Compositions and methods for treating estrogen-related medical disorders

Abstract

Disclosed is a compound of formula (I). or a pharmaceutically acceptable salt thereof. Also disclosed are pharmaceutical compositions including the compound of formula (I) and methods of using the compound of formula (I).

What is claimed is: 
     
         1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein 
         A 1  is selected from the group consisting of halogen, trifluoromethyl, and —OR 1 ; 
         A 2  is selected from the group consisting of halogen, trifluoromethyl, and —OR 2 ; 
         X 1  is selected from the group consisting of alkyl, —O—, —N(H)—, —S—, —S(═O)—, and —C(═O)—; 
         A 3  is selected from the group consisting of alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocycle, and heteroaryl; 
         A 4  is selected from the group consisting of hydrogen, halogen, alkyl, cyano, trifluoromethyl, aryl-heteroaryl wherein the aryl is substituted or unsubstituted, and —OR 3 ; 
         R 1 , R 2  and R 3  are each independently selected from the group consisting of hydrogen, alkyl, —SO 3 R x1 , —PO 3 R y1 R z1 , —C(═O)R a , and -R 4 -G 1 ; 
         R x1 , R y1  and R z1 , at each occurrence, are independently selected from the group consisting of hydrogen and a pharmaceutically acceptable cation; 
         R a  is alkyl or —OH; 
         R 4 , at each occurrence, is independently selected from the group consisting of a substituent comprising 1 to 10 carbon atoms, a substituent comprising 1 to 10 carbon atoms and optionally containing at least one nitrogen atom, a substituent comprising 1 to 10 carbon atoms and optionally containing at least one C═O group, and a substituent comprising 1 to 10 carbon atoms and optionally containing at least one nitrogen and/or at least one C═O group; and 
         G 1 , at each occurrence, is independently selected from the group consisting of hydrogen and —ONO 2 ; 
         wherein at least one of R 1 , R 2  and R 3  is -R 4 -G 1 , and wherein at least one occurrence of G 1  is —ONO 2 . 
       
     
     
         2 . The compound of  claim 1 , wherein R 4 , at each occurrence, is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocyclealkyl, and alkylheterocyclealkyl, wherein any carbon atom on the alkyl group, together with an alkylene, may form a cycloalkyl, and wherein the alkyl group may be unsubstituted or substituted with 1, 2, or 3 oxo substituents. 
     
     
         3 . The compound of  claim 2 , wherein R 4 , at each occurrence, is independently selected from the group consisting of alkyl, alkylheterocyclealkyl, and heterocyclealkyl. 
     
     
         4 . The compound of  claim 1 , wherein A 4  is selected from the group consisting of halogen and —OR 3 . 
     
     
         5 . The compound according to  claim 1 , wherein the compound comprises formula (Ia) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein 
         A 1  is selected from the group consisting of halogen, trifluoromethyl, and —OR 1 ; 
         A 2  is selected from the group consisting of halogen, trifluoromethyl, and —OR 2 ; 
         A 3  is selected from the group consisting of alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocycle, and heteroaryl; 
         R 1  and R 2  are each independently selected from the group consisting of hydrogen, alkyl, —SO 3 R x1 , —PO 3 R y1 R z1 , —C(═O)R a , and -R 4 -G 1 ; 
         R 4 , at each occurrence, is independently selected from the groups consisting of a substituent comprising 1 to 10 carbon atoms, a substituent comprising 1 to 10 carbon atoms and optionally containing at least one nitrogen atom, a substituent comprising 1 to 10 carbon atoms and optionally containing at least one C═O group, and a substituent comprising 1 to 10 carbon atoms and optionally containing at least one nitrogen and/or at least one C═O group; 
         R 5  is selected from the group consisting of hydrogen and C 1 -C 3 -alkyl-G 1 ; 
         G 1 , at each occurrence, is independently selected from the group consisting of hydrogen and —ONO 2 ; 
         wherein at least one of R 1  and R 2  is -R 4 -G 1  and/or R 5  is C 1 -C 3 -alkyl-G 1 , and wherein at least one occurrence of G 1  is —ONO 2 ; 
         R x1 , R y1  and R z1  are each independently selected from the group consisting of hydrogen and a pharmaceutically acceptable cation; and 
         R a  is alkyl or —OH. 
       
