Methylene-bridged selective androgen receptor modulators and methods of use thereof

Abstract

This invention provides a class of androgen receptor targeting agents (ARTA). The agents define a new subclass of compounds, which are selective androgen receptor modulators (SARM). Several of the SARM compounds have been found to have an unexpected androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. Other SARM compounds have been found to have an unexpected antiandrogenic activity of a nonsteroidal ligand for the androgen receptor. The SARM compounds, either alone or as a composition, are useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of acute and/or chronic muscular wasting conditions; e) preventing and/or treating dry eye conditions; f) oral androgen replacement therapy; g) decreasing the incidence of, halting or causing a regression of prostate cancer; and/or h) inducing apoptosis in a cancer cell.

1 . A selective androgen receptor modulator (SARM) compound represented by the structure of formula I: 
     
       
         
         
             
             
         
       
       wherein
 G is O or S; 
 X is a bond or CH 2 ; 
 T is OH, OR, —NHCOCH 3 , or NHCOR; 
 Z is NO 2 , CN, COOH, COR, NHCOR or CONHR; 
 Y is CF 3 , F, T, Br, Cl, CN, C(R) 3  or Sn(R) 3 ; 
 Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C: 
 
     
     
       
         
         
             
             
         
       
       
         R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH; and 
         R 1  is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3  or CF 2 CF 3 ; 
         or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof. 
       
     
   
   
       2 . The selective androgen receptor modulator compound of  claim 1 , wherein X is a bond. 
   
   
       3 . The selective androgen receptor modulator compound of  claim 1 , wherein X is CH 2 . 
   
   
       4 . The selective androgen receptor modulator compound of  claim 1 , wherein G is O. 
   
   
       5 . The selective androgen receptor modulator compound of  claim 1 , wherein Z is NO 2 . 
   
   
       6 . The selective androgen receptor modulator compound of  claim 1 , wherein Z is CN. 
   
   
       7 . The selective androgen receptor modulator compound of  claim 1 , wherein Y is CF 3 . 
   
   
       8 . The selective androgen receptor modulator compound of  claim 1 , wherein T is OH. 
   
   
       9 . The selective androgen receptor modulator compound of  claim 1 , wherein R 1  is CH 3 . 
   
   
       10 . The selective androgen receptor modulator compound of  claim 1 , wherein Z is in the para position. 
   
   
       11 . The selective androgen receptor modulator compound of  claim 1 , wherein Y is in the meta position. 
   
   
       12 . The selective androgen receptor modulator compound of  claim 1 , represented by the structure of formula IIa. 
     
       
         
         
             
             
         
       
     
   
   
       13 . The selective androgen receptor modulator compound of  claim 1 , represented by the structure of formula IIb. 
     
       
         
         
             
             
         
       
     
   
   
       14 . The selective androgen receptor modulator compound of  claim 1 , wherein said compound is an androgen receptor agonist. 
   
   
       15 . A composition comprising the selective androgen receptor modulator compound of  claim 1  and/or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof; and a suitable carrier or diluent. 
   
   
       16 . A pharmaceutical composition comprising an effective amount of the selective androgen receptor modulator compound of  claim 1  and/or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof; and a pharmaceutically acceptable carrier or diluent. 
   
   
       17 . A method of binding a selective androgen receptor modulator compound to an androgen receptor, comprising the step of contacting the androgen receptor with the selective androgen receptor modulator compound of  claim 1  and/or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof, in an amount effective to bind the selective androgen receptor modulator compound to the androgen receptor. 
   
   
       18 . A selective androgen receptor modulator (SARM) compound represented by the structure of formula V: 
     
       
         
         
             
             
         
       
       wherein
 X is a bond or CH 2 ; 
 Z is NO 2 , CN, COOH, COR, NHCOR or CONHR; 
 Y is CF 3 , F, I, Br, Cl, CN, C(R) 3  or Sn(R) 3 ; 
 Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C: 
 
     
     
       
         
         
             
             
         
       
     
     and
 R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH; or its isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof. 
 
   
   
       19 . The selective androgen receptor modulator compound of  claim 18 , wherein X is a bond. 
   
