Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-01
2001-10-02
Raymond, Richard L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S256000
Reexamination Certificate
active
06297250
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to dipyridamole analogues that are of interest as being potentially useful chemotherapeutic agents, especially insofar as they possess an ability to inhibit or modulate the transport of certain purine compounds and nucleosides across cell membranes of at least some cell types and are able thereby to enhance or potentiate the activity of certain cytotoxic drugs.
BACKGROUND
The compound 2,6-bis(diethanolamino)-4,8-dipiperidinopyrimidopyrimidine, known as dipyridamole and referred to as such in the present specification, and some particular close analogues thereof have been known for some considerable time as effective vasodilator and thrombolytic agents, as disclosed for example in patent documents GB799177 and GB807826 which also describe various methods of synthesis of such compounds. Although the pharmacological activity of dipyridamole is diverse, in at least most cases it is believed to arise as a result of its ability to inhibit or modulate the transport of nucleosides across cell membranes, this nucleoside transport being a major factor which is often implicated in the development of antitumor drug resistance. Not only can dipyridamole directly modulate the activity of cytotoxic compounds which are themselves nucleosides, e.g. cytarabine, fluordeoxyuridine and deoxycoformycin, or which are bases that become converted within the cell into nucleosides, e.g. fluorouracil, but dipyridamole can also indirectly modulate the activity of antimetabolites whose cytotoxicity is influenced by levels of normal nucleosides (e.g. methotrexate, the thymidylate synthase inhibitor CB3717, acivicin and PALA). In addition it is also known that dipyridamole can act to increase in vitro cytotoxicity of drugs such as doxrubicin, vinblastine and etoposide. The mechanism of action in the case of the latter cytotoxic compounds appears to involve the induction of higher intracellular drug levels, and it is believed that this may be caused, in part, by dipyridamole inhibiting drug efflux.
These properties of dipyridamole have led to proposals for using it in therapy, especially antitumor therapy, in combination with a range of cytotoxic drugs so as to enhance or potentiate the cytotoxicity of the latter. However, although a high level of activity in enhancing or potentiating the cytotoxicity of such drugs has been demonstrated in some cases in the course of in vitro experiments, clinical testing and use of dipyridamole in this manner, i.e. in combination with cytotoxic drugs, has been severely handicapped by a problem of low solubility and difficulty in satisfactory formulation for effective administration, together with a major problem arising from the fact that dipyridamole has a strong binding affinity to a plasma protein, &agr;-1 acid glycoprotein (AGP). This AGP protein is often present at elevated levels in cancer patients, and the effect of the strong AGP binding affinity of dipyridamole is to reduce the plasma or serum concentration of free dipyridamole. This in turn then reduces the ability of the dipyridamole to potentiate the activity of the drugs concerned since it seems that only free dipyridamole is able to modulate or inhibit the membrane transport of nucleosides and cytotoxic drugs.
DISCLOSURE OF THE INVENTION
One object of the present invention is accordingly to provide pyrimidopyrimidine compounds which can be regarded as being analogues or derivatives of dipyridamole and which, as compared with dipyridamole itself, have a reduced tendency to bind to AGP without any serious loss in ability to modulate or inhibit nucleoside transport across membranes of at least some cell types. A further object is to provide dipyridamole analogues or derivatives for therapeutic use which have a greater solubility in aqueous media, particularly at physiological pH, than dipyridamole itself.
It is also an object of the invention to provide a greater range of dipyridamole analogues or derivatives, which may constitute new chemical entities and/or new therapeutic agents, for increasing the choice available of potentially useful alternatives to dipyridamole itself for administering to patients in conjunction with certain cytotoxic drugs in order to potentiate the cytotoxic effectiveness of the latter.
A yet further object is to provide novel compounds that may be useful as intermediates in the preparation of bioactive dipyridamole analogues or derivatives as specified above for use as therapeutic agents.
Although many dipyridamole analogues or derivatives investigated are not necessarily significantly better than dipyridamole itself in respect of the properties that give rise to the problems mentioned above, certain analogue compounds have now been identified that it is believed will provide useful and viable alternatives to dipyridamole for use as therapeutic agents in chemotherapy. Moreover there are some compounds which not only exhibit a high degree of nucleoside transport inhibiting activity, comparable with or even stronger than dipyridamole itself, but which surprisingly also have a much reduced binding affinity for AGP as compared to dipyridamole whereby significant nucleoside transport inhibiting activity is retained in the presence of AGP, at least in respect of certain cell types. These compounds are accordingly of particular interest as therapeutic agents for use in medicine, especially when administered in conjunction with certain cytotoxic drugs, e.g. antitumor drugs, for increasing the cytotoxic effectiveness of the latter as previously mentioned.
The desirability of developing or identifying further dipyridamole analogues or derivatives for therapeutic use is also emphasised by recent work that has shown dipyridamole can act as an effective inhibitor of hypoxanthine uptake in selected tumour cell lines indicating that dipyridamole and like compounds have a potential for blocking hypoxanthine rescue based on uptake of extracellular purines such as hypoxanthine to counteract the cytotoxic effect of certain antifolate drugs such as liometerxol which normally act by inhibiting de navo purine biosynthesis within target cells. Further information and data about this aspect, and about other bioactive effects including effects relating to a potential for combating multidrug resistance, are presented in a paper by R. N. Turner, G. W. Aherne and N. J. Curtin entitled “Selective potentiation of lometerxol growth inhibition by dipyridamole through cell-specific inhibition of hyposanthine salvage”,
Brit. Journal of Cancer
(1997), 76 (10), 1300-1307, and in reports by P. G. Smith et al “The potentiation of the multi-targeted antifolate (LY231514: MTA) by dipyridamole),
Proc. Amer. Assoc. Cancer Res.
(1998), 39, 2936 and by E. Marshman et al “Dipyridamole selectivity potentiates antipurine antifolates in human tumour cell lines but not normal tissue targets of dose-limiting toxicity”,
Proc. Amer. Assoc. Cancer Res.
(1998), 39, 4143, the contents of which are incorporated herein by reference.
More specifically, from one aspect, the present invention provides pyrimidopyrimidine compounds constituting dipyridamole analogues for use in therapy as agents for modulating or inhibiting transport of nucleosides or purines across cell membranes, said compounds being compounds having the general structural formula I
or pharmaceutically acceptable salts thereof,
characterised in that in structural formula I
R
1
is chloro and R
3
is diethanolamino, or
R
1
and R
3
are identical and are selected from allyl, halo, diethanolamino, solketalo and a group having the formula —O—R
Z
or —NHR
z
,
R
Z
being selected from alkyl, hydroxyalkyl, alkoxyalkyl, dialkoxyalkyl and 2-oxo-alkyl wherein the or each alkyl and/or alkoxy moiety has less than six carbon atoms, and
R
2
and R
4
are identical and are selected from piperidino, N-tetrahydroisoquinolyl, and a benzylamino group having the structural formula II
where
R
5
is H, or an optionally substituted alkyl or benzyl group, and
R
6
and R
7
represent H or optional substituents in the aromatic nucleus selected
Calvert Alan H.
Curtin Nicola J
Golding Bernard T
Griffin Roger J
Newell David R.
Balasubramanian Venkataraman
Newcastle University Ventures Limited
Pillsbury & Winthrop LLP
Raymond Richard L.
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