Use of carbazole compounds for the treatment of congestive heart

Details Use of carbazole compounds for the treatment of congestive heart Use of carbazole compounds for the treatment of congestive heart

1997-12-29

1999-05-11

Spivack, Phyllis G.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

A61K31/40

Patent

active

059028211

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to a new method of treatment using compounds which are dual non-selective .beta.-adrenoceptor and .alpha..sub.1 -adrenoceptor antagonists in particular the carbazolyl-(4)-oxypropanolamine compounds of Formula I, preferably carvedilol, for decreasing the mortality of patients suffering from congestive heart failure (CHF). The invention also relates to a method of treatment using compounds which are dual non-selective .beta.-adrenoceptor and .alpha..sub.1 -adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolamine compounds of Formula I, preferably carvedilol, in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of angiotensin converting enzyme (ACE) inhibitors, diuretics, and cardiac glycosides, for decreasing the mortality of patients suffering from CHF. The invention further relates to an incremental application scheme for administering compounds which are .beta.-adrenoreceptor and .alpha..sub.1 -adrenoreceptor antagonists.


BACKGROUND OF THE INVENTION

Congestive heart failure occurs as a result of impaired pumping capability of the heart and is associated with abnormal retention of water and sodium. Traditionally, treatment of chronic mild failure has included limitation of physical activity, restriction of salt intake, and the use of a diuretic. If these measures are not sufficient, a cardiac glycoside, which is an agent that increases the force of mycardial contraction, is typically added to the treatment regimen.
Subsequently, angiotensin converting enzyme inhibitors, which are compounds that prevent the conversion of angiotensin I into the pressor-active angiotensin II, are prescribed for chronic treatment of congestive heart failure, in conjunction with a diuretic, a cardiac glycoside, or both.
Also, congestive heart failure is a well-known cardiac disorder which results in an excess mortality. Applefeld, M. M., (1986) Am. J. Med. 80, Suppl. 2B, 73-77. Therefore, therapeutic agents that would decrease the mortality resulting from CHF in patients suffering therefrom are highly desirable.


SUMMARY OF THE INVENTION

The present invention provides a new use of compounds which are dual non-selective .beta.-adrenoceptor and .alpha..sub.1 -adrenoceptor antagonists for the preparation of medicaments for the treatment of congestive heart failure. In particular, the carbazolyl-(4)-oxypropanolamine compounds of Formula I are preferred, alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of ACE inhibitors, diuretics, and cardiac glycosides, as therapeutics for decreasing mortality resulting from congestive heart failure in mammals. In particular, the present invention preferably provides a method of treatment, alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of ACE inhibitors, diuretics, and cardiac glycosides, for the compound of Formula I wherein R.sub.1 is --H, R.sub.2 is --H, R.sub.3 is --H, R.sub.4 is --H, X is 0, Ar is phenyl, R.sub.5 is ortho --OCH.sub.3, and R.sub.6 is --H, said compound being better known as carvedilol, which is a pharmaceutically acceptable salt thereof.


DETAILED DESCRIPTION OF THE INVENTION

U.S. Pat. No. 4,503,067 discloses carbazolyl-(4)-oxypropanolamine compounds of Formula I:


TABLE 1 ______________________________________ US Carvedilol Heart Failure Trials-Baseline Characteristics Placebo Carvedilol Characteristic (n .apprxeq. 356) (n = 624) ______________________________________ Age, mean + SD (years) 59.9 + 11.7 58.8 - 11.8 Sex (% men) 62% 62% Etiology (% ischemic) 43% 40% Severity of CHF Class II 41% 41% Class III-IV 40% 39% Unknown 19% 20% LV ejection fraction, mean + SD 0.22 + 0.07 0.23 - 0.08 6 Minute walk (m + SD) 373 + 88 379 + 81 Blood pressure (mmHg) 115/73 115/73 Heart rate (bpm + SD) 85 .+-. 13 86 .+-. 13 ______________________________________ selected from benzoyl, and n

