Patent EA-004540-B1 (EA)
Title: Trisubstituted 1,3,5-triazine derivatives for treatment of hiv infections
Inventor: DAEYAERT FREDERIK FRANS DESIRE
IPC: A61P31/18
Filed: 1999-03-24
Abstract: 1. The use of a compound of formula a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein A' is CH; R<1> is hydrogen, hydroxy, C1-12alkyl, C1-12alkyloxy, C1-12alkylcarbonyl, C1-12alkyloxycarbonyl, aryl, amino, mono- or di(C1-12alkyl) amino, mono- or di(C1-12alkyl) aminocarbonyl; R<2> is hydrogen; R<3> is hydrogen; and R<4'> is cyano or aminocarbonyl; L is -X-R<5> or -X-Alk-R<6>; wherein R<5> and R<6> each independently are indanyl, indolyl or phenyl; each of said indanyl, indolyl or phenyl may be substituted with one, two, three, four or five substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, hydroxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, formyl, cyano, nitro, amino and trifluoromethyl; and X is -NR<3>-, -NH-NH-, -N=N-, -O-, -S-, -S (=O)- or-S (=O)2-; Alk is C1-4alkandiyl; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, cyano, nitro and trifluoromethyl; for the manufacture of a medicine for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection. 2. The use of a compound as claimed in claim 1 wherein L is -X-R<5> wherein R<5> is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, cyano, C1-6alkyl carbonyl, nitro and trifluoromethyl. 3. The use of a compound as claimed in claim 1 or 2 wherein R<4'> is cyano. 4. The use of a compound as claimed in any one of claims 1 to 3 wherein L contains phenyl substituted with two, three, four or five substituents each independently selected from halo, hydroxy, C1-6alkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, cyano, amino, trifluoromethyl, nitro, C1-6alkylcarbonyl and formyl. 5. The use of a compound as claimed in any one of claims 1 to 4 wherein R<1> hydrogen, aryl or hydroxy. 6. The use of a compound of formula a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein A' is CH; R<1> is hydrogen, hydroxy, C1-12alkyl, C1-12alkyloxy, C1-12alkylcarbonyl, C1-12alkyloxycarbonyl, aryl, amino, mono- or di(C1-12alkyl) amino, mono- or di(C1-12alkyl) aminocarbonyl; R<2> is hydrogen; R<3> is hydrogen; and R<4'> is cyano or aminocarbonyl; L is -X-R<5> or -X-Alk-R<6>; wherein R<5> and R<6> each independently are indanyl, indolyl or phenyl; each of said indanyl, indolyl or phenyl may be substituted with one, two, three, four or five substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, hydroxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, formyl, cyano, nitro, amino and trifluoromethyl; and X is -NR<3>-, -NH-NH-, -N=N-, -O-, -S-, -S (=O)- or -S (=O)2-; Alk is C1-4alkandiyl; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, cyano, nitro and trifluoromethyl; with the proviso that when R<4'> is cyano, R<3> is hydrogen, L is -X-R<5> wherein X is NH and R<5> is 4-cyanophenyl or 4-iodophenyl, then NR<1>R<2> is other than NH2, NH[CH2CH2N(C2H5)2, N(C2H5)2, NHCH3, NHC2H5 or NH (4-cyano-phenyl). 7. A compound as claimed in claim 6 wherein L is -X-R<5> wherein R<5> is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, cyano, C1-6alkylcarbonyl, nitro and trifluoromethyl. 