Inhibitors of cognitive decline

Abstract

Compounds that are central nervous system drug candidates for the treatment of cognitive decline and, more particularly, Alzheimer's disease are provided. Methods of treating, inhibiting, and/or abatement of cognitive decline and Alzheimer's disease with a derivative of ginger oil are also provided. Also provided is a method of conditioning biological extracts, such as a medicinal plant extract, by a reductive amination process to give nitrogen-containing derivatives.

1 . A method of inhibiting, treating, or abatement of cognitive decline in a mammal, the method comprising administering a derivative of ginger oil to a mammal. 
     
     
         2 . A method according to  claim 1  wherein a symptom of the cognitive decline is one or more of memory loss, confusion, impaired judgment, personality changes, disorientation, and loss of language skills. 
     
     
         3 . A method according to  claim 1  wherein the treating or abatement of the cognitive decline comprises restoration of long term potentiation. 
     
     
         4 . A method according to  claim 1  wherein the inhibiting, treating, or abatement of cognitive decline comprises inhibiting, treating, or abatement of one or both of neurodegeneration and general amyloidosis. 
     
     
         5 . A method according to  claim 1  wherein the inhibiting, treating, or abatement of cognitive decline comprises inhibiting, treating, or abatement of one or more of amyloid production, amyloid assembly, amyloid aggregation, amyloid oligomer binding, and amyloid deposition. 
     
     
         6 . A method according to  claim 1  wherein the derivative of ginger oil is a compound in purified and isolated form. 
     
     
         7 . A method of inhibiting, treating, or abatement of Alzheimer's disease in a mammal, the method comprising administering a derivative of ginger oil to a mammal. 
     
     
         8 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein,
 R 1  and R 2  are each independently selected from the group consisting of hydrogen, hydroxy, methoxy, halide, haloalkyl, small alkyl, and small alkoxy; 
 R 3 , R 4  and R 5  are each independently selected from the group consisting of hydrogen, small alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; 
 R 6  and R 7  are each independently selected from the group consisting of hydrogen, small alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; or R 6  and R 7  along with the nitrogen to which they are attached form a five or six membered heterocyclic ring, comprising one or two heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein the five or six membered heterocyclic ring is unsubstituted, or substituted with a substituent selected from the group consisting of hydroxy, hydroxyalkyl, halide, haloalkyl, small alkyl, small alkoxy, and —CH 2 OR 9 ; 
 R 8  is selected from the group consisting of hydroxy, small alkoxy, and —NR 10 R 11 ; 
 R 9  is selected from the group consisting of hydrogen, small alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; 
 R 10  and R 11  are each independently selected from the group consisting of hydrogen, small alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; or R 10  and R 11  along with the nitrogen to which they are attached form a five or six membered heterocyclic ring, comprising one or two heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein the five or six membered heterocyclic ring is unsubstituted, or substituted with a substituent selected from the group consisting of hydroxy, hydroxyalkyl, halide, haloalkyl, small alkyl, small alkoxy, and —CH 2 OR 9 ; 
 R 12  is selected from the group consisting of hydrogen, haloalkyl, and small alkyl; 
 R 13  is selected from the group consisting of hydrogen, and small alkyl; 
 R 14  is selected from the group consisting of hydrogen, and small alkyl; 
 R 15  and R 16  are each independently selected from the group consisting of hydrogen, small alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; and 
 n, m, and p are each independently 0, 1, or 2. 
 
     
     
         9 . A compound according to  claim 8  of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         10 . A compound according to  claim 9  of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein,
 R 6  and R 7  along with the nitrogen to which they are attached form a five or six membered heterocyclic ring of the formula: 
 
       
         
           
           
               
               
           
         
         wherein,
 X is selected from the group consisting of —CH 2 , —CHR 11 , —N═, —O—, —S—, and —N—R 17 , wherein each carbon atom of the five or six membered heterocyclic ring, individually, is unsubstituted, or substituted with a substituent selected from the group consisting of hydroxy, hydroxyalkyl, halide, haloalkyl, small alkyl, small alkoxy, and —CH 2 OR 9 ; and 
 R 17  is selected from the group consisting of hydrogen, small alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl. 
 
       
     
     
         11 . A compound according to  claim 8  of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein,
 R 18  is selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halide, haloalkyl, small alkyl, small alkoxy, and —CH 2 OR 9 . 
 
     
     
         12 . A compound according to  claim 11  of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         13 . A compound according to  claim 8  of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         14 . A compound according to  claim 12  of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         15 . A compound according to  claim 8  of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         16 . A compound according to  claim 15  of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein,
 R 14 , R 15  and R 16  are each independently small alkyl; 
 n and m are each independently 0 or 1; and 
 p is 1 or 2. 
 
     
     
         17 . A compound according to  claim 16  of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         18 . A compound according to  claim 8  wherein the compound exhibits activity in a beta-secretase assay. 
     
     
         19 . A composition comprising a compound according to  claim 8  in a pharmaceutically-acceptable carrier. 
     
     
         20 . A method of inhibiting, treating, or abatement of cognitive decline comprising the administration of a compound of  claim 8  to a patient. 
     
     
         21 . A method according to  claim 20  wherein the method of inhibiting, treating, or abatement of cognitive decline comprises inhibiting, treating, or abatement of one or more symptoms of cognitive decline including memory loss, confusion, impaired judgment, personality changes, disorientation, and loss of language skills. 
     
     
         22 . A method according to  claim 20  wherein the method of inhibiting, treating, or abatement of cognitive decline comprises restoration of long term potentiation. 
     
     
         23 . A method according to  claim 20  wherein the inhibiting, treating, or abatement of cognitive decline comprises inhibiting, treating, or abatement of neurodegeneration and general amyloidosis. 
     
     
         24 . A method according to  claim 20  wherein the inhibiting, treating, or abatement of cognitive decline comprises inhibiting, treating, or abatement of one or more of amyloid production, amyloid assembly, amyloid aggregation, amyloid oligomer binding, and amyloid deposition. 
     
     
         25 . A method of inhibiting, treating, or abatement of Alzheimer's disease comprising the administration of a compound of  claim 8  to a patient. 
     
     
         26 . A method of preparing an array of chemical compounds from a biological extract, the method comprising:
 providing a biological extract, the biological extract having one or more biological compounds, each biological compound having one or more reactive electrophilic groups:   reacting the biological compounds with an amine to incorporate the amine into the biological compounds: and   reacting the biological compound having the incorporated amine with a reducing agent to form an array of one or more chemical compounds, wherein the one or more chemical compounds are derivatives of the biological compounds in the biological extract.   
     
     
         27 . A method according to  claim 26  further comprising isolating one or more of the chemical compounds. 
     
     
         28 . A method according to  claim 27  further comprising isolating one or more of the chemical compounds in a purified form. 
     
     
         29 . A method according to  claim 26  further comprising screening one or more of the chemical compounds for biological activity. 
     
     
         30 . A method according to  claim 26  wherein the biological extract is a plant extract.