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Details for Patent: 7,241,458

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Details for Patent: 7,241,458

Title:Antiviral compositions
Abstract: The present invention is concerned with pharmaceutical compositions of antiviral compounds which can be administered to a mammal, in particular a human, suffering from a viral infection. These compositions comprise particles obtainable by melt-extruding a mixture comprising one or more antiviral compounds and one or more appropriate water-soluble polymers and subsequently milling said melt-extruded mixture.
Inventor(s): Verreck; Geert (Malle, BE), Baert; Lieven (Bruges, BE)
Assignee: Janssen Pharmaceutica N.V. (BE)
Filing Date:Aug 31, 2000
Application Number:10/088,805
Claims:1. A particle consisting of a solid dispersion, comprising: (a) a compound of formula ##STR00053## a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein Y is CR.sup.5 or N; A is CH, CR.sup.4 or N; n is 0, 1, 2, 3 or 4; Q is --NR.sup.1R.sup.2 or when Y is CR.sup.5 then Q may also be hydrogen; R.sup.1 and R.sup.2 are each independently selected from hydrogen, hydroxy, C.sub.1-12alkyl, C.sub.1-12alkyloxy, C.sub.1-12alkylcarbonyl, C.sub.1-12alkyloxycarbonyl, aryl, amino, mono- or di(C.sub.1-12alkyl)amino, mono- or di(C.sub.1-12alkyl)aminocarbonyl wherein each of the aforementioned C.sub.1-12alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, C.sub.1-6alkyloxy, hydroxyC.sub.1-6alkyloxy, carboxyl, C.sub.1-6alkyloxycarbonyl, cyano, amino, imino, aminocarbonyl, aminocarbonylamino, mono- or di(C.sub.1-6alkyl)amino, aryl and Het; or R.sup.1 and R.sup.2 taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C.sub.1-12alkyl)aminoC.sub.1-4alkylidene; Het is an aliphatic or aromatic heterocyclic radical, wherein said aliphatic heterocyclic radical is optionally substituted with an oxo group and wherein said aromatic heterocyclic radical is optionally substituted with hydroxy; R.sup.3 is hydrogen, aryl, C.sub.1-6alkylcarbonyl, C.sub.1-6alkyl, C.sub.1-6 alkyloxycarbonyl, C.sub.1-6alkyl substituted with C.sub.1-6alkyloxycarbonyl; each R.sup.4 independently is hydroxy, halo, C.sub.1-6alkyl, C.sub.1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, or when Y is CR.sup.5 then R.sup.4 may also represent C.sub.1-6alkyl substituted with cyano or aminocarbonyl; R.sup.5 is hydrogen or C.sub.1-4alkyl; L is --X.sup.1--R.sup.6 or --X.sup.2-Alk-R.sup.7, wherein R.sup.6 and R.sup.7 each independently are phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkyloxy, C.sub.1-6 alkylcarbonyl, C.sub.1-6alkyloxycarbonyl, formyl, cyano, nitro, amino, and trifluoromethyl; or when Y is CR.sup.5 then R.sup.6 and R.sup.7 may also be selected from phenyl substituted with one, two, three, four or five substituents each independently selected from aminocarbonyl, trihalomethyloxy and trihalomethyl; or when Y is N then R.sup.6 and R.sup.7 may also be selected from indanyl or indolyl, each of said indanyl or indolyl may be substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkyloxy, C.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxycarbonyl, formyl, cyano, nitro, amino, and trifluoromethyl; X.sup.1 and X.sup.2 are each independently --NR.sup.3--, --NH--NH--, --N.dbd.N--, --O--, --S--, --S(.dbd.O)-- or --S(.dbd.O).sub.2--; Alk is C.sub.1-4alkanediyl; or when Y is CR.sup.5 then L may also be selected from C.sub.1-10alkyl, C.sub.3-10alkenyl, C.sub.3-10alkynyl, C.sub.3-7cycloalkyl, or C.sub.1-10alkyl substituted with one or two substituents independently selected from C.sub.3-7 cycloalkyl, indanyl, indolyl and phenyl, wherein said phenyl, indanyl and indolyl may be substituted with one, two, three, four or where possible five substituents each independently selected from halo, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkyloxy, cyano, aminocarbonyl, C.sub.1-6 alkyloxycarbonyl, formyl, nitro, amino, trihalomethyl, trihalomethyloxy and C.sub.1-6alkylcarbonyl; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C.sub.1-6alkyl, C.sub.1-6alkyloxy, cyano, nitro and trifluoromethyl; and (b) one or more pharmaceutically acceptable water-soluble polymers.

