5-aryl indan-1-one and analogs useful as progesterone receptor modulators

Abstract

Compounds of formula I or II and pharmaceutical compositions and kits containing these compounds are provided. Also provided are methods of inducing contraception, providing hormone replacement therapy, treating cycle-related symptoms, or treating or preventing benign or malignant neoplastic disease using the compounds of formula I, formula II, or formula III.

1 . A compound of formula (I) or (II):
 (I) a compound of formula (I):   
     
       
         
         
             
             
         
       
       wherein:
 R 1  and R 2  are, independently, selected from the group consisting of H, halogen, C 1  to C 6  alkyl, CF 3 , CF 2 CF 3 , C 2  to C 6  alkenyl, C 2  to C 6  alkynyl, C 3  to C 8  cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
 provided that both R 1  and R 2  are not H; or 
 R 1  and R 2  are fused to form (a), (b), or (c):
 (a) a carbon-based 3 to 6 membered saturated spirocyclic ring; 
 (b) a carbon-based 3 to 6 membered spirocyclic ring having in its backbone one or more carbon-carbon double bonds; or 
 (c) a carbon-based 3 to 6 membered spirocyclic ring having in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO 2,  and NR C ; 
 wherein rings (a)-(c) are optionally substituted by 1 to 3 substituents selected from the group consisting of F, Cl, and C 1  to C 3  alkyl; 
 R 3  is (i) or (ii): 
 (i) a 5 or 6 membered heteroaryl ring containing in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, and SO 2  and substituted with 0 to 3 substituents selected from the group consisting of H, halogen, CN, NO 2 , OH, amino, C 1  to C 4  alkyl, C 1  to C 4  alkoxy, C 1  to C 4  alkylamino, C═NOR , COR D , and NR C COR D ; or 
 (ii) a 5 or 6 membered heteroaryl ring containing in its backbone 1 or 3 NR C  heteroatoms and substituted with 0 to 3 substituents selected from the group consisting of H, halogen, CN, NO 2 , OH, amino, C 1  to C 4  alkyl, C 1  to C 4  alkoxy, C 1  to C 4  alkylamino, C═NOR C , COR D , and NR C COR D ;
 R C  is absent, H, C 1  to C 4  alkyl, substituted C 1  to C 4  alkyl, CN, or COR D ; 
 R D  is H, C 1  to C 4  alkyl, C 1  to C 4  alkoxy, or C 1  to C 4  alkylamino; 
 
 
 R 4  is H, halogen, CN, OH, NO 2 , alkoxy, or lower alkyl; 
 R 5 , R 6 , R 7 , and R 8  are, independently, H, F, or C 1  to C 3  alkyl; 
 
       or a pharmaceutically acceptable salt thereof; or 
       (II) a compound of formula (II): 
     
     
       
         
         
             
             
         
       
       wherein:
 (i) R 1  and R 2  are, independently, heteroaryl or substituted heteroaryl; or
 R 1  and R 2  are fused to form a carbon-based 3 to 6 membered spirocyclic ring having in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 , and NR C , wherein the carbon-based ring is optionally substituted by 1 to 3 substituents selected from the group consisting of F, Cl, and C 1  to C 3  alkyl; 
 R 3  is a saturated 5 or 6 membered heteroaryl ring containing in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 , and NR C  and substituted with 0 to 3 substituents selected from the group consisting of H, halogen, CN, NO 2 , OH, amino, C 1  to C 4  alkyl, C 1  to C 4  alkoxy, C 1  to C 4  alkylamino, C═NOR C , COR D , and NR C COR D ; or
 R C  is absent, H, C 1  to C 4  alkyl, substituted C 1  to C 4  alkyl, CN, or COR D ; 
 R D  is H, C 1  to C 4  alkyl, C 1  to C 4  alkoxy, or C 1  to C 4  alkylamino; 
 
 R 4  is H, halogen, CN, OH, NO 2 , alkoxy, or lower alkyl; 
 R 5  and R 6  are, independently, H, F, or C 1  to C 3  alkyl; 
 
 or a pharmaceutically acceptable salt thereof; or 
 (ii) R 1  and R 2  are, independently, selected from the group consisting of H, halogen, C 1  to C 6  alkyl, CF 3 , CF 2 CF 3 , C 2  to C 6  alkenyl, C 2  to C 6  alkynyl, C 3  to C 8  cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
 provided that both R 1  and R 2  are not H; or 
 R 1  and R 2  are fused to form (a), (b), or (c):
 (a) a carbon-based 3 to 6 membered saturated spirocyclic ring; 
 (b) a carbon-based 3 to 6 membered spirocyclic ring having in its backbone one or more carbon-carbon double bonds; or 
 (c) a carbon-based 3 to 6 membered spirocyclic ring having in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 , and NR C ; 
 wherein rings (a)-(c) are optionally substituted by 1 to 3 substituents selected from the group consisting of F, Cl, and C 1  to C 3  alkyl; 
 
