Modulation of cell fates and activities by phthalazinediones

Abstract

Phthalazinediones that function as intracellular redox modulators are useful in treating cells in various disease states where intracellular redox status is impaired. By buffering aberrant redox states, phthalazinediones enable cellular processes essential for survival and augment medical treatments. The phthalazinediones of the invention can modulate functions related to cell growth, differentiation, activity, or death, to correct aberrations and restore homeostasis, and can serve as adjunctive therapy in treating various disease conditions.

1 . A method for modulating metabolic distress, comprising administering to a subject a therapeutically effective amount of a phthalazinedione or its pharmaceutically acceptable salt, ester, solvate, hydrate, analogue, metabolite, enantiomer, isomer, tautomer, amide, derivative, prodrug, or free base in treating a condition selected from the group consisting of multiple chemical sensitivity syndrome, Charcot-Marie-Tooth disease, Dejerine-Sottas syndrome, Roussy-Levy syndrome, Rosenberg Chutorian syndrome, Korsakoff syndrome, Friedreich ataxia, Machado-Joseph disorder, progressive supranuclear palsy, Guillain-Barré syndrome, Hodgkin's disease, Wegener's granulomatosis, toxic shock syndrome, systemic lupus erythematosus, scleroderma, Lyme disease, auricular or atrial fibrillation, thromboangiitis obliterans, peritonitis, hantavirus pulmonary syndrome, Wiskott-Aldrich syndrome, and preexcitation syndrome. 
     
     
         2 . The method as in  claim 1 , wherein the phthalazinedione is an amino derivative. 
     
     
         3 . The method as in  claim 2 , wherein the phthalazinedione is a haloamino, alkylamino, acylamino, alkanolamino, alkenylamino, alkoxyamino, haloalkylamino, allylamino, or sulfhydrylamino derivative. 
     
     
         4 . The method as in  claim 1 , wherein the phthalazinedione is administered with an adjuvant, diluent, carrier, excipient, or stabilizer. 
     
     
         5 . The method as in  claim 4 , wherein the phthalazinedione comprises a pharmaceutically acceptable form selected from the group consisting of tablet, capsule, granule, powder, solution, suspension, microsphere, liposome, colloid, lyophilized composition, gel, lotion, ointment, cream, spray, and suppository. 
     
     
         6 . The method as in  claim 5 , wherein the phthalazinedione is administered by a means selected from the group consisting of intravenous, intramuscular, intraperitoneal, subcutaneous, oral, nasal, mucosal, transdermal, parenteral, vaginal, and rectal. 
     
     
         7 . The method as in  claim 6 , wherein the method is used in combination with a standard treatment selected from the group consisting of radiation, chemotherapy, laser therapy, surgery, medication, and nutrition. 
     
     
         8 . A method for modulating metabolic distress, comprising administering to a subject a therapeutically effective amount of a phthalazinedione or its pharmaceutically acceptable salt, ester, solvate, hydrate, analogue, metabolite, enantiomer, isomer, tautomer, amide, derivative, prodrug, or free base with a compound selected from the group consisting of a glutathione, glucocorticoid, dexamethasone, cysteine, lipoic acid, biopterin, hydralazine, rasagiline, thioredoxin, ferulic acid, minocycline, menadione, tetracycline, isosorbate dinitrate, dextromethorphan, dithiothreitol, carnosine, and clomethiazole. 
     
     
         9 . The method as in  claim 8 , wherein the method is used in treating inflammatory conditions. 
     
     
         10 . The method as in  claim 8 , wherein the method is used in treating infectious conditions. 
     
     
         11 . The method as in  claim 8 , wherein the method is used in treating neurological disorders. 
     
     
         12 . The method as in  claim 8 , wherein the method is used in treating immune disorders. 
     
     
         13 . The method as in  claim 8 , wherein the method is used in treating proliferative diseases. 
     
     
         14 . The method as in  claim 8 , wherein the method is used in treating cellular senescence. 
     
     
         15 . The method as in  claim 8 , wherein the phthalazinedione is an amino derivative. 
     
