Aryl Sulfonamides Useful for Modulation of the Progesterone Receptor

Abstract

In one embodiment, compounds of the following structure are described, wherein R 1 to R 7 are described herein. Also provided are methods for preparing these compounds and methods of contraception; treating or preventing fibroids; treating or preventing uterine leiomyomata; treating or preventing endometriosis, dysfunctional bleeding, and polycystic ovary syndrome; treating or preventing hormone-dependent carcinomas; providing hormone replacement therapy; stimulating food intake; synchronizing estrus; and treating cycle-related symptoms using the compounds described herein.

1 . A method of contraception, treating or preventing fibroids, uterine leiomyomata, endometriosis, dysfunctional bleeding, polycystic ovary syndrome, or hormone-dependent carcinomas, providing hormone replacement therapy, stimulating food intake, synchronizing estrus, or treating cycle-related symptoms, said method comprising administering to a mammal in need thereof a compound of formula (I): 
     
       
         
         
             
             
         
       
       wherein:
 R 1  and R 2  are independently selected from the group consisting of H, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 8  cycloalkyl, substituted C 3  to C 8  cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, C 3  to C 6  alkenyl, C 3  to C 6  substituted alkenyl, C 3  to C 6  alkynyl, substituted C 3  to C 6  alkynyl, —(CH m X n ) z CH p X q , O—C 1  to C 6  alkyl, O—C 1  to C 6  substituted alkyl, and O—(CH m X n ) z CH p X q ; or 
 R 1  and R 2  may be taken together to form a ring of 4 to 8 ring atoms containing in its backbone carbon atoms and 1 to 4 N, O, S, or SO 2 , and where any C-atom or N-atom of said ring is optionally substituted with C 1  to C 4  alkyl, F, or CF 3 ; 
 R 3 , R 4 , R 5  and R 6  are independently selected from the group consisting of H, halogen, CN, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, —(CH m X n ) z CH p X q , C 3  to C 6  cycloalkyl, substituted C 3  to C 6  cycloalkyl, O—C 1  to C 6  alkyl, O—C 1  to C 6  substituted alkyl, OH, NH 2 , NH—(CH m X n ) z CH p X q , O—(CH m X n ) z CH p X q , N—{(CH m X n ) n CH p X q } 2 , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; 
 X is halogen; 
 m and n are, independently, 0 to 2, provided that m+n=2; 
 p and q are, independently, 0 to 3, provided that p+q=3; 
 z is 0 to 10; 
 R 7  is selected from the group consisting of H, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 6  cycloalkyl, and substituted C 3  to C 6  cycloalkyl; 
 or a pharmaceutically acceptable salt, tautomer, metabolite or prodrug thereof. 
 
     
   
   
       2 . The method according to  claim 1 , wherein R 7  is a branched C 3  to C 6  alkyl. 
   
   
       3 . The method according to  claim 1 , wherein R 3 , R 4 , R 5 , and R 6  are H. 
   
   
       4 . The method according to  claim 1 , wherein R 4  is H or halogen. 
   
   
       5 . The method according to  claim 1 , wherein R 7  is C 7  to C 6  alkyl. 
   
   
       6 . The method according to  claim 1 , wherein R 1  is H or C 1  to C 6  alkyl. 
   
   
       7 . The method according to  claim 1 , wherein R 2  is H, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 6  cycloalkyl, CF 3 , or CH 2 —C 3  to C 8  cycloalkyl. 
   
   
       8 . The method according to  claim 1 , wherein R 1  and R 2  are joined to form tetrahydropyrrole, pyrrolidine, piperidine, tetrahydropyran, or pyrrole. 
   
   
       9 . The method according to  claim 1 , wherein R 3  is H or OCF 3 . 
   
   
       10 . The method according to  claim 1 , wherein R 4  and R 6  are independently H or F. 
   
   
       11 . The method according to  claim 1 , wherein R 5  is H, CF 3 , N(CH 3 ) 2 , or F. 
   
   
       12 . The method according to  claim 1 , wherein:
 R 1  is H or C 1  to C 6  alkyl;   R 2  is H, C i  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 6  cycloalkyl, or CF 3 ; or   R 1  and R 2  are joined with the N-atom to form tetrahydropyrrole, piperidine, tetrahydropyran, or pyrrole;   R 3  is H or OCF 3 ;   R 4  and R 6  are independently H or F;   R 5  is H, CF 3 , N(CH 3 ) 2 , or F; or   R 7  is to C 6  alkyl.   
   
