Steroid receptor modulator compounds and methods

Abstract

Non-steroidal compounds which are high affinity, high selectivity modulators for steroid receptors are disclosed. Also disclosed are pharmaceutical compositions incorporating such compounds, methods for employing the disclosed compounds and compositions for treating patients requiring steroid receptor agonist or antagonist therapy, intermediates useful in the preparation of the compounds and processes for the preparation of the steroid receptor modulator compounds.

What is claimed is:  
     
         1 . A pharmaceutical composition comprising an effective amount of a steroid receptor modulator compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  through R 3  each independently are hydrogen, a C 1 -C 6  alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl;  
 R 4  is hydrogen, a C 1 -C 6  alkyl, or R 5 C═O, OR 6 , or NR 6 R 7 , where R 5  is hydrogen, a C 1 -C 6  alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl, and wherein R 6  and R 7  each independently are hydrogen, a C 1 -C 6  alkyl, optionally substituted allyl, arylmethyl, aryl, or heteroaryl;  
 R 9  through R 10  each independently are hydrogen, a C 1 -C 6  alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl;  
 R 11  is hydrogen, a C 1 -C 6  alkyl, OR 6  or optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl, where R 6  has the same definition given above, or R 1  and R 2 , R 2  and R 3 , R 1  and R 9 , R 10  and R 11 , R 1  and R 10  and/or R 11  and R 2  when taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, OR 6  or NR 6 R 7 , where R 6  through R 7  have the definitions given above, provided, however, that R 1 , R 2 , R 10  and R 11  cannot form more than two three- to seven-membered rings at a time;  
 Y is O, CHR 6  or NR 6 , where R 6  has the same definition given above; and  
 Z is an aryl or heteroaryl group, including mono- and poly-cyclic structures, optionally substituted at one or more positions with hydrogen, a C 1 -C 6  alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, heteroaryl, F, Cl, Br, I, CN, R 5 C═O, R 6 R 7 NC═O, R 6 OC═O, perfluoroalkyl, haloalkyl, a C 1 -C 6  straight-chain hydroxy alkyl, HOCR 5 R 8 , nitro, R 6 OCH 2 , R 6 O, NH 2 , or R 6 R 7 N, where R 5  through R 7  have the definitions given above and where R 8  is hydrogen, a C 1 -C 6  alkyl or optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl; and  
 a pharmaceutically acceptable carrier.  
 
     
     
         2 . A pharmaceutical composition according to  claim 1 , wherein Z is selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . A composition according to  claim 1 , wherein the compounds comprise steroid receptor modulator compounds.  
     
     
         4 . A composition according to  claim 3 , wherein the compounds comprise progesteron receptor agonists or antagonists.  
     
     
         5 . A composition according to  claim 3 , wherein the compounds comprise androgen receptor agonists or antagonists.  
     
     
         6 . A composition according to  claim 3 , wherein the compounds comprise estrogen receptor agonists or antagonists.  
     
     
         7 . A composition according to  claim 3 , wherein the compounds comprise glucocorticoid receptor agonists or antagonists.  
     
     
         8 . A composition according to  claim 3 , wherein the compounds comprise mineralocorticoid receptor agonists or antagonists.  
     
     
         9 . A composition according to  claim 1 , wherein the composition is formulated for oral, topical, intravenous, suppository or parental administration.  
     
     
         10 . A composition according to  claim 1 , wherein the compound is administered to a patient as a dosage unit at from about 1 μg/kg of body weight to about 500 mg/kg of body weight.  
     
     
         11 . A composition according to  claim 1 , wherein the compound is administered to a patient as a dosage unit at from about 10 μg/kg of body weight to about 250 mg/kg of body weight.  
     
     
         12 . A composition according to  claim 1 , wherein the compound is administered to a patient as a dosage unit at from about 20 μg/kg of body weight to about 100 mg/kg of body weight.  
     
