US 5,852,018 AGranted

Pharmaceutical piperazine compounds

AssigneeXenova Limited

InventorsJustin Stephen Bryans, Christopher John Latham, Stephen James Brocchini

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Abstract

Piperazine derivatives of formula (A): ##STR1## wherein .sub.-------- denotes an optional bond, provided that either .sub.----.sup.a.sub.---- and .sub.----.sup.c.sub.---- are both bonds and .sub.----.sup.b.sub.---- and .sub.----.sup.d.sub.---- are not bonds, or .sub.----.sup.b.sub.---- and .sub.----.sup.d.sub.---- are both bonds and .sub.----.sup.a.sub.---- and .sub.----.sup.c.sub.---- are not bonds; each of R.sub.14 and R.sub.15 is independently selected from hydrogen and C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by an organic functional group; and each of R.sub.1 to R.sub.10, which may be the same or different, is independently hydrogen or an organic functional group; and the pharmaceutically acceptable salts and esters thereof have utility as modulators of multiple drug resistance (MDR).

Claims10

Dependent claims

A compound which is selected from:

(3Z,6Z)-3,6-Dibenzylidene-4-methyl-2,5-dioxo-1-piperazinylpropionaldehyde ethylene acetal;
methyl-3,6-dihydro-2-pyrazinone;
(3Z,6Z)-1-Allyl-3,6-dibenzylidene-4-methyl-2,5-piperazinedione;
(3Z,6Z)-1,4-Dibenzyl-3,6-dibenzylidene-2,5-piperazinedione;
(3Z,6Z)-3,6-Dibenzylidene-1-methyl-4-(3-nitrobenzylidene)-2,5-piperazinedio ne;
(3Z,6Z)-1-(2-Acetoxyethyl)-3,6-dibenzylidene-4-methyl-2,5-piperazinedione;
(3Z,6Z)-3,6-Dibenzylidene-1-(2-bromoethyl)-4-methyl-2,5-piperazinedione;
(3Z,6Z)-3,6-Dibenzylidene-1-methyl-4-(4-nitrobenzylidene)-2,5-piperazinedio ne;
Methyl (3Z,6Z)-3-benzylidene-6-(4-methoxybenzylidene)-2,5-dioxo-1-piperazinylacet ate;
N,N-Dimethyl-((3Z,6Z)-3-benzylidene-6-(4-methoxybenzylidene)-2,5-dioxo-1-pi perazinyl)acetamide;
N,N-Diethyl-(3Z,6Z)-6-benzylidene-3-(4-methoxybenzylidene)-2,5-dioxo-1-pipe razinylacetamide;
(3Z,6Z)-1-Benzyl-3,6-dibenzylidene-4-methyl-2,5-piperazinedione;
(3Z,6Z)-3,6-Dibenzylidene-1-(2-hydroxyethyl)-4-methyl-2,5-piperazinedione;
(3Z,6Z)-3,6-Dibenzylidene-4-methyl-1-phenethyl-2,5-piperazinedione;
(3Z,6Z)-3,6-Dibenzylidene-4-methyl-2,5-dioxo-1-piperazinylacetonitrile;
(3Z,6Z)-3,6-Dibenzylidene-1-(4-bromobut-2-enyl)-4-methyl-2,5-piperazinedion e;
(3Z,6Z)-3,6-Dibenzylidene-1-(but-2-enyl)-4-methyl-2,5-piperazinedione;
(3Z,6Z)-1-Benzyl-6-(2,6-dichlorobenzylidene)-3-(4-methoxybenzylidene)-4-met hyl-2,5-piperazinedione;
(3Z,6Z)-1-Benzyl-6-(4-methoxybenzylidene)-4-methyl-3-(2-nitrobenzylidene)-2 ,5-piperazinedione;
and the pharmaceutically acceptable salts thereof.

