Gonadotropin-releasing hormone receptor antagonists and methods relating thereto

Abstract

GnRH 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 Ar, A, B, Q, R 1 , R 2 , R 3a , R 3b , R 6 , R 7 and m are as defined herein, including stereoisomers, prodrugs and pharmaceutical 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.

We claim:  
     
         1 . A compound having the following structure:  
       
         
           
           
               
               
           
         
       
       and stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, 
 wherein: 
 A is independently selected from N or CR 4;    
 B is independently selected from N or CR 5 ;  
 Q is a direct bond or —(CR 8a R 8b ) r -Z-(CR 10a R 10b ) s —;  
 m, r and s are the same or different and selected from an integer from 0 to 6;  
 Z is a direct bond or —O—, —S—, —NR 9 —, —SO—, —SO 2 —, —OSO 2 —, —SO 2 O—, —SO 2 NR 9 —, —NR 9 SO 2 —, —CO—, —COO—, —OCO—, —CONR 9 —, —NR 9 CO—, —NR 9 CONR 9a , —OCONR 9 — or —NR 9 COO—;  
 R 1  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —C(R 1a )(═NR 1b ), or —C(NR 1a R 1c )(═NR 1b );  
 R 2  is hydrogen, alkyl or substituted alkyl;  
 or R 1  and R 2  taken together with the nitrogen atom to which they are attached form a heterocycle ring or a substituted heterocycle ring;  
 R 3a  and R 3b  are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, heterocycle, heterocyclealkyl, hydroxy, alkoxy, alkylthio, alkylamino, CONR 14 R 15 , or —COOR 14 ;  
 or R 3a  and R 3b  taken together with the carbon atom to which they are attached form a 3-6 membered homocyclic ring, substituted homocyclic ring, heterocyclic ring or substituted heterocyclic ring;  
 or R 3a  and R 3b  taken together form ═NR 3c ;  
 R 4  is hydrogen, halogen, cyano, nitro, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, heterocyclealkyl, substituted heterocyclealkyl, —COR 11 , —COOR 11 , —CONR 12 R 13 , —OR 11 , —OCOR 11 , —OSO 2 R 11 , —SR 11 , —SO 2 R 11 , —NR 12 R 13 , —NR 11 COR 12 , —NR 11 CONR 12 R 13 , —NR 11 SO 2 R 12  or —NR 11 SO 2 NR 12 R 13 ; or R 4  and R 1 , together with the atoms to which they are attached, form a 5-7 member heterocyclic ring or substituted heterocyclic ring;  
 or R 4  and R 3a , together with the atoms to which they are attached, form a 5-7 membered homocyclic ring, substituted homocyclic ring, heterocyclic ring or substituted heterocyclic ring;  
 R 5  is hydrogen, halogen, lower alkyl, arylalkyl, alkoxy, alkylthio, alkylamino, cyano or nitro;  
 R 6  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;  
 R 7  is hydrogen, halogen, cyano, alkyl, substituted alkyl, alkoxy, alkylthio, alkylsulfonyl or alkylamino;  
 Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl; and  
 R 1a , R 1b , R 1c , R 3c , R 8a , R 8b , R 9 , R 9a , R 10a , R 10b , R 11 , R 12 , R 13  and R 14  are the same or different and at each occurrence independently hydrogen, acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl;  
 or R 1a  and R 1b , R 8a  and R 8b , R 10a  and R 10b , or R 12  and R 13  taken together with the atom or atoms to which they are attached form a homocyclic ring, substituted homocyclic ring, heterocyclic ring or substituted heterocyclic ring.  
 
 
     
     
         2 . The compound of  claim 1  wherein Q is a direct bond and having the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         3 . The compounds of  claim 1  wherein Q is —(CR 8a R 8b ) r -Z-(CR 10a R 10b ) s —.  
     
     
         4 . The compound of  claim 3  wherein r is zero.  
     
     
         5 . The compound of  claim 3  wherein s is zero.  
     
     
         6 . The compound of  claim 3  wherein Z is carbonyl.  
     
     
         7 . The compound of  claim 2  wherein A is CR 4 , B is nitrogen and having the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 2  wherein A is CR 4 , B is CR 5  and having the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 2  wherein A is N, B is CR 5  and having the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 2  wherein A is N, B is N and having the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1  wherein R 6  is arylalkyl or substituted arylalkyl.  
     
     
         12 . The compound of  claim 11  wherein R 6  is benzyl or substituted benzyl.  
     
     
         13 . The compound of  claim 1  wherein R 7  is alkyl.  
     
     
         14 . The compound of  claim 13  wherein R 7  is methyl.  
     
     
         15 . The compound of  claim 1  wherein R 5  is hydrogen.  
     
     
         16 . The compound of  claim 1  wherein R 5  is halogen, nitro or cyano.  
     
     
         17 . The compound of  claim 1  wherein R 4  is alkyl or substituted alkyl.  
     
     
         18 . The compound of  claim 1  wherein R 3a  and R 3b  are both hydrogen.  
     
     
         19 . The compound of  claim 1  wherein m is 1.  
     
     
         20 . The compound of  claim 1  wherein R 2  is alkyl.  
     
     
         21 . The compound of  claim 1  wherein R 1  is arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl.  
     
     
         22 . The compound of  claim 21  wherein R 1  is benzyl or substituted benzyl.  
     
     
         23 . The compound of  claim 21  wherein R 1  is —CH 2 (heteroaryl) or —CH 2 CH 2 (heteroaryl).  
     
