Rate-controlled particles

Abstract

Rate-controlled particles, comprising compounds of the formula as a solid dispersion.

1 . (canceled) 
   
   
       2 . Particles according to  claim 16 , wherein the copolymer of N-vinylpyrrolidone is a copolymer with vinyl acetate. 
   
   
       3 . Particles according to  claim 16 , further comprising a surfactant. 
   
   
       4 . Particles according to  claim 3 , wherein the surfactant is a PEG-n-hydrogenated castor oil. 
   
   
       5 . Particles according to  claim 16 , wherein the surfactant is a low molecular weight poly-oxyethylene polyoxypropylene block copolymer. 
   
   
       6 . Particles according to  claim 16 , further comprising citric acid in amounts of up to 5% b.w. 
   
   
       7 . Particles according to  claim 16 , wherein the home- or copolymer of N-vinylpyrrolidone is used in amounts of from 40 to 70% b.w. of the total weight of the dosage form. 
   
   
       8 . Particles according to  claim 7 , wherein the homo- or copolymer of N-vinylpyrrolidone is used in amounts of from 50 to 65% b.w. 
   
   
       9 . Particles according to  claim 16 , wherein the controlled release is an instant release of the drug. 
   
   
       10 . Particles according to a  claim 16 , wherein the controlled release is a sustained release. 
   
   
       11 . Particles according to  claim 10 , further comprising hydroxypropyl methyl cellulose in amounts of from 5 to 10% b.w. 
   
   
       12 . Particles according to  claim 16 , obtained by forming a homogeneous mixture of the components in the form of a melt, extruding said mixture and shaping of the extrudate. 
   
   
       13 . Particles according to  claim 16 , comprising a compound selected from the group consisting of 
     4-[[4-amino-5-chloro-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]-amino]benzonitrile; 
     4-[[5-chloro-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile; 
     4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidin]amino]-benzonitrile; 
     4-[[4-amino-5-chloro-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile; 
     4-[[5-bromo-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]-amino]benzonitrile; 
     4-[[4-amino-5-chloro-6-[(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile; 
     4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile; 
     a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof. 
   
   
       14 . Pharmaceutical dosage form, comprising particles according to  claim 16 . 
   
   
       15 . Pharmaceutical dosage forms according to  claim 14 , further comprising one or more pharmaceutically acceptable excipients 
   
   
       16 . Rate-controlled release particles, comprising a compound of formula II 
     
       
         
         
             
             
         
       
     
     an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein
 -b 1 =b 2 -C(R 2a )=b 3 -b 4 =represents a bivalent radical of formula
   —CH═CH—C(R 2a )═CH—CH═  (b-1); 
   —N═CH—C(R 2a )═CH—CH═  (b-2); 
   —CH═N—C(R 2a )═CH—CH═  (b-3); 
   —N═CH—C(R 2a )═N—CH═  (b-4); 
   —N═CH—C(R 2a )═CH—N═  (b-5); 
   —CH═N-c(R 2a )═N—CH═  (b-6); 
   —N═N—C(R 2a )═CH—CH═  (b-7); 
 
 q is 0, 1, 2; or where possible q is 3 or 4; 
 R 1  is hydrogen, aryl, formyl, C 1-6 alkylcarbonyl, C 1-6 alkyl, C 1-6 alkyloxycarbonyl, C 1-6 alkyl substituted with formyl, C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl; 
 R 2a  is cyano, aminocarbonyl, mono- or di(methyl)aminocarbonyl, C 1-6 alkyl substituted with cyano, aminocarbonyl or mono- or di(methyl)aminocarbonyl, C 2-6 alkenyl substituted with cyano, or C 2-6 alkynyl substituted with cyano; 
 each R 2  independently is hydroxy, halo, C 1-6 alkyl optionally substituted with cyano or —C(═O)R 6 , C 3-7 cycloalkyl, C 2-6 alkenyl optionally substituted with one or more halogen atoms or cyano, C 2-6 alkynyl optionally substituted with one or more halogen atoms or cyano, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C 1-6 alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)R 6 , —NH—S(═O) p R 6 , —C(═O)R 6 , —NHC(═O)H, —C(═O)NHNH 2 , —NHC(═O)R 6 , —C(═NH)R 6  or a radical of formula 
 
     
       
         
         
             
             
         
       
     
     wherein each A independently is N, CH or CR 6 ;
 B is NH, O, S or NR 6 ; 
 p is 1 or 2; and 
 R 6  is methyl, amino, mono- or dimethylamino or polyhalomethyl; 
 L is C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-7 cycloalkyl, whereby each of said aliphatic group may be substituted with one or two substituents independently selected from 
 C 3-7 cycloalkyl, 
 indolyl or isoindolyl, each optionally substituted with one, two, three or four substituents each independently selected from halo, C 1-6 alkyl, hydroxy, C 1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, polyhalomethyl, polyhalomethyloxy and C 1-6 alkylcarbonyl, 
 phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromatic rings may optionally be substituted with one, two, three, four or five substituents each independently selected from the substituents defined in R 2 ; or 
 L is —X—R 3  wherein 
 R 3  is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromatic rings may optionally be substituted with one, two, three, four or five substituents each independently selected from the substituents defined in R 2 ; and 
 X is —NH—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)— or —S(═O) 2 —; 
 Q represents hydrogen, C 1-6 alkyl, halo, polyhaloC 1-6 alkyl or —NR 4 R 5 ; and 
 R 4  and R 5  are each independently selected from hydrogen, hydroxy, C 1-12 alkyl, C 1-12 alkyloxy, C 1-12 alkylcarbonyl, C 1-2 alkyloxycarbonyl, aryl, amino, mono- or di(C 1-12 alkyl)amino, mono- or di(C 1-2 alkyl)aminocarbonyl 
 wherein each of the aforementioned C 1-2 alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, C 1-6 alkyloxy, hydroxyc 1-6 alkyloxy, carboxyl, C 1-6 alkyloxycarbonyl, cyano, amino, imino, mono- or di(C 1-6 alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(O) p R 6 , —NH—S(═O) p R 6 , —C(═O)R 6 , —NHC(═O)H, —C(═O)NHNH 2 , —NHC(O)R 6 , —C(═NH)R 6 , aryl and Het; or 
 R 4  and R 5  taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C 1-2 alkyl)aminoC 1-4 -alkylidene; 
 Y represents hydroxy, halo, C 3-7 cycloalkyl, C 2-6 alkenyl optionally substituted with one or more halogen atoms, C 2-6 alkynyl optionally substituted with one or more halogen atoms, C 1-6 alkyl substituted with cyano or —C(═O)R 6 , C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C 1-6 alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O) p R 6 , —NH—S(═O) p R 6 , —C(═O)R 6 , —NHC(═O)H, —C(═O)NHNH 2 , —NHC(═O)R 6 , —C(NH)R 6  or aryl; 
 aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, cyano, nitro, polyhaloC 1-6 alkyl and polyhaloC 1-6 alkyloxy; 
 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, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein each of said aromatic heterocyclic radical may optionally be substituted with hydroxy, 
 
 as a solid dispersion in a polymeric matrix, wherein the polymeric matrix is consisting of a homo- or copolymer of N-vinylpyrrolidone.