Androgen modulators

Abstract

The present invention is directed to a new class of 4-cycloalkoxy benzonitriles and to their use as androgen receptor modulators. Other aspects of the invention are directed to the use of these compounds to decrease excess sebum secretions and to stimulate hair growth.

1 . A compound of the formula: 
       
         
           
           
               
               
           
         
         the salts, solvates, isomers, and prodrugs thereof, in which; 
         a) X 1  is represented by halogen, cyano, C 1 -C 6  alkoxy, haloalkoxy, or haloalkyl; 
         b) A is represented by a cycloalkyl or cycloalkenyl ring as depicted below: 
       
       
         
           
           
               
               
           
         
         c) n, m and p are each independently represented by an integer from 1 to 8, 
         d) the symbol U indicates the optional presence of one, or more, carbon-carbon double bonds within the ring, 
         e) R 1 , R 1′  and R 2  are each independently represented by a substituent selected from the group consisting of:
 i. hydrogen 
 ii. halogen, 
 iii. cyano, 
 iv. hydroxy, 
 v. (C 1 -C 12 )alkyl, optionally substituted, 
 vi. (C 2 -C 12 )alkenyl, optionally substituted, 
 vii. (C 2 -C 12 )alkynyl, optionally substituted, 
 viii. (C 3 -C 10 )cycloalkyl, optionally substituted, 
 ix. (C 3 -C 10 ) cycloalkyl(C 1 -C 6 )alkyl, in which the alkyl and cycloalkyl moieties may each be optionally substituted, 
 x. (C 6 -C 10 )aryl, optionally substituted, 
 xi. (CH 2 ) z —SR 1 , 
 xii. (CH 2 ) z —O—R 1 , 
 xiii. (CH 2 ) z —NR 1 R 2 , 
 xiv. (CH 2 ) z —COOR 3    
 xv. (CH 2 ) z —CONR 4 , 
 xvi. CH 2 ) z —NCOR 3 , and 
 xvii. (CH 2 ) z OCOR 3 , 
 
         f) z is represented by an integer from 0 to 6, 
         g) R 3  is represented by a substituent selected from the group consisting of hydrogen, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, optionally substituted (C 6 -C 10 )ary, and (C 6 -C 10 )aryl (C 1 -C 6 )alkyl, in which the alkyl and aryl moieties may each be optionally substituted and; 
         h) R 4  is represented by a substituent selected from the group consisting of hydrogen or (C 1 -C 12 )alkyl. 
       
     
     
         2 . A compound according to  claim 1  in which X is halogen or haloalkyl. 
     
     
         3 . A compound according to  claim 1  in which X is chloro or trifluoromethyl and is located at the 2-position. 
     
     
         4 . A compound according to  claim 1  in which A is represented by: 
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound according to  claim 4  in which n is represented by an integer selected from the group consisting of 2, 3, or 4; U is absent, and R 1  represents a substituent selected from the group consisting of hydrogen, cyano, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, and hydroxy. 
     
