Patent EA-004939-B1 (EA)
Title: Respiratory syncytial virus replication inhibitors
Inventor: JANSSENS FRANS EDUARD
IPC: A61K31/00
Filed: 2000-06-20
Abstract: 1. Use of a compound for the manufacture of a medicament for the treatment of viral infections, wherein the compound is a compound of formula a prodrug, N-oxide, addition salt, quaternary amine, metal complex or 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); -CH=N-CH=CH- (a-3); -CH=CH-N=CH- (a-4); or -CH=CH-CH=N- (a-5); wherein each hydrogen atom in the radicals (a-1), (a-2), (a-3), (a-4) and (a-5) may optionally be replaced by halo, C1-6 alkyl, nitro, amino, hydroxy, C1-6 alkyloxy, polyhalo- C1-6 alkyl, carboxyl, amino- C1-6 alkyl, mono-or di (C1-4 alkyl) aminoC1-6 alkyl, C1-6 alkyloxycarbonyl, hydroxy-C1-6 alkyl, or a radical of formula wherein =Z is =O, =CH-C(=O)-NR<5A>R<5B>, =CH2, = C1-6alkyl, =N-OH or =N-O-C1-6alkyl; Q is a radical of formula wherein Alk is C1-6 alkanediyl; Y<1> is a bivalent radical of formula -NR<2>- or -CH(NR<2>R<4>)-; X<1> is NR<4>, S, S((O), S((O)2, O, CH2, C((O), C((CH2), CH(OH), CH(CH3), CH(OCH3), CH(SCH3), CH(NR<5A>R<5B>), CH2-NR<4> or NR<4>-CH2; X<2> is a direct bond, CH2, C((O), NR<4>, C1-4 alkyl-NR<4>, NR<4>-C1-4alkyl; t is 2, 3, 4 or 5; u is 1, 2, 3, 4 or 5; v is 2 or 3; and whereby each hydrogen atom in the carbocycles and the heterocycles defined in radicals (b-4), (b-5), and (b-6) may optionally be replaced by R<3>; with the proviso that when R<3> is hydroxy or C1-6 alkyloxy, then R<3> can not replace a hydrogen atom in the alpha position relative to a nitrogen atom; G is a direct bond or C1-10 alkanediyl; R<1> is a monocyclic heterocycle or aryl selected from piperidinyl, piperazinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, tetrahydrofuranyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, pyrazolyl, isoxazolyl and oxadiazolyl; and each heterocycle may optionally be substituted with 1 or where possible more-substituents selected from halo, hydroxy, amino, cyano, carboxy, C1-6alkyl, C1-6alkyloxy, C1-6alkylthio, C1-6alkyloxy-C1-6alkyl, aryl, aryl-C1-6-alkyl, aryl-C1-6-alkyloxy, hydroxy-C1-6-alkyl, mono- or di(C1-6alkyl)amino, mono- or di(C1-6alkyl)amino-C1-6alkyl, polyhalo-C1-6alkyl, C1-6alkylcarbonylamino, C1-6alkyl-SO2-NR<5C>-, aryl-SO2-NR<5C>-, C1-6alkyloxycarbonyl, -C((O)-NR<5C>R<5D>, HO(-CH2-CH2-O)n-, halo(-CH2-CH2-O)n-, C1-6alkyloxy(-CH2-CH2-O)n-, aryl-C1-6alkyloxy(-CH2-CH2-O)n- and mono- or di(C1-6alkyl)amino(-CH2-CH2-O)n-; each n independently is 1, 2, 3 or 4; R<2> is hydrogen, formyl, C1-6 alkylcarbonyl, Hetcarbonyl, pyrrolidinyl, piperidinyl, homopiperidinyl, C3-7 cycloalkyl substituted with N(R<6>)2, or C1-10 alkyl substituted with N(R<6>)2 and optionally with a second, third or fourth substituent selected from amino, hydroxy, C3-7 cycloalkyl, C2-5 alkanediyl, piperidinyl, mono- or di(C1-6alkyl)amino, C1-6alkyloxycarbonylamino, aryl and aryloxy; R<3> is hydrogen, hydroxy, C1-6alkyl, C1-6alkyloxy, aryl- C1-6 alkyl or aryl- C1-6 alkyloxy; R<4> is hydrogen, C1-6 alkyl or aryl- C1-6 alkyl; R<5A>, R<5B>, R<5C> and R<5D> each independently are hydrogen or C1-6 alkyl; or R<5A>, R<5B>, R<5C> and R<5D> taken together form a bivalent radical of formula -(CH2)s-, wherein s is 4 or 5; R<6> is hydrogen, C1-4 alkyl, formyl, hydroxy-C1-6 alkyl, C1-6 