WO1993005790A1

WO1993005790A1 - Use of 14-aminosteroids for the manufacture of a medicament to slow the rate of progression of myocardial structural damages characteristic of congestive heart failure

Info

Publication number: WO1993005790A1
Application number: PCT/US1992/008049
Authority: WO
Inventors: Bruce Martin Halpryn
Original assignee: Procter and Gamble Pharmaceuticals Inc
Current assignee: Warner Chilcott Pharmaceuticals Inc
Priority date: 1991-09-27
Filing date: 1992-09-21
Publication date: 1993-04-01
Anticipated expiration: 1994-03-27
Also published as: MX9205527A; AU2675092A; PT100907A

Abstract

The present invention is directed to a method of slowing the rate of progression of the myocardial structural damages in a human subject having CHF, comprising administering to said subject a safe and effective amount of a 14-aminosteroid compound or acid salt thereof of general formula (I) wherein a) R1 is (i) COOR5, where R5 is a lower alkyl group containing 1 to 4 carbon atoms, a lower alkyl group containing 2 to 4 carbon atoms substituted by an amino group, or an arylalkyl group containing 6 to 12 carbon atoms, or (ii) CHR6OH, where R6 is a hydrogen atom or lower alkyl group containing 1 to 4 carbon atoms; b) R2 is -NR7R8, where R7 and R8, which may be the same or different, are hydrogen atoms or lower alkyl group containing 1 to 4 carbon atoms; c) R3 is (i) monosaccharide sugar residue, wherein (II) R9 is a hydrogen atom, a hydroxy group, or an acetoxy group, R10 is a hydroxy or acetoxy group, or R9 and R10 together form a divalent alkylenedioxy group, R11 represents a hydroxy group, a methoxy group, or an acetoxy group, and R12 is a methyl group or a hydroxy-methyl group, or (ii) OH; d) R4 is (i) OH, or (ii) H, or (iii) OR13, where R13 is said monosaccharide sugar residue; e) Z is (i) -CH-, where a and b are single bonds, or (ii) =C, where either a or b is a double bond. The 14-aminosteroid is preferably administered in a pharmaceutical composition comprising the 14-aminosteroid and a pharmaceutically acceptable carrier.

Description

USE OF 14-AMINOSTEROIDS FOR THE MANUFACTURE OF A MEDICAMENT TO SLOW THE RATE OF PROGRESSION OF MYOCARDIAL STRUCTURAL DAMAGES CHARCTERISTIC OF CONGESTIVE HEART FAILURE

BACKGROUND OF THE INVENTION

This invention relates to the novel use of 14-aminosteroids to slow the rate of progression of the myocardial structural damages characteristic of Congestive Heart Failure (CHF).

CHF is a progressive disease wherein the heart is increasingly unable to supply adequate cardiac output (CO), which is the volume of blood pumped by the heart over time, to deliver the oxygenated blood to the peripheral tissues. When the heart initially fails, the rest of the body compensates for the loss in

CO and such compensatory mechanisms eventually result in the syndrome known as CHF. As CHF progresses, structural and hemodynamic damages occur. Such structural damage manifests itself macroscopically as ventricular hypertrophy in the myocardium, and microscopically as interstitial, perivascular and replacement fibrosis in the ventricle wall, decreased myocardial capillary density, and myocardial cell death. When fibrosis of the myocardial tissue occurs it compromises the functioning of the heart because the remaining viable myocardial cells have a greater workload.

Hemodynamically, in the failing heart, the capacity to develop force during systole (the phase in the cardiac cycle during which ejection of blood from the ventricles occurs) is reduced. Thus, a greater end-diastolic volume (during the diastolic phase of the cardiac cycle filling of the ventricles occurs) is needed to perform any given level of external work. In cardiac failure, reduced ejection, caused by a mismatch of work capacity and load, results in an increase in end diastolic pressure and pulmonary capillary pressure. Pulmonary congestion and peripheral edema often follow. From the patient's perspective, as CHF progresses, the patient experiences increasingly worsening symptoms of fatigue and dyspnea.

Effective treatment of CHF requires a determination of its etiology, if possible, because some CHF etiologies have their own unique form of treatment. CHF has a variety of etiologies, including diseases of the myocardium such as coronary artery disease or myocarditis; diseases of the valves, such as mitral valve prolapse or aortic stenosis; pericardial diseases; congenital heart disease; pulmonary disease, cardiac arrhythmias, hypertension, and diabetes. For example, if the etiology of CHF is myocarditis or an arrhythmia then treating the patient with an antimicrobial or an anti-arrhythmic agent, respectively, may restore the patient to normal cardiac function.

However, once the etiologies not responding to other treatments have been ruled out, treatment by one or more of three modalities is initiated: 1) improvement of the heart's pumping capacity by administration of an inotropic agent, such as digitalis, 2) reduction of the heart's workload by rest and/or by administration of vasodilators such as captopril, and 3) controlling sodium and water retention by a low sodium diet or administration of a diuretic such as thiazide. Treatment of CHF 1s individualized according to the patients symptomatology and tolerance for certain medications. For example, some patients may have a strong tendency to develop digitalis toxicity, while other patients with mild symptoms may benefit from diuretics which have a greater therapeutic index. Moreover, current wisdom suggests that diuretics are appropriate first line CHF therapy and that diuretic treatment should be followed by vasodilators and digitalis. It has also been noted that digitalis is most effective in patients suffering from severe CHF. See generally, Braunwald, Heart Disease: A Textbook of Cardiovascular Medicine, Vol. (3rd ed. 1988), Chung, E.K., Quick Reference to Cardiovascular Disease, Chapter 27 (2d ed. 1983) and Fowler, N.O., Cardiac Diagnosis and Treatment, Chapter 12 (2d ed. 1976).

