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.

1 - 24 . (canceled)  
     
     
         25 . A particle consisting of a solid dispersion comprising 
 (a) a compound of formula                          a 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) 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 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 —NR 1 —, —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 1-12 alkyloxycarbonyl, aryl, amino, mono- or di(C 1-12 alkyl)amino, mono- or di(C 1-12 alkyl)aminocarbonyl wherein each of the aforementioned C 1-12 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 1-12 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;    and    (b) one or more pharmaceutically acceptable water-soluble polymers.    
     
     
         26 . A particle according to claim  1  wherein the compound of formula (I-B) is a compound wherein -b 1 =b 2 -C(R 2a )=b 3 -b 4 =is a radical of formula (b-1); q is 0; R 2a  is cyano or —C(═O)NH 2 ; Y is cyano, —C(═O)NH 2  or a halogen; Q is hydrogen or —NR 4 R 5 ; L is —X—R 3  wherein R 3  is substituted phenyl.  
     
     
         27 . A particle according to claim  2  wherein the compound of formula (I-B) is a compound wherein R 2a  is cyano; Y is halo; Q is NH 2 ; L is X—R 3  wherein X is NR 1 , O or S, and R 3  is phenyl substituted with C 1-6 alkyl, halogen or cyano.  
     
     
         28 . A particle according to claim  1  wherein the compound of formula (I-B) is a compound wherein L is —X—R 3  wherein R 3  is 2,4,6-trisubstituted phenyl, each substituent independently selected from chloro, bromo, fluoro, cyano or C 1-4 alkyl.  
     
     
         29 . A particle according to claim  1  wherein the compound of formula (I-B) is a compound wherein Y is chloro or bromo and Q is hydrogen or amino.  
     
     
         30 . A particle according to claim  1  wherein the compound of formula (I-B) is a compound wherein the moiety in the 2 position of the pyrimidine ring is a 4-cyano-anilino group.  
     
     
         31 . A particle according to claim  1  wherein the compound of formula (I-B) is a compound wherein the moiety in the 2 position of the pyrimidine ring is a 4-cyano-anilino group, L is —X—R 3  wherein R 3  is a 2,4,6-trisubstituted phenyl, Y is a halogen and Q is hydrogen or NH 2 .  
     
     
         32 . A particle according to claim  1  wherein the compound of formula (I-B) is selected from 
 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-pyrimidinyl]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-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile; and    a N-oxide, a pharmaceutically acceptable addition salt or a quaternary amine thereof.    
     
     
         33 . A particle according to claim  1  wherein the water-soluble polymer is a polymer that has an apparent viscosity of 1 to 5000 mPa·s when dissolved at 20° C. in an aqueous solution at 2% (w/v).  
     
     
         34 . A particle according to claim  1  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.    
     
     
         35 . A particle according to  claim 34  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.  
     
     
         36 . A particle according to  claim 34  wherein the water-soluble polymer is selected from Eudragit E® and hydroxypropyl methylcellulose.  
     
     
         37 . A particle according to  claim 34  wherein the water-soluble polymer is an aminoalkyl methacrylate copolymer.  
     
     
         38 . A particle according to  claim 34  wherein the water-soluble polymer is hydroxypropyl methylcellulose.  
     
     
         39 . A particle according to  claim 38  wherein the hydroxypropyl methylcellulose has an apparent viscosity from about 1 to about 100 mPa·s when dissolved at 20° C. in an aqueous solution at 2% (w/v).  
     
     
         40 . A particle according to  claim 38  wherein the hydroxypropyl methylcellulose has an apparent viscosity from about 3 to about 15 mPa·s when dissolved at 20° C. in an aqueous solution at 2% (w/v).  
     
     
         41 . A particle according to  claim 38  wherein the hydroxypropyl methylcellulose has an apparent viscosity of about 5 mPa·s when dissolved at 20° C. in an aqueous solution at 2% (w/v).  
     
     
         42 . A particle according to  claim 38  wherein the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose HPMC 2910 5 mPa·s.  
     
     
         43 . A particle according to claim  1  wherein the weight-by-weight ratio of (a):(b) is in the range of 1:1 to 1:899.  
     
     
         44 . A particle according to  claim 43  wherein the weight-by-weight ratio of (a):(b) is in the range of 1:1 to 1:100.  
     
     
         45 . A particle according to  claim 44  wherein the weight-by-weight ratio of (a):(b) is in the range of 1:1 to 1:5.  
     
     
         46 . A particle according to  claim 42  wherein the weight-by-weight ratio of (a):(b) is in the range of from about 1:1 to about 1:3.  
     
     
         47 . A particle according to  claim 46  wherein the weight-by-weight ratio of (a):(b) is in the range of about 1:1.5.  
     
     
         48 . A particle according to claim  1  wherein the compound of formula (I-B) is in a non-crystalline phase.  
     
     
         49 . A particle as claimed in claim  1  wherein the solid dispersion is in the form of a solid solution comprising (a) and (b), or in the form of a dispersion wherein amorphous or microcrystalline (a) or amorphous or microcrystalline (b) is dispersed more or less evenly in a solid solution comprising (a) and (b).  
     
