Patent EA-005027-B1 (EA)
Title: Respiratory syncytial virus replication inhibitors
Inventor: JANSSENS FRANS EDUARD
IPC: C07D471/04
Filed: 2000-06-20
Abstract: 1. A compound of formula a prodrug, N-oxide, addition salt, quaternary amine, metal complex or stereochemically isomeric form thereof wherein-al=a2-a3=a4-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-alkoxy, polyhalo C1-6-alkyl, carboxyl, amino C1-6-alkyl, mono-or di(C1-4-alkyl)-amino C1-6-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, =CH-C1-6-alkyl, =N-OH or =N-O-C1-6-C1-6-alkyl; Q is a radical of formula Y<1> is a bivalent radical of formula -NR<2>-; X<1> is NH or CH2; V is 2; and whereby each hydrogen atom in the heterocycle defined in (b-5) radical, 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 C1-10-alkanediyl substituted with one or more hydroxy, C1-6-alkyloxy, aryl-C1-6-alkylthio, aryl- C1-6-alkyloxy, C1-6-alkylthio, HO(CH2-CH2-O)n, C1-6-alkyloxy (-CH2-CH2-O)n- or aryl- C1-6-alkyloxy (-CH2-CH2-O)n-; R<1> is an optionally substituted monocyclic heterocycle or aryl; said heterocycle being selected from piperidinyl, piperazinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, tetrahydrofuranyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl; and each heterocycle may optionally be substituted with 1 or where possible more, such as 2,3 or 4, substituents selected from halo, hydroxy, amino, cyano, carboxy, C1-6-alkylthio, C1-6-alkyloxy- C1-6-alkyl, aryl, C1-6-alkyloxy, hydroxy-C1-6-alkyl, mono- or di(C1-6-alkyl)amino, mono-or aryl- C1-6-alkyl, aryl- C1-6-alkyloxy, C1-6-alkylcarbonylamino, di(C1-6-alkyl)amino- C1-6-alkyl, polyhalo- C1-6-alkyl, C1-6-alkyloxycarbonyl, -C(=O)-NR<5C>R<5D>, C1-6-alkyl-SO2-NR<5C>-, aryl-SO2-NR<5C>-, C1-6-alkyloxy(-CH2-CH2-O)n-, HO(-CH2-CH2-O)n-, halo(-CH2-CH2-O)n-, aryl- C1-6-alkyloxy (-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, Het-carbonyl, pyrrolidinyl, piperidinyl, homopiperidinyl, C3-7cycloalkyl 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, piperidinyl, mono-or di(C1-6-alkyl)amino, C2-5-alkanediyl, 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> and R<5B> or 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, such as 2, 3 or 4, substituents selected from halo, hydroxy, C1-6-alkyl, hydroxy- C1-6-alkyl, polyhalo- C1-6-alkyl, and C1-6-alkyloxy; Het is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl. 2. A compound according to claim 1 wherein -a1=a2-a3=a4- is a radical of formula (a-1) or (a-2). 3. A compound according to claim 1 or 2 wherein R<1> is phenyl optionally substituted with halo, C1-6-alkyl or C1-4-alkyloxy; or pyridyl optionally substituted with 1 or more substituents selected from aryl- C1-6-alkyloxy, C1-6-alkyloxy- C1-6-alkyl, aryl, mono or di(C1-6-alkyl)amino, C(=O)-NR<5C>R<5D>, halo or C1-6-alkyl. 4. A compound according to any one of claims 1 to 3 wherein G is C1-4-alkanediyl substituted with hydroxy, C1-6-alkyloxy, HO(-CH2-CH2-O)n-, C1-6-alkyloxy(-CH2-CH2-O)n- or aryl- C1-6-alkyloxy(-CH2-CH2-O)n-. 5. A compound according to any one of claims 1 to 4 wherein R<2> is hydrogen or C1-10-alkyl substituted with NHR<6> wherein R<6> is hydrogen or C1-6-alkyloxycarbonyl. 6. A compound according to claim 1 wherein the compound is [(A),(S)]-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)-ethoxymethyl]-1H-benzimidazol-2-amine; [(A),(S)]-N-[1-(2-aminopropyl)-4-piperidinyl]-1-[ethoxy(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine; (+-)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(2-methoxyethoxy)(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine; N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-6-chloro-1-[(2-methoxyethoxy)(6-methyl-2-pyridinyl)methyl]-4-methyl-1H-benzimidazol-2-amine trihydrochloride trihydrate; [(A),(R)]-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[ethoxy(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine monohydrate; (+-)-N-[1-(2-aminopropyl)-4-piperidinyl]-1-[ethoxy(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine; [(A)(S)]-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[ethoxy(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine