5-Cycloalkenyl 5H-chromeno[3,4-f]quinoline derivatives as selective progesterone receptor modulator compounds

Abstract

The present invention relates to methods for modulating processes mediated by progesterone receptor using nonsteroidal compounds and compositions which may be high affinity, high specificity agonists, partial agonists (i.e., partial activators and/or tissue-specific activators) and/or antagonists for progesterone receptors.

1 . A method of treating an individual having a condition mediated by a progesterone receptor, comprising administering to the individual a pharmaceutically effective amount of a compound represented by formula (I):  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is selected from the group of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  heteroalkyl, COR 11 , CO 2 R 11 , SO 2 R 11 , and CONR 11 R 12 ;  
 R 2  and R 3  each independently is selected from the group consisting of hydrogen, C 1 -C 6  alkyl, and C 1 -C 6  haloalkyl; or  
 R 2  and R 3  taken together form a cycloalkyl ring of from three to twelve carbons;  
 R 4  through R 7  each independently is selected from the group consisting of hydrogen, F, Cl, Br, CN, OR 11 , C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  heteroalkyl; or  
 R 5  and R 7  taken together form a bond; or  
 R 6  and R 7  taken together are selected from the group consisting of methylidene, mono-substituted methylidene, di-substituted methylidene and carbonyl;  
 R 8  through R 10  each independently is selected from the group consisting of hydrogen, F, Cl, Br, I, NO 2 , CN, OR 11 , NR 11 R 12 , SR 11 , COR 11 , CO 2 R 11 , CONR 11 R 12 , C 1 -C 8  alkyl, C 1 -C 8  heteroalkyl, C 1 -C 8  haloalkyl, allyl, C 2 -C 8  alkenyl and C 2 -C 8  alkynyl;  
 R 11  and R 12  each is independently selected from the group consisting of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, and C 1 -C 4  haloalkyl;  
 R 13  is hydrogen; or  
 R 13  and R 14  taken together form a bond and R 16  and R 18  taken together form a bond when n is 1;  
 R 14  through R 20  each independently is selected from the group consisting of hydrogen, F, Cl, Br, OR 11 , C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  heteroalkyl; or  
 R 14  and R 15  taken together are selected from the group of methylidene, carbonyl and thiocarbonyl; or  
 R 16  and R 17  taken together are selected from the group of methylidene, mono-substituted methylidene, di-substituted methylidene, carbonyl and thiocarbonyl; or  
 R 14  and R 16  taken together form a bond or an “—O—” bridge; and  
 R 16  and R 18  taken together form a bond when n is 1; or  
 R 16  and R 19  taken together form a bond when n is 0;  
 R 21  is hydrogen; or  
 R 21  and R 20  taken together form a bond;  
 n is 0, 1, 2, or 3;  
 or a pharmaceutically acceptable salt thereof;  
 with the proviso that R 13  and R 14  taken together, R 16  and R 18  taken together and R 20  and R 21  taken together may not each form a bond;  
 and thereby treating the individual having a condition mediated by a progesterone receptor.  
 
   
   
       2 . The method of  claim 1 , wherein the condition is selected from among dysfunctional uterine bleeding, dysmenorrhea, endometriosis, leiomyomas (uterine fibroids), hot flushes, mood disorders, meningiomas, hormone-dependent cancers and female osteoporosis.  
   
   
       3 . A method of treating an individual having a condition mediated by a progesterone receptor, comprising administering to said individual a pharmaceutically effective amount of a compound represented by formula (II):  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 2  and R 3  each independently is selected from the group of hydrogen, C 1 -C 4  alkyl, and C 1 -C 4  haloalkyl;  
 R 6  is selected from the group of hydrogen, F, Cl, Br, CN, OR 11 , C 1 -C 4  alkyl, and C 1 -C 4  haloalkyl;  
 R 8  and R 10  each independently is selected from the group of hydrogen, F, Cl, Br, CN, OR 11 , NR 11 R 12 , SR 11 , COR 11 , C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, C 1 -C 4  haloalkyl, allyl, and C 2 -C 4  alkenyl;  
 R 11  and R 12  each is independently selected from the group consisting of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, and C 1 -C 4  haloalkyl;  
 R 13  is hydrogen; or  
 R 13  and R 14  taken together form a bond and R 16  and R 18  taken together form a bond when n is 1;  
 R 14  through R 20  each independently is selected from the group consisting of hydrogen, F, Cl, Br, OR 11 , C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  heteroalkyl; or  
 R 14  and R 15  taken together are selected from the group of methylidene, carbonyl and thiocarbonyl; or  
 R 16  and R 17  taken together are selected from the group of methylidene, mono-substituted methylidene, di-substituted methylidene, carbonyl and thiocarbonyl; or  
 R 14  and R 16  taken together form a bond or an “—O—” bridge; and  
 R 16  and R 18  taken together form a bond when n is 1; or  
 R 16  and R 19  taken together form a bond when n is 0;  
 R 21  is hydrogen; or  
 R 21  and R 20  taken together form a bond;  
 n is 0, 1, 2, or 3;  
 or a pharmaceutically acceptable salt thereof;  
 with the proviso that R 13  and R 14  taken together, R 16  and R 18  taken together and R 20  and R 21  taken together may not each form a bond;  
 and thereby treating the individual having a condition mediated by a progesterone receptor.  
 
