Hiv inhibiting pyrimidines derivatives

Abstract

This invention concerns HIV replication inhibitors of formula the N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and the stereochemically isomeric forms thereof; their use as a medicine, their processes for preparation and pharmaceutical compositions comprising them.

1 . A compound of the following formula 
       
         
           
           
               
               
           
         
         an N-oxide, a pharmaceutically acceptable acid addition salt, a quaternary amine, or a stereochemically isomeric form thereof, wherein 
         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, or C 1-6 alkylcarbonyloxy; or C 1-6 alkyloxyC 1-6 alkylcarbonyl substituted with C 1-6 alkyloxycarbonyl; 
         R 2′  is halo, C 1-6 alkyl, trihalomethyl, cyano, aminocarbonyl, or C 1-6 alkyl substituted with cyano or aminocarbonyl; 
         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 alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C 1-6 alkyl)amino, polyhalomethyl, 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 1  independently is N, CH or CR 6 ; and
 A 2  is NH, O, S or NR 6 ; 
 
         n′ is 0, 1, 2, 3 or 4; 
         X 1  is —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, C 1-4 alkanediyl, —CHOH—, —S—, —S(═O) p —, —X 2 —C 1-4 -alkanediyl-, or —C 1-4 alkanediyl-X 2 -; 
         X 2  is —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, or —S(═O) p —; 
         R 3  is NHR 13 ; NR 13 R 14 ; —C(═O)—NHR 13 ; —C(═O)—NR 13 R 14 ; —C(═O)—R 15 ; —CH═N—NH—C(═O)—R 16 ; C 1-6 alkyl substituted with NR 9 R 10 , —C(═O)—NR 9a R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 1-6 alkyl substituted with two or more substituents each independently selected from cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 1-6 alkyl substituted with one or more substituents each independently selected from cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7  and wherein 2 hydrogen atoms bound at the same carbon atom are replaced by C 1-4 alkanediyl; C 1-6 alkyl substituted with hydroxy and a second substituent selected from cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 1-6 alkyloxyC 1-6 alkyl optionally substituted with one or more substituents each independently selected from cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 2-6 alkenyl substituted with one or more substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 2-6 alkynyl substituted with one or more substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; —C(═N—O—R 8 )—C 1-4 alkyl; R 7  or —X 3 —R 7 ; with R 9a  representing hydroxy; C 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; amino; mono- or di(C 1-6 alkyl)amino; mono- or di(C 1-6 alkyl)aminocarbonyl, —CH(═NR 11 ) or R 7 , wherein each of the aforementioned C 1-6 alkyl groups in the definition of R 9a  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 1-4 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 , R 7 ; and wherein R 9a  may also be taken together with R 10  to form a bivalent radical of formula (d-1), (d-2), (d-3), (d-4), (d-5) or (d-6) as defined for R 9  and R 10 ; 
         X 3  is —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O) p —, —X 2 —C 1-4 alkanediyl-, —C 1-4 alkanediyl-X 2a -, —C 1-4 alkanediyl-X 2b —C 1-4 alkanediyl, or —C(═N—OR 8 )—C 1-4 alkanediyl-;
 with X 2a  being —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, or —S(═O) p —; and 
 with X 2b  being —NH—NH—, —N═N—, —C(═O)—, —S—, or —S(═O) p —; 
 
