WO1997048401A1 - Deoxy and oxygen-substituted sugar-containing 14-aminosteroid compounds for use as an antiarrhythmic - Google Patents
Deoxy and oxygen-substituted sugar-containing 14-aminosteroid compounds for use as an antiarrhythmic Download PDFInfo
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- WO1997048401A1 WO1997048401A1 PCT/US1997/010453 US9710453W WO9748401A1 WO 1997048401 A1 WO1997048401 A1 WO 1997048401A1 US 9710453 W US9710453 W US 9710453W WO 9748401 A1 WO9748401 A1 WO 9748401A1
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- oxygen
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- amino
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
Definitions
- This invention relates to deoxy and oxygen-substituted sugar-containing 14- aminosteroid compounds for use as antiarrhythmics. This invention also relates to
- abnormal electrical activity can interfere with the initiation of, and/or the uniform spread of, the electrical wave (i.e. depolarization followed by repolarization of ⁇ he cardiac muscle) that triggers the heart to contract.
- the electrical wave i.e. depolarization followed by repolarization of ⁇ he cardiac muscle
- Arrhythmias are generally classified into two types: 1) Supraventricular Arrhythmias (for example, atria fibrillation and flutter) and 2) Ventricular Arrhythmias 0 (for example, ventricular tachyarrhythrnia and ventricular fibrillation).
- Supraventricular Arrhythmias for example, atria fibrillation and flutter
- Ventricular Arrhythmias 0 for example, ventricular tachyarrhythrnia and ventricular fibrillation.
- Supraventricular arrhythmias are generally not life-threatening. Individuals with these arrhythmias may experience a wide range of symptoms, from slight to severe intensity. These individuals may feel the physical sensation of missed beats, extra beats, and/or flutter, may occasionally feel slightly light headed or dizzy, and may 5 have shortness of breath and/or chest pain. Since this situation is generally not life threatening, more aggressive therapies such as conventional antiarrhythmic drugs are usually not prescribed, because the side effects usually associated with them may not be acceptable for a non-life threatening condition.
- CHF Congestive Heart Failure
- CO cardiac output
- 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.
- cardiac glycosides are known for their cardiac inotropic effects (i.e. increasing cardiac contractility). It is also known that cardiac glycosides exert effects on the electrophysiological properties of the heart. The electrophysiological actions are exerted either indirectly through the autonomic nervous system (Rosen MR.; Weingart R) or directly dirough effect of the drugs on cardiac cell membrane properties (Weingart R; Hoffman). Cardiac glycosides act by blocking the transmission of the tachyarrhythmias from the atria to the ventricles. The arrhyththmias remain in the atria.
- the 14-aminosteroid compounds of the present invention terminate the arrhythmia in the artria allowing the entire heart to return to normal sinus rhythm.
- the 14-aminosteroid compounds of the prenset invention exhibit enhanced antiarrhythmic potential over other cardiac glycosides.
- Cardioactive steroid nucleus-containing compounds have been described in the following patents: World Patent Publication WO 87/04167 to Chiodini, et al. published July 16, 1987 describes aminoglycoside steroid derivatives substituted by an amino-sugar residue at the 3-position 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 glucose 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.
- World Patent Publication WO 87/04168 to Chiodini et al., July 16, 1987 discloses an aminoglycoside steroid having an alkyl substituted amino sugar at the 3-position, such as 2-amino or 2-alkylamino-2-deoxy- hexopyranosyl, 3-amino or 3-aikylamino-3-deoxy-hexo-pyranosyl, 3-amino or 3-alkyl- amino-3,6-dideoxy-hexopyranosyl, 3 amino or 3-alkylamino-2,3,6-trideoxy- hexopyranosy 4-amino or 4-alkylamino 2,4,6-trideoxy-hexopyranosyl residues, and a cyclic amide (lactam) at the 17-position.
- an aminoglycoside steroid having an alkyl substituted amino sugar at the 3-position, such as 2-amino or 2-alkylamino-2-deoxy- hexo
- the 14-position is substituted with a hydrogen.
- the compound is said to be useful as an antihypertensive.
