Compounds Useful in Therapy

Abstract

Compounds of formula (I), or pharmaceutically acceptable derivatives thereof, wherein: R 1 represents H, C 1-6 alkyl, C 1-6 alkyloxy, C 3-8 cycloalkyl, or halo; R 2 represents H, C 1-6 alkyl (optionally substituted by R 3 ), phenyl (optionally substituted by CN), or Het; R 3 represents OH, CN, Het, —R 4 —C 1-6 alkyl, or CONR 5 R 6 ; R 4 represents —CO 2 —, or —O—; R 5 and R 6 independently represent H, C 1-6 alkyl (optionally substituted by OR 7 ) or C 3-8 cycloalkyl; R 7 represents H or C 1-6 alkyl; Het represents a five or six membered aromatic heterocyclic group containing (i) from one to four nitrogen heteroatom(s) or (ii) one or two nitrogen heteroatom(s) and one oxygen or one sulphur heteroatom or (iii) one or two oxygen or sulphur heteroatom(s), said heterocyclic group being optionally substituted by one or more groups selected from CN and C 1-6 alkyl; R 8 represents C 1-6 alkyl, C 1-6 alkyloxy, C 3-8 cycloalkyl, or halo; and R 9 and R 10 independently represent H, C 1-6 alkyl, C 1-6 alkyloxy, CN, CF 3 or halo; may be useful for treating endometriosis, uterine fibroids (leiomyomata), menorrhagia, adenomyosis, primary and secondary dysmenorrhoea (including symptoms of dyspareunia, dyschexia and chronic pelvic pain), or chronic pelvic pain syndrome.

1 . A method of treatment of a mammal to treat menorrhagia, adenomyosis, or chronic pelvic pain syndrome comprising treating said mammal with a therapeutically effective amount of a compound of formula (I), 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable derivative or composition thereof, wherein:
 R 1  represents H, C 1-6 alkyl, C 1-6 alkyloxy, C 3-8 cycloalkyl, or halo; 
 R 2  represents H, C 1-6 alkyl (optionally substituted by R 3 ), phenyl (optionally substituted by CN), or Het; 
 R 3  represents OH, CN, Het, —R 4 —C 1-6 alkyl, or CONR 5 R 6 ; 
 R 4  represents —CO 2 —, or —O—; 
 R 5  and R 6  independently represent H, C 1-6 alkyl (optionally substituted by OR 7 ) or C 3-8 cycloalkyl; 
 R 7  represents H or C 1-6 alkyl; 
 Het represents a five or six membered aromatic heterocyclic group containing (i) from one to four nitrogen heteroatom(s) or (ii) one or two nitrogen heteroatom(s) and one oxygen or one sulphur heteroatom or (iii) one or two oxygen or sulphur heteroatom(s), said heterocyclic group being optionally substituted by one or more groups selected from CN and C 1-6 alkyl; 
 R 8  represents C 1-6 alkyl, C 1-6 alkyloxy, C 3-8 cycloalkyl, or halo; 
 R 9  and R 10  independently represent H, C 1-6 alkyl, C 1-6 alkyloxy, CN, CF 3  or halo. 
 
   
   
       2 . A process for preparing a compound of formula (I), 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable derivative thereof, wherein:
 R 1  represents H, C 1-6 alkyl, C 1-6 alkyloxy, C 3-8 cycloalkyl, or halo; 
 R 2  represents H, C 1-6 alkyl (optionally substituted by R 3 ), phenyl (optionally substituted by CN), or Het; 
 R 3  represents OH, CN, Het, —R 4 —C 1-6 alkyl, or CONR 5 R 6 ; 
 R 4  represents —CO 2 —, or —O—; 
 R 5  and R 6  independently represent H, C 1-6 alkyl (optionally substituted by OR 7 ) or C 3-8 cycloalkyl; 
 R 7  represents H or C 1-6 alkyl; 
 Het represents a five or six membered aromatic heterocyclic group containing (i) from one to four nitrogen heteroatom(s) or (ii) one or two nitrogen heteroatom(s) and one oxygen or one sulphur heteroatom or (iii) one or two oxygen or sulphur heteroatom(s), said heterocyclic group being optionally substituted by one or more groups selected from CN and C 1-6 alkyl; 
 R 8  represents C 1-6 alkyl, C 1-6 alkyloxy, C 3-8 cycloalkyl, or halo; and 
 R 9  and R 10  independently represent H, C 1-6 alkyl, C 1-6 alkyloxy, CN, CF 3  or halo; 
 
     comprising condensing a compound of formula (II) with a compound of formula (V), or a salt or hydrate thereof, optionally in the presence of an acid or a base 
     
       
         
         
             
             
         
       
     
   
   
