Non-peptide GnRH agents, pharmaceutical compositions and methods for their use

Abstract

Non-peptide GnRH agents capable of inhibiting the effect of gonadotropin-releasing hormone are described. Such compounds and their pharmaceutically acceptable salts, prodrugs, and active metabolites are suitable for treating mammalian reproductive disorders and steroid hormone-dependent tumors as well as for regulating fertility, where suppression of gonadotropin release is indicated. Methods for synthesizing the compounds and intermediates useful in their preparation are also described.

1 - 6 . (canceled)  
   
   
       7 . A compound represented by Formula II:  
     
       
         
         
             
             
         
       
       wherein:  
       R 4  is selected from the group consisting of C 3 -C 10  alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, —O-aryl, —NH-aryl, —O-heteroaryl, —NH-heteroaryl, —O-cycloalkyl, —NH-cycloalkyl, —O-heterocycloalkyl or —NH-heterocycloalkyl group unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogens; ═O; ═S; —CN; and —NO 2 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, —(CH 2 ) x CN where z is an integer from 0 to 4, ═NH, —NHOH, —OH, —C(O)H, —OC(O)H, —C(O)OH, —OC(O)OH, —OC(O)OC(O)H, —OOH, —C(NH)NH 2 , —NHC(NH)NH 2 , —C(S)NH 2 , —NHC(S)NH 2 , —NHC(O)NH 2 , —S(O 2 )H, —S(O)H, —NH 2 , —C(O)NH 2 , OC(O)NH 2 , —NHC(O)H, —NHC(O)OH, —C(O)NHC(O)H, —OS(O 2 )H, —OS(O)H, —OSH, —SC(O)H, —S(O)C(O)OH, —SO 2 C(O)OH, —NHSH, —NHS(O)H, —NHSO 2 H, —C(O)SH, —C(O)S(O)H, —C(O)S(O 2 )H, —C(S)H, —C(S)OH, —C(SO)OH, —C(SO 2 )OH, —NHC(S)H, —OC(S)H, —OC(S)OH, —OC(SO 2 )H, —S(O 2 )NH 2 , —S(O)NH 2 , —SNH 2 , —NHCS(O 2 )H, —NHC(SO)H, —NHC(S)H, and —SH groups unsubstituted or substituted with one or more substituents selected from the group consisting of halogens, ═O, —NO 2 , —CN, —(CH 2 ), —CN where z is an integer from 0 to 4, —R c , —NR c OR c , —NR c R c , —C(O)NR c , —C(O)OR c , —C(O)R c , —NR c C(O)NR c R c , —NR c C(O)R c , —OC(O)OR c , —OC(O)NR c R c , —SR c , unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where R c  is hydrogen, unsubstituted alkyl, unsubstituted alkenyl unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl or unsubstituted heteroaryl, or two or more R c  groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group;  
       Y is selected from the group consisting of C(A 4 )(A 5 ) wherein A 4  and A 5  are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkyl; N(A 6 ) wherein A 6  is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or haloalkyl; S; SO; and SO 2 ;  
       R 5  is hydrogen or an unsubstituted alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, —O-aryl, —NH-aryl, —O-heteroaryl, —NH-heteroaryl, —O-cycloalkyl, —NH-cycloalkyl, —O-heterocycloalkyl, or —NH-heterocycloalkyl group;  
       R 6  is hydrogen or an unsubstituted alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, —O-aryl, —NH-aryl, —O-heteroaryl, —NH-heteroaryl, —O-cycloalkyl, —NH-cycloalkyl, —O-heterocycloalkyl, or —NH-heterocycloalkyl group;  
       Z is selected from the group consisting of: C(A 7 )(A 8 ) wherein A 7  and A 8  are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkyl; N(A 9 ) wherein A 9  is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or haloalkyl; and S; and  
       Ar 2  is selected from the group consisting of aryl, cycloalkyl, heterocycloalkyl, and heteroaryl groups unsubstituted or substituted with one or more substituents independently from the group consisting of: halogens; ═O; ═S; —CN; and —NO 2 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, —(CH 2 ) x CN where z is an integer from 0 to 4, ═NH, —NHOH, —OH, —C(O)H, —OC(O)H, —C(O)OH, —OC(O)OH, —OC(O)OC(O)H, —OOH, —C(NH)NH 2 , —NHC(NH)NH 2 , —C(S)NH 2 , —NHC(S)NH 2 , —NHC(O)NH 2 , —S(O 2 )H, —S(O)H, —NH 2 , —C(O)NH 2 , —OC(O)NH 2 , —NHC(O)H, —NHC(O)OH, —C(O)NHC(O)H, —OS(O 2 )H, —OS(O)H, —OSH, —SC(O)H, —S(O)C(O)OH, —O 2 C(O)OH, —NHSH, —NHS(O)H, —NHSO 2 H, —C(O)SH, —C(O)S(O)H, —C(O)S(O 2 )H, —C(S)H, —C(S)OH, —C(SO)OH, —C(S(O)OH, —NHC(S)H, —OC(S)H, —OC(S)OH, —OC(SO 2 )H, —S(O 2 )NH 2 , —S(O)NH 2 , —SNH 2 , —NHCS(O 2 )H, —NHC(SO)H, —NHC(S)H, and —SH groups unsubstituted or substituted with one or more substituents selected from the group consisting of halogens, ═O, —NO 2 , —CN, —(CH 2 ) z —CN where z is an integer from 0 to 4, —OR c , —NR c OR c , —NR c R c , —C(O)NR c , —C(O)OR c , —C(O)R c , —NR c C(O)NR c R c , —NR c C(O)R c , —C(O)OR c , —OC(O)NR c R c , —SR c , unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where R c  is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more R c  groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group;  
       or a pharmaceutically acceptable salt of said compound.  
     
