Novel IL-5 inhibiting 6-azauracil derivatives for marking and identifying receptors and imaging organs

Abstract

The present invention is concerned with the compounds of formula the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, p and q are 0, 1, 2, 3 or 4 and q is also 5; X is O, S, NR 3 or a direct bond; R 1 is hydrogen, hydroxy, halo, optionally substituted amino, optionally substituted C 1-6 alkyl, C 1-6 alkyloxy, C 3-7 cycloalkyl or aryl; R 2 is aryl, Het 1 , C 3-7 cycloalkyl, optionally substituted C 1-6 alkyl; and if X is O, S or NR 3 , then R 2 may also be a carbonyl or thiocarbonyl linked substituent; R 3 is hydrogen or C 1-4 alkyl; R 4 and R 5 independently are optionally substituted C 1-6 alkyl, halo, hydroxy, mercapto, C 1-6 alkyloxy, C 1-6 alkylthio, C 1-6 alkylcarbonyloxy, aryl, cyano, nitro, Het 3 , R 6 or NR 7 R 8 ; R 6 is substituted sulfonyl or sulfinyl; R 7 and R 8 are hydrogen, optionally substituted C 1-4 alkyl, aryl, a carbonyl or thiocarbonyl linked substituent, C 3-7 cycloalkyl, Het 3 and R 6 ; R 9 and R 10 are each independently selected from hydrogen, optionally substituted C 1-4 alkyl, phenyl, a carbonyl or thiocarbonyl linked substituent, C 3-7 cycloalkyl, Het 3 and R 6 ; R 11 is hydroxy, mercapto, cyano, nitro, halo, trihalomethyl, C 1-4 alkyloxy, carboxyl, C 1-4 alkyloxycarbonyl, trihaloC 1-4 alkylsulfonyloxy, R 6 , NR 7 R 8 , C(═O)NR 7 R 8 , aryl, aryloxy, arylcarbonyl, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, phthalimide- 2 -yl, Het 3 and C(═O)Het 3 ; R 12 and R 13 are each independently selected from hydrogen, optionally substituted C 1-4 alkyl, phenyl, a carbonyl or thiocarbonyl linked substituent, C 3-7 cycloalkyl and R 6 ; aryl is optionally substituted phenyl; Het 1 , Het 2 and Het 3 are optionally substituted heterocycles; to processes for their preparation and compositions comprising them. It further relates to their use as a medicine.

1 . A compound of formula  
       
         
           
           
               
               
           
         
       