- World Patent Publication WO 91/17176 to Kenny, et al. published November 14, 1991 discloses a steroid glycoside, useful as a pressor agent, having a sugar moiety at the 3 -position, such as a pentose, hexose or combinations thereof, and a lactone ring at the 17- position, the 14-position is substituted with an OH, H or a F, Cl, Br or NH2; and DD 296502 A5 to Siemann, et al.
- DD 256,134 Al to Wunderwald, et al., granted April 27, 1988 discloses a process for making cardioactive steroids wherein the 3-position of the steroid molecule is substituted with a morpholinoformyloxy residue, and the 17-position of the steroid molecule is substituted with a lactone ring; and the 14-position is substituted with hydroxy, hydrogen or an olefin. Said compounds are alleged to be useful for increasing cardiac contractility.
- the 14-aminosteroid compounds have been shown to be useful in treating CHF by increasing cardiac contractility. These compounds provide the therapeutic benefit of increased cardiac contractility without the side effects of digitalis.
- These 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 as possessing positive inotropic activity.
- the '868 patent also discloses 14-aminosteroid compounds having supraventricular anti-arrhythmic properties.
- PCT Application WO 95/08558, Liu et al., Pulbished March 30, 1995 describe the 14- aminosteroid compounds of the present invention, as more effective inotropes.
- the present invention relates to the surprising benefits of these compounds in the treatment of supraventricular arrhythmias and/or atrial fibrillation.
- a method of treatment of humans or other mammals afflicted with supraventricular arrhythmias and/or atrial fibrillation comprised of administering to said human or other mammal a safe and effective amount of a deoxy and oxygen- substituted sugar containing 14-aminosteroid compounds and the pharmaceutically- acceptable acid salts or esters thereof of the formula:
- Aminosteroid is a steroid ring compound having an amino group on the steroid nucleus.
- Alkyl is an unsubstituted or substituted, straight-chain, cyclic or branched, saturated hydrocarbon chain having 1 to 8 carbon atoms, and preferably, unless otherwise stated, from 1 to 4 carbon atoms.
- Preferred alkyl groups include, but are not limited to methyl, ethyl, propyl, isopropyl, and butyl; a monovalent radical derived from an aliphatic hydrocarbon by removal of 1 H; as methyl.
- a lower alkyl group contains 1 -6 carbon atoms.
- Heteroalkyl as used herein is an unsubstituted or substituted, saturated chain having from 3 to 8-members and comprising carbon atoms and one or two heteroatoms.
- Alkenyl is an unsubstituted or substituted, straight-chain or branched, hydrocarbon chain having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one olefinic double bond.
- Alkynyl is an unsubstituted or substituted, straight-chain or branched, hydrocarbon chain having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one triple bond.
- Acetate A salt of acetic acid containing the CH3COO- radical.
- Acetyloxy The radical CH3COO-.
- glycoside That component of a glycoside, e.g., plant pigment, which is not a sugar.
- Carbocyclic ring or “Carbocycle” as used herein is an unsubstituted or substituted, saturated, unsaturated or aromatic, hydrocarbon ring, generally containing from 3 to 8 atoms, preferably 5 to 7 atoms.
- Heterocyclic ring or “Heterocycle” as used herein is an unsubstituted or substituted, saturated or unsaturated or aromatic ring comprised of carbon atoms and one or more heteroatoms in the ring. Heterocyclic rings generally contain from 3 to 8, preferably 5 to 7, atoms. Unless otherwise stated, the heteroatom may be independently chosen from nitrogen, sulfur, and oxygen.
- Aryl is an aromatic carbocyclic ring.
- Aryl groups include, but are not limited to, phenyl, tolyl, xylyl, cumenyl, and naphthyl; an organic radical derived from an aromatic hydrocarbon by the removal of one atom; e.g. phenyl from benzene.
- Heteroaryl is an aromatic heterocyclic ring. Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiazolyl, quinolinyl, pyrimidinyl, and tetrazolyl.
- Alkoxy is an oxygen atom having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl or alkenyl (e.g. -O-alkyl or -O-alkenyl); an alkyl radical attached to the remainder of the molecule by oxygen; as, methoxy.
- Preferred alkoxy groups include, but are not limited to, methoxy. ethoxy, propoxy, and alkyloxy.
- Hydrocarbon chain which has a hydroxy substituent (e.g., -OH), and may have other substituents.
