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 pharmaceutical composition comprising a phthalazinedione or its pharmaceutically acceptable salt, ester, solvate, hydrate, metabolite, enantiomer, isomer, tautomer, amide, 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.  
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the phthalazinedione is an aminophthalazinedione.  
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein the phthalazinedione is a haloaminophthalazinedione, alkylaminophthalazinedione, acylaminophthalazinedione, alkanolaminophthalazinedione, alkenylaminophthalazinedione, alkoxyaminophthalazinedione, haloalkylaminophthalazinedione, allylaminophthalazinedione, or sulfhydrylaminophthalazinedione.  
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the phthalazinedione is a bromoaminophthalazinedione, chloroaminophthalazinedione, fluoroaminophthalazinedione, iodoaminophthalazinedione, methylaminophthalazinedione, ethylaminophthalazinedione, propylaminophthalazinedione, isopropylaminophthalazinedione, methanoylaminophthalazinedione, ethanoylaminophthalazinedione, propanoylaminophthalazinedione, hydroxylaminophthalazinedione, carboxylaminophthalazinedione, methanolaminophthalazinedione, ethanolaminophthalazinedione, propanolaminophthalazinedione, methenylaminophthalazinedione, ethenylaminophthalazinedione, propenylaminophthalazinedione, methoxyaminophthalazinedione, ethoxyaminophthalazinedione, propoxyaminophthalazinedione or dimethylaminophthalazinedione.  
     
     
         5 . The pharmaceutical composition of  claim 2 , 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.  
     
     
         6 . The pharmaceutical composition of  claim 4 , 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.  
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the compound is a glutathione, glucocorticoid, dexamethasone, cysteine, lipoic acid, biopterin, hydralazine, rasagiline, thioredoxin, ferulic acid, minocycline, menadione, tetracycline, isosorbate dinitrate, dextromethorphan, dithiothreitol, carnosine, or clomethiazole.  
     
     
         8 . The pharmaceutical composition of  claim 1 , 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.  
     
     
         9 . The pharmaceutical composition of  claim 8 , 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.  
     
     
         10 . The pharmaceutical composition of  claim 9 , 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.  
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is used in treating metabolic distress.  
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is used in treating inflammatory conditions.  
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is used in treating infectious conditions.  
     
     
         14 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is used in treating neurological disorders.  
     
     
         15 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is used in treating immune disorders.  
     
     
         16 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is used in treating proliferative diseases.  
     
     
         17 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is used in treating cellular senescence.  
     
     
         18 . The pharmaceutical composition of  claim 1 , 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.  
     
     
         19 . The pharmaceutical composition of  claim 18 , 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.  
     
     
         20 . The pharmaceutical composition of  claim 19 , 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.  
     
     
         21 . The pharmaceutical composition of  claim 1 , 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.  
     
     
         22 . The pharmaceutical composition of  claim 21 , 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.  
     
     
         23 . The pharmaceutical composition of  claim 22 , 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.  
     
     
         24 . The pharmaceutical composition of  claim 21 , 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.