Microbicidal pyrimidine or triazine for preventing sexual hiv transmission

Abstract

The present invention concerns the microbicidal activity of certain pyrimidine or triazine containing non-nucleoside reverse transcriptase inhibitors. The compounds of the present invention inhibit the systemic infection of a human being with HIV, in particular, the present compounds prevent sexual HIV transmission in humans.

1 - 27 . (canceled) 
     
     
         28 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a microbicidal effective amount of a compound wherein the pharmaceutical composition is in a form adapted to be applied to the site where sexual intercourse or related intimate contact takes place and wherein the compound is a compound having the formula (I), (II) or (III)
 wherein a compound of formula (I) corresponds to   
       
         
           
           
               
               
           
         
         a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein 
         Y is CR 5  or N; 
         A is CH, CR 4  or N; 
         n is 0, 1, 2, 3 or 4; 
         Q is —NR 1 R 2  or when Y is CR 5  then Q may also be hydrogen; 
         R 1  and R 2  are each independently selected from the group consisting of 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, and mono- and di(C 1-12 alkyl)aminocarbonyl wherein each of said C 1-12 alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from the group consisting of hydroxy, C 1-6 alkyloxy, hydroxyC 1-6 alkyloxy, carboxyl, C 1-6 alkyloxycarbonyl, cyano, amino, imino, aminocarbonyl, aminocarbonylamino, mono- or di(C 1-6 alkyl)amino, aryl and Het; or 
         R 1  and R 2  taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C 1-12 alkyl)aminoC 1-4 alkylidene; 
         R 3  is hydrogen, aryl, C 1-6 alkylcarbonyl, C 1-6 alkyl, C 1-6 alkyloxycarbonyl, C 1-6 alkyl substituted with C 1-6 alkyloxycarbonyl; 
         each R 4  independently is hydroxy, halo, C 1-6 alkyl, C 1-6 alkyloxy, cyano, amino carbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, or when Y is CR 5  then R 4  may also represent C 1-6 alkyl substituted with cyano or aminocarbonyl; 
         R 5  is hydrogen or C 1-4 alkyl; 
         L is —X 1 —R 6  or —X 2 -Alk-R 7  wherein 
         R 6  and R 7  each independently are phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from the group consisting of halo, hydroxy, C 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl, formyl, cyano, nitro, amino, and trifluoromethyl; or when Y is CR 5  then R 6  and R 7  may also be selected from the group consisting of 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 6  and R 7  may also be selected from the group consisting of indanyl or indolyl, each of said indanyl or indolyl may be substituted with one, two, three, four or five substituents each independently selected from the group consisting of halo, hydroxy, C 1-6 alkyl, C 1-6  alkyloxy, C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl, formyl, cyano, nitro, amino, and trifluoromethyl; 
         X 1  and X 2  are each independently —NR 3 —, —NH—NH—, —N═N—, —O—, —S—, —S(═O)— or —S(═O) 2 —; 
         Alk is C 1-4 alkanediyl; or 
         when Y is CR 5  then L may also be selected from the group consisting of C 1-10 alkyl, C 3-10 alkenyl, C 3-10 alkynyl, C 3-7 cycloalkyl, and C 1-10 alkyl substituted with one or two substituents independently selected from the group consisting of C 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 the group consisting of halo, hydroxy, C 1-6 alkyl, C 1-6 alkyloxy, cyano, aminocarbonyl, C 1-6 alkyloxycarbonyl, formyl, nitro, amino, trihalomethyl, trihalomethyloxy and C 1-6 alkylcarbonyl; 
         aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkyloxy, cyano, nitro and trifluoromethyl; 
         Het is an aliphatic or aromatic heterocyclic radical; wherein said aliphatic heterocyclic radical is selected from the group consisting of pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and tetrahydrothienyl wherein each of said aliphatic heterocyclic radical may optionally be substituted with an oxo group; and wherein said aromatic heterocyclic radical is selected from the group consisting of pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein each of said aromatic heterocyclic radical may optionally be substituted with hydroxy; 
         and, wherein a compound of formula (II) corresponds to 
       
       
         
           
           
               
               
           
         
