Compounds, Compositions, and Methods for use in Treating Autophagy-Associated Disorders

Abstract

The invention provides compounds and methods of treating autophagy mediated diseases and disorders and related pharmaceutical compositions, diagnostics, screening techniques and kits.

What is claimed is: 
     
         1 . A compound having the following backbone structural formula: 
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1 , wherein the compound is selected from the group consisting of:
 N-(3,4-dimethoxypheny)-1,8-Dioxa-3-aza-2,4-dihydro-2H-5-phenyl-anthracen-7-one,   N-(3,4-dimethoxybenzyl)-1,8-Dioxa-3-aza-2,4-dihydro-2H-5-methyl-anthracen-7-one,   N-benzyl-1,8-Dioxa-3-aza-3,4dihydro-2H-anthracen-7-one series, and   N-(3,4-dimethoxypheny)-1,8-Dioxa-3-aza-2,4-dihydro-2H-5-methyl-anthracen-7-one.   
     
     
         3 . A compound having the following backbone structural formula: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 3 , wherein the compound is selected from the group consisting of:
 3-(4-methoxyphenyl)-1,5-bis(2-methoxyphenyl)-1,5-pentanedione,   3-(4-hydroxyphenyl)-1,5-bis(2-methoxyphenyl)-1,5-pentanedione,   3-(4-methoxyphenyl)-1,5-bis (2-methoxyphenyl)-1,5-pentanedione,   3-(4-allyloxyphenyl)-1,5-bis(2-methoxyphenyl)-1,5-pentanedione,   3-(4- hydroxyphenyl)-1,5-bis(2-methoxyphenyl)-1,5-pentanedione,   3-(3,4,5-trimethoxymethoxyphenyl)-1,5-bis(2-methoxyphenyl)-1,5-pentanedione,   3-(4-allyloxyphenyl)-1,5-bis(2-methoxyphenyl)-1,5-pentanedione, and   3-(4-dimethylaminophenyl)-1,5- bis(2-methoxyphenyl)-1,5-pentanedione.   
     
     
         5 . A method of using the compound of  claim 2  to treat an autophagy-mediated disease state or condition. 
     
     
         6 . A method of using the compound of  claim 4  to treat an autophagy-mediated disease state or condition. 
     
     
         7 . The method  claim 5 , wherein the autophagy-mediated disease state or condition is cancer, lysosomal storage diseases, Alzheimer's disease, Parkinson's disease and other ataxias such as Huntington's disease; a chronic inflammatory disease such as Crohn's disease, diabetes I, diabetes II, metabolic syndrome, an inflammation-associated metabolic disorder, liver disease, renal disease, cardiovascular disease, muscle degeneration and atrophy, frailty in aging, spinal cord injury, infectious disease, chronic pain, depression related syndromes, and developmental disease. 
     
     
         8 . The method  claim 6 , wherein the autophagy-mediated disease state or condition is cancer, lysosomal storage diseases, Alzheimer's disease, Parkinson's disease and other ataxias such as Huntington's disease; a chronic inflammatory disease such as Crohn's disease, diabetes I, diabetes II, metabolic syndrome, an inflammation-associated metabolic disorder, liver disease, renal disease, cardiovascular disease, muscle degeneration and atrophy, frailty in aging, spinal cord injury, infectious disease, chronic pain, depression related syndromes, and developmental disease. 
     
     
         9 . The composition of  claim 2  wherein the composition further comprises an autophagy modulator selected from the group comprising benzethonium, niclosamide, monensin, bromperidol, levobunolol, dehydroisoandosterone 3-acetate, sertraline, tamoxifen, reserpine, hexachlorophene, dipyridamole, harmaline, prazosin, lidoflazine, thiethylperazine, dextromethorphan, desipramine, mebendazole, canrenone, chlorprothixene, maprotiline, homochlorcyclizine, loperamide, nicardipine, dexfenfluramine, nilvadipine, dosulepin, biperiden, denatonium, etomidate, toremifene, tomoxetine, clorgyline, zotepine, beta-escin, tridihexethyl, ceftazidime, methoxy-6-harmalan, melengestrol, albendazole, rimantadine, chlorpromazine, pergolide, cloperastine, prednicarbate, haloperidol, clotrimazole, nitrofural, iopanoic acid, naftopidil, methimazole, trimeprazine, ethoxyquin, clocortolone, doxycycline, pirlindole mesylate, doxazosin, deptropine, nocodazole, scopolamine, oxybenzone, halcinonide, oxybutynin, miconazole, clomipramine, cyproheptadine, doxepin, dyclonine, salbutamol, flavoxate, amoxapine, fenofibrate, pimethixene, pharmaceutically acceptable salts thereof and mixtures thereof. 
     
     
         10 . The composition of  claim 9 , wherein the additional bioactive agent is an antibiotic, an antiviral agent, or an anticancer agent. 
     
     
         11 . A pharmaceutical composition comprising the compound of  claim 2  in an effective amount. 
     
     
         12 . The composition of  claim 11 , further comprising a pharmaceutically-acceptable carrier, additive or excipient. 
     
     
         13 . The composition of  claim 12 , further comprising at least one additional bioactive agent or a secondary condition of the viral infection. 
     
     
         14 . The composition of  claim 4  wherein the composition further comprises an autophagy modulator selected from the group comprising benzethonium, niclosamide, monensin, bromperidol, levobunolol, dehydroisoandosterone 3-acetate, sertraline, tamoxifen, reserpine, hexachlorophene, dipyridamole, harmaline, prazosin, lidoflazine, thiethylperazine, dextromethorphan, desipramine, mebendazole, canrenone, chlorprothixene, maprotiline, homochlorcyclizine, loperamide, nicardipine, dexfenfluramine, nilvadipine, dosulepin, biperiden, denatonium, etomidate, toremifene, tomoxetine, clorgyline, zotepine, beta-escin, tridihexethyl, ceftazidime, methoxy-6-harmalan, melengestrol, albendazole, rimantadine, chlorpromazine, pergolide, cloperastine, prednicarbate, haloperidol, clotrimazole, nitrofural, iopanoic acid, naftopidil, methimazole, trimeprazine, ethoxyquin, clocortolone, doxycycline, pirlindole mesylate, doxazosin, deptropine, nocodazole, scopolamine, oxybenzone, halcinonide, oxybutynin, miconazole, clomipramine, cyproheptadine, doxepin, dyclonine, salbutamol, flavoxate, amoxapine, fenofibrate, pimethixene, pharmaceutically acceptable salts thereof and mixtures thereof. 
     
     
         15 . The composition of  claim 14 , wherein the additional bioactive agent is an antibiotic, an antiviral agent, or an anticancer agent. 
     
     
         16 . A pharmaceutical composition comprising the compound of  claim 4  in an effective amount. 
     
     
         17 . The composition of  claim 16 , further comprising a pharmaceutically-acceptable carrier, additive or excipient. 
     
     
         18 . The composition of  claim 17 , further comprising at least one additional bioactive agent or a secondary condition of the viral infection.