Substituted quinazolines

Abstract

This invention relates to the discovery of 3- and 5-substituted analogues of the selective platelet lowering agent anagrelide with reduced potential for cardiovascular side-effects which should lead to improved patient compliance and safety in the treatment of myeloproliferative diseases. More specifically, the present invention relates to certain imidazoquinazoline derivatives which have utility as platelet lowering agents in humans. The compounds of the present invention function by inhibiting megakaryocytopoeisis and hence the formation of blood platelets.

1 . A compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof 
     
       
         
         
             
             
         
       
       wherein: 
       R 1 , R 2 , R 3  and R 4  independently represent hydrogen or a blocking group which functions to prevent metabolic reaction at the position of substitution; 
       or wherein R 1  and R 2 , and/or R 3  and R 4  together with the carbon to which they are attached form a blocking group which functions to directly or indirectly prevent metabolic reaction at the 3-position, the remainder of groups R 1  to R 4  being hydrogen; 
       R 5  is selected from the group comprising: fluoro, chloro, bromo and iodo; 
       R 6  is selected from the group comprising: fluoro, chloro, bromo and iodo; 
       R 7  and R 8  are independently selected from the group comprising: H; halo; cyano; C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, and C 1-6  haloalkoxy; and 
       R 9  is H, C 1-6  alkyl, or a Group I metal ion; 
       provided always that R 1 , R 2 , R 3  and R 4  are not all hydrogen, or that when one of R 1  and R 2  is methyl and R 3  and R 4  are hydrogen then other of R 1  and R 2  is not hydrogen. 
     
   
   
       2 . A compound according to  claim 1 , wherein R 1  and R 2  are independently selected from the group comprising: H; cyano; C 1-6  alkyl, SC 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl wherein said alkyl, alkenyl, alkynyl or cycloalkyl groups may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C 1-4  alkylsulphonyl and COOH; C 1-6  hydroxyalkyl; C 1-6  carboxyalkyl; and sulphide;
 or R 1  and R 2  together with the carbon to which they are attached form a C 3-8  carbocyclic ring may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C 1-4  haloalkyl, C 1-4  alkylsulphonyl and COOH;   or R 1  and R 2  together with the carbon to which they are attached represent a C 2-6  alkenyl or C 2-6  alkynyl group bound through a double bond to the ring to which it is attached and being optionally substituted by one to three groups independently selected from the group comprising: halo, hydroxyl, cyano, C 1-4  haloalkyl and COOH.   
   
   
       3 . A compound according to  claim 1 , wherein R 3  and R 4  are independently selected from the group comprising: H; cyano; C 1-6  alkyl, SC 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl wherein said alkyl, alkenyl, alkynyl or cycloalkyl groups may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C 1-4  alkylsulphonyl and COOH; C 1-6  hydroxyalkyl; C 1-6  carboxyalkyl; and sulphide;
 or R 3  and R 4  together with the carbon to which they are attached form a C 3-8  carbocyclic ring may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C 1-4  haloalkyl, C 1-4  alkylsulphonyl and COOH;   or R 3  and R 4  together represent a C 2-6  alkenyl or C 2-6  alkynyl group bound through a double bond to the ring to which it is attached and being optionally substituted by one to three groups independently selected from the group comprising: halo, hydroxyl, cyano, C 1-4  haloalkyl and COOH.   
   
   
       4 . A compound as claimed in  claim 1 , wherein R 3  is H or C 1-6  alkyl. 
   
   
       5 . A compound as claimed in  claim 1 , wherein R 4  is H or C 1-6  alkyl. 
   
   
       6 . A compound as claimed in  claim 1 , wherein R 5  is chloro. 
   
   
       7 . A compound as claimed in  claim 1 , wherein R 6  is chloro. 
   
   
       8 . A compound as claimed in  claim 1 , wherein R 7  is H. 
   
   
       9 . A compound as claimed in  claim 1 , wherein R 8  is H. 
   
   
       10 . A compound as claimed in  claim 1 , wherein R 9  is H. 
   
   
       11 . A compound as claimed in  claim 1 , wherein R 9  is methyl. 
   
   
       12 . A compound as claimed in  claim 1 , wherein R 9  is sodium. 
   
   
       13 . A compound as claimed in  claim 1 , wherein R 1  is an optionally substituted C 1-4  alkyl or C 3-8  cycloalkyl group. 
   
   
       14 . A compound as claimed in  claim 1 , wherein R 2  is an optionally substituted C 1-4  alkyl or C 3-8  cycloalkyl group. 
   
   
       15 . A compound as claimed in  claim 1 , wherein R 1  is methyl, cyclopropyl, CF 3  or CHF 2 . 
   
   
       16 . A compound as claimed in  claim 1 , wherein R 2  is methyl, cyclopropyl, CF 3  or CHF 2 . 
   
   
       17 . A compound as claimed in  claim 1 , wherein R 1  and R 2  together form an optionally substituted C 3-8  cycloalkyl group. 
   
   
       18 . A pharmaceutical composition comprising a compound of formula (I) as defined in  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable diluent or carrier, which may be adapted for oral, parenteral or topical administration. 
   
   
       19 . A method of treating myeloprolific diseases or generalised thrombotic diseases in a human, comprising administering to said human an effective amount of a compound of formula (I) as defined in  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing any of the foregoing. 
   
   
       20 . A method of reducing platelet count in a human, comprising administering to said human an effective amount of a compound of formula (I) as defined in  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing any of the foregoing.