   
   
       8 . A compound according to  claim 7  wherein R 4  is selected from the group consisting of aryl, cycloalkyl, heterocycloalkyl, and —O-aryl groups unsubstituted or substituted with one or more substitutents independently selected from the group consisting of: halogens, ═O, alkyl, heteroalkyl, aryl, cycloalkyl, —OH, —C(O)H, and —C(O)NH 2  groups unsubstituted or substituted with one or more substitutents selected from the group consisting of —C(O)NR c , unsubstituted alkyl, unsubstitued aryl, and unsubstituted cycloalkyl, where R c  is hydrogen or unsubstituted alkyl.  
   
   
       9 . A compound according to  claim 7  wherein Y is CH 2  or O.  
   
   
       10 . A compound according to  claim 7  wherein R 5  is hydrogen and R 6  is hydrogen or alkyl.  
   
   
       11 . A compound according to  claim 7  wherein Ar 2  is an aryl or heteroaryl group unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogens; and alkyl, heteroalkyl, haloalkyl, cycloalkyl, —OH, —NH 2 , and —S(O)NH 2  groups unsubstituted or substituted with one or more substitutents selected from the group consisting of unsubstituted alkyl, unsubstituted cycloalkyl, and unsubstituted heterocycloalkyl.  
   
   
       12 . A compound according to  claim 11  wherein: 
 R 4  is selected from the group consisting of aryl, cycloalkyl, heterocycloalkyl, and —O-aryl unsubstituted or substituted with one or more substitutents independently selected from the group consisting of: halogens, ═O, alkyl, heteroalkyl, aryl, cycloalkyl, —OH, —C(O)H, and —C(O)NH 2  groups unsubstituted or substituted with one or more substitutents selected from the group consisting of —C(O)NR c , unsubstituted alkyl, unsubstitued aryl, unsubstituted cycloalkyl, where R c  is hydrogen or unsubstituted alkyl;    Y is CH 2  or O;    R 5  is hydrogen; and    R 6  is hydrogen or alkyl.    
   
   
       13 . A compound selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof.  
   
   
       14 . A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in claim  1  and a pharmaceutically acceptable carrier.  
   
   
       15 . A method for antagonizing gonadotropin-releasing hormone in a patient suffering from a gonadotropin-releasing hormone derived disorder comprising administering an effective amount of a compound as defined in any one of claims  7  or  13 .