Microbicidal Pyrimidine Or Triazine Containing Compounds

1 - 28 . (canceled)

29 . A method for reducing transmission of or infection with Haemophilus ducreyi in a patient, comprising the step of:

administering to said patient a medicament comprising a compound having a formula (I) or (II);

wherein the transmission of or infection with Haemophilus ducreyi is via sexual intercourse or related intimate contact between partners; and

wherein the 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 ;

A is CH;

n is 1;

Q is —NR 1 R 2 or 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;

R 4 is cyano;

R 5 is hydrogen or C 14 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, aminocarbonyl, trihalomethyloxy and trihalomethyl;

X l 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

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 the compound of formula (II) corresponds to

a N-oxide, a pharmaceutically acceptable addition salt, 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);

q is 0;

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 K is 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 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 or 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 hydroxyl.

30 . The method according to claim 29 ,

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.

31 . The method according to claim 29 , wherein the compound is

4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-2-pyrimidinyl]amino]benzonitrile;

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;

44[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]-64[3-(2-oxo-1-pyrrolidinyl)propyl]amino]-2-pyrimidinyl]amino]benzonitrile;

4-[[4-[(2,6-dichlorophenyl)methyl]-64[2-(2-hydroxyethoxy)ethyl]amino]-2-pyrimidinyl ]amino]benzonitrile 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;

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-[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-[(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-dimethyl benzonitrile;

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-[[2,6-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-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;

an N-oxide, a pharmaceutically acceptable addition salt, or a stereochemically isomeric form thereof, or, a quaternary amine thereof wherein the compound corresponds to a compound of formula (II).

32 . The method according to claim 29 ,

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;

an N-oxide, or a pharmaceutically acceptable addition salt thereof, or, a quaternary amine thereof wherein the compound corresponds to a compound of formula (II).

33 . The method according to claim 29 ,

wherein the compound is 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile, an N-oxide, or pharmaceutically acceptable addition salt thereof.

34 . The method according to claim 29 ,

wherein the transmission or infection is via the vagina.

35 . The method according to claim 29 ,

wherein the medicament is in a topical form.

36 . The method according to claim 29 ,

wherein the medicament is bioadhesive to a site of application.

37 . The method according to claim 29 ,

wherein the medicament 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.

38 . The method according to claim 29 ,

wherein the medicament is in the form of an immediate release drug delivery system.

39 . The method according to claim 29 ,

wherein the medicament is in the form of a sustained release drug delivery system.

40 . The method according to claim 29 ,

wherein the medicament is a gel comprising:

a microbicidal effective amount of a compound as defined in claim 29 ,

a gel-forming compound,

a buffer,

a pharmaceutically acceptable diluent,

optionally a humectant, and

optionally a preservative.

41 . The method according to claim 29 ,

wherein the medicament 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.

42 . The method according to claim 29 ,

wherein the medicament comprises one or more additional antiretroviral compounds.

43 . The method according to claim 29 ,

wherein the medicament 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.

44 . The method according to claim 29 ,

wherein the medicament comprises a spermicidal compound.

45 . The method according to claim 29 ,

wherein the compound is

4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]-benzonitrile, an N-oxide, pharmaceutically acceptable addition salt, or quaternary amine thereof.

46 . The method according to claim 29 ,

wherein the medicament is in the form of an intravaginal ring.

47 . The method according to claim 33 ,

wherein the medicament is in the form of an intravaginal ring.