     
         50 . A particle as claimed in claim  1  having a particle size of less than 1500 μm.  
     
     
         51 . A particle as claimed in claim  1  having a particle size of less than 250 μm.  
     
     
         52 . A particle as claimed in claim  1  having a particle size of less than 125 μm.  
     
     
         53 . A particle as claimed in claim  1  further comprising one or more pharmaceutically acceptable excipients.  
     
     
         54 . A solid dispersion comprising 
 (a) a compound of formula (I-B) as defined in claim  1 ; and    (b) one or more pharmaceutically acceptable water-soluble polymers.    
     
     
         55 . A solid dispersion according to  claim 54  wherein the water soluble polymer is a polymer that has an apparent viscosity of 1 to 5000 mPa·s when dissolved at 20° C. in an aqueous solution at 2% (w/v).  
     
     
         56 . A solid dispersion according to  claim 54  wherein the weight-by-weight ratio of components (a):(b) is 1:1 to 1:899.  
     
     
         57 . A solid dispersion according to  claim 54  which is in the form of a solid solution comprising (a) and (b).  
     
     
         58 . A solid dispersion according to  claim 54  wherein the solid dispersion is in the form of a solid solution comprising (a) and (b), or in the form of a dispersion wherein amorphous or microcrystalline (a) or amorphous or microcrystalline (b) is dispersed more or less evenly in a solid solution comprising (a) and (b).  
     
     
         59 . A pharmaceutical dosage form comprising a therapeutically effective amount of particles as claimed in claim  1 .  
     
     
         60 . A dosage form according to  claim 59  which is a tablet.  
     
     
         61 . A dosage form according to  claim 60  for immediate release of a compound of formula (I-B) upon oral ingestion wherein said particles are homogeneously distributed throughout a mixture of a diluent and a disintegrant.  
     
     
         62 . A dosage form according to  claim 59  surrounded by a film-coat comprising a film-forming polymer, a plasticizer and optionally a pigment.  
     
     
         63 . A dosage form according to  claim 61  wherein the diluent is a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25), and the disintegrant is crospovidone or croscarmellose.  
     
     
         64 . A dosage form according to  claim 59  wherein the weight of said particles is at least 40% of the total weight of the dosage form.  
     
     
         65 . A dosage form according to  claim 59  containing from 200 to 400 mg of a compound of formula (I-B) per unit dosage form.  
     
     
         66 . A dosage form according to  claim 59  containing from 5 to 200 mg of a compound of formula (I-B) per unit dosage form.  
     
     
         67 . A process of preparing a particle according to claim  1  characterized by spray-drying of a solution of the components (a) and (b).  
     
     
         68 . A process of preparing a particle according to claim  1  characterized by blending the components (a) and (b), extruding said blend at a temperature in the range of 20-300° C. and grinding the extrudate, and optionally sieving the particles.  
     
     
         69 . A process of preparing a particle according to claim  1  characterized by milling or grinding a solid dispersion comprising (a) a compound of formula (I-B); and (b) one or more pharmaceutically acceptable polymers.  
     
     
         70 . A particle according to claim  1  consisting of a solid solution comprising two parts by weight of a compound of formula (I-B) and three parts by weight of hydroxypropyl methylcellulose HPMC 2910 5 mPa·s, obtainable by blending said components, extruding the blend at a temperature in the range of 20° C.-300° C., grinding the extrudate, and optionally sieving the thus obtained particles.  
     
     
         71 . A process of preparing a solid dispersion according to  claim 54  characterized by 
 (a) spray-drying of a solution of the components (a) and (b);    (b) preparing a solution of the components (a) and (b), pouring said solution onto a large surface so as to form a thin film, and evaporating the solvent therefrom; or    (c) melt-extruding the components (a) and (b).    
     
     
         72 . A process of preparing a pharmaceutical dosage form characterized by blending a therapeutically effective amount of particles according to claim  1  with pharmaceutically acceptable excipients and compressing said blend into tablets or filling said blend in capsules.  
     
     
         73 . Particles according to claim  1  for use in preparing a pharmaceutical dosage form for oral administration to a mammal suffering from a viral infection.  
     
     
         74 . Particles according to claim  1  for use in preparing a pharmaceutical dosage form for oral administration to a mammal suffering from a viral infection, wherein a single such dosage form can be administered once daily to said mammal.  
     
     
         75 . Use of particles according to claim  1  for the preparation of a pharmaceutical dosage form for oral administration to a mammal suffering from a viral infection.  
     
     
         76 . Use of particles according to claim  1  for the preparation of a pharmaceutical dosage form for oral administration to a mammal suffering from a viral infection, wherein a single such dosage form can be administered once daily to said mammal.  
     
     
         77 . A pharmaceutical package suitable for commercial sale comprising a container, an oral dosage form of a compound of formula (I-B) as claimed in  claim 54 , and associated with said package written matter.