       3 . A process for making a compound of formula (I), 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable derivative thereof, wherein:
 R 1  represents H, C 1-6 alkyl, C 1-6 alkyloxy, C 3-8 cycloalkyl, or halo; 
 R 2  represents H, C 1-6 alkyl (optionally substituted by R 3 ), phenyl (optionally substituted by CN), or Het; 
 R 3  represents OH, CN, Het, —R 4 —C 1-6 alkyl, or CONR 5 R 6 ; 
 R 4  represents —CO 2 —, or —O—; 
 R 5  and R 6  independently represent H, C 1-6 alkyl (optionally substituted by OR 7 ) or C 3-8 cycloalkyl; 
 R 7  represents H or C 1-6 alkyl; 
 Het represents a five or six membered aromatic heterocyclic group containing (i) from one to four nitrogen heteroatom(s) or (ii) one or two nitrogen heteroatom(s) and one oxygen or one sulphur heteroatom or (iii) one or two oxygen or sulphur heteroatom(s), said heterocyclic group being optionally substituted by one or more groups selected from CN and C 1-6 alkyl; 
 R 8  represents C 1-6 alkyl, C 1-6 alkyloxy, C 3-8 cycloalkyl, or halo; and 
 R 9  and R 10  independently represent H, C 1-6 alkyl, C 1-6 alkyloxy, CN, CF 3  or halo; 
 
     comprising condensing a compound of formula (VI) with a compound of formula (V), or a salt or hydrate thereof, optionally in the presence of an acid or a base 
     
       
         
         
             
             
         
       
     
     wherein L 1  is suitable leaving group. 
   
   
       4 . A process for making a compound of formula (I), 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable derivative thereof, wherein:
 R 1  represents H, C 1-6 alkyl, C 1-6 alkyloxy, C 3-8 cycloalkyl, or halo; 
 R 2  represents H, C 1-6 alkyl (optionally substituted by R 3 ), phenyl (optionally substituted by CN), or Het; 
 R 3  represents OH, CN, Het, —R 4 —C 1-6 alkyl, or CONR 5 R 6 ; 
 R 4  represents —CO 2 —, or —O—; 
 R 5  and R 6  independently represent H, C 1-6 alkyl (optionally substituted by OR 7 ) or C 3-8 cycloalkyl; 
 R 7  represents H or C 1-6 alkyl; 
 Het represents a five or six membered aromatic heterocyclic group containing (i) from one to four nitrogen heteroatom(s) or (ii) one or two nitrogen heteroatom(s) and one oxygen or one sulphur heteroatom or (iii) one or two oxygen or sulphur heteroatom(s), said heterocyclic group being optionally substituted by one or more groups selected from CN and C 1-6 alkyl; 
 R 8  represents C 1-6 alkyl, C 1-6 alkyloxy, C 3-8 cycloalkyl, or halo; and 
 R 9  and R 10  independently represent H, C 1-6 alkyl, C 1-6 alkyloxy, CN, CF 3  or halo; 
 comprising condensing a compound of formula (VII), with a compound of formula (V), or a salt or hydrate thereof, optionally in the presence of an acid or a base 
 
     
       
         
         
             
             
         
       
     
     wherein L 2  is suitable leaving group. 
   
   
       5 . A pharmaceutical combination comprising a compound of formula (I), 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable derivative thereof, wherein:
 R 1  represents H, C 1-6 alkyl, C 1-6 alkyloxy, C 3-8 cycloalkyl, or halo; 
 R 2  represents H, C 1-6 alkyl (optionally substituted by R 3 ), phenyl (optionally substituted by CN), or Het; 
 R 3  represents OH, CN, Het, —R 4 —C 1-6 alkyl, or CONR 5 R 6 ; 
 R 4  represents —CO 2 —, or —O—; 
 R 5  and R 6  independently represent H, C 1-6 alkyl (optionally substituted by OR 7 ) or C 3-8 cycloalkyl; 
 R 7  represents H or C 1-6 alkyl; 
 Het represents a five or six membered aromatic heterocyclic group containing (i) from one to four nitrogen heteroatom(s) or (ii) one or two nitrogen heteroatom(s) and one oxygen or one sulphur heteroatom or (iii) one or two oxygen or sulphur heteroatom(s), said heterocyclic group being optionally substituted by one or more groups selected from CN and C 1-6 alkyl; 
 R 8  represents C 1-6 alkyl, C 1-6 alkyloxy, C 3-8 cycloalkyl, or halo; and 
 R 9  and R 10  independently represent H, C 1-6 alkyl, C 1-6 alkyloxy, CN, CF 3  or halo; 
 
     and a compound selected from:
 (i) a COX inhibitor, 
 (ii) a PDEV inhibitor, 
 (iii) a V1a receptor antagonist, 
 (iv) an alpha adrenergic receptor antagonist, 
 (v) a 5-alpha reductase inhibitor, 
 (vi) an estrogen receptor antagonist, 
 (vii) an alpha-2-delta ligand, or 
 (viii) an oxytocin receptor antagonist, or pharmaceutically acceptable salts or solvates thereof.