Claims for Patent: 4,791,111

Summary for Patent: 4,791,111

Title:	[[4-[4-(4-phenyl-1-piperazinyl)phenoxymethyl]-1,3-dioxolan-2-yl]methyl]-1H-imidazoles and 1H-1,2,4-triazoles having anti-microbial properties
Abstract:	Novel [[4-[4-(4-phenyl-1-piperazinyl)phenoxymethyl]-1,3-dioxolan-2-yl]methyl]-1H-imidazoles and 1H-1,2,4-triazoles, having anti-microbial activity, compositions containing the same, and methods of inhibiting and/or eliminating the development of fungi and bacteria in warm-blooded animals suffering from diseases caused by these fungi and/or bacteria.
Inventor(s):	Jan Heeres, Leo J. J. Backx, Jozef B. A. Thijssen, Alfonsus G. Knaeps
Assignee:	Janssen Pharmaceutica NV
Application Number:	US06/919,400
Patent Claims:	1. A chemical compound having the formula ##STR17## a pharmaceutically acceptable acid-addition salt or a stereochemically isomeric form thereof, whereinQ is N or CH; Ar is aryl; R is hydrogen or C1-6 alkyl; and Y--R1 is a radical having the formula ##STR18## or a radical having the formula ##STR19## wherein R1 is tetrahydrofuranylC1-6 alkyl; or C1-6 alkyl, C3-6 cycloalkyl, arylC1-6 alkyl or (C3-6 cycloalkyl)C1-6 alkyl all substituted on the C1-6 alkyl and/or C3-6 cycloalkyl moiety with oxo, thioxo or with one or two radicals of formula --Z--R1-a ;said Z being O or S; said R1-a being hydrogen, C1-6 alkyl, aryl, C3-6 cycloalkyl or tetrahydro-2H-pyran-2-yl; or where R1 is substituted with two --Z--R1-a radicals, the two --R1-a radicals, taken together, may form a bivalent radical of formula --CH2 --, --CH(CH3)--, --C(CH3)2 --, --CH2 --CH2 --, --CH(CH3)--CH2 -- or --CH2 --CH2 --CH2 --; X is O, S or NR2 ; said R2 being hydrogen or C1-6 alkyl; A is >C═O, NR3, methylene or methylene substituted with up to two radicals selected from the group consisting of C1-6 alkyl and aryl; said R3 being hydrogen or C1-6 alkyl; B is >C═O or methylene optionally substituted with up to two C1-6 alkyl radicals; or A and B, taken together, form a bivalent radical of formula --N═CH-- (c); A' and B' independently having the same meaning of A and B respectively, or A' and B', taken together, form a bivalent radical of formula --N═CH-- (c) or --CH═CH-- (d); wherein the nitrogen atom in the bivalent radical (c) is connected to NR1 ; wherein one hydrogen in said radical (c) and up to two hydrogens in radical (d) may be replaced by a C1-6 alkyl radical; provided that(i) when Y--R1 is a radical of formula (a) wherein --A--B-- is other than a bivalent radical of formula (c), then R1 is other than C1-6 alkyl substituted with C1-6 alkyloxy; (ii) when Y--R1 is a radical of formula (b) then R1 is other than C1-6 alkyl substituted with C1-6 alkyloxy; wherein aryl is phenyl or substituted phenyl, said substituted phenyl having from 1 to 3 substituents each independently selected from the group consisting of fluoro, chloro, bromo, C1-6 alkyl, C1-6 alkyloxy, and trifluoromethyl. 2. A chemical compound according to claim 1 wherein Y--R1 is a radical of formula (a) or (b), provided that A' and B', taken together, do not form a radical of formula (c) or (d). 3. A chemical compound according to claim 2 wherein Y--R1 is a radical of formula (a). 4. A chemical compound according to claim 3 wherein X is O; A and B are independently >C═O or methylene optionally substituted with up to two C1-6 alkyl radicals, or A and B, taken together, form a bivalent radical of formula (c) wherein the hydrogen atom may be replaced by a C1-6 alkyl radical; and R1 is tetrahydrofuranylC1-6 alkyl, or C3-6 cycloalkyl substituted with oxo or hydroxy, or C1-6 alkyl or arylC1-6 alkyl both substituted on the C1-6 alkyl moiety with oxo or with one or two radicals of formula --O--R1-a, or where R1 is substituted with two --O--R1-a radicals, the two --R1-a radicals, taken together, may form a bivalent radical of formula --C(CH3)2 -- or --CH2 --CH2 --. 