Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-03-07
1996-01-02
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546296, C07D21174, A61K 3144
Patent
active
054808944
DESCRIPTION:
BRIEF SUMMARY
CONTINUING DATA
This application is a 371 of PCT/GB93/01007 filed May 18, 1993.
This invention relates to novel 3-hydroxypyridin-4-one chelating agents of therapeutic value, the compounds being of particular value in the treatment of conditions in which there is a toxic concentration of a metal, for example iron, in the body.
UK Patent No. 2 136 807 and various scientific papers describe the use of 3-hydroxypyridin-4-ones for the treatment of iron overload arising from various causes, particularly that arising from pathological conditions such as thalassaemia, sickle cell anaemia, aplastic anaemia, and idiopathic haemochromatosis, often through the treatment of the first three conditions by regular blood transfusions. Moreover, in addition to use for the treatment of general iron overload, the 3-hydroxpyridin-4-ones are of interest for use in certain pathological conditions where there may be an excess of iron deposited at certain sites even though the patient does not exhibit a general iron overload, this being the case, for example, in certain arthritic and cancerous conditions.
Although the major use described in the literature for these compounds is in the removal of iron, they are also of potential interest for the removal of other metals present in the body in deleterious amounts, for example copper, plutonium and other related transuranic metals, and especially aluminium.
The 3-hydroxypyridin-4-ones are also of interest for use in certain other contexts. Thus the free 3-hydroxypyridin-4-ones have been proposed for use in the treatment of inflammatory and atherosclerotic disease, of neoplastic disease, and as platelet anti-aggregatory agents with a role in the treatment of thrombosis. They are also of interest in various areas where chelating agents can be of value, for example in the treatment of paraquat poisoning.
We have now found that a small group of 3-hydroxypyridin-4-ones falling within the scope of UK Patent No. 2 136 807 but not specifically disclosed therein has properties which render these 3-hydroxypyridin-4-ones particularly suitable for use in the treatment of iron overload.
Accordingly the present invention comprises a compound being a 3-hydroxypyridin-4-one of formula (I) ##STR2## in which R.sub.1 is a methyl, ethyl, 2-(.alpha.-methylpropionyloxy)ethyl or 2-pivaloyloxyethyl group and R.sub.2, R.sub.3 and R.sub.4 are each separately selected from hydrogen and methyl, ethyl, 2-(.alpha.-methylpropionyloxy)ethyl and 2-pivaloyloxyethyl groups with the provisos that (a) one only of R.sub.1 to R.sub.4 is either a 2-(.alpha.-methylpropionyloxy)ethyl group or a 2-pivaloyloxyethyl group, (b) at least one of R.sub.2 and R.sub.3 is other than hydrogen and (c) the total number of carbon atoms in R.sub.1 to R.sub.4 is no more than eleven, the compound optionally being in the form of a physiologically acceptable salt.
We have found that the selection of a particularly suitable chelating agent for the oral treatment of iron overload presents two contradictory requirements in as far as it is desirable firstly that the agent used is efficient at entering the bloodstream and thus the liver from the gastrointestinal tract and secondly that it is not efficient at crossing the blood-brain barrier. It is difficult to reconcile these two requirements. Proposals have been made in European Patent Application 0316279A to modify the 3-hydroxy group of the 3-hydroxypyridin-4-ones to provide a pro-drug form, i.e. in the form of a drug which does not itself possess the desired biological activity but which is converted in vivo to a drug which does. The 3-hydroxypyridin-4-ones highlighted in that patent application do, however, have alkyl and alkoxyalkyl substituents and are themselves therefore quite efficient both at entering the bloodstream and at crossing the blood-brain barrier so that the formulation of these compounds in a pro-drug form which enhances entry to the bloodstream but does not effect crossing of the blood-brain barrier is not directed towards overcoming the basic difficulty.
By way of contrast,
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Dobbin Paul S.
Hider Robert C.
Singh Surinder
Tilbrook Gary S.
British Technology Group Limited
Rotman Alan L.
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