     
         13 . A composition according to  claim 1 , wherein the composition is effective in treating and/or modulating human fertility, female hormone replacement, dysfunctional uterine bleeding, endometriosis, leiomyomas, acne, male-pattern baldness, osteoporosis, prostatic hyperplasia, cancer of the breast, cancer of the ovaries, endometrial cancer, prostate cancer, carbohydrate, protein and lipid metabolism, electrolyte and water balance, and functioning of the cardiovascular, kidney, central nervous, immune and skeletal muscle systems.  
     
     
         14 . A method of affecting steroid receptor activity comprising the in vivo administration of a composition according to  claim 1 .  
     
     
         15 . A method of modulating a process mediated by steroid receptors comprising administering to a patient an effective amount of a composition according to  claim 3 .  
     
     
         16 . A method of treating a patient requiring steroid receptor therapy comprising administering to a patient an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  through R 3  each independently are hydrogen, a C 1 -C 6  alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl;  
 R 4  is hydrogen, a C 1 -C 6  alkyl, or R 5 C═O, OR 6 , or NR 6 R 7 , where R 5  is hydrogen, a C 1 -C 6  alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl, and wherein R 6  and R 7  each independently are hydrogen, a C 1 -C 6  alkyl, optionally substituted allyl, arylmethyl, aryl, or heteroaryl;  
 R 9  through R 10  each independently are hydrogen, a C 1 -C 6  alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl;  
 R 11  is hydrogen, a C 1 -C 6  alkyl, OR 6  or optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl, where R 6  has the same definition given above, or R 1  and R 2 , R 2  and R 3 , R 1  and R 9 , R 10  and R 11 , R 1  and R 10  and/or R 11  and R 2  when taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, OR 6  or NR 6 R 7 , where R 6  through R 7  have the definitions given above, provided, however, that R 1 , R 2 , R 10  and R 11  cannot form more than two three- to seven-membered rings at a time;  
 Y is O, CHR 6  or NR 6 , where R 6  has the same definition given above; and  
 Z is an aryl or heteroaryl group, including mono- and poly-cyclic structures, optionally substituted at one or more positions with hydrogen, a C 1 -C 6  alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, heteroaryl, F, Cl, Br, I, CN, R 5 C═O, R 6 R 7 NC═O, R 6 OC═O, perfluoroalkyl, haloalkyl, a C 1 -C 6  straight-chain hydroxy alkyl, HOCR 5 R 8 , nitro, R 6 OCH 2 , R 6 O, NH 2 , or R 6 R 7 N, where R 5  through R 7  have the definitions given above and where R 8  is hydrogen, a C 1 -C 6  alkyl or optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl.  
 
     
     
         17 . A method according to  claim 16 , wherein the compound comprises a steroid receptor modulator compound.  
     
     
         18 . A method according to  claim 17 , wherein the compound comprises a progesteron receptor agonist or antagonist.  
     
     
         19 . A method according to  claim 17 , wherein the compound comprises an androgen receptor agonist or antagonist.  
     
     
         20 . A method according to  claim 17 , wherein the compound comprises an estrogen receptor agonist or antagonist.  
     
     
         21 . A method according to  claim 17 , wherein the compound comprises a glucocorticoid receptor agonist or antagonist.  
     
     
         22 . A method according to  claim 17 , wherein the compound comprises a mineralocorticoid receptor agonist or antagonist.  
     
     
         23 . A method according to  claim 16 , wherein the compound is administered to the patient as a dosage unit at from about 1 μg/kg of body weight to about 500 mg/kg of body weight.  
     
     
         24 . A method according to  claim 16 , wherein the compound is administered to the patient as a dosage unit at from about 10 μg/kg of body weight to about 250 mg/kg of body weight.  
     
     
         25 . A method according to  claim 16 , wherein the compound is administered to the patient as a dosage unit at from about 20 μg/kg of body weight to about 100 mg/kg of body weight.  
     
     
         26 . A method according to  claim 16 , wherein the compound is effective in treating and/or modulating human fertility, female hormone replacement, dysfunctional uterine bleeding, endometriosis, leiomyomas, acne, male-pattern baldness, osteoporosis, prostatic hyperplasia, cancer of the breast, cancer of the ovaries, endometrial cancer, prostate cancer, carbohydrate, protein and lipid metabolism, electrolyte and water balance, and functioning of the cardiovascular, kidney, central nervous, immune and skeletal muscle systems.  
     