5. A chemical compound according to claim 4 wherein R1 is C3-6 cycloalkyl substituted with oxo or hydroxy, or C1-6 alkyl or arylC1-6 alkyl both substituted on the C1-6 alkyl moiety with oxo or with one or two hydroxy or C1-6 alkyloxy radicals. 6. A chemical compound according to claim 5 wherein Ar is phenyl substituted with two halo atoms; R is hydrogen; A is C(CH3)2 or CH2, B is CH2 or >C═O, or A and B, taken together, form a radical (c) wherein the hydrogen atom may be replaced by a methyl radical; and R1 is C1-6 alkyl substituted with oxo or hydroxy. 7. A composition for combatting microorganisms comprising an inert carrier material and as an active ingredient an antimicrobially effective amount of a compound having the formula ##STR20## a pharmaceutically acceptable acid-addition salt or a stereochemically isomeric form thereof, whereinQ is N or CH; Ar is aryl; R is hydrogen or C1-6 alkyl; and Y--R1 is a radical having the formula ##STR21## or a radical having the formula ##STR22## wherein R1 is tetrahydrofuranylC1-6 alkyl; or C1-6 alkyl, C3-6 cycloalkyl, arylC1-6 alkyl or (C3-6 cycloalkyl)C1-6 alkyl all substituted on the C1-6 alkyl and/or C3-6 cycloalkyl moiety with oxo, thioxo or with one or two radicals of formula --Z--R1-a ; said Z being O or S; said R1-a being hydrogen; C1-6 alkyl, aryl, C3-6 cycloalkyl or tetrahydro-2H-pyran-2-yl; or where R1 is substituted with two --Z--R1-a radicals, the two --R1-a radicals, taken together, may form a bivalent radical of formula --CH2 --, --CH(CH3)--, --C(CH3)2 --, --CH2 --CH2 --, --CH(CH3)--CH2 -- or --CH2 --CH2 --CH2 --; X is O, S or NR2 ; said R2 being hydrogen or C1-6 alkyl; A is >C═O, NR3, methylene or methylene substituted with up to two radicals selected from the group consisting of C1-6 alkyl and aryl; said R3 being hydrogen or C1-6 alkyl; B is >C═O or methylene optionally substituted with up to two C1-6 alkyl radicals; or A and B, taken together, form a bivalent radical of formula --N═CH-- (c); A' and B' independently having the same meaning of A and B respectively, or A' and B', taken together, form a bivalent radical of formula --N═CH-- (c) or --CH═CH-- (d); wherein the nitrogen atom in the bivalent radical (c) is connected to NR1 ; wherein one hydrogen in said radical (c) and up to two hydrogens in radical (d) may be replaced by a C1-6 alkyl radical; provided that(i) when Y--R1 is a radical of formula (a) wherein --A--B-- is other than a bivalent radical of formula (c), then R1 is other than C1-6 alkyl substituted with C1-6 alkyloxy; (ii) when Y--R1 is a radical of formula (b) then R1 is other than C1-6 alkyl substituted with C1-6 alkyloxy; wherein aryl is phenyl or substituted phenyl, said substituted phenyl having from 1 to 3 substituents each independently selected from the group consisting of fluoro, chloro, bromo, C1-6 alkyl, C1-6 alkyloxy, and trifluoromethyl. 8. A composition according to claim 7 wherein Y--R1 is a radical of formula (a) or (b), provided that A' and B', taken together, do not form a radical of formula (c) or (d). 9. A composition according to claim 8 wherein Y--R1 is a radical of formula (a). 10. A composition according to claim 9 wherein X is O; A and B are independently >C═O or methylene optionally substituted with up to two C1-6 alkyl radicals, or A and B, taken together, form a bivalent radical of formula (c) wherein the hydrogen atom may be replaced by a C1-6 alkyl radical; and R1 is tetrahydrofuranylC1-6 alkyl, or C3-6 cycloalkyl substituted with oxo or hydroxy, or C1-6 alkyl or arylC1-6 alkyl both substituted on the C1-6 alkyl moiety with oxo or with one or two radicals of formula --O--R1-a, or where R1 is substituted with two --O--R1-a radicals, the two --R1-a radicals, taken together, may form a bivalent radical of formula --C(CH3)2 -- or --CH2 --CH2 --. 11. A composition according to claim 10 wherein R1 is C3-6 cycloalkyl substituted with oxo or hydroxy, or C1-6 alkyl or arylC1-6 alkyl both substituted on the C1-6 alkyl moiety with oxo or with one or two hydroxy or C1-6 alkyloxy radicals. 