         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; 
         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, wherein 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 the group consisting of 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 ; 
         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 ; 
         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 said C 1-12 alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from the group consisting of 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 optionally 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 the group consisting of halo, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6  alkyloxy, cyano, nitro, polyhaloC 1-6 alkyl and polyhaloC 1-6 alkyloxy; and 
         Het is an aliphatic or aromatic heterocyclic radical; wherein 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 wherein said aromatic heterocyclic radical is selected from the group consisting of pyrrolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein each of said aromatic heterocyclic radical may optionally be substituted with hydroxy; 
         and, wherein a compound of formula (III) corresponds to 
       
       
         
           
           
               
               
           
         
         a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein 
         -a 1 =a 2 -a 3 =a 4 - represents a bivalent radical of formula
   —CH═CH—CH═CH—  (a-1);
 
   —N═CH—CH═CH—  (a-2);
 
   —N═CH—N═CH—  (a-3);
 
   —N═CH—CH═N—  (a-4);
 
   —N═N—CH═CH—  (a-5);
 
 
         n is 0, 1, 2, 3 or 4; and in case -a 1 =a 2 -a 3 =a 4 - is (a-1), then n may also be 5; 
         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; 
         each R 2  independently is hydroxy, halo, C 1-6 alkyl optionally substituted with cyano or —C(═O)R 4 , 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 4 , —NH—S(═O) p R 4 , —C(═O)R 4 , —NHC(═O)H, C(═O)NHNH 2 , —NHC(═O)R 4 , —C(═NH)R 4  or a radical of formula 
       
       
         
           
           
               
               
           
         
         wherein 
         each A independently is N, CH or CR 4 ; 
         B is NH, O, S or NR 4 ; 
         p is 1 or 2; and 
         R 4  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 the group consisting of
 C 3-7 cycloalkyl, 
 indolyl or isoindolyl, each optionally substituted with one, two, three or four substituents each independently selected from the group consisting of 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 —; 
         aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from the group consisting of halo, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, cyano, nitro, polyhaloC 1-6 alkyl and polyhaloC 1-6 alkyloxy; 
         with the proviso that compounds of formula (III) wherein
 L is C 1-3 alkyl; R 1  is selected from hydrogen, ethyl and methyl; -a 1 =a 2 -a 3 =a 4 - represents a bivalent radical of formula (a-1); n is 0 or 1 and R 2  is selected from the group consisting of fluoro, chloro, methyl, trifluoromethyl, ethyloxy and nitro; or 
 L is —X—R 3 , X is —NH—; R 1  is hydrogen; -a 1 =a 2 -a 3 =a 4 - represents a bivalent radical of formula (a-1); n is 0 or 1 and R 2  is selected from the group consisting of chloro, methyl, methyloxy, cyano, amino and nitro and R 3  is phenyl, optionally substituted with one substituent selected from chloro, methyl, methyloxy, cyano, amino and nitro; 
 
         and the compounds
 N,N′-dipyridinyl-(1,3,5)-triazine-2,4-diamine; 
 (4-chloro-phenyl)-(4(1-(4-isobutyl-phenyl)-ethyl)-(1,3,5) triazin-2-yl)-amine are not included. 
 
       
     
     
         29 . The pharmaceutical composition according to  claim 28  wherein Y in the compound of formula (II) 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. 
     
     
         30 . The pharmaceutical composition according to  claim 28  wherein the compound corresponds to 
       
         
           
           
               
               
           
         
         a N-oxide, a pharmaceutically acceptable addition salt, quaternary amine or a stereochemically isomeric forms thereof, wherein 
         n is 0, 1, 2, 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; and 
         R 2a  is cyano; aminocarbonyl; mono- or dimethylaminocarbonyl; C 1-6 alkyl optionally substituted with cyano, aminocarbonyl, or mono- or dimethylaminocarbonyl; 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 4 , 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 4 , —NH—S(═O) p R 4 , —C(═O)R 4 , —NHC(═O)H, —C(═O)NHNH 2 , —NHC(═O)R 4 , —C(═NH)R 4  or a radical of formula 
       
       
         
           
           
               
               
           
         
         
           wherein 
           each A independently is N, CH or CR 4 ; 
           B is NH, O, S or NR 4 ; 
           p is 1 or 2; and 
           R 4  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, each of said aliphatic group substituted with phenyl, which 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, optionally substituted with one, two, three, four or five substituents each independently selected from the substituents defined in R 2 ; 
           X is —NR 1 —, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)— or —S(═O) 2 —; 
           aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from the group consisting of halo, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, cyano, nitro, polyhaloC 1-6 alkyl and polyhaloC 1-6 alkyloxy; 
           with the proviso that the compound 2,4-di-p-cyanoanilino-1,3,5-triazine is not included. 
         
