Use of a specific cyclic amine derivative or the pharmaceutically acceptable salts thereof for the treatment or prevention of heart failure
Inactive Publication Date: 2006-03-23
BOEHRINGER INGELHEIM PHARM KG
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- Description
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Benefits of technology
[0039] However, as shall be discussed below, it has surprisingly been found that cilobradine presents an advantage over zatebradine not only in terms of its pharmacologically longer duration of action and dose potency, but more importantly in its cardioselectivity, resulting in decreased or absent visual side effects when compared to therapeutic doses of zatebradine.
[0040] Hence, a first object of the present invention is that cilobradine has intrinsically different pharmacological properties than zatebradine, which permit full cardiac ion channel blockade with absent or diminished retinal effects. This unexpected cardioselective property represents a clear advantage for cilobradine over, for example, zatebradine, for the treatment of cardiac disorders such as heart failure.
[0041] A further object of the present invention is that cilobradine is effective for the treatment or prevention of heart failure of any aetiology and thus, is able to reduce the mortality and morbidity associated with heart failure of any aetiology.
Problems solved by technology
Heart failure is a major world-wide public health problem and is the only cardiac disorder that is increasing in incidence.
Unless treated, heart failure may lead to death.
However, diastolic dysfunction is becoming increasingly recognised as an important cause of heart failure too.
This occurs when the heart chambers are unable to expand sufficiently during diastole (period of heart relaxation in which the chambers fill with blood) and hence blood volume in the ventricles is inadequate.
Right sided heart failure is most commonly a consequence of left sided heart failure, although diseases of the lung (such as chronic obstructive pulmonary disease), the right ventricle (e.g. right ventricular infarction) or the vasculature (primary or secondary pulmonary hypertension, the latter due to conditions such as pulmonary embolism for example), may result in predominate right sided heart failure.
As cardiac output is normally 5 litres / minute, although this can increase five fold with heavy exercise, in essence, heart failure occurs when the heart is unable to meet this demand.
However, as with all therapies, there are constraints to their use.
Certain drug classes may not be tolerated due to unwanted side effects, e.g. cough with ACE inhibitors, fatigue, dizziness or impotence in association with beta-blockers, and hyponatraemia with diuretics.
Furthermore, a slow and careful titration period may be required upon drug initiation, as with beta-blockers, where if not performed, the initial negative effects on the heart's pumping action (negative inotropy) may result in drug intolerance and deterioration in heart failure status.
In the long term, this response is ultimately damaging.
In the failing heart, maintenance of adequate ventricular contraction is sought, but occurs at the expense of oxygen and energy consumption by the myocardium.
Heart rate influences such energy demand, with increased heart rate requiring greater expenditure of energy.
It should be noted that these two studies are small and do not attempt to evaluate the benefits of chronic zatebradine administration on the haemodynamic or clinical manifestations of heart failure.
Furthermore, the relationships between heart rate reduction, left ventricular function and prognosis in heart failure are complex.
However, these cyclic amine derivatives, and more specifically cilobradine, have not been suggested for the treatment or prevention of heart failure.
Method used
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Embodiment Construction
[0043] In accordance with one embodiment, the present invention provides for a novel use of the cyclic amine derivative (+)-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, named cilobradine, or its pharmaceutically acceptable salts.
[0044] For the preparation of cilobradine or the pharmaceutically acceptable salts of cilobradine, reference is made to EP 0 224 794 and its US counterpart U.S. Pat. No. 5,175,157, which describes the chemical synthesis of these compounds.
[0045] In accordance with a further embodiment of the present invention, amongst the pharmaceutically acceptable salts of cilobradine described in EP 0 224 794 and its US counterpart U.S. Pat. No. 5,175,157, the hydrochloride and hydrobromide salts of cilobradine are preferred.
[0046] More particularly, the present invention is directed to the use of cilobradine, or its pharmaceutically acceptable salts, for the preparation of a pharmaceutical c...
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Abstract
The present invention provides the use in a pharmaceutical composition of a specific cyclic amine derivative, or its pharmaceutically acceptable salts, for the treatment of heart failure of any aetiology.
Description
RELATED APPLICATIONS [0001] The present application is a continuation of U.S. application Ser. No. 10 / 626,138, filed Jul. 24, 2003 which claims priority to U.S. Provisional Application No. 60 / 405,915, filed Aug. 26, 2002 and priority to EP 02 016 602.1, filed Jul. 25, 2002 all of which are incorporated by reference herein.FIELD OF THE INVENTION [0002] The present invention relates to the novel use of a cyclic amine derivative, namely cilobradine, or the pharmaceutically acceptable salts thereof, for the treatment or prevention of heart failure of any aetiology. BACKGROUND OF THE INVENTION [0003] Heart failure is a major world-wide public health problem and is the only cardiac disorder that is increasing in incidence. In the United States alone, 5 million patients suffer from heart failure, with a new diagnosis made in 0.5 million patients per year. Despite advances in therapy over the last decade, the annual number of hospitalisations has increased from 550 000 to 900 000 as a prima...
Claims
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Patent Timeline
Login to View More IPC IPC(8): A61K31/195A61K9/00A61K31/55A61K45/06
CPCA61K9/0095A61K31/195A61K31/55A61K45/06A61K2300/00A61P9/00
InventorGUTH, BRIANSEIDLER, RANDOLPHDAEMMGEN, JUERGEN
OwnerBOEHRINGER INGELHEIM PHARM KG