MXPA97006042A - Use of carbazol compounds for the treatment of cardiac congest insufficiency - Google Patents

Abstract

The present invention relates to the use of a compound which is both the α-adrenoreceptor antagonist and the alpha 1 -adrenoceptor antagonist, for the manufacture of a medicament, for decreasing the mortality resulting from congestive heart failure, in mammals, alone or together with one or more other therapeutic agents, wherein those agents are selected from the group consisting of the angiotensin-converting enzyme inhibitor, a diuretic and cardiac glycosides

Description

USE OF CARBAZOL COMPOUNDS FOR THE TREATMENT OF CONGESTIVE CARDIAC INSUFFICIENCY FIELD OF THE INVENTION The present invention relates to a new method of treatment using compounds that are dual, non-selective antagonists of the β-adrenoreceptor and the Oi-a renoreceptor. In particular the carbazolyl- (4) -oxypropanolamine compounds, of Formula I, preferably carvedilol, for decreasing the mortality of patients suffering from congestive heart failure (CHF, for its acronym in English). The invention also relates to a method for the treatment using compounds that are dual non-selective antagonists of the β-adrenoreceptor and the α-adrenoreceptor, in particular the carbazolyl- (4) -oxypropanolamine compounds of Formula I, preferably carvedilol, together with one or more other therapeutic agents wherein the agents are selected from the group consisting of angiotensin-converting enzyme (ACE) inhibitors, REF. : 25308 diuretics, and cardiac glycosides to decrease the mortality of patients suffering from CHF. The invention also relates to an application scheme that is increased, to administer compounds, which are antagonists of the β-adrenoreceptor and the α-adrenoreceptor.

BACKGROUND OF THE INVENTION Congestive heart failure occurs as a result of the deterioration of the heart's pumping capacity and is associated with abnormal retention of water and sodium. Traditionally, the treatment of chronic, mild insufficiency has included the limitation of physical activity, the restriction of salt intake and the use of a diuretic. If these measures are not sufficient, a cardiac glycoside is added to the treatment regimen, which is an agent that increases the force of iocardial contraction. Subsequently, angiotensin-converting enzyme inhibitors, which are compounds that prevent the conversion of angiotensin I to angiotensin II, activate the suppressor, are prescribed for the chronic treatment of congestive heart failure, together with a diuretic, a glycoside cardiac, or both. Also, congestive heart failure is a well-known cardiac disorder that results in excess mortality. Applefeld, M.M., (1986) Am. J. Med., 8_0, Suppl. , 2B, 73-77. Therefore, therapeutic agents that decrease the mortality resulting from CHF, in patients suffering from it, are highly desirable.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a new use of compounds that are dual, nonselective antagonists of the β-adrenoreceptor and of the α-adrenoreceptor for the preparation of medicaments, for the treatment of congestive heart failure. Particularly preferred are carbazolyl- (4) -oxypropanolamine compounds, of Formula I, alone or together with one or more other therapeutic agents, wherein these agents are selected from the group consisting of ACE inhibitors, diuretics, and of cardiac glycosides, as therapeutic agents to reduce mortality resulting from congestive heart failure, particularly in mammals. In particular, the present invention preferably provides a method for treatment, alone or in conjunction with one or more other therapeutic agents, wherein the agents are selected from the group consisting of ACE inhibitors, diuretics, and cardiac glycosides, with the compound of Formula I wherein Ri is -H, R2 is -H, R3 is -H, R4 is -H, X is 0, Ar is phenyl, R5 is ortho -OCH3, and R6 is -H, and this compound it is better known as carvedilol, which is (1- (carbazol-4-yloxy-3- [[2- (2-methoxyphenoxy) ethyl] amino] 2-propanolol), or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION U.S. Patent No. 4,503,067 discloses carbazolyl- (4) -oxypropanolamine compounds of Formula I: where Ri is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl; R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl; R3 is hydrogen or lower alkyl of up to 6 carbon atoms; R is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent -CH2-0-; X is a valence bond. -CH2, oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl; R5 and R6 are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a -CONH2- group, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms. carbon, lower alkylsulfonyl of up to 6 carbon atoms and lower alkylsulfonyl of up to 6 carbon atoms; or R5 and Re, collectively, represent methylenedioxy; and the pharmaceutically acceptable salts thereof. This patent further discloses a compound of Formula I, better known as carvedilol, which is (1- (carbazol-4-yloxy-3- [[2- (2-methoxyphenoxy) ethyl] amino] (2-propanol), which has the structure shown in Formula II.

