Isoflavone metabolites

Abstract

There are disclosed compounds of formulae (I) or (II) in which A is selected from the group consisting of (1), (2), (3) and (4); OH, and one of R 1 and R 2 is selected from H, OH and OCH 3 , and the other of R 1 and R 2 is selected from OH and OCH 3 ; one of R3 and R4 is selected from H, OH and OCH3, and the other of R3 and R4 is selected from OH and OCH3; provided that at least one of the pairs R 1 , R 2 and R 3 , R 4 are both OH; R 5 is selected from OH and OCH 3 ; and denotes a single or double bond; and pharmaceutically acceptable salts and prodrugs thereof. The compounds of the invention are useful for the treatment of hormone-dependent conditions and cancers.

1 . A compound of the formula I or formula II 
       
         
           
           
               
               
           
         
       
       in which A is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       one of R 1  and R 2  is selected from H, OH and OCH 3 , and the other of R 1  and R 2  is selected from OH and OCH 3 ; 
       one of R 3  and R 4  is selected from H, OH and OCH 3 , and the other of R 3  and R 4  is selected from OH and OCH 3 ; 
       provided that at least one of the pairs R 1 , R 2  and R 3 , R 4  are both OH; 
       R 5  is selected from OH and OCH 3 ; and 
       
         
       
       denotes a single or double bond; 
       or a pharmaceutically acceptable salt or prodrug thereof; 
       with the proviso that 
       (a) when A is 
       
         
           
           
               
               
           
         
       
       and R 3  and R 4  are both OH then R 2  is other than H; and 
       (b) when A is 
       
         
           
           
               
               
           
         
       
       and R 3  and R 4  are both OH and R 2  is OCH 3 , then R 1  is other than H or OCH 3 . 
     
     
         2 . A compound according to  claim 1 , wherein 
       one of R 1  and R 2  is selected from H and OH, and the other of R 1  and R 2  is OH; 
       one of R 3  and R 4  is selected from H and OH, and the other of R 3  and R 4  is OH; 
       provided that at least one of the pairs R 1 , R 2  and R 3 , R 4  are both OH; 
       R 5  is OH; and 
       
         
       
       denotes a single or double bond. 
     
     
         3 . A compound according to  claim 1  of the formula (IA) or (IIA) 
       
         
           
           
               
               
           
         
       
       wherein A is as defined in  claim 1 ; 
       R 2  is H, and R 1  is selected from OH and OCH 3 ; 
       R 3  and R 4  are each OH; 
       R 5  is selected from OH and OCH 3 ; and 
       
         
       
       denotes a single or double bond. 
     
     
         4 . A compound according to  claim 1  of the formula (IB) or (IIB) 
       
         
           
           
               
               
           
         
       
       wherein A is as defined in  claim 1 ; 
       R 1  and R 2  are each OH; 
       R 3  is H, and R 4  is selected from OH and OCH 3 ; 
       R 5  is selected from OH and OCH 3 ; and 
       
         
       
       denotes a single or double bond. 
     
     
         5 . A compound according to  claim 1  which is 5-hydroxy-O-demethylangolesin (5-hydroxy-O-Dma) [1-(2,4,5-trihydroxyphenyl)-2-(4-hydroxyphenyl)-propan-1-one] having the structure (IV): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutical acceptable salt or prodrug thereof. 
     
     
         6 . A compound according to  claim 1  which is 3′-hydroxy-O-demethylangolesin (3′-hydroxy-O-Dma) [1-(2,4, dihydroxyphenyl)-2-(3,4-dihydroxyphenyl)-propan-1-one] having the structure (V): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         7 . A compound according to  claim 1  which is 3′-hydroxy-O-demethyldehydroangolesin(3′-hydroxydehydro-O-Dma) [1-(2,4-dihydroxyphenyl)-2-(3,4-dihydroxyphenyl)-prop-2-en-1-one] having the structure (VI): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         8 . A compound according to  claim 1  which is 3′-hydroxy-dihydrodaidzein having the structure (VII): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         9 . A compound according to  claim 1  which is 1-(2,4,5-trihydroxyphenyl)-2-(4-hydroxyphenyl)-prop-2-en-1-one having the structure (VIII): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         10 . A pharmaceutical composition comprising one or more compounds according to  claim 1 , in association with one or more pharmaceutically acceptable carriers, adjuvants, diluents and/or excipients. 
     
     
         11 . A food or drink composition, which contains one or more compounds according to  claim 1 . 
     
     
         12 . A method for the treatment, prophylaxis, amelioration, defense against, and/or prevention of a condition selected from the group consisting of menopausal syndrome; osteoporosis; rheumatic diseases; atherosclerosis; premenstrual syndrome; coronary artery spasm; vascular diseases; Buergers Disease; migraine headaches; hypertension; benign prostatic hypertrophy; cancer; Alzheimers disease; inflammatory diseases; baldness; psoriasis; acne; and diseases associated with oxidant stress; in a patient in need of said treatment, prophylaxis, amelioration, defense against, and/or prevention, which method comprises administering to said patient a therapeutically effective amount of one or more compounds according to  claim 1 , either alone or in association with one or more pharmaceutically acceptable carriers, diluents, adjuvants and/or excipients. 
     