       a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically-isomeric form thereof, wherein: 
 p represents an integer being 0, 1, 2, 3 or 4;  
 q represents an integer being 0, 1, 2, 3, 4 or 5;  
 X represents O, S, NR 3  or a direct bond;  
 R 1  represents hydrogen, hydroxy, halo, amino, mono- or di(C 1-4 alkyl)amino, C 1-6 alkyl, C 1-6 alkyloxy, C 3-7 cycloalkyl, aryl, arylC 1-6 alkyl, aminoC 1-4 alkyl, mono- or di(C 1-4 alkyl)aminoC 1-4 alkyl or mono- or di(C 1-4 alkyl)aminoC 1-4 alkylamino;  
 R 2  represents aryl, Het 1 , C 3-7 cycloalkyl, C 1-6 alkyl or C 1-6 alkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono- or di(C 1-4 alkyl)amino, C 1-6 alkyloxy, C 1-6 alkylsulfonyloxy, C 1-6 alkyloxycarbonyl, C 3-7 cycloalkyl, aryl, aryloxy, arylthio, Het 1 , Het 1 oxy and Het 1 thio; and if X is O, S or NR 3 , then R 2  may also represent aminocarbonyl, aminothiocarbonyl, C 1-4 alkylcarbonyl, C 1-4 alkylthiocarbonyl, arylcarbonyl or arylthiocarbonyl;  
 R 3  represents hydrogen or C 1-4 alkyl;  
 each R 4  independently represents C 1-6 alkyl, halo, polyhaloC 1-6 alkyl, hydroxy, mercapto, C 1-6 alkyloxy, C 1-6 alkylthio, C 1-6 alkylcarbonyloxy, aryl, cyano, nitro, Het 3 , R 6 , NR 7 R 8  or C 1-4 alkyl substituted with Het 3 , R 6  or NR 7 R 8 ;  
 each R 6  independently represents C 1-6 alkyl, halo, polyhaloC 1-6 alkyl, hydroxy, mercapto, C 1-6 alkyloxy, C 1-6 alkylthio, C 1-6 alkylcarbonyloxy, aryl, cyano, nitro, Het 3 , R 6 , NR 7 R 8  or C 1-4 alkyl substituted with Het 3 , R 6  or NR 7 R 8 ;  
 each R 6  independently represents C 1-6 alkylsulfonyl, aminosulfonyl, mono- or di(C 1-4 alkyl)aminosulfonyl, mono- or di(benzyl)aminosulfonyl, polyhaloC 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, phenylC 1-4 alkylsulfonyl, piperazinylsulfonyl, aminopiperidinylsulfonyl, piperidinylaminosulfonyl, N—C 14 alkyl-N-piperidinylaminosulfonyl;  
 each R 7  and each R 8  are independently selected from hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl, dihydroxyC 1-4 alkyl, aryl, arylC 1-4 alkyl, C 1-4 alkyloxyC 1-4 alkyl, C 1-4 alkylcarbonyl, arylcarbonyl, C 1-4 alkylcarbonyloxyC 1-4 alkylcarbonyl, hydroxyC 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonylcarbonyl, mono- or di(C 1-4 alkyl)aminoC 1-4 alkyl, arylaminocarbonyl, arylaminothiocarbonyl, Het 3 aminocarbonyl, Het 3 aminothiocarbonyl, C 3-7 cycloalkyl, pyridinylC 1-4 alkyl, Het 3  and R 6 ;  
 R 9  and R 10  are each independently selected from hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl, dihydroxyC 1-4 alkyl, phenyl, phenylC 1-4 alkyl, C 1-4 alkyloxyC 1-4 alkyl, C 1-4 alkylcarbonyl, phenylcarbonyl, C 1-4 akylcarbonyloxyC 1-4 alkylcarbonyl, hydroxyC 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonylcarbonyl, mono- or di(C 1-4 alkyl)aminoC 1-4 alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, Het 3 aminocarbonyl, Het 3 aminothiocarbonyl, C 3-7 cycloalkyl, pyridinylC 1-4 alkyl, Het 3  and R 6 ;  
 each R 11  independently being selected from hydroxy, mercapto, cyano, nitro, halo, trihalomethyl, C 1-4 alkyloxy, carboxyl, C 1-4 alkyloxycarbonyl, trihaloC 1-4 akylsulfonyloxy, R 6 , NR 7 R 8 , C(═O)NR 7 R 8 , aryl, aryloxy, arylcarbonyl, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, phthalimide-2-yl, Het 3  and C(═O)Het 3 ;  
 R 12  and R 13  are each independently selected from hydrogen, C 1-4 -alkyl, hydroxyC 1-4 alkyl, dihydroxyC 1-4 alkyl, phenyl, phenylC 1-4 alkyl, C 1-4 alkyloxyC 1-4 alkyl, C 1-4 alkylcarbonyl, phenylcarbonyl, C 1-4 alkylcarbonyloxyC 4 alkylcarbonyl, hydroxyC 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonylcarbonyl, mono- or di(C 1-4 alkyl)aminoC 1-4 alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, C 3-7 cycloalkyl, pyridinylC 1-4 alkyl and  
 aryl represents phenyl optionally substituted with one, two or three substituents each independently selected from nitro, azido, halo, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy, polyhaloC 1-4 alkyl, NR 9 R 10 , R 6 , phenyl, Het 3  and C 1-4 alkyl substituted with NR 9 R 10 ;  
 Het 1  represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl, imidazo[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het 2 , R 11  and C 1-4 alkyl optionally substituted with Het 2  or R 11 ;  
 Het 2  represents a monocyclic heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, dioxanyl, dithianyl, trithianyl and triazinyl; wherein said monocyclic heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from R 11  and C 1-4 alkyl optionally substituted with R 11 ;  
 Het 3  represents a monocyclic heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; wherein said monocyclic heterocycles each independently may optionally be substituted with, where possible, one, two or three substituents each independently selected from C 1-4 alkyl, C 1-4 alkyloxy, carboxyl, C 1-4 alkyloxycarbonyl; C 1-4 alkylcarbonyl, phenylC 1-4 alkyl, piperidinyl, NR 12 R 13 , R 6  and C 1-4 alkyl substituted with R 6  or NR 12 R 13 .  
 