Current CHF treatment 1s limited to ameliorating the symptoms associated with the hemodynamic problems of CHF. While digitalis is useful for ameliorating the symptoms associated with the hemodynamic problems characteristic of severe CHF, its low therapeutic index, in effect, limits Its therapeutic utility. See generally, Braunwald, Heart Disease: A Textbook of Cardiovascular Medicine, Vol. (3rd ed. 1988), Chung, E.K., Quick Reference to Cardiovascular Disease, Chapter 27 (2d ed. 1983) and Fowler, N.O., Cardiac Diagnosis and Treatment, Chapter 12 (2d ed. 1976) and Goodman and Gilman, The Pharmacological Basis of Therapeutics, Chapter 34 (8th ed., 1990).

Given the toxicity problems with therapy directed toward treating the hemodynamic problems, a need exists for a compound that ameliorates the myocardial structural damages associated with CHF. Interest in a compound that slows the structural pathology of CHF as it progresses began initially with the inotrope digitalis despite its toxicity problems. See Williams, J. F. and Braunwald, E., "Studies on Digitalis - Effects of Digitoxin on the Development of Cardiac Hypertrophy in the Rat Subjected to Aortic Constriction", 16 An. J. Cardiol . 534 (1965) (hereinafter Williams and Braunwald). Williams and Braunwald concluded that, digitoxin administered prior to and following aortic constriction, may thus be considered to exert a protective effect on the heart since it diminishes the hypertrophy which results from a chronic pressure load. The Williams and Braunwald study, however, never demonstrated that digitoxin slowed the rate of replacement fibrosis in the myocardium.

It has been also disclosed in a medical textbook, widely known to those skilled in the art, that digitalization "can decrease the rate of progression of cardiac disease." See Goodman and Gilman, The Pharmacological Basis of Therapeutics, Chapter 34, (8th ed., 1990) (hereinafter Goodman and Gilman). However, the utility of digitalis to decrease the rate of progression of CHF is questionable. Another, investigator compared digoxin and propranolol to determine if propranolol or digoxin protected turkeys against dilation of the left ventricle. This study concluded that propranolol but not digoxin prevented left ventricular dilation. See Gwathmey, J. and Hamlin, R., "Protection of Turkeys Against Furazolidone Induced Cardiomyopathy", Am. J. Cardiol.52:626 (1983).

The questionable utility of digitalis to slow the progression of CHF along with its toxicity problems prompted Investigators to attempt to develop safer cardioactive compounds. Cardioactive steroid nucleus containing compounds have been described in the following patents. World Patent Publication W087/04167 to Chiodini, et al. published July 16, 1987 describes aminoglycoside steroid derivatives substituted at the 3-position by an amino-sugar residue and an acetal linkage at the 14-position. The disclosure states that the compounds are useful for the treatment of hypertension. French Patent 2,642,973 of Guina published August 17, 1990 describes a digitalis-like compound, 2,3-dioxymethyl-6-methyl-3-beta-D-glucose-strophanthidine, which contains the steroid nucleus substituted at the 3-position with a giucose moiety and at the 17-position with the lactone moiety, and at the 14-position with a hydroxyl group. The disclosure states that the compound is useful in preventing pathologic states resulting from cardiac insufficiencies for which digitalis is prescribed and for preventing pathologic states resulting from hypertension due to arterial calcification. The Guina compound is also alleged to be a positive inotrope, a peripheral vasodilator, and an antiarrhythmic agent. Neither Chiodini or Guina, however, disclose a compound that slows the progression of the structural damage associated with CHF.

Additionally, angiotensin converting enzyme inhibitors (ACEI) have been shown to reduce mortality in CHF patients by ameliorating the hemodynamic symptoms. However, ACEI administration has not been shown to slow the deposition of replacement fibrosis in the myocardium and thus slow the progression of the structural damages associated with CHF. See Nicklas, J. M. and Pitt, B., et al. (The SOLVD Investigators). "Effect of Enalapril on Survival in Patients with Reduced Left Ventricular Ejection Fractions and Congestive Heart Failure", H. Engl . J. Med. 325(5):293 (1991).

Clearly, the prior art does not disclose a compound able to slow the progression of the structural damages associated with

CHF. The facts that four million people suffer from CHF and that the five year mortality after diagnosis of CHF is 60% for men and

45% for women, indicate that current therapies directed toward ameliorating the hemodynamic disturbances are not slowing the inexorable structural pathology of the CHF syndrome. See

Parmley, W.W., "Pathophysiology and Current Therapy of Congestive

Heart Failure", J. Am. Col . Cardiol . 13:771-785 (1989).

Accordingly, the method of this invention provides a novel therapeutic approach to slow the inevitable progression of the structural damages associated with CHF.

It has now been discovered that administration of certain 14-aminosteroid compounds slows the progress of the structural abnormalities associated with CHF by slowing the deposition of interstitial, perivascular, and replacement fibrosis in the myocardium. The 14-aminosteroids are described in the following three patents, all incorporated by reference herein: U.S. Patent 4,552,868, Jarreau, et al., issued November 12, 1985; U.S. Patent 4,584,289 Jarreau, et al., issued April 22, 1986 and U.S. Patent 4,885,280 Jarreau, et al., issued December 5, 1989. These three patents describe 14-aminosteroid compounds possessing positive inotropic activity. It has never been suggested, however, that these 14-aminosteroid compounds can alter the progression of the structural damages associated with CHF. The compounds of the present invention are not merely inotropic, they also slow the structural damages that occur as CHF progresses as indicated by a reduction in the amount of replacement fibrosis in the myocardium. A reduction in myocardial replacement fibrosis indicates that fewer myocardial cells are dying. Additionally, the compounds of the present invention, being substantially less toxic than digitalis can be safely administered in the early stages of CHF. Therefore, if the progression of CHF is slowed, the need for a variety of medications, i. e. the vasodilators, the diuretics, and other purely inotropic drugs or surgery, for the worsening symptoms may be diminished.