2. A particle according to claim 1 having a particle size of less than 1500 .mu.m.

3. A particle consisting of a solid dispersion, comprising: (a) a compound selected from the group consisting of 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile; 4-[[2-[(cyanophenyl)amino]-4-pyrimidinyl]amino]-3,5-dimethylbenzonitrile; and (b) one or more pharmaceutically acceptable water-soluble polymers.

4. A particle according to claim 1, wherein said compound (a) is 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile.

5. A particle according to claim 1, wherein said water-soluble polymer is a polymer that has an apparent viscosity of 1 to 5000 mPas when dissolved at 20.degree. C. in an aqueous solution at 2% (w/v).

6. A particle according to claim 5, wherein the water-soluble polymer is a polymer selected from the group consisting of: alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkyl alkylcelluloses, carboxyalkylcelluloses, alkali metal salts of carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters, starches, pectines, chitin derivatives, di-, oligo- or polysaccharides, polyacrylic acids and the salts thereof, polymethacrylic acids, the salts and esters thereof, methacrylate copolymers, polyvinylalcohol, and polyalkylene oxides.

7. A particle according to claim 6, wherein said water-soluble polymer is hydroxypropyl methylcellulose.

8. A particle according to claim 7, wherein the weight ratio of (a):(b) is in the range of 1:1 to 1:899.

9. A particle according to claim 1, consisting of a solid solution, comprising: (a) two parts by weight of said compound (a); and (b) three parts by weight of hydroxypropyl methylcellulose.

10. A particle according to claim 1, further comprising one or more pharmaceutically acceptable excipients.

11. A solid dispersion comprising: (a) a compound of formula ##STR00054## a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein Y is CR.sup.5 or N; A is CH, CR.sup.4 or N; n is 0, 1, 2, 3 or 4; Q is --NR.sup.1R.sup.2 or when Y is CR.sup.5 then Q may also be hydrogen; R.sup.1 and R.sup.2 are each independently selected from hydrogen, hydroxy, C.sub.1-12alkyl, C.sub.1-12alkyloxy, C.sub.1-12alkylcarbonyl, C.sub.1-12alkyloxycarbonyl, aryl, amino, mono- or di(C.sub.1-12alkyl)amino, mono- or di(C.sub.1-12alkyl)aminocarbonyl wherein each of the aforementioned C.sub.1-12alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, C.sub.1-6alkyloxy, hydroxyC.sub.1-6alkyloxy, carboxyl, C.sub.1-6alkyloxycarbonyl, cyano, amino, imino, aminocarbonyl, aminocarbonylamino, mono- or di(C.sub.1-6alkyl)amino, aryl and Het; or R.sup.1 and R.sup.2 taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C.sub.1-2alkyl)aminoC.sub.1-4alkylidene; R.sup.3 is hydrogen, aryl, C.sub.1-6alkylcarbonyl, C.sub.1-6alkyl, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkyl substituted with C.sub.1-6alkyloxycarbonyl; and each R.sup.4 independently is hydroxy, halo, C.sub.1-6alkyl, C.sub.1-6alkyloxy, cyano, amino-carbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, or when Y is CR.sup.5 then R.sup.4 may also represent C.sub.1-6alkyl substituted with cyano or aminocarbonyl; R.sup.5 is hydrogen or C.sub.1-4alkyl; L is --X.sup.1--R.sup.6 or --X.sup.2-Alk-R.sup.7 wherein R.sup.6 and R.sup.7 each independently are phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkyloxy, C.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxycarbonyl, formyl, cyano, nitro, amino, and trifluoromethyl; or when Y is CR.sup.5 then R.sup.6 and R.sup.7 may also be selected from phenyl substituted with one, two, three, four or five substituents each independently selected from aminocarbonyl, trihalomethyloxy and trihalomethyl; or when Y is N then R.sup.6 and R.sup.7 may also be selected from indanyl or indolyl, each of said indanyl or indolyl may be substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkyloxy, C.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxycarbonyl, formyl, cyano, nitro, amino, and trifluoromethyl; X.sup.1 and X.sup.2 are each independently --NR.sup.3--, --NH--NH--, --N.dbd.N--, --O--, --S--, --S(.dbd.O)-- or --S(.dbd.O).sub.2--; Alk is C.sub.1-4alkanediyl; or when Y is CR.sup.5 then L may also be selected from C.sub.1-10alkyl, C.sub.3-10alkenyl, C.sub.3-10alkynyl, C.sub.3-7cycloalkyl, or C.sub.1-10alkyl substituted with one or two substituents independently selected from C.sub.3-7cycloalkyl, indanyl, indolyl and phenyl, wherein said phenyl, indanyl and indolyl may be substituted with one, two, three, four or where possible five substituents each independently selected from halo, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkyloxy, cyano, aminocarbonyl, C.sub.1-6alkyloxycarbonyl, formyl, nitro, amino, trihalomethyl, trihalomethyloxy and C.sub.1-6alkylcarbonyl; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C.sub.1-6alkyl, C.sub.1-6alkyloxy, cyano, nitro and trifluoromethyl; Het is an aliphatic or aromatic hetercyclic radical, wherein said aliphatic heterocyclic radical is optionally substituted with an oxo group and wherein said aromatic heterocyclic radical is optionally substituted with hydroxyl; and (b) one or more pharmaceutically acceptable water-soluble polymers.