12. A composition according to claim 11 wherein Ar is phenyl substituted with two halo atoms; R is hydrogen; A is C(CH3)2 or CH2, B is CH2 or >C═O, or A and B, taken together, form a radical (c) wherein the hydrogen atom may be replaced by a methyl radical; and R1 is C1-6 alkyl substituted with oxo or hydroxy. 13. A method of inhibiting and/or eliminating the development of fungi and bacteria in warm-blooded animals suffering from diseases caused by these fungi and/or bacteria by the systemic or topical a aministration of an antimicrobially effective amount of a compound having the formula ##STR23## a pharmaceutically acceptable acid-addition salt or a stereochemically isomeric form thereof, whereinQ is N or CH; Ar is aryl; R is hydrogen or C1-6 alkyl; and Y--R1 is a radical having the formula ##STR24## or a radical having the formula ##STR25## wherein R1 is tetrahydrofuranylC1-6 alkyl; or C1-6 alkyl, C3-6 cycloalkyl, arylC1-6 alkyl or (C3-6 cycloalkyl)C1-6 alkyl all substituted on the C1-6 alkyl and/or C3-6 cycloalkyl moiety with oxo, thioxo or with one or two radicals of formula --Z--R1-a ; said Z being O or S; said R1-a being hydrogen, C1-6 alkyl, aryl, C3-6 cycloalkyl or tetrahydro-2H-pyran-2-yl; or where R1 is substituted with two --Z--R1-a radicals, the two --R1-a radicals, taken together, may form a bivalent radical of formula --CH2 --, --CH(CH3)--, --C(CH3)2 --, --CH2 --CH2 --, --CH(CH3)--CH2 -- or --CH2 --CH2 --CH2 --; X is O, S or NR2 ; said R2 being hydrogen or C1-6 alkyl; A is >C═O, NR3, methylene or methylene substituted with up to two radicals selected from the group consisting of C1-6 alkyl and aryl; said R3 being hydrogen or C1-6 alkyl; B is >C═O or methylene optionally substituted with up to two C1-6 alkyl radicals; or A and B, taken together, form a bivalent radical of formula --N═CH-- (c); A' and B' independently having the same meaning of A and B respectively, or A' and B', taken together, form a bivalent radical of formula --N═CH-- (c) or --CH═CH-- (d); wherein the nitrogen atom in the bivalent radical (c) is connected to NR1 ; wherein one hydrogen in said radical (c) and up to two hydrogens in radical (d) may be replaced by a C1-6 alkyl radical; provided that(i) when Y--R1 is a radical of formula (a) wherein --A--B-- is other than a bivalent radical of formula (c), then R1 is other than C1-6 alkyl substituted with C1-6 alkyloxy; (ii) when Y--R1 is a radical of formula (b) then R1 is other than C1-6 alkyl substituted with C1-6 alkyloxy; wherein aryl is phenyl or substituted phenyl, said substituted phenyl having from 1 to 3 substituents each independently selected from the group consisting of fluoro, chloro, bromo, C1-6 alkyl, C1-6 alkyloxy, and trifluoromethyl. 14. A method according to claim 13 wherein Y--R1 is a radical of formula (a) or (b), provided that A' and B', taken together, do not form a radical of formula (c) or (d). 15. A method according to claim 14 wherein Y--R1 is a radical of formula (a). 16. A method according to claim 15 wherein X is O; A and B are independently >C═O or methylene optionally substituted with up to two C1-6 alkyl radicals, or A and B, taken together, form a bivalent radical of formula (c) wherein the hydrogen atom may be replaced by a C1-6 alkyl radical; and R1 is tetrahydrofuranylC1-6 alkyl, or C3-6 cycloalkyl substituted with oxo or hydroxy, or C1-6 alkyl or arylC1-6 alkyl both substituted on the C1-6 alkyl moiety with oxo or with one or two radicals of formula --O--R1-a, or where R1 is substituted with two --O--R1-a radicals, the two --R1-a radicals, taken together, may form a bivalent radical of formula --C(CH3)2 -- or --CH2 --CH2 --. 17. A method according to claim 16 wherein R1 is C3-6 cycloalkyl substituted with oxo or hydroxy, or C1-6 alkyl or arylC1-6 alkyl both substituted on the C1-6 alkyl moiety with oxo or with one or two hydroxy or C1-6 alkyloxy radicals. 