Non-estrogenic estradiol derivative compounds with antioxidative activity

Abstract

New non-estrogenic derivative compounds of estradiol, which have no estrogenic activity and comparatively high anti-oxidative activity, are disclosed. These new non-estrogenic derivative compounds are potentially useful as non-estrogenic antioxidants, especially for administration in post-menopausal women and in men. The compounds of the invention can also inhibit aromatase and sulfatase.

We claim:  
     
         1 . A non-estrogenic estradiol derivative compound with antioxidative activity of the formula I:  
       
         
           
           
               
               
           
         
         wherein R 1  is H or OH,  
         R 2  and R 3  are the same or different and are each, independently of each other, H or CH 3 ,  
         R 4  and R 5  are the same or different and are each, independently of each other, —OH, —O(CO)R 6 , —OR 6  or —OSO 2 NR 7 R 8 , wherein R 6  represents an aryl group or an alkyl group having 1 to 4 carbon atoms, and the R 7  and R 8  groups are each, independently of each other, H or an alkyl group having one to four carbon atoms, or R 7  and R 8  together with the N atom represent a polymethylenimino group with 4 to 6 carbon atoms or a morpholino group,  
         each of the dashed lines represent either an additional bond or not in the ring positions indicated by the respective dashed lines so that either a double bond or a single bond is present at said ring positions;  
         but with the proviso that the compounds of formula I do not include 4-methyl-estra-1,3,5(10)-trien-1,17β-diol.  
       
     
     
         2 . A non-estrogenic estradiol derivative compound with antioxidative activity of the formula II:  
       
         
           
           
               
               
           
         
         wherein R 1  is H or OH,  
         R 2  and R 3  are the same or different and are each, independently of each other, H or CH 3 ,  
         Z is an unsubstituted group represented by (CH 2 ) n APh, wherein Ph represents a phenyl group and A represents a bond for n=0 or a bond, O, S or Se for n=1, or Z is a 17α-substituent group containing a phenyl group, Ph, having from 1 to 2 hydroxy group substituents and 0 to 2 methyl group substituents or a dimethylaminophenyl group and 0 to 2 methyl group substituents;  
         R 4  and R 5  are the same or different and are each, independently of each other, —OH, —O(CO)R 6 , —OR 6  or —OSO 2 NR 7 R 8 , wherein R 6  represents an aryl group or an alkyl group having 1 to 4 carbon atoms, and the R 7  and R 8  groups are each, independently of each other, H or an alkyl group having one to four carbon atoms, or R 7  and R 8  together with the N atom represent a polymethylenimino group with 4 to 6 carbon atoms or a morpholino group, and  
         each of the dashed lines represent either an additional bond or not in the ring positions indicated by the respective dashed lines so that either a double bond or a single bond is present at said ring positions.  
       
     
     
         3 . A non-estrogenic estradiol derivative compound selected from the group consisting of 4-methyl-estra-1,3,5(10)-trien-1,17α-diol, 4-methyl-estra-1,3,5(10),6-tetraen-1,17α-diol, 4-methyl-estra-1,3,5(10),6-tetraen-1,17β-diol, 4-methyl-estra-1,3,5 (10),6,8-pentaen-1,17β-diol, 4-methyl-estra-1,3,5 (10),6,8-pentaen-1,17α-diol, 17α-4′-hydroxyphenyl-methyl-4-methyl-estra-1,3,5 (10)-trien-1,17β-diol, 17α-4′-hydroxy-phenoxymethyl-4-methyl-estra-1,3,5(10)-trien-1,17β-diol, 17α-4′-hydroxy-thiophenoxymethyl-4-methyl-estra-1,3,5 (10)-trien-1,17β-diol, 17α-4′-dimethylamino-phenylmethyl-4-methyl-estra-1,3,5 (10)-trien-1,17β-diol, 17α-3′,5′-dimethyl-4′-hydroxy-phenylmethyl-4-methyl-estra-1,3,5 (10)-trien-1,17β-diol, 17α-3′, 5′-dimethyl-4′-hydroxy-phenylmethyl-4-methyl-estra-1,3,5 (10),6-tetraen-1,17β-diol and 17α-41-hydroxy-phenoxymethyl-4-methyl-estra-1,3,5(10),6-tetraen-1,17β-diol.  
     
     
         4 . 4-methyl-estra-1,3,5(10)-trien-1,17β-diol or 4-methyl-estra-1,3,5 (10)-trien-1,17α-diol or 4-methyl-estra-1,3,5 (10),6-tetraen-1,17β-diol.