The compounds of Formula I, of which carvedilol is exemplary, are novel multi-action drugs useful in the treatment of mild to moderate hypertension. It is known that carvedilol is both a competitive, nonselective antagonist of the β-adrenoreceptor, a vasodilator, and that it is also an antagonist of calcium channels at higher concentrations. The vasodilatory actions of carvedilol result mainly from blockade of the aradrenoreceptor while the β-adrenoreceptor blocking activity of the drug prevents reflex tachycardia when used in the treatment of hypertension. These multiple actions of carvedilol are responsible for the anti-hypertensive efficacy of the drug in animals and particularly in humans. See Willette, R.N., Sauermelch, C.F. & Ruffolo, R.R., Jr. (1990) Eur. J. Pharmacol., 176, 237-240; Nichols, A.J., Gellai, M. & Ruffolo, R.R., Jr. (1991) Funda. Clin. Pharmacol., 5j_ 25-38; Ruffolo, R.R., Jr., Gellai, M., Hieble, J.P., Willette, R.N. & Nichols, A.J. (1990) Eur. J.

Clin. Pharmacol., 38_, 582-588; Ruffolo R.R., Jr., Boyle. D.A., Venuti, R.P. & Lukas, M.A. (1991) Drugs of Today, 2_7, 465-492; and Yue, T.-L., Cheng, H., Lysko. P.G., Mckenna, P.J., Feuerstein. R., Gu, I., Lysko, K.A., Davis, L.L. & Feuerstein, G. (1992) J. Pharmacol. Exp. Ther., 263, 92-98. The anti-hypertensive action of carvedilol is mediated mainly by the decrease in total peripheral vascular resistance, without causing concomitant reflex changes in cardiac rhythm commonly associated with other anti-hypertensive agents. Willette, R.N., et al. supra; Nichols. A.J., et al. Supra; Ruffolo, R.R., Jr., Gellai. M., Hible. J.P., Willette. R.N. & Nichols. To the. (1990) Eur. J. Clin. Pharmacol., 38, S83-S88. Carvedilol also markedly reduces the severity of infarction, in porcine, canine, and rat models, of acute myocardial infarction, Ruffolo, RR, Jr., et al., Current drugs, supra, possibly as a consequence of its action antioxidant in the attenuation of lipid peroxidation initiated by free oxygen radicals. Yue, T.-L., et al. supra It has recently been discovered, in clinical studies, that pharmaceutical compounds which are dual, non-selective, antagonists of the β-adrenoreceptor and the cti-adrenoreceptor, in particular the compounds of Formula I, preferably carvedilol, alone or in conjunction with conventional agents , where the agents are ACE inhibitors diuretics and cardiac glycosides, are effective therapeutic agents for the treatment of CHF. The use of agents, such as carvedilol, in the treatment of CHF, is surprising, given that, in general, β-blockers are contraindicated in patients suffering from heart failure because β-blockers are known to have undesirable cardiodepressive effects. The most surprising observation of the studies in which the compounds of the present were used to treat CHF, is that these compounds, in particular, carvedilol, are capable of decreasing the mortality resulting from CHF in humans, by approximately 67%. %. Furthermore, this result is present throughout all CHF classifications and in both etiologies (ischemic and nonischemic). This result is surprising given that two recent mortality studies, using ß blockers, metoprolol (Waagstein, et al., (1993) Lancet, 342, 1441-1446) and bisoprolol (researchers and CIBIS committees, (1994) Circulation 9 ^ 0, 1765-1773) in the treatment of CHF showed no difference in mortality between patients treated with the drug and patients treated with placebos. In accordance with the method of treatment of the present invention, the desirable therapeutic effect of the compounds of Formula I, particularly carvedilol, can be increased by the use of any of those compounds, of any pharmaceutically acceptable salt of those compounds, together with ACF inhibitors, diuretics, and cardiac glycosides. which are effective therapeutic agents for the treatment of CHF. In particular, the preferred ACE inhibitors of the present invention are selected from the group consisting of captopril, lisinopril, fosinopril and enalapril, or any pharmaceutically acceptable salts thereof, the preferred diuretics of the present invention are furosemide. of hydrochlorothiazide, or the torosemide or any pharmaceutically acceptable salts. The preferred cardiac glycosides of the present invention are digoxin, β-methyldigoxin or digitoxin. the desirable therapeutic benefits of the compounds of Formula I, particularly carvedilol, are additive with those of the ACE inhibitors, or diuretics, or cardiac glycosides, when administered in combination therewith. Captopril is commercially available from E.R. Squibb & Sons, Inc. Lisinopril, enalapril and hydrochlorothiazide, are commercially available from Merck & Co. Furosemide is commercially available from Hoechst-Rousell Pharmaceutical Inc., digitoxin is commercially available from Burroughs Wellcome Co. and Boehringer Mannheim GmbH. Digitoxin, ß-Met and digoxin, fosinopril and torasemide are commercially available from Boehringer Mannheim GmbH. The compounds of Formula I can be conveniently prepared as described in US Pat. No. 4,503,067. Carvedilol is commercially available from SmithKline Beecham Corporation and Boehringer Mannheim GmbH (Germany). Pharmaceutical compositions of the compounds of Formula I that include carvedilol, alone or in combination with ACE inhibitors, or diuretics, or cardiac glycosides, may be administered to patients, in accordance with the present invention, in any medically acceptable manner, preferably orally. For parenteral administration, the pharmaceutical composition will be in the form of a sterile injectable liquid, stored in a suitable container such as in an ampule or in the form of a liquid, aqueous or non-aqueous suspension. The nature and composition of the carrier, diluent or excipient, pharmacist, will of course depend on the route of administration to be used, for example either by intravenous or intramuscular injection. The pharmaceutical compositions of the compounds of Formula I for use in accordance with the present invention can be formulated as solutions or as lyophilized powders for parenteral administration. The powders can be reconstituted by the addition of an appropriate diluent or other pharmaceutically acceptable carrier, before use. The liquid formulation is generally an aqueous, isotonic, buffered solution. Examples of suitable diluents are saline, isotonic, normal, 5% standard dextrose in water or buffered solution of sodium or ammonium acetate. That formulation is especially suitable for parenteral administration but can also be used for oral administration or it can be contained in an inhaler or nebulizer with graduated dose, for insufflation. It may be desirable to add excipients such as ethanol, polyvinylpyrrolidone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.

