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Claims for Patent: 4,791,111

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Claims 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): Heeres; Jan (Vosselaar, BE), Backx; Leo J. J. (Arendonk, BE), Thijssen; Jozef B. A. (Kasterlee, BE), Knaeps; Alfonsus G. (Herentals, BE)
Assignee: Janssen Pharmaceutica, N.V. (Beerse, BE)
Application Number:06/919,400
Patent Claims: 1. A chemical compound having the formula ##STR17## a pharmaceutically acceptable acid-addition salt or a stereochemically isomeric form thereof, wherein

Q is N or CH;

Ar is aryl;

R is hydrogen or C.sub.1-6 alkyl; and

Y--R.sup.1 is a radical having the formula ##STR18## or a radical having the formula ##STR19## wherein R.sup.1 is tetrahydrofuranylC.sub.1-6 alkyl; or C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, arylC.sub.1-6 alkyl or (C.sub.3-6 cycloalkyl)C.sub.1-6 alkyl all substituted on the C.sub.1-6 alkyl and/or C.sub.3-6 cycloalkyl moiety with oxo, thioxo or with one or two radicals of formula --Z--R.sup.1-a ;

said Z being O or S;

said R.sup.1-a being hydrogen, C.sub.1-6 alkyl, aryl, C.sub.3-6 cycloalkyl or tetrahydro-2H-pyran-2-yl;

or where R.sup.1 is substituted with two --Z--R.sup.1-a radicals, the two --R.sup.1-a radicals, taken together, may form a bivalent radical of formula --CH.sub.2 --, --CH(CH.sub.3)--, --C(CH.sub.3).sub.2 --, --CH.sub.2 --CH.sub.2 --, --CH(CH.sub.3)--CH.sub.2 -- or --CH.sub.2 --CH.sub.2 --CH.sub.2 --;

X is O, S or NR.sup.2 ;

said R.sup.2 being hydrogen or C.sub.1-6 alkyl;

A is >C.dbd.O, NR.sup.3, methylene or methylene substituted with up to two radicals selected from the group consisting of C.sub.1-6 alkyl and aryl;

said R.sup.3 being hydrogen or C.sub.1-6 alkyl;

B is >C.dbd.O or methylene optionally substituted with up to two C.sub.1-6 alkyl radicals;

or A and B, taken together, form a bivalent radical of formula

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

wherein the nitrogen atom in the bivalent radical (c) is connected to NR.sup.1 ; wherein one hydrogen in said radical (c) and up to two hydrogens in radical (d) may be replaced by a C.sub.1-6 alkyl radical; provided that

(i) when Y--R.sup.1 is a radical of formula (a) wherein --A--B-- is other than a bivalent radical of formula (c), then R.sup.1 is other than C.sub.1-6 alkyl substituted with C.sub.1-6 alkyloxy;

(ii) when Y--R.sup.1 is a radical of formula (b) then R.sup.1 is other than C.sub.1-6 alkyl substituted with C.sub.1-6 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, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, and trifluoromethyl.

2. A chemical compound according to claim 1 wherein Y--R.sup.1 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--R.sup.1 is a radical of formula (a).

4. A chemical compound according to claim 3 wherein X is O; A and B are independently >C.dbd.O or methylene optionally substituted with up to two C.sub.1-6 alkyl radicals, or A and B, taken together, form a bivalent radical of formula (c) wherein the hydrogen atom may be replaced by a C.sub.1-6 alkyl radical; and R.sup.1 is tetrahydrofuranylC.sub.1-6 alkyl, or C.sub.3-6 cycloalkyl substituted with oxo or hydroxy, or C.sub.1-6 alkyl or arylC.sub.1-6 alkyl both substituted on the C.sub.1-6 alkyl moiety with oxo or with one or two radicals of formula --O--R.sup.1-a, or where R.sup.1 is substituted with two --O--R.sup.1-a radicals, the two --R.sup.1-a radicals, taken together, may form a bivalent radical of formula --C(CH.sub.3).sub.2 -- or --CH.sub.2 --CH.sub.2 --.