     
         13 . A method for the treatment, prophylaxis, amelioration, defense against, and/or prevention of a hormone-dependent condition in a patient in need of said treatment, prophylaxis, amelioration, defense against, and/or prevention, comprising administering to said patient a therapeutically effective amount of one or more compounds according to  claim 1 , either alone or in association with one or more pharmaceutically acceptable carriers, diluents, adjuvants and/or excipients. 
     
     
         14 . A method for the treatment, prophylaxis, amelioration, defense against, and/or prevention of a hormone-dependent condition in a patient in need of said treatment, prophylaxis, amelioration, defense against, and/or prevention, comprising administering to said patient a therapeutically effective amount of one or more compounds of formula I or formula II 
       
         
           
           
               
               
           
         
       
       in which A is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       one of R 1  and R 2  is selected from H, OH and OCH 3 , and the other of R 1  and R 2  is selected from OH and OCH 3 ; 
       one of R 3  and R 4  is selected from H, OH and OCH 3 , and the other of R 3  and R 4  is selected from OH and OCH 3 ; 
       provided that at least one of the pairs R 1 , R 2  and R 3 , R 4  are both OH; 
       R 5  is selected from OH and OCH 3 ; and 
       
         
       
       denotes a single or double bond; 
       or a pharmaceutically acceptable salt or prodrug thereof; said compound or compounds being administered either alone or in association with one or more pharmaceutically acceptable earners, diluents, adjuvants and/or excipients. 
     
     
         15 . A method for the treatment, prophylaxis, amelioration, defense against, and/or prevention of cancer in a patient in need of said treatment, prophylaxis, amelioration, defense against, and/or prevention, comprising administering to said patient a therapeutically effective amount of one or more compounds of formula I or formula II 
       
         
           
           
               
               
           
         
       
       in which A is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       one of R 1  and R 2  is selected from H, OH and OCH 3 , and the other of Ri and R 2  is selected from OH and OCH 3 ; 
       one of R 3  and R 4  is selected from H, OH and OCH 3 , and the other of R 3  and R 4  is selected from OH and OCH 3 ; 
       provided that at least one of the pairs R 1 , R 2  and R 3 , R 4  are both OH; 
       R 5  is selected from OH and OCH 3 ; and 
       
         
       
       denotes a single or double bond; 
       or a pharmaceutically acceptable salt or prodrug thereof; said compound or compounds being administered either alone or in association with one or more pharmaceutically acceptable carriers, diluents, adjuvants and/or excipients. 
     
     
         16 . The method according to  claim 13  wherein said hormone dependent condition is selected from the group consisting of hormone dependent cancers, hormone dependent cardiovascular disorders and hormone dependent menopausal disorders. 
     
     
         17 . The use of one or more compounds according to  claim 1  for the manufacture of a medicament for the treatment, amelioration, defense against, prophylaxis and/or prevention of one or more conditions selected from the group consisting of menopausal syndrome; osteoporosis; rheumatic diseases; atherosclerosis; premenstrual syndrome; coronary artery spasm; vascular diseases; Buergers Disease; migraine headaches; hypertension; benign prostatic hypertrophy; cancer; Alzheimers disease; inflammatory diseases; baldness; psoriasis; acne; and diseases associated with oxidant stress. 
     
     
         18 . Use of one or more compounds according to  claim 1  for the treatment, amelioration, defense against, prophylaxis and/or prevention of one or more conditions selected from the group consisting of menopausal syndrome; osteoporosis; rheumatic diseases; atherosclerosis; premenstrual syndrome; coronary artery spasm; vascular diseases; Buergers Disease; migraine headaches; hypertension; benign prostatic hypertrophy; cancer; Alzheimers disease; inflammatory diseases; baldness; psoriasis; acne; and diseases associated with oxidant stress. 
     
     
         19 . A microbial culture or a food or drink composition containing at least one microbial strain which microbial strain is capable of producing one or more compounds according to  claim 1  from daidzein and/or glycitein. 
     
     
         20 . A method for the treatment, prophylaxis, amelioration, defense against, and/or prevention of a hormone-dependent condition in a patient in need of said treatment, prophylaxis, amelioration, defense against, and/or prevention, comprising administering to said patient a therapeutically effective amount of 6,7,4′-trihydroxyisoflavone, or a pharmaceutically acceptable salt or prodrug thereof, either alone or in association with one or more pharmaceutically acceptable carriers, diluents, adjuvants and/or excipients. 
     
     
         21 . The use of 6,7,4′-trihydroxyisoflavone for the manufacture of a medicament for the treatment, prophylaxis, amelioration, defense against, and/or prevention of one or more conditions selected from the group consisting of menopausal syndrome; osteoporosis; rheumatic diseases; atherosclerosis; premenstrual syndrome; coronary artery spasm; vascular diseases; Buergers Disease; migraine headaches; hypertension; benign prostatic hypertrophy; cancer; Alzheimers disease; inflammatory diseases; baldness; psoriasis; acne; and diseases associated with oxidant stress. 
     
     
         22 . The use of 6,7,4′-trihydroxyisoflavone for the manufacture of a medicament for the treatment, prophylaxis, amelioration, defense against, and/or prevention of a hormone-dependent condition. 
     
     
         23 . The method according to  claim 14  wherein said hormone dependent condition is selected from the group consisting of hormone dependent cancers, hormone dependent cardiovascular disorders and hormone dependent menopausal disorders.