Patent EA-004746-B1 (EA)
Title: Benzimidazole and imidazopyridine as respiratory syncytial virus replication inhibitors
Inventor: JANSSENS FRANS EDWARD
IPC: A61K31/496
Filed: 2000-06-20
Abstract: 1. A compound of the formula an addition salt thereof, or stereochemically isomeric form thereof, wherein in said formula -a1=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 or 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>; X<2> is C1-4alkyl-NR<4>; t is 4; u is 3; v is 2; G is a direct bond or C1-10alkanediyl optionally substituted with a substituent selected from C1-6alkyloxy and -O-CH2CH2-O-C1-6alkyl; R<1> is a bicyclic heterocycle selected from quinolinyl, isoquinolinyl, quinoxalinyl, benzofuranyl, benzotienyl, benzoimidazolyl, benzoxazolyl, benthiazolyl, naphthypyridinyl, 1H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyridinyl, 2,3-dihydro-1,4-dioxino-[2,3-b]pyridinyl or a radical of formula (c-1), (c-3) or (c-4): and said bicyclic heterocycles may optionally be substituted in any of two cycles 1 or where possible with 2 substituents selected from halogen, oxo, C1-6alkyl, C1-6alkoxy or polyhalogen- C1-6alkyl; each m independently is 1 or 2; R<2> independently is hydrogen, formyl, C1-6-alkylcarbonyl, alkyloxycarbonyl or C1-10-alkyl, substituted N(R<6>)2, and optionally substituted C1-6-alkyloxycarbonylamino; R<4> is hydrogen; and R<6> is hydrogen or C1-6-6alkoxycarbonyl. 2. A compound of claim 1, wherein -a1=a2-a3=a4- represents a radical of formula (a-1), (a-2) or (a-3). 3. A compound of claim 1 or 2, wherein Q is a radical of formula (b-5), wherein v is 2, and Y<1> is -NR<2>-. 4. A compound of any one of claims 1-3, wherein R<2> is C1-10-alkyl, substituted with NHR<6>. 5. A compound of any one of claims 1-4, wherein G is a direct bond or C1-10alkanediyl optionally substituted with a substituent selected from C1-6alkyloxy and -O-CH2CH2-O-C1-6alkyl. 6. A compound of claim 1, wherein said compound is selected from the group comprising (+-)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(2,4-dimethyl-5-oxazolyl)methyl]-1H-benzimidazol-2-amine; (+-)-N-[1-(2-amino-3-methylbuthyl)-4-piperidinyl]-1-(2-bromo-5,6,7,8-tetrahydro-8-quinolinyl)-1H-benzimidazol-2-amine trihydrochloride trihydrate; (+-)-N-[1-(2-amino-3-methylbuthyl)-4-piperidinyl]-1-[(2-ethoxyethoxy)8-quinolilyl-methyl]4-methyl-1H-benzimidazol-2-amine; (+-)-N-[1-(2-amino-3-methylbuthyl)-4-piperidinyl]-1-(2-chloro-5,6,7,8-tetrahydro-5-quinoxalinyl)-1H-benzimidazol-2-amine trihydrochloride trihydrate; (+-)-N-[1-(2-amino-3-methylbuthyl)-4-piperidinyl]-1-(-ethoxy-8-quinolilylmethy)-1-1H-benzimidazol-2-amine; (+-)-N-[1-(2-amino-3-methylbuthyl)-4-piperidinyl]-4-methyl-1-(5,6,7,8-tetrahydro-5-quinoxalinyl)-1H-benzimidazol-2-amine; (+-)-N-[1-(2-aminoethyl)-4-piperidinyl]-7-methyl-3-(8-quinolinylmethyl)-3H-imidazo[4,5-b]pyridin-2-amine tetrahydrochloride trihydrate; (+-)-N-[1-(2-amino-3-methylbuthyl)-4-piperidinyl]-7-methyl-3-(8-quinolinylmethyl)-3H-imidazo[4,5-b]pyridin-2-amine tetrahydrochloride monohydrate; (+-)-N-[1-(2-amino-3-methylbuthyl)-4-piperidinyl]-1-(8-quinolinylmethyl)-1H-imidazo[4,5-c]pyridin-2-amine trihydrochloride dihydrate; N-[1-(2-aminoethyl)-4-piperidinyl]-4-methyl-1-(8-quinolinylmethyl)-1H-benzimidazol-2-amine; N-[1-(8-quinolinylmethyl)1H-bensimidazol-2-yl]-1,3-propanediamin- trihydrochloride monohydrate; (+-)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(2-ethoxyethoxy) 8-quinolinylmethyl)-1H-benzimidazol-2-amine trihydrochloride dihydrate; (+-)-N-[1-(2-amino-3-methylbuthyl)-4-piperidinyl]-1-(8-quinolinylmethyl)-1H-imidazo-[4,5-b]pyridin-2-amine trihydrochloride dihydrate; (+-)-N-[1-(2-aminoethyl)-2-methy[-3-methylpropyl)-4-piperidinyl]-1-[(2-ethoxyethoxy)-8-quinolilylmethy)-1-1H-benzimidazol-1-amine; (+-)-N-[1-(2-aminoethyl)-4-piperidinyl]-3-(2-quinolinylmethyl)-3H-imidazo[4,5-b]pyridin-2-amine trihydrochloride trihydrate; (+-)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-(5,6,7,8-tetrahydro-2,3-dimethyl-5-quinoxalinyl)-1H-benzimidazol-2-amine trihydrochloride trihydrate; (+-)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-(5,6,7,8-tetrahydro-5-quinoxalinyl)-1H-benzimidazol-2-amine trihydrochloride trihydrate; (+-)-N-[1-(2-amino-3-methylbuthyl)-4-piperidinyl]-3-(quinolinylmethyl)-3H-imidazo-[4,5-b]pyridin-2-amine; (+-)-N-[1-(2-amino-3-methylbuthyl)-4-piperidinyl]-4-methyl-1-(8-quinolinylmethyl)-1H-benzimidazol-2-amine; (+-)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-(2-chloro-5,6,7,8-tetrahydro-5-quinoxalinyl)-4-methyl-1H-benzimidazol-2-amine