     
     
         6 . The compound of  claim 5 , wherein R 4 -G 1  is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound according to  claim 1 , wherein the compound comprises formula (Ib) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein 
         A 1  is selected from the group consisting of halogen, trifluoromethyl, and —OR 1 ; 
         A 2  is selected from the group consisting of halogen, trifluoromethyl, and —OR 2 ; 
         R 1  and R 2  are each independently selected from the group consisting of hydrogen, alkyl, —SO 3 R x1 , —PO 3 R y1 R z1 , —C(═O)R a , and -R 4 -G 1 ; 
         R 4 , at each occurrence, is independently selected from the groups consisting of a substituent comprising 1 to 10 carbon atoms, a substituent comprising 1 to 10 carbon atoms and optionally containing at least one nitrogen atom, a substituent comprising 1 to 10 carbon atoms and optionally containing at least one C═O group, and a substituent comprising 1 to 10 carbon atoms and optionally containing at least one nitrogen and/or at least one C═O group; 
         R 5  is selected from the group consisting of hydrogen and C 1 -C 3 -alkyl-G 1 ; 
         G 1 , at each occurrence, is independently selected from the group consisting of hydrogen and —ONO 2 ; 
         wherein at least one of R 1  and R 2  is -R 4 -G 1  and/or R 5  is C 1 -C 3 -alkyl-G 1 , and wherein at least one occurrence of G 1  is —ONO 2 ; 
         R x1 , R y1  and R z1  are each independently selected from the group consisting of hydrogen and a pharmaceutically acceptable cation; and 
         R a  is alkyl or —OH. 
       
     
     
         8 . The compound of  claim 7 , wherein R 4 -G 1  is 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound according to  claim 1 , wherein the compound comprises formula (Ic) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein 
         A 1  is selected from the group consisting of halogen, trifluoromethyl, and —OR 1 ; 
         A 2  is selected from the group consisting of halogen, trifluoromethyl, and —OR 2 ; 
         A 3  is selected from the group consisting of alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocycle, and heteroaryl; 
         A 4  is selected from the group consisting of hydrogen, halogen, alkyl, cyano, trifluoromethyl, aryl-heteroaryl wherein the aryl is substituted or unsubstituted, and —OR 3 ; 
         R 1 , R 2  and R 3  are each independently selected from the group consisting of hydrogen, alkyl, —SO 3 R x1 , —PO 3 R y1 R z1 , —C(═O)R a , and -R 4 -G 1 ; 
         R x1 , R y1  and R z1 , at each occurrence, are independently selected from the group consisting of hydrogen and a pharmaceutically acceptable cation; and 
         R a  is alkyl or —OH. 
       
     
     
