Novel benzopyran compounds, compositions and uses thereof

Abstract

Benzopyran compounds with strong anti-estrogenic activity and essentially no estrogenic activity are provided, which are OP-1038, which is 3-(4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-1-yl]ethoxy}phenyl)-2H-chromen-7-ol, and OP-1074, which is (2S)-3-(4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-1-yl]ethoxy}phenyl)-2H-chromen-7-ol. OP-1074 is a pure anti-estrogen when tested in the agonist mode and a complete anti-estrogen when tested in the antagonist mode. These compounds are useful for the treatment or prevention of a variety of conditions that are modulated through the estrogen receptor in mammals including humans.

What is claimed is: 
     
         1 . The compound 3-(4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-1-yl]ethoxy}phenyl)-2H-chromen-7-ol, which has the chemical structure: 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         2 . The compound (2S)-3-(4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-1-yl]ethoxy}phenyl)-2H-chromen-7-ol which has the chemical structure: 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         3 . The compound 3-(4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-1-yl]ethoxy}phenyl)-2H-chromen-7-ol, which has the chemical structure: 
       
         
           
           
               
               
           
         
         in the form of a solvate, hydrate, or N-oxide. 
       
     
     
         4 . The compound (2S)-3-(4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-1-yl]ethoxy}phenyl)-2H-chromen-7-ol, which has the chemical structure: 
       
         
           
           
               
               
           
         
         in the form of a solvate, hydrate, or N-oxide. 
       
     
     
         5 . The compound of  claim 1  wherein the salt is pharmaceutically acceptable. 
     
     
         6 . The compound of  claim 2  wherein the salt is pharmaceutically acceptable. 
     
     
         7 . The compound of  claim 1  which is not in the form of a salt. 
     
     
         8 . The compound of  claim 2  which is not in the form of a salt. 
     
     
         9 . A compound of the structure: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently either: 
         (ii) R 9  which is independently selected from H, halogen (Cl, Br, I or F), natural or non-naturally occurring amino acid (bound through either the OC(O)— or C(O)O— (an ester) or the amino (through either —C(O)—N— or —N—C(O)— (an amide linkage)), R 10 , —OR 10 , or —SR 10  
 where R 10  is —C(═O)R C1 , —C(═O)OR C1 , —C(═O)SR C1 , —C(═O)N(R C1 ) 2 ; or polyethylene glycol, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; —S(═O) 2 OR C1 , —S(═O) 2 OR C1 , —S(═O)R C1 , —S(═O)OR C1 , —P(═O) 2 R C2 , —P(═O) 2 OR C1 , —P(═O)(OR C1 ) 2 , —P(═O)(R C1 ) 2 , or —P(R C1 )(OR C1 ); or oxygen attached to an oxygen protecting group (to produce OH on administration), sulfur attached to a sulfur protecting group (to produce SH or a disulfide on administration), or nitrogen attached to a nitrogen protecting group (to produce —NH— on administration); and R C1  can be independently selected from hydrogen, polyethylene glycol, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R C1  groups are joined to form an substituted or unsubstituted heterocyclic ring, 
 
         or its pharmaceutically acceptable salt. 
       
     
     
         10 . A compound of the structure: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently either:
 R 9  which is independently selected from H, halogen (Cl, Br, I or F), natural or non-naturally occurring amino acid (bound through either the OC(O)— or C(O)O— (an ester) or the amino (through either —C(O)—N— or —N—C(O)— (an amide linkage)), R 10 , —OR 10 , or —SR 10  
 where R 10  is —C(═O)R C1 , —C(═O)OR C1 , —C(═O)SR C1 , —C(═O)N(R C1 ) 2 ; or polyethylene glycol, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; —S(═O) 2 R C1 , —S(═O) 2 OR C1 , —S(═O)OR C1 , —P(═O) 2 R C1 , —P(═O) 2 OR C1 , —P(═O)(OR C1 ) 2 , —P(═O)(R C1 ) 2 , or —P(R C1 )(OR C1 ); or oxygen attached to an oxygen protecting group (to produce OH on administration), sulfur attached to a sulfur protecting group (to produce SH or a disulfide on administration), or nitrogen attached to a nitrogen protecting group (to produce —NH— on administration); and R C1  can be independently selected from hydrogen, polyethylene glycol, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R C1  groups are joined to form an substituted or unsubstituted heterocyclic ring, 
 
 
         or its pharmaceutically acceptable salt. 
       
     
     
         11 . The compound of  claim 9 , wherein R 1  and R 2  are OR 9 . 
     
     
         12 . The compound of  claim 10 , wherein R 1  and R 2  are OR 9 . 
     
     
         13 . The compound of  claim 9 , wherein R 1  is hydrogen. 
     
     
         14 . The compound of  claim 10 , wherein R 1  is hydrogen. 
     
     
         15 . The compound of  claim 11 , wherein OR 9  is C(O)alkyl. 
     