- Preferred hydroxyalkyl groups include, but are not limited to, hydroxyethyl, hydroxypropyl, pheny Ihydroxyalky 1.
- Carboxyalkyl is a substituted hydrocarbon chain which has a carboxy substituent (e.g. -COOH) and may have other substituents. Preferred carboxyalkyl groups include carboxymethyl, carboxyethyl, and their acids and esters.
- Oxosilane is an oxygen and silicone repeating unit Si-O-Si-O-, also known in the art as “siloxane.”
- Aminoalkyl is a hydrocarbon chain, (e.g. alkyl) substituted widi an amine moiety (e.g. NH-alkyl-), such as dimethylamino alkyl.
- Alkylamino is an amino moiety having one or two alkyl substituents (e.g. -N- alkyl).
- Alkenylamino is an amino moiety having one or two alkenyl substituents (e.g. -N-alkenyl).
- Alkynylamino is an amino moiety having one or two alkynyl substituents (e.g. -N-alkynyl).
- Alkylimino is an imino moiety having one or two alkyl substituents (e.g.,
- N alkyl-
- Arylalkyloxy is an oxygen atom having an aryl alkyl substituent, e.g., phenylmethoxy or phenylmethyleneoxy
- Heteroarylalkyloxy is an oxygen atom having a “heteroarylalkyl” substituent, e.g.,
- Arylalkyl is an alkyl moiety substituted with an aryl group.
- Preferred arylalkyl groups include benzyl and phenylethyl.
- Heteroaryl alkyl is an alkyl moiety substituted with a heteroaryl group.
- Arylamino is an amino moiety substituted with an aryl group (e.g., -NH-aryl).
- Aryloxy is an oxygen atom having an aryl substituent (e.g., -O-aryl).
- Preferred alkylacyl groups include, but are not limited to, acetyl, propionyl, and butanoyl.
- Benzoyl The aryl radical, C6H5CO-, derived from benzoic acid.
- Benzoyloxy e.g., Benzoxy.
- “Carbamate” A salt of carbamic acid; it contains the -NCO2- radical, also known in the art as urethanes or carbamic esters.
- Carboxy Prefix indicating the acidic carboxyl group.
- “Ester” An organic salt formed from an alcohol (base) and an organic acid by elimination of water; functional group derivatives of carboxylic acids are those compounds that are transformed into carboxylic acids by simple hydrolysis. The most common such derivatives are esters, in which die hydroxy group is replaced by an alkoxy group.
- Glycoside A natural compound of a sugar with another substance, which hydrolyzes a sugar plus a principle: (e.g., coniferin yields glucose plus coniferyl alcohol as the principle; glucosides yield glucose, fructosides yield fructose, galactosides yield galactose, etc.; the cyclic acetal of a carbohydrate.
- "Halo”, “halogen”, or “halide” is a chloro, bromo, fluoro, or iodo atom radical Chloro, bromo, and fluoro are preferred halides
- a "pharmaceutically-acceptable" salt is a cationic salt formed at any acidic (e.g., carboxyl) group, or an anionic salt formed at any basic (e g , amino) group
- Preferred cationic salts include the alkali-metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and calcium)
- Suitable anionic salts include the halides (such as chloride) salts, as well as the carboxylate (such as maleate) salts
- Step nucleus Generic name for a family of lipid compounds comprising the sterols, bile acids, cardiac glycosides, saponins, and sex hormones
- Substituent groups may themselves be substituted Such substitution may be with one or more substituents
- substituents include, but are not limited to, those listed in C Hansch and A Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979), hereby incorporated by reference herein Preferred
- substituents include, but are not limited to, alkyl, alkenyl, alkoxy, hydroxy, oxo, amino,
- aminoalkyl e.g., aminomethyl, etc.
- cyano e.g., cyano, halo, carboxy, alkoxyacetyl (e.g. carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl, and combinations thereof.
- a "monosaccharide” is a single sugar moiety; e.g., hexose, 2-deoxyglucose, 6- deoxyhexose, 2,6-dideoxyhexose, etc., rhamnose, glucose, arabinose, digitoxose, fructose, galactose; rhamnopyranose, hexopyranose, 6-deoxyglucose, 4,6-dideoxy- glycopyranose, mannose, cymarose, xylose, lyxose, ribose, digitalose, 4-amino-2,4,6- trideoxylyxohexopyranose, 4-amino-4,6, dideoxyglucopyranose, 2,3- dideoxyrhamnopyranose, 4-methoxy 4,6-dideoxyrhamnopyranose.