         R 4  is halo, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonyl, formyl, amino, mono- or di(C 1-4 alkyl)amino, or R 7 ; 
         m is 1, 2, 3 or 4; 
         R 5  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 or C 1-6 alkylcarbonyloxy; or C 1-6 alkyloxyC 1-6 alkylcarbonyl substituted with C 1-6 alkyloxycarbonyl; 
         R 6  is C 1-4 alkyl, amino, mono- or di(C 1-4 alkyl)amino, or polyhaloC 1-4 alkyl; 
         R 7  is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono or di(C 1-6 alkyl)aminoC 1-6 alkyl, formyl, C 1-6 alkylcarbonyl, C 3-7 cyclo alkyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, C 1-6 alkylthio, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, —CH(═N—O—R 8 ), R 7a , —X 3 —R 7a , and R 7a —C 1-4 alkyl; 
         R 7a  is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono or di(C 1-6 alkyl)aminoC 1-6 alkyl, formyl, C 1-6 alkylcarbonyl, C 3-7 cyclo alkyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, C 1-6 alkylthio, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, and —CH(═N—O—R 8 ); 
         R 8  is hydrogen, C 1-4 alkyl, aryl, or arylC 1-4 alkyl; 
         R 9  and R 10  each independently are hydrogen; hydroxy; C 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; amino; mono- or di(C 1-6 alkyl)amino; mono- or di(C 1-6 alkyl)aminocarbonyl; —CH(═NR 11 ); or R 7 ; wherein each of the aforementioned C 1-6 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 1-4 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 , and R 7 ; or 
         R 9  and R 10  may be taken together to form a bivalent radical of formula
   —CH 2 —CH 2 —CH 2 —CH 2 —  (d-1),
 
   —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —  (d-2),
 
   —CH 2 —CH 2 —O—CH 2 —CH 2 —  (d-3),
 
   —CH 2 —CH 2 —S—CH 2 —CH 2 —  (d-4),
 
   —CH 2 —CH 2 —NR 12 —CH 2 —CH 2 —  (d-5),
 
   —CH 2 —CH═CH—CH 2 —  (d-6);
 
 
         R 11  is cyano; C 1-4 alkyl optionally substituted with C 1-4 alkyloxy, cyano, amino, mono- or di(C 1-4 alkyl)amino or aminocarbonyl; C 1-4 alkylcarbonyl; C 1-4 alkyloxycarbonyl; aminocarbonyl; or mono- or di(C 1-4 alkyl)aminocarbonyl; 
         R 12  is hydrogen or C 1-4 alkyl; 
         R 13  and R 14  each independently are C 1-6 alkyl optionally substituted with cyano or aminocarbonyl, C 2-6 alkenyl optionally substituted with cyano or aminocarbonyl, or C 2-6 alkynyl optionally substituted with cyano or aminocarbonyl; 
         R 15  is C 1-6 alkyl substituted with cyano or aminocarbonyl; 
         R 16  is C 1-6 alkyl optionally substituted with cyano or aminocarbonyl, or R 7 ; 
         p is 1 or 2; 
         aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono or di(C 1-6 alkyl)aminoC 1-6 alkyl, C 1-6 alkylcarbonyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, C 1-6 alkylthio, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, R 7 , and -X 3 -R 7 . 
       
     
     
         2 . A compound according to  claim 1  wherein
 R 3  is C 1-6 alkyl substituted with NR 9 R 10  or R 7 ; C 1-6 alkyl substituted with two or more substituents selected from cyano, aminocarbonyl, NR 9 R 10  or R 7 ; C 1-6 alkyl substituted with at least one substituent selected from cyano, aminocarbonyl, NR 9 R 10  or R 7  and wherein 2 hydrogen atoms bound at the same carbon atom are replaced by C 1-4 alkanediyl; C 1-6 alkyl substituted with hydroxy and a second substituent selected from cyano, aminocarbonyl, NR 9 R 10  or R 7 ; C 1-6 alkyloxyC 1-6 alkyl substituted with at least one substituent selected from cyano, aminocarbonyl, NR 9 R 10  or R 7 ; C 2-6 alkenyl substituted with at least one substituent selected from cyano, aminocarbonyl, NR 9 R 10  or R 7 ; C 2-6 alkynyl substituted with at least one substituent selected from cyano, aminocarbonyl, NR 9 R 10  or R 7 ; —C(═N—O—R 8 )—C 1-4 alkyl; R 7  or -X 3 -R 7 ; 
 R 4  is halo, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonyl, formyl, amino, mono- or di(C 1-4 alkyl)amino; 
 R 7  is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono or di(C 1-6 alkyl)aminoC 1-6 alkyl, C 1-6 alkylcarbonyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, C 1-6 alkylthio, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, R 7a , —X 3 —R 7a  or R 7a —C 1-4 alkyl; 
 R 7a  is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono or di(C 1-6 alkyl)aminoC 1-6 alkyl, C 1-6 alkylcarbonyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, C 1-6 alkylthio, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy or aminocarbonyl; 
 R 9  and R 10  each independently are hydrogen; hydroxy; C 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; amino; mono- or di(C 1-6 alkyl)amino; mono- or di(C 1-6 alkyl)aminocarbonyl or R 7 , wherein each of the aforementioned C 1-6 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 1-4 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 R 7 . 
 
