Use of bradycardiac substances in the treatment of myocardial diseases associated with hypertrophy and novel medicament combinations

This application is a 35 USC 371 case of PCT/EP01/04034 which claims priority to German application 100 18 401.4 filed Apr. 13, 2000.

Elevated heart rate may be treated with bradycardiac substances, particularly Ca ++ channel blockers such as diltiazem and verapamil or beta-receptor blockers such as atenolol, bisoprolol, carvedolol, metoprolol or propanolol and i f channel blockers such as zatebradine [1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-propane] (see EP-B-0 065 229), 3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin-3-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (see EP-B-0 224 794) and its enantiomers cilobradine [(+)-3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one] or alinidine [2-(N-allyl-2,6-dichloro-anilino)-2-imidazolidine), cf. also U.S. Pat. No. 3,708,485], while zatebradine is also known to have a favourable activity in the treatment of cardiac insufficiency (see EP-B-0 471 388).

Moreover it is known that bradycardiac substances, particularly the abovementioned compounds, of which the i f channel blockers such as zatebradine, cilobradine or alinidine, and in particular cilobradine, are preferred, can have a beneficial effect on the symptoms of myocardial diseases accompanied by hypertrophy, particularly for the treatment of idiopathic hypertrophic cardiomyopathies (HCM) such as hypertrophy of the remainder of the myocardium after myocardial infarction, ischaemic cardiomyopathy, hypertrophy of the myocardium in valve defects and myocarditis under toxic or iatrogenic influences.

Surprisingly it has now been found that bradycardiac substances, of which the i f channel blockers such as zatebradine, cilobradine or alinidine, and in particular cilobradine, are preferred, not only have a favourable effect on the clinical symptoms of hypertrophic cardiomyopathy, but will even induce regression of these serious heart diseases.

The present invention thus relates to the new use of bradycardiac substances, particularly the abovementioned compounds, of which the i f channel blockers such as zatebradine, cilobradine or alinidine, and in particular cilobradine, are preferred, to induce the regression of myocardial diseases accompanied by hypertrophy, particularly for the treatment of idiopathic hypertrophic cardiomyopathies (HCM) in humans and domestic pets.

In order to achieve the effect according to the invention it is expedient to use the dosage known from the literature for the treatment of elevated heart rate for the individual bradycardiac substances. For example the single dose

for cilobradine is 0.1 to 0.5 mg/kg per os, preferably 0.2 to 0.4 mg/kg, 1 to 3× daily, for zatebradine it is 0.2 to 1 mg/kg 2× daily and for alinidine it is 0.5 to 5 mg/kg 2× daily.

The new use of the bradycardiac substances according to the invention was investigated with the i f channel blocker cilobradine by way of example, using the following method:

A cat with severe hypertrophic cardiomyopathy (heart rate about 200 beats/minute), ECG with ST accentuations as a sign of myocardial ischaemia, increased creatinine kinase activity in the plasma and in the ultrasound image, massive compression of the ventricular wall with a reduction in the ventricular volume and the ejection fraction, exhibited a significant improvement in clinical symptoms after treatment with the i f channel blocker cilobradine (0.3 mg/kg per os, 2× daily) (relief from pain, normal ECG, return of normal physiological activity pattern).

Follow-up investigations after one year and after about 2 years' treatment surprisingly showed a regression in myocardial hypertrophy while the improvement in symptoms was maintained.

The hypertrophic cardiomyopathy in the cat serves as a model for the corresponding disease in humans (Kittleson et al., Circulation 91, 3172–3180 (1999)).

Treatment with the i f channel blocker cilobradine thus leads not only to an improvement in symptoms but also to regression of the disease.

The present invention also relates to drug combinations, containing at least one bradycardiac substance, particularly one of the abovementioned compounds, preferably an i f channel blocker, and at least one cardioactive substance such as

a cardioglycoside, e.g. methyldigoxin or digitoxin, a vasodilator, e.g. nitroglycerine, an ACE inhibitor, e.g. captopril or enalapril, an angiotensin-II antagonist, e.g. losartan or telmisartan,

which are also suitable for treating myocardial diseases accompanied by hypertrophy, particularly for the treatment of idiopathic hypertrophic cardiomyopathies (HCM), if a rise in heart rate can be prevented by combining them with a bradycardiac substance.

To achieve the effect according to the invention it is convenient to use the dosages known from the literature for the individual bradycardiac substances for the treatment of elevated heart rate and the dosages known from the literature for the cardioactive compound used.

For this purpose the bradycardiac substances, either on their own or combined with other cardioactive compounds, are formulated with one or more conventional inert carriers and/or diluents, e.g. with maize starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, stearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional Galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, sprays or suppositories.

Thus, for example, the combination consisting of cilobradine and a cardioactive compound conveniently contains 0.1 to 0.5 mg/kg, preferably 0.2 to 0.4 mg/kg of cilobradine per os

plus 0.01 to 1 mg of methyldigoxin, 1 to 2× daily, 0.01 to 1 mg of digoxin, 1× daily, 0.1 to 2 mg of nitroglycerine, 2 to 3× daily, 10 to 100 mg of captopril, 1 to 2× daily, 2 to 20 mg of enalapril, 1× daily, 10 to 200 mg of losartan, 2× daily, or 20 to 80 mg of telmisartan, 1× daily.

As the partners for the i f channel blockers in the drug combination additionally act on an independent biological system and i f channel blockers inhibit reflex increases in heart rate, which may occur in connection with the above combination partner, these have a synergistic activity.

The Examples that follow are intended to illustrate the invention without restricting it: