hereby incorporated herein by reference in their entirety.

[0148] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.