     
         27 . A method of affecting the activity of a steroid receptor comprising the in vivo administration of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  through R 3  each independently are hydrogen, a C 1 -C 6  alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl;  
 R 4  is hydrogen, a C 1 -C 6  alkyl, or R 5 C═O, OR 6 , or NR 6 R 7 , where R 5  is hydrogen, a C 1 -C 6  alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl, and wherein R 6  and R 7  each independently are hydrogen, a C 1 -C 6  alkyl, optionally substituted allyl, arylmethyl, aryl, or heteroaryl;  
 R 9  through R 10  each independently are hydrogen, a C 1 -C 6  alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl;  
 R 11  is hydrogen, a C 1 -C 6  alkyl, OR 6  or optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl, where R 6  has the same definition given above, or R 1  and R 2 , R 2  and R 3 , R 1  and R 9 , R 10  and R 11 , R 1  and R 10  and/or R 11  and R 2  when taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, OR 6  or NR 6 R 7 , where R 6  through R 7  have the definitions given above, provided, however, that R 1 , R 2 , R 10  and R 11  cannot form more than two three- to seven-membered rings at a time;  
 Y is O, CHR 6  or NR 6 , where R 6  has the same definition given above; and  
 Z is a polycyclic aryl group or a monocyclic or polycyclic heteroaryl group, optionally substituted at one or more positions with hydrogen, a C 1 -C 6  alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, heteroaryl, F, Cl, Br, I, CN, R 5 C═O, R 6 R 7 NC═O, R 6 OC═O, perfluoroalkyl, haloalkyl, a C 1 -C 6  straight-chain hydroxy alkyl, HOCR 5 R 8 , nitro, R 6 OCH 2 , R 6 O, NH 2 , or R 6 R 7 N, where R 5  through R 7  have the definitions given above and where R 8  is hydrogen, a C 1 -C 6  alkyl or optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl.  
 
     
     
         28 . A method of modulating a process mediated by a steroid receptor comprising administering to a patient an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  through R 3  each independently are hydrogen, a C 1 -C 6  alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl;  
 R 4  is hydrogen, a C 1 -C 6  alkyl, or R 5 C═O, OR 6 , or NR 6 R 7 , where R 5  is hydrogen, a C 1 -C 6  alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl, and wherein R 6  and R 7  each independently are hydrogen, a C 1 -C 6  alkyl, optionally substituted allyl, arylmethyl, aryl, or heteroaryl;  
 R 9  through R 10  each independently are hydrogen, a C 1 -C 6  alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl;  
 R 11  is hydrogen, a C 1 -C 6  alkyl, OR 6  or optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl, where R 6  has the same definition given above, or R 1  and R 2 , R 2  and R 3 , R 1  and R 9 , R 10  and R 11 , R 1  and R 10  and/or R 11  and R 2  when taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, OR 6  or NR 6 R 7 , where R 6  through R 7  have the definitions given above, provided, however, that R 1 , R 2 , R 10  and R 11  cannot form more than two three- to seven-membered rings at a time;  
 Y is O, CHR 6  or NR 6 , where R 6  has the same definition given above; and  
 Z is a polycyclic aryl group or a monocyclic or polycyclic heteroaryl group, including mono- and poly-cyclic structures, optionally substituted at one or more positions with hydrogen, a C 1 -C 6  alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, heteroaryl, F, Cl, Br, I, CN, R 5 C═O, R 6 R 7 NC═O, R 6 OC═O, perfluoroalkyl, haloalkyl, a C 1 -C 6  straight-chain hydroxy alkyl, HOCR 5 R 8 , nitro, R 6 OCH 2 , R 6 O, NH 2 , or R 6 R 7 N, where R 5  through R 7  have the definitions given above and where R 8  is hydrogen, a C 1 -C 6  alkyl or optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl.