Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-08-29
1999-08-10
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514252, 514253, 514255, 544121, 544295, 544357, 544360, 544361, 544363, 544385, A61K 31495, C07D24102, C07D40112, C07D40314
Patent
active
059359552
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to compounds useful as modulators of multi-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 piperazinedione derivatives have activity as modulators of multi-drug resistance. The present invention therefore provides a piperazinedione derivative of formula (I): ##STR4## wherein R.sup.1 is selected from: hydrogen; is selected from: ##STR5## wherein v is 0 when t is 1 and v is 1 when t is 0; and wherein n is 0 or 1 and m is 0, 1, 2 or 3, at least one of n and m being other than 0, and either: alkyl optionally substituted by one or two phenyl groups, the phenyl group or groups being optionally substituted by one or two C.sub.1 -C.sub.6 alkoxy groups; or attached, form a heterocyclic group selected from (1) to (4): ##STR6## wherein R.sup.6 and R.sup.7, which are the same or different, are H or C.sub.1 -C.sub.6 alkoxy or R.sup.6 and R.sup.7 form together a methylenedioxy group; Y is 0 or --NR.sup.8 wherein R.sup.8 is C.sub.1 -C.sub.6, alkyl or a phenyl group optionally substituted by CF.sub.3 ; optionally substituted by C.sub.1 -C.sub.6 alkoxy; and ##STR7## wherein R.sup.9 is C.sub.1 -C.sub.6 alkyl, pyrimidinyl or a phenyl group optionally substituted by C.sub.1 -C.sub.6 alkoxy; and ##STR8## wherein w is 1, 2 or 3 and L is a heterocyclic group of formula (1) as defined above; ##STR9## wherein each of R.sup.10 and R.sup.11, which may be the same or different, is C.sub.1 -C.sub.6 alkyl; and ##STR10## wherein s is 0 or 1 and each r, which may be the same or different, is 1, 2 or 3 and L is a heterocyclic group of formula (1) as defined above; provided that one of R.sup.1 and R.sup.2 is hydrogen and the other is not hydrogen; or a pharmaceutically acceptable salt thereof.
An alkyl group may be linear or branched. 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 or tert-butyl group. A C.sub.1 -C.sub.6 alkoxy group is typically a C.sub.1 -C.sub.4 alkoxy group, for example a methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, sec-butoxy or tert-butoxy group.
When R.sup.1 is a group of formula --(NH).sub.t --COR.sup.3, t may be 0 in which case the group has the formula --COR.sup.3. The integer v in formula (A) is then 1. When R.sup.3 is a group of formula (A), n is typically 1 and m is 0, 1, 2 or 3, or n is 0 and m is 2. R.sup.4
REFERENCES:
patent: 5700804 (1997-12-01), Collins et al.
patent: 5750530 (1998-05-01), Bryans et al.
Bellamy et al, Cancer Investigations8 pp. 547-562, 1990.
Hill, International Journal of Oncology 9 197-203 1996 "Drug Resistance: An overview of the current state of the art".
Dale et al, British J. of Cancer (1998) 78 (7), 885 to 892 Reversal of P-glycoprotein-mediated multidrug etc.
Germann, European J. of Cancer vol. 32 A, No. 6, pp. 927-944, 1996 "P-glycoprotein--A Mediator of Multidrug Resistance in Tumour Cells".
British Journal of Cancer (1997), 75 (suppl 1), abstracts 1.8 and P58 of two posters by Tuffley et al and Mistry et al.
Annals of Oncology 7 (suppl. 1) Mar. 1996, No. 434, Luscombe et al.
Ann. Rev. of Biochemistry 62 (1993) 385-427: Gottesman et al.
Prospectus for the public offering of shares in Xenova Limited Dec. 19, 1996 (cover, inside sheet and p. 51) by Xenova Limited.
Ashworth Philip A.
Brocchini Stephen J.
Hunjan Sukhjit
Pretswell Ian A.
Ryder Harnish
Bernhardt Emily
Xenova Limited
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