- oligosaccharide is a sugar having 2-8 monosaccharide sugar residues, preferably 2-3. The last monosaccharide residue of the oligosaccharide is known as the "terminal" oligosaccharide residue.
- glucose a monosaccharide
- the present invention encompasses certain deoxy or oxygen-substituted sugar- containing 14-aminosteroid compounds for use in the treatment of supraventricular arrhythmia and/or atrial fibrillation in humans or other mammals.
- Specific compounds and compositions to be used in the invention must, accordingly, be pharmaceutically- acceptable.
- a "pharmaceutically acceptable" component is one that is suitable for use with humans and/or other mammals in the treatment of supraventricular arrhythmias and/or cardiac fibrillation and without undue adverse side effects (such as toxicity, irritation, and allergic response), commensurate with a reasonable benefit/risk ratio.
- SUBSTITIIT ⁇ SHEET (RULE 28) ACTIVE MATERIALS Deoxy or oxygen-substituted sugar-containing 14-aminosteroid compounds and the pharmaceutically-acceptable acid salts or esters thereof of the general formula:
- Electrophysicological properties are assessed in whole animal models.
- the ability of the novel deoxy and oxygen-substituted sugar-containing 14-aminosteroid compounds of the present invention to favorably affect sinus node functional, heart rate, atrial effective refractory period, atrioventricular node effective refractory period, sinus node recovery tiem and to terminate atrial fibillation/flutter refractory periods and atrial flutter are assessed.
- the deoxy and oxygen-substituted sugar-containing 14-aminosteroid compounds of the present invention may be administered to humans or other mammals by a variety of routes, including, but not limited to, oral dosage forms and injections (intravenous, intramuscular, intraperitoneal and subcutaneous). Numerous other dosage forms containing the deoxy and oxygen-substituted sugar-containing 14- aminosteroid compounds of the present invention can be readily formulated by one skilled in the art, utilizing the suitable pharmaceutical excipients as defined below. For considerations of patient compliance and chronic therapy, oral dosage forms are generally most preferred. For acute use, intravenous dose forms are preferred to rapidly terminate the arrhythmia.
- composition means a combination comprised of a safe and effective amount of me novel deoxy and oxygen-substituted sugar-containing 14-aminosteroid compound active ingredient, or mixtures thereof, and pharmaceutically acceptable excipients.
- safe and effective amount means an amount of a compound or composition large enough to significantly alleviate the symptoms and/or condition to be treated, but small 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 pharmaceutical compositions to be used in the method of the invention herein will vary with the particular condition being treated, 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 active ingredient being employed, the particular pharmaceutically acceptable excipients utilized, and like factors widiin the knowledge and expertise of the attending physician.
- pharmaceutically acceptable excipients includes any physiologically inert, pharmacologically inactive material known to one skilled in the art, which is compatible with the physical and chemical characteristics of the particular deoxy or oxygen-substituted sugar containing 14-aminosteroid compound active ingredient selected for use.
- Pharmaceutically acceptable excipients include, but are not limited to, polymers, resins, plasticizers, fillers, binders, lubricants, glidants, disintegrants, solvents, co-solvents, buffer systems, surfactants, preservatives. sweetening agents, flavoring agents, pharmaceutical grade dyes or pigments, and viscosity agents.
- oral dosage form means any pharmaceutical composition intended to be systemically administered to an individual by delivering said composition to the gastrointestinal tract of an individual, via the mouth of said individual.
- the delivered form can be in the form of a tablet, coated or non-coated; solution; suspension; or a capsule, coated or non-coated.
- injection means any pharmaceutical composition intended to be systemically administered to a human or other mammal, via delivery of a solution or emulsion containing the active ingredient, by puncturing the skin of said individual, in order to deliver said solution or emulsion to the circulatory system of the individual either by intravenous, intramuscular, intraperitoneal or subcutaneous injection.
- the rate of systemic delivery can be satisfactorily controlled by one skilled in the art, by manipulating any one or more of the following:
- pharmaceutically-acceptable excipients include, but are not limited to, resins, fillers, binders, lubricants, solvents, glidants, disintegrants co- solvents, surfactants, preservatives, sweetener agents, flavoring agents, buffer systems, pharmaceutical-grade dyes or pigments, and viscosity agents.
