WO1993005790A1 - Emploi de 14-aminosteroides dans la fabrication d'un medicament destine a ralentir la vitesse de progression d'alterations structurelles myocardiques caracteristique de l'insuffisance cardiaque congestive - Google Patents

Emploi de 14-aminosteroides dans la fabrication d'un medicament destine a ralentir la vitesse de progression d'alterations structurelles myocardiques caracteristique de l'insuffisance cardiaque congestive Download PDF

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Publication number
WO1993005790A1
WO1993005790A1 PCT/US1992/008049 US9208049W WO9305790A1 WO 1993005790 A1 WO1993005790 A1 WO 1993005790A1 US 9208049 W US9208049 W US 9208049W WO 9305790 A1 WO9305790 A1 WO 9305790A1
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group
amino
hydroxy
carbon atoms
deoxy
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PCT/US1992/008049
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English (en)
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Bruce Martin Halpryn
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Procter & Gamble Pharmaceuticals, Inc.
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Publication of WO1993005790A1 publication Critical patent/WO1993005790A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol

Definitions

  • 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 Congestive Heart Failure
  • 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.
  • CO cardiac output
  • CHF chronic myocardial disease
  • 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.
  • fibrosis of the myocardial tissue occurs it compromises the functioning of the heart because the remaining viable myocardial cells have a greater workload.
  • 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.
  • 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.
  • treating the patient with an antimicrobial or an anti-arrhythmic agent, respectively may restore the patient to normal cardiac function.
  • 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.
  • 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.
  • angiotensin converting enzyme inhibitors have been shown to reduce mortality in CHF patients by ameliorating the hemodynamic symptoms.
  • 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).
  • 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
  • the method of this invention provides a novel therapeutic approach to slow the inevitable 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.
  • 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:
  • R 1 is (i) COOR 5 , wherein a) R 1 is (i) COOR 5 , wherein a) R 1 is (i) COOR 5 , wherein a) R 1 is (i) COOR 5 , wherein a) R 1 is (i) COOR 5 , wherein a) R 1 is (i) COOR 5 , wherein a) R 1 is (i) COOR 5 , wherein a) R 1 is (i) COOR 5 , wherein a) R 1 is (i) COOR 5 , wherein a) R 1 is (i) COOR 5 , wherein a) R 1 is (i) COOR 5 , wherein a) R 1 is (i) COOR 5 , wherein a) R 1 is (i) COOR 5 , wherein a) R 1 is (i) COOR 5 , wherein a) R 1 is (i) COOR 5 , wherein a) R 1 is (i) COOR 5 , wherein
  • R 5 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
  • R 6 is a hydrogen atom or lower alkyl group containing 1 to 4 carbon atoms; b) R 2 is -NR 7 R 8 , where
  • R 7 and R 8 which may be the same or different, ar hydrogen atoms or lower alkyl group containing 1 to carbon atoms; c) R 3 Is (1) monosaccharide sugar residue, where
  • R 10 is a hydroxy or acetoxy group, or R 9 and R 10 together from a divalent alkylenedioxy group
  • R 11 represents a hydroxy group, a methoxy group, or an acetoxy group
  • R 12 is a methyl group or a hydroxy-methyl group, or
  • the 14-aminosteroid is preferably administered in a pharmaceutical composition comprising the 14-aminosteroid and a pharmaceutically-acceptable carrier.
  • 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.
  • a 14-aminosteroid compound includes one or more compounds of the following general formula:
  • R 1 is (i) COOR 5 , where
  • R 5 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
  • R 6 is a hydrogen atom or lower alkyl group containing 1 to 4 carbon atoms, preferably a methyl group; b) R 2 is -NR 7 R 8 , where R 7 and R 8 , which may be the same or different, ar hydrogen atoms or lower alkyl group containing 1 to 4 carbon atoms, preferably methyl groups; c) R 3 is (i) a monosaccharide sugar residue, where
  • R 9 is a hydrogen atom, a hydroxy group, or an acetoxy group preferably a hydroxy group
  • R 10 is a hydroxy or acetoxy group preferably a hydroxy group
