Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1997-10-14
2000-01-11
Spivack, Phyllis
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
A61K 31135
Patent
active
060136782
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the use of 5,6-diisobutyroyloxy-2-methylaminotetralin in the preparation of pharmaceutical compositions for the therapy of cardiac disorders, particularly congestive heart failure.
Notwithstanding the therapeutical progresses of the last years, congestive heart failure is still one of the main death causes.
The symptomatic therapy usually aims at reducing the workload of the decompensed heart and improving the mechanical function.
Recently, cardiac failure was proved to be related with important biochemical and neurohumoral changes involving different factors.
In fact, when cardiac output diminishes, compensatory mechanisms act in the body in order to maintain the circulatory homeostasis.
In heart failure, vasoconstriction associated with the activation of said mechanisms cause an increase in peripheral vascular resistances.
As a consequence, the after-load increases which can in turn further strain the already weakened heart, triggering a vicious circle which leads to a progress of the pathology.
This generalized vasoconstriction is mainly caused by the activation of the sympathetic nervous system consequent to the increase of plasma catecholamines, particularly adrenalin, which is an early signal of cardiac decompensation.
A close relationship between degree of sympathetic activation and severity of the disease seems to exist, and a direct connection between noradrenalin plasmatic levels and mortality seems moreover established.
Therefore, the therapy of congestive heart failure has to be directed to the improvement of the hemodynamic factors, on one hand, and to the pharmacological modulation of the neurohumoral system on the other.
Dopaminergic drugs appear as candidates to become established as drugs for heart failure in the majority of patients.
In particular, dopamine has peculiar characteristics, compared with the other medicaments, since it stimulates both dopaminergic and alpha and beta-adrenergic receptors.
Two types of dopaminergic receptors exist: those located on the smooth muscle of the vascular system (DA.sub.1 receptors) which mediate vasodilation in the renal, mesenteric, cerebral and coronary districts, and those in pre-synaptic position (DA.sub.2 receptors), which inhibit noradrenalin release from post-ganglionic sympathetic nerve endings to blood vessels and heart.
The usefulness of dopamine in the treatment of heart failure is however restricted by it being inactive orally.
Analogously dobutamine, a synthetic analogue of dopamine, can be used only intravenously.
Aminotetralin derivatives have been studied for a long time as dopamine structural analogues for any uses as medicaments.
However, none of these compounds has up to now been introduced in therapy.
One of them, 5,6-dihydroxy 2-methylaminotetralin hydrobromide, was disclosed as coronary vasodilator in the U.S. Pat. No. 4,134,997 in the name of Joseph G. Cannon.
Cannon administered the compound to dogs at a rate of approximately 10 .mu.g/kg animal weight per minute (rante 8.5-13.9) by a continuous intravenous infusion and demonstrated a substantial increase in coronary blood flow.
5,6-Diisobutyroyloxy-2-methylaminotetralin, herein-after referred to as CHF 1035, has been described first in GB Pat. 2123410 among a series of aminotetralin derivatives disclosed as potential antibronchospastic due to their activity on adrenergic receptors.
Both 5,6-dihydroxy-2-methylaminotetralin (herein-after indicated with the experimental abbreviation CHF 1024) and CHF 1035 have been formerly characterized as compounds having previling selective activity on .beta..sub.2 adrenergic receptors.
Now it has been surprisingly found that CHF 1024 and CHF 1035, in addition to the already known .beta..sub.2 agonist activity, have remarkable peripheral DA.sub.2 and .alpha..sub.2 presynaptic activities leading to a reduction of the sympathetic tone, which is elevated in heart failure patients.
Studies carried out in the animal proved that CHF 1024 and CHF 1035 have a vasodilating activity due the combination of their effects o
REFERENCES:
Carine Morisoco et al , "Hemodynamic Effects of Graded Oral Doses of a New Dopaminergic Analogue CHF 1035 in Patients with Congestive Heart Failure", Special Issue, Journal of the American College of Cardiology, Feb. 1995.
Enrico Redenti et al , Application of .gamma.-Cyclodextrin to Enantiomeric Purity Determination of a New 2-Amino-Tetralin Derivative Y .sup.1 H-NMR Spectroscopy, Chirality 4:404-405 (1992).
Bongrani Stefano
Chiesi Paolo
Civelli Maurizio
Razzetti Roberta
Umile Alberto
Chiesi Farmaceutici S.p.A.
Spivack Phyllis
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