 R 3  is a saturated 6 membered heteroaryl ring containing in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 , and NR C  and substituted with 0 to 3 substituents selected from the group consisting of H, halogen, CN, NO 2 , OH, amino, C 1  to C 4  alkyl, C 1  to C 4  alkoxy, C 1  to C 4  alkylamino, C═NOR C , COR D , and NR C COR D ; or
 R C  is absent, H, C 1  to C 4  alkyl, substituted C 1  to C 4  alkyl, CN, or COR D ; 
 R D  is H, C 1  to C 4  alkyl, C 1  to C 4  alkoxy, or C 1  to C 4  alkylamino; 
 
 R 4  is H, halogen, CN, OH, NO 2 , alkoxy, or lower alkyl; 
 R 5  and R 6  are, independently, H, F, or C 1  to C 3  alkyl; 
 
 or a pharmaceutically acceptable salt thereof. 
 
     
   
   
       2 . The compound according to  claim 1 , which is of formula I and comprises 1-methyl-5-(5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrrole-2-carbonitrile. 
   
   
       3 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 
   
   
       4 . A method of inducing contraception, providing hormone replacement therapy, or treating cycle-related symptoms, or treating or preventing benign or malignant neoplastic disease, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of  claim 1 . 
   
   
       5 . A method of providing hormone replacement therapy or treating cycle-related symptoms, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula III: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 2  is selected from the group consisting of H, halogen, C 1  to C 6  alkyl, CF 3 , CF 2 CF 3 , C 2  to C 6  alkenyl, C 2  to C 6  alkynyl, C 3  to C 8  cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
 R 3  is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; 
 R 4  is H, halogen, CN, OH, NO 2 , alkoxy, or lower alkyl; 
 R 9  is H, F, or C 1  to C 3  alkyl; 
 
     or a pharmaceutically acceptable salt thereof. 
   
   
       6 . A method of inducing contraception or treating or preventing benign or malignant neoplastic disease, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula III: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 2  is selected from the group consisting of H, halogen, C 1  to C 6  alkyl, CF 3 , CF 2 CF 3 , C 2  to C 6  alkenyl, C 2  to C 6  alkynyl, C 3  to C 8  cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
 R 3  is heteroaryl or substituted heteroaryl; 
 R 4  is H, halogen, CN, OH, NO 2 , alkoxy, or lower alkyl; 
 R 9  is H, F, or C 1  to C 3  alkyl; 
 
     or a pharmaceutically acceptable salt thereof. 
   
   
       7 . 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 structure:   
     
       
         
         
             
             
         
       
       wherein:
 (I) R 2  is selected from the group consisting of H, halogen, C 1  to C 6  alkyl, CF 3 , CF 2 CF 3 , C 2  to C 6  alkenyl, C 2  to C 6  alkynyl, C 3  to C 8  cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
 R 3  is heteroaryl or substituted heteroaryl; 
 R 4  is H, halogen, CN, OH, NO 2 , alkoxy, or lower alkyl; 
 R 9  is H, F, or C 1  to C 3  alkyl; 
 
 or a pharmaceutically acceptable salt thereof; or 
 (II) R 2  is selected from the group consisting of H, halogen, C 1  to C 6  alkyl, CF 3 , CF 2 CF 3 , C 2  to C 6  alkenyl, C 2  to C 6  alkynyl, C 3  to C 8  cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
 R 3  is heteroaryl or substituted heteroaryl; 
 R 4  is H, halogen, CN, OH, NO 2 , alkoxy, or lower alkyl; 
 R 9  is H, F, or C 1  to C 3  alkyl; 
 
 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. 
     