Alternatively these compounds can be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. The pharmaceutically acceptable solid or liquid carriers can be added to improve or stabilize the composition, or to facilitate the preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, ethanol, and water. Solid carriers include starch, lactose, calcium sulfate dihydrate, alabaster, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier may also include a material for sustained release such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of the solid carrier varies but preferably it will be between 20 mg and about 1 g per dosage unit. The pharmaceutical preparations are manufactured following conventional pharmacy techniques that involve grinding, mixing, granulating, and compressing, when necessary, for tablet forms; or grinding, mixing, filling for the forms in soft gelatin capsules. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. One of these liquid formulations can be administered directly p.o. or it can be filled in a soft gelatin capsule. The compounds having the dual properties, mentioned above, are preferably administered after an application scheme in three stages. This scheme is characterized by the fact that increasing or progressive doses of the active ingredient are administered to patients for a certain period of time until the regular maintenance dose is received. If this maintenance dosage is defined as the adjustment value of 100%, it was found that the application regime in a first phase should be extended for a period of 7 to 28 days, for which only 10-30% was administered. of the regulation dose. After this phase a second application regimen would follow, where the patient is administered a dose of 20 to 70% of the regulation dose, for a period of 7 to 28 days. After the termination of this phase, the third application period follows where the daily complete regulation dose (maintenance dose) is administered. The maintenance dose, daily, can vary between 10 and 100 mg of the active ingredient. In the case of carvedilol, the dosage in humans for the treatment of the disease, in accordance with the present invention, should not exceed a dosage range from about 3.125 to about 50 mg of the compounds of Formula I, particularly carvedilol, supplied preferably twice a day. As will be readily understood by a person skilled in the art, the patient should start with a low dosage regimen of the desired compound of Formula I, particularly carvedilol, and the symptoms of well-known intolerances should be inspected, for example, dizziness due to that compound. Once it is found that the patient tolerates that compound, the doses will be increased slowly until reaching the maintenance dose. The preferred course of treatment is to start with a dosage regimen consisting of formulations containing either 3.125 or 6.25 mg of the active compound per particular unit, preferably delivered twice a day, for a period of 7 to 28 days. The choice of the most appropriate initial dosage for the particular patient is determined by the physician using well-known medical principles including, but not limited to, body weight. In the case in which the patient exhibits medically acceptable tolerance of the compound, for two weeks, the dosage is doubled at the end of the two weeks and the patient is maintained with the new higher dosage, for an additional period, preferably two more weeks, and signs of intolerance are observed. This course is continued until the patient is taken to a maintenance dose. The preferred maintenance dose is 25.0 mg of the active compound per particular unit, preferably given twice a day, for patients having a body weight of up to 85 kg. For patients having a body weight above 85 kg, the maintenance dose is between approximately 25.0 mg and between approximately 50.0 mg, preferably given twice a day; preferably an approximate amount of 50.0 mg of the active compound per particular unit, preferably given twice a day. The present invention also relates to a method of treatment for decreasing mortality resulting from congestive heart failure in mammals, which comprises administering internally to the mammal in need thereof, an effective amount of carvedilol according to the following schedule: (a) a pharmaceutical formulation containing either 3.25 mg of carvedilol per particular unit, for a period of 7 to 28 days, supplied once or twice a day, (b) afterwards, a pharmaceutical formulation containing 2.5 mg of carvedilol per particular unit, for an additional period of 7 to 28 days, supplied once or twice a day, and (c) finally, a pharmaceutical formulation containing, either 25.0 or 50.0 mg of carvedilol, per individual unit, given once or twice a day as a maintenance dose.

