Estrogen modulators

Abstract

The present application is directed to a new class of isoxazoles and their use as estrogen modulators.

1 . A compound of the formula: 
     
       
         
         
             
             
         
       
       or a salt there of, in which: 
       X is represented by hydrogen, 
       X 1  is absent, or is represented by a substituent selected from the group consisting of halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy, C 1 -C 6  thioalkyl and cyano; 
       A is represented by a substituent selected from the group consisting of:
 i) hydrogen, 
 ii) cyano, 
 iii) (C 1 -C 6 )alkyl, optionally substituted, 
 iv) (C 3 -C 10 )cycloalkyl, optionally substituted, 
 v) (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, in which the alkyl and cycloalkyl moieties may each be optionally substituted, 
 vi) (C 6 -C 10 )aryl optionally substituted, 
 vii) (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, in which the alkyl and aryl moieties may each be optionally substituted, 
 viii) heteroaryl, optionally substituted, 
 ix) heteroaryl(C 1 -C 6 )alkyl, in which the heteroaryl and alkyl moieties may each be optionally substituted, 
 x) heterocyclic, optionally substituted, 
 xi) heterocyclic(C 1 -C 6 )alkyl, in which the alkyl and heterocyclic moieties may each be substituted, 
 xii) (CH 2 ) z Y 1 —Y 2 , 
 xiii) (CH 2 ) z —S(O) t R, 
 xiv) (CH 2 ) z —OR, 
 xv) (CH 2 ) z —NRR 1 , 
 xvi) (CH 2 ) z —COOR, 
 xvii) (CH 2 ) z OCOR, and; 
 xviii) ((CH 2 ) z COR, 
 
       Y 1  and Y 2  are each independently represented by a substituent selected from the group consisting of:
 v) (C 3 -C 10 )cycloalkyl, optionally substituted, 
 vi) (C 6 -C 10 )aryl optionally substituted, 
 vii) heteroaryl, optionally substituted, and; 
 viii) heterocyclic, optionally substituted, 
 
       z is represented by an integer from 0 to 5, 
       t is represented by the integer 0, 1, or 2, 
       R 1  is represented by hydrogen or (C 1 -C 6 )alkyl, optionally substituted, 
       R is represented by a substituent selected from the group consisting of:
 i) hydrogen, 
 ii) (C 1 -C 6 )alkyl, optionally substituted, 
 xii) (C 3 -C 10 )cycloalkyl, optionally substituted, 
 xiii) (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, in which the alkyl and cycloalkyl moieties may each be optionally substituted, 
 xiv) (C 6 -C 10 )aryl optionally substituted, 
 xv) (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, in which the alkyl and aryl moieties may each be optionally substituted, 
 xvi) heteroaryl, optionally substituted, 
 xvii) heteroaryl(C 1 -C 6 )alkyl, in which the heteroaryl and alkyl moieties may each be optionally substituted, 
 xviii) heterocyclic, optionally substituted, 
 xix) heterocyclic(C 1 -C 6 )alkyl, in which the alkyl and heterocyclic moieties may each be substituted, and; 
 xx) (C 1 -C 6 )alkylene-Y 3 —(C 1 -C 6 )alkyl, in which the alkylene and alkyl moieties may be substituted, and; 
 
       Y 3  is O or S. 
     
   
   
       2 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
   
   
       3 . A compound according to  claim 2 , in which X 1  is absent. 
   
   
       4 . A compound according to  claim 2 , in which X is hydrogen. 
   
   
       5 . A compound according to  claim 2 , in which A is optionally substituted (C 1 -C 6 )alkyl. 
   
   
       6 . A compound according to  claim 2 , in which A is methyl, ethyl, propyl, or isopropyl, any of which is substituted by hydroxyl. 
   
   
       7 . (±)-4-{5-[1-(1-Hydroxy-ethyl)-cyclopropyl]-4-phenyl-isoxazol-3-yl}-phenol, or a pharmaceutically acceptable salt thereof. 
   
   
       8 . (R)-(−)-4-{5-[1-(1-Hydroxy-ethyl)-cyclopropyl]-4-phenyl-isoxazol-3-yl}-phenol, or a pharmaceutically acceptable salt thereof. 
   
   
       9 . (S)-(+)-4-{5-[1-(1-Hydroxy-ethyl)-cyclopropyl]-4-phenyl-isoxazol-3-yl}-phenol, or a pharmaceutically acceptable salt thereof. 
   
   
       10 . A pharmaceutical composition comprising a compound according to  claim 2  in admixture with at least one pharmaceutically acceptable excipient. 
   
   
       11 . A topical pharmaceutical composition comprising a compound according to  claim 2  in admixture with at least one pharmaceutically acceptable excipient suitable for topical application. 
   
   
       12 . A method for alleviating wrinkles comprising the administration of an effective amount of a compound according to  claims 2  to a patient in need thereof. 
   
   
       13 . The method according to  claim 2 , in which said compound is administered topically. 
   
   
       14 . A method for enhancing collagen production comprising the topical administration of a compound according to  claim 2  to a patient in need thereof. 
   
   
       15 . A kit comprising a compound according to  claim 2 , packaged for retail distribution, which advises a consumer how to utilize the compound to alleviate wrinkles. 
   
   
       16 . A pharmaceutical composition comprising a compound according to  claim 7  in admixture with at least one pharmaceutically acceptable excipient. 
   
   
       17 . A topical pharmaceutical composition comprising a compound according to  claim 7  in admixture with at least one pharmaceutically acceptable excipient suitable for topical application. 
   
   
       18 . A method for alleviating wrinkles comprising the administration of an effective amount of a compound according to  claim 7  to a patient in need thereof. 
   
   
       19 . The method according to  claim 18 , in which said compound is administered topically. 
   
   
       20 . A method for enhancing collagen production comprising the topical administration of a compound according to  claim 7  to a patient in need thereof. 
   
   
       21 . A kit comprising a compound according to  claim 7 , packaged for retail distribution, which advises a consumer how to utilize the compound to alleviate wrinkles. 
   
   
       22 . A pharmaceutical composition comprising a compound according to  claim 8  in admixture with at least one pharmaceutically acceptable excipient. 
   
   
       23 . A topical pharmaceutical composition comprising a compound according to  claim 8  in admixture with at least one pharmaceutically acceptable excipient suitable for topical application. 
   
   
       24 . A method for alleviating wrinkles comprising the administration of an effective amount of a compound according to  claim 8  to a patient in need thereof. 
   
   
       25 . The method according to  claim 24 , in which said compound is administered topically. 
   
   
       26 . A method for enhancing collagen production comprising the topical administration of a compound according to  claim 8  to a patient in need thereof. 
   
   
       27 . A kit comprising a compound according to  claim 8 , packaged for retail distribution, which advises a consumer how to utilize the compound to alleviate wrinkles.