17 more elements

A compound selected from the group consisting of a piperazine of formula (Aa):

##STR20## wherein each of R.sub.14 and R.sub.15 is independently selected from hydrogen and C.sub.2 -C.sub.6 alkyl which is unsubstituted or substituted by a group selected from halogen, phenyl, C.sub.1 -C.sub.6 alkenylene, cyano, hydroxy, --OC(O)R.sub.11, --N(R.sub.11 R.sub.12), --CON(R.sub.11 R.sub.12), --COOR.sub.11, a group succinimidyl, phthalimidyl or ##STR21## provided that at least one of R.sub.14 and R.sub.15 is C.sub.1 -C.sub.6 alkyl substituted as defined above;
and each of R.sub.1 to R.sub.10, which may be the same or different, is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by one or more halogen atoms, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, halogen, hydroxy, nitro, phenyl, cyano, --CH.sub.2 OH, --CH.sub.2 COOH, --CO.sub.2 R.sub.11, --NHCOR.sup.11, --NHSO.sub.2 R.sup.13, --SO.sub.2 R.sup.13, --CON(R.sup.11 R.sup.12), --SOR.sup.13, --SO.sub.2 N(R.sup.11 R.sup.12), --N(R.sup.11 R.sup.12), --O(CH.sub.2).sub.n N(R.sup.11 R.sup.12), --O(CH.sub.2).sub.n CO.sub.2 R.sup.11, --OCOR.sup.11, --CH.sub.2 OCOR.sup.11, --CH.sub.2 NHCOR.sup.11, --CH.sub.2 NHCOOR.sup.13, --CH.sub.2 SR.sup.11, --CH.sub.2 SCOR.sup.11, --CH.sub.2 S(O).sub.m R.sup.13 wherein m is 1 or 2, --CH.sub.2 NHCO(CH.sub.2).sub.n CO.sub.2 R.sup.11, --N(R.sup.11)COR.sup.12, --NHCOCF.sub.3, --NHCO(CH.sub.2).sub.n CO.sub.2 R.sup.11, --NHCO(CH.sub.2).sub.n OCOR.sup.11 and --NHCO(CH.sub.2).sub.n OR.sup.11,
wherein n is 0 or is an integer of from 1 to 6, each of R.sup.11 and R.sup.12 is independently H or C.sub.1 -C.sub.6 alkyl or, when R.sup.11 and R.sup.12 are attached to the same nitrogen atom, they may alternatively form with the nitrogen atom an N,N-tetramethylene group;
and R.sup.13 is C.sub.1 -C.sub.6 alkyl;
the pharmaceutically acceptable salts thereof and the pharmaceutically acceptable esters thereof selected from the group consisting of branched and unbranched, saturated and unsaturated C.sub.1 -C.sub.6 alkyl esters.

2 more elements

A method of treating resistance to an anthracycline antibiotic having neoplastic activity in a patient harboring a tumour, which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of a piperazine of formula (A):

