Piperazinyl-or piperidinylamine-sulfamic acid amides as inhibitors of steroid sulfatase

Abstract

Piperazinyl- or piperidinylamine-sulfamic acid amides and their use for the manufacture of a medicament in diseases mediated by the action of steroid sulfatase.

1 . A compound of formula 
     
       
         
         
             
             
         
       
       wherein either
 R 1  and R 2  together with the nitrogen atom to which they are attached are piperazinyl, wherein the second nitrogen atom is substituted by (C 1-6 )alkoxycarbonyl or by (C 6-18 )aryl, which (C 6-18 )aryl is substituted by one or more halogen, (C 1-6 )haloalkyl, aminocarbonyl, 
 
       or
 R 1  is hydrogen and R 2  is piperidinyl, attached via a carbon atom of the piperidinyl ring, wherein the nitrogen atom is substituted by (C 1-6 )alkoxycarbonyl or by (C 6-18 )aryl, 
 
       and 
       R 3  is (C 6-18 )aryl or (C 6-18 )aryl(C 1-4 )alkyl, which aryl is substituted by one or more halogen, aminocarbonyl, or (C 1-6 )haloalkyl. 
     
   
   
       2 . A compound of  claim 1  selected from the group consisting of compounds of formula 
     
       
         
         
             
             
         
       
       wherein 
       a. R 3ss  is 3,5-bis(trifluoromethyl)phenyl and R 4ss  is 2-aminocarbonyl-5-trifluoromethylphenyl, 
       b. R 3ss  is 2,3-dichlorophenyl, R 4ss  is 2-aminocarbonyl-5-trifluoromethylphenyl, 
       c. R 3ss  is 3,5-dichlorophenyl R 4ss  is 2-aminocarbonyl-5-trifluoromethylphenyl, and 
       d. R 3ss  is 3,5-bis(trifluoromethyl)phenyl and R 4ss  is tert.butoxycarbonyl. 
     
   
   
       3 . A compound of  claim 1  which is a compound of 
     
       
         
         
             
             
         
       
     
   
   
       4 . A compound of  claim 1  selected from the group consisting of compounds of formula 
     
       
         
         
             
             
         
       
       wherein 
       a. R 3s  is 3,5-bis(trifluoromethyl)phenyl and R 4s  is tert.butoxycarbonyl, 
       b. R 3s  is 2,3-dichlorophenyl and R 4s  is tert.butoxycarbonyl, 
       c. R 3s  is 3,5-dichlorophenyl and R 4s  is tert.butoxycarbonyl, 
       d. R 3s  is 3,5-bis(trifluoromethyl)phenyl and R 4s  is benzyloxycarbonyl, 
       e. R 3s  is 2,3-dichlorophenyl and R 4s  is benzyloxycarbonyl, 
       f. R 3s  is 3,5-dichlorophenyl and R 4s  is benzyloxycarbonyl, 
       g. R 3s  is 3,5-dichlorophenyl and R 4s  is benzyloxycarbonyl, 
       h. R 3s  is 3,5-bis(trifluoromethyl)phenyl and R 4s  is 2-aminocarbonyl-5-trifluoromethylphenyl, 
       i. R 3s  is 3,5-dichlorophenyl and R 4s  is 2-aminocarbonyl-5-trifluoromethylphenyl, 
       j. R 3s  is 2,3-dichlorophenyl and R 4s  is 2-aminocarbonyl-5-trifluoromethylphenyl, and 
       k. R 3s  is 2-(3,5-bis(trifluoromethyl)phenyl)ethyl and R 4s  is tert.butoxycarbonyl. 
     
   
   
       5 . A compound of  claim 1  in the form of a salt. 
   
   
       6 . Use of a compound of  claim 1  for the manufacture of a medicament for the treatment of disorders mediated by the action of steroid sulfatase. 
   
   
       7 . A compound of  claim 1  for use as a pharmaceutical. 
   
   
       8 . A method of treatment of disorders mediated by the action of steroid sulfatase which treatment comprises administering to a subject in need of such treatment an effective amount of a compound of  claim 1 , wherein the disorder is selected from the group consisting of acne, seborrhea, androgenic alopecia, hirsutism, breast cancer, and Alzheimer's disease. 
   
   
       9 . A pharmaceutical composition comprising a compound of  claim 1  in association with at least one pharmaceutical excipient. 
   
   
       10 . A pharmaceutical composition according to  claim 9 , further comprising another pharmaceutically active agent.