The dosage in humans, for the treatment of the disease, according to the present invention, includes the combination of compounds of Formula I, with conventional agents. For example, the usual dosage in adults, of hydrochlorothiazide, is from 25 to 100 mg daily as a single dose or as a divided dose. The recommended initial dose for enalapril is 2.5 mg given once or twice a day. The therapeutic dose range, usual for enalapril, is 5 to 20 mg daily, given as a single dose or as a divided dose. For most patients, the usual initial daily dose of captopril is 25 mg three times a day and most patients have a satisfactory clinical improvement when roasting 50 or 100 mg three times a day. It will be appreciated that the preferred real doses of the compounds used in the compositions of this invention will vary according to the particular composition that is formulated, the mode of administration, the particular site of administration and the host or patient in question. . When the compounds of Formula I, including the compound of Formula II, are used in accordance with the present invention, no unacceptable toxicological effects are expected. It is expected that the following example does not limit the scope of this invention in any way, but is provided to illustrate how to use the compounds of this invention. Many other modalities will become readily apparent to those skilled in the art.

EXPERIMENTAL PART.

Mortality Studies in Patients with CHF.

Summary. To determine if ß-adrenergic blockade could inhibit the damaging effects on the sympathetic nervous system, in surviving heart failure (CHF), 1,052 patients with CHF prospectively enrolled in a multi-center testing program, in which patients they were randomized (double blind) to a treatment of 6 to 12 months with placebo (PBO) or carvedilol (CRV). After a common classification period, patients with CHF class II-IV (see the next paragraph for definitions of Cl classification) and a rejection fraction < 0.35, were assigned to one of four protocols based on the performance of a 6-minute walk test. PBO or CRV was added to the existing therapy with dioxin, diuretics and an ACE inhibitor. Mortality from all causes was inspected through a Council for the Inspection of Data and Security, constituted prospectively (DSMB, for its acronym in English). After 25 months of follow-up, the DSBM recommended the completion of the program due to the favorable effect of CRV on survival. Mortality was 8.2% in the PBO group but only 2.9% in the CRV group (P = 0.001, Cochran-Mantel-Haensel analysis). This represented a reduction in the risk of death by CRV of 67% (95% CI: from 42% to 81%). The effect of the treatment was similar in patients with symptoms of class II and class III and IV. Mortality was reduced in class II patients from 5.9% to 1.9%, a 68% reduction (95% CI: from 20% to 97%) [P = 0.015), and in class III and IV patients from 11.0% to 4.2%, a reduction of 67% (95% CI: from 30% to 84%), [P = 0.004, logarithmic interval]. Importantly, the effect of CRV is similar in ischemic heart disease (the risk was reduced by 67%, P = 0.003) and in dilated cardiomyopathy, non-ischemic (risk reduced by 67%, P = 0.014). In conclusion, the addition of CRV to conventional therapy is associated with a substantial reduction (67%) in mortality in patients with chronic CHF. The effect of the treatment is observed through a wide range of severity and etiology of the disease. As used herein, "CHF class II" means patients with heart disease resulting in a mild or moderate limitation of physical activity.These patients feel comfortable at rest.Ordinary physical activity results in fatigue , palpitations, dyspnea, or anginal pain.