SUMMARY Of THE INVENTION

The present invention is directed to a method of slowing the rate of progression of the myocardial structural damages in a human subject having CHF, comprising administering to said subject a safe and effective amount of a 14-aminosteroid compound or acid salt thereof of the following general formula:

wherein a) R₁ is (i) COOR₅, where

R₅ is a lower alkyl group containing 1 to 4 carbon atoms, a lower alkyl group containing 2 to 4 carbon atoms substituted by an amino group, or an arylalkyl group containing 6 to 12 carbon atoms, or

(i)) CHR₆OH, where

R₆ is a hydrogen atom or lower alkyl group containing 1 to 4 carbon atoms; b) R₂ is -NR₇R₈, where

R₇ and R₈, which may be the same or different, ar hydrogen atoms or lower alkyl group containing 1 to carbon atoms; c) R₃ Is (1) monosaccharide sugar residue, where

R₉ Is a hydrogen atom, a hydroxy group, or an acetoxy group, R₁₀ is a hydroxy or acetoxy group, or R₉ and R₁₀ together from a divalent alkylenedioxy group, R₁₁ represents a hydroxy group, a methoxy group, or an acetoxy group, and R₁₂ is a methyl group or a hydroxy-methyl group, or

(ii) OH; d) R₄ Is (i) OH, or

(ii) H, or

(iii) QR₁₃, where R₁₃ is said monosaccharide sugar residue; e) Z is (i) -CH-, where a and b are single bonds, or

(ii) =C, where either a or b Is a double bond.

The 14-aminosteroid is preferably administered in a pharmaceutical composition comprising the 14-aminosteroid and a pharmaceutically-acceptable carrier. DESCRIPTION OF THE INVENTION

This Invention provides a method of slowing the rate of progression of the myocardial structural damages associated with CHF, comprising administering a 14-aminosteroid compound.

ACTIVE MATERIALS

The methods of this invention Involve the administration of a 14-aalnosterold compound. A 14-aminosteroid compound includes one or more compounds of the following general formula:

Wherein: a) R₁ is (i) COOR₅, where

R₅ 1s a lower alkyl group containing 1 to 4 carbon atoms, preferably a methyl or ethyl group, a lower alkyl group containing 2 to 4 carbon atoms substituted by an amino group, forming a 2-amlnoethyl 3-aminopropyl group, or an arylalkyl group containing 6 to 12 carbon atoms, preferably a phenyl, benzyl or tolyl group, or

(ii) CHR₆OH, where

R₆ is a hydrogen atom or lower alkyl group containing 1 to 4 carbon atoms, preferably a methyl group; b) R₂ is -NR₇R₈, where R₇ and R₈, which may be the same or different, ar hydrogen atoms or lower alkyl group containing 1 to 4 carbon atoms, preferably methyl groups; c) R₃ is (i) a monosaccharide sugar residue, where

R₉ is a hydrogen atom, a hydroxy group, or an acetoxy group preferably a hydroxy group, R₁₀ is a hydroxy or acetoxy group preferably a hydroxy group, or R₉ and R₁₀ together form a divalent alkylenedioxy group, such as methylene dloxy, ethylene dioxy or Isopropylidenedioxy, Rll represents a hydroxy group, a methoxy group, or an acetoxy group preferably a hydroxy group, and R₁₂ is a methyl group or a hydroxy-methyl group, or

(ii) OH; d) R₄ is (i) OH, or

(ii) H, or

(iii) OR₁₃, where R₁₃ is said monosaccharide sugar residue; e) Z Is (1) -CH-, where a and b are single bonds, or

(ii) =C, where either a or b is a double bond.

One group of preferred compounds is the 14-aminosteroids wherein R₁ is CHR₆OH, R₂ is NH₂, R₃ is a monosaccharide sugar residue, R₄ 1s OH or H and Z is CH where a and b are single bonds. Specifically, the preferred compounds are (3β,5β,14β,17β)-14-amino-17-(hydroxymethyl)androstan-3-yl 6-deoxy -α-L-mannopyranoside; (3β,5β,14β,20S)-14-amino-20-hydroxypregnan- 3-yl 6-deoxy-α-L-mannopyranoside and its 20R isomer; (3β,5β,14β,20S)-14-amino-20-hydroxypregnan-3-yl 2,6-dideoxy-β-D- ribo-hexopyranoside and its 20R isomer; (3β,5β,14β,20S)-14-amino- 20-hydroxypregnan-3-yl 4-amino-2,4,6-trideoxy-α-L-lyxo-hexopyranoside and its 20R isomer; (3β,5β,12β,14β,17β)-14-amino-12- hydroxy-17-(hydroxymethyl)androstan-3-yl 6-deoxy-α-L-mannopyranoside; (3β,5β,12β,14β,20R)-14-amino-12,20-dihydroxypregnan-3-yl 6- deoxy-α-L-mannopyranoside and its 20S isomer; (3β,5β,12β,14β,20S) -14-amino-12,20-dihydroxypregnan-3-yl 2,6-dideoxy-β-D-ribo-hexopyranoside and its 20R isomer; (3β,5β,12β,14β,20R)-14-amino-20- hydroxypregnane-3,12-diyl bis[6-deoxy-α-L-mannopyranoside] and its 20S isomer. These compounds and methods for their manufacture are described in U.S. Patent 4,552,868, Jarreau, et al., issued November 12, 1985; incorporated by reference herein.

Another group of preferred compounds is the 14-aminosteroids wherein R₃ is an OH group. Specific compounds wherein R₃ is an OH group are (3β,5β,12β,14β,20R)-14-amino-pregnane-3,12,20-triol and its 20S isomer and (3β,5β,12β,14β,17β)-14-amino-3,12-di- hydroxy-androstane-17-methanol. These compounds and their methods of manufacture are described in U.S. Patent 4,584,289,. Jarreau, et al., issued April 22, 1986 incorporated herein by reference.