     
     
         3 . A compound according to  claim 1  wherein R 2′  is cyano, aminocarbonyl, or C 1-6 alkyl substituted with cyano or aminocarbonyl. 
     
     
         4 . A pharmaceutical composition comprising as an active ingredient a compound as claimed in  claim 1 . 
     
     
         5 . A process for preparing a pharmaceutical composition according to  claim 4 , comprising mixing a therapeutically effective amount of said compound with a pharmaceutically acceptable carrier. 
     
     
         6 . A pharmaceutical composition according to  claim 4 , further comprising a pharmaceutically acceptable carrier. 
     
     
         7 . A compound according to  claim 1  wherein R 3  is —CH═N—NH—C(═O)—R 16 ; C 1-6 alkyl substituted with NR 9 R 10 , —C(═O)—NR 9a R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 1-6 alkyl substituted with two or more substituents each independently selected from cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 1-6 alkyl substituted with one or more substituents each independently selected from cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7  and wherein 2 hydrogen atoms bound at the same carbon atom are replaced by C 1-4 alkanediyl; C 1-6 alkyl substituted with hydroxy and a second substituent selected from cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 1-6 alkyloxyC 1-6 alkyl optionally substituted with one or more substituents each independently selected from cyano, NR 9 R 10 ), —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 2-6 alkenyl substituted with one or more substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 2-6 alkynyl substituted with one or more substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; —C(═N—O—R 8 )—C 1-4 alkyl; R 7  or —X 3 —R 7 ; with R 9a  representing hydroxy; C 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; amino; mono- or di(C 1-6 alkyl)amino; mono- or di(C 1-6 alkyl)aminocarbonyl, —CH(═NR 11 ) or R 7 , wherein each of the aforementioned C 1-6 alkyl groups in the definition of R 9a  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 1-4 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 , R 7 ; and wherein R 9a  may also be taken together with R 10  to form a bivalent radical of formula (d-1), (d-2), (d-3), (d-4), (d-5) or (d-6) as defined for R 9  and R 10 . 
     
     
         8 . A compound according to  claim 1  wherein R 3  is C 2-6 alkenyl substituted with cyano. 
     
     
         9 . A compound according to  claim 1  wherein R 3  is R 7 ; C 1-6 alkyl substituted with cyano and R 7 ; C 2-6 alkenyl substituted with cyano and R 7 ; C 1-6 alkyl substituted with R 7 ; —C(═N—O—R 8 )—C 1-4 alkyl; C 1-6 alkyl substituted with hydroxy and a second substituent selected from cyano or R 7 . 
     
     
         10 . A compound according to  claim 1  wherein R 3  is R 7 , NR 13 R 14 , —C(═O)R 15 , —CH═N—NH—C(═O)R 16 , —C(═O)NHR 13 , —C(═O)NR 13 R 14 , —C(═N—OR 8 )—C 1-4 alkyl, C 1-6 alkyl substituted twice with cyano, C 1-6 alkyl substituted with NR 9 R 10 , C 1-6 alkyl substituted with hydroxy and cyano, C 1-6 alkyl substituted with hydroxy and R 7 , C 1-6 alkyloxy C 1-6 alkyl, C 1-6 alkyloxy C 1-6 alkyl substituted with cyano, C 2-6 alkenyl substituted with R 7 , C 2-6 alkenyl substituted with cyano, C 2-6 alkenyl substituted twice with cyano, C 2-6 alkenyl substituted with cyano and R 7 , C 2-6 alkenyl substituted with cyano and —C(═O)—C 1-6 alkyl, C 2-6 alkenyl substituted with cyano and halo, C 2-6 alkenyl substituted with —C(═O)—NR 9 R 10 , C 2-6 alkenyl substituted with halo, C 2-6 alkenyl substituted twice with halo or C 2-6 alkenyl substituted with NR 9 R 10 . 
     
