Method of treating neurodegenerative disorders

Abstract

The present disclosure is directed, at least in part, to disease-modifying treatments for neurodegenerative disorders. In one embodiment, a method of delaying worsening of one or more symptoms and/or progression of a neurodegenerative disorder is provided. In one embodiment, a method of treating or ameliorating one or more symptoms of a neurodegenerative disorder is provided. In one embodiment, the methods of the present invention comprise administering to a subject in need thereof, a compound having the structure of Formula ( 1 a ):Formula ( 1 a ); and/or a pharmaceutically acceptable salt thereof. In one embodiment, the the compound of ( 1 a ) and/or a pharmaceutically acceptable salt thereof is administered in combination with one or more pharmacologic ally active agents.

We claim: 
     
         1 . A method of slowing down, preventing progression of, treating or ameliorating one or more symptoms of a neurodegenerative disorder, comprising administering to a subject in need thereof, a compound having a structure selected from Formula (1), Formula (1a) or Formula (1b): 
       
         
           
           
               
               
           
         
       
       and/or a pharmaceutically acceptable salt thereof at a dose in a ranging from about 0.001 mg/Kg body weight to about 2000 mg/Kg body weight or from about 0.001 mg/m 2  to about 160 mg/m 2 . 
     
     
         2 . (canceled) 
       
         
           
           
               
               
           
         
       
     
     
         3 . (canceled) 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 1 , wherein the compound of Formula (1), (1a), or (1b) and/or the pharmaceutically acceptable salt thereof is administered in a single dose or in divided doses. 
     
     
         5 . The method of  claim 4 , wherein the compound of Formula (1), (1a), or (1b), and/or the pharmaceutically acceptable salt thereof is administered in a single dose per day or in divided doses per day. 
     
     
         6 . The method of  claim 4 , wherein the compound of Formula (1), (1a), or (1b), and/or a pharmaceutically acceptable salt thereof dose is administered in two or more equally divided doses per day. 
     
     
         7 . The method of  claim 4 , wherein the compound of Formula (1), (1a), or (1b), and/or the pharmaceutically acceptable salt thereof dose is administered in two and/or more unequally divided doses per day. 
     
     
         8 . The method of  claim 4 , wherein the compound of Formula (1), (1a), or (1b), and/or the pharmaceutically acceptable salt thereof is administered in two and/or three divided doses per day. 
     
     
         9 . The method of  claim 4 , wherein the compound of Formula (1), (1a), or (1b), and/or the pharmaceutically acceptable salt thereof dose is administered in two and/or four divided doses per day. 
     
     
         10 . The method of  claim 1 , wherein the compound of Formula (1), (1a), or (1b) and/or the pharmaceutically acceptable salt thereof is administered at least once daily for at least two successive days. 
     
     
         11 . The method of  claim 1 , wherein the compound of Formula (1), (1a), or (1b) and/or the pharmaceutically acceptable salt thereof is administered at least once daily on alternative days. 
     
     
         12 . The method of  claim 1 , wherein the compound of Formula (1), (1a), or (1b) and/or the pharmaceutically acceptable salt thereof is administered weekly. 
     
     
         13 . The method of  claim 12 , wherein the compound of Formula (1), (1a), or (1b) and/or the pharmaceutically acceptable salt thereof is administered weekly divided into equal and/or unequal doses. 
     
     
         14 . The method of  claim 13 , wherein the compound of Formula (1), (1a), or (1b) and/or the pharmaceutically acceptable salt thereof is administered weekly given either on three alternate days and/or 6 times per week. 
     
     
         15 . The method of  claim 1 , wherein the compound of Formula (1), (1a), or (1b) and/or the pharmaceutically acceptable salt thereof is administered in divided doses on alternate days, every third day, every fourth day, every fifth day, every sixth day and/or weekly. 
     
     
         16 . The method of  claim 1 , wherein the compound of Formula (1), (1a), or (1b) and/or the pharmaceutically acceptable salt thereof is administered monthly. 
     
     
         17 . The method of  claim 4 , wherein the compound of Formula (1), (1a), or (1b), and/or the pharmaceutically acceptable salt thereof is administered in a single dose per month and/or in divided doses per month. 
     
     
         18 . The method of  claim 4 , wherein the compound of Formula (1), (1a), or (1b) and/or a pharmaceutically acceptable salt thereof dose is administered in two and/or more equally divided doses per month. 
     
     
         19 . The method of  claim 4 , wherein the compound of Formula (1), (1a), or (1b) and/or the pharmaceutically acceptable salt thereof dose is administered in two and/or more unequally divided doses per month. 
     
