Progesterone receptor modulators comprising pyrrole-oxindole derivatives and uses thereof

Abstract

Pyrrole-oxindole derivatives useful as progesterone receptor antagonists, and methods for preparing the same, are provided. Pharmaceutical compositions containing these derivatives are described, as is the use thereof in contraception and hormone-related conditions.

1 . A method of inducing contraception in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, alkyl, substituted alkyl, cycloalkyl, C 3  to C 6  alkenyl, or C 3  to C 6  alkynyl;  
 R 2  and R 3  are each independently selected from the group consisting of hydrogen, alkyl, and substituted alkyl; or  
 R 2  and R 3  are taken together to form a ring and together contain —CH 2 —(CH 2 ) n —CH 2 —;  
 n is 0, 1, 2, or 3;  
 R 5  is hydrogen;  
 R 7  is hydrogen, alkyl, or halogen;  
 R 8  is hydrogen;  
 R 9  is hydrogen, alkyl, substituted alkyl, or COOR A ;  
 R A  is alkyl or substituted alkyl; and  
 (i) R 4  is halogen and R 6  is hydrogen or halogen; or  
 (ii) R 4  is hydrogen or halogen and R 6  is halogen;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The method according to  claim 1 , wherein: 
 R 1  is hydrogen or alkyl;    R 2  and R 3  are taken together to form a ring and together contain —CH 2 —(CH 2 ) n —CH 2 —;    n is 1 or 2.    
     
     
         3 . The method according to  claim 1 , wherein R 2  and R 3  are alkyl.  
     
     
         4 . The method according to  claim 3 , wherein R 2  or R 3  is methyl or ethyl.  
     
     
         5 . The method according to  claim 1 , wherein: 
 R 1  is hydrogen;    R 2  and R 3  are alkyl; or    R 2  and R 3  are taken together to form a ring and together contain —CH 2 —(CH 2 ) n —CH 2 —;    n is 0 to 2;    R 4  is hydrogen;    R 6  is fluorine;    R 7  is hydrogen; and    R 9  is alkyl.    
     
     
         6 . The method according to  claim 3 , wherein R 9  is methyl or COOR A  and R A  is tert-butyl.  
     
     
         7 . The method according to  claim 1 , wherein said compound is selected from the group consisting of 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(4-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(7′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-5′-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(7-fluoro-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; tert-butyl 2-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-pyrrole-1-carboxylate; tert-butyl 2-cyano-5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-pyrrole-1-carboxylate; 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-pyrrole-2-carbonitrile; Methyl-[5-(5-cyano-1-methyl-1H-pyrrol-2-yl)-7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate; 5-(1-ethyl-7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(7-fluoro-3,3-dimethyl-2-oxo-1-prop-2-yn-1-yl-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-[7-fluoro-3,3-dimethyl-2-oxo-1-(2-phenylethyl)-2,3-dihydro-1H-indol-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile; 5-(1-benzyl-7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(7-fluoro-3,3-dimethyl-2-oxo-1-propyl-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(7-fluoro-1-isobutyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(7-fluoro-1-isopropyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(1-allyl-7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(1-cyclohexyl-7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(1-cyclopentyl-7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile.  
     
     
         8 . A method for hormone replacement therapy, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, alkyl, substituted alkyl, cycloalkyl, C 3  to C 6  alkenyl, or C 3  to C 6  alkynyl;  
 R 2  and R 3  are each independently selected from the group consisting of hydrogen, alkyl, and substituted alkyl; or  
 R 2  and R 3  are taken together to form a ring and together contain —CH 2 —(CH 2 ) n —CH 2 —;  
 n is 0, 1, 2, or 3;  
 R 5  is hydrogen;  
 R 7  is hydrogen, alkyl, or halogen;  
 R 8  is hydrogen;  
 R 9  is hydrogen, alkyl, substituted alkyl, or COOR A ;  
 R A  is alkyl or substituted alkyl; and  
 (i) R 4  is halogen and R 6  is hydrogen or halogen; or  
 (ii) R 4  is hydrogen and halogen and R 6  is halogen  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         9 . A method of treating hormone-dependent neoplastic disease in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, alkyl, substituted alkyl, cycloalkyl, C 3  to C 6  alkenyl, or C 3  to C 6  alkynyl;  
 R 2  and R 3  are each independently selected from the group consisting of hydrogen, alkyl, and substituted alkyl; or  
 R 2  and R 3  are taken together to form a ring and together contain —CH 2 —(CH 2 ) n —CH 2 —;  
 n is 0, 1, 2, or 3;  
 R 5  is hydrogen;  
 R 7  is hydrogen, alkyl, or halogen;  
 R 8  is hydrogen;  
 R 9  is hydrogen, alkyl, substituted alkyl, or COOR A ;  
 R A  is alkyl or substituted alkyl; and  
 (i) R 4  is halogen and R 6  is hydrogen or halogen; or  
 (ii) R 4  is hydrogen and halogen and R 6  is halogen  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         10 . The method according to  claim 9 , wherein the hormone-dependent neoplastic disease is selected from the group consisting of uterine myometrial fibroids, endometriosis, benign prostatic hypertrophy; carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary, and meningioma.  
     