     
         16 . The method as in  claim 15 , wherein the phthalazinedione is a haloamino, alkylamino, acylamino, alkanolamino, alkenylamino, alkoxyamino, haloalkylamino, allylamino, or sulfhydrylamino derivative. 
     
     
         17 . The method as in  claim 16 , wherein the phthalazinedione is a bromoamino, chloroamino, fluoroamino, iodoamino, methylamino, ethylamino, propylamino, isopropylamino, methanoylamino, ethanoylamino, propanoylamino, hydroxylamino, carboxylamino, methanolamino, ethanolamino, propanolamino, methenylamino, ethenylamino, propenylamino, methoxyamino, ethoxyamino, propoxyamino, or dimethylamino derivative. 
     
     
         18 . The method as in  claim 15 , wherein the phthalazinedione is 5-amino-2,3-dihydrophthalazine-1,4-dione, 6-amino-2,3-dihydrophthalazine-1,4-dione, or 5-amino-2,3-dihydrophthalazine-1,4-dion-8-yl. 
     
     
         19 . The method as in  claim 17 , wherein the phthalazinedione is N-bromo-5-amino-2,3-dihydrophthalazine-1,4-dione, N-chloro-5-amino-2,3-dihydrophthalazine-1,4-dione, N-fluoro-5-amino-2,3-dihydrophthalazine-1,4-dione, N-iodo-5-amino-2,3-dihydrophthalazine-1,4-dione, N-methyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-ethyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-propyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-isopropyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-methanoyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-ethanoyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-propanoyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-hydroxyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-carboxyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-methanol-5-amino-2,3-dihydrophthalazine-1,4-dione, N-ethanol-5-amino-2,3-dihydrophthalazine-1,4-dione, N-propanol-5-amino-2,3-dihydrophthalazine-1,4-dione, N-methenyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-ethenyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-propenyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-methoxy-5-amino-2,3-dihydrophthalazine-1,4-dione, N-ethoxy-5-amino-2,3-dihydrophthalazine-1,4-dione, N-propoxy-5-amino-2,3-dihydrophthalazine-1,4-dione, N,N-dimethyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-acetylcysteine-5-amino-2,3-dihydrophthalazine-1,4-dione, or N-acetylglutathione-5-amino-2,3-dihydrophthalazine-1,4-dione. 
     
     
         20 . The method as in  claim 8 , wherein the phthalazinedione is administered with an adjuvant, diluent, carrier, excipient, or stabilizer. 
     
     
         21 . The method as in  claim 20 , wherein the phthalazinedione comprises a pharmaceutically acceptable form selected from the group consisting of tablet, capsule, granule, powder, solution, suspension, microsphere, liposome, colloid, lyophilized composition, gel, lotion, ointment, cream, spray, and suppository. 
     
     
         22 . The method as in  claim 21 , wherein the phthalazinedione is administered by a means selected from the group consisting of intravenous, intramuscular, intraperitoneal, subcutaneous, oral, nasal, mucosal, transdermal, parenteral, vaginal, and rectal. 
     
     
         23 . The method as in  claim 22 , wherein the method is used in combination with a standard treatment selected from the group consisting of radiation, chemotherapy, laser therapy, surgery, medication, and nutrition. 
     
     
         24 . The method as in  claim 8 , wherein the phthalazinedione is administered in an amount of about 0.01 mg/kg to about 100.0 mg/kg of body weight. 
     
     
         25 . The method as in  claim 24 , wherein the phthalazinedione is administered in an amount of about 0.05 mg/kg to about 50.0 mg/kg of body weight. 
     
     
         26 . The method as in  claim 25 , wherein the phthalazinedione is administered in an amount of about 0.1 mg/kg to about 10.0 mg/kg of body weight. 
     
     
         27 . The method as in  claim 8 , wherein the phthalazinedione is administered in an amount of about 1.0 mg per day to about 10,000.0 mg per day. 
     
     
         28 . The method as in  claim 27 , wherein the phthalazinedione is administered in an amount of about 50.0 mg per day to about 5000.0 mg per day. 
     