     
         11 . A compound according to  claim 1  wherein R 2′  is cyano or aminocarbonyl. 
     
     
         12 . A compound according to  claim 1  wherein R 2′  is cyano. 
     
     
         12 . A compound according to  claim 1  wherein X 3  is —C(═O)—, —CH 2 —C(═O)—, or —C(═N—OR 8 )—C 1-4 alkanediyl-. 
     
     
         14 . A compound according to  claim 1  wherein n′ is 0. 
     
     
         15 . A compound according to  claim 1  wherein m is 2. 
     
     
         16 . A compound according to  claim 1  wherein R 4  is C 1-6 alkyl; nitro; amino; halo; C 1-6 alkyloxy or R 7 . 
     
     
         17 . A compound according to  claim 1  wherein R 4  is C 1-6 alkyl. 
     
     
         18 . A compound according to  claim 1  wherein R 4  is methyl. 
     
     
         19 . A compound according to  claim 1  wherein X 1  is NH or O. 
     
     
         20 . A compound according to  claim 1  wherein X 1  is NH. 
     
     
         21 . A compound according to  claim 1  wherein R 1  is hydrogen or C 1-4 alkyl. 
     
     
         22 . A compound according to  claim 1  wherein R 1  is hydrogen. 
     
     
         23 . A pharmaceutical composition according to  claim 4  wherein said compound is in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm. 
     
     
         24 . A composition according to  claim 23  wherein the surface modifier is a non-ionic or anionic surfactant. 
     
     
         25 . A solid dispersion comprising:
 (a) a compound according to  claim 1 ; and   (b) one or more pharmaceutically acceptable water-soluble polymers.   
     
     
         26 . A solid dispersion according to  claim 25  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). 
     
     
         27 . A solid dispersion according to  claim 25  wherein the water-soluble polymer is a polymer that has an apparent viscosity of 1 to 700 mPa·s when dissolved at 20° C. in an aqueous solution at 2% (w/v). 
     
     
         28 . A solid dispersion according to  claim 25  wherein the water-soluble polymer is a polymer that has an apparent viscosity of 1 to 100 mPa·s when dissolved at 20° C. in an aqueous solution at 2% (w/v). 
     
     
         29 . A solid dispersion according to  claim 25  wherein the water-soluble polymer is selected from alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkyl alkylcelluloses, carboxyalkylcelluloses, alkali metal salts of carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters, starches, pectines, chitin derivates, di-, oligo- and polysaccharides, alginic acid or alkali metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar-agar, gummi arabicum, guar gummi and xanthan gummi, polyacrylic acids and the salts thereof, polymethacrylic acids and the salts thereof, methacrylate copolymers, polyvinylalcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, combinations of polyvinylalcohol and polyvinylpyrrolidone, polyalkylene oxides, copolymers of ethylene oxide and propylene oxide, cyclodextrins. 
     
     
         30 . A solid dispersion according to  claim 25  wherein the water-soluble polymer is hydroxypropyl methylcellulose. 
     
     
         31 . A solid dispersion according to  claim 25  wherein the ratio of components (a):(b) varies between 1/100 to 100/1. 
     
     
         32 . A solid dispersion according to  claim 25  wherein the ratio of components (a):(b) varies between 1/10 to 10/1. 
     
     
         33 . A solid dispersion according to  claim 25  wherein the ratio of components (a):(b) varies between 1/5 to 5/1. 
     
     
         34 . A solid dispersion according to  claim 25  which is in the form of a solid solution comprising (a) and (b). 
     
     
         35 . A particle consisting of a solid dispersion according to  claim 25 . 
     
     
         36 . A particle according to  claim 35  wherein the particle has a particle size of less than 600 μm. 
     
     
         37 . A particle according to  claim 35  wherein the particle has a particle size of less than 400 μm. 
     
     
         38 . A particle according to  claim 35  wherein the particle has a particle size of less than 125 μm. 
     
     
         39 . A process for preparing a solid dispersion according to  claim 35  comprising the steps of dissolving the two components (a) and (b) in an appropriate solvent and spraying the resulting solution through the nozzle of a spray dryer followed by evaporating the solvent from the resulting droplets at elevated temperatures.