"CHF class II" means patients with heart disease that result in marked limitations of physical activity. These patients feel comfortable at rest. Less than ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain. "Cl class IV" means patients with heart disease resulting in the inability to carry out any physical activity without feeling bad or without heart failure, or the anginal syndrome. "Less than ordinary physical activity" means climbing a flight of stairs, or walking about 183 meters (200 yards).

Study design. Patients with previous therapy based on diuretics, ACE inhibitors and / or digoxin, were stratified based on exercise performance below the maximum, as a baseline, in one of four tests: - study 220, a dose-response study in moderate CHF (NYHA II-IV) with exercise analysis as a primary end point - study 221, a dose titration study in moderate Cl (NYHA II-IV) with Exercise analysis as a primary end point - study 239, a dose titration study in severe CHF (NYHA III-IV) with quality of life as a primary endpoint - study 240, a dose titration study in moderate CHF (NYHA II-III) with progression of CHF as a primary endpoint. 64 centers in the United States participated in the test program. All sites implemented protocols 239 and 240, while 33 implemented protocol 220 and 31 implemented protocol 221. Although each test had its own individual objectives, the overall objective of the program, defined prospectively, was the evaluation of mortality due to all causes. Based on a projected recruitment of 1,100 patients, the program was 90% effective in detecting a 50% reduction in mortality (from both sides) between carvedilol and placebo, assuming a mortality rate, from the placebo group , of 12% during the duration of the tests (a = 0.005). The randomization was preceded by a classification and challenge period, common to the four protocols. The purpose of the classification period was to qualify patients to enter the study, obtain baseline, reproducible measurements, and stratify patients in the trial or appropriate trial based on an exercise analysis below the maximum. During the challenge period, patients received low-dose carvedilol (6.25 mg b.i.d) for two weeks. The patients who were unable to tolerate this dose were not randomized. Patients who tolerated low doses of carvedilol were randomized to a blind medication (carvedilol or placebo) with the titrated dose for several weeks, at intervals of 6.25 to 50 mg b.i.d. (or equivalent level of placebo). The maintenance phase of each study varied from 6 to 12 months, after which patients had the option of receiving open label carvedilol, in an extension study.

Results The analysis presented below corresponds to the set of data on the basis of which the DSMB made the recommendation to complete the tests or trials. Included in this analysis of attempted treatment, all patients involved in the tests, in the United States, on the date of January 20, 1995; 624 received carvedilol and 356 placebo. An analysis of the characteristics of the baseline patients (Table 1) shows good balance between the randomized groups.

Table 1: Tests in heart failure, with carvedilol, in the United States - baseline characteristics.

* SD = Standard Deviation The results of the overall mortality for the program are shown in Table 2. All deaths that occurred during the period of attempted treatment are included. Treatment with carvedilol resulted in a 67% reduction in the risk of mortality from all causes. The analysis of mortality by certain baseline characteristics shows that this is a broad effect without taking into account the severity or the etiology of Cl. The effect was uniform in patients with moderate or moderate heart failure in severe heart failure. Similarly, the reduction in mortality was equivalent in patients with ischemic and non-ischemic heart failure.

Table 2: Evaluation of mortality in CHF studies, using carvedilol, in the United States.

* Analysis by Cochran-Mantel-Haensel The foregoing is illustrative of the use of the compounds of this invention. However, this invention is not limited to the precise embodiment described therein, but encompasses all modifications that fall within the scope of the following claims. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates. Having described the invention as above, the content of the following is claimed as property:

Claims (12)

1. The use of a compound that is both a β-adrenoreceptor antagonist and an α-adrenoreceptor antagonist, for the manufacture of a medicament, to decrease mortality resulting from congestive heart failure, in mammals, alone or in conjunction with one or more agents Different therapeutic agents, wherein those agents are selected from the group consisting of the angiotensin-converting enzyme inhibitor, a diuretic and cardiac glycosides.

