Androgen modulators

Abstract

The present invention is directed to a new class of 4-cyano-phenoxy-alkyl carboxyl derivatives 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: 
       
         
           
           
               
               
           
         
         in which; 
         a) X 1  is represented by cyano, halogen or haloalkyl, 
         b) R 1  and R 2  are each independently represented by hydrogen or (C 1 -C 6 ) alkyl, optionally substituted, 
         c) Alk 1  is represented by a C 1 -C 2  linear alkylene group, in which up to two hydrogen atoms are optionally replaced by a substituent selected from the group consisting of C 1 -C 6  alkyl optionally substituted, halogen, hydroxy, thiol, and cyano, 
         d) n is represented by the integer 0 or 1, 
         e) Y is represented by NX 2 X 3  or O—X 3 , 
         f) X 2  is represented by hydrogen or (C 1 -C 6 ) alkyl optionally substituted, 
         g) X 3  is represented by
 i. hydrogen, 
 ii. (C 1 -C 12 )alkyl, optionally substituted, 
 iii. (C 2 -C 12 )alkenyl, optionally substituted, 
 iv. (C 2 -C 12 )alkynyl, optionally substituted, 
 v. (C 3 -C 10 )cycloalkyl, optionally substituted, 
 vi. (C 3 -C 10 ) cycloalkyl(C 1 -C 6 )alkyl, in which the alkyl and cycloalkyl moieties may each be optionally substituted, 
 vii. (C 6 -C 10 )aryl, optionally substituted, 
 viii. (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, in which the alkyl and aryl moieties may each be optionally substituted, 
 ix. —(CH 2 )-(Alk 2 ) q -C(O)R 3 , in which Alk 2  is represented by a (C 1 -C 8 ) linear alkylene group, in which up to eight hydrogen atoms may optionally be replaced by a substituent, selected from the group consisting of (C 1 -C 6 ) alkyl optionally substituted, (C 1 -C 6 ) alkoxy, halogen, hydroxy, thiol, cyano, and NR 8 R 9  in which R 8  and R 9  are each independently represented by hydrogen or (C 1 -C 6 ) alkyl, q is the integer 0 or 1, R 3  is represented by hydrogen, (C 1 -C 12 )alkyl, (C 6 -C 10 )aryl, or (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, in which the alkyl and aryl moieties may each be optionally substituted, 
 x. —(CH 2 )-(Alk 2 ) q -C(O)—O—R 4 , in which Alk 2  and q, are as defined above, and R 4  is represented by hydrogen, (C 1 -C 12 )alkyl, (C 6 -C 10 )aryl, or (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, in which the alkyl and aryl moieties may be optionally substituted, 
 xi. —(CH 2 )-(Alk 2 ) q -C(O)—NR 5 R 6  in which Alk 2  and q are as described above, and R 5  and R 6  are each independently represented by hydrogen, (C 1 -C 12 )alkyl, (C 6 -C 10 )aryl, or (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, in which the alkyl and aryl moieties may be optionally substituted, 
 xii. —(CH 2 )-(Alk 2 ) q -Y—R 7 , in which Alk 2  and q are as defined above, Y is O or S, and R 7  is selected from the group consisting of hydrogen, (C 1 -C 12 )alkyl, (C 6 -C 10 )aryl, or (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, in which the alkyl and aryl moieties may be optionally substituted, 
 xiii. heteroaryl, optionally substituted, 
 xiv. heteroaryl(C 1 -C 6 )alkyl, in which the heteroaryl and alkyl moieties may each be optionally substituted, 
 xv. heterocyclic, optionally substituted, 
 xvi. heterocyclic(C 1 -C 6 )alkyl, in which the alkyl
 and heterocyclic moieties may each be substituted, or, 
 
 
         h) for those compounds in which Y is N, X 2  and X 3 , along with the adjacent nitrogen atom, may form a heterocyclic ring, which may optionally be substituted, or a salt, solvate, or prodrug thereof. 
       
     
     
         2 . A compound according to  claim 1  in which one of R 1  or R 2  is hydrogen and the other of R 1  or R 2  is selected from the group consisting of isobutyl, propyl, n-butyl, isopropyl, and ethyl. 
     
     
         3 . A compound according to  claim 1  or  2  in which n is 0. 
     
     
         4 . A compound according to  claim 1 ,  2 , or  3  in which X 1  is trifluoromethyl and is located at the 3-position of the phenyl ring. 
     
     
         5 . A compound according to  claim 1 ,  2 ,  3 , or  4  in which Y is NX 2 X 3 . 
     
     
         6 . A compound according to  claim 5  in which X 2  is hydrogen. 
     
     
         7 . A compound according to  claim 6  in which X 3  is represented by a substituent selected from the group consisting of (C 1 -C 12 )alkyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 alkyl, heteroaryl(C 1 -C 6 )alkyl, and heterocyclic(C 1 -C 6 )alkyl. 
     
     
         8 . A compound according to  claim 1 ,  2 ,  3 , or  4  in which Y is OX 3 . 
     
     
         9 . A compound according to anyone of  claims 1 - 8  in which X 1  is represented by halogen or haloalkyl. 
     
     
         10 . Use of a compound according to anyone of  claims 1 - 9  as a medicine. 
     
     
         11 . Use of a compound according to anyone of  claims 1 - 9  in the manufacture of a medicament for inhibiting activation of the androgen receptor 
     
     
         12 . Use of a compound according to anyone of  claims 1 - 9  in the manufacture of a medicament for the 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. 
     
     
         13 . A pharmaceutical composition comprising a compound according to anyone of  claims 1 - 9  in admixture with 1, or more, pharmaceutically acceptable excipients. 
     
     
         14 . A topical pharmaceutical formulation comprising a compound according to anyone of  claims 1 - 9  in admixture with 1, or more, pharmaceutically acceptable excipients suitable for dermal application. 
     
     
         15 . An article of manufacture comprising a compound according to anyone of  claims 1 - 9  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.