     
         6 . A compound according to  claim 1  selected from the group consisting of:
 a) 4-(5-hydroxy-5-methyl-bicyclo[2.2.1]-hept-2-yloxy)-2-trifluoromethyl-benzonitrile;   b) 4-(2-methyl-cyclopentyloxy)-2-trifluoromethyl-benzonitrile;   c) 4-cyclohexyloxy-2-trifluoromethyl-benzonitrile;   d) 4-(1-allyl-cyclohexyloxy)-2-trifluoromethyl-benzonitrile;   e) 4-cycloheptyloxy-2-trifluoromethyl-benzonitrile;   f) 4-(2,3-dimethyl-cyclohexyloxy)-2-trifluoromethyl-benzonitrile;   g) 4-(2-ethyl-cyclohexyloxy)-2-trifluoromethyl-benzonitrile;   h) 4-(2-methyl-cyclohexyloxy)-2-trifluoromethyl-benzonitrile;   i) 4-cyclopentyloxy-2-trifluoromethyl-benzonitrile;   j) 4-(2,6-dimethyl-cyclohexyloxy)-2-trifluoromethyl-benzonitrile;   k) 4-(5-isopropenyl-2-methylcyclohexyloxy)-2-trifluoromethyl-benzonitrile;   l) 4-(5-isopropenyl-2-methyl-cyclohexyloxy)-2-trifluoromethyl-benzonitrile;   m) 4-(2-cyano-cyclohexyloxy)-2-trifluoromethyl-benzonitrile;   n) 4-(3-methoxy-cyclohexyloxy)-2-trifluoromethyl-benzonitrile;   o) 4-(3-methyl-cyclohexyloxy)-2-trifluoromethyl-benzonitrile;   p) 4-cyclobutyloxy)-2-trifluoromethyl-benzonitrile;   q) 2-chloro-4-(5-hydroxy-5-methyl-bicyclo[2.2.1]-hept-2-yloxy)-benzonitrile;   r) 2-chloro-4-(2,3-dimethyl-cyclohexyloxy)-benzonitrile;   s) 4-(1-butyl-cyclopentyloxy)-2-chloro-benzonitrile;   t) 2-chloro-4-(2-ethyl-cyclohexyloxy)-benzonitrile;   u) 2-chloro-4-(3-methyl-cyclopentyloxy)-benzonitrile;   v) 4-bicyclo[2.2.1]-hept-2-yloxy)-2-chloro-benzonitrile;   w) 2-chloro-4-(3-hydroxy-cyclohexyloxy)-benzonitrile;   x) 2-chloro-4-(2-ethyl-cyclohexyloxy)-benzonitrile;   y) 2-chloro-4-(2-methyl-cyclohexyloxy)-benzonitrile;   z) 2-chloro-4-(2-phenyl-cyclohexyloxy)-benzonitrile;   aa) 2-chloro-4-(4-methyl-cyclohexyloxy)-benzonitrile;   bb) 2-chloro-4-(2-methoxy-cyclopentyloxy)-benzonitrile;   cc) 2-chloro-4-(2-methoxy-cyclohexyloxy)-benzonitrile;   dd) 4-(2-allyloxy-cyclopentyloxy)-2-chloro-benzonitrile;   ee) 3-chloro-4-(2-methoxy-cyclohexyloxy)-benzonitrile;   ff) 3-chloro-4-(3,3,5,5-tetramethyl-cyclohexyl)-benzonitrile;   gg) 3-chloro-4-cycloheptyloxy-benzonitrile;   hh) 2-chloro-4-cyclohexyloxy-benzonitrile;   ii) 2-chloro-4-cyclopentyloxy-benzonitrile;   jj) 2-chloro-4-(2-isopropyl-5-methyl-cyclohexyloxy)-benzonitrile;   kk) 2-chloro-4-(3-methyl-cyclohexyloxy)-benzonitrile;   ll) 2-chloro-4-(5-isopropenyl-2-methylcyclohexyloxy)-benzonitrile;   mm) 2-chloro-4-(2-cyano-cyclohexyloxy)-benzonitrile;   nn) 2-chloro-4-(3,4-dimethyl-cyclohexyloxy)-benzonitrile;   oo) 2-chloro-4-(2,3-dimethyl-cyclohexyloxy)-benzonitrile;   pp) 2-chloro-4-(2,6-dimethyl-cyclohexyloxy)-benzonitrile;   qq) 3-chloro-4-(4-methyl-cyclohexyloxy)-benzonitrile;   rr) 2-chloro-4-(2-phenyl-cyclohexyloxy)-benzonitrile;   ss) 3-chloro-4-(4-methyl-cyclohexyloxy)-benzonitrile;   tt) 2-chloro-4-(2-isopropyl-5-methyl-cyclohexyloxy)-benzonitrile;   uu) 4-(bicyclo[2.2.1]hept-2-yloxy)-2-chloro-benzonitrile;   vv) 3-chloro-4-(2,3-dimethyl-cyclohexyloxy)-benzonitrile;   ww) 2-chloro-4-(3,5-dimethyl-cyclohexyloxy)-benzonitrile;   xx) 3-chloro-4-(2-methyl-cyclopentyloxy)-benzonitrile   yy) 2-chloro-4-(2-methyl-cyclopentyloxy)-benzonitrile;   zz) 2-chloro-4-cyclobutyloxy-benzonitrile;   aaa) 4-(2-ethoxy-cyclohexyloxy)-2-trifluoromethyl-benzonitrile;   bbb) 4-(2-methoxy-cyclohexyloxy)-2-trifluoromethyl-benzonitrile;   ccc) 2-chloro-4-(3-hydroxy-cyclohexyloxy)-benzonitrile;   ddd) 4-(2-allyloxy-cyclohexyloxy)-2-trifluoromethyl-benzonitrile;   eee) 4-(2-cyano-cyclohexyloxy)-2-trifluoromethyl-benzonitrile;   fff) (trans)-(+)-4-(2-cyano-cyclohexyloxy)-2-trifluoromethyl-benzonitrile, and;   ggg) (trans)-(−)-4-(2-cyano-cyclohexyloxy)-2-trifluoromethyl-benzonitrile.   
     
     
         7 . 4-(2-Cyano-cyclohexyloxy)-2-trifluoromethyl-benzonitrile, a salt thereof, or an isomer thereof. 
     
     
         8 . (trans)-(−)-4-(2-Cyano-cyclohexyloxy)-2-trifluoromethyl-benzonitrile, or a pharmaceutically acceptable salt thereof. 
     
     
         9 . A method for alleviating a condition selected from the group consisting of hormone dependent cancers, benign hyperplasia of the prostate, acne, hirsutism, excess sebum, alopecia, premenstrual syndrome, lung cancer, precocious puberty, osteoporosis, hypogonadism, age-related decrease in muscle mass, and anemia comprising, administering a compound according to  claim 1  to a patient in need thereof. 
     
     
         10 . A pharmaceutical composition comprising a compound according to  claim 1  in admixture with one or more pharmaceutically acceptable excipients. 
     
     
         11 . A topical pharmaceutical formulation comprising a compound according to  claim 1  in admixture with one, or more, pharmaceutically acceptable excipients suitable for dermal application. 
     
     
         12 . An article of manufacture comprising a compound according to  claim 1 , packaged for retail distribution, which advises a consumer how to utilize the compound to alleviate a condition selected from the group consisting of acne, alopecia, and oily skin. 
     
     
         13 . A method for alleviating alopecia comprising the administration of a compound according to  claim 8  to a patient in need thereof. 
     
     
         14 . A method for decreasing sebum secretion comprising the administration of a compound according to  claim 8  to a patient in need thereof. 
     
     
         15 . A topical formulation comprising a compound according to  claim 8  in admixture with one, or more, pharmaceutically acceptable excipients suitable for dermal application. 
     
     
         16 . A method for treating dermal disorders associated with excess sebum comprising the topical administration of a compound according to  claim 8  to a patient in need thereof. 
     
     
         17 . A method according to  claim 16  in which said disorder is acne. 
     
     
         18 . A method according to  claim 16  in which said disorder is oily skin.