Compounds and methods for cytoprotection

Abstract

Compounds, compositions and methods for treating degenerative diseases and disorders are disclosed, the compounds having the following structure (I): including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein R 1 and R 2 are as defined herein.

1 . A compound having the structure: 
       
         
           
           
               
               
           
         
       
       or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, wherein:
 R 1  is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; 
 R 2  is —NR 3a R 3b , —O—R 3a , or —NR 3a C(═O)R 3b ; and 
 R 3a  and R 3b  are the same or different and independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle and substituted heterocycle. 
 
     
     
         2 . The compound of  claim 1 , wherein R 2  is —NR 3a R 3b . 
     
     
         3 . The compound of  claim 2 , wherein R 1  is alkyl. 
     
     
         4 . The compound of  claim 3 , wherein R 1  is adamantyl. 
     
     
         5 . The compound of  claim 4 , wherein R 3a  and R 3b  are both hydrogen. 
     
     
         6 . The compound of  claim 1 , wherein R 2  is —O—R 3a . 
     
     
         7 . The compound of  claim 6 , wherein R 1  is alkyl. 
     
     
         8 . The compound of  claim 7 , wherein R 1  is adamantyl. 
     
     
         9 . The compound of  claim 8 , wherein R 3a  is hydrogen. 
     
     
         10 . The compound of  claim 8 , wherein R 3a  is lower alkyl. 
     
     
         11 . The compound of  claim 10 , wherein R 3a  is methyl. 
     
     
         12 . The compound of  claim 1 , wherein R 2  is —NR 3a C(═O)R 3b . 
     
     
         13 . The compound of  claim 12 , wherein R 1  is alkyl. 
     
     
         14 . The compound of  claim 13 , wherein R 1  is adamantyl. 
     
     
         15 . The compound of  claim 14 , wherein R 3a  is hydrogen and R 3b  is lower alkyl. 
     
     
         16 . The compound of  claim 15 , wherein R 3b  is methyl. 
     
     
         17 . A pharmaceutical composition comprising a compound of  claim 1  in combination with a pharmaceutically acceptable carrier. 
     
     
         18 . A method for treating a degenerative disorder, comprising administering, to a subject having or suspected of being at risk for having a degenerative disorder, a therapeutically effective amount of the pharmacutical composition of  claim 17 . 
     
     
         19 . The method of  claim 18  wherein the degenerative disorder is selected from the group consisting of (i) a neurodegenerative disorder, (ii) an ophthalmic disease, (iii) a cardiovascular disease, (iv) a disorder of bone, joint, connective tissue or cartilage, (v) a disorder associated with altered activity of an excitotoxic pathway, (vi) tissue transplantation and (vi) a mitochondrial disorder. 
     
     
         20 . The method of  claim 18  wherein the degenerative disorder is a neurodegenerative disorder selected from the group consisting of Alzheimer's disease, mild cognitive impairment, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. 
     
     
         21 . The method of  claim 18  wherein the degenerative disorder is an ophthalmic disease that is selected from the group consisting of glaucoma, retinitis pigmentosa, macular degeneration, elevated intraocular pressure and Leber's hereditary optic neuropathy. 
     
     
         22 . The method of  claim 18  wherein the degenerative disorder is a cardiovascular disease that is selected from the group consisting of stroke, ischemia and myocardial infarction. 
     
     
         23 . The method of  claim 18  wherein the degenerative disorder is a disorder of bone, joint, connective tissue or cartilage that is selected from the group consisting of osteoarthritis, rheumatoid arthritis and psoriatic arthritis. 
     
     
         24 . The method of  claim 18  wherein the degenerative disorder is Friedreich's ataxia. 
     
     
         25 . A pharmaceutical composition comprising (i) a first cytoprotective compound that is a compound of  claim 1 ; (ii) at least one second compound that is selected from the group consisting of an antioxidant, an antiestrogen, a hormone, a mineral, a vitamin, a neuropeptide, a cholesterol-lowering agent, an Alzheimer's disease-treating agent, a stroke-treating agent and a therapeutic antibody; and (iii) a pharmaceutically acceptable carrier. 
     
     
         26 . A method for treating a degenerative disorder, comprising administering, to a subject having or suspected of being at risk for having a degenerative disorder, a therapeutically effective amount of the pharmacutical composition of  claim 25 . 
     
     
         27 . A method for treating a degenerative disorder, comprising administering, to a subject having or suspected of being at risk for having a degenerative disorder, a therapeutically effective amount of (i) a first cytoprotective compound that is a compound of  claim 1 , and (ii) at least one second compound that is selected from the group consisting of an antioxidant, an antiestrogen, a hormone, a mineral, a vitamin, a neuropeptide, a cholesterol-lowering agent, an Alzheimer's disease-treating agent, a stroke-treating agent and a therapeutic antibody. 
     
     
         28 . The method of  claim 27  wherein the first cytoprotective compound and the second compound are administered separately. 
     
     
         29 . The method of  claim 27  wherein the first cytoprotective compound and the second compound are administered together. 
     
     
         30 . A method for isolating a molecular component of an excitotoxic pathway, comprising contacting a biological sample with a compound of  claim 1  under conditions and for a time sufficient to permit a binding interaction between the compound and the molecular component, and thereby isolating the molecular component. 
     
     
         31 . The method of  claim 30  wherein the compound is immobilized, detectably labeled or retrievably tagged.