Effective Amounts of (3aR)-1,3a,8-Trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b]indol-5-yl Phenylcarbamate and Methods of Treating or Preventing Neurodegeneration

Abstract

The invention includes an amount of (3aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl phenylcarbamate for administering to a subject and also a method of preventing or treating neurotoxicity or neurodegenerative processes in a subject in need thereof using the amount thereof.

1 . An amount of (3aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl phenylcarbamate (Compound (1)) or a salt thereof, wherein administering said amount to a subject results in a peak plasma circulating level of Compound (1) ranging from about 10 ng/mL to about 160 ng/ml in said subject. 
     
     
         2 . The amount of  claim 1 , wherein said peak plasma circulating level ranges from about 80 ng/mL to about 160 ng/ml in said subject. 
     
     
         3 . The amount of  claim 1 , wherein said peak plasma circulating level is reached within about 6 hours after said administering. 
     
     
         4 . The amount of  claim 3 , wherein said peak plasma circulating level is reached within about 3 hours after said administering. 
     
     
         5 . The amount of  claim 1 , wherein the plasma circulating level of Compound (1) is equal to or greater than about 20 ng/mL for at least 12 hours after said administering. 
     
     
         6 . The amount of  claim 5 , wherein the plasma circulating level of Compound (1) is equal to or greater than about 20 ng/mL for at least 9 hours after said administering. 
     
     
         7 . The amount of  claim 1 , wherein said administering results in a peak plasma concentration of Compound (2) ranging from about 15% to about 30% of the peak plasma concentration of Compound (1) in said subject. 
     
     
         8 . The amount of  claim 1 , wherein said administering results in a peak plasma concentration of Compound (3) ranging from about 15% to about 30% of the peak plasma concentration of Compound (1) in said subject. 
     
     
         9 . The amount of  claim 1 , wherein said administering results in a peak plasma concentration of Compound (4) ranging from about 1% to about 9% of the peak plasma concentration of Compound (1) in said subject. 
     
     
         10 . The amount of  claim 1 , wherein said administering results in a steady state plasma concentration of Compound (1) of at least about 100 ng/ml in said subject. 
     
     
         11 . The amount of  claim 1 , wherein said administering results in a steady state plasma concentration of Compound (2) of at least about 10 ng/ml in said subject. 
     
     
         12 . The amount of  claim 1 , wherein said administering results in a steady state plasma concentration of Compound (3) of at least about 10 ng/ml in said subject. 
     
     
         13 . The amount of  claim 1 , wherein said administering results in a steady state plasma concentration of Compound (4) of at least about 3 ng/ml in said subject. 
     
     
         14 . The amount of  claim 1 , wherein said administering results in a brain level of Compound (1) that ranges from about 4 to about 10 times the plasma level of Compound (1) in said subject. 
     
     
         15 . The amount of  claim 14 , wherein the brain level of Compound (2) ranges from about 15% to about 150% of the brain level of Compound (1) in said subject. 
     
     
         16 . The amount of  claim 14 , wherein the brain level of Compound (3) ranges from about 15% to about 150% of the brain level of Compound (1) in said subject. 
     
     
         17 . The amount of  claim 14 , wherein the brain level of Compound (4) is lower than the brain level of Compound (2) or Compound (3) in said subject. 
     
     
         18 . The amount of  claim 1 , wherein said subject is a human. 
     
     
         19 . A method of inhibiting production of a neurotoxic aggregating protein in a subject, said method comprising administering to said subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount of Compound (1) or a salt thereof, wherein administering said composition to said subject results in a peak plasma circulating level of Compound (1) ranging from about 10 ng/ml to about 160 mg/ml in said subject, whereby production of said neurotoxic aggregating protein in said subject is inhibited. 
     
     
         20 . The method of  claim 16 , wherein said neurotoxic aggregating protein is selected from the group consisting of APP, Aβ, SOD, Tau, alpha-synuclein (SNCA), NAC, TSE prion, and HTT. 
     
     
         21 . The method of  claim 19 , wherein said peak plasma circulating level ranges from about 80 ng/mL to about 160 ng/ml in said subject. 
     
     
         22 . The method of  claim 19 , wherein said peak plasma circulating level is reached within about 6 hours after said administering. 
     
     
         23 . The method of  claim 22 , wherein said peak plasma circulating level is reached within about 3 hours after said administering. 
     
     
         24 . The method of  claim 19 , wherein the plasma circulating level of Compound (1) is equal to or greater than about 20 ng/mL for at least 12 hours after said administering. 
     
     
         25 . The method of  claim 24 , wherein the plasma circulating level of Compound (1) is equal to or greater than about 20 ng/mL for at least 9 hours after said administering. 
     
     
         26 . The method of  claim 19 , wherein said administering results in a peak plasma concentration of Compound (2) ranging from about 15% to about 30% of the peak plasma concentration of Compound (1) in said subject. 
     
     
         27 . The method of  claim 19 , wherein said administering results in a peak plasma concentration of Compound (3) ranging from about 15% to about 30% of the peak plasma concentration of Compound (1) in said subject. 
     
     
         28 . The method of  claim 19 , wherein said administering results in a peak plasma concentration of Compound (4) ranging from about 1% to about 9% of the peak plasma concentration of Compound a) in said subject. 
     
     
         29 . The method of  claim 19 , wherein said administering results in a steady state plasma concentration of Compound (1) of at least about 100 ng/ml in said subject. 
     