     
         29 . The method as in  claim 28 , wherein the phthalazinedione is administered in an amount of about 100.0 mg per day to about 1000.0 mg per day. 
     
     
         30 . The method as in  claim 27 , wherein the phthalazinedione is administered in an amount of about 1.0 mg, 10.0 mg, 50.0 mg, 100.0 mg, 200.0 mg, 300.0 mg, 400.0 mg, 500.0 mg, 600.0 mg, 700.0 mg, 800.0 mg, 900.0 mg, 1000.0 mg, 2000.0 mg, 3000.0 mg, 4000.0 mg, 5000.0 mg, 6000.0 mg, 7000.0 mg, 8000.0 mg, 9000.0 mg, or 10,000.0 mg per day. 
     
     
         31 . A pharmaceutical composition comprising a phthalazinedione or its pharmaceutically acceptable salt, ester, solvate, hydrate, analogue, metabolite, enantiomer, isomer, tautomer, amide, derivative, prodrug, or free base; a compound that is an amino acid, antibiotic, antiviral agent, antiinflammatory agent, antioxidant, immunomodulator, reductant, oxidative protector, steroid, or vitamin; and one or more pharmaceutically acceptable excipients. 
     
     
         32 . The pharmaceutical composition of  claim 31 , wherein the phthalazinedione is an amino derivative. 
     
     
         33 . The pharmaceutical composition of  claim 32 , wherein the phthalazinedione is a haloamino, alkylamino, acylamino, alkanolamino, alkenylamino, alkoxyamino, haloalkylamino, allylamino, or sulfhydrylamino derivative. 
     
     
         34 . The pharmaceutical composition of  claim 33 , wherein the phthalazinedione is a bromoamino, chloroamino, fluoroamino, iodoamino, methylamino, ethylamino, propylamino, isopropylamino, methanoylamino, ethanoylamino, propanoylamino, hydroxylamino, carboxylamino, methanolamino, ethanolamino, propanolamino, methenylamino, ethenylamino, propenylamino, methoxyamino, ethoxyamino, propoxyamino, or dimethylamino derivative. 
     
     
         35 . The pharmaceutical composition of  claim 32 , wherein the phthalazinedione is 5-amino-2,3-dihydrophthalazine-1,4-dione, 6-amino-2,3-dihydrophthalazine-1,4-dione, or 5-amino-2,3-dihydrophthalazine-1,4-dion-8-yl. 
     
     
         36 . The pharmaceutical composition of  claim 34 , wherein the phthalazinedione is N-bromo-5-amino-2,3-dihydrophthalazine-1,4-dione, N-chloro-5-amino-2,3-dihydrophthalazine-1,4-dione, N-fluoro-5-amino-2,3-dihydrophthalazine-1,4-dione, N-iodo-5-amino-2,3-dihydrophthalazine-1,4-dione, N-methyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-ethyl-S-amino-2,3-dihydrophthalazine-1,4-dione, N-propyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-isopropyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-methanoyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-ethanoyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-propanoyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-hydroxyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-carboxyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-methanol-5-amino-2,3-dihydrophthalazine-1,4-dione, N-ethanol-5-amino-2,3-dihydrophthalazine-1,4-dione, N-propanol-5-amino-2,3-dihydrophthalazine-1,4-dione, N-methenyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-ethenyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-propenyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-methoxy-5-amino-2,3-dihydrophthalazine-1,4-dione, N-ethoxy-5-amino-2,3-dihydrophthalazine-1,4-dione, N-propoxy-5-amino-2,3-dihydrophthalazine-1,4-dione, N,N-dimethyl-5-amino-2,3-dihydrophthalazine-1,4-dione, N-acetylcysteine-5-amino-2,3-dihydrophthalazine-1,4-dione, or N-acetylglutathione-5-amino-2,3-dihydrophthalazine-1,4-dione. 
     