##STR23## wherein .sub.-------- denotes an optional bond, provided that either .sub.----.sup.a.sub.---- and .sub.----.sup.c.sub.---- are both bonds and .sub.----.sup.b.sub.---- and .sub.----.sup.d.sub.---- are not bonds, or .sub.----.sup.b.sub.---- and .sub.----.sup.d.sub.---- are both bonds and .sub.----.sup.a.sub.---- and .sub.----.sup.c.sub.---- are not bonds;
each of R.sub.14 and R.sub.15 is independently selected from hydrogen and C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by a group selected from halogen, phenyl, C.sub.2 -C.sub.6 alkenylene, cyano, hydroxy, --OC(O)R.sub.11, --N(R.sub.11 R.sub.12), --CON(R.sub.11 R.sub.12), --COOR.sub.11, a group succinimidyl, phthalimidyl or ##STR24## provided that when .sub.----.sup.b.sub.---- and .sub.----.sup.d.sub.---- are both bonds at least one of R.sub.14 and R.sub.15 is C.sub.1 -C.sub.6 alkyl substituted as defined above;
R.sub.16 is C.sub.1 -C.sub.6 alkyl unsubstituted or substituted either as defined above for R.sub.14 and R.sub.15 or substituted by a 4-pyridyl group;
and each of R.sub.1 to R.sub.10, which may be the same or different, is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by one or more halogen atoms, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, halogen, hydroxy, nitro, phenyl, cyano, --CH.sub.2 OH, --CH.sub.2 COOH, --CO.sub.2 R.sup.11, --NHCOR.sup.11, --NHSO.sub.2 R.sup.13, --SO.sub.2 R.sup.13, --CON(R.sup.11 R.sup.12), --SOR.sup.13, --SO.sub.2 N(R.sup.11 R.sup.12), --N(R.sup.11 R.sup.12), --O(CH.sub.2).sub.n N(R.sup.11 R.sup.12), --O(CH.sub.2).sub.n CO.sub.2 R.sup.11, --OCOR.sup.11, --CH.sub.2 OCOR.sup.11, --CH.sub.2 NHCOR.sup.11, --CH.sub.2 NHCOOR.sup.13, --CH.sub.2 SR.sup.11, --CH.sub.2 SCOR.sup.11, --CH.sub.2 S(O).sub.m R.sup.13 wherein m is 1 or 2, --CH.sub.2 NHCO(CH.sub.2).sub.n CO.sub.2 R.sup.11, --N(R.sup.11)COR.sup.12, --NHCOCF.sub.3, --NHCO(CH.sub.2).sub.n CO.sub.2 R.sup.11, --NHCO(CH.sub.2).sub.n OCOR.sup.11 and --NHCO(CH.sub.2).sub.n OR.sup.11 ;
wherein n is 0 or is an integer of from 1 to 6, each of R.sup.11 and R.sup.12 is independently H or C.sub.1 -C.sub.6 alkyl or, when R.sup.11 and R.sup.12 are attached to the same nitrogen atom, they may alternatively form with the nitrogen atom an N,N-tetramethylene group;
and R.sup.13 is C.sub.1 -C.sub.6 alkyl;
the pharmaceutically acceptable salts thereof and the pharmaceutically acceptable esters thereof selected from the group consisting of branched and unbranched, saturated and unsaturated C.sub.1 -C.sub.6 alkyl esters.

4 more elements

A method of treating resistance to an anthracycline antibiotic having neoplastic activity in a patient harbouring a tumour, which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of a piperazine of formula (Aa):

##STR25## wherein each of R.sub.14 and R.sub.15 is independently selected from hydrogen and C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by a group selected from halogen, phenyl, optionally substituted C.sub.2 -C.sub.6 alkenylene, cyano, hydroxy, --OC(O)R.sub.11, --N(R.sub.11 R.sub.12), --CON(R.sub.11 R.sub.12), --COOR.sub.11, a group succinimidyl, phthalimidyl or ##STR26## provided that at least one of R.sub.14 and R.sub.15 is C.sub.1 -C.sub.6 alkyl substituted as defined above;
and each of R.sub.1 to R.sub.10, which may be the same or different, is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by one or more halogen atoms, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, halogen, hydroxy, nitro, optionally substituted phenyl, cyano, --CH.sub.2 OH, --CH.sub.2 COOH, --CO.sub.2 R.sup.11, --NHCOR.sup.11, --NHSO.sub.2 R.sup.13, --SO.sub.2 R.sup.13, --CON(R.sup.11 R.sup.12), --SOR.sup.13, --SO.sub.2 N(R.sup.11 R.sup.12), --N(R.sup.11 R.sup.12), --O(CH.sub.2).sub.n N(R.sup.11 R.sup.12), --O(CH.sub.2).sub.n CO.sub.2 R.sup.11, --OCOR.sup.11, --CH.sub.2 OCOR.sup.11, --CH.sub.2 NHCOR.sup.11, --CH.sub.2 NHCOOR.sup.13, --CH.sub.2 SR.sup.11, --CH.sub.2 SCOR.sup.11, --CH.sub.2 S(O).sub.m R.sup.13 wherein m is 1 or 2, --CH.sub.2 NHCO(CH.sub.2).sub.n CO.sub.2 R.sup.11, --N(R.sup.11)COR.sup.12, --NHCOCF.sub.3, --NHCO(CH.sub.2).sub.n CO.sub.2 R.sup.11, --NHCO(CH.sub.2).sub.n OCOR.sup.11 and --NHCO(CH.sub.2).sub.n OR.sup.11 ;
wherein n is 0 or is an integer of from 1 to 6, each of R.sup.11 and R.sup.12 is independently H or C.sub.1 -C.sub.6 alkyl or, when R.sup.11 and R.sup.12 are attached to the same nitrogen atom, they may alternatively form with the nitrogen atom an N,N-tetramethylene group;
and R.sup.13 is C.sub.1 C.sub.6 alkyl;
the pharmaceutically acceptable salts thereof and the pharmaceutically acceptable esters thereof selected from the group consisting of branched and unbranched, saturated and unsaturated C.sub.1 -C.sub.6 alkyl esters.