2. The use of a compound according to claim 1, wherein the compound is subject to Formula I (I) where Ri is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl; R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl; R3 is hydrogen or lower alkyl of up to 6 carbon atoms; R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent -CH2-0-; X is a valence bond. -CH2, oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl; R5 and R6 are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a group -CONH2-, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms. carbon, lower alkylsulfonyl of up to 6 carbon atoms and lower alkylsulfonyl of up to 6 carbon atoms; or R5 and Re, collectively, represent methylenedioxy; and the pharmaceutically acceptable salts thereof.

3. The use of a compound according to claim 1 or 2, wherein the compound is carvedilol.

4. The use of a compound according to claim 3, wherein a pharmaceutical formulation containing either 3.125 or 6.25 mg of carvedilol, in a single unit, is administered for a period of 7 to 28 days, once or twice a day. day, as an initial dose.

5. The use of a compound according to claim 3, wherein a pharmaceutical formulation containing 12.5 mg of carvedilol, in a single unit, is administered for a period of 7 to 28 days, once or twice a day.

6. The use of a compound according to claim 3, wherein a pharmaceutical formulation containing either 25.0 or 50.0 mg of carvedilol, in a single unit, is administered once or twice a day, as a maintenance dose.

7. The use of a compound according to claim 1, wherein the angiotensin converting enzyme (ACE) inhibitor is selected from the group consisting of captopril, lisinopril, fosinopril or enalapril, or any pharmaceutically acceptable salt thereof.

8. The use of a compound according to claim 1, characterized in that the diuretic is selected from the group consisting of hydrochlorothiazide, torasemide or furosemide, or any pharmaceutically acceptable salt thereof.

9. the use of a compound according to claim 1, wherein the cardiac glycoside is selected from the group consisting of digoxin, β-met il-digoxin or digitoxin.

10. The use of carvedilol for the manufacture of a drug, to reduce the mortality resulting from congestive heart failure, in mammals, in accordance with the following regimen: (a) administer a pharmaceutical formulation containing either 3.125 or 6.25 mg of carvedilol per particular or single unit, for a period of 7 to 28 days, supplied once or twice a day, (b) then administering a pharmaceutical formulation containing 12.5 mg of carvedilol, per individual unit or location, for a period of 7 to 28 additional days, delivered once or twice a day, and (c) Administer finally a pharmaceutical formulation containing either 25.0 or 50.0 mg of carvedilol per particular or single unit, given once or twice a day, as a maintenance dose.

11. The use of carvedilol according to claim 10, whereby carvedilol is administered together with one or more other therapeutic agents, wherein the agents are selected from the group consisting of the angiotensin-converting enzyme inhibitor, a diuretic and a cardiac glycoside

12. The use of a compound according to claim 1, for the preparation of a medicament for the treatment, of congestive heart failure (CHF) which is to be administered in a maintenance dose, daily, from 10 to 100 mg, the medicament is administered in dosing schemes that are increased, comprising three dosing regimens, the first regimen comprises administering an amount of 10 to 30% of the daily maintenance dose, of the compound, for a period of 7 to 28 days, the The second regimen comprises administering an amount of 20 to 70% of that daily dose, for a period of 7 to 28 days, and a third regimen comprises administering 100% of that daily dose, starting after the end of the second regimen. SUMMARY OF THE INVENTION. The present invention relates to a method of treatment using a compound of Formula I, wherein Ri is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl; R 2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylphenyl; R3 is hydrogen or lower alkyl of up to 6 carbon atoms; R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent -CH2-0-; X is a valence bond, -CH2, oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl; R5 and Re are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a group -CONH2-, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms. carbon, lower foncil alkylate of up to 6 carbon atoms and lower alkylsulfonyl of up to 6 carbon atoms; or Rs and Re, collectively represent methylenedioxy; or a pharmaceutically acceptable salt thereof, preferably carvedilol alone or in conjunction with one or more other therapeutic agents, and those agents are selected from the group consisting of the Angiotensin Converting Enzyme (ACE), diuretics, and cardiac glycosides, for decrease the mortality resulting from congestive heart failure (CHF) in mammals, particularly in humans.