8. A compound as claimed in claim 6 or 7 wherein whereinR<4> is aminocarbonyl, trifluoromethyl or cyano and L is 2,3,4,5,6-pentachloro-phenoxy, 2,3,5,6-tetrafluoro 4-hydroxy-phenoxy, 2,3,6-trichloro-phenoxy, 2,4,6-tribromo-3,5-dimethyl-phenoxy, 2,4,6-tribromo-phenoxy, 2,4,6-trichloro-phenoxy, 2,4,6-trifluoro-phenoxy, 2,4,6-trimethyl-phenoxy, 2,4-dichloro-3,5,6-trimethyl-phenoxy, 2,4-dichloro-6-methyl-phenoxy, 2,4-dichloro-phenoxy, 2,4-dimethyl-phenoxy, 2,5-dimethyl-phenoxy, 2,6-dibromo-4-chloro-3,5-dimethyl-phenoxy, 2,6-dibromo-4-methyl-phenoxy, 2,6-dichloro-4-fluoro-phenoxy, 2,6-dichloro-phenoxy, 2,6-dimethoxy-phenoxy, 2,6-dimethyl-4-nitro-phenoxy, 2,6-dimethyl-phenoxy, 2-acetyl-4,6-dichloro phenoxy, 2-acetyl-4,6-difluoro-phenoxy, 2-amino-4,6-dichloro-5-methyl-phenoxy, 4-acetyl-2,6-dimethyl-phenoxy, 4-amino-2,6-dimethyl-phenoxy, 4-bromo-2,6-dimethyl-phenoxy, 4-bromo-2-chloro-6-methyl-phenoxy, 4-chloro-2,3,6-trimethyl-phenoxy, 4-chloro-2,6-dimethyl-phenoxy, 4-cyano-2-methoxy-phenoxy, 4-formyl-2,6-dimethyl-phenoxy, 4-iodo-2,6-dimethyl-phenoxy, 2,3,4,5,6-pentafluoro-anilino, 2,3,4-trimethoxy-6-(methyloxycarbonyl)-anilino, 2,4,6-tribromo-anilino, 2,4,6-trichloro-anilino, 2,4,6-trimethoxy-anilino, 2,4,6-trimethyl-anilino, 2,4-dichloro-6 methyl-anilino, 2,4-dichloro-6-trifluoromethyl-anilino, 2,6-dibromo-4-isopropyl-anilino, 2,6-dibromo-4-methyl-anilino, 2,6-dichloro-4-trifluoromethyl-anilino, 2,6-dichloro-anilino, 2,6-diethyl-anilino, 2,6-dimethyl-anilino, 2-acetyl-5-methyl-anilino, 2-bromo-4,6-difluoro-anilino, 2-chloro-4,6-dimethyl-anilino,2-chloro-4-fluoro-5-methyl-anilino, 2-chloro-6-methyl-anilino, 2-ethyl-6-methyl-anilino, 2-isopropyl-6-methyl-anilino, 3-amino-2,4,6-trimethyl-anilino, 3-bromo-2,4,6-trimethyl-anilino, 3-chloro-2,6-dimethyl-anilino, 4-bromo-2,6-diethyl-anilino, 4-bromo-2,6-dimethyl-anilino, 4-bromo-2-chloro-6-methyl-anilino, 4-methyl-anilino, N-methyl-2,4,6-trimethyl-anilino, 2,4,5-trichloro-phenylthio, 2,4,6-trimethyl-phenylthio, 2,4-dichloro-phenylthio, 2,4-difluoro-phenylthio, 2,4-dimethyl-phenylthio, 2,6-dichloro-phenylthio, 2-chloro-4-fluoro-phenylthio, 2,4,6-trichloro-phenylhydrazinyl, 2,6-dichloro-phenylhydrazinyl, 2,4-dichloro-6-methyl-benzyl-amino, 2,4-dimethoxy-benzylamino, indol-4-yl-oxy, or 5-acetyl-7-methyl-indan-4-yl-oxy. 9. A compound as claimed in any one of claims 6 to 8 wherein R<4'> is cyano, L is -X-R<5> and R<5> is other than 4-cyanophenyl or 4-iodophenyl. 10. A compound as claimed in any one of claims 6 to 9 wherein L contains phenyl substituted with two, three, four or five substituents each independently selected from halo, hydroxy, C1-6alkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, cyano, amino, trifluoromethyl, nitro, C1-6alkylcarbonyl and formyl. 11. A compound as claimed in any one of claims 6 to 10 wherein L is -X-R<5> wherein X is -NR<3>-, -NH-NH-, -N=N- or -O- and R<5> is indanyl, indolyl or phenyl; each of said indanyl, indolyl or phenyl may be substituted with two, three, four or five substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, hydroxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, formyl, cyano, nitro, amino and trifluoromethyl. 12. A compound as claimed in any one of claims 6 to 11 wherein R<4'> is cyano, X is -O- or-NH- and R<5> or R<6> is phenyl substituted with two or three substituents each independently selected from halo, C1-6alkyl, C1-6alkylcarbonyl, formyl, nitro or cyano. 13. A compound as claimed in claim 6 wherein the compound is 4-[[4-amino-6-(2,6-dimethylphenoxy)-1,[[4-amino-6-(2,6-dimethylphenoxy)-1,3,5-triazin-2-yl] amino] benzonitrile; 4-[[4-amino-6-[(2-chloro-6-methylphenyl) amino]-1,[[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] benzontrile; 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, 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; a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof. 14. A compound as claimed in any one of claim 6 to 13 for use as a medicine. 15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound as claimed in claim 6 to 13. 16. A process for preparing a pharmaceutical composition as claimed in claim 15, characterized in that a therapeutically effective amount of a compound as claimed in claim 6 to 13 is intimately mixed with a pharmaceutically acceptable carrier. 17. A proce