Patent EA-001004-B1 (EA)
Title: Fused imidazole derivatives as multidrug resistance modulators
Inventor: JANSSENS FRANS EDUARD
IPC: A61K31/00
Filed: 1997-03-11
Abstract: 1. A compound of formula (I)   a N-oxide form thereof, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein the dotted line is direct bond, n is 1 or 2; R<1> is hydrogen; halo; formyl; C1-4 alkyl; C1-4 alkyl substituted with 1 or 2 substituents each independently selected from hydroxy, C1-4alkoxy, C1-4alkylcarbonyloxy, imidazolyl, thiazolyl or oxazolyl; or a radical of formula: -X-CO-OR<5> (a-l); -X-CO-NR<6>R<7> (a-2); or -X-CO-R<10> (a-3); wherein -X- is a direct bond, C1-4alkanediyl or C2-6alkenediyl; R<5> is hydrogen; C1-12alkyl; Ar; Het; C1-6alkyl substituted with C1-4alkyloxy, C1-4alkyloxycarbonyl C1-4alkyloxy, Ar, Het; R<6> and R<7> each independently are hydrogen or C1-4alkyl; R<10> is imidazolyl, thiazolyl or oxazolyl; R<2> is hydrogen, halo, C1-4alkyl, hydroxy C1-4alkyl, C1-4alkyloxycarbonyl, carboxyl, formyl or phenyl; R<3> is hydrogen, C1-4alkyl or C1-4alkyloxy; R<4> is hydrogen, halo, C1-4alkyl, C1-4alkyloxy or haloC1-4alkyl; Z is Z<1> or Z<2>; Z<1> is a bivalent radical of formula -CH2-, -CH2-CH2- or -CH=CH-; provided that when the dotted line is a bond, then Z<1> is other than -CH2-; Z<2> is a bivalent radical of formula -CHOH-CH2-, -O-CH2-, -C(=O)-CH2- or -C(=NOH)-CH2-; -A-B- is a bivalent radical of formula -Y-CR<8>=CH-  (b-1); -CH=CR<8>-Y-  (b-2); -CH=CR<8>-CH=CH- (b-3); -CH=CH-CR<8>=CH- (b-4); or -CH=CH-CH=CR<8>- (b-5); wherein each R<8> independently is hydrogen, halo, C1-4alkyl, C1-4alkyloxy, hydroxy C1-4alkyl, hydroxycarbonyl C1-4alkyl, formyl, carboxyl,ethenyl substituted with carboxyl, or ethenyl substituted with C1-4alkyloxycarbonyl; each Y independently is a bivalent radical of formula -O-, -S- or -NR<9>-; wherein R<9> is hydrogen, C1-4alkyl or C1-4alkylcarbonyl; -A<1>- is a direct bond; C1-6alkanediyl; C1-6alkanediyl-oxy-C1-6alkanediyl; C1-6alkanediyloxy; C1-6alkanediylcarbonyl; C1-6alkanediyloxy substituted with hydroxy; or C1-6alkanediyl substituted with hydroxy or =NOH; -A<2>- is a direct bond or C1-6alkanediyl; Q is phenyl; phenyl substituted with one or two substituents selected from hydrogen, halo, hydroxy, C1-4alkyl, C1-4alkyloxy or halo C1-4alkyl; naphthalinyl; naphthalinyl substituted with one or two substituents selected from hydrogen, halo, hydroxy, C1-4alkyl, C1-4alkyloxy or halo C1-4alkyl; pyridinyl; pyridinyl substituted with one or two substituents selected from hydrogen, halo, hydroxy, C1-4alkyl, C1-4alkyloxy or halo C1-4alkyl; quinolinyl or quinolinyl substituted with one or two substituents selected from hydrogen, halo, hydroxy, C1-4alkyl, C1-4alkyloxy or halo C1-4alkyl; Ar is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from hydrogen, halo, C1-4alkyl or C1-4alkyloxy; Het is furanyl; furanyl substituted with C1-4alkyl, C1-4alkyloxy or hydroxy C1-4alkyl; oxazolyl; oxazolyl substituted with C1-4alkyl or C1-4alkyloxy or quinolinyl. 2. A compound according to claim l wherein -A-B- is a bivalent radical of formula (b-2), (b-3) or (b-4); Z is Z<1> wherein Z<1> is a bivalent radical of formula -CH2-CH2- or -CH2-, or Z is Z<2> wherein Z<2> is a bivalent radical of formula -C(=O)-CH2-; -A<1>- is C1-6alkanediyl, C1-6alkanediyloxy, carbonyl, C1-6alkanediyloxy substituted with hydroxy, or C1-6alkanediyl substituted with hydroxy; -A<2>- is a direct bond or C1-6alkanediyl; Q is phenyl, naphthalinyl, pyridinyl, quinolinyl, phenyl substituted with halo or C1-6alkyloxy, naphthalinyl substituted with halo or C1-6alkyloxy,pyridinyl substituted with halo or C1-6alkyloxy or quinolinyl substituted with halo or C1-6alkyloxy; R<1> is hydrogen, halo, formyl, C1-4alkyl substituted with hydroxy, or a radical of formula (a-1) wherein X is a direct bond or C1-4alkanediyl and R<5> is hydrogen, C1-12alkyl, Ar or C1-6alkyl substituted with Het; R<2> is hydrogen, halo, C1-4alkyl, formyl, hydroxy C1-4alkyl or C1-4alkyloxycarbonyl; R<3> is hydrogen; R<4> is hydrogen, halo, C1-6alkyl or C1-6alkyloxy and the dotted line is a bond. 3. A compound according to any of claims 1-2, wherein Z is -CH2-CH2-; -A-B- is -CH=CH-CH=CH-; -A<1>- is -CH2-CH2-, -CH2-CH2-CH2- or -O-CH2-CH2-; -A<2>- is -CH2-; R<1> is hydrogen, halo, formyl or a radical of formula (a-l), wherein X is a direct bond and R<5> is hydrogen, C1-12alkyl, Ar or C1-6alkyl substituted with Het; R<2> is hydrogen, C1-4alkyl, formyl or C1-4alkyloxycarbonyl; R<3> is hydrogen; R<4> is hydrogen or C1-4alkyloxy and the dotted line is a direct bond. 4. A compound according to claim 1 wherein the compound is methyl-6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate; or dimethyl-6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-2,3-dicarboxylate; or ethyl-6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]-ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate; methyl-11-[1-[[3,5-dimethoxy-4-(2-quinolinylmethoxy)phenyl]-methyl]-4-piperidinylidene]-6,11-dihydro-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate; methyl-6,11-dihydro-11-[1-[3-[4-(2-quinolinylmethoxy)phenyl]propyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate; methyl-6,11-dihydro-11-[1-[2-[4-(2-naphthalinylmethoxy)phenyl]-ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate; methyl-6,11-dihydro-11-[1-[2-[4-(phenylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate; and methyl-6,11-dihydro-11-[1-[2-(4-(1-naphthalinylmethoxy)phenyl]-ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate; the stereoisomeric forms and the pharmaceutically acceptable addition salts thereof. 