   
       20 . The selective androgen receptor modulator compound of  claim 18 , wherein Z is NO 2 . 
   
   
       21 . The selective androgen receptor modulator compound of  claim 18 , wherein Z is CN. 
   
   
       22 . The selective androgen receptor modulator compound of  claim 18 , wherein Y is CF 3 . 
   
   
       23 . The selective androgen receptor modulator compound of  claim 18 , represented by the structure of formula VIa: 
     
       
         
         
             
             
         
       
     
   
   
       24 . The selective androgen receptor modulator compound of  claim 18 , represented by the structure of formula VIb. 
     
       
         
         
             
             
         
       
     
   
   
       25 . The selective androgen receptor modulator compound of  claim 18 , wherein said compound is an androgen receptor agonist. 
   
   
       26 . A composition comprising the selective androgen receptor modulator compound of  claim 18  or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof; and a suitable carrier or diluent. 
   
   
       27 . A pharmaceutical composition comprising an effective amount of the selective androgen receptor modulator compound of  claim 18  or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof; and a pharmaceutically acceptable carrier or diluent. 
   
   
       28 . A method of binding a selective androgen receptor modulator compound to an androgen receptor, comprising the step of contacting the androgen receptor with the selective androgen receptor modulator compound of  claim 18  or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof, in an amount effective to bind the selective androgen receptor modulator compound to the androgen receptor. 
   
   
       29 . A method of suppressing spermatogenesis in a subject comprising contacting an androgen receptor of the subject with the selective androgen receptor modulator compound of formula I: 
     
       
         
         
             
             
         
       
       wherein
 G is O or S; 
 X is a bond or CH 2 ; 
 T is OH, OR, —NHCOCH 3 , or NHCOR; 
 Z is NO 2 , CN, COOH, COR, NHCOR or CONHR; 
 Y is CF 3 , F, I, Br, Cl, CN, C(R) 3  or Sn(R) 3 ; 
 Q is alkyl, F, Cl, Br, I, CF 3 , CN, C(R) 3 , Sn(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R or SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C: 
 
     
     
       
         
         
             
             
         
       
       R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH; and
 R 1  is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof, in an amount effective to suppress sperm production. 
 
     
   
   
       30 . A method of contraception in a male subject, comprising the step of administering to said subject the selective androgen receptor modulator compound of  claim 1 . 
   
   
       31 . A method of hormone therapy comprising the step of contacting an androgen receptor of a subject with the selective androgen receptor modulator compound of  claim 1 . 
   
   
       32 . A method of hormone replacement therapy comprising the step of contacting an androgen receptor of a subject with the selective androgen receptor modulator compound of  claim 1 . 
   
   
       33 . A method of treating a subject having a hormone related condition, comprising the step of administering to said subject the selective androgen receptor modulator compound of  claim 1 . 
   
   
       34 . A method of treating a subject suffering from prostate cancer, comprising the step of administering to said subject the selective androgen receptor modulator compound of  claim 1 . 
   
   
       35 . A method of preventing prostate cancer in a subject, comprising the step of administering to said subject the selective androgen receptor modulator compound of  claim 1 . 
   
   
       36 . A method of delaying the progression of prostate cancer in a subject suffering from prostate cancer, comprising the step of administering to said subject the selective androgen receptor modulator compound of  claim 1 . 
   
   
       37 . A method of preventing the recurrence of prostate cancer in a subject suffering from prostate cancer, comprising the step of administering to said subject the selective androgen receptor modulator compound of  claim 1 . 
   
   
       38 . A method of treating the recurrence of prostate cancer in a subject suffering from prostate cancer, comprising the step of administering to said subject the selective androgen receptor modulator compound of  claim 1 . 
   
   
       39 . A method of treating a dry eye condition in a subject suffering from dry eyes, comprising the step of administering to said subject the selective androgen receptor modulator compound of  claim 1 . 
   
   
       40 . A method of preventing a dry eye condition in a subject, comprising the step of administering to said subject the selective androgen receptor modulator compound of  claim 1 . 
   
   
       41 . A method of inducing apoptosis in a cancer cell, comprising the step of contacting said cell with the selective androgen receptor modulator compound of  claim 1 .