alkylcarbonyl or C1-6 alkyloxycarbonyl; aryl is phenyl or phenyl substituted with 1 or more-substituents selected from halo, hydroxy, C1-6 alkyl, hydroxy-C1-6 alkyl, polyhalo-C1-6 alkyl, and C1-6 alkyloxy; and Het is pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl. 2. A compound of formula (I`) a prodrug, N-oxide, addition salt, quaternary amine, metal complex or 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); -CH=N-CH=CH- (a-3); -CH=CH-N=CH- (a-4); or -CH=CH-CH=N- (a-5); wherein each hydrogen atom in the radicals (a-1), (a-2), (a-3), (a-4) and (a-5) may optionally be replaced by halo, C1-6 alkyl, nitro, amino, hydroxy, C1-6 alkyloxy, polyhalo-C1-6alkyl, carboxyl, amino- C1-6 alkyl, mono-or di (C1-4 alkyl) aminoC1-6 alkyl, C1-6 alkyloxycarbonyl, hydroxy-C1-6 alkyl, or a radical of formula wherein =Z is =O, =CH-C(=O)-NR<5A>R<5B>, =CH2, =C1-6alkyl, =N-OH or =N-O-C1-6alkyl; Q is a radical of formula wherein Alk is C1-6alkanediyl; Y<1> is a bivalent radical of formula -NR<2>- or -CH(NR<2>R<4>)-; X<1> is NR<4>, S, S((O), S((O)2, O, CH2, C((O), C((CH2), CH(OH), CH(CH3), CH(OCH3), CH(SCH3), CH(NR<5A>R<5B>), CH2-NR<4> or NR<4>-CH2; X<2> is a direct bond, CH2, C((O), NR<4>, C1-4 alkyl-NR<4>, NR<4>-C1-4 alkyl; t is 2, 3, 4 or 5; u is 1, 2, 3, 4 or 5; v is 2 or 3; and whereby each hydrogen atom in the carbocycles and the heterocycles defined in radicals (b-4), (b-5), and (b-6) may optionally be replaced by R<3>; with the proviso that when R<3> is hydroxy or C1-6 alkyloxy, then R<3> can not replace a hydrogen atom in the alpha position relative to a nitrogen atom; G is a direct bond or C1-10 alkanediyl; R<1> is a monocyclic heterocycle or aryl selected from piperidinyl, piperazinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, tetrahydrofuranyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, pyrazolyl, isoxazolyl and oxadiazolyl; and each heterocycle may optionally be substituted with 1 or where possible more-substituents selected from halo, hydroxy, amino, cyano, carboxy, C1-6 alkyl, C1-6 alkyloxy, C1-6 alkylthio, C1-6 alkyloxy- C1-6 alkyl, aryl, aryl-C1-6-alkyl, aryl- C1-6-alkyloxy, hydroxy-C1-6-alkyl, mono- or di(C1-6 alkyl)amino, mono- or di(C1-6 alkyl)amino- C1-6 alkyl, polyhalo-C1-6alkyl, C1-6alkylcarbonylamino, C1-6 alkyl-SO2-NR<5C>-, aryl-SO2-NR<5C>-, C1-6alkyloxycarbonyl, -C((O)-NR<5C>R<5D>, HO(-CH2-CH2-O)n-, halo(-CH2-CH2-O)n-, C1-6alkyloxy(-CH<2>-CH2-O)n-, aryl-C1-6alkyloxy(-CH2-CH2-O)n- and mono- or di(C1-6 alkyl)amino(-CH2-CH2-O)n-; each n independently is 1, 2, 3 or 4; R<2> is hydrogen, formyl, C1-6 alkylcarbonyl, Hetcarbonyl, pyrrolidinyl, piperidinyl, homopiperidinyl, C3-7 cycloalkyl substituted with N(R<6>)2, or C1-10 alkyl substituted with N(R<6>)2 and optionally with a second, third or fourth substituent selected from amino, hydroxy, C3-7 cycloalkyl, C2-5alkanediyl, piperidinyl, mono- or di(C1-6 alkyl)amino, C1-6 alkyloxycarbonylamino, aryl and aryloxy; R<3> is hydrogen, hydroxy, C1-6 alkyl, C1-6 alkyloxy, aryl- C1-6 alkyl or aryl- C1-6 alkyloxy; R<4> is hydrogen, C1-6 alkyl or aryl- C1-6 alkyl; R<5A>, R<5B>, R<5C> and R<5D> each independently are hydrogen or C1-6 alkyl; or R<5A>, R<5B>, R<5C> and R<5D> taken together form a bivalent radical of formula -(CH2)s-, wherein s is 4 or 5; R<6> is hydrogen, C1-4 alkyl, formyl, hydroxy-C1-6 