N-oxides of n-phenyl-2-pyrimidine-amine derivatives

Abstract

The invention relates to N-phenyl-2-pyrimidine-amine derivatives derivatives in which at least one nitrogen atom carries an oxygen atom to form the corresponding N-oxides, to processes for the preparation thereof, to pharmaceutical compositions comprising those compounds, and to the use thereof in the preparation of pharmaceutical compositions for the therapeutic treatment of warm-blooded animals, including humans.

1 . A compound of formula I 
     
       
         
         
             
             
         
       
       wherein 
       R 1  is hydrogen or hydroxy, 
       R 2  is hydrogen, lower alkyl or hydroxy-lower alkyl, 
       A is —NR 5 R 6 , —CHR 5 R 6  or —OR 5 R 6 , 
       R 5 R 6  together is alkylene with four, five or six carbon atoms, oxa-lower alkylene with one oxygen and three or four carbon atoms, or aza-lower alkylene with one or two nitrogen and two, three or four carbon atoms wherein the nitrogen atom is unsubstituted or substituted by lower alkyl, hydroxy-lower alkyl, or acetyl, and wherein lower alkylene in each case may be partially or totally unsaturated and/or the carbon atoms of lower alkylene may be substituted by lower alkyl, hydroxyl, lower alkoxy or oxo group when lower alkylene is not totally unsaturated, and 
       wherein at least one nitrogen atom carries an oxygen atom to form the corresponding N-oxide or when no nitrogen atom carries an oxygen atom, A is substituted by oxo, 
       or a pharmaceutically acceptable salt of such a compound. 
     
   
   
       2 . A compound of formula I according to  claim 1 , wherein
 A is pyrrolidino, piperidyl, piperidino, piperazinyl, pyridyl, pyrrolidinyl, morpholino, lower alkylpiperazino, N-methylpiperazino, 4-methyl-3-oxo-1-piperazinyl, 3-oxo-1-piperazinyl, 1H-imidazolyl, 1H-2-methylimidazolyl, 1H-4-methylimidazolyl, 1H-2,4-dimethylimidazolyl, cyclohexyl or phenyl, optionally substituted by oxo on a ring carbon,   or a pharmaceutically acceptable salt of such a compound.   
   
   
       3 . A compound of formula I according to  claim 1 , wherein
 A is a piperazinyl group of the following formula A′   
     
       
         
         
             
             
         
       
       optionally substituted by oxo on a ring carbon, and 
       R 3  is hydrogen, lower alkyl or acetyl, 
       or a pharmaceutically acceptable salt of such a compound. 
     
   
   
       4 . A compound of formula I according to  claim 3 , wherein
 R 1  is hydrogen,   R 2  is hydrogen, methyl or hydroxymethyl,   R 3  is methyl or hydrogen,   or a pharmaceutically acceptable salt of such a compound.   
   
   
       5 . A compound of formula I according to  claim 1  which is 4-[(3-Oxo-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide, or a pharmaceutically acceptable salt thereof. 
   
   
       6 . A compound of formula I according to  claim 1  which is 4-[(4-Methyl-3-oxo-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide, or a pharmaceutically acceptable salt thereof. 
   
   
       7 . A compound of formula II 
     
       
         
         
             
             
         
       
       wherein 
       R 1  is hydrogen or hydroxy, 
       R 2  is lower alkyl or hydroxy-lower alkyl, 
       R 3  is hydrogen, methyl or acetyl, and 
       the stars indicate the nitrogen atoms which optionally carry an oxygen atom to form the corresponding N-oxides, 
       with the proviso that at least one of the three nitrogen atoms marked by a star carries an oxygen atom if R 1  is hydrogen, R 2  is methyl and R 3  is hydrogen or methyl, 
       or a salt thereof. 
     
   
   
       8 . A compound of formula II according to  claim 7 , wherein
 R 1  is hydrogen,   R 2  is methyl or hydroxymethyl,   R 3  is methyl, and   the stars indicate the nitrogen atoms which optionally carry an oxygen atom to form the corresponding N-oxides,   with the proviso that at least one of the three nitrogen atoms marked by a star carries an oxygen atom if R 2  is methyl,   or a salt thereof.   
   
   
       9 . A compound of formula II according to  claim 7 , wherein
 R 1  is hydrogen,   R 2  is hydroxy-lower alkyl,   R 3  is methyl, and   the stars indicate the nitrogen atoms which optionally carry an oxygen atom to form the corresponding N-oxides,   or a salt thereof.   
   
   
       10 . A compound of formula II according to  claim 8  which is 4-[(4-methyl-1-piperazinyl)-methyl]-N-[4-methyl-3-[[4-(1-oxido-3-pyridinyl-2-pyrimidinyl]-amino]-phenyl]-benzamide, or a pharmaceutically acceptable salt thereof. 
   
   
       11 . A compound of formula II according to  claim 8  which is 4-[(4-methyl-1-piperazinyl)-methyl]-N-{4-hydroxymethyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]-phenyl}-benzamide, or a pharmaceutically acceptable salt thereof. 
   
   
       12 . A compound according to  claim 1  in purified form, or a pharmaceutically acceptable salt thereof. 
   
   
       13 . A compound according to  claim 1  or a pharmaceutically acceptable salt thereof for use in a method for the therapeutic treatment of warm-blooded animals, including humans. 
   
   
       14 . A pharmaceutical composition for the treatment of a proliferative disorder in warm-blooded animals, including humans, comprising as an active ingredient a compound according to  claim 1  or a pharmaceutically acceptable salt of such a compound, together with a pharmaceutically acceptable carrier. 
   
   
       15 . Use of a compound according to  claim 1  or a pharmaceutically acceptable salt of such a compound for the preparation of a pharmaceutical composition for the treatment of a proliferative disorder. 
   
   
       16 . Use of a compound according to  claim 1  or a pharmaceutically acceptable salt of such a compound for the treatment of a proliferative disorder. 
   
   
       17 . A method of treating warm-blooded animals, including humans, which comprises administering to such a warm-blooded animal suffering from a proliferative disorder, in a dose effective against said disorder, a compound according to  claim 1  or a pharmaceutically acceptable salt of such a compound. 
   
   
       18 . A process for the preparation of a compound of formula II according to  claim 7  or a salt thereof characterized in that a compound of formula II 
     
       
         
         
             
             
         
       
       wherein R 1  and R 2  have the meanings as defined for a compound of formula I according to  claim 1  and the star indicates a nitrogen atom which optionally carries an oxygen atom, is reacted with a compound of formula III 
     
     
       
         
         
             
             
         
       
       wherein R 3  has the meanings as defined for a compound of formula I according to  claim 1  and the stars indicate the nitrogen atoms which optionally carry an oxygen atom; 
       and a compound thus obtained is optionally converted into a N-oxide of formula I with a suitable oxidizing agent; 
       whereby functional groups which are present in the compounds of formula II and III and are not intended to take part in the reaction, are present in protected form if necessary, and protecting groups that are present are cleaved, whereby the compounds of formula II and III may also exist in the form of salts provided that a salt-forming group is present and a reaction in salt form is possible; 
       and, if so desired, a compound of formula I thus obtained is converted into another compound of formula I, an obtained free compound of formula I is converted into a salt, an obtained salt of a compound of formula I is converted into the free compound or another salt, and/or a mixture of isomeric compounds of formula I is separated into the individual isomers.