     
         30 . The method of  claim 19 , wherein said administering results in a steady state plasma concentration of Compound (2) of at least about 10 ng/ml in said subject. 
     
     
         31 . The method of  claim 19 , wherein said administering results in a steady state plasma concentration of Compound (3) of at least about 10 ng/ml in said subject. 
     
     
         32 . The method of  claim 19 , wherein said administering results in a steady state plasma concentration of Compound (4) of at least about 3 ng/ml in said subject. 
     
     
         33 . The method of  claim 19 , wherein said administering results in a brain level of Compound (1) that ranges from about 4 to about 10 times the plasma level of Compound (1) in said subject. 
     
     
         34 . The method of  claim 33 , wherein the brain level of Compound (2) ranges from about 15% to about 150% of the brain level of Compound (1) in said subject. 
     
     
         35 . The method of  claim 33 , wherein the brain level of Compound (3) ranges from about 15% to about 150% of the brain level of Compound (1) in said subject. 
     
     
         36 . The method of  claim 33  wherein the brain level of Compound (4) is lower than the brain level of Compound (2) or Compound (3) in said subject. 
     
     
         37 . The amount of  claim 19 , wherein said subject is a human. 
     
     
         38 . The method of  claim 19 , wherein said administering results in a reduction equal to or greater than about 25% in a cerebrospinal fluid marker selected from the group consisting of sAPP α, sAPP β, Tau and pTau in said subject. 
     
     
         39 . The method of  claim 38 , wherein said administering results in a reduction equal to or greater than about 30% in a cerebrospinal fluid marker selected from the group consisting of sAPP α, sAPP β, Tau and pTau in said subject. 
     
     
         40 . A method of treating dementia in a subject, said method comprising administering to said subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount of Compound (1) or a salt thereof, wherein administering said composition to said subject results in a peak plasma circulating level of Compound (1) ranging from about 10 ng/mL to about 160 ng/ml in said subject, whereby said dementia in said subject is treated. 
     
     
         41 . The method of  claim 40 , wherein said dementia is Alzheimer's disease. 
     
     
         42 . The method of  claim 41 , wherein said dementia is selected from the group consisting of Parkinson's disease, Huntington's disease, Prion's disease, Amyloid Lateral Sclerosis and a tauopathy. 
     
     
         43 . The method of  claim 40 , wherein said peak plasma circulating level ranges from about 80 ng/mL to about 160 ng/ml in said subject. 
     
     
         44 . The method of  claim 40 , wherein said peak plasma circulating level is reached within about 6 hours after said administering. 
     
     
         45 . The method of  claim 44 , wherein said peak plasma circulating level is reached within about 3 hours after said administering. 
     
     
         46 . The method of  claim 40 , wherein the plasma circulating level of Compound (1) is equal to or greater than about 20 ng/mL for at least 12 hours after said administering. 
     
     
         47 . The method of  claim 46 , wherein the plasma circulating level of Compound (1) is equal to or greater than about 20 ng/mL for at least 9 hours after said administering. 
     
     
         48 . The method of  claim 40 , wherein said administering results in a peak plasma concentration of Compound (2) ranging from about 15% to about 30% of the peak plasma concentration of Compound (1) in said subject. 
     
     
         49 . The method of  claim 40 , wherein said administering results in a peak plasma concentration of Compound (3) ranging from about 15% to about 30% of the peak plasma concentration of Compound (1) in said subject. 
     
     
         50 . The method of  claim 40 , wherein said administering results in a peak plasma concentration of Compound (4) ranging from about 1% to about 9% of the peak plasma concentration of Compound (1) in said subject. 
     
     
         51 . The method of  claim 40 , wherein said administering results in a steady state plasma concentration of Compound (1) of at least about 100 ng/ml in said subject. 
     
     
         52 . The method of  claim 40 , wherein said administering results in a steady state plasma concentration of Compound (2) of at least about 10 ng/ml in said subject. 
     
     
         53 . The method of  claim 40 , wherein said administering results in a steady state plasma concentration of Compound (3) of at least about 10 ng/ml in said subject. 
     
     
         54 . The method of  claim 40 , wherein said administering results in a steady state plasma concentration of Compound (4) of at least about 3 ng/ml in said subject. 
     
     
         55 . The method of  claim 40 , wherein said administering results in a brain level of Compound (1) that ranges from about 4 to about 10 times the plasma level of Compound (1) in said subject. 
     
     
         56 . The method of  claim 55 , wherein the brain level of Compound (2) ranges from about 15% to about 150% of the brain level of Compound (1) in said subject. 
     
     
         57 . The method of  claim 55 , wherein the brain level of Compound (3) ranges from about 15% to about 150% of the brain level of Compound (1) in said subject. 
     
     
         58 . The method of  claim 55  wherein the brain level of Compound (4) is lower than the brain level of Compound (2) or Compound (3) in said subject. 
     
     
         59 . The amount of  claim 40 , wherein said subject is a human. 
     
     
         60 . The method of  claim 40 , wherein said administering results in a reduction equal to or greater than about 25% in a cerebrospinal fluid marker selected from the group consisting of sAPP α, sAPP β, Tau and pTau in said subject. 
     
     
         61 . The method of  claim 60 , wherein said administering results in a reduction equal to or greater than about 30% in a cerebrospinal fluid marker selected from the group consisting of sAPP α, sAPP β, Tau and pTau in said subject.