5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound as described in any one of claims 1-4. 6. A process for preparing a pharmaceutical composition as claimed in claim 5, characterised in that, a therapeutically active amount of a compound as claimed in any one of claims 1-4 is intimately mixed with a pharmaceutically acceptable carrier. 7. The use of a compound according to any one of claims 1-4 as a medicine. 8. A product containing: a) composition comprising a pharmaceutically effective amount of a compound according to any of claims 1-4 and a pharmaceutically acceptable carrier; and b) composition comprising a pharmaceutically effective amount of an anti-tumor agent and a pharmaceutically acceptable carrier, as a combined preparation for simultaneous, separate or sequential use in anti-tumor therapy. 9. A product containing: a) composition comprising a pharmaceutically effective amount of a compound according to any of claims 1-4 and a pharmaceutically acceptable carrier; and  b) composition comprising a pharmaceutically effective amount of a anti-tumor agent useful to treat conditions caused by pathogens and a pharmaceutically acceptable carrier, as a combined preparation for simultaneous, separate or sequential use in the treatment of conditions caused by pathogens. 10. A compound of formula (II-b)   a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof, wherein n is 1 or 2; R<4> is hydrogen, halo, C1-4alkyl, C1-4alkyloxy or halo C1-4alkyl; Q<1> is phenyl substituted with one or two substituents selected from hydrogen, hydroxy, C1-4alkyl, C1-4alkyloxy or halo C1-4alkyl; naphthalinyl; naphthalinyl, substituted with one or two substituents selected from hydrogen, hydroxy, C1-4alkyl, C1-4alkyloxy or halo C1-4alkyl; pyridinyl; pyridinyl substituted with one or two substituents selected from hydrogen, hydroxy, C1-4alkyl, C1-4alkyloxy or halo C1-4alkyl; quinolinyl; or quinolinyl substituted with one or two substituents selected from hydrogen, hydroxy, C1-4alkyl, C1-4alkyloxy or halo C1-4alkyl; -A<1>- is C1-6alkanediyl, C1-6alkanediyloxy or C1-6alkanediyloxy C1-6alkanediyl; -A<2>- is a direct bond or C1-6alkanediyl; and W is halo, methanesulfonyloxy or benzenesulfonyloxy. 11. A process for preparing a compound of formula (I), characterised in that a reagent of formula (III), wherein T represents the fused imidazole radical   is reacted with an intermediate of formula (II), wherein W represents an appropriate leaving group;     or, converting compounds of formula (I) into each other following art-known transformation reactions; and further, if desired, converting the compounds of formula (I), into an acid addition salt by treatment with an acid, or into a base addition salt by treatment with a base, or conversely, converting the base addition salt into the free acid by treatment with acid; and, if desired, preparing N-oxide and/or stereochemically isomeric forms thereof. 12. A process for preparing a compound of formula (I), characterised in that an intermediate of formula (IV), wherein W represents an appropriate leaving group, is O-alkylated with a reagent of formula (V);   or converting compounds of formula (I) into each other following art-known transformation reactions; and further, if desired, converting the compounds of formula (I), into an acid addition salt by treatment with an acid, or into a base addition salt by treatment with a base, or conversely, converting the base addition salt into the free acid by treatment with acid; and, if desired, preparing N-oxide and/or stereochemically isomeric forms thereof. 13. A process for preparing a compound as claimed in claim 10 wherein an intermediate of formula (VI) is O-alkylated with an intermediate of formula (IV), in a reaction-inert solvent and subsequently the hydroxy group of an intermediate of formula (VII) is converted into a leaving group W;   in the above reaction scheme n, R<4>, Q<1>, A<1'>, A<2> and W are as defined in claim 10 and W<1> is an appropriate leaving group; or an intermediate compound of formula (II-a) is converted into an acid addition salt, or conversely, an acid addition salt is converted i