Particularly preferred compounds are the 14-aminosteroids wherein R₁ is a COOR₅ group where R₅ is a lower alkyl group containing 1 to 4 carbon atoms, a lower alkyl group containing 2 to 4 carbon atoms substituted by an amino group, or an aralkyl group containing 6 to 12 carbon atoms, R₂ is NR₇R₈ where R_{7 a}nd R₈ which may be the same or different, are hydrogen atoms or lower alkyl groups containing 1 to 4 carbon atoms, and R₃ is a monosaccharide sugar residue and R₁, R₂ and R₃ are in the most pharmacologically active β (beta) position. R4 is either -OH or H. Z can be either -CH where a and b are single bonds or =C where the double bond is located at either the a or b position on the steroid nucleus. Specific particularly preferred compounds are (3β,5β,14β,17β)-14-methylamino-3-[(6-deoxy-α-L-mannopyranosyl)oxy]androstane-17-carboxylic acid, methyl ester; (3β,14β,17β)-14-amino-3-[(6-deoxy-α-L-mannopyranosyl)oxy]androst- 4-ene-17-carboxylic acid, methyl ester; (3β,5β,14β,17β)-14-amino- 3-[(6-deoxy-α-L-mannopyranosyl)oxy]androstane-17-carboxylic acid, methyl ester and (3β,5β,14β,20R)-14-amino-20-hydroxypregnan-3-yl 6-deoxy-α-L-mannopyranoslde and its 20S isomer. These compounds and methods for their manufacture are described in U.S. Patent 4,885,280 Jarreau, et al., Issued December 5, 1989 Incorporated herein by reference.

COMPOSITIONS

The compounds of the present invention are administered in a pharmaceutical composition comprising a safe and effective amount of a 14-aminosteroid active ingredient and a pharmaceutically- acceptable carrier.

The phrase "safe and effective amount," as used herein means an amount of a compound or composition high enough to significantly positively modify the symptoms and/or condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. The safe and effective amount of active ingredient for use in the method of the invention herein will vary with the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular pharmaceutically-acceptable excipients utilized, and like factors within the knowledge and expertise of the attending physician.

The compositions of this invention are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition of this invention containing an amount of a 14-aminosteroid that is suitable for administration to a human subject, in a single dose, according to good medical practice. These compositions preferably contain from about .001 mg (milligrams) to about 5 mg and more preferably from about .01 mg to about 2.0 mg of a 14-aminosteroid. The compositions of this invention may be in any of a variety of forms, suitable (for example) for oral, sublingual, buccal, rectal, topical, inhalation or parenteral administration or administration as a subcutaneous Implant. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. These include solid or liquid fillers, diluents, hydrotropes, surface-active agents, and encapsulating substances. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references, all incorporated by reference herein: 7 Modern Pharmaceutics. Chapters 9 and 10 (Baker & Rhodes, editors, 1979; Lieberman et al., Pharmaceutical Dosaoe Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2d Edition (1976).

In particular, pharmaceutically-acceptable carriers for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceutically-acceptable carrier, in compositions for parenteral administration, comprises at least about 95% by weight by the total composition.

Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. These oral dosage forms comprise a safe and effective amount, preferably from about 0.5 mg to about 2.0 mg, of the

14-aminosteroid. More preferably these oral dosage forms comprise 1.0 mg of the 14-aminosteroid. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents. Preferred carriers for oral administration Include gelatin, propylene glycol, cottonseed oil and sesame oil.

The compositions of this invention can also be administered topically to a subject, i.e., by the direct laying on or spreading of the composition on the epidermal or epithelial tissue of the subject. Such compositions include, for example, lotions, creams, solutions, gels and solids. These topical compositions comprise a safe and effective amount, preferably from about 0.5 mg to 2.0 mg, of the 14-aminosteroid. More preferably these topical compositions comprise 1.0 mg of the 14-aminosteroid. Suitable carriers for topical administration preferably remain in place on the skin as a continuous film, and resist being removed by perspiration or immersion in water. Generally, the carrier is organic in nature and capable of having dispersed or dissolved therein the 14-aminosteroid. The carrier may include pharmaceutically-acceptable emolients, emulsifiers, thickening agents, and solvents.

The compositions of this invention can also be administered via the inhalation route. Such compositions are prepared in a matrix comprising a solvent such as water or a glycol, preservatives such as methyl or propyl paraben and propellants such as nitrogen or carbon dioxide.

Additionally, the compositions of this invention can be administered via a subcutaneous implant formed from silicone elastomers, ethylene vinyl acetate co-polymers or lactic-glycolic co-polymers.

METHODS OF TREATMENT

The term, "CHF" as used herein, denotes a progressive disease wherein the hemodynamic capacity as well as the structure of the heart Itself is increasingly and irreversibly compromised.

The progression of CHF according to the patient's symptoms has been classified Into four functional classifications by the New

York Heart Association (NYHA).

New York Heart Association

Functional Classification

Class

I. Patients with cardiac disease but without resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.

II. Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.

III. Patients with, cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain.

IV. Patient with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.

NYHA Classes III and IV, also referred to as overt congestive heart failure, are often treated by administering compounds that increase cardiac contractility by exerting a positive inotropic effect. The reference compound for increasing cardiac contractility is oral digoxin. Treating the symptoms of the overt CHF by administering inotropes to increase CO to meet the metabolic needs of the body can improve the quality of life for a CHF patient because the heart can better supply the metabolic need of the body. Conventional wisdom, however, indicates that an inotrope, such as digitalis, might increase mortality rates because the inotropic action creates an extra work load for the heart. Furthermore, digitalis has a narrow therapeutic:toxic dose ratio and administration of digitalis at an earlier than Class III NYHA functional classification may not be prudent.