12. A solid dispersion according to claim 11, wherein the compound of formula (I-A) is a compound wherein Y is CR.sup.5 or N; A is CH, CR.sup.4 or N; n is 0, 1, 2, 3 or 4; Q is --NR.sup.1R.sup.2; R.sup.1 and R.sup.2 are each independently selected from hydrogen, hydroxy, C.sub.1-12alkyl, C.sub.1-12alkyloxy, C.sub.1-12alkylcarbonyl, C.sub.1-12alkyloxycarbonyl, aryl, amino, mono- or di(C.sub.1-12alkyl)amino, mono- or di(C.sub.1-12alkyl)aminocarbonyl wherein each of the aforementioned C.sub.1-12alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, C.sub.1-6alkyloxy, hydroxyC.sub.1-6alkyloxy, carboxyl, C.sub.1-6alkyloxycarbonyl, cyano, amino, imino, aminocarbonyl, aminocarbonylamino, mono- or di(C.sub.1-6alkyl)amino, aryl and Het; or R.sup.1 and R.sup.2 taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C.sub.1-12alkyl)aminoC.sub.1-4alkylidene; R.sup.3 is hydrogen, aryl, C.sub.1-6alkylcarbonyl, C.sub.1-6alkyl, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkyl substituted with C.sub.1-6alkyloxycarbonyl; each R.sup.4 independently is hydroxy, halo, C.sub.1-6alkyl, C.sub.1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy; R.sup.5 is hydrogen or C.sub.1-4alkyl; L is --X.sup.1--R.sup.6 or --X.sup.2-Alk-R.sup.7 wherein R.sup.6 and R.sup.7 each independently are phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkyloxy, C.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxycarbonyl, formyl, cyano, nitro, amino, and trifluoromethyl, X.sup.1 and X.sup.2 are each independently --NR.sup.3--, --NH--NH--, --N.dbd.N--, --O--, --S--, --S(.dbd.O)-- or --S(.dbd.O).sub.2--, and Alk is C.sub.1-4alkanediyl; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C.sub.1-6alkyl, C.sub.1-6alkyloxy, cyano, nitro and trifluoromethyl; Het is an aliphatic or aromatic heterocyclic radical; said aliphatic heterocyclic radical is selected from pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and tetrahydrothienyl wherein each of said aliphatic heterocyclic radical may optionally be substituted with an oxo group; and said aromatic heterocyclic radical is selected from pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein each of said aromatic heterocyclic radical may optionally be substituted with hydroxy.