   
   
       4 . The method of  claim 3 , wherein the condition is selected from among dysfunctional uterine bleeding, dysmenorrhea, endometriosis, leiomyomas (uterine fibroids), hot flushes, mood disorders, meningiomas, hormone-dependent cancers and female osteoporosis.  
   
   
       5 . A method of modulating fertility in an individual, comprising administering to the individual a pharmaceutically effective amount of a compound represented by formula (I):  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is selected from the group of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  heteroalkyl, COR 11 , CO 2 R 11 , SO 2 R 11 , and CONR 11 R 12 ;  
 R 2  and R 3 each independently is selected from the group of hydrogen, C 1 -C 6  alkyl, and C 1 -C 6  haloalkyl; or  
 R 2  and R 3 taken together form a cycloalkyl ring of from three to twelve carbons;  
 R 4  through R 7  each independently is selected from the group of hydrogen, F, Cl, Br, CN, OR 11 , C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  heteroalkyl; or  
 R 5  and R 7  taken together form a bond; or  
 R 6  and R 7  taken together are selected from the group of methylidene, mono-substituted methylidene, di-substituted methylidene and carbonyl;  
 R 8  through R 10  each independently is selected from the group of hydrogen, F, Cl, Br, I, NO 2 , CN, OR 11 , NR 11 R 12 , SR 11 , COR 11 , CO 2 R 11 , CONR 11 R 12 , C 1 -C 8  alkyl, C 1 -C 8  heteroalkyl, C 1 -C 8  haloalkyl, allyl, C 2 -C 8  alkenyl and C 2 -C 8  alkynyl;  
 R 11  and R 12  each is independently selected from the group consisting of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, and C 1 -C 4  haloalkyl;  
 R 13  is hydrogen; or  
 R 13  and R 14  taken together form a bond and R 16  and R 18  taken together form a bond when n is 1;  
 R 14  through R 20  each independently is selected from the group consisting of hydrogen, F, Cl, Br, OR 11 , C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  heteroalkyl; or  
 R 14  and R 15  taken together are selected from the group of methylidene, carbonyl and thiocarbonyl; or  
 R 16  and R 17  taken together are selected from the group of methylidene, mono-substituted methylidene, di-substituted methylidene, carbonyl and thiocarbonyl; or  
 R 14  and R 16  taken together form a bond or an “—O—” bridge; and  
 R 16  and R 18  taken together form a bond when n is 1; or  
 R 16  and R 19  taken together form a bond when n is 0;  
 R 21  is hydrogen; or  
 R 21  and R 20  taken together form a bond;  
 n is 0, 1, 2, or 3;  
 or a pharmaceutically acceptable salt thereof;  
 with the proviso that R 13  and R 14  taken together, R 16  and R 18  taken together and R 20  and R 21  taken together may not each form a bond;  
 and thereby modulating fertility in the individual.  
 
   
   
       6 . The method of  claim 5 , wherein the modulation of fertility is providing contraception to an individual.  
   
   
       7 . The method of  claim 5 , wherein the modulation of fertility is maintaining pregnancy.  
   