       
     
     
         31 . The pharmaceutical composition according to  claim 28  wherein the compound is
 4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-2-pyrimidinyl]amino]benzonitrile; 
 6-[(2,6-dichlorophenyl)methyl]-N2-(4-fluorophenyl)-2,4-pyrimidinediamine; 
 4-[[4-[(2,4-dichlorophenyl)methyl]-6-[(4-hydroxybutyl)amino]-2-pyrimidinyl]amino]-benzonitrile; 
 4-[[4-[(2,6-dichlorophenyl)methyl]-6-[(3-hydroxypropyl)amino]-2-pyrimidinyl]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-pyrimidinyl]-amino]benzonitrile; 
 4-[[4-[(2,6-dichlorophenyl)methyl]-6-[[3-(2-oxo-1-pyrrolidinyl)propyl]amino]-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-pyrimidinyl]-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-pyrimidinyl]-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-pyrimidinediamine; 
 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile; 
 4-[[2-[(2,4,6-trimethylphenyl)amino]-4-pyrimidinyl]amino]benzonitrile; 
 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]benzonitrile; 
 4-[[4-[[2,6-dichloro-4-(trifluoromethyl)phenyl]amino]-2-pyrimidinyl]amino]benzonitrile; 
 4-[[4-[(2,4-dichloro-6-methylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile; 
 4-[[2-[(cyanophenyl)amino]-4-pyrimidinyl]amino]-3,5-dimethylbenzonitrile; 
 4-[[4-[(2,4-dibromo-6-fluorophenyl)amino]-2-pyrimidinyl]amino]benzonitrile; 
 4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-5-methyl-2-pyrimidinyl]amino]-benzeneacetonitrile; 
 4-[[4-[methyl(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile; 
 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]benzonitrile; 
 4-[[2-amino-6-[(2,4,6-trimethylphenyl)amino]-4-pyrimidinyl]amino]benzonitrile; 
 4-[[4-(2-bromo-4-chloro-6-methylphenoxy)-2-pyrimidinyl]amino]benzonitrile; 
 4-[[4-[(4-chloro-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile; 
 3,5-dichloro-4-[[2-[(4-cyanophenyl)amino]-4-pyrimidinyl]amino]benzonitrile; 
 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]benzonitrile; 
 4-[[4-[(2,6-dibromo-4-propylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile; 
 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzamide; 
 4-[[4-[(4-(1,1-dimethylethyl)-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]-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-dimethylbenzonitrile; 
 4-[[4-[[4-(1,1-dimethylethyl)-2,6-dimethylphenyl]amino]-5-methyl-2-pyrimidinyl]-amino]benzonitrile; 
 4-[[4-[(4-bromo-2,6-dimethylphenyl)amino]-5-methyl-2-pyrimidinyl]amino]benzonitrile; 
 4-[[5-methyl-4-[(2,4,6-trimethylphenyl)thio]-2-pyrimidinyl]amino]benzonitrile; 
 4-[[4-[(2,6-dibromo-4-propylphenyl)amino]-5-methyl-2-pyrimidinyl]amino]benzonitrile; 
 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzamide, N3-oxide; 
 N2-(4-chlorophenyl)-N4-(2,4,6-trimethylphenyl)-2,4-pyrimidinediamine; 
 4-[[4-[[2,6-dibromo-4-(1-methylethyl)phenyl]amino]-5-methyl-2-pyrimidinyl]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]benzonitrile; 
 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]benzonitrile; 
 4-[[4-amino-6-[(2,6-dichlorophenyl)thio]-1,3,5-triazin-2-yl]amino]benzonitrile; 
 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]benzonitrile; 
 4-[[4-(hydroxyamino)-6-(2,4,6-trimethylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile; 
 4-[[4-amino-6-[(2,4-dichloro-6-methylphenyl)amino]-1,3,5-triazin-2-yl]amino]-benzonitrile; 
 4-[[4-[(2,4-dichloro-6-methylphenyl)amino]-6-(hydroxyamino)-1,3,5-triazin-2-yl]-amino]benzonitrile; 
 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]benzonitrile; 
 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]benzonitrile; 
 4-[[4-amino-6-(2,6-dibromo-4-methylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile; 
 4-[[4-amino-6-(4-formyl-2,6-dimethylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile; 
 4-[[4-amino-6-[(2,4-dichlorophenyl)thio]-1,3,5-triazin-2-yl]amino]benzonitrile; 
 4-[[4-[(5-acetyl-2,3-dihydro-7-methyl-1H-inden-4-yl)oxy]-6-amino-1,3,5-triazin-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]amino]-benzonitrile; 
 4-[[4-amino-6-[[2,4-dichloro-6-(trifluoromethyl)phenyl]amino]-1,3,5-triazin-2-yl]-amino]benzonitrile; 
 4-[[4-amino-6-[methyl(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]-benzonitrile; 
 4-[[4-amino-6-[(2,6-dibromo-4-methylphenyl)amino]-1,3,5-triazin-2-yl]amino]-benzonitrile; 
 4-[[4-amino-6-[[2,6-dibromo-4-(1-methylethyl)phenyl]amino]-1,3,5-triazin-2-yl]-amino]benzonitrile; 
 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; 
 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]-benzonitrile; 
 4-[[4-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile; 
 a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof. 
 