     
         20 . The method of  claim 4 , wherein the compound of Formula (1), (1a), or (1b) and/or the pharmaceutically acceptable salt thereof is administered in two and/or three divided doses per month. 
     
     
         21 . The method of  claim 4 , wherein the compound of Formula (1), (1a), or (1b) and/or the pharmaceutically acceptable salt thereof dose is administered in two and/or four divided doses per month. 
     
     
         22 . The method of  claim 1 , wherein the compound of Formula (1), (1a), or (1b) and/or the pharmaceutically acceptable salt thereof is administered at least once monthly for at least two successive months. 
     
     
         23 . The method of  claim 1 , wherein the compound of Formula (1), (1a), or (1b) and/or the pharmaceutically acceptable salt thereof is administered at least once monthly on alternative months. 
     
     
         24 . The method of  claim 1 , wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease (AD), Parkinsonian syndromes (PD), Huntington's disease (HD), Dementia pugilistica (DP), Prion diseases, cerebral amyloid angiopathy (CAA), and mild cognitive impairment (MCI). 
     
     
         25 . The method of  claim 1 , wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy and frontotemporoparietal dementia. 
     
     
         26 . The method of  claim 1 , wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, frontotemporal dementias, Parkinson's disease, and polyglutamine diseases, sporadic and familial Alzheimer's disease, Dementia pugilistica (DP), Down's syndrome, progressive supranuclear palsy, Huntington's disease, sporadic and familial synucleinopathies, multiple system atrophy, neurodegeneration with brain iron accumulation, neuronal intranuclear inclusion disease, hereditary spastic paraplegias, Charcot-Marie-Tooth disease, and sporadic and/or hereditary prion disease. 
     
     
         27 . The method of  claim 1 , wherein the neurodegenerative disorder is selected from the group consisting of a cognitive disorder, Alzheimer's disease, a neuro-degenerative disorder, age-related dementia, age-induced memory impairment, and movement disorder. 
     
     
         29 . The method of  claim 1 , wherein the neurodegenerative disorder is Alzheimer's disease. 
     
     
         30 . The method of  claim 1 , wherein the symptoms of the neurodegenerative disorder is selected from the group consisting of cognitive deficits, memory impairment, movement disorders, and motor complications. 
     
     
         31 . The method of  claim 1 , wherein the compound of Formula (1), (1a), or (1b) and/or a pharmaceutically acceptable salt thereof is administered in a dose ranging from about 0.001 mg/Kg body weight to about 20 mg/Kg body weight. 
     
     
         32 . The method of  claim 1 , wherein the compound of Formula (1), (1a), or (1b) and/or a pharmaceutically acceptable salt thereof is administered in a dose ranging from about 0.001 mg/Kg body weight to about 10 mg/Kg body weight. 
     
     
         33 . The method of  claim 1 , wherein the compound of Formula (1), (1a), or (1b) and/or a pharmaceutically acceptable salt thereof is administered in a dose ranging from about 0.001 mg/Kg body weight to about 5 mg/Kg body weight. 
     
     
         34 . The method of  claim 1 , wherein the compound of Formula (1), (1a), or (1b) and/or a pharmaceutically acceptable salt thereof is administered in a dose ranging from about 0.001 mg/Kg body weight to about 3 mg/Kg body weight. 
     
     
         35 . The method of  claim 1 , wherein the compound of Formula (1), (1a), or (1b) and/or a pharmaceutically acceptable salt thereof is administered in a dose ranging from about 0.001 mg/Kg body weight to about 2 mg/Kg body weight. 
     
     
         36 . The method of  claim 1 , wherein the compound of Formula (1), (1a), or (1b) and/or a pharmaceutically acceptable salt thereof is administered in a dose ranging from about 0.001 mg/Kg body weight to about 30 mg/Kg body weight. 
     
     
         37 . The method of  claim 1 , wherein the compound of Formula (1), (1a), or (1b) and/or a pharmaceutically acceptable salt thereof is administered in a dose ranging from about 0.001 mg/Kg body weight to about 40 mg/Kg body weight. 
     
     
         38 . The method of  claim 1 , wherein the compound of Formula (1), (1a), or (1b) and/or a pharmaceutically acceptable salt thereof is administered in a dose ranging from about 0.001 mg/Kg body weight to about 50 mg/Kg body weight. 
     