         10 . The compound of  claim 9 , wherein R 4 -G 1  is 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1 , selected from the group consisting of:
 3-(1-(2-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)piperidin-4-yl)propyl nitrate;   4-(6-hydroxy-3-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)benzo[b]thiophen-2-yl)phenyl 1-((nitrooxy)methyl)cyclopropanecarboxylate;   2-(4-fluorophenyl)-3-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)benzo[b]thiophen-6-yl 1-((nitrooxy)methyl)cyclopropanecarboxylate;   3-(1-(2-(4-((6-hydroxy-3-(4-hydroxyphenyl)benzo[b]thiophen-2-yl)oxy)phenoxy)ethyl)piperidin-4-yl)propyl nitrate;   4-(6-hydroxy-2-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)benzo[b]thiophen-3-yl)phenyl 1-((nitrooxy)methyl)cyclopropanecarboxylate;   3-(4-fluorophenyl)-2-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)benzo[b]thiophen-6-yl 1-((nitrooxy)methyl)cyclopropanecarboxylate;   2-(4-fluorophenyl)-3-(4-(trifluoromethyl)benzoyl)benzo[b]thiophen-6-yl 1-((nitrooxy)methyl)cyclopropanecarboxylate;   (1-(((2-(4-fluorophenyl)-3-(4-(trifluoromethyl)benzoyl)benzo[b]thiophen-6-yl)oxy)methyl)cyclopropyl)methyl nitrate;   3-(4-fluorophenyl)-2-(4-(trifluoromethyl)benzoyl)benzo[b]thiophen-6-yl 1-((nitrooxy)methyl)cyclopropanecarboxylate;   (1-(((3-(4-fluorophenyl)-2-(4-(trifluoromethyl)benzoyl)benzo[b]thiophen-6-yl)oxy)methyl)cyclopropyl)methyl nitrate;   3-(cyclopropanecarbonyl)-2-(4-fluorophenyl)benzo[b]thiophen-6-yl 1-((nitrooxy)methyl)cyclopropanecarboxylate;   (1-(((3-(cyclopropanecarbonyl)-2-(4-fluorophenyl)benzo[b]thiophen-6-yl)oxy)methyl)cyclopropyl)methyl nitrate;   2-(cyclopropanecarbonyl)-3-(4-fluorophenyl)benzo[b]thiophen-6-yl 1-((nitrooxy)methyl)cyclopropanecarboxylate;   (1-(((2-(cyclopropanecarbonyl)-3-(4-fluorophenyl)benzo[b]thiophen-6-yl)oxy)methyl)cyclopropyl)methyl nitrate;   2-(4-fluorophenyl)-3-isonicotinoylbenzo[b]thiophen-6-yl 1-((nitrooxy)methyl)cyclopropanecarboxylate;   (1-(((2-(4-fluorophenyl)-3-isonicotinoylbenzo[b]thiophen-6-yl)oxy)methyl)cyclopropyl)methyl nitrate;   3-(4-fluorophenyl)-2-isonicotinoylbenzo[b]thiophen-6-yl 1-((nitrooxy)methyl)cyclopropanecarboxylate;   (1-(((3-(4-fluorophenyl)-2-isonicotinoylbenzo[b]thiophen-6-yl)oxy)methyl)cyclopropyl)methyl nitrate;   2-(4-fluorophenyl)-3-isobutyrylbenzo[b]thiophen-6-yl 1-((nitrooxy)methyl)cyclopropanecarboxylate;   (1-(((2-(4-fluorophenyl)-3-isobutyrylbenzo[b]thiophen-6-yl)oxy)methyl)cyclopropyl)methyl nitrate;   3-(4-fluorophenyl)-2-isobutyrylbenzo[b]thiophen-6-yl 1-((nitrooxy)methyl)cyclopropanecarboxylate;   (1-(((3-(4-fluorophenyl)-2-isobutyrylbenzo[b]thiophen-6-yl)oxy)methyl)cyclopropyl)methyl nitrate;   3-(4-ethynylbenzoyl)-2-(4-fluorophenyl)benzo[b]thiophen-6-yl 1-((nitrooxy)methyl)cyclopropanecarboxylate;   (1-(((3-(4-ethynylbenzoyl)-2-(4-fluorophenyl)benzo[b]thiophen-6-yl)oxy)methyl)cyclopropyl)methyl nitrate;   2-(4-ethynylbenzoyl)-3-(4-fluorophenyl)benzo[b]thiophen-6-yl 1-((nitrooxy)methyl)cyclopropanecarboxylate;   (1-(((2-(4-ethynylbenzoyl)-3-(4-fluorophenyl)benzo[b]thiophen-6-yl)oxy)methyl)cyclopropyl)methyl nitrate;   2-(4-fluorophenyl)-3-(4-methylbenzoyl)benzo[b]thiophen-6-yl 1-((nitrooxy)methyl)cyclopropanecarboxylate;   (1-(((2-(4-fluorophenyl)-3-(4-methylbenzoyl)benzo[b]thiophen-6-yl)oxy)methyl)cyclopropyl)methyl nitrate;   3-(4-fluorophenyl)-2-(4-methylbenzoyl)benzo[b]thiophen-6-yl 1-((nitrooxy)methyl)cyclopropanecarboxylate;   (1-(((3-(4-fluorophenyl)-2-(4-methylbenzoyl)benzo[b]thiophen-6-yl)oxy)methyl)cyclopropyl)methyl nitrate;   2-(4-fluorophenyl)-3-(4-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)benzoyl)benzo[b]thiophen-6-yl 1-((nitrooxy)methyl)cyclopropanecarboxylate;   (1-(((2-(4-fluorophenyl)-3-(4-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)benzoyl)benzo[b]thiophen-6-yl)oxy)methyl)cyclopropyl)methyl nitrate;   3-(4-fluorophenyl)-2-(4-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)benzoyl)benzo[b]thiophen-6-yl 1-((nitrooxy)methyl)cyclopropanecarboxylate;   (1-(((3-(4-fluorophenyl)-2-(4-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)benzoyl)benzo[b]thiophen-6-yl)oxy)methyl)cyclopropyl)methyl nitrate;   3-((3r,5r,7r)-adamantane-1-carbonyl)-2-(4-fluorophenyl)benzo[b]thiophen-6-yl 1-((nitrooxy)methyl)cyclopropanecarboxylate;   (1-(((3-((3r,5r,7r)-adamantane-1-carbonyl)-2-(4-fluorophenyl)benzo[b]thiophen-6-yl)oxy)methyl)cyclopropyl)methyl nitrate;   2-((3r,5r,7r)-adamantane-1-carbonyl)-3-(4-fluorophenyl)benzo[b]thiophen-6-yl 1-((nitrooxy)methyl)cyclopropanecarboxylate; and   (1-(((2-((3r,5r,7r)-adamantane-1-carbonyl)-3-(4-fluorophenyl)benzo[b]thiophen-6-yl)oxy)methyl)cyclopropyl)methyl nitrate;   or a pharmaceutically acceptable salt thereof.   
     