13. A solid dispersion according to claim 11, wherein the compound of formula (I-A) is selected from 4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-2-pyrimidinyl]amino]benzonitri- le; 6-[(2,6-dichlorophenyl)methyl]-N2-(4-fluorophenyl)-2,4-pyrimidinediami- ne; 4-[[4-[(2,4-dichlorophenyl)methyl]-6-[(4-hydroxybutyl)amino]-2-pyrimid- inyl]amino]benzonitrile; 4-[[4-[(2,6-dichlorophenyl)methyl]-6-[(3-hydroxypropyl)amino]-2-pyrimidin- yl]amino]benzonitrile; N-[2-[(4-cyanophenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-4-pyrimidinyl]- -acetamide; N-[2-[(4-cyanophenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-4-pyrimidinyl]- -butanamide; 4-[[2-amino-6-(2,6-dichlorophenoxy)-4-pyrimidinyl]amino]benzonitrile; 4-[[4-[(2,6-dichlorophenyl)methyl]-6-[(2-hydroxy-2-phenylethyl)amino]-2-p- yrimidinyl]amino]benzonitrile; 4-[[4-[(2,6-dichlorophenyl)methyl]-6-[[3-(2-oxo-1-pyrrolidinyl)propyl]ami- no]-2-pyrimidinyl]amino]benzonitrile; 4-[[4-[(2,6-dichlorophenyl)methyl]-6-[[2-(2-hydroxyethoxy)ethyl]amino]-2-- pyrimidinyl]amino]benzontrile monohydrochloride; 4-[[4-[(2,6-dichlorophenyl)methyl]-6-[(2,3-dihydroxypropyl)amino]-2-pyrim- idinyl]amino]benzonitrile; 4-[[4-[(2,6-dichlorophenyl)methyl]-6-(hydroxyamino)-2-pyrimidinyl]amino]-- benzonitrile; 4-[[4-[(2-cyanoethyl)amino]-6-[(2,6-dichlorophenyl)methyl]-2-pyrimidinyl]- amino]-benzonitrile; 4-[[4-[(2,6-dichlorophenyl)methyl]-6-[[2-(1-pyrrolidinyl)ethyl]amino]-2-p- yrimidinyl]amino]benzonitrile; 4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-5-methyl-2-pyrimidinyl]amino]-- benzonitrile; N2-(4-bromophenyl)-6-[(2,6-dichlorophenyl)methyl]-5-methyl-2,4-pyrimidine- diamine; 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonit- rile; 4-[[2-[(2,4,6-trimethylphenyl)amino]-4-pyrimidinyl]amino]benzonitril- e; 4-[[4-[(2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile; 4-[[4-(2,4,6-trimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile; 4-[[4-[(2,6-dichlorophenyl)thio]-2-pyrimidinyl]amino]benzonitrile; 4-[[4-[[2,6-dibromo-4-(1-methylethyl)phenyl]amino]-2-pyrimidinyl]amino]-b- enzonitrile; 4-[[4-[[2,6-dichloro-4-(trifluoromethyl)phenyl]amino]-2-pyrimidinyl]amino- ]-benzonitrile; 4-[[4-[(2,4-dichloro-6-methylphenyl)amino]-2-pyrimidinyl]amino]benzonitri- le; 4-[[2-[(cyanophenyl)amino]-4-pyrimidinyl]amino]-3,5-dimethylbenzonitri- le; 4-[[4-[(2,4-dibromo-6-fluorophenyl)amino]-2-pyrimidinyl]amino]benzonit- rile; 4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-5-methyl-2-pyrimidinyl]am- ino]-benzeneacetonitrile; 4-[[4-[methyl(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitri- le; 4-[[4-[(2,4,6-trichlorophenyl)amino]-2-pyrimidinyl]amino]benzonitrile; 4-[[4-[(2,4,6-trimethylphenyl)thio]-2-pyrimidinyl]amino]benzonitrile; 4-[[4-[(2,4,6-trimethylphenyl)amino-2-pyrimidinyl]amino]benzonitrile; 4-[[4-amino-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonit- rile; 4-[[2-amino-6-[(2,4,6-trimethylphenyl)amino]-4-pyrimidinyl]amino]ben- zonitrile; 4-[[4-(2-bromo-4-chloro-6-methylphenoxy)-2-pyrimidinyl]amino]be- nzonitrile; 4-[[4-[(4-chloro-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitri- le; 3,5-dichloro-4-[[2-[(4-cyanophenyl)amino]-4-pyrimidinyl]amino]benzonit- rile; 4-[[4-[[2,6-dichloro-4-(trifluoromethoxy)phenyl]amino]-2-pyrimidinyl- ]amino]-benzonitrile; 4-[[4-[(2,4-dibromo-3,6-dichlorophenyl)amino]-2-pyrimidinyl]amino]benzoni- trile; 4-[[4-[(2,6-dibromo-4-propylphenyl]amino]-2-pyrimidinyl]amino]benzo- nitrile; 