     
         24 . The compound of  claim 1  wherein R 1  and R 2  taken together with the nitrogen atom to which they are attached form a heterocycle ring or substituted heterocycle ring.  
     
     
         25 . The compound of  claim 1  wherein the compound is: 
 3-(N-Benzyl-N-methyl)aminomethyl-2-(tert-butyl)-6-methyl-7-(2-fluorobenzyl)-5-(3-methoxyphenyl)imidazolo[1,2-a]pyrimid-4-one;  
 3-(N-(2-Pyridylmethyl))aminomethyl-2-(tert-butyl)-6-methyl-7-(2-fluorobenzyl)-5-(3-methoxyphenyl)imidazolo[1,2-a]pyrimid-4-one;  
 3-(N-(2-Pyridylmethyl)-N-methyl)aminomethyl-2-(tert-butyl)-6-methyl-7-(2-fluorobenzyl)-5-(3-methoxyphenyl)imidazolo[1,2-a]pyrimid-4-one;  
 3-[N-Methyl-N-(2-pyridylethyl)]aminomethyl-2-(tert-butyl)-6-methyl-7-(2-fluorobenzyl)-5-(3-methoxyphenyl)imidazolo[1,2-a]pyrimid-4-one;  
 3-[N-(2-Furanmethyl)-N-methyl]aminomethyl-2-(tert-butyl)-6-methyl-7-(2-fluorobenzyl)-5-(3-methoxyphenyl)imidazolo[1,2-a]pyrimid-4-one;  
 3-[N-Methyl-N-(2-pyridylethyl)]aminomethyl-2-(ethoxycarbonylmethyl)-6-methyl-7-(2-fluorobenzyl)-5-(3-methoxyphenyl)imidazolo [1,2-a]pyrimid-4-one;  
 1-(N-Benzyl-N-methyl)aminomethyl-2-(tert-butyl)-4-(2-fluorobenzyl)-6-(3-phenylpropylaminocarbonyl)pyrrolo[1,2-a]pyrimid-7-one;  
 1-[(N-Methyl-N-(2-pyridylethyl)]aminomethyl-2-(tert-butyl)-4-(2-fluorobenzyl)-6-(3-phenylpropylaminocarbonyl)pyrrolo[1,2-a]pyrimid-7-one;  
 1-[(N-Methyl-N-(2-pyridylethyl)] aminomethyl-2-(tert-butyl)-4-(2-fluorobenzyl)-5-methyl-6-(3-methoxyphenyl)pyrrolo [1,2-a]pyrimid-7-one;  
 3-(N-Benzyl-N-methyl)aminomethyl-2-(t-butyl)-4-(2-fluorobenzyl)-5-methyl-6-(3-methoxyphenyl)imidazolo[3,4-a]pyrimid-7-one;  
 1-[N-Methyl-N-(2-pyridylethyl)]aminomethyl-4-(2-fluorobenzyl)-5-methyl-6-(3-methoxyphenyl)imidazolo [3,4-a]pyrimid-7-one;  
 1-[N-(2-Furanmethyl)-N-methyl]aminomethyl-4-(2-fluorobenzyl)-5-methyl-6-(3-methoxyphenyl)imidazolo[3,4-a]pyrimid-7-one;  
 3-(N-Benzyl-N-methyl)aminomethyl-6-methyl-7-(2-fluorobenzyl)-5-(3-methoxyphenyl)-1,2,4-triazolo[4,3-a]pyrimid-4-one;  
 3-[N-Methyl-N-(2-pyridylethyl)]aminomethyl-6-methyl-7-(2-fluorobenzyl)-5-(3-methoxyphenyl)-1,2,4-triazolo[4,3-a]pyrimid-4-one;  
 3-[N-(2-Furanmethyl)-N-methyl]aminomethyl-6-methyl-7-(2-fluorobenzyl)-5-(3-methoxyphenyl)-1,2,4-triazolo[4,3-a]pyrimid-4-one;  
 1-(N-Benzyl-N-methyl)aminomethyl-2-(1-methoxycarbonyl-1-methylethyl)-7-(2-fluorobenzyl)-6-methyl-5-(3-methoxyphenyl)imidazolo [1,2-a]pyrimid-4-one; or  
 1-[N-(2-Pyridylethyl)-N-methyl]aminomethyl-2-(1-methoxycarbonyl-1-methylethyl)-7-(2-fluorobenzyl)-6-methyl-5-(3-methoxyphenyl)imidazolo[1,2-a]pyrimid-4-one.  
 
     
     
         26 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier or diluent.  
     
     
         27 . A method for antagonizing gonadotropin-releasing hormone in a subject in need thereof, comprising administering to the subject an effective amount of a compound of  claim 1 .  
     
     
         28 . A method for treating an sex-hormone related condition of a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition of  claim 26 .  
     
     
         29 . The method of  claim 28  wherein the sex-hormone related condition is cancer, benign prostatic hypertrophy or myoma of the uterus.  
     
     
         30 . The method of  claim 29  wherein the cancer is prostatic cancer, uterine cancer, breast cancer or pituitary gonadotroph adenomas.  
     
     
         31 . The method of  claim 28  wherein the sex-hormone related condition is endometriosis, polycystic ovarian disease, uterine fibroids or precocious puberty.  
     
     
         32 . A method for preventing pregnancy of a subject in need thereof, comprising administering an effective amount of the pharmaceutical composition of  claim 26 .  
     
     
         33 . 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 the pharmaceutical composition of  claim 26.