4-oxoquinazolin-3-yl benzamide derivatives for the treatment of cytokine diseases

Abstract

The invention concerns a compound of the Formula (I) wherein m is 1-2 and each R 1 is a group such as cyano halogeno, trifluoromethyl heterocyclyl and heterocyclyloxy; R 2 is trifluoromethyl or (1-6C)alkyl; R 3 is hydrogen or halogeno; and R 4 is isoxazolyl; or pharmaceutically-acceptable salts thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical conditions mediated by cytokines.

1 . A compound of the Formula I 
     
       
         
         
             
             
         
       
       wherein m is 0, 1 or 2; 
       R 1  is halogeno, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, (1-6C)alkyl, (1-6C)alkoxy, (2-6C)alkenyl, (2-6C)alkynyl, (2-6C)alkanoyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, hydroxy-(2-6C)alkoxy, amino-(2-6C)alkoxy, cyano-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, (1-6C)alkoxy-(2-6C)alkoxy, carbamoyl-(1-6C)alkoxy,  N -(1-6C)alkylcarbamoyl-(1-6C)alkoxy, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di[(1-6C)alkyl]amino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl,  N -(1-6C)alkylcarbamoyl-(1-6C)alkyl, hydroxy-(2-6C)alkylamino, cyano-(2-6C)alkylamino, halogeno-(2-6C)alkylamino, amino-(2-6C)alkylamino, (1-6C)alkoxy-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyl]amino-(2-6C)alkylamino, heteroaryl, heteroaryl-(1-6C)alkyl, heteroaryloxy, heteroaryl-(1-6C)alkoxy, heteroarylamino, heterocyclyl, heterocyclyl-(1-6C)alkyl, heterocyclyloxy, heterocyclyl-(1-6C)alkoxy and heterocyclylamino, 
       and wherein any aryl, heteroaryl or heterocyclyl group in a R 1  substituent may optionally bear 1 or 2 substituents selected from hydroxy, halogeno, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (3-6C)cycloalkyl-(1-6C)alkoxy, (1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl-(1-6C)alkyl,  N -(1-6C)alkylcarbamoyl,  N , N -di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, carboxy-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl, 
       and wherein any of the R 1  substituents defined hereinbefore which comprises a CH 2  group which is attached to 2 carbon atoms or a CH 3  group which is attached to a carbon or nitrogen atom may optionally bear on each said CH 2  or CH 3  group one or more substituents selected from halogeno, hydroxy, amino, trifluoromethyl, trifluoromethoxy, oxo, carboxy, carbamoyl, acetamido, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkoxy, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, halogeno-(1-6C)alkyl, (1-6C)alkoxy-(2-6C)alkoxy, (1-6C)alkoxycarbonyl, carbamoyl,  N -(1-6C)alkylcarbamoyl,  N , N -di-[(1-6C)alkyl]carbamoyl, (1-6C)sulphonyl, (1-6C)sulphamoyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl and heterocyclyloxy, 
       and wherein any heterocyclyl group in a R 1  substituent may optionally bear 1 or 2 oxo or thioxo substituents; 
       R 2  is halogeno, trifluoromethyl or (1-6C)alkyl; 
       R 3  is hydrogen, halogeno or (1-6C)alkyl; and 
       R 4  is isoxazolyl, and R 4  may be optionally substituted by one or more substituents selected from halogeno, hydroxy, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; 
       or a pharmaceutically-acceptable salt thereof. 
     
   
   
       2 . A compound of the Formula I according to  claim 1  wherein R 1  is amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyl]amino-(2-6C)alkylamino, aryl, aryl-(1-6C)alkyl, aryl-(1-6C)alkoxy, aryloxy, arylamino, heteroaryl, heteroaryl-(1-6C)alkyl, heteroaryloxy, heteroaryl-(1-6C)alkoxy, heteroarylamino, heterocyclyl, heterocyclyl-(1-6C)alkyl, heterocyclyloxy, heterocyclyl-(1-6C)alkoxy or heterocyclylamino,
 and wherein any aryl, heteroaryl or heterocyclyl group in a R 1  substituent may optionally bear 1 or 2 substituents selected from hydroxy, halogeno, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (3-6C)cycloalkyl-(1-6C)alkoxy, (1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl-(1-6C)alkyl,  N -(1-6C)alkylcarbamoyl,  N , N -di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, carboxy-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl,   and wherein any of the R 1  substituents defined hereinbefore which comprises a CH 2  group which is attached to 2 carbon atoms or a CH 3  group which is attached to a carbon atom may optionally bear on each said CH 2  or CH 3  group one or more substituents selected from hydroxy, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino,   and wherein any heterocyclyl group in a R 1  substituent may optionally bear 1 or 2 oxo or thioxo substituents;   or a pharmaceutically-acceptable salt thereof.   
   
   
       3 . A compound of the Formula I according to  claim 1  or  claim 2  wherein R 1  is heterocyclyl, heterocyclyl-(1-6C)alkyl, heterocyclyloxy, heterocyclyl-(1-6C)alkoxy or heterocyclylamino, and wherein any heterocyclyl group in a R 1  substituent may optionally bear 1 or 2 substituents selected from hydroxy, halogeno, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (3-6C)cycloalkyl-(1-6C)alkoxy, (1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl-(1-6C)alkyl,  N -(1-6C)alkylcarbamoyl,  N , N -di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, carboxy-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl,
 and wherein any of the R 1  substituents defined hereinbefore which comprises a CH 2  group which is attached to 2 carbon atoms or a CH 3  group which is attached to a carbon atom may optionally bear on each said CH 2  or CH 3  group one or more substituents selected from hydroxy, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino;   or a pharmaceutically-acceptable salt thereof.   
   
