Development of new selective estrogen receptor modulators

Abstract

The present disclosure concerns a new class of selective estrogen receptor modulators (SERMs). The disclosure also includes the identification of a previously unknown membrane associated estrogen receptor. Methods for making and using the disclosed SERMs are disclosed, including pharmaceutical formulations of the disclosed novel compounds in useful compositions.

1 - 43 . (canceled) 
     
     
         44 . A method for treating a condition characterized by estrogen insufficiency in a subject, comprising administering to the subject an effective amount of a compound according to formula I: 
       
         
           
           
               
               
           
         
         wherein R is H or a lower aliphatic group; M is a ketone, amide or sulfonamide group; Ar is an aromatic group; X is a hydrogen, hydroxy, alkoxy, or a halogen; Y is a heteroatom; G is a linker group; and Z is hydroxyl or a charged moiety. 
       
     
     
         45 . The method of  claim 44 , wherein the condition characterized by estrogen insufficiency is ovarian failure. 
     
     
         46 . The method of  claim 45 , wherein the condition characterized by estrogen insufficiency is menopause. 
     
     
         47 . The method of  claim 44 , wherein the condition characterized by estrogen insufficiency is an autonomic dysfunction, sleep cycle disruption, cognitive disorder, motor dysfunction, mood disorder, eating disorder or cardiovascular disorder. 
     
     
         48 . The method of  claim 44 , wherein condition characterized by estrogen insufficiency is ischemia-induced neuronal death, head trauma, Alzheimer's disease, hot flushes, Parkinson's disease, tardive diskinesia, depression, schizophrenia, anorexia nervosa, bulimia nervosa, cardiovascular disease, atherosclerosis, long QTL syndrome, Romano-Ward syndrome or Torsades de Pointes syndrome, osteoporosis, rheumatoid arthritis, osteoarthritis, bone fracture, multiple sclerosis or combinations thereof. 
     
     
         49 . The method of  claim 44 , further comprising administering an effective amount of a second compound comprising a steroid hormone to the subject. 
     
     
         50 . The method of  claim 44 , further comprising administering an effective amount of a second compound comprising a selective estrogen receptor modulator to the subject. 
     
     
         51 . The method of  claim 44 , wherein the compound has the formula 
       
         
           
           
               
               
           
         
       
     
     
         52 . The method of  claim 44 , wherein the compound has the formula 
       
         
           
           
               
               
           
         
       
     
     
         53 . The method of  claim 44 , wherein Ar is a phenyl group. 
     
     
         54 . The method of  claim 44 , wherein the compound has the formula 
       
         
           
           
               
               
           
         
       
     
     
         55 . The method of  claim 44 , wherein the compound has the formula 
       
         
           
           
               
               
           
         
       
     
     
         56 . The method of claim  1 , wherein M is an amide group. 
     
     
         57 . The method of  claim 56 , wherein the compound has the formula 
       
         
           
           
               
               
           
         
       
       wherein R 1  is hydrogen, lower alkyl or an aralkyl group. 
     
     
         58 . The method of  claim 44 , wherein G is a lower alkyl group. 
     
     
         59 . The method of  claim 44 , wherein Z is an anionic group. 
     
     
         60 . The method of  claim 44 , wherein Z is a cationic group. 
     
     
         61 . The method of  claim 44 , wherein Z is an amino group or a carboxy group. 
     
     
         62 . The method of  claim 44 , wherein Y is oxygen and -G-Z has a formula selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         63 . The method of  claim 44 , wherein R is hydrogen or lower alkyl. 
     
     
         64 . The method of  claim 44 , wherein X is a hydroxy group. 
     
     
         65 . The method of  claim 44 , wherein X is hydrogen. 
     
     
         66 . The method of  claim 44 , wherein the compound has the formula 
       
         
           
           
               
               
           
         
       
     
     
         67 . The method of  claim 44 , wherein the compound has the formula 
       
         
           
           
               
               
           
         
       
     
     
         68 . The method of  claim 44 , wherein the compound has the formula 
       
         
           
           
               
               
           
         
       
     
     
         69 . The method of  claim 44 , wherein the compound has the formula 
       
         
           
           
               
               
           
         
       
     
     
         70 . A method for providing hormone replacement therapy, comprising administering to the subject an effective amount of a compound according to formula I: 
       
         
           
           
               
               
           
         
         wherein R is H or a lower aliphatic group; M is a ketone, amide or sulfonamide group; Ar is an aromatic group; X is a hydrogen, hydroxy, alkoxy, or a halogen; Y is a heteroatom; G is a linker group; and Z is hydroxyl or a charged moiety.