Trifluoromethyl-containing phenylsulfonamide beta amyloid inhibitors

Abstract

A compound of Formula (I), or pharmaceutically acceptable salts and/or hydrates or prodrugs thereof, wherein Formula (I) has the structure: is provided, wherein R 1 -R 7 are defined herein. These compounds are useful in medicaments for treating a disease selected from the group consisting of Alzheimer's disease, amyloid angiopathy, cerebral amyloid angiopathy, systemic amyloidosis, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, inclusion body myositis, mild cognitive impairment (MCI) and Down's syndrome, in a subject.

1 . A method of inhibiting beta amyloid production in a subject, said method comprising delivering a compound of Formula (I), or pharmaceutically acceptable salts and/or hydrates or prodrugs thereof, to said subject, wherein Formula (I) has the structure: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  through R 5  are independently selected from the group consisting of H, halogen, lower alkyl, lower alkoxy, OCF 3 , OCF 2 H, CF 3 , NO 2 , CN, CH 3 CO, and SCH 3 ; 
       R 6  and R 7  are independently selected from the group consisting of lower alkyl and CF 3 (CH 2 ) n ; and 
       n is independently selected from the group consisting of 0, 1, 2 and 3, provided that at least one of R 6  and R 7  are CF 3 (CH 2 ) n . 
     
   
   
       2 . The method according to  claim 1 , wherein said compound is delivered orally, by injection, by inhalation, transdermally and suppository. 
   
   
       3 . The method according to  claim 1 , wherein one of R 6  or R 7  is CF 3 (CH 2 ) n  and the other is CH 3 . 
   
   
       4 . The method according to  claim 1 , wherein the compound is selected from the group consisting of:
 4-chloro-N-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide;   4-chloro-N-[(1S,2R)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide;   3,4-dichloro-N-[( 1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide;   4-fluoro-N-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide; and   N-[( 1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]-4-(trifluoromethyl)benzenesulfonamide.   
   
   
       5 . The method according to  claim 1 , wherein R 3  is halogen. 
   
   
       6 . The method according to  claim 1 , wherein R 3  is CF 3 . 
   
   
       7 . The method according to  claim 1 , wherein one of R 6  or R 7  is CF 3 (CH 2 ) n  where n is 1, 2 or 3 and the other is selected from lower alkyl and CF 3 (CH 2 ) n , wherein n is 2 or 3. 
   
   
       8 . The method according to  claim 1 , wherein said compound has a chiral center at the C attached to the N and S-stereochemistry at the chiral center. 
   
   
       9 . The method according to  claim 1 , wherein R 1 , R 2 , R 4,  and R 5  are H 
   
   
       10 . The method according to  claim 1 , wherein R 6  and R 7  are CF 3 (CH 2 ) n  and n is 0. 
   
   
       11 . The method according to  claim 1 , wherein said compound is selected from the group consisting of:
 4-chloro-N-[(1S)-3,3,3 -trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide;   4-chloro-N-[(1S)-4,4,4-trifluoro-1-(hydroxymethyl)-2-(2,2,2-trifluoroethyl)butyl]benzenesulfonamide;   4-chloro-3-methoxy-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide;   4-chloro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]-3-(trifluoromethyl)benzenesulfonamide;   4-chloro-3-nitro-N-[3,3,3 -trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide;   3-acetyl-N-[3 ,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide;   4-(difluoromethoxy)-N-[3,3,3-trifluoro-1-(hydroxym ethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide;   3-(difluoromethoxy)-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide;   4-ethyl-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide;   4-isopropyl-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide;   4-methoxy-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide;   3-methoxy-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide;   4-propyl-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide;   4-methyl-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide;   3-methyl-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide;   N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]-3 -(trifluoromethyl)benzenesulfonamide;   N-[3,3,3-trifluoro-1-(hydroxyrnethyl)-2-(trifluoromethyl)propyl]-4-(trifluoromethyl)benzenesulfonamnide;   4-cyano-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide;   4-nitro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide;   N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-4-trifluoromethoxy-benzenesulfonamide   4-chloro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide;   3,5-difluoro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide;   4-chloro-3-(methylthio)-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide;   4-chloro-3-fluoro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifiuoromethyl)propyl]benzenesulfonamide;   4-fluoro-3-methyl-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonairide;   4-fluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide;   3-fluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide;   2-fluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide;   3-chloro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide;   2-chloro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide;   4-bromo-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide;   3-bromo-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide;   N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide;   3,4-difluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide;   2,4-difluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide;   3,5-dichloro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide;   2,3-dichloro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide;   3,4-dichloro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide;   3-chloro-4-fluoro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide;   2,3,4-trifluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide;   3,4-dichloro-N-[(1S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide;   4-chloro-N-[4,4,4-trifluoro-1-hydroxymethyl-2-(2,2,2-trifluoro-ethyl)-butyl]-benzenesulfonamide; and   3,4,5-trifluoro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide.   
   
   
       12 . The method according to  claim 1 , wherein the pharmaceutically acceptable salt is selected from the group consisting of salts of bases. 
   
   
       13 . The method according to  claim 11 , wherein the salts of bases are selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, and mixtures thereof. 
   
   
       14 . The method according to  claim 1 , wherein said compound of Formula (I) is in a composition. 
   
   
       15 . The method according to  claim 14 , wherein said composition is delivered orally, by injection, by inhalation, transdermally and suppository. 
   
   
       16 . A method of treating a disease selected from the group consisting of Alzheimer's disease, anmyloid angiopathy, cerebral amyloid angiopathy, systemic amyloidosis, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, inclusion body myositis, mild cognitive impairment (MCI) and Down's syndrome, in a subject, said method comprising the step of administering a compound of Formula (I) , or pharmaceutically acceptable salts and/or hydrates or prodrugs thereof, to said subject in an amount sufficient to alleviate the symptoms or progress of said disease, wherein Formula (I) has the structure: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  through R 5  are independently selected from the group consisting of H, halogen, lower alkyl, lower alkoxy, OCF 3 , OCF 2 H, CF 3 , NO 2 , CN, CH 3 CO, and SCH 3 ; 
       R 6  and R 7  are independently selected from the group consisting of lower alkyl and CF 3 (CH 2 ) n ; and 
       n is independently selected from the group consisting of 0, 1, 2 and 3, provided that at least one of R 6  and R 7  are CF 3 (CH 2 ) n . 
     
   
   
       17 . The method according to  claim 16 , wherein said compound of formula (I) is in a composition. 
   
   
       18 . The method according to  claim 16 , wherein said compound of formula (I) is present in an amount sufficient to alleviate the symptoms or progress of said disease. 
   
   
       19 . A pharmaceutical kit comprising a container comprising a pharmaceutical composition, wherein said pharmaceutical composition comprises a compound of Formula (I), or pharmaceutically acceptable salts and/or hydrates or prodrugs thereof: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  through R 5  are independently selected from the group consisting of H, halogen, lower alkyl, lower alkoxy, OCF 3 , OCF 2 H, CF 3 , NO 2 , CN, CH 3 CO, and SCH 3 ; 
       R 6  and R 7  are independently selected from the group consisting of lower alkyl and CF 3 (CH 2 ) n ; and 
       n is independently selected from the group consisting of 0, 1, 2 and 3, provided that at least one of R 6  and R 7  are CF 3 (CH 2 ) n .