Selective Estrogen Receptor Modulators for the Treatment of Vasomotor Symptoms

Abstract

The present invention relates to a selective estrogen receptor modulator of formula I or Ia: (I) (Ia); or a pharmaceutical acid addition salt thereof; useful for treating vasomotor symptoms, in particular hot flashes, night sweats and other symptoms that affect women around menopause.

1 . A compound of formula I: 
     
       
         
         
             
             
         
       
     
     wherein:
 m is 0, 1 or 2; 
 n is 1, 2, 3 or 4; 
 R is H or methyl provided that if m is 1 or 2, then R must be H and that if m is 0, then R must be methyl; 
 R 1  is H, SO 2 (n-C 4 -C 6  alkyl) or COR 2 ; 
 X is O or NR 3 ; 
 Y is O, S, SO or NR 4 ; 
 R 2  is C 1 -C 6  alkyl; C 1 -C 6  alkoxy; NR 5 R 5a ; phenoxy; or phenyl optionally substituted with halo; 
 R 3  and R 4  are independently H or C 1 -C 6  alkyl; and 
 R 5  and R 5a  are independently H, C 1 -C 6  alkyl or phenyl; or a pharmaceutical acid addition salt thereof. 
 
   
   
       2 . The compound of  claim 1  wherein m is 1 or 2. 
   
   
       3 . The compound of  claim 2  wherein R 1  is H or COR 2  and R 2  is C 1 -C 4  alkyl, NHCH 3  or phenyl. 
   
   
       4 . The compound of  claim 3  wherein R 1  is H. 
   
   
       5 . The compound of  claim 4  wherein X is O. 
   
   
       6 . The compound of  claim 5  wherein Y is O or S. 
   
   
       7 . The compound of  claim 6  wherein m is 1. 
   
   
       8 . The compound of  claim 6  wherein m is 1 and Y is O. 
   
   
       9 . The compound of  claim 6  wherein m is 1 and Y is S. 
   
   
       10 . The compound of  claim 9  wherein n is 1, 2 or 3. 
   
   
       11 . The compound of  claim 10  wherein n is 1 or 2. 
   
   
       12 . The compound of  claim 11  of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       13 . The compound of  claim 11  wherein n is 1 and the corresponding fluoro moiety is at the 4-position. 
   
   
       14 . (canceled) 
   
   
       15 . (canceled) 
   
   
       16 . (canceled) 
   
   
       17 . (canceled) 
   
   
       18 . A compound of formula II: 
     
       
         
         
             
             
         
       
     
     wherein:
 m is 0, 1 or 2; 
 n is 1, 2, 3 or 4; 
 R is H or methyl provided that if m is 1 or 2, then R must be H and that if m is 0, then R must be methyl; 
 R 1a  is H, SO 2 CH 3 , SO 2 (n-C 4 -C 6  alkyl), COR 2 , C 1 -C 6  alkyl or benzyl; 
 X 2  is O or NR 7 ; 
 Y is O, S, SO or NR 4 ; 
 R 2  is C 1 -C 6  alkyl; C 1 -C 6  alkoxy; NR 5 R 5a ; phenoxy; or phenyl optionally substituted with halo; 
 R 4  is H or C 1 -C 6  alkyl; 
 R 5  and R 5a  are independently H, C 1 -C 6  alkyl or phenyl; 
 R 7  is H, C 1 -C 6  alkyl or CO 2 (C 1 -C 6  alkyl); provided that if R 1a  is H, SO 2 (n-C 4 -C 6  alkyl) or COR 2 , then X 2  is NR 7  and R 7  is CO 2 (C 1 -C 6  alkyl); or an acid addition salt thereof. 
 
   
   
       19 . The compound of  claim 18  wherein m is 1 or 2 and R 1a  is SO 2 CH 3 , benzyl or methyl. 
   
   
       20 . The compound of  claim 19  wherein X 2  is O. 
   
   
       21 . The compound of  claim 20  wherein Y is O or S. 
   
   
       22 . The compound of  claim 21  wherein m is 1. 
   
   
       23 . The compound of  claim 21  wherein m is 1. 
   
   
       24 . The compound of  claim 21  wherein m is 1 and Y is S. 
   
   
       25 . The compound of  claim 24  wherein n is 1, 2 or 3. 
   
   
       26 . The compound of  claim 25  wherein n is 1 or 2. 
   
   
       27 . The compound of  claim 26  wherein n is 2 and the corresponding fluoro moieties are at the 3- and 5-positions. 
   
   
       28 . The compound of  claim 26  wherein n is 1 and the corresponding fluoro moiety is at the 4-position. 
   
   
       29 - 36 . (canceled)