- the preferred solvent is water.
- Flavoring agents among those useful herein include those described in Remington's Pharmaceutical Sciences. 18th Edition, Mack Publishing Company, 1990, pp. 1288-1300, incorporated by reference herein.
- the pharmaceutical compositions suitable for use herein generally contain from 0-2% flavoring agents.
- Dyes or pigments among those useful herein include those described in
- compositions herein generally contain from 0-2% dyes or pigments.
- Preferred co-solvents include, but are not limited to, ethanol, glycerin, propylene glycol, polyethylene glycols.
- the pharmaceutical compositions of the present invention include from 0-50% co-solvents.
- Preferred buffer systems include, but are not limited to, acetic, boric, carbonic, phosphoric, succinic, malaic, tartaric, citric, acetic, benzoic, lactic, glyceric, gluconic, glutaric and glutamic acids and their sodium, potassium and ammonium salts.
- composition of the present invention generally contain from 0-5% buffer systems.
- Preferred surfactants include, but are not limited to, polyoxyemylene sorbitan fatty acid esters, polyoxyemylene monoalkyl ethers, sucrose monoesters and lanolin esters and ethers, alkyl sulfate salts, sodium, potassium, and ammonium salts of fatty acids.
- the pharmaceutical compositions of the present invention include 0-2% surfactants.
- Preferred preservatives include, but are not limited to, phenol, alkyl esters of parahydroxybenzoic acid, o-phenylphenol benzoic acid and the salts thereof, boric acid and the salts thereof, sorbic acid and the salts thereof, chlorobutanol, benzyl alcohol, thimerosal, phenylmercuric acetate and nitrate, nitromersol, benzalkonium chloride, cetylpyridinium chloride, methyl paraben, and propyl paraben. Particularly preferred are the salts of benzoic acid, cetylpyridinium chloride, methyl paraben and propyl paraben.
- the compositions of the present invention generally include from 0-2% preservatives.
- Preferred sweeteners include, but are not limited to, sucrose, glucose, saccharin, sorbitol, mannitol, and aspartame. Particularly preferred are sucrose and saccharin.
- compositions of the present invention include 0-5% sweeteners.
- Preferred viscosity agents include, but are not limited to, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropyl- cellulose, sodium alginate, carbomer, povidone, acacia, guar gum, xanman gum and tragacanth. Particularly preferred are methylcellulose, carbomer, xanthan gum, guar gum, povidone, sodium carboxymethylcellulose, and magnesium aluminum silicate.
- compositions of the present invention include 0-5% viscosity agents.
- Preferred fillers include, but are not limited to, lactose, mannitol, sorbitol, tribasic calcium phosphate, dibasic calcium phosphate, compressible sugar, starch, calcium sulfate, dextro and microcrystalline cellulose.
- the compositions of the present invention contain from 0-75% fillers.
- Preferred lubricants include, but are not limited to, magnesium stearate, stearic acid, and talc.
- the pharmaceutical compositions of the present invention include 0.5- 2% lubricants.
- Preferred glidants include, but are not limited to, talc and colloidal silicon dioxide.
- the compositions of the present invention include from 1-5% glidants.
- Preferred disintegrants include, but are not limited to, starch, sodium starch glycolate, crospovidone, croscarmelose sodium, and microcrystalline cellulose.
- the pharmaceutical compositions of the present invention include from 4-15% disintegrants.
- Preferred binders include, but are not limited to, acacia, tragacanth, hydroxypropylcellulose, pregelatinized starch, gelatin, povidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, sugar solutions, such as sucrose and sorbitol, and ethylcellulose.
- the compositions of the present invention include 1-10% binders.
- Compounds of the present invention may comprise from 0.1% to 99.9% by weight of the pharmaceutical compositions of the present invention.
- the compounds of the present invention comprise from about 20% to about 80% by weight of the pharmaceutical compositions of the present invention.