Additionally, the bipyridine Inotrope, Milrinone, has been shown to aggravate ventricular arrhythmias and possibly increase mortality. See DiBianco, R., et al. "A Comparison of Oral Milrinone, Digoxin, and Their Combination in the Treatment of Patients with Chronic Heart Failure", N. Engl. J. Hed. 320:677 (1989).

The term "hemodynamic" as used herein, refers to the mechanical capability of the heart. The initial hemodynamic consequence of heart failure is a decrease in stroke volume which is a measurement of the amount of blood ejected with each heart beat. The heart then compensates to increase the CO to maintain flow to the vital organs. As the heart failure worsens, intracardiac filling pressures are elevated as well as pulmonary and venous pressures. The heart is increasingly unable to supply the required CO.

The term "structural damage" as used herein, refers to the microscopic and macroscopic changes in the heart of a person suffering from CHF. Structurally, on a microscopic level the following changes occur: The early stage of cardiac hypertrophy is characterized morphologically by increases in the size of myofibrils and mitochondria as well as enlargement of mitochondria and nuclei. Muscle cells are larger than normal, but cellular organization is largely preserved. At a more advanced stage of hypertrophy, preferential increases in the size or number of specific organelles, such as mitochondria, as well as irregular addition of new contractile elements in localized areas of the cell, result in subtle abnormalities of cellular organization and contour. Adjacent cells may vary in their degree of enlargement. Administration of a 14-aminosteroid at this stage slows the inevitable deposition of replacement fibrosis in the myocardium which is characteristic of long standing cardiac hypertrophy.

Cells subjected to long-standing hypertrophy show more obvious disruptions in cellular organization, such as markedly enlarged nuclei with highly lobulated membranes, which displace adjacent myofibrils and cause breakdown of normal Z-band registration. The early preferential increase in mitochondria is supplanted by a predominance by volume of myofibrils. The late stage of hypertrophy is characterized by cell death and a loss of contractile elements with marked disruption of Z bands, severe disruption of the normal parallel arrangement of the sarcomeres, dilation and increased tortuosity of T tubules, and replacement of the contractile elements with fibrosis tissue. See Braunwald, Heart Disease: A Textbook of Cardiovascular Medicine, Vol. 1 (3rd ed. 1988). These microscopic changes are revealed on a macroscopic level by cardiac hypertrophy or enlargement of the heart. The hypertrophying heart becomes less efficient due to microscopic changes causing loss of contractile elements and fibrotic deposition and the patient's clinical symptoms worsen as he progresses through each NYHA functional classification.

The compounds of the present Invention alter the progression of CHF by slowing the myocardial structural damages associated with CHF. The dosage range can be between .001 mg and 5 mg/kg per day as determined by the attending physician according to the mode of administration, the severity of the CHF and the duration of treatment. In a preferred method of administration, the rate of deposition of replacement fibrosis in the myocardium of a human subject is slowed. A preferred mode of administration is oral since therapy is likely to be long term in order to slow the progression of the structural damages associated with CHF.

Because the compounds' effectiveness is at the cellular level, the endomyocardial biopsy is an effective, though not widely used, diagnostic tool for monitoring the slowing of the structural damages associated with CHF. See generally, Braunwald, Heart Disease: A Textbook of Cardiovascular Medicine, Vol. (3rd ed. 1988), Chung, E.K., Quick Reference to Cardiovascular Disease, Chapter 27 (2d ed. 1983) and Fowler, N.O., Cardiac Diagnosis and Treatment, Chapter 12 (2d ed. 1976). The effectiveness of the 14-aminosteroid compounds to slow the progression of the CHF associated structural damages is more widely monitored by, but not limited to, the following non-invasive diagnostic tools: echocardlography and radiography to determine if the left ventricular hypertrophy is being slowed. Such macroscopic Improvement is indicative of a slowing of the microscopic damage to the Individual cardiac cells. See generally, Braunwald, Heart Disease: A Textbook of Cardiovascular Medicine, Vol. (3rd ed. 1988), Chung, E.K., Quick Reference to Cardiovascular Disease, Chapter 27 (2d ed. 1983) and Fowler, N.O., Cardiac Diagnosis and Treatment, Chapter 12 (2d ed. 1976). Additionally, the compounds effectiveness in slowing the structural progression of CHF is monitored by evaluating the patients' symptoms. As the structural damage is slowed the patient is experiencing less severe symptoms and does not progress as rapidly through the NYHA Functional Classifications. See generally, Braunwald, Heart Disease: A Textbook of Cardiovascular Medicine, Vol. (3rd ed. 1988), Chung, E.K., Quick Reference to Cardiovascular Disease, Chapter 27 (2d ed. 1983) and Fowler, N.O., Cardiac Diagnosis and Treatment, Chapter 12 (2d ed. 1976).

In order to illustrate the particular utility of these unique 14-aminosteroid compounds the following non-limiting examples are presented.

EXAMPLE1

An immediate release oral dosage form according to this invention is made comprising:

COMPONENT AMOUNT (mg)

(3β,5β,14β,17β)-14- 1.0 mg

amϊno-3-[(6-deoxy-β-

L-mannopyranosyl)oxy]

androstane-17-carboxylic

acid, methyl ester microcrystalline cellulose 70.0 mg

lactose 30.0 mg

crospovidone 3.0 mg

magnesium stearate 0.3 mg

Manufacturing directions: (for 10,000 tablets)

1) 10.0 g of the drug, 700.0 g of microcrystalline cellulose, 300.0 of lactose and 30.0 g of crospovidone are mixed in a Patterson-Kelly or other suitable blender.

2) the above mixture is blended with 3.0 g of magnesium stearate in a suitable blender.

3) the above final blend is compressed Into 104.3 mg tablets on a suitable tableting machine.