5. A chemical compound according to claim 4 wherein R.sup.1 is C.sub.3-6 cycloalkyl substituted with oxo or hydroxy, or C.sub.1-6 alkyl or arylC.sub.1-6 alkyl both substituted on the C.sub.1-6 alkyl moiety with oxo or with one or two hydroxy or C.sub.1-6 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(CH.sub.3).sub.2 or CH.sub.2, B is CH.sub.2 or >C.dbd.O, or A and B, taken together, form a radical (c) wherein the hydrogen atom may be replaced by a methyl radical; and R.sup.1 is C.sub.1-6 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, wherein

Q is N or CH;

Ar is aryl;

R is hydrogen or C.sub.1-6 alkyl; and

Y--R.sup.1 is a radical having the formula ##STR21## or a radical having the formula ##STR22## wherein R.sup.1 is tetrahydrofuranylC.sub.1-6 alkyl; or C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, arylC.sub.1-6 alkyl or (C.sub.3-6 cycloalkyl)C.sub.1-6 alkyl all substituted on the C.sub.1-6 alkyl and/or C.sub.3-6 cycloalkyl moiety with oxo, thioxo or with one or two radicals of formula --Z--R.sup.1-a ;

said Z being O or S;

said R.sup.1-a being hydrogen; C.sub.1-6 alkyl, aryl, C.sub.3-6 cycloalkyl or tetrahydro-2H-pyran-2-yl;

or where R.sup.1 is substituted with two --Z--R.sup.1-a radicals, the two --R.sup.1-a radicals, taken together, may form a bivalent radical of formula --CH.sub.2 --, --CH(CH.sub.3)--, --C(CH.sub.3).sub.2 --, --CH.sub.2 --CH.sub.2 --, --CH(CH.sub.3)--CH.sub.2 -- or --CH.sub.2 --CH.sub.2 --CH.sub.2 --;

X is O, S or NR.sup.2 ;

said R.sup.2 being hydrogen or C.sub.1-6 alkyl;

A is >C.dbd.O, NR.sup.3, methylene or methylene substituted with up to two radicals selected from the group consisting of C.sub.1-6 alkyl and aryl;

said R.sup.3 being hydrogen or C.sub.1-6 alkyl;

B is >C.dbd.O or methylene optionally substituted with up to two C.sub.1-6 alkyl radicals;

or A and B, taken together, form a bivalent radical of formula

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

wherein the nitrogen atom in the bivalent radical (c) is connected to NR.sup.1 ; wherein one hydrogen in said radical (c) and up to two hydrogens in radical (d) may be replaced by a C.sub.1-6 alkyl radical; provided that

(i) when Y--R.sup.1 is a radical of formula (a) wherein --A--B-- is other than a bivalent radical of formula (c), then R.sup.1 is other than C.sub.1-6 alkyl substituted with C.sub.1-6 alkyloxy;

(ii) when Y--R.sup.1 is a radical of formula (b) then R.sup.1 is other than C.sub.1-6 alkyl substituted with C.sub.1-6 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, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, and trifluoromethyl.

8. A composition according to claim 7 wherein Y--R.sup.1 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--R.sup.1 is a radical of formula (a).

10. A composition according to claim 9 wherein X is O; A and B are independently >C.dbd.O or methylene optionally substituted with up to two C.sub.1-6 alkyl radicals, or A and B, taken together, form a bivalent radical of formula (c) wherein the hydrogen atom may be replaced by a C.sub.1-6 alkyl radical; and R.sup.1 is tetrahydrofuranylC.sub.1-6 alkyl, or C.sub.3-6 cycloalkyl substituted with oxo or hydroxy, or C.sub.1-6 alkyl or arylC.sub.1-6 alkyl both substituted on the C.sub.1-6 alkyl moiety with oxo or with one or two radicals of formula --O--R.sup.1-a, or where R.sup.1 is substituted with two --O--R.sup.1-a radicals, the two --R.sup.1-a radicals, taken together, may form a bivalent radical of formula --C(CH.sub.3).sub.2 -- or --CH.sub.2 --CH.sub.2 --.

11. A composition according to claim 10 wherein R.sup.1 is C.sub.3-6 cycloalkyl substituted with oxo or hydroxy, or C.sub.1-6 alkyl or arylC.sub.1-6 alkyl both substituted on the C.sub.1-6 alkyl moiety with oxo or with one or two hydroxy or C.sub.1-6 alkyloxy radicals.