monohydrate; (+-)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[ethoxy(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine; [(A),(R)]-N-[1-(2-aminopropyl)-4-piperidinyl]-1-[ethoxy(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine monohydrate; (+-)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)ethoxymethyl]-2-benzimidazol-2-amine; (+-)N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(2-ethoxyethoxy)(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine; (B),(S)]N-[1-(2-aminopropyl)-4-piperidinyl]-1-(ethoxy(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine monohydrate; (+-)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-3-[(2-methoxyethoxy)(6-methyl-2-pyridinyl)methyl]-7-methyl-3H-imidazo[4,5-b]pyridin-2-amine; (+-)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(2-ethoxyethoxy)(6-phenyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine; (+-)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(2-methoxyethoxy)(6-metyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine; (+-)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)ethoxymethyl]-4-methyl-1H-benzimidazol-2-amine monohydrate; [(A),(R)]-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)ethoxymethyl]-1H-benzimidazol-2-amine; (+-)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)ethoxymethyl]-1H-benzimidazol-2-amine; a prodrug, N-oxide, addition salt, quaternary amine, metal complex or stereochemically isomeric form thereof. 7. A compound as claimed in any one of claims 1 to 6 for use as a medicine. 8. A compound as claimed in claim 7 useful for treating or prevention of virus infections. 9. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound as described in any one of claims 1 to 6. 10. A process of preparing a composition as claimed in claim 10, characterized in that, a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as described in any one of claims 1 to 6. 11. An intermediate of formula with R<1>, G and -a<1>=a<2>-a<3>=a<4>- defined as in claim 1, P being a protective group, and Q1 being defined as Q according to claim 1 provided that it is devoided of the R<2> or R<6> substituent. 12. An intermediate of formula with R<1>, G and -a<1>=a<2>-a<3>=a<4>- defined as in claim 1, and (O=)Q3 being a carbonyl derivative of Q, said Q being defined according to claim 1, provided that it is devoided of the -NR<2>R<4> or -NR<2>- substituent. 13. An intermediate of formula with R<1>, Q and -a<1>=a<2>-a<3>=a<4>- defined as in claim 1, and (O=)G2 being a carbonyl derivative of G, said G being defined according to claim 1. 14. A process of preparing a compound as claimed in claim 1, characterized by amination of an intermediate of formula (IX) with R<1>, G, and -a<1>=a<2>-a<3>=a<4>- defined as in claim 1, and H2 N-Q3H being defined as Q according to claim 1, provided that both R<6> substituents are hydrogen or R<2> and R<4> are both hydrogen, and the carbon adjacent to the nitrogen carrying the R<6>, or R<2> and R<4> substituents contains at least one hydrogen, in the presence of a suitable amination reagent; and further, if desired, converting the compounds of formula (I), into a therapeutically active non-toxic acid addition salt by treatment with an acid, or into a therapeutically active non-toxic base addition salt by treatment with a base, or conversely, converting the acid addition salt form into the free base by treatment with alkali, or converting the base addition salt into the free acid by treatment with acid; and, if desired, preparing stereochemically isomeric forms, metal complexes, quaternary amines or N-oxide forms thereof. 15. A product containing (a) a compound as defined in claim 1, and (b) another antiviral compound, as a combined preparation for simultaneous, separate or sequential use in the treatment or the prevention of viral infections. 16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredients (a) a compound as defined in claim 1, and (b) another antiviral compound.