     
         39 . The method of  claim 1 , wherein the compound of Formula (1), (1a), or (1b) and/or a pharmaceutically acceptable salt thereof is administered in a dose selected from the group consisting of 25 mg/Kg body weight, about 50 mg/Kg body weight, about 75 mg/Kg body weight, about 100 mg/Kg body weight, about 125 mg/Kg body weight, about 150 mg/Kg body weight, about 175 mg/Kg body weight, about 200 mg/Kg body weight, about 225 mg/Kg body weight, about 250 mg/Kg body weight, about 275 mg/Kg body weight, about 300 mg/Kg body weight, about 325 mg/Kg body weight, about 350 mg/Kg body weight, about 375 mg/Kg body weight, about 400 mg/Kg body weight, about 425 mg/Kg body weight, about 450 mg/Kg body weight, about 475 mg/Kg body weight, about 500 mg/Kg body weight, about 525 mg/Kg body weight, about 550 mg/Kg body weight, about 575 mg/Kg body weight, about 600 mg/Kg body weight, about 625 mg/Kg body weight, about 650 mg/Kg body weight, about 675 mg/Kg body weight, about 700 mg/Kg body weight, about 725 mg/Kg body weight, about 750 mg/Kg body weight, about 775 mg/Kg body weight, about 800 mg/Kg body weight, about 825 mg/Kg body weight, about 850 mg/Kg body weight, about 875 mg/Kg body weight, about 900 mg/Kg body weight, about 925 mg/Kg body weight, about 950 mg/Kg body weight, about 975 mg/Kg body weight, and about 1000 mg/Kg body weight. 
     
     
         40 . The method of  claim 1 , wherein the compound of Formula (1), (1a), or (1b) and/or the pharmaceutically acceptable salt thereof is administered is administered orally, subcutaneously, intravenously, intramuscularly, intranasally, transdermally and/or sublingually. 
     
     
         41 . The method of  claim 1 , wherein the compound of Formula (1), (1a), or (1b) and/or the pharmaceutically acceptable salt thereof is administered at a dose selected from the group consisting of from about 0.001 mg/m 2  to about 160 mg/m 2 , from about 0.001 mg/m 2  to about 155 mg/m 2 , from about 0.001 mg/m 2  to about 150 mg/m 2 , from about 0.001 mg/m 2  to about 145 mg/m 2 , from about 0.001 mg/m 2  to about 140 mg/m 2 , from about 0.001 mg/m 2  to about 135 mg/m 2 , from about 0.001 mg/m 2  to about 130 mg/m 2 , from about 0.001 mg/m 2  to about 125 mg/m 2 , from about 0.001 mg/m 2  to about 120 mg/m 2 , from about 0.001 mg/m 2  to about 115 mg/m 2 , from about 0.001 mg/m 2  to about 110 mg/m 2 , from about 0.001 mg/m 2  to about 105 mg/m 2 , from about 0.001 mg/m 2  to about 100 mg/m 2 , from about 0.001 mg/m 2  to about 95 mg/m 2 , from about 0.001 mg/m 2  to about 90 mg/m 2 , from about 0.001 mg/m 2  to about 85 mg/m 2 , from about 0.001 mg/m 2  to about 80 mg/m 2 , from about 0.001 mg/m 2  to about 75 mg/m 2 , from about 0.001 mg/m 2  to about 70 mg/m 2 , from about 0.001 mg/m 2  to about 65 mg/m 2 , from about 0.001 mg/m 2  to about 60 mg/m 2 , from about 0.001 mg/m 2  to about 55 mg/m 2 , from about 0.001 mg/m 2  to about 50 mg/m 2 , from about 0.001 mg/m 2  to about 45 mg/m 2 , from about 0.001 mg/m 2  to about 40 mg/m 2 , from about 0.001 mg/m 2  to about 35 mg/m 2 , from about 0.001 mg/m 2  to about 30 mg/m 2 , from about 0.001 mg/m 2  to about 25 mg/m 2 , from about 0.001 mg/m 2  to about 20 mg/m 2 , from about 0.001 mg/m 2  to about 15 mg/m 2 , from about 0.001 mg/m 2  to about 10 mg/m 2 , and from about 0.001 mg/m 2  to about 5 mg/m 2 . 
     
     
         42 . The method of  claim 1 , wherein the compound of Formula (1), (1a), or (1b) and/or the pharmaceutically acceptable salt thereof is administered at a dose selected from the group consisting of less than about 160 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 155 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 150 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 145 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 140 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 135 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 130 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 125 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 120 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 115 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 110 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 105 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 100 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 95 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 90 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 85 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 80 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 75 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 70 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 65 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 60 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 55 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 50 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 45 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 40 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 35 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 30 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 25 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 20 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 15 mg/m 2  but greater than about 0.001 mg/m 2 , less than about 10 mg/m 2  but greater than about 0.001 mg/m 2 , and less than about 5 mg/m 2  but greater than about 0.001 mg/m 2 .