2 more elements

A method of treating resistance to an anthracycline antibiotic having a neoplastic activity in a patient harbouring a tumour, which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of a piperazine of formula (Ab):

##STR27## wherein R.sub.14 is selected from hydrogen and C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by a group selected from halogen, optionally substituted phenyl, optionally substituted C.sub.2 -C.sub.6 alkenyl, cyano, hydroxy, --OC(O)R.sub.11, --N(R.sub.11 R.sub.12), --CON(R.sub.11 R.sub.12), --COOR.sub.11, a group succinimidyl, phthalimidyl or ##STR28## R.sub.16 is C.sub.1 -C.sub.6 alkyl unsubstituted or substituted either as defined above for R.sub.14 or substituted by a 4-pyridyl group;
and each of R.sub.1 to R.sub.10, which may be the same or different, is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by one or more halogen atoms, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, halogen, hydroxy, nitro, optionally substituted phenyl, cyano, --CH.sub.2 OH, --CH.sub.2 COOH, --CO.sub.2 R.sup.11, --NHCOR.sup.11, --NHSO.sub.2 R.sup.13, --SO.sub.2 R.sup.13, --CON(R.sup.11 R.sup.12), --SOR.sup.13, --SO.sub.2 N(R.sup.11 R.sup.12), --N(R.sup.11 R.sup.12), --O(CH.sub.2).sub.n N(R.sup.11 R.sup.12), --O(CH.sub.2).sub.n CO.sub.2 R.sup.11, --OCOR.sup.11, --CH.sub.2 OCOR.sup.11, --CH.sub.2 NHCOR.sup.11, --CH.sub.2 NHCOOR.sup.13, --CH.sub.2 SR.sup.11, --CH.sub.2 SCOR.sup.11, --CH.sub.2 S(O).sub.m R.sup.13 wherein m is 1 or 2, --CH.sub.2 NHCO(CH.sub.2).sub.n CO.sub.2 R.sup.11, --N(R.sup.11)COR.sup.12, --NHCOCF.sub.3, --NHCO(CH.sub.2).sub.n CO.sub.2 R.sup.11, --NHCO(CH.sub.2).sub.n OCOR.sup.11 and --NHCO(CH.sub.2).sub.n OR.sup.11 ;
wherein n is 0 or is an integer of from 1 to 6, each of R.sup.11 and R.sup.12 is independently H or C.sub.1 -C.sub.6 alkyl or, when R.sup.11 and R.sup.12 are attached to the same nitrogen atom, they may alternatively form with the nitrogen atom an N,N, tetramethylene group;
and R.sup.13 is C.sub.1 -C.sub.6 alkyl;
the pharmaceutically acceptable salts thereof and the pharmaceutically acceptable esters thereof selected from the group consisting of branched and unbranched, saturated and unsaturated C.sub.1 -C.sub.6 alkyl esters.

2 more elements

Dependencies are inferred from the claim text.