Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-01-23
1999-07-27
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514353, 544318, 546306, C07D21375, C07D23947, A61K 3144, A61K 31505
Patent
active
059290820
DESCRIPTION:
BRIEF SUMMARY
This invention relates to compounds which have the ability to block potassium ion channels. In particular, the invention relates to sulphonylurea, sulphonylthiourea and sulphonylguanidine compounds which act to block potassium ion channels regulated by intracellular concentrations of adenosine triphosphate (ATP). The compounds of the invention are therefore useful in the treatment of conditions such as type II diabetes, cardiac arrhythmias, and ischaemic and hypoxic cardiovascular incidents.
BACKGROUND OF THE INVENTION
Potassium ion channels are responsible for the control and maintenance of many physiological responses, and a wide variety of such channels is known The many classes and subclasses of potassium ion channels allow for the development of new chemical entities which specifically allow or impede the passage of potassium ions (K.sup.+) through these channels, thus altering the physiological state of the cell. Compounds which have the ability to modulate the passage of K.sup.+ through a subset of potassium ion channels which is regulated by the concentration of adenosine triphosphate (ATP) are known as K.sub.ATP channel blockers or K.sub.ATP openers, depending on whether they impede or enhance the passage of K.sup.+.
Alteration of potassium ion channel flux causes variations in the excitable state of a number of tissues; open potassium channels allow the membrane potential to come closer to the potassium equilibrium potential, so that the membrane potential is more stable and less likely to fire (Cook, 1990). Potassium ion channels are also associated with the resting potential, and periods of excitability are terminated by these channels. Thus, by modulating the K.sup.+ ion movement through these channels, the ensuing responses may be of therapeutic benefit.
Type II diabetes is an example of a disease that is effectively treated with, potassium ion channel blockers of the sulphonylurea type with relative safety. Such drugs include tolbutamide and glyburide. Ideally these drugs display both rapid onset and short duration of action, thus reducing the risk of chronic hyperinsulinaemia, which is a risk factor for atherosclerosis, and of potentially fatal hypoglycaemic incidents Thus discontinuous exposure appears to be best during long term treatment, because the plasma drug concentration falls below the threshold level during at least part of the night, since desensitisation appears to be associated with the use of high concentrations of and continuous exposure to sulphonylureas (Palmer and Brogden, 1993).
The K.sub.ATP blockers alter the regulation of insulin secretion from pancreatic .beta. cells. This effect results from the fact that the K.sub.ATP channels which maintain the cell membrane resting potential are generally open in resting conditions, but close due to an increase in intracellular ATP following glucose metabolism Depolarisation of the .beta. cell membrane occurs upon closure of these channels. This induces the activation of the voltage-dependent calcium channels, promoting an influx of Ca.sup.2+ into the cells, which facilitates the secretion of insulin from .beta. cells (Gopalakrishnan et al, 1993). These compounds have also been demonstrated to have the ability to alter K.sup.+ channel flux in a variety of non-pancreatic tissues by blocking ATP dependent channels, and may be beneficial for the treatment of other diseases (Robertson and Steinberg, 1990).
The possibilities for therapeutic effects on the heart are numerous, as during diastole the myocardium exhibits a stable high resting membrane potential which is maintained predominantly by K.sup.+ channel currents These currents also regulate the termination of excitation in the myocardium and pacemaker tissue (Cook, 1990). Thus many conditions requiring both emergency care and post-emergency care have the potential to be ameliorated by agents modulating the relevant K.sup.+ channel currents associated with the particular problem Furthermore, under abnormal conditions other parts of the heart, particularly the A-V node and Purki
REFERENCES:
J. Med. Chem. 1990, vol. 33, No. 9, pp. 2393-2407; "Novel Agents Effective against . . . ", Howbert, et al.
Chemical Abstracts, vol. 106, No. 13, Mar. 30, 1987, Abstract No. 95588.
Chambers Noel John
Johnston Graham Allen Ross
Davis Zinna Northington
Polychip Pharmaceuticals Pty Ltd
The University of Sydney
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