Pharmaceutical compounds

Details Pharmaceutical compounds Pharmaceutical compounds

1996-11-04

1999-01-19

Bernhardt, Emily

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514253, 514255, 544360, 544364, 544372, 544373, 544379, 544385, 544405, 544408, A61K 31495, C07D40106, C07D40306, C07D40506

Patent

active

058614001

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 act on 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 diketopiperazine derivatives have activity as modulators of multiple drug resistance. The present invention therefore provides a piperazine of general formula (A): ##STR2## wherein denotes an optional bond, provided that both ##STR3## and ##STR4## are bonds and ##STR5## and ##STR6## are not bonds, or both ##STR7## and ##STR8## are bonds and ##STR9## and ##STR10## are not bonds; X and Y, which may be the same or different, are independently selected from indole, the indole ring being optionally N-substituted by phthalimidyl-C.sub.1 -C.sub.6 -alkyl, succinimidyl-C.sub.1 -C.sub.6 -alkyl, oxo- or dioxo-indolenyl, --(CH.sub.2).sub.n COOR.sub.11, or --(CH.sub.2).sub.n COOCH.sub.2 Ph, wherein R.sub.11 is H or C.sub.1 -C.sub.6 alkyl and n is 0, 1 or 2; substituents selected from halogen, C.sub.1 -C.sub.6 alkoxy, --NO.sub.2 and NR.sub.11 R.sub.12 wherein R.sub.11 and R.sub.12 are each, independently, H or C.sub.1 -C.sub.6 alkyl; substituted phenyl, the optional substituents on the phenyl ring in each case being selected from halogen, --NO.sub.2, --N(R.sub.11 R.sub.12) wherein R.sub.11 and R.sub.12 are as defined above and C.sub.1 -C.sub.6 alkoxy; N-phthalimidyl, N-succinimidyl or oxo- or dioxo-indolenyl group and N-phthalimidyl, N-succinimidyl or oxo- or dioxo-indolenyl group; ##STR11## and ##STR12## are both bonds at least one of R.sub.14 and R.sub.15 is other than hydrogen;
In one embodiment the piperazine is of the following formula (Aa): ##STR13## wherein R.sub.14, R.sub.15, X and Y are as defined above.
In another embodiment the piperazine is of the following formula (Ab): ##STR14## wherein R.sub.14, R.sub.16, X and Y are as defined above.
When either X or Y is a substituted phenyl ring, the benzene ring may be substituted at any of the ortho, meta and para positions by one or more substituents, for example one, two or three substituents, which may be the same or different, independently selected from the groups specified under (ii) above.
An alkyl group may be linear or branched, or may comprise a cycloalkyl group. A C.sub.1 -C.sub.6 alkyl group is typically a C.sub.1 -C.sub.4 alkyl group, for example a methyl, ethyl, propyl, i-propyl, n-butyl, sec-butyl, tert-butyl or cyclopropylmethyl group. A halogen is, for

REFERENCES:
Chemical Abstracts, vol. 109, No. 3, 1988, Columbus, Ohio, U.S.; abstract No.16593a, Toshio Yokoi et al,.
Chemical Abstracts, vol. 69, No. 28, 1968, Columbus, Ohio, US; abstract No. 96654q, R.F.C. Brown.
Bellamy et al, Cancer Investigation 8(5), pp. 547-562 (1990).
Yokoi et al, J. of Antiobiotics vol. XLI, No. 4 pp. 494-501 (1988).
Wu et al, Chemical Abstracts, vol.. 113, No. 17408p (1990).
Kamel et al, J. of Antibiotics vol. XLIII, No. 8, pp. 1018-1020 (1990).

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