     
         11 . A method of synchronizing estrus in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, alkyl, substituted alkyl, cycloalkyl, C 3  to C 6  alkenyl, or C 3  to C 6  alkynyl;  
 R 2  and R 3  are each independently selected from the group consisting of hydrogen, alkyl, and substituted alkyl; or  
 R 2  and R 3  are taken together to form a ring and together contain —CH 2 —(CH 2 ) n —CH 2 —;  
 n is 0, 1, 2, or 3;  
 R 5  is hydrogen;  
 R 7  is hydrogen, alkyl, or halogen;  
 R 8  is hydrogen;  
 R 9  is hydrogen, alkyl, substituted alkyl, or COOR A ;  
 R A  is alkyl or substituted alkyl; and  
 (i) R 4  is halogen and R 6  is hydrogen or halogen; or  
 (ii) R 4  is hydrogen and halogen and R 6  is halogen;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         12 . A method of treating dysmenorrhea in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, alkyl, substituted alkyl, cycloalkyl, C 3  to C 6  alkenyl, or C 3  to C 6  alkynyl;  
 R 2  and R 3  are each independently selected from the group consisting of hydrogen, alkyl, and substituted alkyl; or  
 R 2  and R 3  are taken together to form a ring and together contain —CH 2 —(CH 2 ) n —CH 2 —;  
 n is 0, 1, 2, or 3;  
 R 5  is hydrogen;  
 R 7  is hydrogen, alkyl, or halogen;  
 R 8  is hydrogen;  
 R 9  is hydrogen, alkyl, substituted alkyl, or COOR A ;  
 R A  is alkyl or substituted alkyl; and  
 (i) R 4  is halogen and R 6  is hydrogen or halogen; or  
 (ii) R 4  is hydrogen and halogen and R 6  is halogen;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         13 . A method of treating dysfunctional uterine bleeding in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, alkyl, substituted alkyl, cycloalkyl, C 3  to C 6  alkenyl, or C 3  to C 6  alkynyl;  
 R 2  and R 3  are each independently selected from the group consisting of hydrogen, alkyl, and substituted alkyl; or  
 R 2  and R 3  are taken together to form a ring and together contain —CH 2 —(CH 2 ) n —CH 2 —;  
 n is 0, 1, 2, or 3;  
 R 4  is halogen;  
 R 5  is hydrogen;  
 R 6  is hydrogen or halogen;  
 R 7  is hydrogen, alkyl, or halogen;  
 R 8  is hydrogen;  
 R 9  is hydrogen, alkyl, substituted alkyl, or COOR A ;  
 R A  is alkyl or substituted alkyl; and  
 (i) 4 is halogen and R 6  is hydrogen or halogen; or  
 (ii) R 4  is hydrogen and halogen and R 6  is halogen  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         14 . A method of inducing amenorrhea in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, alkyl, substituted alkyl, cycloalkyl, C 3  to C 6  alkenyl, or C 3  to C 6  alkynyl;  
 R 2  and R 3  are each independently selected from the group consisting of hydrogen, alkyl, and substituted alkyl; or  
 R 2  and R 3  are taken together to form a ring and together contain —CH 2 —(CH 2 ) n —CH 2 —;  
 n is 0, 1, 2, or 3;  
 R 5  is hydrogen;  
 R 7  is hydrogen, alkyl, or halogen;  
 R 8  is hydrogen;  
 R 9  is hydrogen, alkyl, substituted alkyl, or COOR A ;  
 R A  is alkyl or substituted alkyl; and  
 (i) R 4  is halogen and R 6  is hydrogen or halogen; or  
 (ii) R 4  is hydrogen and halogen and R 6  is halogen;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         15 . A method of treating symptoms of premenstrual syndrome and premenstrual dysphoric disorder, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, alkyl, substituted alkyl, cycloalkyl, C 3  to C 6  alkenyl, or C 3  to C 6  alkynyl;  
 R 2  and R 3  are each independently selected from the group consisting of hydrogen, alkyl, and substituted alkyl; or  
 R 2  and R 3  are taken together to form a ring and together contain —CH 2 —(CH 2 ) n —CH 2 —;  
 n is 0, 1, 2, or 3;  
 R 5  is hydrogen;  
 R 7  is hydrogen, alkyl, or halogen;  
 R 8  is hydrogen;  
 R 9  is hydrogen, alkyl, substituted alkyl, or COOR A ;  
 R A  is alkyl or substituted alkyl; and  
 (i) R 4  is halogen and R 6  is hydrogen or halogen; or  
 (ii) R 4  is hydrogen and halogen and R 6  is halogen;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         16 . A method of contraception which comprises administering to a female of child bearing age for 28 consecutive days: 
 (a) a first phase of from 14 to 24 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 100 μg levonorgestrel;    (b) a second phase of from 1 to 11 daily dosage units, at a daily dosage of from about 2 to 50 mg, of a compound of the formula:                          wherein: 
 R 1  is hydrogen, alkyl, substituted alkyl, cycloalkyl, C 3  to C 6  alkenyl, or C 3  to C 6  alkynyl;  
 R 2  and R 3  are each independently selected from the group consisting of hydrogen, alkyl, and substituted alkyl; or  
 R 2  and R 3  are taken together to form a ring and together contain —CH 2 —(CH 2 ) n —CH 2 —;  
 n is 0, 1, 2, or 3;  
 R 5  is hydrogen;  
 R 7  is hydrogen, alkyl, or halogen;  
 R 8  is hydrogen;  
 R 9  is hydrogen, alkyl, substituted alkyl, or COOR A ;  
 R A  is alkyl or substituted alkyl; and  
 (i) R 4  is halogen and R 6  is hydrogen or halogen; or  
 (ii) R 4  is hydrogen and halogen and R 6  is halogen;  
 or a pharmaceutically acceptable salt thereof; and  
   (c) optionally, a third phase of daily dosage units of an orally and pharmaceutically acceptable placebo for the remaining days of the 28 consecutive days in which no antiprogestin, progestin or estrogen is administered; wherein the total daily dosage units of the first, second and third phases equals 28.    
     