   
   
       8 . A pharmaceutically useful kit adapted for daily oral administration which comprises:
 (a) a first phase of from 14 to 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 μg levonorgestrel;   (b) a second phase of from 1 to 11 daily dosage units of a compound of the structure:   
     
       
         
         
             
             
         
       
       wherein:
 (I) R 2  is selected from the group consisting of H, halogen, C 1  to C 6  alkyl, CF 3 , CF 2 CF 3 , C 2  to C 6  alkenyl, C 2  to C 6  alkynyl, C 3  to C 8  cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
 R 3  is heteroaryl or substituted heteroaryl; 
 R 4  is H, halogen, CN, OH, NO 2 , alkoxy, or lower alkyl; 
 R 9  is H, F, or C 1  to C 3  alkyl; 
 
 or a pharmaceutically acceptable salt thereof; or 
 (II) R 2  is selected from the group consisting of H, halogen, C 1  to C 6  alkyl, CF 3 , CF 2 CF 3 , C 2  to C 6  alkenyl, C 2  to C 6  alkynyl, C 3  to C 8  cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
 R 3  is heteroaryl or substituted heteroaryl; 
 R 4  is H, halogen, CN, OH, NO 2 , alkoxy, or lower alkyl; 
 R 9  is H, F, or C 1  to C 3  alkyl; 
 
 or a pharmaceutically acceptable salt thereof; and 
 
       wherein, each daily dosage unit contains said compound at a daily dosage of from about 2 to 50 mg; and 
       (c) a third phase of daily dosage units of an orally and pharmaceutically acceptable placebo;
 wherein the total number of the daily dosage units in the first phase, second phase and third phase equals 28. 
 
     
   
   
       9 . A pharmaceutical composition comprising a compound of formula II or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, wherein said compound of formula II is: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  and R 2  are, independently, selected from the group consisting of H, halogen, C 1  to C 6  alkyl, CF 3 , CF 2 CF 3 , C 2  to C 6  alkenyl, C 2  to C 6  alkynyl, C 3  to C 8  cycloalkyl, aryl, and substituted aryl; 
 provided that both R 1  and R 2  are not H; or 
 R 1  and R 2  are fused to form (a) or (b):
 (a) a carbon-based 3 to 6 membered saturated spirocyclic ring; or 
 (b) a carbon-based 3 to 6 membered spirocyclic ring having in its backbone one or more carbon-carbon double bonds; 
 wherein rings (a)-(b) are optionally substituted by 1 to 3 substituents selected from the group consisting of F, Cl, and C 1  to C 3  alkyl; 
 
 R 3  is a saturated 5 membered heteroaryl ring containing in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO 2,  and NR C  and substituted with 0 to 3 substituents selected from the group consisting of H, halogen, CN, NO 2 , OH, amino, C 1  to C 4  alkyl, C 1  to C 4  alkoxy, C 1  to C 4  alkylamino, C═NOR C , COR D , and NR C COR D ; or
 R C  is absent, H, C 1  to C 4  alkyl, substituted C 1  to C 4  alkyl, CN, or COR D ; 
 R D  is H, C 1  to C 4  alkyl, C 1  to C 4  alkoxy, or C 1  to C 4  alkylamino; 
 
 R 4  is H, halogen, CN, OH, NO 2 , alkoxy, or lower alkyl; 
 R 5  and R 6  are, independently, H, F, or C 1  to C 3  alkyl; 
 
     or a pharmaceutically acceptable salt thereof. 
   
   
       10 . A method of inducing contraception, providing hormone replacement therapy, treating cycle-related symptoms, or treating or preventing benign or malignant neoplastic disease, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula II: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  and R 2  are, independently, selected from the group consisting of H, halogen, C 1  to C 6  alkyl, CF 3 , CF 2 CF 3 , C 2  to C 6  alkenyl, C 2  to C 6  alkynyl, C 3  to C 8  cycloalkyl, aryl, and substituted aryl; 
 provided that both R 1  and R 2  are not H; or 
 R 1  and R 2  are fused to form (a) or (b):
 (a) a carbon-based 3 to 6 membered saturated spirocyclic ring; or 
 (b) a carbon-based 3 to 6 membered spirocyclic ring having in its backbone one or more carbon-carbon double bonds; 
 wherein rings (a)-(b) are optionally substituted by 1 to 3 substituents selected from the group consisting of F, Cl, and C 1  to C 3  alkyl; 
 
 R 3  is a saturated 5 membered heteroaryl ring containing in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 , and NR C  and substituted with 0 to 3 substituents selected from the group consisting of H, halogen, CN, NO 2 , OH, amino, C 1  to C 4  alkyl, C 1  to C 4  alkoxy, C 1  to C 4  alkylamino, C═NOR C , COR D , and NR C COR D ; or
 R C  is absent, H, C 1  to C 4  alkyl, substituted C 1  to C 4  alkyl, CN, or COR D ; 
 R D  is H, C 1  to C 4  alkyl, C 1  to C 4  alkoxy, or C 1  to C 4  alkylamino; 
 
 R 4  is H, halogen, CN, OH, NO 2 , alkoxy, or lower alkyl; 
 R 5  and R 6  are, independently, H, F, or C 1  to C 3  alkyl; 
 
     or a pharmaceutically acceptable salt thereof.