  • R 9 and R 10 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
  • R 12 is a methyl group or a hydroxy-methyl group, or
  • R 4 is (i) OH, or
  • R 1 is CHR 6 OH
  • R 2 is NH 2
  • R 3 is a monosaccharide sugar residue
  • R 4 1s OH or H
  • Z is CH where a and b are single bonds.
  • the preferred compounds are (3 ⁇ ,5 ⁇ ,14 ⁇ ,17 ⁇ )-14-amino-17-(hydroxymethyl)androstan-3-yl 6-deoxy - ⁇ -L-mannopyranoside; (3 ⁇ ,5 ⁇ ,14 ⁇ ,20S)-14-amino-20-hydroxypregnan- 3-yl 6-deoxy- ⁇ -L-mannopyranoside and its 20R isomer; (3 ⁇ ,5 ⁇ ,14 ⁇ ,20S)-14-amino-20-hydroxypregnan-3-yl 2,6-dideoxy- ⁇ -D- ribo-hexopyranoside and its 20R isomer; (3 ⁇ ,5 ⁇ ,14 ⁇ ,20S)-14-amino- 20-hydroxypregnan-3-yl 4-amino-2,4,6-trideoxy- ⁇ -L-lyxo-hexopyranoside and its 20R isomer; (3 ⁇ ,5 ⁇ ,12 ⁇ ,14 ⁇ ,17 ⁇ )-14-amino-12- hydroxy-17-(hydroxymethyl)androstan-3
  • R 3 is an OH group.
  • R 3 is an OH group.
  • Specific compounds wherein R 3 is an OH group are (3 ⁇ ,5 ⁇ ,12 ⁇ ,14 ⁇ ,20R)-14-amino-pregnane-3,12,20-triol and its 20S isomer and (3 ⁇ ,5 ⁇ ,12 ⁇ ,14 ⁇ ,17 ⁇ )-14-amino-3,12-di- hydroxy-androstane-17-methanol.
  • Particularly preferred compounds are the 14-aminosteroids wherein R 1 is a COOR 5 group where R 5 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, R 2 is NR 7 R 8 where R 7 a nd R 8 which may be the same or different, are hydrogen atoms or lower alkyl groups containing 1 to 4 carbon atoms, and R 3 is a monosaccharide sugar residue and R 1 , R 2 and R 3 are in the most pharmacologically active ⁇ (beta) position.
  • R4 is either -OH or H.
  • Specific particularly preferred compounds are (3 ⁇ ,5 ⁇ ,14 ⁇ ,17 ⁇ )-14-methylamino-3-[(6-deoxy- ⁇ -L-mannopyranosyl)oxy]androstane-17-carboxylic acid, methyl ester; (3 ⁇ ,14 ⁇ ,17 ⁇ )-14-amino-3-[(6-deoxy- ⁇ -L-mannopyranosyl)oxy]androst- 4-ene-17-carboxylic acid, methyl ester; (3 ⁇ ,5 ⁇ ,14 ⁇ ,17 ⁇ )-14-amino- 3-[(6-deoxy- ⁇ -L-mannopyranosyl)oxy]androstane-17-carboxylic acid, methyl ester and (3 ⁇ ,5 ⁇ ,14 ⁇ ,20R)-14-amino-20-hydroxypregnan-3-yl 6-deoxy- ⁇
  • 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.
  • safe and effective amount 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.
  • compositions of this invention are preferably provided in unit dosage form.
  • 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.
  • 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).
  • 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.
  • the pharmaceutically-acceptable carrier, in compositions for parenteral administration comprises at least about 95% by weight by the total composition.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • CHF denotes a progressive disease wherein the hemodynamic capacity as well as the structure of the heart Itself is increasingly and irreversibly compromised.
  • 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.
  • an inotrope such as digitalis, might increase mortality rates because the inotropic action creates an extra work load for the heart.
  • 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.
  • hemodynamic 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.
  • intracardiac filling pressures are elevated as well as pulmonary and venous pressures.
  • the heart is increasingly unable to supply the required CO.
  • structural damage 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • An immediate release oral dosage form according to this invention is made comprising:
  • a patient presents with severe CHF (NYHA IV) secondary to chronic hypertension, diabetes, and several mild myocardial infarcts.
  • CHF CHF
  • 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 (3 ⁇ ,5 ⁇ ,14 ⁇ ,17 ⁇ )-14-amino-3- [(6-deoxy- ⁇ -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.
  • a parenteral dosage form according to this invention is made comprising:
  • 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 (3 ⁇ ,5 ⁇ ,14 ⁇ ,20R)-14-amino- 20-hydroxypregnan-3-yl 6-deoxy- ⁇ -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.
  • diuretics 3 ⁇ ,5 ⁇ ,14 ⁇ ,20R)-14-amino- 20-hydroxypregnan-3-yl 6-deoxy- ⁇ -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 progress
  • a subllngual dosage form according to this invention is made comprising:
  • 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 (3 ⁇ ,14 ⁇ ,17 ⁇ )-14-amino-3-[(6-deoxy- ⁇ -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 (3 ⁇ ,14 ⁇ ,17 ⁇ )-14-amino-3-[(6- deoxy- ⁇ -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.