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzamid- e; 4-[[4-[(4-(1,1-dimethylethyl)-2,6-dimethylphenyl)amino]-2-pyrimidinyl]a- mino]-benzonitrile; 4-[[2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile; 4-[[4-[(4-chloro-2,6-dimethylphenyl)amino]-5-methyl-2-pyrimidinyl]amino]-- benzonitrile; 4-[[2-[(4-cyanophenyl)amino]-5-methyl-4-pyrimidinyl]amino]-3,5-dimethyl benzonitrile; 4-[[4-[[4-(1,1-dimethylethyl)-2,6-dimethylphenyl]amino]-5-methyl-2-pyrimi- dinyl]amino]benzonitrile; 4-[[4-[(4-bromo-2,6-dimethylphenyl)amino]-5-methyl-2-pyrimidinyl]amino]-b- enzonitrile; 4-[[5-methyl-4-[(2,4,6-trimethylphenyl)thio]-2-pyrimidinyl]amino]benzonit- rile; 4-[[4-[(2,6-dibromo-4-propylphenyl)amino]-5-methyl-2-pyrimidinyl]ami- no]-benzonitrile; 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzamide, N3-oxide; N2-(4-chlorophenyl)-N4-(2,4,6-trimethylphenyl)-2,4-pyrimidinedi- amine; 4-[[4-[[2,6-dibromo-4-(1-methylethyl)phenyl]amino]-5-methyl-2-pyrim- idinyl]amino]benzonitrile; 4-[[2-[(4-cyanophenyl)amino]-5-methyl-4-pyrimidinyl]amino]-3,5-dimethyl benzonitrile; 4-[[4-[(phenylmethyl)amino]-2-pyrimidinyl]amino]benzonitrile; 4-[[4-amino-6-(2,6-dimethylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile- ; 4-[[4-amino-6-[(2-chloro-6-methylphenyl)amino]-1,3,5-triazin-2-yl]amino]- benzonitrile; 4-[[4-amino-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]-be- nzonitrile; 4-[[4-(hydroxyamino)-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]- amino]-benzonitrile; 4-[[4-amino-6-[(2-ethyl-6-methylphenyl)amino]-1,3,5-triazin-2-yl]amino]be- nzonitrile; 4-[[4-amino-6-[(2,6-dichlorophenyl)thio]-1,3,5-triazin-2-yl]amino]benzoni- trile; 4-[[4-(hydroxyamino)-6-[(2,4,6-trichlorophenyl)amino]-1,3,5-triazin- -2-yl]amino]-benzonitrile; 4-[[4-amino-6-(2,4,6-trimethylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitr- ile; 4-[[4-(hydroxyamino)-6-(2,4,6-trimethylphenoxy)-1,3,5-triazin-2-yl]am- ino]-benzonitrile; 4-[[4-amino-6-[(2,4-dichloro-6-methylphenyl)amino]-1,3,5-triazin-2-yl]ami- no]-benzonitrile; 4-[[4-[(2,4-dichloro-6-methylphenyl)amino]-6-(hydroxyamino)-1,3,5-triazin- -2-yl]-amino]benzontrile; 4-[[4-(hydroxyamino)-6-(2,4,6-trichlorophenoxy)-1,3,5-triazin-2-yl]amino]- benzonitrile trifluoroacetate (1:1); 4-[[4-(4-acetyl-2,6-dimethylphenoxy)-6-amino-1,3,5-triazin-2-yl]amino]ben- zonitrile; 4-[[4-amino-6-(2,4,6-tribromophenoxy)-1,3,5-triazin-2-yl]amino]- benzonitrile; 4-[[4-amino-6-(4-nitro-2,6-dimethylphenoxy)-1,3,5-triazin-2-yl]amino]benz- onitrile; 4-[[4-amino-6-(2,6-dibromo-4-methylphenoxy)-1,3,5-triazin-2-yl]a- mino]benzonitrile; 4-[[4-amino-6-(4-formyl-2,6-dimethylphenoxy)-1,3,5-triazin-2-yl]amino]ben- zonitrile; 4-[[4-amino-6-[(2,4-dichlorophenyl)thio]-1,3,5-triazin-2-yl]ami- no]benzonitrile; 4-[[4-[(5-acetyl-2,3-dihydro-7-methyl-1H-inden-4-yl)oxy]-6-amino-1,3,5-tr- iazin-2-yl]amino]benzonitrile; 4-[[4-amino-6-[(4-bromo-2-chloro-6-methylphenyl)amino]-1,3,5-triazin-2-yl- ]amino]-benzonitrile; 4-[[4-amino-6-[(2-chloro-4,6-dimethylphenyl)amino]-1,3,5-triazin-2-yl]ami- no]-benzonitrile; 4-[[4-amino-6-[[2,4-dichloro-6-(trifluoromethyl)phenyl]amino]-1,3,5-triaz- in-2-yl]-amino]benzonitrile; 4-[[4-amino-6-[methyl(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]ami- no]-benzonitrile; 4-[[4-amino-6-[(2,6-dibromo-4-methylphenyl)amino]-1,3,5-triazin-2-yl]amin- o]-benzonitrile; 4-[[4-amino-6-[[2,6-dibromo-4-(1-methylethyl)phenyl]amino]-1,3,5-triazin-- 2-yl]-amino]benzonitrile; a N-oxide, a pharmaceutically acceptable addition salt thereof.

