Novel cyclohexyl sulphones

Abstract

Novel sulphones of formula I are disclosed: The compounds modulate the processing of amyloid precursor protein by gamma-secretase, and hence are useful in the treatment or prevention of Alzheimer's disease.

1 . A compound of formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 m is 0 or 1;  
 Z represents halogen, CN, NO 2 , N 3 , CF 3 , OR 2a , N(R 2a ) 2 , CO 2 R 2a , OCOR 2a , COR 2a , CON(R 2a ) 2 , OCON(R 2a ) 2 , CONR 2a (OR 2a ), CON(R 2a )N(R 2a ) 2 , CONHC(═NOH)R 2a , heterocyclyl, phenyl or heteroaryl, said heterocyclyl, phenyl or heteroaryl bearing 0-3 substituents selected from halogen, CN, NO 2 , CF 3 , OR 2a , N(R 2a ) 2 , CO 2 R 2a , COR 2a , CON(R 2a ) 2  and C 1-4 alkyl;  
 R 1b  represents H, C 1-4 alkyl or OH;  
 R 1c  represents H or C 1-4 alkyl;  
 with the proviso that when m is 1, R 1b  and R 1c  do not both represent C 1-4 alkyl;  
 Ar 1  represents C 6-10 aryl or heteroaryl, either of which bears 0-3 substituents independently selected from halogen, CN, NO 2 , CF 3 , OH, OCF 3 , C 1-4 alkoxy or C 1-4 alkyl which optionally bears a substituent selected from halogen, CN, NO 2 , CF 3 , OH and C 1-4 alkoxy;  
 Ar 2  represents C 6-10 aryl or heteroaryl, either of which bears 0-3 substituents independently selected from halogen, CN, NO 2 , CF 3 , OH, OCF 3 , C 1-4 alkoxy or C 1-4 alkyl which optionally bears a substituent selected from halogen, CN, NO 2 , CF 3 , OH and C 1-4 alkoxy;  
 R 2a  represents H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-6 alkyl, C 2-6 alkenyl, any of which optionally bears a substituent selected from halogen, CN, NO 2 , CF 3 , OR 2b , CO 2 R 2b , N(R 2b ) 2 , CON(R 2b ) 2 , Ar and COAr; or R 2a  represents Ar; or two R 2a  groups together with a nitrogen atom to which they are mutually attached may complete an N-heterocyclyl group bearing 0-4 substituents independently selected from ═O, ═S, halogen, C 1-4 alkyl, CN, NO 2 , CF 3 , OH, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, CO 2 H, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, carbamoyl, Ar and COAr;  
 R 2b  represents H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-6 alkyl, C 2-6 alkenyl, any of which optionally bears a substituent selected from halogen, CN, NO 2 , CF 3 , OH, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, CO 2 H, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, carbamoyl, Ar and COAr; or R 2b  represents Ar; or two R 2b  groups together with a nitrogen atom to which they are mutually attached may complete an N-heterocyclyl group bearing 0-4 substituents independently selected from ═O, ═S, halogen, C 1-4 alkyl, CN, NO 2 , CF 3 , OH, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, CO 2 H, amino, C 4 alkylamino, di(C 4 alkyl)amino, carbamoyl, Ar and COAr;  
 Ar represents phenyl or heteroaryl bearing 0-3 substituents selected from halogen, C 1-4 alkyl, CN, NO 2 , CF 3 , OH, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, carbamoyl, C 1-4 alkylcarbamoyl and di(C 1-4 alkyl)carbamoyl;  
 “heterocyclyl” at every occurrence thereof means a cyclic or polycyclic system of up to 10 ring atoms selected from C, N, O and S, wherein none of the constituent rings is aromatic and wherein at least one ring atom is other than C; and  
 “heteroaryl” at every occurrence thereof means a cyclic or polycyclic system of up to 10 ring atoms selected from C, N, O and S, wherein at least one of the constituent rings is aromatic and wherein at least one ring atom of said aromatic ring is other than C;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       2 . A compound according to  claim 1  wherein Ar 1  is selected from phenyl groups substituted in the 4-position with halogen, methyl or trifluoromethyl, and phenyl groups substituted in the 3- and 4-positions by halogen.  
   
   
       3 . A compound according to  claim 1  wherein Ar 2  is selected from phenyl groups substituted in the 2- and 5-positions by halogen.  
   
   
       4 . A compound according to  claim 1  wherein Z represents N(R 2a ) 2  and the R 2a  groups complete an N-heterocyclyl group.  
   
   
       5 . A compound according to  claim 1  wherein Z represents CO 2 R 2a  and R 2a  represents H or C 1-6 alkyl.  
   
   
       6 . A compound according to  claim 1  wherein Z represents COR 2a  and R 2a  represents Ar.  
   
   
       7 . A compound according to  claim 1  wherein Z represents CON(R 2a ) 2  or OCON(R 2a ) 2 , and the R 2a  groups independently represent H or optionally substituted alkyl, cycloalkyl, cycloalkylalkyl or alkenyl, or together complete an N-heterocyclyl group.  
   
   
       8 . A compound according to  claim 1  wherein Z represents CON(R 2a )(OR 2a ) or CON(R 2a )N(R 2a ) 2 , and each R 2a  represents H or C 1-6 alkyl.  
   
   
       9 . A compound according to  claim 1  wherein Z represents a 5-membered heteroaryl group.  
   
   
       10 . A compound according to  claim 5  wherein m is 1, Ar 1  represents 4-chlorophenyl, Ar 2  represents 2,5-difluorophenyl, R 1b  and R 1c  both represent H, and Z represents CO 2 H.  
   
   
       11 . A compound according to  claim 5  wherein m is 1, Ar 1  represents 4-trifluoromethylphenyl, Ar represents 2,5-difluorophenyl, R 1b  and R 1c  both represent H, and Z represents CO 2 H.  
   
   
       12 . A compound according to  claim 7  wherein m is 0, Ar 1  represents 4-chlorophenyl, Ar 2  represents 2,5-difluorophenyl, R 1c  represents H and Z represents CONH 2 .  
   
   
       13 . A compound according to  claim 7  wherein m is 0, Ar 1  represents 4-trifluoromethylphenyl, Ar 2  represents 2,5-difluorophenyl, R 1c  represents H and Z represents CONH 2 .  
   
   
       14 . A compound according to  claim 7  wherein m is 0, Ar 1  represents 4-chlorophenyl, Ar 2  represents 2,5-difluorophenyl, R 1c  represents H and Z represents CONHCH 2 CH 3 .  
   
   
       15 . A compound according to  claim 9  wherein m is 0, Ar 1  represents 4-chlorophenyl, Ar 2  represents 2,5-difluorophenyl, R 1c  represents H and Z represents 1,2,3,4-tetrazol-5-yl.  
   
   
       16 . A pharmaceutical composition comprising a compound of formula I as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.  
   
   
       17 . A compound of formula I as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human body.  
   
   
       18 . A method of treatment of a subject suffering from or prone to a condition associated with the deposition of β-amyloid which comprises administering to that subject an effective amount of a compound of formula I as defined in  claim 1  or a pharmaceutically acceptable salt thereof.  
   
   
       19 . A method according to  claim 18  wherein the condition is Alzheimer's disease.