- the pharmaceutical compositions of the present invention include from 15-95% of a deoxy and oxygen-substituted sugar-containing 14-aminosteroid compound active ingredient, or mixture, thereof; 0-2% flavoring agents; 0-50% co- solvents; 0-5% buffer system; 0-2% surfactants; 0-2% preservatives; 0-5% sweeteners; 0-5% viscosity agents; 0-75% fillers; 0.5-2% lubricants; 1-5% glidants; 4-15% disintegrants; and 1-10% binders.
- Suitable pharmaceutical compositions are described herein. It is well within the capabilities of one skilled in the art to vary the non-limiting examples described herein to achieve a broad range of pharmaceutical compositions.
- a pharmaceutically acceptable excipient to be used in conjunction with die deoxy or oxygen-substituted sugar-containing 14-aminosteroid compounds of the present invention is basically determined by the way the compound is to be administered. If the compound is to be injected, die preferred pharmaceutical carrier is sterile physiological saline, the pH of which has been adjusted to about 7.4. Suitable pharmaceutically-acceptable carriers for topical application include those suited for use in creams, gels, tapes and the like.
- the preferred mode of administering the deoxy and oxygen-substituted sugar- containing 14-aminosteroid compounds of the present invention is oral.
- the preferred unit dosage form is therefore tablets, capsules and the like, comprising a safe and effective amount of the deoxy or oxygen-substituted sugar-containing 14-aminosteroid compounds of the present invention.
- Pharmaceutically acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well known in the art. Their selection will depend on secondary considerations such as taste, cost, and shelf stability, which are not critical for the purposes of the present invention, and can be made wimout difficulty by a person skilled in the art.
- 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 0.1 mg to 5.0 mg of the deoxy and oxygen- substituted sugar-containing 14-aminosteroid. More preferably Uiese oral dosage forms comprise 0.25 - 1.0 mg of the deoxy and oxygen-substituted sugar-containing 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 0.5 mg to 2.0 mg, of the deoxy and oxygen- substituted sugar-containing 14-aminosteroid. More preferably these topical compositions comprise 1.0 mg of the deoxy and oxygen-substituted sugars-containing 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 deoxy and oxygen-substituted sugar-containing 14- aminosteroid.
- the carrier may include pharmaceutically-acceptable emollients, emulsifiers, dvickening 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 propellanis 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.
- An immediate release oral dosage form (tablet) containing the (3 ⁇ ,5 ⁇ ,14 ⁇ ,17 ⁇ )- 14-Amino-3-[3',6 , -dideoxy- ⁇ -L-mannopyranosyl)oxy]androstane-17-carboxylic acid, methyl ester has the following composition:
- a parenteral dosage form containing, the (3 ⁇ .5 ⁇ ,14 ⁇ ,17 ⁇ )-14-Amino-3-[(3',6'-dioxy- ⁇ - L-mannopyranosyl) hydrochloride and suitable for use as an intravenous (I.V.) injection has the following composition:
- the above solution is filtered through a 0.22 micron sterile membrane filter, 3) 2.2 ml of me 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 bromobutyl or other suitable stoppers and sealed.
- the lyophilized product is reconstituted with 2.0 ml of sterile water for injection immediately prior to use.
- a sustained release oral dosage form (tablet) containing the (3 ⁇ ,5 ⁇ ,146,17 ⁇ )-14- Amino-3-[(3 , ,6'-dideoxy- ⁇ -L-mannopyranosyl)oxy]androstane-17-carboxylic acid, methyl ester has the following composition:
- the drug active ingredient is formulated into a number of different dosage forms:
- a pharmaceutical aerosol containing solvent e.g. water, glycols
- preservatives methyl or propyl parabens
- propellants nitrogen, carbon dioxide or other suitable excipients
- a buccal mucoadhesive patch containing hydrocolloid polymers (hydroxyethyl cellulose, hydroxy-propyl cellulose, povidone) and other suitable polymers.
- the novel compounds of the present invention are efficacious in treating humans or other mammals afflicted with supraventricular arrhythmias and/or atrial fibrillation.
- supraventricular arrhythmias are not deemed to be life drreatening and are generally not aggressively treated with conventional antiarrhythmic drugs due to their undesirable side effects.
- this type of arrhythmia is usually not aggressively treated to merely relieve symptoms which are characterized as mild to severe.
- this type of arrhdimia may lead to strokes of if chronic may cause CHF.