REFERENCES:
patent: 4888179 (1989-12-01), Appelgren et al.
patent: 5308862 (1994-05-01), Ohlstein
patent: 5312828 (1994-05-01), Finkelstein et al.
J. of Cardiovascular Pharm; Senior, et al., "Effects of Carvedilol on Ventricular Arrhythmias", 1992, vol. 19, (Supp. 1): pp. S117-S121.
J. of Cardiovascuclar Pharm; DasGupta, et al., "The Effects of Intravenous Carvedilol, A New Multiple Action Vasodilatory .beta.-Blocker, in Congestive Heart Failure", 1991, vol. 18, (Suppl. 1): pp. S12-S16.
American J. of Cardiology; DasGupta, et al., "Value of Carvedilol in Congestive Heart Failure Secondary to Coronary Artery Disease", 1990, vol. 66, pp. 1118-1123.
Z. Kardiol; A. Buchwald, et al., "Acute Hemodynamic Effects of the Beta-blocker Carvedilol in Heart Failure", 1990, vol. 79, No. 6, pp. 424-428.
JACC; DiLenarda, et al., "Acute Hemodynamic Effects of Carvedilol Versus Metroprolol In Idiopathic Dilated Cardiomyopathy", 1991, vol. 17, No. 2, Abstract 142A.
Frontiers in CHF; D. Tepper, "Multicenter Oral Carvedilol Heart Failure Assessment", 1996, vol. 2, No. 1, pp. 39-40.
J. of Cardiovascular Pharm; DasGupta, et al., 1992, vol. 19, (Suppl. 1): pp. S62-S67.
J. of Hypertension; C. Rosendorff, "Beta-blocking agents with vasodilator activity", 1993, vol. 11, (Suppl. 4): pp. S37-S40.
Cardiology; J. Lessem, et al., "Development of a Multiaction Beta-blocker", 1993, vol. 82, (Suppl. 3): pp. 50-58.
Drug Safety; W.J. Louis, et al., "A Risk-Benefit Assessment of Carvedilol in the Treatment of Cardiovascular Disorders", 1994, vol. 11, No. 2, pp. 86-93.
1994 American Heart Association, Inc., "A Randomized Trial of .beta.-Blockade in Heart Failure", Circulation 90(4), Oct. 1994, pp. 1765-1773.
Waagstein et al., The Lancet, vol. 342, Dec. 11, 1993, "Beneficial effects of metroprolol in idiopathic dilated cardiomyopathy", pp. 1441-1446.
Ruffolo et al., Cardiology 1993; 82(suppl 3):24-28, "Cardioprotective Potential of Carvedilol", pp. 24-28.
Feuerstein et al., Journal of Hypertension 1993, vol. 11(suppl 4)., "Myocardial protection by the novel vasodilating beta-blocker, carvedilol; potential relevance of anti-oxidant activity".
Feuerstein et al., Journal of Cardiovascular Pharmacology, 19(suppl. 1) S138-141, "Myocardial Protection with Carvedilol"(1992).
DiBianco et al., The New England Journal of Medicine, vol. 320, Mar. 16, 1989, No. 11, "A comparison of oral milrinone, digoxin, and their combination in the treatment of patients . . . ", pp. 677-678.
Cohn et al., The New England Journal of Medicine, vol. 313, No. 24, "Effect of vasodilator therapy on mortality in chronic congestive heart failure", Jun., 1986, pp. 1547-1552.
McTavish et al., Drugs, 45(2): 232-258, 1993, "Carvedilol, A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy".
Drugs; McTavish, et al., "Carvedilol--A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therepeutic Efficacy", 1993, vol. 45, No. 2, pp. 232-258.
Circulation; H. Krum, et al., "Effects of Carvedilol, a Vasodilator-.beta.-Blocker, in Patients with Congestive Heart Failure Due to Ischemic Heart Disease", 1995, vol. 92, No. 2, pp. 212-218.
CBS-TV; CBS Evening News, Transcript, Jan. 27, 1993, 6:30-7:00pm.
CNBC; Steals and Deals, Transcript, Jan. 29, 1993, 8:30pm.
Circulation; DasGupta, et al., 1989, vol. 80, No. 4, (Suppl. II): pp. 116-117.
Drugs of Today; Ruffolo, et al., "Carvedilol (Kredex): A Novel Multiple Action Cardiovascular Agent", 1991, vol. 27, No. 7, pp. 465-492.

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