   
       13 . The method according to  claim 1  which is selected from the group consisting of 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-methylbenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-dimethylbenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethylbenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-propylbenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isopropylbenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isobutylbenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-N-methylbenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethylbenzenesulfonamide; N-(tert-butyl)-4-(5-cyano-1-methyl-1H-pyrrol-2-yl)benzenesulfonamide; 1-methyl-5-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile; 1-methyl-5-[4-(piperidin-1-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile; 1-methyl-5-[4-(morpholin-4-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutylbenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropylbenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclohexylbenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(2,2,2-trifluoroethyl)benzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)benzenesulfonamide; 1-methyl-5-[4-(1H-pyrrol-1-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethyl)benzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-dimethyl-2-(trifluoromethyl)benzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-methyl-2-(trifluoromethyl)benzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-2-(trifluoromethyl)benzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isopropyl-2-(trifluoromethyl)benzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-2-(trifluoromethyl)benzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-propyl-2-(trifluoromethyl)benzenesulfonamide; 1-methyl-5-[4-(pyrrolidin-1-ylsulfonyl)-3-(trifluoromethyl)phenyl]-1H-pyrrole-2-carbonitrile; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2-(trifluoromethyl)benzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2-(trifluoromethyl)benzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutyl-2-(trifluoromethyl)benzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluorobenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N-methylbenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N,N-dimethylbenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-3-fluorobenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-3-fluorobenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N-isopropylbenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N-propylbenzenesulfonamide; 5-[2-fluoro-4-(pyrrolidin-1-ylsulfonyl)phenyl]-1-methyl-1H-pyrrole-2-carbonitrile; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-3-fluorobenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-3-fluorobenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutyl-fluorobenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-2-fluorobenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-fluoro-N-isopropylbenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2-fluorobenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2-fluorobenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutyl-2-fluorobenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethoxy)benzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-methyl-2-(trifluoromethoxy)benzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-dimethyl-2-(trifluoromethoxy)benzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-2-(trifluoromethoxy)benzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-2-(trifluoromethoxy)benzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isopropyl-2-(trifluoromethoxy)benzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-propyl-2-(trifluoromethoxy)benzenesulfonamide; 1-methyl-5-[4-(pyrrolidin-1-ylsulfonyl)-3-(trifluoromethoxy)phenyl]-1H-pyrrole-2-carbonitrile; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2-(trifluoromethoxy)benzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2-(trifluoromethoxy)benzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutyl-2-(trifluoromethoxy)benzenesulfonamide; N-tert-butyl-4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethoxy)benzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(dimethylamino)-N,N-dimethylbenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2,5-difluoro-N-methylbenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2,5-difluoro-N-isopropylbenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2,5-difluorobenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2,5-difluorobenzenesulfonamide; and a pharmaceutically acceptable salt, tautomer, metabolite or prodrug thereof. 
   
   
       14 . The method according to  claim 1 , wherein said fibroids are uterine fibroids. 
   
   
       15 . The method according to  claim 1 , wherein said carcinomas are selected from the group consisting of carcinomas of the endometrium, breast, uterine, ovarian and prostate cancer. 
   
   
       16 . The method according to  claim 1 , wherein said cycle-related symptoms comprise psychological symptoms and physical symptoms. 
   
   
       17 . The method according to  claim 16 , wherein said psychological symptoms comprise mood changes, irritability, anxiety, lack of concentration, or decrease in sexual desire. 
   
   
       18 . The method according to  claim 16 , wherein said physical symptoms comprise dysmenorrhea, breast tenderness, bloating, fatigue, or food cravings. 
   
   
       19 . A method for preparing a compound of formula I: 
     
       
         
         
             
             
         
       
       wherein:
 R 1  and R 2  are independently selected from the group consisting of H, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 8  cycloalkyl, substituted C 3  to C 6  cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, C 3  to C 6  alkenyl, C 3  to C 6  substituted alkenyl, C 3  to C 6  alkynyl, substituted C 3  to C 6  alkynyl, —(CH m X n ) n CH p X q , O—C 1  to C 6  alkyl, O—C 1  to C 6  substituted alkyl, and O—(CH m X n ) z CH p X q ; or 
 R 1  and R 2  may be taken together to form a ring of 4 to 8 ring atoms containing in its backbone carbon atoms and 1 to 4 N, O, S, or SO 2 , and where any C-atom or N-atom of said ring is optionally substituted with C 1  to C 4  alkyl, F, or CF 3 ; 
 R 3 , R 4 , R 5  and R 6  are independently selected from the group consisting of H, halogen, CN, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, —(CH m X n ) z CH p X q , C 3  to C 6  cycloalkyl, substituted C 3  to C 6  cycloalkyl, O—C 1  to C 6  alkyl, O—C 1  to C 6  substituted alkyl, OH, NH 2 , NH—(CH m X n ) z CH p X q , O—(C m X n ) z CH p X q , N—{(CH m X n ) z CH p X q } 2 , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; 
 X is halogen; 
 m and n are, independently, 0 to 2, provided that m+n=2; 
 p and q are, independently, 0 to 3, provided that p+q=3; 
 z is 0 to 10; 
 R 7  is selected from the group consisting of H, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 6  cycloalkyl, and substituted C 3  to C 6  cycloalkyl; 
 or a pharmaceutically acceptable salt, tautomer, metabolite or prodrug thereof; 
 
       said method comprising:
 (a) reacting HNR 1 R 2  and an arylsulfonyl of the structure: 
 
     
     
       
         
         
             
             
         
       
       
         wherein:
 LG is a first leaving group; and 
 D is halogen or sulfonate; 
 
         (b) coupling the product of step (a) with a pyrrole comprising a second leaving group. 
       
     
   
   
       20 . The method according to  claim 19 , wherein said first leaving group is Cl, Br, F, or imidazole.