alkyl, C1-6 alkylcarbonyl or C1-6 alkyloxycarbonyl; aryl is phenyl or phenyl substituted with 1 or more-substituents selected from halo, hydroxy, C1-6 alkyl, hydroxy-C1-6 alkyl, polyhalo-C1-6 alkyl, and C1-6 alkyloxy; with the proviso that when G is methylene, and R<1> is 2-pyridyl, 3-pyrpdyl, 6-methy;-2-pyridyl, 2-pyrazinyl or 5-methylimidazol-4-yl, and a<1>=a<2>-a<3>=a<4> is -CH(=)CH-CH=CH- or -N=CH-CH=CH-, then Q is other than 3. A compound according to claim 2, where the following restrictions apply: when Q is where X<1> is NR<4>, O, S(=O), S(=O)2, CH2, C(=O), C(=CH2) or CH(CH3), then R<1> is other then pyridyl, pyridyl substituted with C1-6 alkyl, pyrimidinyl, pyrazinyl, imidazolyl, and imidazolyl substituted with C1-6 alkyl. 4. A compound according to claim 2, where the following restrictions apply: when Q is where X<1> is NR<4>, O, S(=O), S(=O)2, CH2, C(=O), C(=CH2) or CH(CH3), then R<1> is other then pyridyl, pyridyl substituted with C1-6 alkyl, pyridyl substituted with 1 or 2 C1-6 alkyl, pyrazinyl, pyrrolyl, pyrrolyl substituted with C1-6 alkyl, imidazolyl, and imidazolyl substituted with C1-6 alkyl. 5. A compound according to claim 2, where the following limits restrictions apply: when Q is where X<1> is NR<4>, O, S(=O), S(=O)2, CH2, C(=O), C(=CH2) or CH(CH3), then R<1> is other then pyridyl, pyridyl substituted with C1-6 alkyl, pyrimidinyl, pyrazinyl, imidazolyl, and imidazolyl substituted with C1-6 alkyl. 6. A compound according to claim 2, where the following limits are introduced: when Q is then R<1> is other then pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, and imidazolyl substituted with C1-6 alkyl. 7. A compound according to claim 2, where the following restrictions apply: when Q is where X<2> is CH2 and a direct bond, then R<1> is other then pyridyl, pyridyl substituted with C1-6 alkyl, pyrimidinyl, pyrazinyl, imidazolyl, and imidazolyl substituted with C1-6 alkyl. 8. A compound according to claim 2, wherein the compound is selected from the group consisting of: (+-)-2-[[2-[[1-(2-amino-3-methylbutyl)-4-pipendinyl]amino]-7-methyl-7H-benzimidazol-1-yl]methyl]-6-methyl-3-pyndinol tetrahydrochloride monohydrate, 2 [[2-[[1-(2-arninoethyl)-4-pipendinyl]amino]-1H-benzimidazol-1-yl]methyl-3-pyndinol, (+-)-H-[1-(2-amino-3-methylbutyl)-4-pipendinyl]-6-chloro-1-[(1,4-dimethyl-1H-imidazol-5-yl)methyl]-1H-bcnzimidazol-2-amine monohydrate, (+-)-H-[1-(2-amino-3-metnylbutyl)-4-pipendinyl]-6-chloro-1-[(6-methyl-2-pyndinyl)methyl]-1H-benzimidazol-2-amine, (+-)-2-[[2-[(3-amino-2-hydroxypropyl)amino]-1H-benzlmldazol-1-yl]methyl]-6-methyl-3-pyridinol, N-[1-(2-aminoethyl)-4-pipendinyl]-1-[[3-(2-ethoxyethoxy)-6-methyl-2-pyndmyl]methyl]-1H-benzimidazol-2-amme tetrahydrochloride dihydrate, (+-)-N-[1-(2-amino-3-methylbutyl)-4-pipendinyl]-1-[(2-chloro-1,4-dimethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazol-2-amine, (+-)-N-[1-(2-amino-3-methylbutyl)-4-pipendinyl]-6 chloro-1-[(2-chloro-1,4-dimethyl-1H-imidazol-5-yl)methyl]-1H-benzirmdazol-2-amine, (+-)-N-[1-(2-amino-3-methylbutyl)-4-pipendinyl]-6-methyl-1-[(6-methyl-2-pyndinyl)methyl]-1H-benzimidazol-2-amine, (+-)-N-[1-(2-dminopropyl)-4-pipendinyl]-1-[(3,5,6-trimethylpyrazinyl)methyl]-1H benzimidazol-2-amine tetrahydrochloride dihydrate, (+-)-N-[1-(2-amino-3-methylbutyl)-4-pipendiny]]-1-[(3,5,6-tri