     
         17 . The method according to  claim 16 , wherein the progestational agent is tanaproget.  
     
     
         18 . The method according to  claim 16 , wherein the first phase further comprises co-administering an estrogen at a daily dose of 10 to 35 μg.  
     
     
         19 . The method according to  claim 18 , wherein the estrogen is ethinyl estradiol.  
     
     
         20 . The method according to  claim 18 , wherein the first phase comprises 18 to 24 days.  
     
     
         21 . The method according to  claim 20 , wherein the first phase comprises 21 days.  
     
     
         22 . The method according to  claim 18 , wherein the second phase comprises 3 days.  
     
     
         23 . The method according to  claim 19 , wherein the third phase comprises 4 days.  
     
     
         24 . A method of inducing contraception, hormone replacement therapy, treating hormone-dependent neoplastic disease, synchronizing estrus, treating dysmenorrheal, treating dysfunctional uterine bleeding, inducing amenorrhea, and treating symptoms of premenstrual syndrome and premenstrual dysphoric disorder, in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, alkyl, substituted alkyl, cycloalkyl, C 3  to C 6  alkenyl, or C 3  to C 6  alkynyl;  
 R 2  and R 3  are each independently selected from the group consisting of hydrogen, C 1  to C 2  alkyl, and substituted C 1  to C 2  alkyl; or  
 R 2  and R 3  are taken together to form a ring and together contain —CH 2 —(CH 2 ) n —CH 2 —;  
 n is 0 or 1;  
 R 5  is hydrogen;  
 R 7  is hydrogen, alkyl, or halogen;  
 R 8  is hydrogen;  
 R 9  is hydrogen, alkyl, substituted alkyl, or COOR A ;  
 R A  is alkyl or substituted alkyl; and  
 (i) R 4  is halogen and R 6  is hydrogen or halogen; or  
 (ii) R 4  is hydrogen or halogen and R 6  is halogen;  
 or a pharmaceutically acceptable salt thereof.