- the compounds of the present invention are generally well tolerated and exhibit a different electrophysiological effects than do many of the more conventional cardiac glycosidic drugs, and may be an acceptable therapy to alleviate die symptoms suffered by individuals exhibiting supraventricular arrhythmias who are experiencing discomfort, even though not in an immediately life threatening situation.
- the present invention relates to a method for treating a human or omer mammal suffering from supraventricular arrhythmia and/or atroa; fibrillation which comprises administering to said human or other mammal a safe and effective amount of a pharmaceutical composition comprising by weight of the composition from 15- 90% of a substituted sugar-containing 14-aminosteroid compound, and from 10-85% pharmaceutically acceptable excipients.
- a pharmaceutical composition comprising by weight of the composition from 15- 90% of a substituted sugar-containing 14-aminosteroid compound, and from 10-85% pharmaceutically acceptable excipients.
- Patient X has a "tachy-brady" syndrome.
- Digoxin controls his tachycardia but produces such low heart rates that he is somewhat symptomatic. His bradycardic episodes are not frequent. He is switched to (3 ⁇ , 5 ⁇ , 14 ⁇ , 17 ⁇ )-14-Amino-3-[(3',6'- dideoxy- ⁇ -L-mannopyranosyl)-oxy]-androstane-17-carboxyIic acid memyl ester.
- the tachycardias are controlled without severe bradycardia.
- Patient Y is on digoxin and has atrial fibrillation witii a ventricular rate of 85. However, he has very little cardiac reserve. His physician would prefer him in sinus rhythm to increase his cardiac output. He is switched from digoxin to (3 ⁇ , 5 ⁇ , 14 ⁇ , 17 ⁇ )- 14- Amino-3-[(3',6'-dideoxy- ⁇ -L-mannopyranosyl)-oxy]-androstane- 17- carboxylic acid methyl ester. He converts to sinus rhythm and with the increased cardiac output due to me added contribution of the atrial contraction to ventricular filling. The patient is doing much better.
- Patient Z is on digoxin and has atrial fibrillation with a ventricular rate of 85. He has low cardiac reserve, so needs inotropic support. However, his physician is concerned about his patient having a stroke due to die arrhythmia. The patient has a history of frequent falls so the physician does not want to anticoaqulate the patient. The patient is switched from digoxin to (3 ⁇ , 5 ⁇ , 14 ⁇ , 17 ⁇ )-14-Amino-3-[(3 ⁇ 6'- dideoxy- ⁇ -L-mannopyranosyl)-oxy]-androstane-17-carboxylic acid memyl ester. He converts to sinus rhythm and does well. His cardiac output is increased due to the added contribution of the atrial contraction to ventricular filling.
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- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
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- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Molecular Biology (AREA)
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Abstract
Description
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Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP10503230A JP2000514046A (en) | 1996-06-17 | 1997-06-13 | Deoxy- and oxygen-substituted sugar-containing 14-aminosteroid compounds for use as antiarrhythmic drugs |
AU33125/97A AU3312597A (en) | 1996-06-17 | 1997-06-13 | Deoxy and oxygen-substituted sugar-containing 14-aminosteroid compounds for use as an antiarrhythmic |
EP97928991A EP0918527A1 (en) | 1996-06-17 | 1997-06-13 | Deoxy and oxygen-substituted sugar-containing 14-aminosteroid compounds for use as an antiarrhythmic |
IL12744497A IL127444A0 (en) | 1996-06-17 | 1997-06-13 | Deoxy and oxygen-substituted sugar-containing 14-aminosteroid compounds for use as an antiarrhythmic |
