Compounds, Compositions, and Methods for Treating Alzheimer's Disease

Abstract

Novel methods and compounds for treating Alzheimer's Disease are provided. In one aspect, the invention provides methods for treating Alzheimer's Disease by administering certain phenothiazine derivatives. In one embodiment, the methods include administering an effective amount of a 3-oxo-7-dialkyl-amino-phenothiazine derivative, or 3-oxo-7-dialkyl-amino-phenothiazine. In another embodiment, the invention provides methods for treating Alzheimer's Disease by administering an effective amount of a 3,7-diazetidin-1-yl-phenothiazine or a derivative thereof. In another aspect, the invention provides novel azetidinyl phenothiazine compounds.

What is claimed: 
     
         1 . A method for treating Alzheimer's Disease, comprising administering to a mammal suffering from such disease a therapeutically effective amount of a compound having the structure: 
       
         
           
           
               
               
           
         
         and its pharmaceutically acceptable salts, hydrates, and coordination compounds, wherein: 
         R 1 , R 2 , R 4 , R 5 , R 7 , and R 8  are selected independently from the group consisting of: hydrogen, halo, cyano, nitro, nitrilo, hydroxy, thio, amino, carboxyl, formyl, and optionally substituted alkyl, alkylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, cycloalkylcarbonyloxy, cycloheteroalkylcarbonyloxy, aralkycarbonyloxy, heteroaralkylcarbonyloxy, (cycloalkyl)alkylcarbonyloxy, (cycloheteroalkyl)alkylcarbonyloxy, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, cycloalkycarbonyl, cycloheteroalkycarbonyl, aralkycarbonyl, heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl, (cycloheteroalkyl)alkylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl, heteroaralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, cycloalkylcarbonylamino, cycloheteroalkylcarbonylamino, aralkylcarbonylamino, heteroaralkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, (cycloheteroalkyl)alkylcarbonylamino, dialkylamino, arylamino, diarylamino, aralkylamino, diaralkylamino, heteroarylamino, diheteroarylamino, heteroaralkylamino, diheteroaralkylamino, alkylsulfonyl, arylsulonyl, heteroarylsulfonyl, cycloalkylsulfonyl, aralkycarbonylthioooxy, carbonylythio, heteroaralkylcarbonylthio, (cycloalkyloxy)carbonylthio, (cycloheteroalkyl)alkylcarbonylthio, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, cycloalkyloxycarbonyl, cycloheteroalkyloxycarbonyl, aralyoxycarbonyloxloxycarbonyl, heteroaralkyloxycarbonyl, (cycloalkyl)alkyloxycarbonyl, (cycloheteroalkyl)alkyloxycarbonyl, iminoalkyl, iminocycloalkyl, iminocycloheteroalkyl, iminoaralkyl, iminoheteroaralkyl, (cycloalkyl)iminoalkyl, and (cycloheteroalkyl)iminoalkyl; 
         R 3  and R 6  are selected independently from the group consisting of: optionally substituted four-, five-, six-, or seven-membered cycloheteroalkyl, said cycloheteroalkyl including a first ring nitrogen heteroatom bonded at the position indicated by R 3  or R 6 , respectively, and an optional second heteroatom selected from the group consisting of optionally substituted nitrogen, oxygen, sulfur, sulfinyl, and sulfonyl; and oxo, thiocarbonyl, imino, and optionally substituted dialkylimino, diarylimino, diheteroarylimino, alkylarylimino, alkylheteroarylimino, arylheteroarylimino, amino, alkylamino, dialkylamino, alkyloxyalkylamino, di-(alkyloxyalkyl)amino, alkylthioalkylamino, di-(alkylthioalkyl)amino, alkylaminoalkylamino, di-(alkylaminoalkyl)amino, aryloxyalkylamino, di-(aryloxyalkyl)amino, arylthioalkylamino, di-(arylthioalkyl)amino, arylaminoalkylamino, di-(arylaminoalkyl)amino, heteroaryloxyalkylamino, di-(heteroaryloxyalkyl)amino, heteroarylthioalkylamino, di-(heteroarylthioalkyl)amino, heteroarylaminoalkylamino, and di-(heteroarylaminoalkyl)amino; and 
         at least one of R 3  and R 6  is optionally substituted dialkylamino or optionally substituted five-, six-, or seven-membered cycloheteroalkyl, said cycloheteroalkyl including a first ring nitrogen heteroatom bonded at the position indicated by R 3  or R 6 , respectively. 
       
     
     
         2 . The method of  claim 1 , wherein each of R 3  and R 6  is optionally substituted dialkylamino. 
     
     
         3 . The method of  claim 2 , wherein each of R 1 , R 2 , R 4 , R 5 , R 7 , and R 8  is hydrogen. 
     
     
         4 . The method of  claim 3 , wherein each of R 3  and R 6  is dialkylamino. 
     
     
         5 . The method of  claim 4 , wherein each of R 3  and R 6  is diethylamino or dimethylamino. 
     
     
         6 . The method of  claim 5 , wherein each of R 3  and R 6  is dimethylamino. 
     
     
         7 . The method of  claim 2 , wherein each of R 2 , R 4 , R 5 , and R 7  is hydrogen. 
     
     
         8 . The method of  claim 1 , wherein R 3  is oxo. 
     
     
         9 . The method of  claim 8 , wherein R 6  is optionally substituted dialkylamino. 
     
     
         10 . The method of  claim 9 , wherein R 6  is dimethylamino. 
     
     
         11 . The method of  claim 1 , wherein each of R 3  and R 6  is optionally substituted four-, five-, six-, or seven-membered cycloheteroalkyl, said cycloheteroalkyl including a first ring nitrogen heteroatom bonded at the position indicated by R 3  or R 6 , respectively, and an optional second heteroatom selected from the group consisting of optionally substituted nitrogen, oxygen, sulfur, sulfinyl, and sulfonyl. 
     
     
         12 . The method of  claim 11 , wherein each of R 3  and R 6  is optionally substituted five-membered cycloheteroalkyl, said cycloheteroalkyl including a first ring nitrogen heteroatom bonded at the position indicated by R 3  or R 6 , respectively, and an optional second heteroatom selected from the group consisting of optionally substituted nitrogen, oxygen, sulfur, sulfinyl, and sulfonyl. 
     
     
         13 . The method of  claim 12 , wherein each of R 3  and R 6  is optionally substituted pyrrolidin-1-yl. 
     
     
         14 . The method of  claim 13 , wherein each of R 3  and R 6  is pyrrolidin-1-yl. 
     
     
         15 . The method of  claim 14 , wherein each of R 1 , R 2 , R 4 , R 5 , R 7 , and R 8  is hydrogen. 
     
     
         16 . The method of  claim 11 , wherein each of R 3  and R 6  is optionally substituted four-membered cycloheteroalkyl, said cycloheteroalkyl including a first ring nitrogen heteroatom bonded at the position indicated by R 3  or R 6 , respectively, and an optional second heteroatom selected from the group consisting of optionally substituted nitrogen, oxygen, sulfur, sulfinyl, and sulfonyl. 
     
     
         17 . The method of  claim 16 , wherein each of R 3  and R 6  is optionally substituted azetidin-1-yl. 
     
     
         18 . The method of  claim 17 , wherein each of R 3  and R 6  is azetidin-1-yl. 
     
     
         19 . The method of  claim 18 , wherein each of R 1 , R 2 , R 4 , R 5 , R 7 , and R 8  is hydrogen.