     
         16 . The compound of  claim 12 , wherein OR 9  is C(O)alkyl 
     
     
         17 . The compound of  claim 11 , wherein OR 9  is C(O)aryl. 
     
     
         18 . The compound of  claim 12 , wherein OR 9  is C(O)aryl. 
     
     
         19 . The compound of  claim 11 , wherein OR 9  is OPO 3 H 3 . 
     
     
         20 . The compound of  claim 12 , wherein OR 9  is OPO 3 H 3 . 
     
     
         21 . The compound of  claim 9 , selected from 
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound of  claim 10 , selected from 
       
         
           
           
               
               
           
         
       
     
     
         23 . A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of  claim 1  in a pharmaceutically acceptable carrier. 
     
     
         24 . A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of  claim 2  in a pharmaceutically acceptable carrier. 
     
     
         25 . A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of  claim 3 ,  5 ,  7 ,  9 ,  11 ,  13 ,  15 ,  17 , or  19  in a pharmaceutically acceptable carrier. 
     
     
         26 . A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of  claim 4 ,  6 ,  8 ,  10 ,  12 ,  14 ,  16 ,  18  or  20  in a pharmaceutically acceptable carrier. 
     
     
         27 . The pharmaceutical composition of  claim 21  wherein the carrier is suitable for oral delivery. 
     
     
         28 . The pharmaceutical composition of  claim 22  wherein the carrier is suitable for oral delivery. 
     
     
         29 . A method for treating a disorder mediated by the estrogen receptor in a patient, which comprises administering to the patient a therapeutically effective amount of the compound of  claim 1 , optionally in a pharmaceutically acceptable carrier 
     
     
         30 . A method for treating a disorder mediated by the estrogen receptor in a patient, which comprises administering to the patient a therapeutically effective amount of the compound of  claim 2 , optionally in a pharmaceutically acceptable carrier. 
     
     
         31 . A method for treating a disorder mediated by the estrogen receptor in a patient, which comprises administering to the patient a therapeutically effective amount of the compound of  claim 3 ,  5 ,  7 ,  9 ,  11 ,  13 ,  15 ,  17 , or  19 , optionally in a pharmaceutically acceptable carrier 
     
     
         32 . A method for treating a disorder mediated by the estrogen receptor in a patient, which comprises administering to the patient a therapeutically effective amount of the compound of  claim 4 ,  6 ,  8 ,  10 ,  12 ,  14 ,  16 ,  18  or  20 , optionally in a pharmaceutically acceptable carrier. 
     
     
         33 . The method of  claim 27 , wherein the disorder is breast cancer. 
     
     
         34 . The method of  claim 28 , wherein the disorder is breast cancer. 
     
     
         35 . The method of  claim 29 , wherein the disorder is breast cancer. 
     
     
         36 . The method of  claim 30 , wherein the disorder is breast cancer. 
     
     
         37 . The method of  claim 27 , wherein the disorder is selected from the group consisting of ovarian, endometrial, or vaginal cancer, endometriosis or lung cancer. 
     
     
         38 . The method of  claim 28 , wherein the disorder is selected from the group consisting of ovarian, endometrial, or vaginal cancer, endometriosis or lung cancer. 
     
     
         39 . The compound of  claim 1  for use in medical therapy. 
     
     
         40 . The compound of  claim 2  for use in medical therapy. 
     
     
         41 . The compound of  claim 3 ,  5 ,  7 ,  9 ,  11 ,  13 ,  15 ,  17 , or  19 , for use in medical therapy. 
     
     
         42 . The compound of  claim 4 ,  6 ,  8 ,  10 ,  12 ,  14 ,  16 ,  18  or  20 , for use in medical therapy. 
     
     
         43 . The method of  claim 29 , further comprising administering the compound in combination or alternation with another anti-cancer agent for the treatment of cancer. 
     
     
         44 . The method of  claim 30 , further comprising administering the compound in combination or alternation with another anti-cancer agent for the treatment of cancer. 
     
     
         45 . The method of  claim 31 , further comprising administering the compound in combination or alternation with another anti-cancer agent for the treatment of cancer. 
     
     
         46 . The method of  claim 32 , further comprising administering the compound in combination or alternation with another anti-cancer agent for the treatment of cancer. 
     
     
         47 . The method of  claim 29 , further comprising administering the compound in combination or alternation with estrogen or a partial estrogen receptor angatonist for the treatment of a postmenopausal disorder. 
     
     
         48 . The method of  claim 30 , further comprising administering the compound in combination or alternation with estrogen or a partial estrogen receptor angatonist for the treatment of a postmenopausal disorder. 
     
     
         49 . The method of  claim 31 , further comprising administering the compound in combination or alternation with estrogen or a partial estrogen receptor angatonist for the treatment of a postmenopausal disorder another anti-cancer agent. 
     
     
         50 . The method of  claim 32 , further comprising administering the compound in combination or alternation with estrogen or a partial estrogen receptor angatonist for the treatment of a postmenopausal disorder.