Pharmaceutical piperazine compounds

Details Pharmaceutical piperazine compounds Pharmaceutical piperazine compounds

1996-11-04

1998-12-22

Bernhardt, Emily

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514183, 514250, 514253, 514255, 540480, 544344, 544360, 544372, 544373, 544374, 544385, A61K 31495, C07D24108, C07D40306

Patent

active

058520180

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to compounds useful as modulators of multiple drug resistance (MDR), to their preparation and to pharmaceutical and veterinary compositions containing them.
The resistance of tumours to treatment with certain cytotoxic agents is an obstacle to the successful chemotherapeutic treatment of cancer patients. A tumour may acquire resistance to a cytotoxic agent used in a previous treatment. A tumour may also manifest intrinsic resistance, or cross-resistance, to a cytotoxic agent to which it has not previously been exposed, that agent being unrelated by structure or mechanism of action to any agent used in previous treatments of the tumour.
Analogously, certain pathogens may acquire resistance to pharmaceutical agents used in previous treatments of the diseases or disorders to which those pathogens give rise. Pathogens may also manifest intrinsic resistance, or cross resistance, to pharmaceutical agents to which they have not previously been exposed. Examples of this effect include multi-drug resistant forms of malaria, tuberculosis, leishmaniasis and amoebic dysentery.
The above phenomena are referred to collectively as multi-drug resistance (MDR). As discussed more fully later on, a plasma membrane glycoprotein (P-gp) is implicated in the mechanism which underlies MDR. P-gp has drug binding properties. Certain agents which have the capacity to modulate MDR may therefore also be useful in facilitating the delivery of drugs across the blood-brain barrier and in treating AIDS and AIDS-related complex.
Disadvantages of drugs which have so far been used to modulate MDR, termed resistance modifying agents or RMAs, are that they frequently possess a poor pharmacokinetic profile and/or are toxic at the concentrations required for MDR modulation.
It has now been found that a series of piperazine derivatives have activity as modulators of multiple drug resistance. The present invention therefore provides a piperazine of formula (A): ##STR2## 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, optionally substituted phenyl, optionally substituted C.sub.1 -C.sub.6 alkenyl, cyano, hydroxy, --OC(O)R.sup.11, --N(R.sup.11 R.sup.12) --CON(R.sup.11 R.sup.12), --COOR.sup.11, succinimido, phthalimido, and ##STR3## 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; or R.sub.14 forms a --CH.sub.2 -- linkage to ring a, thereby completing a 6-membered N-containing heterocycle with the nitrogen to which it is attached; 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 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,

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