     
         12 . A compound of formula (II) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein 
         A 1  is selected from the group consisting of halogen, trifluoromethyl, and —OR 1 ; 
         A 2  is selected from the group consisting of halogen, trifluoromethyl, and —OR 2 ; 
         A 3  is selected from the group consisting of alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocycle, and heteroaryl; 
         A 4  is selected from the group consisting of hydrogen, halogen, alkyl, cyano, trifluoromethyl, aryl-heteroaryl wherein the aryl is substituted or unsubstituted, and —OR 3 ; 
         R 1 , R 2  and R 3  are each independently selected from the group consisting of hydrogen, alkyl, —SO 3 R x1 , —PO 3 R y1 R z1 , and —C(═O)R a ; R x1 , R y1  and R z1 , at each occurrence, are independently selected from the group consisting of hydrogen and a pharmaceutically acceptable cation; and 
         R a  is alkyl or —OH. 
       
     
     
         13 . The compound of  claim 12 , selected from the group consisting of:
 (2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)(4-(trifluoromethyl)phenyl)methanone;   (3-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-2-yl)(4-(trifluoromethyl)phenyl)methanone;   cyclopropyl(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)methanone;   cyclopropyl(3-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-2-yl)methanone;   (2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)(pyridin-4-yl)methanone;   (3-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-2-yl)(pyridin-4-yl)methanone;   1-(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)-2-methylpropan-1-one;   1-(3-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-2-yl)-2-methylpropan-1-one;   (4-ethynylphenyl)(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)methanone;   (4-ethynylphenyl)(3-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-2-yl)methanone;   (2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)(p-tolyl)methanone;   (3-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-2-yl)(p-tolyl)methanone;   (4-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)phenyl)(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)methanone;   (4-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)phenyl)(3-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-2-yl)methanone;   (3r,5r,7r)-adamantan-1-yl(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)methanone; and   (3r,5r,7r)-adamantan-1-yl(3-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-2-yl)methanone;   or a pharmaceutically acceptable salt thereof.   
     
     
         14 . A method for treatment of an estrogen-related medical disorder, the method comprising administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of at least one compound of formula (I) as claimed in  claim 1  or at least one compound of formula (II) as claimed in  claim 12 , or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The method of  claim 14 , wherein the estrogen-related medical disorder is selected from the group consisting of: cancer, inflammation, osteoporosis, vaginal atrophy, central nervous system diseases, and cardiovascular system diseases. 
     
     
         16 . The method of  claim 15 , wherein the central nervous system disease is selected from the group consisting of Alzheimer's Disease and mild cognitive impairment. 
     
     
         17 . The method of  claim 16 , wherein the cardiovascular system disease is thrombosis. 
     
     
         18 . The method of  claim 17 , wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, and lung cancer. 
     
     
         19 . The method of  claim 14 , wherein the estrogen-related medical disorder is a breast cancer. 
     
     
         20 . The method of  claim 19 , wherein the breast cancer is a tamoxifen resistant breast cancer. 
     
     
         21 . The method of  claim 19 , wherein the breast cancer is a triple negative breast cancer. 
     
     
         22 . A method of identifying a cancer in a subject, the method comprising:
 (a) obtaining a test sample from the subject having cancer; and   (b) determining an amount of protein kinase C alpha (PKCα) in the test sample;   
       wherein if the amount of PKCα in the test sample is greater than an amount of PKCα in a test sample from a subject not having cancer, then the cancer is sensitive to at least one compound of formula (I) as claimed in  claim 1  or at least one compound of formula (II) as claimed in  claim 12 , or a pharmaceutically acceptable salt thereof.