12. A composition according to claim 11 wherein Ar is phenyl substituted with two halo atoms; R is hydrogen; A is C(CH.sub.3).sub.2 or CH.sub.2, B is CH.sub.2 or >C.dbd.O, or A and B, taken together, form a radical (c) wherein the hydrogen atom may be replaced by a methyl radical; and R.sup.1 is C.sub.1-6 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, wherein

Q is N or CH;

Ar is aryl;

R is hydrogen or C.sub.1-6 alkyl; and

Y--R.sup.1 is a radical having the formula ##STR24## or a radical having the formula ##STR25## wherein R.sup.1 is tetrahydrofuranylC.sub.1-6 alkyl; or C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, arylC.sub.1-6 alkyl or (C.sub.3-6 cycloalkyl)C.sub.1-6 alkyl all substituted on the C.sub.1-6 alkyl and/or C.sub.3-6 cycloalkyl moiety with oxo, thioxo or with one or two radicals of formula --Z--R.sup.1-a ;

said Z being O or S;

said R.sup.1-a being hydrogen, C.sub.1-6 alkyl, aryl, C.sub.3-6 cycloalkyl or tetrahydro-2H-pyran-2-yl;

or where R.sup.1 is substituted with two --Z--R.sup.1-a radicals, the two --R.sup.1-a radicals, taken together, may form a bivalent radical of formula --CH.sub.2 --, --CH(CH.sub.3)--, --C(CH.sub.3).sub.2 --, --CH.sub.2 --CH.sub.2 --, --CH(CH.sub.3)--CH.sub.2 -- or --CH.sub.2 --CH.sub.2 --CH.sub.2 --;

X is O, S or NR.sup.2 ;

said R.sup.2 being hydrogen or C.sub.1-6 alkyl;

A is >C.dbd.O, NR.sup.3, methylene or methylene substituted with up to two radicals selected from the group consisting of C.sub.1-6 alkyl and aryl;

said R.sup.3 being hydrogen or C.sub.1-6 alkyl;

B is >C.dbd.O or methylene optionally substituted with up to two C.sub.1-6 alkyl radicals;

or A and B, taken together, form a bivalent radical of formula

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

wherein the nitrogen atom in the bivalent radical (c) is connected to NR.sup.1 ; wherein one hydrogen in said radical (c) and up to two hydrogens in radical (d) may be replaced by a C.sub.1-6 alkyl radical; provided that

(i) when Y--R.sup.1 is a radical of formula (a) wherein --A--B-- is other than a bivalent radical of formula (c), then R.sup.1 is other than C.sub.1-6 alkyl substituted with C.sub.1-6 alkyloxy;

(ii) when Y--R.sup.1 is a radical of formula (b) then R.sup.1 is other than C.sub.1-6 alkyl substituted with C.sub.1-6 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, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, and trifluoromethyl.

14. A method according to claim 13 wherein Y--R.sup.1 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--R.sup.1 is a radical of formula (a).

16. A method according to claim 15 wherein X is O; A and B are independently >C.dbd.O or methylene optionally substituted with up to two C.sub.1-6 alkyl radicals, or A and B, taken together, form a bivalent radical of formula (c) wherein the hydrogen atom may be replaced by a C.sub.1-6 alkyl radical; and R.sup.1 is tetrahydrofuranylC.sub.1-6 alkyl, or C.sub.3-6 cycloalkyl substituted with oxo or hydroxy, or C.sub.1-6 alkyl or arylC.sub.1-6 alkyl both substituted on the C.sub.1-6 alkyl moiety with oxo or with one or two radicals of formula --O--R.sup.1-a, or where R.sup.1 is substituted with two --O--R.sup.1-a radicals, the two --R.sup.1-a radicals, taken together, may form a bivalent radical of formula --C(CH.sub.3).sub.2 -- or --CH.sub.2 --CH.sub.2 --.

17. A method according to claim 16 wherein R.sup.1 is C.sub.3-6 cycloalkyl substituted with oxo or hydroxy, or C.sub.1-6 alkyl or arylC.sub.1-6 alkyl both substituted on the C.sub.1-6 alkyl moiety with oxo or with one or two hydroxy or C.sub.1-6 alkyloxy radicals.

18. A method according to claim 17 wherein Ar is phenyl substituted with two halo atoms; R is hydrogen; A is C(CH.sub.3).sub.2 or CH.sub.2, B is CH.sub.2 or >C.dbd.O, or A and B, taken together, form a radical (c) wherein the hydrogen atom may be replaced by a methyl radical; and R.sup.1 is C.sup.1-6 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 C.sub.1-6 alkyl radicals.

