Halogenated esters of cyclopropanated unsaturated fatty acids for use in the treatment of neurodegenerative diseases

Abstract

The present disclosure describes novel PKC-ε activators chosen from halogenated esters of unsaturated fatty acids and derivatives thereof, including halogenated esters of both polyunsaturated and monounsaturated fatty acids and derivatives thereof. The disclosure further relates to compositions, kits, and methods for treatment using the halogenated esters.

1 - 41 . (canceled) 
     
     
         42 . A method for treating a disease, condition, or disorder comprising administering to a patient in need thereof an effective amount of at least one halogenated alkyl or aryl ester of an unsaturated fatty acid, wherein the disease, condition, or disorder is chosen from a disease associated with synaptic loss or synaptic damage, a neurodegenerative disease or condition, a neuroaffective disorder, stroke, mental retardation, and brain injury. 
     
     
         43 . The method of  claim 42 , wherein the disease, condition, or disorder is a neurodegenerative disease or condition chosen from Alzheimer's Disease, Parkinson's Disease, Fragile X, Niemann-Pick C, and dementia. 
     
     
         44 . (canceled) 
     
     
         45 . The method of  claim 42 , wherein the unsaturated fatty acid is a polyunsaturated fatty acid chosen from linoleic acid, arachidonic acid, eicosadienoic acid, dihomo-gamma-linolenic acid, docosadienoic acid, adrenic acid, calendic acid, docosapentaenoic acid, jacaric acid, pinolenic acid, podocarpic acid, tetracosatetraenoic acid, tetracosapentaenoic acid, vernolic acid, docosahexaenoic acid, eicosapentaenoic acid, rumelenic acid, parinaric acid, linolenic acid, eicosenoic acid, mead acid, erucic acid, nervonic acid, rumenic acid, alpha-elostearic acid, catalpic acid, and punicic acid. 
     
     
         46 . The method of  claim 42 , wherein the unsaturated fatty acid is a monounsaturated fatty acid chosen from oleic acid and elaidic acid. 
     
     
         47 . (canceled) 
     
     
         48 . (canceled) 
     
     
         49 . The method of  claim 42 , wherein the at least one halogenated ester is a halogenated alkyl ester. 
     
     
         50 . The method of  claim 42 , wherein the at least one halogenated ester is a halogenated aryl ester. 
     
     
         51 . The method of  claim 49 , wherein the halogenated alkyl ester is chosen from methyl ester, ethyl ester, isopropyl ester, tert-butyl ester, and benzyl ester. 
     
     
         52 . (canceled) 
     
     
         53 . (canceled) 
     
     
         54 . The method of  claim 42 , wherein the at least one halogenated alkyl or aryl ester of an unsaturated fatty acid is a halogenated alkyl or aryl ester of 8-[2-(2-pentylcyclopropylmethyl)-cyclopropyl]-octanoic acid (DCPLA). 
     
     
         55 . The method of  claim 54 , wherein the disease, condition, or disorder is a neurodegenerative disease or condition chosen from Alzheimer's Disease, Parkinson's Disease, Fragile X, Niemann-Pick C, and dementia. 
     
     
         56 . The method of  claim 54 , wherein the at least one halogenated ester is a halogenated alkyl ester. 
     
     
         57 . The method of  claim 54 , wherein the at least one halogenated ester is a halogenated aryl ester. 
     
     
         58 . The method of  claim 56 , wherein the halogenated alkyl ester is chosen from methyl ester, ethyl ester, isopropyl ester, tert-butyl ester, and benzyl ester. 
     
     
         59 . (canceled) 
     
     
         60 . (canceled) 
     
     
         61 . The method of  claim 54 , wherein the at least one halogenated ester is a trifluoroalkyl ester. 
     
     
         62 . The method of  claim 61 , wherein the trifluoroalkyl ester is chosen from 
       
         
           
           
               
               
           
         
       
     
     
         63 . The method of  claim 42 , wherein the at least one halogenated ester is a trifluoroalkyl ester. 
     
     
         64 . The method of  claim 43 , wherein the neurodegenerative disease or condition is dementia chosen from Parkinson's dementia, frontotemporal dementia, and vascular dementia. 
     
     
         65 . The method of  claim 42 , wherein the disease, condition, or disorder is a neuroaffective disorder chosen from depression, bipolar disorder, schizophrenia, and Post-Traumatic Stress Disorder. 
     
     
         66 . The method of  claim 42 , wherein the disease, condition, or disorder is brain injury chosen from traumatic brain injury and brain injury induced by irradiation. 
     
     
         67 . The method of  claim 55 , wherein the neurodegenerative disease or condition is dementia chosen from Parkinson's dementia, frontotemporal dementia, and vascular dementia. 
     
     
         68 . The method of  claim 54 , wherein the disease, condition, or disorder is a neuroaffective disorder chosen from depression, bipolar disorder, schizophrenia, and Post-Traumatic Stress Disorder. 
     
     
         69 . The method of  claim 54 , wherein the disease, condition, or disorder is brain injury chosen from traumatic brain injury and brain injury induced by irradiation. 
     
     
         70 . A method of improving at least one of memory and learning, comprising administering to a subject in need thereof an effective amount of at least one halogenated alkyl or aryl ester of an unsaturated fatty acid, wherein the unsaturated fatty acid is cyclopropanated, and the alkoxy or aryloxy group of the ester comprises a —CF 3  group. 
     
     
         71 - 82 . (canceled) 
     
     
         83 . A method for treating ischemia and/or hypoxia as a result of open-heart surgery, comprising administering to a patient in need thereof an effective amount of at least one halogenated alkyl or aryl ester of an unsaturated fatty acid, wherein the unsaturated fatty acid is cyclopropanated, and the alkoxy or aryloxy group of the ester comprises a —CF3 group. 
     
     
         84 - 116 . (canceled) 
     
     
         117 . The method of  claim 42 , wherein the alkoxy or aryloxy group of the ester comprises a —CF 3  group. 
     
     
         118 . The method of  claim 42 , wherein the unsaturated fatty acid is cyclopropanated.