     
         37 . The pharmaceutical composition of  claim 31 , wherein the compound is a glutathione, glucocorticoid, dexamethasone, cysteine, lipoic acid, biopterin, hydralazine, rasagiline, thioredoxin, ferulic acid, minocycline, menadione, tetracycline, isosorbate dinitrate, dextromethorphan, dithiotireitol, carnosine, or clomethiazole. 
     
     
         38 . The pharmaceutical composition of  claim 31 , further comprising a pharmaceutically acceptable form selected from the group consisting of tablet, capsule, granule, powder, solution, suspension, microsphere, liposome, colloid, lyophilized composition, gel, lotion, ointment, cream, spray, and suppository. 
     
     
         39 . The pharmaceutical composition of  claim 38 , wherein the pharmaceutical composition is administered by a means selected from the group consisting of intravenous, intramuscular, intraperitoneal, subcutaneous, oral, nasal, mucosal, transdermal, parenteral, vaginal, and rectal. 
     
     
         40 . The pharmaceutical composition of  claim 39 , wherein the pharmaceutical composition is used in combination with a standard treatment selected from the group consisting of radiation, chemotherapy, laser therapy, surgery, medication, and nutrition. 
     
     
         41 . The pharmaceutical composition of  claim 31 , wherein the pharmaceutical composition is used in treating metabolic distress. 
     
     
         42 . The pharmaceutical composition of  claim 31 , wherein the pharmaceutical composition is used in treating inflammatory conditions. 
     
     
         43 . The pharmaceutical composition of  claim 31 , wherein the pharmaceutical composition is used in treating infectious conditions. 
     
     
         44 . The pharmaceutical composition of  claim 31 , wherein the pharmaceutical composition is used in treating neurological disorders. 
     
     
         45 . The pharmaceutical composition of  claim 31 , wherein the pharmaceutical composition is used in treating immune disorders. 
     
     
         46 . The pharmaceutical composition of  claim 31 , wherein the pharmaceutical composition is used in treating proliferative diseases. 
     
     
         47 . The pharmaceutical composition of  claim 31 , wherein the pharmaceutical composition is used in treating cellular senescence. 
     
     
         48 . The pharmaceutical composition of  claim 31 , wherein the pharmaceutical composition is administered in a dose comprising the phthalazinedione in an amount of about 0.01 mg/kg to about 100.0 mg/kg of body weight. 
     
     
         49 . The pharmaceutical composition of  claim 48 , wherein the pharmaceutical composition is administered in a dose comprising the phthalazinedione in an amount of about 0.05 mg/kg to about 50.0 mg/kg of body weight. 
     
     
         50 . The pharmaceutical composition of  claim 49 , wherein the pharmaceutical composition is administered in a dose comprising the phthalazinedione in an amount of about 0.1 mg/kg to about 10.0 mg/kg of body weight. 
     
     
         51 . The pharmaceutical composition of  claim 31 , wherein the pharmaceutical composition is administered in a dose comprising the phthalazinedione in an amount of about 1.0 mg per day to about 10,000.0 mg per day. 
     
     
         52 . The pharmaceutical composition of  claim 51 , wherein the pharmaceutical composition is administered in a dose comprising the phthalazinedione in an amount of about 50.0 mg per day to about 5000.0 mg per day. 
     
     
         53 . The pharmaceutical composition of  claim 52 , wherein the pharmaceutical composition is administered in a dose comprising the phthalazinedione in an amount of about 100.0 mg per day to about 1000.0 mg per day. 
     
     
         54 . The pharmaceutical composition of  claim 51 , wherein the pharmaceutical composition is administered in a dose comprising the phthalazinedione in an amount of about 1.0 mg, 10.0 mg, 50.0 mg, 100.0 mg, 200.0 mg, 300.0 mg, 400.0 mg, 500.0 mg, 600.0 mg, 700.0 mg, 800.0 mg, 900.0 mg, 1000.0 mg, 2000.0 mg, 3000.0 mg, 4000.0 mg, 5000.0 mg, 6000.0 mg, 7000.0 mg, 8000.0 mg, 9000.0 mg, or 10,000.0 mg per day.