A patient presents with severe CHF (NYHA IV) secondary to chronic hypertension, diabetes, and several mild myocardial infarcts. The patient's symptoms include orthostatic Intolerance, dyspnea, edema of the Tower extremities and incapacity for even limited exercise. The patient has been experiencing episodes of acute decompensation with increasing frequency, requiring emergency hospital ization three times in the last fifteen weeks. The patient is not receiving adequate symptomatic relief with the standard regime of diuretics, digoxin, and ACE-inhibitor vasodilators. The cardiologist switches the patient from digoxin to (3β,5β,14β,17β)-14-amino-3- [(6-deoxy-α-L-mannopyranosyl)oxy]androstane-17-carboxylic acid, methyl ester administered orally in the above composition at a 1 mg/day dose. The patient has a significant reduction in symptoms and a corresponding Improvement in quality of life. Within 14 days of switching from digoxin to (3β,5β,14β,17β)-14-amino-3- [(6-deoxy-α-L-mannopyranosyl)oxylandrostane-17-carboxylic acid, methyl ester, the edema resolves, the patient no longer exhibits orthostatic intolerance, echocardiographic analysis indicates that the ejection fraction increases from 18% to 42%. After one month the patient is able to get out of bed unassisted and perform simple functions of daily l iving such as going to the bathroom and eating. Average mortality in severe CHF patients is 50% by the end of a year, however, after use of the therapy according to this invention this patient is still alive, with their CHF under control two years later.

EXAMPLE 2

A parenteral dosage form according to this invention is made comprising:

COMPONENT AMOUNT (mg/ml) (3β,5β,14β,20R)-14- 1.0 mg

amino-20-hydroxypregnan- 3-yl 6-deoxy-α-L mannopyranoside mannitol 200.0 mg Manufacturing directions: (for 1000 vials)

1) 1.0 g of the drug and 200.0 g of mannitol are dissolved in 1200.0 ml of deionized water.

2) the above solution is filtered through a 0.22 micron pore size sterile membrane filter,

3) 1.2 ml of the above sterile solution is filled into Type I glass vials and then lyophilized in a suitable lyophilizer,

4) the vials, after lyophilization, are stoppered with neoprene or other suitable stoppers and sealed.

A patient complaining of fatigue is determined to have mild CHF (NYHA II) as a result of an extensive physical examination. The patient had a history of coronary ischemia as a result of coronary artery atherosclerosis. Nuclear ventriculography suggests a history of repeated diffuse myocardial infarctions. Chest X-ray reveals a moderately enlarged left ventricle, and nuclear ventriculography indicates an ejection fraction of 32%. The patient is prescribed diuretics and (3β,5β,14β,20R)-14-amino- 20-hydroxypregnan-3-yl 6-deoxy-α-L mannopyranoside administered as a subcutaneous injection of the above composition dissolved in saline at a 1.0 mg/day dose, which should adequately alleviate the symptoms within six weeks. The natural history of CHF from initial diagnosis, in patients on diuretics, digoxin and vasodilators, is a continuing increase in the severity of the symptoms, with periodic episodes of acute decompensation requiring emergency hospitalization and an average mortality of 50% within 5 years. Histologic examination of cardiac tissue shows that as the disease progresses, there is an increasing number of myocardial cells that have died and been replaced with scar tissue. This patient dies in an automobile accident five years after diagnosis with his/her CHF now moderate (NYHA III). The average patient would have progressed to severe CHF (NYHA class IV) by this time. However, autopsy on this (3β,5β,14β, 20R)-14-amino-20-hydroxypregnan-3-yl 6-deoxy-α-L mannopyranoside treated patient reveals a remarkably low rate of cell death and replacement fibrosis (<30%) for a patient suffering from CHF for five years. After five years, one would have predicted that greater than 50% of the myocardium would have been replaced by scar tissue. EXAMPLE 3

A subllngual dosage form according to this invention is made comprising:

COMPONENT AMOUNT (mg)

(3β,14β,17β)-14-amino-3-[(6- 0.5 mg

deoxy-α-L-mannopyranosyl)oxy]

androst-4-ene-17-carboxylic acid,

methyl ester lactose 35.0 mg sucrose 1.5 mg alcohol-water (60:40) q.s.

Manufacturing directions:

1) 5.0 g of the drug, 350.0 g of lactose and 15.0 g of sucrose are screened and mixed in a suitable blender,

2) a sufficient quantity of alcohol-water (60:40) is added to moisten the above mixture,

3) the above moist mixture is placed in tablet molds and dried in a hot air oven, 4) the dry tablets, weighing 37 mg, are ejected from the molds and packaged for use.

A patient is diagnosed as being a NYHA mid-class III individual, as evidenced by an ejection fraction of less than 35%, limited inability to exercise, evidence of ventricular enlargement by echocardiography or chest X-ray and pulmonary capillary wedge pressure greater than 25 mmHg. The patient is initially treated with the standard therapy of diuretics, vasodilators and digoxin. The patient is switched to (3β,14β,17β)-14-amino-3-[(6-deoxy-α-L-mannoyranosyl)oxy]androst- 4-ene-17-carboxylic acid, methyl ester administered sublingually in the above composition at a 0.5 mg/day dose when the standard therapy proves ineffective. Endomyocardial biopsy is performed three months after treatment with (3β,14β,17β)-14-amino-3-[(6- deoxy-α-L-mannopyranosyl)oxy]androst-4-ene-17-carboxylic acid, methyl ester. Fibrotic tissue deposition and loss of contractile elements is less than would be expected in this patient. As a result of the slowing of the structural damage associated with CHF, the progression of this patient from NYHA mid-class III symptomatology to class IV symptomatology is slowed.