trihydrochloride trihydrate; (+-)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-(5,6,7,8-tetrahydro-2,3-dimethyl-5-quinoxalinyl)-1H-benzimidazol-2-amine trihydrochloride trihydrate; (+-)-N-[1-(2-amino-3-methylbuthyl)-4-piperidinyl]-1-[(2-ethoxyethoxy)-8-quinolinylmethyl]-1H-benzimidazol-2-amine; (+-)-N-[1-(2-amino-3-methylbuthyl)-4-piperidinyl]-1-(3-chloro-5,6,7,8-tetrahydro-5-quinoxalinyl)-1H-benzimidazol-2-amine trihydrochloride monohydrate; (+-)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-(3-chloro-5,6,7,8-tetrahydro-5-quinoxalinyl)-4-methyl-1H-benzimidazol-2-amine trihydrochloride dihydrate; (+-)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(2-ethoxyethoxy)-8-quinolinylmethyl)-4-methyl-1H-benzimidazol-2-amine monohydrate; (+-)-N-[1-(2-amino-3-methylbuthyl)-4-piperidinyl]-3-(8-quinolinylmethyl)-3H-imidazo[4,5-c]pyridin-2-amine trihydrochloride tetrahydrate; (+-)-N-[1-(2-aminoethyl)-4-piperidinyl]-3-(8-quinolinylmethyl)-3H-imidazo[4,5-b]pyridinl-2-amine; (+-)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-4-methyl-1-[(1-methyl-1H-benzimidazol-4-yl)methyl]-1H-benzimidazol-2-amine; (+-)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-(2-chloro-5,6,7,8-tetrahydro-5-quinoxalinyl)-4-methyl-1H-benzimidazol-2-amine; a prodrug, N-oxide, addition salt, quaternary amine, metal complex and stereochemically isomeric form thereof. 7. A compound as claimed in any one of claims 1 to 6 for use as a medicine. 8. A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in any one of claims 1-6 as an active ingredient and a pharmaceutically acceptable carrier. 9. A process of preparing a composition as claimed in claim 8 characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as claimed in any one of claims 1-6. 10. An intermediate compound of formula wherein R<1>, G, Q and -a<1>=a<2>-a<3>=a<4>- defined as in claim 1, wherein P is a leaving group and Q1 is Q as claimed in claim 1, but without a substituent R<2> or R<6>. 11. An intermediate compound of formula wherein R<1>, G, Q and -a<1>=a<2>-a<3>=a<4>- defined as in claim 1, and (O()Q3 is a carbonyl derivative Q, wherein said Q is as defined in claim 1, provided that it has no substituent CH-NR<2>R<4> or NR<2>. 12. An intermediate compound of formula wherein R<1>, Q and -a<1>=a<2>-a<3>=a<4>- defined as in claim 1, and (O()Q3 is a carbonyl derivative Q, wherein said G is as defined in claim 1. 13. A process of preparing a compound as claimed in claim 1, characterized by deprotecting an intermediate of formula (IV) wherein R<1>, G, and -a<1>=a<2>-a<3>=a<4>- defined as in claim 1, H-Q1 being defined as Q according to claim 1 provided that R<2> or at least one R<6> substituent is hydrogen, and P being a protective group; and, if desired, converting compounds of formula(I) into each other following art known transformations, 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. 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 -a1=a2-a3=a4- defined as in claim 2, and H2N-Q3H being defined as Q according to claim 2 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; wherein R<1>, G, and -a<1>=a<2>-a<3>=a<4>- defined as in claim 1, and H2N-Q3H-defined as Q according to claim 1 provided that both substituents R<2> and R<4> are hydrogen or both substituents R<2> and R<4> are hydrogen and the carbon atom adjacent to the nitrogen atom carrying the R<2> and R<4> substituents, carries also at least one hydrogen atom, in the presence of a suitable reducing agent; and, if desired, converting compounds of formula(I) into each other following art known transformations, 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. 15. A process of preparing a compound as claimed in claim 1, characterized by reducing an intermediate of formula (X) wherein R<1> G, and -a<1>=a<2>-a<3>=a<4>-a1=a2-a3=a4- defined as in claim 1, H2N-CH2-Q4 being defined as Q according to claim 1 provided that Q comprises a -CH2-NH2 moiety in the presence of a suitable reducing agent; and, if desired, converting compounds of formula(I) into each other following art known transformations, and further, if desired, converting the compounds of formula(I), into a therapeutically active non-toxic acid additi