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Abstract

L'invention concerne un procédé de ralentissement de la vitesse de progression d'altérations structurelles myocardiques chez un sujet humain présentant une insuffisance cardiaque congestive, consistant à administrer audit sujet une dose sans danger et efficace d'un composé de 14-aminostéroide ou d'un sel d'acide de celui-ci de la formule générale (I), dans laquelle a) R1 représente (i) COOR5, où R5 représente un groupe alkyle inférieur contenant 1 à 4 atomes de carbone, un groupe alkyle inférieur contenant 2 à 4 atomes de carbone substitués par un groupe amino, ou un groupe arylalkyle contenant 6 à 12 atomes de carbone, ou (ii) CHR6OH, où R6 représente un atome d'hydrogène ou un groupe alkyle inférieur contenant 1 à 4 atomes de carbone; b) R2 représente -NR7R8, où R7 et R8 pouvant être identiques ou différents représentent des atomes d'hydrogène ou un groupe alkyle inférieur contenant 1 à 4 atomes de carbone; c) R3 représente (i) un reste de sucre monosaccharidique de la formule (II) dans laquelle R9 représente un atome d'hydrogène, un groupe hydroxy, ou un groupe acétoxy, R10 représente un groupe hydroxy ou acétoxy, ou R9 et R10 forment ensemble un groupe alkylènedioxy divalent, R11 représente un groupe hydroxy, un groupe méthoxy ou un groupe acétoxy, et R12 représente un groupe méthyle ou bien un groupe hydroxy-méthyle, ou (ii) OH; d) R4 représente (i) OH, ou (ii) H, ou (iii) OR13, où R13 représente ledit reste de sucre monosaccharidique; e) Z représente (i) -CH-, où a et b représentent des liaisons individuelles, ou (ii) =C, où soit a soit b représente une double liaison. Le 14-aminostéroïde est de préférence administré dans une composition pharmaceutique comprenant ledit 14-aminostéroïde ainsi qu'un excipient pharmaceutiquement acceptable.
PCT/US1992/008049 1991-09-27 1992-09-21 Emploi de 14-aminosteroides dans la fabrication d'un medicament destine a ralentir la vitesse de progression d'alterations structurelles myocardiques caracteristique de l'insuffisance cardiaque congestive WO1993005790A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995008558A1 (fr) * 1993-09-24 1995-03-30 The Procter & Gamble Company Nouveaux composes 14-aminosteroides contenant du sucre a substitution oxygene et desoxy
WO1995008557A1 (fr) * 1993-09-24 1995-03-30 The Procter & Gamble Company Nouveaux composes 14-aminosteroides contenant un oligosaccharide, et nouveaux procedes de traitement chimique a l'aide des nouveaux aminosteroides diastereoselectifs
US5629295A (en) * 1992-06-26 1997-05-13 Pfizer Inc. Steroidal glycosides for treating hypercholesterolemia
US5695738A (en) * 1995-06-15 1997-12-09 Glycomed Incorporated Steroidal C-glycosides
WO1998048812A1 (fr) * 1997-04-29 1998-11-05 Imperial College Of Science, Technology & Medecine Utilisation de derives de steroides anabolisants pour traiter l'insuffisance cardiaque chronique

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5629295A (en) * 1992-06-26 1997-05-13 Pfizer Inc. Steroidal glycosides for treating hypercholesterolemia
US5703052A (en) * 1992-06-26 1997-12-30 Pfizer Inc. Sterodial glycosides for treating hypercholesterolemia
WO1995008558A1 (fr) * 1993-09-24 1995-03-30 The Procter & Gamble Company Nouveaux composes 14-aminosteroides contenant du sucre a substitution oxygene et desoxy
WO1995008557A1 (fr) * 1993-09-24 1995-03-30 The Procter & Gamble Company Nouveaux composes 14-aminosteroides contenant un oligosaccharide, et nouveaux procedes de traitement chimique a l'aide des nouveaux aminosteroides diastereoselectifs
US5721217A (en) * 1993-09-24 1998-02-24 The Procter & Gamble Company Deoxy and oxygen-substituted sugar-containing 14-aminosteroid compounds
AU692187B2 (en) * 1993-09-24 1998-06-04 Procter & Gamble Company, The Novel oligosaccharide-containing 14-aminosteroid compounds and novel diastereoselective aminosteroid process chemistry
AU692474B2 (en) * 1993-09-24 1998-06-11 Procter & Gamble Company, The Novel deoxy and oxygen-substituted sugar-containing 14-aminosteroid compounds
EP0863149A1 (fr) * 1993-09-24 1998-09-09 The Procter & Gamble Company Procédé pour introduire des groupes amino dans la position 14 d'un stéroide
US5695738A (en) * 1995-06-15 1997-12-09 Glycomed Incorporated Steroidal C-glycosides
WO1998048812A1 (fr) * 1997-04-29 1998-11-05 Imperial College Of Science, Technology & Medecine Utilisation de derives de steroides anabolisants pour traiter l'insuffisance cardiaque chronique

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AU2675092A (en) 1993-04-27
MX9205527A (es) 1994-06-30
PT100907A (pt) 1993-11-30

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