Claims

WHAT IS CLAIMED IS:

1. A method of slowing the progress of the myocardial structural abnormalities in a human subject having CHF, comprising administering to said subject a safe and effective amount of a 14-aminosteroid compound or the acid salt thereof of the general formula:

wherein a) R₁ is (i) COOR₅, where

(ii) CHR₆OH, where

R₇ and R₈, which may be the same or different, are hydrogen atoms or lower alkyl group containing 1 to 4 carbon atoms; c) R₃ is (i) monosaccharide sugar residue, where

R₉ is a hydrogen atom, a hydroxy group, or an acetoxy group, R₁₀ is a hydroxy or acetoxy group, or R₉ and R₁₀ together from a divalent alkylenedioxy group, Rn represents a hydroxy group, a methoxy group, or an acetoxy group, and R₁₂ is a methyl group or a hydroxy-methyl group, or

(ii) OH; d) R₄ is (ii) OH, or

(ii) H, or

(iii) OR₁₃, where R₁₃ is said monosaccharide sugar residue; e) Z is (i) -CH-, where a and b are single bonds, or

(ii) =C, where either a or b is a double bond.

2. A method according to Claim -1, wherein R₁ is COOR₅, R₂ is -NR₇R₈, R₃ is a monosaccharide sugar residue, R₄ is OH or H, Z is CH where a and b are single bonds or =C where the double bond is at either the a or b position on the steroid nucleus, and R₅ is a lower alkyl group containing 1 to 4 carbon atoms, a lower alkyl group containing 2 to 4 carbon atoms substituted by an amino group, or an arylalkyl group containing 6 to 12 carbon atoms, R₇ and R₈, which may be the same or different, are a hydrogen atom or a lower alkyl group containing 1 to 4 carbon atoms, R₉ is a hydrogen atom, a hydroxy group, or an acetoxy group, R₁₀ is a hydroxy or acetoxy group, or R₉ and R₁₀ together form a divalent alkylenedioxy group, R₁₁ represents a hydroxy group, a methoxy group, or an acetoxy group, and R₁₂ is a methyl group or a hydroxymethyl group.

3. A method according to Claim 2, wherein R₅ is a methyl or an ethyl group.

4. A method according to Claim 2, wherein the R₁₀ and R₁₁ substituents on the R₃ monosaccharide sugar represent hydroxy groups.

5. A method according to Claim 2, wherein R₉ and R₁₀ are combined to form an alkylenedioxy group containing 1-4 carbon atoms in the alkylene moiety thereof.

6. A method according to Claim 2, wherein R₉ represents a hydroxy group.

7. A method according to Claim 2, wherein the R₁ group, the R₂ group, and the R₃ group are in the β configuration.

8. A method according to Claim 2, wherein said 14-aminosteroid is selected from the group consisting of (3β,5β,14β,17β)-14-amino-3-[(6-deoxy-α-L-mannopyranosyl)oxy] androstane-17-carboxylic acid, methyl ester; (3β,5β,14β,17β)- 14-methylamino-3-[(6-deoxy-α-L-mannopyranosyl)oxy]androstane- 17-carboxylic acid, methyl ester and (3β,14β,17β)-14-amino-3-[(6- deoxy-α-L-mannopyranosyl)oxy]androst-4-ene-17-carboxylic acid, methyl ester.

9. A method of slowing the progress of the myocardial structural abnormalities in a human subject having CHF, comprising administering to said subject a safe and effective amount of (3β,5β,14β,17β)-14-amino-3-[(6-deoxy-α-L-mannopyranosyl)oxy] androstane-17-carboxylic acid, methyl ester.

10. A method of slowing the rate of progression of the myocardial structural abnormalities characteristic of CHF, comprising administering to said subject a safe and effective amount of (3β,5β,14β,20R)-14-amino-20-hydroxypregnan-3-yl 6-deoxy-α-L-mannopyranoside and its 20S isomer.

11. A method according to Claim 1, wherein R₁ is CHR₆OH, R₂ is NH₂, Z 1s CH, and R₄ is H or OH.

12. A method according to Claim 11, wherein, R₃ is OH.

13. A method according to Claim 12, wherein R₆ is a hydrogen atom or a methyl group.

14. A method according to Claim 12, wherein R₆ and R₄ are not both hydrogen atoms.

15. A method according to Claim 12, wherein R₆ is a methyl group.

16. A method according to Claim 11, wherein R₃ is a monosaccharide sugar residue.

17. A method according to Claim 16, wherein R₆ represents a hydrogen atom or a methyl group.

18. A method according to Claim 16, wherein R₃ is a monosaccharide sugar residue, and R₄ is a hydrogen atom or a hydroxy group.

19. A method according to Claim 16, wherein R₃ represents a modified or substituted or unsubstituted pentose or hexose residue. 20. A method according to Claim 16, wherein R₃ represents a substituted or unsubstituted glucose residue, rhamnose residue, galactose residue, fucose residue or digitoxose residue.

24. The use of a 14-aminosteroid compound according to

Claim 23, wherein R₁ is COOR₅, R₂ is -NR₇R₈, R₃ is a monosaccharide sugar residue; preferably the R₁, R₂, and R₃ groups are in the β configuration, R₄ is OH or H, Z is CH where a and b are single bonds or =C where the double bond is at either the a or b position on the steroid nucleus, and R₅ is a lower alkyl group containing 1 to 4 carbon atoms; preferably a methyl or ethyl group, a lower alkyl group containing 2 to 4 carbon atoms substituted by an amino group, or an arylalkyl group containing 6 to 12 carbon atoms, R₇ and R₈, which may be the same or different, are a hydrogen atom or a lower alkyl group containing 1 to 4 carbon atoms, R₉ is a hydrogen atom, a hydroxy group, or an acetoxy group; preferably a hydroxy group, R₁₀ is a hydroxy or acetoxy group; preferably a hydroxy group, or R₉ and

R₁₀ together form a divalent alkylenedioxy group; preferably R₉ and R₁₀ are combined to form an alkylenedioxy group containing

1-4 carbon atoms in the alkylene moiety, R₁₁ represents a hydroxy group, a methoxy group, or an acetoxy group; preferably a hydroxy group, and R₁₂ is a methyl group or a hydroxymethyl group.