   
       8 . A method of treating hormone-dependent cancer, comprising administering to a patient in need thereof an effective amount of a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is selected from the group of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  heteroalkyl, COR 11 , CO 2 R 11 , SO 2 R 11 , and CONR 11 R 12 ;  
 R 2  and R 3  each independently is selected from the group of hydrogen, C 1 -C 6  alkyl, and C 1 -C 6  haloalkyl; or  
 R 2  and R 3  taken together form a cycloalkyl ring of from three to twelve carbons;  
 R 4  through R 7  each independently is selected from the group of hydrogen, F, Cl, Br, CN, OR 11 , C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  heteroalkyl; or  
 R 5  and R 7  taken together form a bond; or  
 R 6  and R 7  taken together are selected from the group of methylidene, mono-substituted methylidene, di-substituted methylidene and carbonyl;  
 R 8  through R 10  each independently is selected from the group of hydrogen, F, Cl, Br, I, NO 2 , CN, OR 11 , NR 11 R 12 , SR 11 , COR 11 , CO 2 R 11 , CONR 11 R 12 , C 1 -C 8  alkyl, C 1 -C 8  heteroalkyl, C 1 -C 8  haloalkyl, allyl, C 2 -C 8  alkenyl and C 2 -C 8  alkynyl;  
 R 11  and R 12  each is independently selected from the group consisting of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, and C 1 -C 4  haloalkyl;  
 R 13  is hydrogen; or  
 R 13  and R 14  taken together form a bond and R 16  and R 18  taken together form a bond when n is 1;  
 R 14  through R 20  each independently is selected from the group consisting of hydrogen, F, Cl, Br, OR 11 , C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  heteroalkyl; or  
 R 14  and R 15  taken together are selected from the group of methylidene, carbonyl and thiocarbonyl; or  
 R 16  and R 17  taken together are selected from the group of methylidene, mono-substituted methylidene, di-substituted methylidene, carbonyl and thiocarbonyl; or  
 R 14  and R 16  taken together form a bond or an “—O—” bridge; and  
 R 16  and R 18  taken together form a bond when n is 1; or  
 R 16  and R 19  taken together form a bond when n is 0;  
 R 21  is hydrogen; or  
 R 21  and R 20  taken together form a bond;  
 n is 0, 1, 2, or 3;  
 or a pharmaceutically acceptable salt thereof;  
 with the proviso that R 13  and R 14  taken together, R 16  and R 18  taken together and R 20  and R 21  taken together may not each form a bond;  
 and thereby treating hormone-dependent cancer in the individual.  
 
   
   
       9 . The method of  claim 8 , wherein the cancer is selected from the group consisting of ovarian cancer, breast cancer, endometrium cancer and prostate cancer.  
   
   
       10 . A method of modulating a progesterone receptor in an individual, comprising administering to the individual a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is selected from the group of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  heteroalkyl, COR 11 , CO 2 R 11 , SO 2 R 11 , and CONR 11 R 12 ;  
 R 2  and R 3  each independently is selected from the group of hydrogen, C 1 -C 6  alkyl, and C 1 -C 6  haloalkyl; or  
 R 2  and R 3  taken together form a cycloalkyl ring of from three to twelve carbons;  
 R 4  through R 7  each independently is selected from the group of hydrogen, F, Cl, Br, CN, OR 11 , C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  heteroalkyl; or  
 R 5  and R 7  taken together form a bond; or  
 R 6  and R 7  taken together are selected from the group of methylidene, mono-substituted methylidene, di-substituted methylidene and carbonyl;  
 R 8  through R 10  each independently is selected from the group of hydrogen, F, Cl, Br, I, NO 2 , CN, OR 11 , NR 11 R 12 , SR 11 , COR 11 , CO 2 R 11 , CONR 11 R 12 , C 1 -C 8  alkyl, C 1 -C 8  heteroalkyl, C 1 -C 8  haloalkyl, allyl, C 2 -C 8  alkenyl and C 2 -C 8  alkynyl;  
 R 11  and R 12  each is independently selected from the group consisting of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, and C 1 -C 4  haloalkyl;  
 R 13  is hydrogen; or  
 R 13  and R 14  taken together form a bond and R 16  and R 18  taken together form a bond when n is 1;  
 R 14  through R 20  each independently is selected from the group consisting of hydrogen, F, Cl, Br, OR 11 , C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  heteroalkyl; or  
 R 14  and R 15  taken together are selected from the group of methylidene, carbonyl and thiocarbonyl; or  
 R 16  and R 17  taken together are selected from the group of methylidene, mono-substituted methylidene, di-substituted methylidene, carbonyl and thiocarbonyl; or  
 R 14  and R 16  taken together form a bond or an “—O—” bridge; and  
 R 16  and R 18  taken together form a bond when n is 1; or  
 R 16  and R 19  taken together form a bond when n is 0;  
 R 21  is hydrogen; or  
 R 21  and R 20  taken together form a bond;  
 n is 0, 1, 2, or 3;  
 or a pharmaceutically acceptable salt thereof;  
 with the proviso that R 13  and R 14  taken together, R 16  and R 18  taken together and R 20  and R 21  taken together may not each form a bond;  
 in an amount effective to modulate a progesterone receptor and thereby modulate a progesterone receptor in the individual.  
 
   
   
       11 . The method of  claim 10 , wherein the modulation is activation.  
   
   
       12 . The method of  claim 11 , wherein the compound provides at least 50% maximal activation of the progesterone receptor at a concentration of less than 100 nM.  
   
   
       13 . The method of  claim 11 , wherein the compound provides at least 50% maximal activation of the progesterone receptor at a concentration of less than 50 nM.  
   
   
       14 . The method of  claim 11 , wherein the compound provides at least 50% maximal activation of the progesterone receptor at a concentration of less than 20 nM.  
   
   
       15 . The method of  claim 11 , wherein the compound provides at least 50% maximal activation of the progesterone receptor at a concentration of less than 10 nM.