     
     
         32 . The pharmaceutical composition according to  claim 28   wherein the compound is   4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]-benzonitrile,   4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile, or   4-[[4-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile;   a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amines or a stereochemically isomeric form thereof.   
     
     
         33 . The pharmaceutical composition according to  claim 28   wherein the compound is 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile, a N-oxide, a pharmaceutically acceptable addition salt or a quaternary amine form thereof.   
     
     
         34 . The pharmaceutical composition according to  claim 28  wherein the composition is bioadhesive to the site of application. 
     
     
         35 . The pharmaceutical composition according to  claim 28  wherein the composition is in the form of a gel, jelly, cream, paste, emulsion, dispersion, ointment, film, sponge, foam, aerosol, powder, intravaginal ring, cervical cap, implant, patch, suppository, pessary, tablet or mouthwash. 
     
     
         36 . The pharmaceutical composition according to  claim 35  wherein the composition is in the form of an intravaginal ring. 
     
     
         37 . The pharmaceutical composition according to  claim 28  wherein the composition is in the form of an immediate release drug delivery system. 
     
     
         38 . The pharmaceutical composition according to  claim 28  wherein the composition is in the form of a sustained release drug delivery system. 
     
     
         39 . The pharmaceutical composition according to  claim 28   wherein the composition is a gel comprising:   a microbicidal effective amount of a compound as defined in  claim 28 ,   a gel-forming compound,   a buffer,   a pharmaceutically acceptable diluent,   optionally a humectant, and   optionally a preservative.   
     
     
         40 . The pharmaceutical composition according to  claim 28  wherein the compound is 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile or a pharmaceutically acceptable addition salt thereof. 
     
     
         41 . The pharmaceutical composition according to  claim 28  wherein the compound is 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile. 
     
     
         42 . The pharmaceutical composition according to  claim 36  wherein the compound is 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile. 
     
     
         43 . The pharmaceutical composition according to  claim 39  wherein the compound is 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile. 
     
     
         44 . The pharmaceutical composition according to  claim 28  wherein the composition comprises 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile, hydroxyethyl cellulose, glycerol, methyl paraben, propyl paraben, lactic acid, sodium hydroxide, and water. 
     
     
         45 . The pharmaceutical composition according to  claim 28  wherein the compound is 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile or a pharmaceutically acceptable addition salt thereof. 
     
     
         46 . The pharmaceutical composition according to  claim 28  wherein the compound is 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile. 
     
     
         47 . The pharmaceutical composition according to  claim 36  wherein the compound is 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile. 
     
     
         48 . The pharmaceutical composition according to  claim 28  wherein the composition comprises one or more additional antiretroviral compounds. 
     
     
         49 . The pharmaceutical composition according to  claim 28  wherein the composition comprises one or more components selected from an antibody, a detergent or surfactant, a coating for the pathogen, a coating for the site of transmission, an antibiotic peptide or a pH regulator. 
     
     
         50 . The pharmaceutical composition according to  claim 28  wherein the medicament comprises a spermicidal compound.