25. The use of a 14-aminosteroid compound according to Claim 24, wherein said 14-aminosteroid is selected from the group consisting of (3β,5β,14β,17β)-14-amino-3-[(6-deoxy-α-L-manno- pyranosyl)oxy] androstane-17-carboxylic acid, methyl ester; (3β,5β,14β,20S)14-methylamino-3-[(6-deoxy-α-L-manno- pyranosyl)oxy)androstane-17-carboxylic acid, methyl ester and (3β, 14β, 17β)-14-amino-3- [ (6-deoxy-α-L-mannopyranosyl )oxy]androst- 4-ene-17-carboxylic acid, methyl ester; (3β, 5β, 14β, 20R)-14-amino-20-hydroxypregnan-3-yl 6-deoxy-α-L-mannopyranoside and its 20S isomer.

26. The use of a 14-aminosteroid compound according to Claim 23, wherein R₁ is CHR₆OH, R₂ is NH₂, Z is CH, and R₄ is H or OH.

27. The use of a 14-aminosteroid compound according to Claim 26, wherein, R₃ is OH.

28. The use of a 14-aminosteroid compound according to Claim 27, wherein R₆ is a hydrogen atom or a methyl group.

29. The use of a 14-aminosteroid compound according to Claim 26, wherein R₃ is a monosaccharide sugar residue; preferably R₃ is a substituted or unsubstituted pentose, hexose, glucose, rhamnose, galactose or digitoxose residue.

30. The use of a 14-aminosteroid compound according to Claim 29, wherein R₆ represents a hydrogen atom or a methyl group.

31. The use of a 14-aminosteroid compound according to Claim 29, wherein said 14-aminosteroid compound is selected from the group consisting of (3β,5β,14β,17β)-14-amino-17-(hydroxy- methyl)androstan-3-yl 6-deoxy-α-L-mannopyranoside; (3β,5β,14β, 20S)-14-amino-20-hydroxypregnan-3-yl 6-deoxy-α-L-mannopyranoside and its 20R isomer; (3β,5β,14β,20S)-14-amino-20-hydroxypregnan- 3-yl 2,6-dideoxy-α-D-ribo-hexopyranoside and its 20R isomer; (3β,5β,14β,20S)-14-amino-20-hydroxypregnan-3-yl 4-amino-2,4,6- trideoxy-α-L-lyxo-hexopyranoside and its 20R isomer; (3β,5β,12β,14β,17β)-14-amino-12-hydroxy-17-(hydroxy- methyl)androstan-3-yl 6-deoxy-α-L-mannopyranoside; (3β,5β,12β,14β,20R)-14-amino-12,20-dihydroxypregnan-3-yl 6- deoxy-α-L-mannopyranoside and its 20S isomer; (3β,5β,12β,14β,20S)-14-amino-12,

20-dihydroxypregnan-3-yl 2,6- dideoxy-β-D-ribo-hexopyranoside and its 20R isomer; (3β,5β,12β,14β,20R)-14-amino-20-hydroxypregnane-3,12-diyl bis[6- deoxy-α-L-mannopyranoside] and its 20S isomer.

21. A method according to Claim 16, wherein said 14-aminosteroid compound is selected from the group consisting of (3β,5β,14β,17β)-14-amino-17-(hydroxymethyl)androstan-3-yl 6- deoxy-α-L-mannopyranoside; (3β,5β,14β,20S) -14-amino-20-hydroxypregnan-3-yl 6-deoxy-α-L-mannopyranoside and its 20R isomer; (30,50,140,20S)-14-amino-20-hydroxypregnan-3-yl 2,6-dideoxy-0-D- ribo-hexopyranoside and Its 20R isomer; (3β,5β,14β,20S)-14-amino- 20-hydroxypregnan-3-yl 4-amino-2,4,6-trideoxy-o-L-lyxo-hexopyranoside and Its 20R Isomer; (3β,5β,12β,14β,17β)-14-amino-12- hydroxy-17-(hydroxymethyl)androstan-3-yl 6-deoxy-α-L-manno- pyranoside; (3β,5β,12β,14β,20R)-14-amino-12,20-dihydroxypregnan- 3-yl 6-deoxy-α-L-mannopyranoside and its 20S isomer; (3β,5β,12β,14β,20S)-14-amino-12,20-dihydroxypregnan-3-yl 2,6- dideoxy-α-D-ribo-hexopyranoside and its 20R isomer; (3β,5β,12β,14β,20R)-14-amino-20-hydroxypregnane-3,12-diyl bis[6- deoxy-α-L-mannopyranoside] and its 20S isomer.

22. A method according to Claim 1 wherein the rate of deposition of replacement fibrosis in the myocardium of said human subject is slowed.

23. The use of a 14-aminosteroid compound or the acid salt thereof for the manufacture of a medicament to slow the progress of the myocardial structural abnormalities in a human subject having CHF, characterized by administering to said subject a safe and effective amount of said 14-aminosteroid compound having the general formula:

wherein

a) R₁ is (i) COOR₅, where

(ii) CHR₆OH, where

R₆ is a hydrogen atom or lower alkyl group containing 1 to 4 carbon atoms;

b) R₂ is -NR₇R₈, where

R₇ and R₈, which may be the same or different, are hydrogen atoms or lower alkyl group containing 1 to 4 carbon atoms;

c) R₃ is (i) monosaccharide sugar residue, where

(ii) OH;

d) R₄ is (ii) OH, or

(ii) H, or

(iii) OR₁₃, where R₁₃ is said monosaccharide sugar residue;

e) Z is (i) -CH-, where a and b are single bonds, or

(ii) =C, where either a or b is a double bond.