   
       4 . A compound of the Formula I according to any preceding claim wherein R 3  is hydrogen or halogeno; or a pharmaceutically-acceptable salt thereof. 
   
   
       5 . A compound of the Formula I according to any preceding claim wherein R 2  is (1-6C)alkyl; or a pharmaceutically-acceptable salt thereof. 
   
   
       6 . A compound of the Formula I according to any preceding claim wherein R 4  is isoxazolyl, and R 4  may be optionally substituted by one or more substituents selected from halogeno and (1-6C)alkyl; or a pharmaceutically-acceptable salt thereof. 
   
   
       7 . A compound of the Formula I according to  claim 1  wherein m is 1;
 R 1  is heterocyclyl or heterocyclyloxy,   and wherein any heterocyclyl group in a R 1  substituent may optionally bear 1 or 2 substituents selected from (1-6C)alkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl-(1-6C)alkyl and hydroxy-(1-6C)alkyl;   R 2  is methyl;   R 3  is hydrogen; and   R 4  is isoxazol-3-yl or isoxazol-5-yl; or a pharmaceutically-acceptable salt thereof.   
   
   
       8 . A compound of the Formula I according to  claim 1  selected from:
 N-isoxazol-3-yl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide;   N-isoxazol-5-yl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide;   3-[6-(4-isopropylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide;   3-[6-(4-ethylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide;   3-[6-(4-(2-methoxyethyl)piperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide;   N-isoxazol-3-yl-4-methyl-3-[4-oxo-6-(2-piperidin-1-ylethoxy)quinazolin-3(4H)-yl]benzamide;   3-[8-cyano-6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide;   3-[8-Cyano-6-(4-ethylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide;   3-[6-[4-(cyclopropylmethyl)piperazin-1-yl]-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide;   4-Methyl-N-(5-methylisoxazol-4-yl)-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide;   3-[6-{2-[Isopropyl(methyl)amino]ethoxy}-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide;   N-isoxazol-3-yl-4-methyl-3-[4-oxo-6-(2-pyrrolidin-1-ylethoxy)quinazolin-3 (4H)-yl]benzamide;   N-isoxazol-3-yl-4-methyl-3-[6-[2-(1,4-oxazepan-4-yl)ethoxy]-4-oxoquinazolin-3(4H)-yl]benzamide;   3-[6-[4-(Cyclobutyl)piperazin-1-yl]-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide;   3-[6-{2-[Dimethylamino]ethoxy}-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide;   3-[6-{[(3S)-1-Isopropylpyrrolidin-3-yl]oxy}-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide; and   N-isoxazol-3-yl-4-methyl-3-[6-(morpholin-4-ylmethyl)-4-oxoquinazolin-3(4H)-yl]benzamide;   or a pharmaceutically-acceptable salt thereof.   
   
   
       9 . A process for preparing a compound of the Formula I according to  claim 1 , or pharmaceutically-acceptable salt thereof which comprises:—
 reacting an  N -phenyl-2-aminobenzamide of the Formula II   
     
       
         
         
             
             
         
       
       with a carboxylic acid of the Formula III, or a reactive derivative thereof, 
     
     
       
         
         
             
             
         
       
       wherein m, R 1 , R 2 , R 3  and R 4  are as defined in  claim 1  and wherein any functional group is protected if necessary, and:
 (i) removing any protecting groups; and 
 (ii) optionally forming a pharmaceutically-acceptable salt. 
 
     
   
   
       10 . A pharmaceutical composition for use in the treatment of diseases mediated by cytokines which comprises a compound of the Formula I as claimed in any one of  claims 1  to  8 , or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier. 
   
   
       11 . A compound of the Formula I claimed in any one of  claims 1  to  8 , or a pharmaceutically-acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy. 
   
   
       12 . A method of treating diseases or medical conditions mediated by cytokines which comprises administering to a warm-blooded animal an effective amount of a compound of the Formula I claimed in any one of  claims 1  to  8 , or a pharmaceutically-acceptable salt thereof. 
   
   
       13 . A method of treating a disease or medical condition mediated by cytokines which comprises administering to a warm-blooded animal in need thereof a cytokine inhibiting amount of a compound of the Formula I claimed in any one of  claims 1  to  8 , or a pharmaceutically-acceptable salt thereof. 
   
   
       14 . A method of treating a disease or medical condition mediated by the production or effect of cytokines which comprises administering to a warm-blooded animal in need thereof a cytokine inhibiting amount of a compound of the Formula I claimed in any one of  claims 1  to  8 , or a pharmaceutically-acceptable salt thereof. 
   
   
       15 . A method of treating rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, inflammatory bowel disease, multiple sclerosis, AIDS, septic shock, congestive heart failure, ischaemic heart disease or psoriasis which comprises administering to a warm-blooded animal an effective amount of a compound of the Formula I claimed in any one of  claims 1  to  8 , or a pharmaceutically-acceptable salt thereof. 
   
   
       16 . A compound of the Formula I claimed in any one of  claims 1  to  8 , or a pharmaceutically-acceptable salt thereof, in the manufacture of a medicament. 
   
   
       17 . A compound of the Formula I claimed in any one of  claims 1  to  8 , or a pharmaceutically-acceptable salt thereof, in the manufacture of a medicament for use in the treatment of medical conditions mediated by cytokines. 
   
   
       18 . The use of a compound of the Formula I claimed in any one of  claims 1  to  8 , or a pharmaceutically-acceptable thereof, in the manufacture of a medicament for use in the treatment of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, inflammatory bowel disease, multiple sclerosis, AIDS, septic shock, congestive heart failure, ischaemic heart disease or psoriasis.