14. A solid dispersion according to claim 13, wherein the compound of formula (I-A) is 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile; a N-oxide, or a pharmaceutically acceptable addition salt thereof.

15. A solid dispersion according to claim 13, wherein the compound of formula (I-A) is 4-[[2-[(cyanophenyl)amino]-4-pyrimidinyl]amino]-3,5-dimethylbenzonitrile;- a N-oxide, or a pharmaceutically acceptable addition salt thereof.

16. A solid dispersion according to any one of claims 11 15, wherein the water-soluble polymer is a polymer that has an apparent viscosity of 1 to 5000 mPas when dissolved at 20.degree. C. in an aqueous solution at 2% (w/v).

17. A solid dispersion according to any one of claims 11 15, wherein the water-soluble polymer is selected from the group comprising alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkyl alkylcelluloses, carboxyalkylcelluloses, alkali metal salts of carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters, starches, pectines, chitin derivates, di-, oligo- or polysaccharides, polyacrylic acids and the salts thereof, polymethacrylic acids, the salts and esters thereof, methacrylate copolymers, polyvinylalcohol, polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide.

18. A solid dispersion according to claim 17, wherein the water-soluble polymer is selected from the group comprising methylcellulose; hydroxymethylcellulose; hydroxyethylcellulose; hydroxypropylcellulose; hydroxybutylcellulose; hydroxyethyl methylcellulose; hydroxypropyl methylcellulose; carboxymethylcellulose; sodium carboxymethylcellulose; carboxymethylethylcellulose; sodium carboxymethylamylopectine; chitosan; trehalose; cyclodextrins or a derivative thereof, alginic acid, alkali metal and ammonium salts thereof, carrageenans; galactomannans; tragacanth; agar--agar; gummi arabicum; guar gummi; xanthan gummi; polyethylene oxide; polypropylene oxide; and copolymers of ethylene oxide and propylene oxide.

19. A solid dispersion according to claim 17, wherein the water-soluble polymer is selected from Eudragit E.RTM. and hydroxypropyl methylcellulose.

20. A solid dispersion according to any one of claim 17, wherein the water-soluble polymer is an aminoalkyl methacrylate copolymer.

21. A solid dispersion according to any one of claim 17, wherein the water-soluble polymer is hydroxypropyl methylcellulose.

22. A solid dispersion according to claim 21 wherein the hydroxypropyl methylcellulose has an apparent viscosity from about 1 to about 100 mPas when dissolved at 20.degree. C. in an aqueous solution at 2% (w/v).

23. A solid dispersion according to claim 22, wherein the hydroxypropyl methylcellulose has an apparent viscosity from about 3 to about 15 mPas when dissolved at 20.degree. C. in an aqueous solution at 2% (w/v).

24. A solid dispersion according to claim 23, wherein the hydroxypropyl methylcellulose has an apparent viscosity of about 5 mPas when dissolved at 20.degree. C. in an aqueous solution at 2% (w/v).

25. A solid dispersion according to claim 24, wherein the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose HPMC 2910 5 mPas.

26. A solid dispersion according to 11, wherein the weight-by-weight ratio of (a): (b) is in the range of 1:1 to 1:899.

27. A solid dispersion according to claim 26, wherein the weight-by-weight ratio of (a):(b) is in the range of 1:1 to 1:100.

28. A solid dispersion according to claim 27, wherein the weight-by-weight ratio of (a):(b) is in the range of 1:1 to 1:5.

29. A solid dispersion according to claim 28, wherein the weight-by-weight ratio of (a):(b) is in the range of from about 1:1 to about 1:3.

30. A solid dispersion according to claim 28, wherein the weight-by-weight ratio of (a):(b) is in the range of about 1:3 to about 1:5.

31. A solid dispersion according to claim 29 wherein the weight-by-weight ratio of (a):(b) is in the range of about 1:1 to about 1:1.5.

32. A solid dispersion according to claim 29 wherein the weight-by-weight ratio of (a):(b) is in the range of about 1:1.5 to about 1:3.
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