Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-10-08
2001-04-17
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S469000
Reexamination Certificate
active
06218414
ABSTRACT:
The present invention relates to the combined use of an angiotensin II antagonist and a benzofuran derivative for the treatment of cardiovascular complaints, in particular the treatment of cardiac insufficiency.
The present invention relates more particularly to the use of irbesartan and amiodarone in the treatment of cardiovascular complaints, in particular in the treatment of cardiac insufficiency.
The present invention also relates to a novel pharmaceutical composition which is useful in particular for the treatment of cardiac insufficiency. This pharmaceutical composition consists of 2 active principles, one being a benzofuran derivative known for its antiarrhythmic activity, the other being an angiotensin II antagonist compound.
Cardiac insufficiency is defined as a pathological state associated with a decrease in the contractility of the myocardium and in which the heart is incapable of pumping the amount of blood required to satisfy the metabolic demand of various organs and tissues of the body.
According to the study by Framingham (P. A. McKee et al., New Engl. J. Med. 1971, 285, 1441-1446), it appears that cardiac insufficiency is not a disease in itself but a clinical manifestation of various heart disorders. Indeed, several forms of heart pathology may lead to ventricular dysfunction and cause the syndrome of cardiac insufficiency. Thus, with cardiac insufficiency being a sum of syndromes developing differently and having various etiologies, it is clear that a single therapeutic agent is not sufficient to treat it.
There is a strong relationship between left ventricular hypertrophy and sudden death, this relationship being partly explained by the combination of left ventricular hypertrophy and ventricular arrhythmia.
Patients suffering from severe cardiac insufficiency have a high level of ectopic ventricular activity and sudden death due to cardiac arrhythmias is the cause of more than 40% of deaths by cardiac insufficiency.
The high mortality rate in patients suffering from cardiac insufficiency has led to the search for new therapeutic agents enabling their lives to be prolonged.
The use of vasodilators appears justified for the treatment of cardiac insufficiency. Furthermore, an improvement in the hemodynamics and in the neuroendocrine profile are obtained by a prolonged treatment with digitalis-like compounds, glycosides and/or diuretics and vasodilators.
An improvement in the treatment of cardiac insufficiency can also be expected using an inhibitor of the conversion enzyme alone or in combination with other therapeutic agents.
The results of the CONSENSUS I study (N. Engl. J. Med., 1992, 327, 678-684), of the SAVE study (N. Engl. J. Med., 1992, 327, 669-677) and of SOLVD (N. Engl. J. Med., 1991, 325, 293-302) show clearly that conversion enzyme inhibitors can be used to treat patients suffering from mild, moderate or serious cardiac insufficiency associated with left ventricular systolic dysfunctions. In this case, conversion enzyme inhibitors improve the quality of life and survival of the patients.
Currently, irrespective of the origin of the cardiac insufficiency, patients are treated in most cases with a combination of several medicinal products: digitalis-like compounds, diuretics and conversion enzyme inhibitors (J. G. F. Cleland et al., Br. Heart J., 1994, 72 (2, suppl.) 573-579).
International patent application Wo 93/20839 describes the long-term use of an inhibitor of the renin-angiotensin system, such as a conversion enzyme inhibitor, a renin inhibitor or an angiotensin II antagonist, in order to reduce the mortality after myocardial infarction. According to this invention, the inhibitor of the renin-angiotensin system may be administered in combination with another active principle such as a beta-adrenergic blocker, an anticoagulant or aspirin.
Canadian patent application 2,070,085 describes a sustained-release pharmaceutical composition which is useful for the treatment of hypertension, cardiac insufficiency and other coronary problems, comprising a calcium-channel blocker and a conversion enzyme inhibitor.
The beneficial action of losartan, an angiotensin II inhibitor, on patients suffering from cardiac insufficiency is shown in J. Hypertension, 1994, 12 (suppl. 2), p. S31-S35.
U.S. Pat. No. 4,868,179 claims a method for reducing the mortality associated with chronic cardiac insufficiency, comprising the oral administration of a pharmaceutical composition comprising hydralazine and isosorbide dinitrate.
European patent 0,527,720 describes a method of treating cardiac insufficiency by administration of a pharmaceutical composition comprising a conversion enzyme inhibitor and 7-fluoro-1-methyl-3-methylsulfinyl-4-quinolone.
International patent application WO 90/09171 describes cardioprotective medicinal preparations which are useful in coronary insufficiency and in the prevention of the occurrence of an infarction or sudden death, comprising amiodarone, a nitro derivative and, optionally, a beta-blocker.
The expression benzofuran derivative with antiarrhythmic activity is understood to refer to a compound such as that described in one of the following documents: U.S. Pat. No. 3,248,401 and 5,223,510, European patent 338,746 and patent applications Wo 88/07996, WO 89/02892, WO 90/2743 and WO 94/29289.
Among these compounds, amiodarone described in U.S. Pat. No. 3,248,401 and N,N-dibutyl-3-[4-((2-butyl-5-methylsulfonamido)benzofuran-3-ylcarbonyl)phenoxy]-propylamine or dronedarone, also known as SR 33589, and the salts thereof described in U.S. Pat. No. 5,223,510 are preferred.
The active metabolites of these compounds are also preferred compounds, in particular N-desethylamiodarone and the salts thereof described in French patent 2,550,091 and N-butyl-3-[4-(2-butyl-5-methylsulfonamido)benzofuran-3-ylcarbonyl)phenoxy]propylamine and the salts thereof described in U.S. Pat. No. 5,223,510.
Amiodarone is considered to be a class III antiarrhythmic agent (B. N. Singh et al., Current Opinion in Cardiology, 1994, 9, 12-22). It is used worldwide to treat ventricular and supraventricular arrhythmias.
Furthermore, preliminary studies relating to the prophylactic use of amiodarone in patients suffering from cardiac insufficiency, non-sustained ventricular tachycardia or these 2 syndromes give promising results.
Indeed, the GESICA study (H. C. Doval et al., Lancet, 1994, 344, 493-498) describes observations made on patients suffering from serious cardiac insufficiency, who were monitored for 2 years. This study shows that the treatment with amiodarone at low dose decreases the mortality and hospitalizations in all the subgroups examined and independently of a possible non-sustained ventricular tachycardia.
Another study (J. J. Mahmaria et al., Am. J. Cardiol. 1994, 74, 681-686) conducted on patients exhibiting a fraction of left ventricular ejection of less than 40% shows that amiodarone administered at daily doses of 50 to 100 mg improves the heart hemodynamics and contractility.
In patients exhibiting severe arrhythmia following a congestive cardiomyopathy, amiodarone constitutes a treatment of choice, in combination with conversion enzyme inhibitors, digitalis-like compounds or diuretics (Acta Med. Austriaca, 1992, 19 (3), 83-87).
Patent application WO 95/09625 describes the use of amiodarone in the treatment of cardiac insufficiency; in this case, amiodarone can be combined with another therapeutic agent such as, for example, a diuretic, a cardiotonic, a vasodilator or a conversion enzyme inhibitor.
Thus, the combination of an angiotensin II antagonist with amiodarone has never been envisaged hitherto for the treatment of cardiovascular complaints.
According to the present invention, the term angiotensin II antagonist is understood to refer to nonpeptide compounds which have a strong affinity for the receptors of angiotensin II of the subtype AT1: (M. I. Steinberg et al., Cardiovascular Drug Reviews, 1993, 11(3), 312-358). This generally concerns nitrogen-containing heterocycles substituted with a biphenylmethyl group itself bearing an
Bacon & Thomas
Henley III Raymond
Sanofi
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