BR9709835A BR9709835A (en) | 1996-06-17 | 1997-06-13 | 14-Amino-steroidal compounds containing sugar replaced with deoxy and oxygen for use as an antiarrhythmic |
NO985852A NO985852L (en) | 1996-06-17 | 1998-12-14 | Deoxy and oxy substituted sugar-containing 14-amine period compound for use as an antiarrhythmic agent |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US1997896P | 1996-06-17 | 1996-06-17 | |
US60/019,978 | 1996-06-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997048401A1 true WO1997048401A1 (en) | 1997-12-24 |
Family
ID=21796104
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1997/010453 WO1997048401A1 (en) | 1996-06-17 | 1997-06-13 | Deoxy and oxygen-substituted sugar-containing 14-aminosteroid compounds for use as an antiarrhythmic |
Country Status (15)
Country | Link |
---|---|
EP (1) | EP0918527A1 (en) |
JP (1) | JP2000514046A (en) |
CN (1) | CN1306432A (en) |
AR (1) | AR013825A1 (en) |
AU (1) | AU3312597A (en) |
BR (1) | BR9709835A (en) |
CA (1) | CA2258202A1 (en) |
CO (1) | CO4970822A1 (en) |
CZ (1) | CZ413298A3 (en) |
HU (1) | HUP9904322A2 (en) |
ID (1) | ID17062A (en) |
IL (1) | IL127444A0 (en) |
NO (1) | NO985852L (en) |
WO (1) | WO1997048401A1 (en) |
ZA (1) | ZA975254B (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4885280A (en) * | 1987-10-02 | 1989-12-05 | Norwich Eaton Pharmaceuticals, Inc. | Novel 14-amino steroids |
WO1995001335A1 (en) * | 1993-06-30 | 1995-01-12 | Merck & Co., Inc. | Novel spirocycles |
WO1995008558A1 (en) * | 1993-09-24 | 1995-03-30 | The Procter & Gamble Company | Novel deoxy and oxygen-substituted sugar-containing 14-aminosteroid compounds |
-
1997
- 1997-06-13 IL IL12744497A patent/IL127444A0/en unknown
- 1997-06-13 CZ CZ984132A patent/CZ413298A3/en unknown
- 1997-06-13 CN CN97195536A patent/CN1306432A/en active Pending
- 1997-06-13 CA CA002258202A patent/CA2258202A1/en not_active Abandoned
- 1997-06-13 EP EP97928991A patent/EP0918527A1/en not_active Withdrawn
- 1997-06-13 BR BR9709835A patent/BR9709835A/en not_active Application Discontinuation
- 1997-06-13 AU AU33125/97A patent/AU3312597A/en not_active Abandoned
- 1997-06-13 HU HU9904322A patent/HUP9904322A2/en unknown
- 1997-06-13 JP JP10503230A patent/JP2000514046A/en active Pending
- 1997-06-13 ZA ZA9705254A patent/ZA975254B/en unknown
- 1997-06-13 AR ARP970102594A patent/AR013825A1/en unknown
- 1997-06-13 WO PCT/US1997/010453 patent/WO1997048401A1/en not_active Application Discontinuation
- 1997-06-16 ID IDP972044A patent/ID17062A/en unknown
- 1997-06-16 CO CO97033187A patent/CO4970822A1/en unknown
-
1998
- 1998-12-14 NO NO985852A patent/NO985852L/en not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4885280A (en) * | 1987-10-02 | 1989-12-05 | Norwich Eaton Pharmaceuticals, Inc. | Novel 14-amino steroids |
WO1995001335A1 (en) * | 1993-06-30 | 1995-01-12 | Merck & Co., Inc. | Novel spirocycles |
WO1995008558A1 (en) * | 1993-09-24 | 1995-03-30 | The Procter & Gamble Company | Novel deoxy and oxygen-substituted sugar-containing 14-aminosteroid compounds |
Non-Patent Citations (1)
Title |
---|
CUMMINGS ET AL: "Positive inotropic and antiarrhytmic actions of actodigin in dogs", ARCH. INT. PHARMACODYN., vol. 228, 1977, pages 92 - 8, XP002042448 * |
Also Published As
Publication number | Publication date |
---|---|
AR013825A1 (en) | 2001-01-31 |
CO4970822A1 (en) | 2000-11-07 |
EP0918527A1 (en) | 1999-06-02 |
CZ413298A3 (en) | 1999-09-15 |
AU3312597A (en) | 1998-01-07 |
JP2000514046A (en) | 2000-10-24 |
NO985852L (en) | 1999-02-16 |
HUP9904322A2 (en) | 2000-05-28 |
IL127444A0 (en) | 1999-10-28 |
NO985852D0 (en) | 1998-12-14 |
BR9709835A (en) | 1999-08-10 |
ID17062A (en) | 1997-12-04 |
ZA975254B (en) | 1998-04-01 |
CA2258202A1 (en) | 1997-12-24 |
CN1306432A (en) | 2001-08-01 |
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