     
     
         2 . A compound according to  claim 1  wherein R 1  is hydrogen, hydroxy, halo, amino, C 1-6 alkyl, C 1-6 alkyloxy or mono- or di(C 1-4 alkyl)aminoC 1-4 alkylamino.  
     
     
         3 . A compound according to  claim 1  or  2  wherein R 2  is aryl, Het 1 , C 3-7 cycloalkyl, or C 1-6 alkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono- or di(C 1-4 alkyl)amino, C 1-6 alkyloxy, C 1-6 alkylsulfonyloxy, C 1-6 alkyloxycarbonyl, C 3-7 cycloalkyl, aryl, aryloxy, arylthio, Het 1 , Het 1 oxy and Het 1 thio; and if X is O, S or NR 3 , then R 2  may also represent aminocarbonyl, aminothiocarbonyl, C 1-4 alkylcarbonyl, C 1-4 alkylthiocarbonyl, arylcarbonyl or arylthiocarbonyl.  
     
     
         4 . A compound according to any one of  claims 1  to  3  wherein the 6-azauracil moiety is in the para position relative to the central carbon atom.  
     
     
         5 . A compound according to any one of  claims 1  to  4  wherein q is 1 or 2 and one R 4  substituent is in the 4 position; and p is 1 or 2 and the one or two R 5  substituents are in the ortho position relative to the central carbon atom.  
     
     
         6 . A composition comprising a pharmaceutically acceptable, carrier and, as active ingredient, a therapeutically effective amount of a compound as claimed in any one of  claims 1  to  5 .  
     
     
         7 . A process for preparing a composition as claimed in  claim 6 , wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as defined in any one of  claims 1  to  5 .  
     
     
         8 . A compound as claimed in any one of  claims 1  to  5  for use as a medicine.  
     
     
         9 . Use of a compound as claimed in any one of  claims 1  to  5  in the manufacture of a medicament for treating eosinophil-dependent inflammatory diseases.  
     
