Gonadotropin-releasing hormone receptor antagonists and methods relating thereto

Abstract

GnPRH receptor antagonists are disclosed which have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure: wherein A, R 1 , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 R 7 and n are as defined herein, including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for antagonizing gonadotropin-releasing hormone in a subject in need thereof.

1 - 5 . (canceled)  
   
   
       6 . A method for antagonizing gonadotropin-releasing hormone in a subject in need thereof, comprising administering to the subject an effective amount of a compound having the following structure:  
     
       
         
         
             
             
         
       
     
     or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, 
 wherein: 
 A is 0 or a bond;  
 n is 1, 2, 3 or 4;  
 R 1  and R 2  are the same or different and independently hydrogen alky, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, —C(R 8 )(═NR 9 ) or —C(NR 10 R 11 )(═NR 9 );  
 
 or R 1  and R 2  taken together with the nitrogen atom to which they are attached form a heterocycle or a substituted heterocycle,  
 R 3a  and R 3b  are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, alkoxy, alkylthio, alkylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, —COOR 12  or —CONR 10 R 11 ;  
 or R 3a  and R 3b  taken together with the carbon atom to which they are attached form a homocycle, substituted homocycle, heterocycle or substituted heterocycle,  
 or R 3a  and the carbon to which it is attached taken together with R 1  and the nitrogen to which it is attached form a heterocycle or substituted heterocycle;  
 R 4  is hydrogen, alkyl or substituted alkyl;  
 R 5  is arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl;  
 R 6  is aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 R 7  is hydrogen, alkyl or substituted alkyl,  
 R 8 , R 9 , R 10  and R 11  are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl; and  
 R 12  is hydrogen, alkyl or substituted alkyl.  
 
   
   
       7 . A method for treating a sex-hormone related condition of a subject in need thereof, comprising administering to the subject an effective amount of a compound having the following structure:  
     
       
         
         
             
             
         
       
     
     or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, 
 wherein: 
 A is 0 or a bond;  
 n is 1, 2, 3 or 4;  
 R 1  and R 2  are the same or different and independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, —C(R 8 )(═NR 9 ) or —C(NR 10 R 11 )(═NR 9 );  
 
 or R 1  and R 2  taken together with the nitrogen atom to which they are attached form a heterocycle or a substituted heterocycle;  
 R 3a  and R 3b  are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, alkoxy, alkylthio, alkylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, —COOR 12  or —CONR 10 R 11 ;  
 or R 3a  and R 3b  taken together with the carbon atom to which they are attached form a homocycle, substituted homocycle, heterocycle or substituted heterocycle,  
 or R 3a  and the carbon to which it is attached taken together with R 1  and the nitrogen to which it is attached form a heterocycle or substituted heterocycle;  
 R 4  is hydrogen, alkyl or substituted alkyl;  
 R 5  is arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl;  
 R 6  is aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 R 7  is hydrogen, alkyl or substituted alkyl;  
 R 8 , R 9 , R 10  and R 11  are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl; and  
 R 12  is hydrogen, alkyl or substituted alkyl.  
 
   
   
       8 . The method of  claim 7  wherein the sex-hormone related condition is cancer, benign prostatic hypertrophy or myoma of the uterus.  
   
   
       9 . The method of  claim 8  wherein the cancer is prostatic cancer, uterine cancer, breast cancer or pituitary gonadotroph adenomas.  
   
   
       10 . The method of  claim 7  wherein the sex-hormone related condition is endometriosis, polycystic ovarian disease, uterine fibroids or precocious puberty.  
   
   
       11 . A method for preventing pregnancy of a subject in need thereof, comprising administering an effective amount of a compound having the following structure:  
     
       
         
         
             
             
         
       
     
     or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, 
 wherein: 
 A is 0 or a bond;  
 n is 12, 3 or 4;  
 R 1  and R 2  are the same or different and independently hydrogen, alkyl substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, —C(R 8 )(═NR 9 ) or —C(NR 10 R 11 )(═NR 9 );  
 
 or R 1  and R 2  taken together with the nitrogen atom to which they are attached form a heterocycle or a substituted heterocycle;  
 R 3a  and R 3b  are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, alkoxy, alkylthio, alkylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, —COOR 12  or —CONR 10 R 11 ;  
 or R 3a  and R 3b  taken together with the carbon atom to which they are attached form a homocycle, substituted homocycle, heterocycle or substituted heterocycle;  
 or R 3a  and the carbon to which it is attached taken together with R 1  and the nitrogen to which it is attached form a heterocycle or substituted heterocycle;  
 R 4  is hydrogen, alkyl or substituted alkyl;  
 R 5  is arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl;  
 R 6  is aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 R 7  is hydrogen, alkyl or substituted alkyl;  
 R 8 , R 9 , R 10  and R 11  are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl; and  
 R 12  is hydrogen, alkyl or substituted alkyl.  
 
   
   
       12 . A method for treating lupus erythematosis, irritable bowel syndrome, premenstrual syndrome, hirsutism, short stature or sleep disorders of a subject in need thereof, comprising administering to the subject an effective amount of a compound having the following structure:  
     
       
         
         
             
             
         
       
     
     or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof. 
 wherein: 
 A is 0 or a bond;  
 n is 1, 2, 3 or 4;  
 R 1  and R 2  are the same or different and independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, —C(R 8 )(═NR 9 ) or —C(NR 10 R 11 )(═NR 9 );  
 or R 1  and R 2  taken together with the nitrogen atom to which they are attached form a heterocycle or a substituted heterocycle;  
 R 3a  and R 3b  are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, alkoxy, alkylthio, alkylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, —COOR 12  or —CONR 10 R 11 ;  
 or R 3a  and R 3b  taken together with the carbon atom to which they are attached form a homocycle, substituted homocycle, heterocycle or substituted heterocycle;  
 or R 3a  and the carbon to which it is attached taken together with R 1  and the nitrogen to which it is attached form a heterocycle or substituted heterocycle;  
 R 4  is hydrogen, alkyl or substituted alkyl;  
 
 R 5  is arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl; 
 R 6  is aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 R 7  is hydrogen, alkyl or substituted alkyl;  
 R 8 , R 9 , R 10  and R 11  are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl; and  
 R 12  is hydrogen, alkyl or substituted alkyl.