Heterocyclyl-condensed benzoylguanidines, their production and u

Details Heterocyclyl-condensed benzoylguanidines, their production and u Heterocyclyl-condensed benzoylguanidines, their production and u

1999-03-30

2000-02-22

Lambkin, Deborah C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514367, 514432, 514443, 514439, 514434, 544 59, 548171, 549 28, 549 53, 549 32, 549 15, 549 23, A61K 3154, A61K 31425, A61K 3138, C07D27762, C07D32706

Patent

active

060280697

DESCRIPTION:

BRIEF SUMMARY
The invention relates to cyclic sulfones of the formula I ##STR2## in which R.sup.1 and R.sup.2 in each case independently of one another are H, A, CF.sub.3, CH.sub.2 F, CHF.sub.2, C.sub.2 F.sub.5, Hal, OH, OA, NH.sub.2, NHA, NA.sub.2, NO.sub.2 or CN, another are H, A, R.sup.3, Hal, OH, OA, SH, SA, NH.sub.2, NHA or NA.sub.2 or else bond, it being possible in each molecule for a maximum of only one bond of this type to occur; O--(CH.sub.2).sub.3 --O, trisubstituted by A, OA, NH.sub.2, NHA, NA.sub.2, F, Cl, Br and/or CF.sub.3 and
The invention was based on the object of finding novel compounds having useful properties, in particular those which can be used for the production of medicaments.
It has been found that the compounds of the formula I and their physiologically acceptable salts have useful pharmacological properties together with good tolerability.
The novel compounds are inhibitors of the cellular Na.sup.+ /H.sup.+ antiporter, i.e. active compounds which inhibit the Na.sup.+ /H.sup.+ exchange mechanism of the cells (Dusing et al., Med. Klin. 87, 378-384 (1992)) and which are thus good antiarrhythmics which are particularly suitable for the treatment of arrhythmias which occur as a result of oxygen deficiency.
The best known active compound of the acylguanidines group is amiloride. However, this substance primarily shows a hypotensive and saluretic action, which is undesirable, in particular in the treatment of cardiac arrhythmias, while the antiarrhythmic properties are only very weakly pronounced.
Benzoylguanidines are described, for example, in DE 44 04 183. The compounds described in the prior art, however, are structurally clearly different from those claimed here.
The invention relates to compounds of the formula I and their physiologically acceptable salts.
The substances according to the invention of the present application show a good cardioprotective action and are therefore particularly suitable for infarct treatment, infarct prophylaxis and for the treatment of angina pectoris. The substances furthermore counteract all pathological hypoxic and ischaemic damage so that the diseases caused primarily or secondarily thereby can be treated. The active compounds are likewise highly suitable for preventive applications.
On account of the protective actions of these substances in pathological, hypoxic or ischaemic situations, further application possibilities result in surgical interventions for the protection of temporarily undersupplied organs, in organ transplantations for the protection of the removed organs, in angioplastic vascular or cardiac interventions, in ischaemias of the nervous system, in the therapy of states of shock and for the preventive treatment of essential hypertension.
Furthermore, the compounds can also be employed as therapeutics in disorders caused by cell proliferation, such as arteriosclerosis, diabetic late complications, oncoses, fibrotic disorders, in particular of the lung, liver and kidneys, and organ hypertrophies and hyperplasias. Moreover, the substances are suitable for diagnostic application for the recognition of diseases which are accompanied by an increased activity of the Na.sup.+ /H.sup.+ -antiporter, e.g. in erythrocytes, platelets or leucocytes.
The actions of the compounds can be determined with the aid of methods known per se, such as are indicated, for example, by N. Escobales and J. Figueroa in J. Membrane Biol. 120, 41-49 (1991) or by L. Counillon, W. Scholz, H. J. Lang and J. Pouyssegur in Mol. Pharmacol, 44, 1041-1045 (1993).
Suitable experimental animals are, for example, mice, rats, guinea-pigs, dogs, cats, monkeys or pigs.
The compounds can therefore be used as pharmaceutical active compounds in human and veterinary medicine. They can furthermore be used as intermediates for the preparation of other pharmaceutical active compounds.
In the formulae indicated, A is a branched or unbranched alkyl group having 1-6, preferably 1-4, in particular 1, 2 or 3 C atoms, specifically preferably methyl, additionally preferably ethyl, propyl, isopropyl, bu

REFERENCES:
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Yamamoto et al, "Preparation and formulation of benzothiazine derivatives as NA + /H+ exchange inhibitors", CA 128:244058, 1998.

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