     
         10 . A process for preparing a compound as claimed in  claim 1 , characterized by, 
 a) reacting an intermediate of formula (II) wherein W 1  is a suitable leaving group with an appropriate reagent of formula (III) optionally in a reaction-inert solvent and in the presence of a base;                          wherein R 1 , R 2 , R 4 , X and q are as defined in  claim 1 , and D represents                          wherein R 5  and p are defined as in  claim 1;     b) eliminating the group E of a triazinedione of formula (V)                          wherein R 1 , R 2 , R 4 , R 5 , X and q are as defined in  claim 1;     c) reacting a ketone of formula (X) with an intermediate of formula (III-a) in the presence of a base and in a reaction-inert solvent; thus obtaining a compound of formula (I-a-2);                          wherein R 2 , R 4  and q are as defined in  claim 1  and D is defined as in claim  9 a);    d) converting a compound of formula (I-a-2) to a compound of formula (I-a-3) using art-known group transformation reactions,                          wherein R 2 , R 4  and q are as defined in  claim 1  and D is defined as in claim  9 a);    e) converting a compound of formula (I-a-2) to a compound of formula (I-a4) using art-known group transformation reactions,                          wherein R 2 , R 4  and q are as defined in  claim 1  and D is defined as in claim  9 a);    f) converting a compound of formula (I-a-4) to a compound of formula (I-a-5) using art-known group transformation reactions,                          wherein R 2 , R 4  and q are as defined in  claim 1  and D is defined as in claim  9 a);    g) reacting an intermediate of formula (XII) wherein W 4  is a suitable leaving group with an intermediate of formula (III) optionally in the presence of a suitable base; thus obtaining a compounds of formula (I-b);                          wherein R 1 , R 4 , X and q are as defined in  claim 1  and D is defined as in claim  9 a);    h) reacting an intermediate of formula (XIV) with an intermediate of formula (XV) wherein W 3  is a suitable leaving group, in the presence of a suitable base and optionally in the presence of a reaction-inert solvent; thus obtaining a compound of formula (I-c);                          wherein R 4  and q are as defined in  claim 1  and D is defined as in claim  9 a);    i) cyclizing an-intermediate of formula (XX) wherein Y is O, S or NR 3 , to a compound of formula (I-d-1), in the presence of a suitable solvent at an elevated temperature;                          wherein R, R 1 , R 4  and q are as defined in  claim 1  and D is defined as in claim  9 a);    j) cyclizing an intermediate of formula (XXI) to a compound of formula (I-d-2) in a reaction-inert solvent at an elevated temperature,                          wherein R, R 1 , R 4  and q are as defined in  claim 1  and D is defined as in claim  9 a);    k) cyclizing an intermediate of formula (XXII) wherein Y is O, S or NR 3 , to a compound of formula (I-d-3), in a suitable solvent,                          wherein R, R 1 , R 4  and q are as defined in  claim 1  and D is defined as in claim  9 a);    l) cyclizing an intermediate of formula (XXIII) wherein Y is O, S or NR 3 , to a compound of formula (I-d-4), in a reaction-inert solvent and in the presence of an acid,                          wherein R, R 1 , R 4  and q are as defined in  claim 1  and D is defined as in claim  9 a);    m) cyclizing an intermediate of formula (XXIII) wherein Y is O, S or NR 3 , to a compound of formula (I-d-5), in a reaction-inert solvent and in the presence of an acid,                          wherein R, R 1 , R 4  and q are as defined in  claim 1  and D is defined as in claim  9 a);    n) reacting an intermediate of formula (XXIV) with an intermediate of formula (XXV) wherein Y is O, S or NR 3 , and W 5  is a suitable leaving group; thus forming a compound of formula (I-d-6) in a reaction-inert solvent and in the presnece of a base,                          wherein R, R 1 , R 4  and q are as defined in  claim 1  and D is defined as in claim  9 a);    o) reacting an intermediate of formula (XXVI) with an intermediate of formula (XXVII) wherein W 6  is a suitable leaving group; thus forming a compound of formula (I-d-7), in a reaction-inert solvent and in the presnece of an acid;                          wherein R, R 1 , R 4  and q are as defined in  claim 1  and D is defined as in claim  9 a);    p) reacting an intermediate of formula (XXXIII) with a thioamide of formula (XXXIV); thus forming a compound of formula (I-d-9) in a reaction-inert solvent at an elevated temperature;                          wherein R, R 1 , R 4  and q are as defined in  claim 1  and D is defined as in claim  9 a);    and if desired, converting compounds of formula (I) into each other following art-known transformations, and further, if desired, converting the compounds of formula (I), into a therapeutically active non-toxic acid addition salt by treatment with an acid, or into a therapeutically active non-toxic base addition salt by treatment with a base, or conversely, converting the acid addition salt form into the free base by treatment with alkali, or converting the base addition salt into the free acid by treatment with acid; and also, if desired, preparing stereochemically isomeric forms or N-oxide forms thereof.    
     
     
         11 . A process of marking a receptor comprising the steps of 
 a) radiolabelling a compound as defined in  claim 1;     b) administering said radiolabelled compound to biological material,    c) detecting the emissions from the radiolabelied compound.    
     
     
         12 . A process of imaging an organ, characterized by, administering a sufficient amount of a radiolabelled compound of formula (I) in an appropriate composition, and detecting the emissions from the radioactive compound.