20. A substituted phenol of the following formula (V): ##STR26## or a stereochemically isomeric form thereof, wherein R is hydrogen or C.sub.1-6 alkyl; and

Y--R.sup.1 is a radical having the formula ##STR27## or a radical having the formula ##STR28## wherein R.sup.1 is tetrahydrofuranylC.sub.1-6 alkyl; or C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, arylC.sub.1-6 alkyl or (C.sub.3-6 cycloalkyl)C.sub.1-6 alkyl all substituted on the C.sub.1-6 alkyl and/or C.sub.3-6 cycloalkyl moiety with oxo, thioxo or with one or two radicals of formula --Z--R.sup.1-a ;

said Z being O or S;

said R.sup.1-a being hydrogen, C.sub.1-6 alkyl, aryl, C.sub.3-6 cycloalkyl or tetrahydro-2H-pyran-2-yl;

or wherein R.sup.1 is substituted with two --Z--R.sup.1-a radicals, the two --R.sup.1-a radicals, taken together, may form a bivalent radical of formula --CH.sub.2 --, --CH(CH.sub.3)--, --C(CH.sub.3).sub.2 --, --CH.sub.2 --CH.sub.2 --, --CH(CH.sub.3)--CH.sub.2 -- or --CH.sub.2 --CH.sub.2 --CH.sub.2 --;

X is O, S or NR.sup.2 ;

said R.sup.2 being hydrogen or C.sub.1-6 alkyl;

A is >C.dbd.O, NR.sup.3, methylene or methylene substituted with up to two radicals selected from the group consisting of C.sub.1-6 alkyl and aryl;

said R.sup.3 being hydrogen or C.sub.1-6 alkyl;

B is >C.dbd.O or methylene optionally substituted with up to two C.sub.1-6 alkyl radicals;

or A and B, taken together, form a bivalent radical of formula

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

wherein the nitrogen atom in the bivalent radical (c) is connected to NR.sup.1 ; wherein one hydrogen in said radical (c) and up to two hydrogens in radical (d) may be replaced by a C.sub.1-6 alkyl radical; provided that

(i) when Y--R.sup.1 is a radical of formula (a) wherein --A--B-- is other than a bivalent radical of formula (c), then R.sup.1 is other than C.sub.1-6 alkyl substituted with C.sub.1-6 alkyloxy;

(ii) when Y--R.sup.1 is a radical of formula (b) then R.sup.1 is other than C.sub.1-6 alkyl substituted with C.sub.1-6 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, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy and trifluoromethyl.

21. A chemical compound according to claim 20, wherein Y--R.sup.1 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--R.sup.1 is a radical of formula (a).

23. A chemical compound according to claim 21, wherein X is O; A and B are independently >C.dbd.O, methylene or methylene optionally substituted with up to two C.sub.1-6 alkyl radicals, or A and B, taken together, form a bivalent radical of formula (c) wherein the hydrogen atom may be replaced by a C.sub.1-6 alkyl radical; and R.sup.1 is tetrahydrofuranylC.sub.1-6 alkyl, or C.sub.3-6 cycloalkyl substituted with oxo or hydroxy, or C.sub.1-6 alkyl or arylC.sub.1-6 alkyl both substituted on the C.sub.1-6 alkyl moiety with oxo or with one or two radicals of formula --O--R.sup.1-a, or where R.sup.1 is substituted with two --O--R.sup.1-a radicals, the two --R.sup.1-a radicals, taken together, may form a bivalent radical of formula --C(CH.sub.3).sub.2 -- or --CH.sub.2 --CH.sub.2 --.

24. A chemical compound according to claim 23, wherein R.sup.1 is C.sub.3-6 cycloalkyl substituted with oxo or hydroxy, or C.sub.1-6 alkyl or arylC.sub.1-6 alkyl both substituted on the C.sub.1-6 alkyl moiety with oxo or with one or two hydroxy or C.sub.1-6 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-hydroxyphe nyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one;

2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(2-oxocyclope ntyl)-3H-1,2,4-triazol-3-one;

2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(2-oxocyclohe xyl)-3H-1,2,4-triazol-3-one.
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