18. A method according to claim 17 wherein Ar is phenyl substituted with two halo atoms; R is hydrogen; A is C(CH3)2 or CH2, B is CH2 or >C═O, or A and B, taken together, form a radical (c) wherein the hydrogen atom may be replaced by a methyl radical; and R1 is C1-6 alkyl substituted with oxo or hydroxy. 19. A chemical compound according to claim 1, wherein A' and B' are both methylene or methylene substituted with up to two C1-6 alkyl radicals. 20. A substituted phenol of the following formula (V): ##STR26## or a stereochemically isomeric form thereof, wherein R is hydrogen or C1-6 alkyl; andY--R1 is a radical having the formula ##STR27## or a radical having the formula ##STR28## wherein R1 is tetrahydrofuranylC1-6 alkyl; or C1-6 alkyl, C3-6 cycloalkyl, arylC1-6 alkyl or (C3-6 cycloalkyl)C1-6 alkyl all substituted on the C1-6 alkyl and/or C3-6 cycloalkyl moiety with oxo, thioxo or with one or two radicals of formula --Z--R1-a ; said Z being O or S; said R1-a being hydrogen, C1-6 alkyl, aryl, C3-6 cycloalkyl or tetrahydro-2H-pyran-2-yl; or wherein R1 is substituted with two --Z--R1-a radicals, the two --R1-a radicals, taken together, may form a bivalent radical of formula --CH2 --, --CH(CH3)--, --C(CH3)2 --, --CH2 --CH2 --, --CH(CH3)--CH2 -- or --CH2 --CH2 --CH2 --; X is O, S or NR2 ; said R2 being hydrogen or C1-6 alkyl; A is >C═O, NR3, methylene or methylene substituted with up to two radicals selected from the group consisting of C1-6 alkyl and aryl; said R3 being hydrogen or C1-6 alkyl; B is >C═O or methylene optionally substituted with up to two C1-6 alkyl radicals; or A and B, taken together, form a bivalent radical of formula --N═CH═ (c); A' and B' independently having the same meaning of A and B respectively, or A' and B', taken together, form a bivalent radical of formula --N═CH-- (c) or --CH═CH-- (d); wherein the nitrogen atom in the bivalent radical (c) is connected to NR1 ; wherein one hydrogen in said radical (c) and up to two hydrogens in radical (d) may be replaced by a C1-6 alkyl radical; provided that(i) when Y--R1 is a radical of formula (a) wherein --A--B-- is other than a bivalent radical of formula (c), then R1 is other than C1-6 alkyl substituted with C1-6 alkyloxy; (ii) when Y--R1 is a radical of formula (b) then R1 is other than C1-6 alkyl substituted with C1-6 alkyloxy; wherein aryl is phenyl or substituted phenyl, said substituted phenyl having from 1 to 3 substituents each independently selected from the group consisting of fluoro, chloro, bromo, C1-6 alkyl, C1-6 alkyloxy and trifluoromethyl. 21. A chemical compound according to claim 20, wherein Y--R1 is a radical of formula (a) or (b), provided that A' and B', taken together, do not form a radical of formula (c) or (d). 22. A chemical compound according to claim 21, wherein Y--R1 is a radical of formula (a). 23. A chemical compound according to claim 21, wherein X is O; A and B are independently >C═O, methylene or methylene optionally substituted with up to two C1-6 alkyl radicals, or A and B, taken together, form a bivalent radical of formula (c) wherein the hydrogen atom may be replaced by a C1-6 alkyl radical; and R1 is tetrahydrofuranylC1-6 alkyl, or C3-6 cycloalkyl substituted with oxo or hydroxy, or C1-6 alkyl or arylC1-6 alkyl both substituted on the C1-6 alkyl moiety with oxo or with one or two radicals of formula --O--R1-a, or where R1 is substituted with two --O--R1-a radicals, the two --R1-a radicals, taken together, may form a bivalent radical of formula --C(CH3)2 -- or --CH2 --CH2 --. 24. A chemical compound according to claim 23, wherein R1 is C3-6 cycloalkyl substituted with oxo or hydroxy, or C1-6 alkyl or arylC1-6 alkyl both substituted on the C1-6 alkyl moiety with oxo or with one or two hydroxy or C1-6 alkyloxy radicals. 25. A compound according to claim 20, wherein the compound is:2-[2-(4-bromophenyl)-1-methyl-2-oxoethyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one; 2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(2-oxocyclopentyl)-3H-1,2,4-triazol-3-one; 2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(2-oxocyclohexyl)-3H-1,2,4-triazol-3-one.